Gout

David S. Newcombe

Gout
Basic Science and Clinical Practice

Edited by Dwight R. Robinson

Author Editor
David S. Newcombe, M.D. Dwight R. Robinson, M.D.
Weston Department of Rheumatology
Massachusetts Massachusetts General Hospital
USA Boston
USA

ISBN 978-1-4471-4263-8 ISBN 978-1-4471-4264-5 (eBook)

DOI 10.1007/978-1-4471-4264-5
Springer London Heidelberg New York Dordrecht

Library of Congress Control Number: 2012950015

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This book is dedicated to Dr. Newcombe’s daughters:
Catherine L. Newcombe, Kirsten N. Shilling and Sarah N. Faucett.
Preface

One might ask why a book devoted to a single disorder like gout is necessary
since standard textbooks adequately review the usual clinical findings and
management of this disorder. The answer to that question is multifaceted.
Gout is now clearly associated with several different clinical presentations
that are often not described in detail in modern textbooks. Familial juvenile
hyperuricemic nephropathy, autosomal dominant polycystic kidney disease,
glycogen storage disease, and other disorders associated with hyperuricemia
and gout are dysfunctions that need to be recognized early to avoid serious
consequences. These and other clinical subsets of gout, in some cases, have
also been defined at the molecular level. Such advances in molecular biology
provide another rationale for amplifying a physician’s knowledge of gout and
the mechanisms of inflammation associated with this disease. Furthermore,
the inflammatory and anti-inflammatory mediators, their mechanisms of
action, and their real and putative roles in gout have recently been elucidated
in greater detail and contribute to a better understanding of the pathogenesis
of gout. Such new discoveries also provide a perspective on the capacity of
the host to generate natural anti-inflammatory molecules, and such data may
lead to new therapeutic initiatives. Uric acid, the precursor of gout, has also
begun to attain more significance in relation to renal disease, hypertension,
and obesity, and these interrelationships have been characterized in specialty
journals but are not linked to textbook discussions of hyperuricemia and gout.
These findings alert the physician to evaluate uric acid associated disorders
such as hypertension and obesity more extensively than has been the custom
previously.
Perhaps of greatest significance to the subjects of hyperuricemia and gout
are the epidemiological studies showing that fewer than 10% of patients with
gout are referred to rheumatologists. This circumstance leads to multiple
errors in the management of this disease by physicians as well as patients. For
example, the literature clearly documents the misuse of allopurinol since a
number of patients are prescribed this agent for inappropriate reasons.
Treating asymptomatic hyperuricemia with allopurinol in the absence of a
sound rationale for the reduction in uric acid levels places patients at risk for
the serious side effects of this agent including renal failure and even death. In
addition, allopurinol has also been used as the sole agent for the treatment of
acute gouty arthritis in elderly patients suffering from diuretic-induced gout
as well as in other inappropriate settings where allopurinol is not indicated.
Although uric acid is often the precursor of acute gouty arthritis, allopurinol

vii
viii Preface

has no role in the management of acute gouty arthritis since it has no effect
on an acute inflammatory response. Patients with hand deformities due to
extensive tophaceous deposits may often be mistakenly diagnosed as rheu-
matoid arthritis, and the need for the reduction of tophaceous deposits com-
pletely ignored. Neglecting the treatment of chronic tophaceous gout may
have serious consequences such as the collapse of a urate-laden vertebra or
aseptic necrosis of the hip.
Another important aspect of gout in modern times is the increasing
identification of genetic dysfunctions associated with hyperuricemia and
gout. Thus, a family history becomes a critical part of the evaluation of the
hyperuricemic patient and avoids the pitfalls related to a delay in the early
detection and treatment of affected family members. Often a cooperative
patient who researches the family for underlying disorders may provide the
physician with a most rewarding experience and be most useful in the early
treatment of family members.
The contents of this monograph provide the practicing physician with a
ready source of information concerning hyperuricemia and gout as well as
discussions of the management goals for the optimal treatment of these
disorders.
About the Author

David Sugden Newcombe, M.D., graduated from Amherst College in 1952,

cum laude in Biology. He received his medical degree from McGill University
in 1956. Dr. Newcombe did his postdoctoral training at Boston City Hospital,
Duke University, Boston University, and the Peter Brent Brigham Hospital at
Harvard. He completed his military service in Korea in 1958.
From 1965 to 1967, he was an Assistant Professor of Medicine at the
University of Virginia. He then served as an Associate Professor of Medicine
at the University of Vermont where he subsequently became the Director of
Rheumatology. In 1977, he went to The Johns Hopkins University where he
rose to the rank of Professor of Environmental Health Science in the
University’s School of Hygiene and Public Health and held a Joint
Appointment in the Department of Medicine in the University’s School of
Medicine.
Upon retiring from Johns Hopkins in 1992, he moved to Massachusetts
where he was Associate Chief of Staff at the Bedford Veterans Administration
Hospital until 1999. He then served as an Associate Physician at the Federal
Medical Center (Devens) Massachusetts until he retired in 2001.
Dr. Newcombe wrote two books: Inherited Biochemical Disorders and
Uric Acid Metabolism (1975 University Park Press) and Clinical
Immunotoxicology (1992 Raven Press). He also authored over one hundred
medical and scientific articles.
At the time of his retirement, Dr. Newcombe began the project that eventu-
ally became this book on gout. He had a life-long interest in the disease and
its complexities. The 1,000 page manuscript was completed just five days
before his death. Almost a year later his family requested that Dr. Robinson
arrange for the publication of his work. The manuscript was then modified
and updated. At this time the book represents the most comprehensive publi-
cation available on gout, which is the world’s most common inflammatory
rheumatic disease.
The Editor, Dwight R. Robinson, M.D., is a rheumatologist at the
Massachusetts General Hospital and Professor of Medicine, Harvard Medical
School.

ix
Acknowledgment

The Newcombe family is profoundly grateful to Dr. Dwight Robinson.

Dr. Newcombe’s manuscript on gout would never have been published had it
not been for Dr. Robinson’s expert knowledge of this disease and his unwav-
ering dedication to the substantial task of editing the valuable piece of medi-
cal scholarship that Dr. Newcombe produced.

xi
Contents

1 A Brief History of Gout ................................................................. 1

Egyptian Archeology ....................................................................... 1
Byzantine Empire ............................................................................. 2
Seventeenth Century ........................................................................ 2
Eighteenth Century........................................................................... 2
Nineteenth Century .......................................................................... 4
Twentieth Century ............................................................................ 4
Famous Sufferers.............................................................................. 6
References ........................................................................................ 7
2 The Prevalence and Risk Factors for Gout .................................. 9
Prevalence of Gout ........................................................................... 9
Diet, Disease States, and Heredity Associated with Gout ............... 9
Genetic Abnormalities in Renal Tubular Transport Leading
to Reduced Renal Excretion of Urate............................................... 13
References ........................................................................................ 18
3 Purine Biochemistry....................................................................... 25
Structure ........................................................................................... 25
Nucleic Acid Degradation ................................................................ 25
De Novo Purine Nucleotide Synthesis ............................................. 30
The Key Intermediate, PRPP ........................................................... 33
Biosynthesis of AMP and GMP ....................................................... 33
Nucleotide Interconversions and Catabolism ................................... 34
Purine Salvage Pathways.................................................................. 34
Phosphoribosylpyrophosphate Synthetase ....................................... 36
PRPP Amidotransferase ................................................................... 40
Hypoxanthine-Guanine Phosphoribosyltransferase (HPRTase)....... 42
Adenine Phosphoribosyltransferase ................................................. 47
Isotopes in the Evaluation of Uric Acid Metabolism ....................... 54
References ........................................................................................ 55
4 Uric Acid Metabolism in Humans ................................................ 69
Overview .......................................................................................... 69
Purine Biosynthesis .......................................................................... 69
Miscible Pool of Urate ..................................................................... 70
Urate Turnover Rate ......................................................................... 72
Mechanisms of Hyperuricemia and Gout ........................................ 72
Elevated PRPP Levels ...................................................................... 72

xiii
xiv Contents

Decreased Hypoxanthine Reutilization ............................................ 73

Glutamine Hypothesis ...................................................................... 75
Accelerated ATP Degradation .......................................................... 75
Increased Nucleic Acid Turnover..................................................... 81
Accelerated Nucleotide Degradation ............................................... 83
Excessive Purine Intake.................................................................... 84
Elimination of Uric Acid.................................................................. 84
Renal Mechanisms of Hyperuricemia and Gout .............................. 85
Renal Mechanisms of Hyperuricemia and Secondary Gout ............ 86
References ........................................................................................ 87
5 Clinical Aspects of Gout and Associated Disease States ............. 91
Introduction ...................................................................................... 91
Clinical Gout ............................................................................... 91
Intercritical Gout ......................................................................... 93
Chronic (Tophaceous) Gouty Arthritis ........................................ 94
Differential Diagnosis ...................................................................... 96
Diagnostic Criteria for Hyperuricemia and Gout ............................. 99
Urinary Uric Acid Measurements .................................................... 102
Overproduction of Uric Acid ........................................................... 102
Lesch-Nyhan Syndrome .............................................................. 103
Kelley-Seegmiller Syndrome ...................................................... 104
Phosphoribosylpyrophosphate Synthetase Overactivity ............. 106
Idiopathic Gout ............................................................................ 106
Secondary Hyperuricemia and Gout due to Overproduction
of Purines..................................................................................... 107
Glycogen Storage Diseases (GSD).............................................. 108
Fatty Acid Oxidation Deficiencies .............................................. 113
Decreased Uric Acid Excretion........................................................ 114
Introduction ................................................................................. 114
Primary Underexcretor Gout ....................................................... 114
Secondary Hyperuricemia and Gout due to the Underexcretion
of Uric Acid ................................................................................. 114
Urate Nephropathy ...................................................................... 115
Acute Uric Acid Nephropathy..................................................... 117
Autosomal Dominant Polycystic Kidney Disease (ADPKD) ..... 118
Medullary Cystic Disease (MCD) ............................................... 119
Familial Juvenile Gouty Nephropathy (FJGN) ........................... 120
Nephrogenic Diabetes Insipidus (NDI) ....................................... 121
Uric Acid Nephrolithiasis ................................................................ 122
Introduction ................................................................................. 122
Heritable Causes of Uric Acid Nephrolithiasis ........................... 124
Acquired Causes of Uric Acid Nephrolithiasis ........................... 128
Nephrolithiasis Mimicking Uric Acid Stones ............................. 129
Drug-Induced Hyperuricemia and Gout........................................... 135
Diuretics ...................................................................................... 135
Salicylates .................................................................................... 136
Ethanol ........................................................................................ 136
Contents xv

Cytotoxic Agents ......................................................................... 136

Allopurinol-Induced Gout ........................................................... 136
Antituberculous Drugs ................................................................ 137
Cyclosporine................................................................................ 137
Nicotinic Acid ............................................................................. 139
Fructose-Induced Hyperuricemia ................................................ 139
Megaloblastic Anemia ................................................................. 140
Summary of Drug-Induced Hyperuricemia and Gout ................. 141
Saturnine Gout (Lead-Induced Gout)............................................... 141
Gaucher Disease (Glucocerebrosidase Deficiency) ......................... 144
Gout in Females ............................................................................... 144
Juvenile Hyperuricemia and Gout ............................................... 144
Premenopausal Hyperuricemia and Gout .................................... 145
Hyperuricemia and Gout in Pregnancy ....................................... 146
Postmenopausal Hyperuricemia and Gout .................................. 146
Associated Disorders........................................................................ 147
Obesity ........................................................................................ 147
Hyperlipidemia ............................................................................ 148
Glucose Intolerance ..................................................................... 152
Hypertension ............................................................................... 152
Atherosclerosis ............................................................................ 153
Critical Illnesses .......................................................................... 153
References ........................................................................................ 154

6 Diagnostic Procedures in the Management of Gout ................... 187

Introduction ...................................................................................... 187
Hyperuricemia .................................................................................. 187
Synovial Fluid Analysis ................................................................... 188
Arthrocentesis Techniques .......................................................... 188
Synovial Fluid Culture ................................................................ 189
Synovial Fluid Gram Stain .......................................................... 190
Synovial Fluid White Blood Cell Counts .................................... 190
Synovial Fluid Differential Cell Count ....................................... 191
Synovial Fluid Wet Preparations for Crystal Identification ........ 191
Additional Clinical Data Concerning Synovial Fluid ................. 192
References ........................................................................................ 194

7 Roentgenographic Findings and Musculoskeletal Ultrasound .. 199

Introduction ...................................................................................... 199
Soft Tissue Swelling and Joint Effusions ......................................... 199
Bony Erosions .................................................................................. 200
Extra-articular Tophi ........................................................................ 201
Uric Acid Calculus ........................................................................... 201
Avascular Necrosis ........................................................................... 202
Chondrocalcinosis ............................................................................ 202
Musculoskeletal Ultrasound ............................................................. 203
Dual-Energy Computed Tomography (DECT) ................................ 203
References ........................................................................................ 204
xvi Contents

8 Mechanisms of the Acute Attack of Gout and Its Resolution .... 207
Overview .......................................................................................... 207
Synovial Membrane ......................................................................... 208
Monosodium Urate Crystallization .................................................. 211
Inflammasome: Innate Immunity; Inflammation
in Gout Is Mediated by the Innate Immune System......................... 213
Introduction ................................................................................. 213
Interleukin-1b and Interleukin-18 ............................................... 216
Mechanisms of NLRP3 Activation ............................................. 217
Neutrophil Chemoattractants ........................................................... 218
Overview ..................................................................................... 218
Proteinases and Neutrophil Migration......................................... 219
The Complement Fragments: C5a and C5a des Arg ................... 220
C5a Receptor (C5aR) .................................................................. 221
Platelet-Activating Factor (PAF) ................................................. 222
PAF Receptor ................................................................................... 227
Biological Functions of PAF ....................................................... 227
Regulation of PAF: Acetylhydrolase ........................................... 228
Leukotriene B4 (LTB4) ............................................................... 229
LTB4 Biosynthesis via Phospholipase/Lipoxygenase
and Its Release ............................................................................. 230
LTA4 Hydrolase .......................................................................... 231
Transcellular Metabolism and LTB4 Production ........................ 231
Phospholipase Classification and Functions ............................... 232
Interleukin-8 (IL-8) ..................................................................... 235
Cell Sources................................................................................. 236
IL-8 Gene .................................................................................... 236
IL-8, MSU Crystals, and Gout .................................................... 237
Adhesion Molecules ......................................................................... 238
An Overview of Selectins and Integrins ...................................... 238
Selectin Structures ....................................................................... 238
P-Selectin Glycoprotein Ligand-1 ............................................... 239
L-Selectin .................................................................................... 239
Unique L-Selectin Properties ...................................................... 240
E-Selectin .................................................................................... 242
Integrins ....................................................................................... 243
Integrin Structure ......................................................................... 243
Ligands for Integrins ................................................................... 245
Oxygen Radical Generation ............................................................. 247
NADPH Oxidase Assembly ........................................................ 249
Oxidants and Oxidant-Mediated Destructive Responses ............ 250
Myeloperoxidase ......................................................................... 251
Nitric Oxide and Bacterial Killing .............................................. 251
Oxidants and Uric Acid Destruction ........................................... 252
Proinflammatory Mediators ............................................................. 253
Non-chemotactic, Proinflammatory Cell Mediators ................... 253
Vasoactive Arachidonic Acid Metabolites .................................. 253
Contents xvii

Bradykinin ................................................................................... 254

Tumor Necrosis Factor ................................................................ 254
Monosodium Urate Crystal-Induced Inflammation ......................... 255
Proinflammatory Mediators and MSU Crystals .......................... 255
Regulation of Synovial Fibroblast-Like Cells ............................. 256
MAP Kinase and MSU Crystal-Induced Neutrophil Activation . 256
Phospholipase D and MSU Crystals ........................................... 257
MSU Crystals and Other Phospholipids Metabolizing Enzymes 258
Other Pathways Stimulated by MSU Crystals ............................ 258
MSU Crystal-Induced Proinflammatory Mediators .................... 259
MSU Crystals and Cell Membrane Interactions.......................... 259
Neutrophil and Macrophage Apoptosis ........................................... 260
Overview ..................................................................................... 260
Endogenous and Exogenous Anti-inflammatory Agents ................. 260
Overview ..................................................................................... 260
Anti-inflammatory Eicosanoids ....................................................... 262
Overview ..................................................................................... 262
Lipoxin Biosynthesis........................................................................ 263
Anti-inflammatory Effects of Lipoxins ....................................... 265
Proinflammatory to Anti-inflammatory Switch........................... 266
Resolvin Biosynthesis ................................................................. 266
Resolvin Receptors ...................................................................... 266
PAF Acetylhydolase and Anti-inflammation............................... 270
Apoptosis and Anti-inflammation ............................................... 271
Nitric Oxide and Anti-inflammation ........................................... 272
Drugs ........................................................................................... 274
Glucocorticoid .................................................................................. 274
Overview ..................................................................................... 274
Mode of Action ........................................................................... 275
Histone Acetylation and Glucocorticoids.................................... 277
Annexins and Glucocorticoids .................................................... 278
References ........................................................................................ 278
9 Management of Hyperuricemia and Gout ................................... 291
Overview .......................................................................................... 291
Management of Asymptomatic Hyperuricemia ............................... 292
Symptomatic Drug-Induced Hyperuricemia .................................... 294
Hyperuricemia Associated with the Treatment
of Neoplastic Disease ....................................................................... 295
Treatment of Acute Gouty Arthritis ................................................. 295
Colchicine Use in Acute and Chronic Gout ..................................... 296
Treatment Schedules ................................................................... 296
Mechanism of Action .................................................................. 297
Pharmacokinetics of Colchicine .................................................. 298
Colchicine Toxicity ..................................................................... 299
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) .......................... 301
Toxicity of NSAIDs..................................................................... 304
Other Toxicities of NSAIDs ........................................................ 305
xviii Contents

Indomethacin (Indocin) .................................................................... 313

Treatment Schedules ................................................................... 314
Toxicity ........................................................................................ 314
Naproxen .......................................................................................... 315
Glucocorticoids ................................................................................ 316
Therapeutic Regimens ................................................................. 320
Interleukin 1 Inhibitors..................................................................... 322
Urate-Lowering Therapy: Uricosuric
and Other Hypouricemic Drugs ....................................................... 323
Uricosuric Drugs: Sulfinpyrazone, Probenecid,
and Benzbromarone ......................................................................... 325
Sulfinpyrazone ............................................................................. 325
Probenecid ................................................................................... 326
Salicylates .................................................................................... 327
Benzbromarone ........................................................................... 328
Xanthine Oxidase Inhibitors: Allopurinol and Febuxostat .............. 329
Allopurinol .................................................................................. 329
Determination of Renal Function ................................................ 334
Newer Urate-Lowering Drugs ..................................................... 335
Low-Purine Diet ............................................................................... 339
Special Treatment Regimens ............................................................ 339
Management of Acute Uric Acid Nephropathy .......................... 339
Management of Tophaceous Deposits ......................................... 340
Lesch-Nyhan Syndrome .............................................................. 341
Glycogen Storage Disease ........................................................... 341
Hereditary Fructose Intolerance (HFI) ........................................ 341
Refractory Gout ........................................................................... 342
Pegloticase ................................................................................... 344
Other Agents with Urate-Lowering Effects ..................................... 345
Fenofibrate ................................................................................... 345
Losartan ....................................................................................... 345
Management of Nephrolithiasis ....................................................... 346
Allopurinol Treatment of Stones ...................................................... 348
The Role of Diet and Comorbidities
and Their Management in Gout ....................................................... 348
Hypertension ............................................................................... 349
Summary .......................................................................................... 353
Summary of Principles of Management........................................... 354
Lifestyle ....................................................................................... 354
Acute Attacks .............................................................................. 354
Chronic Gout ............................................................................... 354
References ........................................................................................ 355
Index ....................................................................................................... 387
 A Brief History of Gout
Ancient Greek and Roman civilization Gout
appeared to be well recognized both by ancient
Greek and Roman writers as well as physicians
even though confusion with other forms of
arthritis may have existed. The term gout arose
from the Latin word, gutta, which means drop
and was selected as a term to explain the con-
cept that bad humors entered the afflicted part
drop by drop [1]. The first clinical descriptions
of gout are attributed to Hippocrates (460–
377 B.C.) who documented the rarity of gout in
premenopausal women, young boys (ante usum
veneris – prepubertal), and eunuchs [2]. Indeed,
the same author termed the affliction in the big
toe, podagra, based on the topographical loca-
tion of the affliction rather than as an etiological
concept. Chiagra and gonagra were the terms
given to those with gout affecting the wrist or
knee. Hippocrates also noted the periodicity of
gouty episodes and the recurrence of gout in the
spring and fall. In the early descriptions of gout,
there was a general concept that prior to the
deposition of chalk (tophi), the disease could be
controlled, but after the occurrence of such
deposits, the disease became more difficult to
control. The elder Garrod summarized the role
of Greek physicians in describing the diagnosis
and management of gout [3]. As the Augustan
poet, Publius Ovid (43 B.C.), wrote in his Pontic
epistles, “Tollere nodosam nescit medicina
pologram.” Translated from the Latin, this
means that the gouty swellings defied the art of
medicine.
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_1, © Springer-Verlag London 2013
1
Aulus Cornelius Celsus (25 B.C.–50 A.D.),
author of the most comprehensive Roman medical
text of the time (De medicina), first proposed
venesection at the outset of a gouty episode both
to initiate a cure and to utilize as a prophylactic
measure. Aretaeus the Cappadocian, another sec-
ond century physician and contemporary of
Galen, was the first to propose that a specific toxic
substance in the blood was the cause for the gout.
He also provided a precise clinical description of
gouty arthritis: “The joints begin to be affected in
this way: pain seizes the great toe then the fore-
part of the heel on which we rest; next it comes
into the arch of the foot, but the ankle-joint swells
last of all. All sufferers at first wish to blame the
wrong cause - some function of a new shoe, oth-
ers a long walk, others an accident, or being trod-
den upon ---but the true cause is seldom believed
by the patient when he hears it from the physi-
cian.” Galen (130–200 A.D.) provided a more
radical approach to the disorder; bleeding and
purgation along with local applications were used
as treatments. He was also the first to describe
tophi, the term arising from the Greek word mean-
ing rough crumbling rock. Galen is also credited
with the first description of the tophus [4].
Egyptian Archeology
Two findings of archeological studies are of
interest to the historical analysis of gout. Smith
and Jones [5] discovered a large mass of urates
1
2 1
in the great toe of an elderly male buried in a
cemetery in Upper Egypt. The chemical compo-
sition of this mass was shown to be urates by
chemical analysis. A renal calculus found in an
Egyptian mummy on analysis was shown to
contain a nucleus of uric acid [6]. The age of
this mummy was estimated to be about
7,000 years old. Thus, these studies documented
chronic tophaceous gout and urate calculi as
disorders of antiquity.
Byzantine Empire
Alexander of Tralles (525–605 A.D.), a Byzantine
physician, and his contemporary, Aetius, were
the first to indicate the usefulness of colchicum in
the treatment of gout [2, 7]. “Hermodactylon (the
finger of Hermes) confestim minuit dolores,”
noted Alexander. There has been speculation that
these early Byzantine physicians were referring
to Colchicum variegatum rather than Colchicum
autumnale, the present-day source of colchicine.
In fact, the use of this medication dates back to
the Ebers Papyrus of 1500 B.C., but historical
records document its use in more detail in pub-
lished works in Latin [8].
Seventeenth Century
The actual usage of the word gout has been attrib-
uted to Geoffroi de Villehardouin writing in the
1200s that Count Hugues de Saint Paul suffered
from “une grant maladie de gote.” To the present
day, gout is used in most languages (French –
goutte, Spanish – gota, Italian – gotta, and
German – gicht) to describe this malady. The
modern history of gout probably begins with Sir
Thomas Sydenham (1624–1689) who was
afflicted with the disease and provided physicians
with one of the best clinical descriptions of the
disease. This talented English physician is
responsible for differentiating gout from other
forms of arthritis. In his book entitled, A Treatise
on Gout and Dropsy, he provided the literature
with a remarkably accurate description of gouty
arthritis based on his own personal experiences
A Brief History of Gout
[9]. In his writings, he differentiated acute and
chronic gouty arthritis for the first time and
recorded this classical description:
Towards the end of January or the beginning of
February suddenly, and with scarcely any premon-
itory feelings, the disease breaks out. Its only fore-
runner is indigestion and crudity of the stomach,
which troubles the patient for some weeks previ-
ous to the attack. His body also feels swollen,
heavy, and windy - symptoms which increase from
day to day until the fit breaks out. But a few days
before this torpor comes on, and a feeling of flatus
along the legs and thighs. Besides this, there is a
spasmodic affection, whilst the day before the fit,
the appetite is unnaturally hearty. The victim goes
to bed in good health and sleeps. About two o’clock
in the morning he is awakened by a severe pain,
generally in the great toe, more rarely in the heel,
ankle, or instep. This pain is like that of a disloca-
tion of the bones of these parts, and is accompa-
nied by a sensation as of chilly water poured over
the membranes of the suffering joint. Then follows
chills and shivers and a little fever. The pain, which
at first moderated, becomes gradually more intense,
and while it increases the chills and shivers die out.
Every hour that passes finds it greater, until at
length at nighttime it reaches its worst intensity,
and insinuates itself with most exquisite cruelty
among the numerous small bones of the tarsus and
metatarsus, in the ligaments of which it is lurking.
Now it is a violent stretching and tearing of the
ligaments, now it is gnawing pain, and now a pres-
sure and tightening. So exquisite and lively mean-
while is the feeling of the part affected that it
cannot bear the weight of the bedclothes nor the jar
of a person walking in the room. Hence the night is
passed in torture and a restless rolling first to one
side, then to the other, of the suffering limb, with
perpetual change of posture, the tossing about of
the body being as incessant as the pain of the tor-
tured joint, and being at its worst as the fit is com-
ing on. Hence the vain efforts by change of posture,
both in the body and the limb affected, to obtain an
abatement of the pain.
Thus, Sydenham documented the presence of
low-grade fever in association with involvement
of the distal extremities and related to overeating.
Eighteenth Century
Anton van Leeuwenhoek (1632–1723), the Dutch
biologist who became the father of microscopy,
discovered that the gouty tophus was made up of
crystals, but the actual nature of the crystal
Eighteenth Century
remained unknown. The discovery of uric acid as
a component of tophi was discovered by the
English physician turned chemist, William
Wollaston, a nephew of William Heberden whose
name is now associated with osteoarthritis of the
distal interphalangeal joints [10, 11]. In the pub-
lished letters of van Leeuwenhoek, the following
remarkable description of crystals from a gouty
tophus is recorded.
In your previous letter you ask me to examine the
chalk which gouty persons have on their joints or
which will break out. Now, although I am familiar
with many people suffering severely from gout, the
joints of whose fingers are very thick, I never
observed a perforation. Consequently, I always
thought that I could not discover anything worth
noting in the chalky matter, imagining that the
chalk would consist only of globules, because, if it
should contain pointed particles, the gouty patient
would never be free from pain, whereas we observe
the contrary to be the fact.
A certain gentleman who is related to me and who is
severely affected by gout, having heard about three
years ago that I had some Moxa and that I had burnt
myself with it for research, asked me for some of it
in order to burn himself with it. I was glad to give it
to him, after which he went to Utrecht where he
caused himself to be burnt several times, but
obtained no relief from it. When this gentleman
returned to this place after having lived in another
town for some time, I was told that he had had a very
sudden and severe attack. This gentleman passing
my house a few days afterwards, I inquired after his
health upon which he told me about his last illness,
which I will now describe for your information.
For two days consecutively he had gone to stool
many times, after which he felt so weak that he had
a doctor sent for. After this he fainted and had ner-
vous twitches, reason why only cordials were pre-
scribed, because it was supposed that his life would
last but a short time. He next was seized with cramp
in many limbs, so that, as he complained to me, if
he moved a limb in order to rub the cramped part
he was at once seized again with cramp in the arm
or leg which he moved. The stools ceased sponta-
neously and all his joints became so thin as if all
the gouty swellings had been carried off in the
stools. But he complained that they already began
to grow again. A few days later I asked this gentle-
man if it had ever happened to him that chalk came
out of his joints; he told me that some time ago the
chalk in the heel of his foot, in which there was a
large hole, came out in such quantity that he formed
almost a new heel, and that there was also a hole in
his arm on his elbow from which the chalk had
come during quite six months on end, but not so
much by far, nor so thick as from his heel. I asked
3
him to let me have some of the chalk, which he
willingly granted me, mentioning the time when he
would bandage his arm. For this purpose I brought
two small glasses in which there had never been
anything, to put the chalk in; the substance which
issued from the arm was not only chalk but was
mixed with some pus and a little blood, as also with
a viscous fluid in which there were many whitish
spots, some of which were so small that they could
hardly be seen by the naked eye. All this substance
I separated as well as I could with the point of a
knife, in order to be able to distinguish it all the
better. First of all I observed the solid matter which
to our eyes resembles chalk, and saw to my great
astonishment that I was mistaken in my opinion,
for it consisted of nothing but long, transparent lit-
tle particles, many pointed at both ends and about 4
“axes” of the globules in length, others shorter and
a few only half as long. And the proportion of their
thickness as compared to their length, I cannot bet-
ter describe than by supposing that we saw with
our naked eye pieces from a horse-tail cut to a
length of one sixth of an inch. In a quantity of mat-
ter of the size of a course grain of sand, there lay
some thousands of these long figures, mixed with a
small quantity of fluid. And roundabout this chalk
there flowed a small quantity of a thin fluid which
I judged to be the watery fluid of our blood, mixed
with globules of blood and globules which were
very white, which I judged to be also blood and
which is generally called pus. In some places the
above-mentioned long particles lay in regular
order, one next to the other, and not in a mass as if
they formed one body, but in a manner in which
glands lie. The clear matter was so viscous and
tough that I would not have thought that such a
humid matter could be found in our body, the more
so because after several observations I could not
but judge that it consisted of closely joined glob-
ules, in many places mixed with the above men-
tioned long figures which in one place lay very
close together and in another place lay widely scat-
tered. These were whitish spots that I had observed
with my native eye in the clear matter, and which
were whitest where they lay closest together. For
all transparent parts, lying one upon the other with-
out being closely united, look white, such as snow,
pounded glass or resin, sugar, paper, etc.
This description, of course, provided no clue
as to the chemical composition of the so-called
chalk and was completely dependent on the sub-
sequent chemical characterization of uric acid by
Carl Scheele (1742–1786), a Swedish chemist
and pharmacist who is responsible for an unparal-
leled description of new chemicals [12]. The char-
acterization of the material from a tophus as uric
acid was reported by W. H. Wollaston in 1797 and
4 1
marked the end of the humoral theories of gout
and the introduction of the chemical hypothesis as
the explanation for the etiology of gout [11].
Nineteenth Century
In the mid-1800s, Sir Alfred B. Garrod published his
identification of increased levels of uric acid in the
blood of gouty patients using the murexide test and
subsequently the “thread” test [3, 13–15]. He sum-
marized his clinical conclusions as follows:
First, in true gout, uric acid, in the form of urate of
soda, is invariably present in the blood in abnormal
quantities, both prior to and at the period of the
seizure, and is essential to its production; but this
acid may occasionally exist largely in the circulat-
ing fluid without the development of inflammatory
symptoms, as for example in some cases of lead
poisoning, and a few other instances. Its mere pres-
ence, therefore, does not explain the occurrence of
the gouty paroxysm.
Secondly, the investigations recently made in the
morbid anatomy of gout prove incontestably that
true gouty inflammation is always accompanied with
a deposition of urate of soda in the inflamed part
(This fact I wish to impress forcibly on the minds of
my readers, because in the constancy of such deposi-
tion, lies the clue which has long been wanting: the
occurrence of the deposit is perfectly pathogno-
monic, and at once separates gout from other disease
which at first sight may appear allied to it).
Thirdly, the deposit is crystalline and interstitial,
and when once the cartilages and ligamentous
structures become infiltrated, such deposition
remains for a lengthened time.
Fourthly, the deposited urate of soda may be looked
upon as the cause, and not the effect, of gouty
inflammation.
Fifthly, the inflammation which occurs in the gouty
paroxysm tends to the destruction of the urate of
soda in the blood of the inflamed part, and conse-
quently of the system generally.
Sixthly, the kidneys are implicated in gout, proba-
bly in its early, and certainly in its chronic stages,
and the renal affection, perhaps only functional at
first, subsequently becomes structural; the urinary
secretion is also altered in composition.
Seventhly, the impure state of the blood, arising
principally from the presence of urate of soda, is
the probable cause of the disturbance which pre-
cedes the seizure, and of many of the anomalous
symptoms to which gouty subjects are liable.
Eighthly, the causes which predispose to gout,
independently of those connected with individual
peculiarity, are either such as produce an increased
A Brief History of Gout
formation of uric acid in the system, or which lead
to its retention in the blood. (The discussion of the
eighth proposition is of much interest and consid-
erable importance, for if we can prove the truth of
the statement that the predisposing causes are of
different kinds, one leading to the increased forma-
tion of the morbid matter, the other to its retention
in the blood, we at once have a clue to the varieties
of the disease, popularly known as the rich and the
poor man’s gout).
Ninthly, the causes exciting a gouty fit, are those
which induce a less alkaline condition of the blood,
or which greatly augment for the time, the forma-
tion of uric acid, or such as temporarily check the
eliminating power of the kidney.
Tenthly, in no disease but true gout is there a depo-
sition of urate of soda in the inflamed tissues.
Garrod’s propositions set the stage for the
investigations that characterize many of the
aspects of clinical gout as clinicians know it today.
Parallel with the descriptions of the clinical
aspects of gout, the biochemical and pharmaco-
logic aspects of purine metabolism and their rela-
tion to gout were developing. In 1898, Emil
Fischer (1852–1919), a Nobel laureate, first estab-
lished that uric acid was a purine compound and
related to the nucleic acid constituents, adenine
and guanine [16]. Folin and Denis in 1913
described a colorimetric method for the measure-
ment of blood uric acid levels, which led the way
to clinical and metabolic studies of patients with
gout [17]. After its early discovery as a therapeu-
tic modality, colchicine was rediscovered in the
mid-1700s by Baron Anton de Storck, the physi-
cian for Empress Maria Theresa of Austria who
used it principally for the treatment of dropsy and
not gout [8]. Benjamin Franklin (1706–1790)
brought a concoction called L’Eau d’Husson from
France for the treatment of his gouty episodes,
and in 1814, Dr. James Want determined the active
ingredient of Nicolas Husson’s elixir was colchi-
cine [18, 19]. Thus, Franklin is credited with the
introduction of colchicine to the United States.
Twentieth Century
For more than a century, little progress was made
in the pharmacologic treatment of gout until
probenecid, Benemid, was synthesized by Beyer
Twentieth Century
and his colleagues as an analog of carinamide and
a putative inhibitor of penicillin secretion [20, 21].
The objective of this investigative program was to
find an organic acid inhibitor of the renal tubular
secretion of penicillin that would serve to increase
the blood levels of this antibiotic and delay its
excretion. Subsequently, it was determined that
probenecid was a competitive inhibitor of many
organic acids, and its primary effect of uric acid
was to inhibit the renal tubular reabsorption of
filtered urate. Alexander Gutman and his col-
league, Tsai F. Yu, as well as John Talbott’s group
contributed to the present-day understanding of
the clinical usefulness of this drug in the manage-
ment of chronic tophaceous gout [22–27].
The next major breakthrough in the manage-
ment of gout came when the recent Nobel laure-
ates, George Hitchings and Gertrude Elion, in the
early 1960s studied the effect of allopurinol on
the thiopurine metabolism, hyperuricemia, and
gout [28]. Allopurinol, a hypoxanthine analog,
was originally synthesized as a potential chemo-
therapeutic agent [29, 30]. Although it had no
effect on experimental tumors, it was found to be
a very effective inhibitor of xanthine oxidase
[31]. The initial clinical usage of allopurinol was
as an adjunct in the treatment of leukemia for
patients receiving 6-mercaptopurine. The marked
reduction in serum and urinary uric acid levels
observed by investigators at Duke University
(James Wyngaarden, Wayne Rundles, and their
colleagues) and the Burroughs Wellcome group
(George Hitchings, Gertrude Elion, and their col-
leagues) in 1963 led to trials of this drug in the
treatment of gout [32]. This agent is now rou-
tinely used and perhaps overused as an effective
agent for the treatment of certain forms of gout
and uric acid lithiasis and for the prevention of
obstructive uropathies due to uric acid in patients
with tumors sensitive to chemotherapeutic or
radiotherapeutic modalities.
With the advent of biochemical genetics and
the postulate put forth in 1931 by Sir Archibald
E. Garrod, the distinguished Regius Professor of
Medicine at Oxford and the son of Alfred Garrod,
that gout represented an inherited disorder and an
inborn error of metabolism ushered in the mod-
ern era of molecular medicine as it applied to
5
purine metabolism [33]. Two decades later,
DeWitt Stetten and his colleagues at the National
Institutes of Health initiated studies using purine
isotopes to investigate the synthesis and disposal
or uric acid in the human [34]. At the same time,
John Buchanan and his students at the
Massachusetts Institute of Technology and others
purified and characterized the enzymes of the
de novo purine biosynthetic pathway. More
recently, Zalkin and Smith and their colleagues at
Purdue University have extended the biochemis-
try of the purine enzymes. A number of eminent
physician-scientists including Alexander Gutman,
Jay Seegmiller, and James Wyngaarden sought
the mechanisms by which gouty patients differed
from nongouty individuals [35–44]. These stud-
ies focused on the purine pathway to investigate
the regulation of urate synthesis and on the renal
handling of urate to evaluate purine excretion.
In 1965, Michael Lesch, a medical student at
the time, and William Nyhan, a pediatrician,
first described a metabolic abnormality of
purine metabolism that now bears their name
[45]. The Lesch-Nyhan syndrome is character-
ized at the molecular level by the complete
absence of the purine salvage enzyme, hypoxan-
thine-guanine phosphoribosyltransferase, and,
interestingly, usually presents with evidence of a
marked increase in purine production, self-muti-
lation, choreoathetosis, but no stigmata of gouty
arthritis. It was determined subsequently that this
disorder was inherited as an X-linked recessive
trait [46, 47]. Soon after this publication, William
Kelley and Jay Seegmiller and their colleagues at
the National Institutes of Health described adults
with gouty arthritis, renal calculi, and purine
overproduction who were found to have a partial
deficiency of the same purine salvage enzyme
[48, 49]. Then, in 1972, Oded Sperling and his
colleagues described another X-linked recessive
disorder, phosphoribosylpyrophosphate syn-
thetase overactivity, in patients with purine over-
production, gout, and uric acid lithiasis [50, 51].
Although there have been a few reports of other
inherited forms of gout, these are rarer than the
ones discussed here and less well characterized
from a mechanistic standpoint. Studies of purine
metabolism continue today focusing on the early
6 1 A Brief History of Gout

detection and treatment of heritable disorders of

purine metabolism and the characterization of the
molecular basis of human purine mutants.

Famous Sufferers

Gout has been described as the disease of the

aristocracy since it has been an affliction of
statesmen, scientists, warriors, theologians, art-
ists, and men of letters through the centuries.
John Hunter (founder of experimental and surgi-
cal pathology), William Harvey (discoverer of
blood circulation), Charles Darwin (father of
modern biology), Carl Linnaeus (Swedish natu-
ralist and physician), and Isaac Newton (mathe-
matician and inventor of the telescope) as well as
others noted previously were all victims of the
disorder as were the warriors, Lord Howe,
Marshal Saxe (commander in the war of Polish
and Austrian succession), Albrecht Wallenstein
(Bohemian commander), Charlemagne (emperor
of the Holy Roman Empire), and Alexander the
Great (conqueror of Asia Minor and commander
of the Macedonian army) who also suffered from
the disease. Queen Anne (queen of England, Fig. 1.1 Consolation in the gout (Reproduced with per-
Scotland, and Ireland), Lord Beaverbrook mission from the American College of Rheumatology)
(Canadian-born millionaire, newspaper publisher,
and member of the British parliament), John citing an apt recipe to avoid the misfortune of the
Calvin (theologian and author), Benjamin disease when he wrote,
Franklin (American author and inventor), The rule of not too much, by temperance taught
Alexander Hamilton (American political leader), In what thou eat’st and drink’st, seeking from thence
Cotton Mather (fomenter of witchcraft hysteria Due nourishment, not gluttonous delight
in Salem and preacher), William Pitt the Elder
and the Younger (British statesmen and prime or as John Dryden described gout afflicting the
ministers), George Mason (American statesman hands,
and drafter of the constitution), Cardinal Wolsey Knots upon his gouty joints appear,
(the last medieval prince of the church), Count and Chalk is in his crippled fingers found.
Nikolaus Ludwig von Zinzendorff (German theo-
or the cure recommended by Charles Dickens,
logian), and other statesmen were afflicted with
gout. A number of distinguished artists and ‘The gout, sir,’ replied Mr. Weller, ‘The gout is a
authors were plagued by the disease including complaint as arises from too much ease and com-
fort. If ever you’re attacked with the gout, sir, just
John Milton, John Dryden, William Congreve,
you marry a widder as has got a good loud voice,
Henry Fielding, Johann Wolfgang von Goethe, with a decent notion of usin’ it and you’ll never
Samuel Johnson, Leonardo da Vinci, Thomas have the gout agin. It’s a capital prescription, sir. I
Gray, Ben Johnson, Martin Luther, and John takes it reg’lar, and I can warrant it to drive any
illness as is caused by too much jollity.’ Having
Wesley (English evangelist and theologian). Not
imparted this valuable secret, Mr. Weller drained
surprisingly, some writers transcribed their his glass once more, produced a laboured wink,
thoughts about gout as Milton may have done in sighed deeply and slowly retired. (Fig. 1.1)
References 7

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ment of gout. Am J Med. 1952;13:744.
24. Yu TF, Dayton PG, Gutman AB. Mutual suppression
1. Hartung EF. Historical considerations. Metabolism.
of the uricosuric effects of sulfinpyrazone and salicy-
1957;6:196.
late: a study in interaction between drugs. J Clin
2. Hippocrates: The genuine works of Hippocrates, vol.
Invest. 1963;42:1330.
I and II, translated from the Greek with a preliminary
25. Gutman AB. Uricosuric drugs, with special reference
discourse and annotations by Francis Adams. New
to probenecid and sulfinpyrazone. Adv Pharmacol.
York: Wood; 1886.
1966;4:91.
3. Garrod AB. The nature and treatment of gout and
26. Yu TF, Berger L, Gutman AB. Hypoglycemic and uri-
rheumatic gout. London: Walton and Maberly; 1859.
cosuric properties of acetohexamide and hydroxyhex-
4. Neuwirth E. Milestones in the diagnosis and treat-
amide. Metabolism. 1968;17:309.
ment of gout. Arch Intern Med. 1943;72:377.
27. Talbott JH. Gout. 3rd ed. New York: Grune and
5. Smith GE, Jones FW. The archeological survey of
Stratton, Inc; 1967.
Nubia, report for 1907–8. vol. 2, Cairo, National
28. Rundles RW, Wyngaarden JB, Hitchings GW, et al.
Printing Department; 1910. p. 44 and p. 269.
Effects of a xanthine oxidase inhibitor on thiopurine
6. Kittredge WE, Downs R. The role of gout in the for-
metabolism, hyperuricemia, and gout. Trans Assoc
mation of urinary calculi. J Urol. 1952;67:841.
Am Phys. 1963;76:126.
7. Ghalioungui P. Rheumatic disorders in ancient
29. White FR. 4-Aminopyrazolo(3,4-d)pyrimidine and
Egyptian papyri. Egypt Rheumatol. 1964;1:4.
three derivatives. Cancer Chemother. 1959;3:26.
8. von Storch A. An assay on the use and effects of the
30. Shaw RK, Shulman RN, Davidson JK, et al. Studies
root of the Colchicum autumnale, or meadow saffron,
with the experimental antitumor agent 4-aminopyra-
translated from the Latin, T. Becket and PA deHonet;
zolo (3,4-d)pyrimidine. Cancer. 1960;13:482.
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31. Feigelson P, Davidson JK, Robins PK. Pyrazol-
9. Sydenham T. A treatise of the gout and dropsy.
opyrimidines as inhibitors and substrates of xanthine
London: GGJ, J Robinson, W Otridge, S Hayes and
oxidase. J Biol Chem. 1957;226:993.
E Newbery; 1683.
32. Wyngaarden JB, Rundles RW, Silberman HR, et al.
10. McCarty DJ. A historical note: Leeuwenhoek’s
Control of hyperuricemia with hydroxypyrazolopy-
description of crystals from a gouty tophus. Arthritis
rimidine, a purine analogue which inhibits uric acid
Rheum. 1970;13:414.
synthesis. Arthritis Rheum. 1963;6:306.
11. Wollaston WH. On gouty and urinary concretions.
33. Garrod AE. The inborn factors in disease: an
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12. Scheele KW. Examen chemicum calculi urinarii.
(Clarendon); 1931.
Opuscula. 1776;2:73.
34. Wyngaarden JB, Stetten Jr D. Uricolysis in normal
13. Garrod AB. Observations on certain pathological
man. J Biol Chem. 1953;203:9.
conditions of the blood and urine in gout. Trans
35. Gutman AB, Yu TF. Renal function in gout with a
M-Chir Soc (Edinb). 1848;31:83.
commentary on the renal regulation of urate excre-
14. Garrod AB. On the blood and effused fluids in gout,
tion, and the role of the kidney in the pathogenesis of
rheumatism and Bright’s disease. Trans M-Chir Soc
gout. Am J Med. 1957;23:600.
(Edinb). 1854;37:49.
36. Gutman AB, Yu TF, Black H, et al. Incorporation of
15. Garrod AB. The nature and treatment of gout and
glycine-1–C14, glycine-2–C14, and glycine-N15 into
rheumatic gout. 2nd ed. London: Walton and Maberly;
uric acid in normal and gouty subjects. Am J Med.
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1958;25:917.
16. Fischer E. Untersuchungen in der puringruppe. Berlin/
37. Sperling O, Wyngaarden JB, Starmer CF. The kinetics
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of intramolecular distribution of 15N-glycine: a rein-
17. Folin O, Denis W. A new (colorimetric) method for
terpretation of the basis for the hypothesis of an
the determination of uric acid in the blood. J Biol
abnormality of glutamine metabolism in primary
Chem. 1912–1913;13:469.
gout. J Clin Invest. 1973;52:2468.
18. Schnitker MA. A history of the treatment of gout. Bull
38. Wyngaarden JB, Blair AE, Hilley L. On the mecha-
Inst Hist Med. 1936;4:89.
nism of overproduction in patients with primary gout.
19. Want J. The use of Colchicum autumnale in rheuma-
J Clin Invest. 1958;37:579.
tism. Med Physiol J (Lond). 1814;32:312.
39. Wyngaarden JB. Overproduction of uric acid as the
20. Beyer KH, Miller K, Russo HF, et al. The inhibitory
cause of hyperuricemia in primary gout. J Clin Invest.
effect of carinamide on the renal elimination of peni-
1957;36:1508.
cillin. Am J Physiol. 1947;149:355.
40. Seegmiller JE, Grayzel AI, Howell RR, et al. The
21. Beyer KH, Russo HF, Schuchardt DS, et al. 3-hydroxy-
renal excretion of uric acid in gout. J Clin Invest.
2-phenylcinchoninic acid (HPC): its absorption, excre-
1962;41:1094.
tion, and its effect of certain renal functions and
41. Gutman AB, Yu TF. An abnormality of glutamine
enzyme systems. J Pharmacol Exp Ther. 1951;103:79.
metabolism in primary gout. Am J Med. 1963;35:820.
22. Gutman AB, Yu TF. Benemid, (p-[di-n-propylsulfamyl]
42. Seegmiller JE, Klinenberg JR, Miller J, et al.
-benzoic acid) as uricosuric agent in chronic gouty
Suppression of glycine-N15 incorporation into urinary
arthritis. Trans Assoc Am Phys. 1951;64:279.
8 1
uric acid by adenine-8-C14 in normal and gouty
subjects. J Clin Invest. 1968;47:1193.
43. Kelley WN, Rosenbloom FM, Seegmiller JE. The
effect of azathioprine (Imuran) on purine synthesis in
clinical disorders of purine metabolism. J Clin Invest.
1967;46:1518.
44. Seegmiller JE, Laster L, Stetten Jr D. Incorporation of
4-amino-5-imidazolecarboxamide-4-C13 into uric acid
in the normal human. J Biol Chem. 1955;216:653.
45. Lesch M, Nyhan WL. A familial disorder of uric acid
metabolism and central nervous system function. Am
J Med. 1964;36:561.
46. Shapiro SL, Sheppard GL, Dreifuss FE, Newcombe
DS. X-linked recessive pattern of inheritance of a syn-
drome of mental retardation with hyperuricemia. Proc
Soc Exp Biol Med. 1966;122:609.
47. Nyhan WL, Pesek J, Sweetman L, et al. Genetics of
an X-linked disorder of uric acid metabolism and
cerebral function. Pediatr Res. 1967;1:5.
A Brief History of Gout
48. Kelley WN, Greene ML, Rosenbloom JF, et al.
A specific enzyme defect in gout associated with
overproduction of uric acid. Proc Natl Acad Sci USA.
1967;57:1735.
49. Kelley WN, Greene ML, Rosenbloom JF, et al.
Hypoxanthine-guanine phosphoribosyltransferase
deficiency in gout. Ann Intern Med. 1969;70:155.
50. Sperling O, Eilam G, Persky-Brosh S, et al.
Accelerated erythrocyte 5’-phosphoribosylpyrophos-
phate synthesis. A familial abnormality associated
with excessive uric acid production and gout. Biochem
Med. 1972;6:310.
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 The Prevalence and Risk Factors
for Gout
Prevalence of Gout
Gout is the most common inflammatory rheu-
matic disease, at least in the Western world, and
several surveys have shown that the prevalence
of gout continues to increase into the twenty-
first century. Estimates from the United States
National Health and Nutrition Examination
Survey (NHANES III) showed that the preva-
lence of gout in the USA more than doubled in
the last half of the twentieth century. And further
studies indicate the prevalence of gout continues
to increase. A study of data from the NHANES
2007–2008 estimated that the prevalence of gout
among US adults was 3.9 % or 8.3 million indi-
viduals. Among men, the prevalence was 5.9 %
and among women 2.0 %. The prevalence of
hyperuricemia was also increasing. This sur-
vey led to the conclusions that over the past two
decades, the prevalence of gout had increased by
1.2 % and hyperuricemia by 3.2 %. If hyperu-
ricemia is defined as levels over 7.0 mg/dl, the
prevalence of hyperuricemia was 13.2 % of US
adults. Most of these increases were attributed to
the increasing prevalences of obesity and hyper-
tension [1]. Moreover, the increasing prevalence
has been found in several countries other than the
USA. A survey in the UK found that the preva-
lence of gout there had increased threefold in the
two decades prior to 1991, and similar studies
from New Zealand, China, and African countries
have also found similar increases [1, 2].
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_2, © Springer-Verlag London 2013
2
Diet, Disease States, and Heredity
Associated with Gout
Scientific research has now changed the way uric
acid is characterized as to its role in the human,
and this new evidence has altered the clinical
assessment and follow-up evaluations in patients
with gout. Originally, uric acid was considered
a nitrogenous waste product of human metabo-
lism that was excreted by the kidney and bowel.
Despite a host of hypotheses generated to the
contrary, this nonfunctional concept of uric acid
has remained in vogue until recent studies have
begun to provide the scientific evidence with
respect to the potential biological functions
of uric acid [3–7]. A variety of investigations
have now linked the causes of hypertension, salt
retention, hypertriglyceridemia, cardiovascular
adverse events, and obesity to increased serum
uric acid levels [3, 8–40]. In addition to clinical
data implicating uric acid levels with cardiovas-
cular events like hypertension, the pathological
mechanisms for such associations including the
development of renal disease, renin-angiotensin
system activation, and endothelial dysfunction
have been characterized [12, 14–18, 27, 41–48].
Although the data relating to the generation of
reactive oxygen species (ROS) and nitric oxide
and the production of endothelial dysfunction
remains controversial, there is an increasing body
of evidence that links hyperuricemia with hyper-
tension and renal damage [11, 12, 27, 41, 49–52].
9
10
Despite the fact that absolute correlations do not
exist between uric acid and hypertension and its
pathologic mechanisms, sufficient data do exist
to encourage the careful monitoring for the onset
of hypertension in gouty patients. Furthermore,
evidence also suggests that the hyperuricemic
state accompanying gout should be treated with
hypouricemic agents along with the aggressive
management of hypertension [53]. Although uric
acid and hyperuricemia have been associated
with these morbidities, the role of uric acid in the
pathogenesis of these disease states remains to be
determined in most cases. However, some evi-
dence does indicate that gout is an independent
risk factor for cardiovascular disease [2, 54].
Gout has also been documented to be associ-
ated with obesity, dyslipidemia, and hyperglyce-
mia along with hypertension [55–59]. With
respect to obesity and the insulin resistance syn-
drome, elevated serum uric acid levels have
been observed with these clinical findings as well
[60–62]. Further evidence of the association
between gout and obesity comes from studies
showing that the risk of gout diminishes with
weight reduction [63, 64]. Recently, obesity,
hypertension, lipidemia, and hyperglycemia have
been considered as a cluster of findings charac-
teristic of a syndrome of multiple interrelated
conditions called the metabolic syndrome [65].
This so-called metabolic syndrome is diagnosed
on the basis of the following revised criteria:
abdominal obesity (waist circumference of >102
cm in men and >88 cm in women), hypertriglyc-
eridemia (>150 mg/dl or 1.69 mmol/l), low high-
density lipoprotein (HDL) cholesterol (<40 mg/
dl or 1.04 mmol/l in men and <50 mg/dl or 1.29
mmol/l in women), a blood pressure reading of
less than 130/80 mm of HG, and a fasting glucose
level of more than 100 mg/dl or more than 5.6
mmol/l [66]. Two facts stress the importance of
identifying the metabolic syndrome in gouty
patients. First, the metabolic syndrome increases
the risk of cardiovascular disease up to three
times and the risk for type 2 diabetes mellitus up
to five times [67, 68]. It also causes an increase in
mortality from cardiovascular diseases as well as
all-cause mortality [60–70]. Second, the preva-
lence of the metabolic syndrome in gouty patients
2 The Prevalence and Risk Factors for Gout
is strikingly high (62.8 % in US adults and 43.6 %
in Korean adults) as compared with a general
population without gout (25.4 % in the USA and
5.2 % in Korea) [71, 72]. This association between
gout and the metabolic syndrome has been
confirmed in other studies as well [73, 74].
Cardiovascular disease in gouty patients at high
risk, those with type 2 diabetes mellitus, stroke,
congestive heart failure, or coronary heart dis-
ease, showed an independent association of
gout with cardiovascular disease and mortality
[75, 76]. Low-risk gouty patients without these
accompanying findings have determined that
serum uric acid levels are poor predictors of car-
diovascular morbidity and mortality [36, 76].
There are a number of publications that address
components and complications of the metabolic
syndrome in connection with the risk of vascular
disease, the occurrence of insulin resistance, the
presence of ischemic heart disease, cardiovascu-
lar mortality, and the presence of accompanying
disorders at the time of the initial diagnosis of
gout [49, 73, 77–89]. Hyperuricemia is associ-
ated with an increased risk for vascular disease
in some studies, but other investigations only
demonstrate a link between gout and death from
cardiovascular diseases but not with hyperurice-
mia [78, 81]. The prevalence of insulin resistance
is higher in patients with gout than in normal
healthy control groups [79]. Patients with gout in
one study were all shown to manifest the meta-
bolic syndrome, and 16 % had ischemic heart
disease [77]. A recent review of the clinical sta-
tus of patients with respect to their first episode
of gout and the diagnosis of the metabolic syn-
drome and its components and complications
showed that 90 % of the first attacks of gout pre-
ceded the diagnosis of the metabolic syndrome,
its components, and its complications [80]. At
the time of the inclusion of gouty patients into
this study (a mean of 13.7 years after the first
attack of gout), 93 % of these patients had at least
one associated disorder. The most common asso-
ciated disorders included hypertriglyceridemia,
63 %; obesity, 54 %; hypertension, 45.6 %; meta-
bolic syndrome, 40 %; hyperglycemia, 37 %;
low HDL, 17 %, diabetes mellitus, 15 %, chronic
renal failure, 17 %; and ischemic heart disease,
Diet, Disease States, and Heredity Associated with Gout
6.6 %. These data emphasize the need for care-
ful follow-up evaluations of patients with gout.
Another study showed a 2:1 ratio of the preva-
lence of essential hypertension, hyperlipidemia,
diabetes mellitus without complications, and
coronary atherosclerosis in patients with gout
as compared with subjects without gout [90]. A
strong correlation has also been shown to exist
between diminished urinary uric acid levels and
the presence of the metabolic syndrome [89].
The proposed mechanism for this abnormality of
uric acid excretion is an impairment of renal uric
acid excretion mediated by hyperinsulinemia-
enhanced proximal tubule sodium reabsorption
and the diminished uric acid excretion [49, 88].
Although medications are usually the means
by which recurrent gouty episodes are controlled,
there are certain dietary restrictions that may be
useful as well. It has been shown that meat and
seafood intake are associated with an increased
risk of gout. Meat including beef, lamb, and pork
as well as bologna, sausage, salami, bacon, hot
dogs, chicken, turkey, hamburger, chicken liver,
and beef liver are the most well-characterized
offenders as inducers of gouty episodes. Seafood
associated with an increase risk of gout include
tuna, dark fish, shrimp, lobster, clams, and scal-
lops. There are also some purine-rich vegetables
like peas, lentils, spinach, mushrooms, oatmeal,
and cauliflower, but they do not appear to increase
the risk of gout [56, 91–94]. In contrast these
high-purine-containing foods, there are some
foods with low purine content such as milk,
cheese, yogurt, ice cream, breads, pasta, vegeta-
bles other than those with a high purine content,
fruits, nuts, sugars, and sweets. Of course, it is
important to recognize that beef, cheese, ice
cream, and some other foods are not appropriate
for those with lipid abnormalities. Usually, gout
is associated with type IV hyperlipidemia or
hypertriglyceridemia. These dyslipidemias occur
in about 25–60 % of gouty patients [55, 56]. It is
also worth remembering that roughly two-thirds
of the purines in the human are produced by cell
and tissue turnover, whereas only one-third of
purines are contributed by dietary intake.
Excessive fructose intake has been implicated
in the causation of the metabolic syndrome and
11
gout [31, 95, 96]. Fructose-induced hyperurice-
mia has been known since the 1970s, but it has
only recently been implicated in the causation of
the metabolic syndrome and gout [97–100]. Two
mechanisms have been proposed as the means by
which fructose causes the hyperuricemia of the
metabolic syndrome. The need for fructose to be
phosphorylated by ATP during its metabolism to
form fructose-1-phosphate leads to the break-
down of ATP and ultimate production of uric
acid. The presence of low phosphorus levels
impedes the regeneration of ATP and favors the
degradation of adenosine monophosphate. The
second mechanism postulates that tissue isch-
emia leads to the degradation of ATP causing an
increase in uric acid synthesis. In addition, the
enzyme, xanthine dehydrogenase, is converted to
xanthine oxidase in the ischemic state, and the
latter enzyme uses molecular oxygen as an elec-
tron donor leading to the formation of superoxide
anion and hydrogen peroxide (oxygen free radi-
cals). Thus, tissue ischemia leads to an increased
production of both oxygen free radicals and uric
acid. Recent data have also shown that excessive
fructose ingestion causes not only the metabolic
syndrome but also a hypertensive response [31].
In the foregoing study, reducing uric acid levels
also decreases the blood pressure, and this is per-
tinent to the data showing that hyperuricemia
may have a role in the production of hypertension
in man. Fructose ingestion has also been associ-
ated with an increased risk of gout and kidney
stones as well as its capacity to increase post-
prandial levels of triglycerides [95].
Two studies have examined the dietary intake
of fructose as it relates to the risks of the devel-
opment of gout [101, 102]. Sugar-sweetened
soft drink ingestion significantly increases the
serum uric acid levels, and such increments
were entirely independent of age, sex, body
mass index, alcohol use, renal function, hyper-
tension, and diuretic use. For example, the dif-
ference between the serum uric acid levels and
the extreme categories of sugar-sweetened soft
drink intake was 0.4 mg/dl. The latter increment
in serum uric acid level was equal to the con-
sumption of one beer/day and caused a 50 %
increase in the risk of incident gout [103, 104].
12
In fact, another study showed the risk of incident
gout was 85 % higher among men who ingested
two or more servings of sugar-sweetened soft
drinks daily as compared to those who con-
sumed less than one serving per month [102].
Furthermore, fructose-induced hyperuricemia is
greater in those patients with gout or hyperuri-
cemia [105–108]. These data suggest that
patients with gout might improve their health
and well-being by avoiding the excessive use of
sugar-sweetened soft drinks or shift to diet soft
drinks that do not increase serum uric acid lev-
els [101]. There is another means by which fruc-
tose intake may also affect humans since it
contributes to insulin resistance, glucose intol-
erance, and hyperinsulinemia [109–113]. In
summary, fructose intake increases insulin lev-
els, enhances insulin resistance, fosters obesity,
and causes significant increments in serum uric
acid levels, especially in gouty patients [57, 71,
114, 115]. In animal studies, female sex hor-
mones protect women against fructose-induced
hyperuricemia, but hyperinsulinemia causes a
decrease in renal urate excretion and is corre-
lated with the increase in serum uric acid levels
[55, 116–120]. One final point should be made
regarding the metabolic syndrome. A recent
study has proposed that hyperuricemia is
strongly associated with the metabolic syn-
drome and should be included as a parameter of
the metabolic syndrome [121]. This fact coupled
with the frequency of the metabolic syndrome
in patients with gout (63 %) provides the impe-
tus to assess and monitor patients with gout for
the metabolic syndrome [71, 122]. Therefore, it
is recommended that blood pressure levels of
greater than 130/80 mmHg be treated aggres-
sively to maintain blood pressure levels lower
than this. Abdominal obesity with a waist cir-
cumference of greater than 102 cm in men or
greater than 88 cm in women should be treated
with weight reduction. Patients with hypertrig-
lyceridemia who manifest triglyceride levels of
greater than 150 mg/dl and/or low high-density
lipoprotein levels (less than 40 mg/dl in men
and less than 50 mg/dl in women) should be
treated to alter these elevated lipid levels. Blood
lipid levels should always be measured in samples
2 The Prevalence and Risk Factors for Gout
taken after a 12-h fast. Patients who have abnor-
mal blood lipids should reduce their alcohol use,
should institute a weight reducing diet contain-
ing only 10–20 % fat, and be treated with either
fenofibrate or gemfibrozil to reduce their trig-
lyceride levels. These dietary restrictions should
also be accompanied by an exercise program to
increase HDL levels. Treatment regimens for
hypertriglyceridemia and the risk of mortality
have been published and can be consulted
for additional information [123–128]. Finally,
blood sugar levels should be maintained below
100 mg/dl.
Alcohol ingestion in excess and its association
with gout has been known since antiquity [56,
129–132]. Beer has a special capacity to raise the
serum uric acid levels and put patients at risk for
gouty episodes since it contains guanosine, a
purine that is easily converted enzymatically to
uric acid. Finally, many patients will tell their
physician that particular foods or alcoholic bev-
erages will trigger an attack of gout. In these
cases, physicians should heed the patient’s infor-
mation and ask the patient to restrict their intake
of the offending agent (Fig. 2.1).
There are four general rules that are useful
when considering dietary modifications for
patients with gout. Overweight patients should
make a concerted effort to lose weight by diet and
exercise. Measurement of fasting blood lipids is
essential to exclude hyperlipidemia as a contrib-
uting factor to underlying health problems.
Appropriate diets and medications should be
instituted to decrease the low-density lipoprotein
(LDL) levels (bad cholesterol) and increase the
high-density lipoprotein (HDL) levels (good cho-
lesterol) if hyperlipidemia exists. Gouty patients
should also be encouraged to eat a balanced diet
with less red meat and less seafood than usual. In
general, the three foods/beverages that place
patients at risk for gout are red meat, beer, and
fructose, a sugar commonly found in sugar-
sweetened soft drinks. Finally, patients with gout
should decrease their use of hard liquor and beer
with a substitution of wine if necessary.
Hyperuricemia is the precursor of gout and
kidney stones, and therefore, the mechanisms
that increase serum uric acid levels become
Genetic Abnormalities in Renal Tubular Transport Leading to Reduced Renal Excretion of Urate
Fig. 2.1 Champaign driving away real pain (Reproduced with permission from the American College of
Rheumatology)
important to understand and modify, if necessary.
Serum uric acid levels represent a balance
between cell and tissue breakdown, the synthesis
of uric acid and its precursors by the de novo
purine and salvage pathways, the renal elimina-
tion of urate, and the dietary intake of purines and
other chemicals known to influence urinary uric
acid excretion. Genetic parameters have been
described in monogenic disorders including
hypoxanthine-guanine phosphoribosyltransferase
deficiency, phosphoribosylpyrophosphate syn-
thetase overactivity, familial juvenile hyperurice-
mic nephropathy, and glycogen storage disease,
but these disorders account for only a very small
proportion of patients with gout. The majority of
patients with gout have a drug-induced or
undefined alteration in their renal elimination of
uric acid. Most gout therefore is associated with
reduced renal excretion of uric acid rather than
13
overproduction, and many studies have indicated
genetic abnormalities of several renal tubular
proteins that are involved in urate transport in
addition to the lifestyle issues discussed above.
Genetic Abnormalities in Renal
Tubular Transport Leading to
Reduced Renal Excretion of Urate
Recently, genome-wide association studies have
been applied to assess serum uric acid concentra-
tions [133–140]. Studies have begun to link an
excessive fructose intake, hyperuricemia, and a
transport system in the kidney. The gene involved
in this process, SLC2A9, encodes a glucose/fruc-
tose transporter [133, 138–146]. This gene con-
tains 14 exons and 12 transmembrane helical
domains and is highly expressed in the liver and
14
kidney [147, 148]. There are two isoforms of this
gene, a long isoform (GLUT9L) and a short iso-
form (GLUT9S), and the gene itself is localized
to chromosome 4p15.3-16 [144]. The gene that
maps to chromosome 4p15.3-16 consists of 12
exons and encodes a 540 amino acid protein
[147]. A splice variant of this gene has also been
cloned from human kidney cDNA, and this vari-
ant consists of 13 exons and encodes a protein of
512 amino acids. This splice variant has been
termed GLUT9DN to delineate that GLUT9 and
GLUT9DN only differ in their N terminus.
GLUT9 was found to be present in the kidney,
placenta, liver, and leukocytes, whereas
GLUT9DN has been localized to the kidney and
placenta. In the Madrin-Darby canine kidney,
GLUT9 was localized in the basolateral mem-
brane of the proximal renal tubule epithelial cells,
and GLUT9DN localizes to the apical membrane
of the proximal tubule epithelial cells.
Recent studies using GLUT9 isoforms 1 and 2
have proposed that SLC2A9 (isoform 2) is cou-
pled with URAT1, the principal renal urate reab-
sorption transporter, to cause the excretion of
urate from the tubule cells [149]. GLUT9, in these
experiments, manifested saturable kinetics, and
the Eadie-Hofstee plot showed a Km value of
365 ± 42 uM and a Vmax value of 5,521 ± 291
pmol/h/oocyte (mean ± S.E.). Experimental data
supported a voltage sensitivity transport system
when external potassium ions depolarized the cell
membrane and the net negative charge remained
with the cell. The uptake of urate by GLUT9 was
not influenced by glucose, fructose, lactate, nico-
tinamide, orotate, or ketone bodies like acetoace-
tate or b-hydroxybutyrate. However, probenecid,
benzbromarone, and losartan did manifest mod-
erate inhibition of urate uptake. These data sug-
gest that GLUT9 confined to the basolateral
membrane of the proximal tubules may be a new
target for uricosuric agents. As is known, muta-
tions in URAT1 can result in a hereditary disease
characterized by an inborn error in kidney cell
membrane transport leading to a defect in urate
reabsorption and resulting in hypouricemia.
However, not all patients manifesting idiopathic
hypouricemia express mutations in URAT1. The
recent report of a hypouricemic patient with a
2 The Prevalence and Risk Factors for Gout
mutation in the SLC2A9 gene (heterozygous C to
G alteration in nucleotide 1296 in exon 11 leads
to a change from proline 412 to arginine 412 –
CCC to CGC). When examined in experimental
systems, this mutant significantly reduced urate
transport activity. The foregoing data leave under
consideration mutant apical renal membrane sites
for SLC2A9, mutant basolateral membrane sites
for SLC2A9, or single nucleotide polymorphisms
of this gene as putative mediators of hyperurice-
mia [147, 150, 151].
Genetic polymorphisms of SLC2A9/GLUT9
have been identified from genome-wide associa-
tion studies either by genetic variations in the
human genome sequence, single nucleotide poly-
morphisms (SNPs), or HapMap databases to be
related to low uric acid levels or low fractional
clearance of urate by the kidney (elevated serum
uric acid levels) [133, 135, 137, 138, 140, 143].
The SNPs associated with gout include the fol-
lowing: rs 12510549, rs 1014290, rs 6449213, rs
7442295, rs 6855991, rs 737267, and rs 16890979.
The long isoform of GLUT9 (GLUT9L) is local-
ized to the basolateral membranes of the proxi-
mal tubule epithelial cells, whereas the short
splice variant (GLUT9S) is localized to the apical
membranes of the proximal tubule epithelial
cells. It is now well accepted that GLUT9L is the
principal mediator of urate transport from the
intracellular compartment of the renal tubular
epithelial cells to the interstitium/blood space,
and it is postulated that GLUT9S is responsible
for the secretion of urate into the lumen of the
renal tubules. These SNPs associated with gout
showed no significant associations with coronary
artery disease or myocardial infarction [146].
Additional studies of New Zealand populations
of Maoris and Pacific Islanders also showed a
strong correlation between specific SNPs and
gout [152]. The SNPs evaluated for this associa-
tion were the following: rs 16890979, rs 5028843,
rs 11942223, and rs 12510549. However, the data
published in this study suggest that additional
parameters may also contribute to the increased
frequency of gout in these population groups
known to have an increased frequency of gout.
A recent study has also related glucose and
fructose transport to the SLC2A9 gene [145].
Genetic Abnormalities in Renal Tubular Transport Leading to Reduced Renal Excretion of Urate
These investigations evaluated two variants of
SLC2A9 (SNPs – rs 7442295 and rs 13113918).
These SNPs were delineated as SLC2A9a and
SLC2A9b in the publication. Both of these SNPs
demonstrated urate fluxes with identical kinetic
analyses and provided a Km value of 981 uM and
a Vmax value of 304 pmol/oocyte/20 min.
Additional experiments were done to determine
whether any compounds altered urate transport.
Benzbromarone showed a dose–response inhibi-
tion of urate uptake between concentrations of
10 uM (34 % inhibition) and 100 uM (80 %
inhibition), and a Dixon plot for benzbromarone
inhibition of urate transport by SLC2A9 showed
a Ki value of 27 uM. The only other inhibitor of
urate transport was determined to be lactate, and
1 mM concentrations of this metabolite were
found to be a very weak inhibitor of urate trans-
port. Benemid, pyruvate, butyrate, and phloretin
(a hexose transport inhibitor) caused no inhibi-
tion of urate transport.
An evaluation of hexose transport (glucose
and fructose) by SLC2A9 showed that urate
transport was 40- to 60-fold faster than hexose
transport. When urate uptake was examined in
the face of d-glucose, d-fructose, and l-glucose,
the presence of glucose or fructose accelerated
urate transport. d-glucose increased urate trans-
port by sevenfold, whereas fructose enhanced
urate transport by threefold. Thus, sugars like
fructose enhance urate transport. These experi-
ments also determined that glucose and fructose
bind to a different site on the transporter protein
than urate. These data relating fructose and urate
transport support population studies showing that
the consumption of sugar-sweetened soft drinks
and fructose are strongly associated with elevated
serum uric acid levels and an increased risk of
gouty arthritis [101, 102, 153]. Finally, in addi-
tion to gout, excessive fructose intake has also
been implicated as a cause of the metabolic syn-
drome in association with gout. One final point
about the protein product of the SLC2A9 gene is
the fact that this gene is also expressed in chon-
drocytes [140, 147, 150, 154–156]. This capacity
of cartilage to transport urate may contribute to
the clinical expression of gout since cartilage is
often the site of urate crystal deposition. It is also
15
of some interest to indicate that IL-1b, the
proinflammatory cytokine produced by the
inflammasome in gout, stimulates the transport
of glucose in articular cartilage. Since GLUT9
mediates urate transport at very high rates and at
rates significantly faster than its facilitated trans-
port of either glucose or fructose, this SLC2A9
gene product transporter may be a key to the
deposition of monosodium urate crystals in the
joint space and cartilage. In addition, since IL-1b
enhances glucose transport, it would be of inter-
est to determine what effect this proinflammatory
cytokine might have on urate transport by carti-
lage via this protein transporter.
Although the identification of monogenic
mutations in the human has clearly delineated
the biochemical rationales behind the increase in
serum uric acid levels associated with these
human mutations, there is no question that serum
uric acid levels may also be dependent, in many
cases, on the renal elimination of uric acid. This
renal determinant becomes increasingly impor-
tant since it contributes to the development of
gout and kidney stones, but it is also linked to the
metabolic syndrome and cardiovascular disease
[50, 157–159]. The renal transport of urate has
been found to be mediated by transmembrane
proteins localized to the proximal renal tubular
cells of the kidney [159–161]. The direction of
urate transport in the kidney is primarily depen-
dent on the concentration gradients of the trans-
ported substrates and their countertransported
substrates even though transporter proteins such
as URAT1 are described as being primarily
responsible for urate reabsorption by the proxi-
mal renal tubules [160]. However, mutations in
the transport proteins of the kidney and single
nucleotide polymorphisms in these same trans-
port proteins have begun to characterize the roles
these transmembrane proteins play in the gener-
ation of hyperuricemia and gout. In addition to
the SNPs associated with gout in the SLC2A9
gene as discussed previously, there are other
mutations in the renal transport proteins as well
as SNPs that are associated with hyperuricemia
and gout. A homozygous frameshift mutation
has been described in URAT1 (SLC22A12 gene)
in an individual that manifested hyperuricemia
16
and gout in contrast to the usual function of
URAT1 as principally a transporter of urate reab-
sorption in exchange for lactate at the apical
membrane of the proximal tubules [162].
Furthermore, defects in URAT1 cause hypouri-
cemia because the kidney cannot reabsorb urate
[163–165]. Thus, these are two different muta-
tions, one of which enhances urate urinary excre-
tion through its failure to reabsorb urate leading
to hypouricemia and the other appears to enhance
urate reabsorption leading to hyperuricemia and
gout. Several drugs and metabolites effect the
excretion of uric acid through interactions with
URAT1, leading to either urate retention or
increased urate excretion. For example, lactate,
nicotinate, and pyrazinoate interact with URAT1
to increase the reabsorption of uric acid. On the
other hand, the uricosuric agents, benzbroma-
rone, probenecid, and losartan, interact with
URAT1 to inhibit urate reabsorption and thus
increase urate excretion [166].
In addition to these mutations causing an
alteration in the renal transport of urate, there are
functional polymorphisms associated with hype-
ruricemia and gout. The GLUT9 or SLC2A9
gene associated with glucose and fructose inges-
tion has already been discussed in relation to
fructose intake, but other polymorphisms have
also been characterized. The ATP-binding cas-
sette subfamily G member 2 (ABCG2) gene has
been identified as influencing serum urate levels
and the occurrence of gout [137, 167]. This trans-
porter causes the export of uric acid out of the
proximal tubules and decreases the intracellular
urate concentration over time [168]. The intro-
duction of the mutation Q141K (glutamine-141
lysine) in the ABCG2 encodes a common SNP
(rs 2231142), and this polymorphism causes a
54 % reduction in the urate transport rates com-
pared to the wild-type ABCG2 gene. These inves-
tigations also determined that about 10 % of the
individuals with gout in white males could be
attributed to this polymorphism. This SNP also
appears to be responsible for gout in the Chinese
Han male population [169]. This same polymor-
phism also accounts for much of the gout in Asian
populations. Another SNP involves the SLC17A1
gene that is associated with serum urate concen-
2 The Prevalence and Risk Factors for Gout
trations and is also presumed to function as a
urate secretor in the kidney [136, 170, 171]. This
T806C genotype in the voltage-dependent urate
transporter NPT1 was found to be associated with
a significant degree of weight loss in obese
Japanese men [172]. The authors of the foregoing
publication also suggest that SLC17A1 polymor-
phisms are associated with the development of
gout. Thus, these SNPs and mutations in the
transmembrane proteins localized to the proxi-
mal tubules of the kidney demonstrate clearly
that understanding the mechanisms of urate trans-
port in the kidney are likely to make inroads into
the genetics of gout and emphasize the significant
contributions of the kidney to the generation of
hyperuricemia and gout. Such studies related to
the renal transport of urate also provide new tar-
gets for the design of drugs for the treatment of
hyperuricemia. The further definition of SNPs
related to hyperuricemia and gout will also lead
to a better understanding of at-risk individuals
and populations. Finally, more emphasis has been
placed on the exclusion of parameters associated
with the metabolic syndrome because of its high
prevalence in gouty patients. Components of the
metabolic syndrome should probably be evalu-
ated annually in patients with gout and treatment
instituted when appropriate.
The handling of urate by the proximal renal
tubule is summarized in the diagram in Fig. 2.2.
Monocarboxylates are transported from the
lumen into the cell through the monocarboxylate
transporters SLC5A8 and SLC 5A12. Urate is
transported into the cell through URAT1 in
exchange for monocarboxylates and in exchange
for dicarboxylates by OAT4. Urate also enters the
cell through SLC2A9v2 and is transported from
the cell into the blood through SLC2A9v1. Urate
may be secreted into the lumen by MRP4 and
OATv1, and OAT 1 and OAT 3 may also be
involved in urate transport. As noted above, the
presence of glucose and fructose may facilitate
the tubular reabsorption of urate, through the
SCLA transporters, and this may contribute to
the association with excessive intakes of these
substances with gout.
A report of a meta-analysis of genome-wide
association studies (GWAS) found significant
Genetic Abnormalities in Renal Tubular Transport Leading to Reduced Renal Excretion of Urate 17

The uric acid transportasome.

Basolateral Apical

Uric acid
reabsorption

Na+
SLC5A8
SLC5A12
Monocarboxylate Monocarboxylate
Uric acid
URAT1
Uric acid
OAT1
OAT3 Uric acid
Dicarboxylates Dicarboxylate OAT4
SLC13A3
Na+
Uric acid
SLC2A9v2 Glucose
Fructose
Uric acid
Glucose SLC2A9v1
Frucose Uric acid
MRP4 secretion
Uric acid
OATv1
(NPT1)

Fig. 2.2 The uric acid transportasome. Current under-
standing of uric acid transport in the proximal renal tubule.
Monocarboxylates accumulate in the tubular cell through
sodium-dependent monocarboxylate transporters SLC5A8
and SLC5A12 and dicarboxylates through SLC13A3.
Uric acid enters the cell in exchange for monocarboxylate
via apical URAT1 and for dicarboxylate via apical OAT4.
Apical SLC2A9v2 plays a significant role in uric acid
reabsorption, the reabsorbed uric acid exiting the cell
through basolateral SLC2A9v1. For efflux of uric acid
into the lumen, MRP4 and a voltage-driven organic anion
transporter (vOAT1/NPT1) are candidates. OAT1 and
OAT3 are known to transport uric acid, although the direc-
tion of transport is not clear (Reproduced with permission
from Dalbeth and Merriman [173]. ©The Author 2008.
Published by Oxford University Press on behalf of the
British Society for Rheumatology)

associations of single nucleotide polymorphisms
at eight genetic loci with serum uric acid levels.
However, only two loci, one in SLC2A9 and one
in ABCG2 showed significant associations with
gout. A genetic urate score showed significant
associations with serum urate levels and gout,
but not with blood pressure, chronic kidney dis-
ease, or coronary heart disease [173]. These
observations suggest that some genetic factors
that predispose to gout are not responsible for
other disease states that are often associated
with gout.
18 2 The Prevalence and Risk Factors for Gout

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 Purine Biochemistry
Structure
Emil Fischer and his colleagues were the first to
interrelate the various purines discovered prior to
their work and to devise the correct formula for
uric acid. The purine ring is the product of a
fusion between an imidazole ring and a pyrimi-
dine in which the carbon atoms 4 and 5 are shared.
Its chemical name is 7(9)-H-imidazole (4,5-d)
pyrimidine. The purine ring and numbering sys-
tem are shown in Fig. 3.1, and the hexagonal rep-
resentation conforms closely to the structure
found by X-ray diffraction studies. Although
Fischer also determined the actual structure of
the purine base, adenine (6-aminopurine), it was
not recognized that this base was a constituent of
deoxyribonucleic acid (DNA) until it was iso-
lated from beef pancreas by Kossel in 1885.
Kossel also recognized guanine (2-amino-6-
hydroxypurine) as a constituent of DNA. Further,
Kossel, his colleagues, and others were also
responsible for isolating the pyrimidine constitu-
ents of DNA including thymine, cytosine, uracil,
5-methylcytosine, and 5-hydroxymethylcytosine.
In studies in the late 1800s, both xanthine
(2,6-dihydroxypurine) and hypoxanthine (6-hydro-
xypurine) were characterized. Another purine
base of significance to the understanding of
gout is the hypoxanthine analog, allopurinol
(4-hydroxypyrazolo (3,4-d) pyrimidine). The
carbon in position 8 of the purine ring and
the nitrogen in position 7 are transposed in the
allopurinol molecule, and a hydroxy group is
attached to what was position 6 of the purine ring
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_3, © Springer-Verlag London 2013
3
and which then becomes position 4 in the pyrazo-
lopyrimidine ring (Fig. 3.2). This structural ana-
log of hypoxanthine has become an important
therapeutic agent for gout since it lowers serum
uric acid levels (hypouricemia) through its capac-
ity to inhibit the enzyme, xanthine oxidase, which
catalyzes the oxidation of hypoxanthine and xan-
thine to uric acid (2,6,8-trioxopurine).
The other by-product from these studies of
purine metabolism was the chemical synthesis of
6-mercaptopurine by the treatment of hypoxan-
thine with phosphorus pentasulfide. This purine
analog was subsequently found to have antitumor
properties and also, as will be discussed subse-
quently, is a feedback inhibitor of de novo purine
biosynthesis when converted from its free base to
its corresponding nucleotide. A number of gen-
eral references are available for more detailed
information concerning purine synthesis [1–4]
(Fig. 3.3).
Nucleic Acid Degradation
Gout is an inherited metabolic disorder, and
understanding its pathogenesis requires knowl-
edge of both the endogenous and exogenous
sources of uric acid. There are three sources for
which uric acid can be generated in the human:
dietary intake, tissue turnover, and de novo purine
nucleotide biosynthesis from small molecules.
Dietary purines consist mainly of free purine
bases and purine nucleotides that are ingested
and then broken down to uric acid. Tissue turnover
25
26 3 Purine Biochemistry

Fig. 3.1 The purine ring H

is a fusion between a C
five-membered imidazole 6 N
N 5 7
ring and a six-membered 1
pyrimidine ring. The atoms 8 CH
of the purine ring are 2 4
HC 3 9
numbered as shown in the top N
figure. The pyrazolopyrimi- N
H
dine ring is numbered in a
different manner from the
purine ring as shown in the Purine ring
middle figure. The middle
figure represents the structure OH
of the hypoxanthine analog,
allopurinol. As can be seen
from the structure, the carbon
atom at position 8 and 4
N 3
nitrogen atom at position 7 of 5
the purine ring are transposed 2 N
and a hydroxy group 6 1
substituted in position 6 of 7
N
the purine ring to form N
4-hydroxypyrazolo(3,4-d) H
pyrimidine (allopurinol). The
bottom figure shows the
origin of the purine ring 4-Hydroxypyrazolo (3,4-d)pyrimidine
atoms from their parent small
molecules. N5, N10-MTHFA
is an abbreviation for N5,
N10-methenyltetrahydrofolic CO2
acid. Glycine (NH2-CH2- glycine
COOH) contributes carbon
atoms 4 and 5 as well as
nitrogen atom 7 to the purine H
ring C
N
Aspartic acid N C
5 10
CH N , N - MTHFA
5 10
N , N − MTHFA HC C
N
N
H

Amide nitrogen of glutamine

Sources of the atoms in the purine ring

represents the process by which cells and tissue
components are broken down and subsequently
renewed. The cell and tissue purine metabolites
from the degradative process are catabolized fur-
ther by various enzymes to the purine end prod-
uct, uric acid. Nucleic acids (DNA and RNA) are
hydrolyzed both by endonucleases, which attack
chemical bonds in the middle of polynucleotide
chains, and by exonucleases that hydrolyze suc-
cessive terminal bonds. These nucleases have
specificity for DNA, RNA, or both. The action of
most nucleases leads to the formation of 5¢-nucle-
otides. The general structure of such nucleotides
is a purine base conjugated to either ribose phos-
phate or deoxyribose phosphate. The pathway for
degradation of ribose nucleotides such as guanylic
Nucleic Acid Degradation 27

Fig. 3.2 Allopurinol is a Hypoxanthine and its analog allopurinol

structural analog of hypoxanthine
in which the nitrogen atom in the
seventh position and the carbon HO OH
atom in the eighth position of H
hypoxanthine are transposed. The
chemical name for allopurinol is N
N N
4-hydroxy(3,4-d)pyrimidine. It is H N
converted to oxipurinol by the
enzyme, xanthine oxidase. N H N
H N N
Oxipurinol is an analog of
xanthine and its chemical name H H
is 4, 6-dihydroxypyrazolo(3,4-d)
pyrimidine Hypoxanthine 4-Hydroxypyrazolo(3,4-d)pyrimidine

Fig. 3.3 Two of the most Structure of the purine analogs

commonly used purine
analogs are 6-mercaptopurine SH
and azathioprine. They have
both anticancer and
immunosuppressive N
activities. The rationale for N
synthesizing azathioprine was
to protect the sulfhydryl CH
group of 6-mercaptopurine
from rapid methylation and
N
oxidation. The slow liberation N
of 6-mercaptopurine from
azathioprine gives the H
molecule increased potency
as an immunosuppressive 6-Mercaptopurine
drug in comparison with
6-mercaptopurine
S C N CH3

N
N N
O2N
CH

N
N
H

Azathioprine

and adenylic acids is as follows. Adenylic acid is
deaminated by adenylate deaminase to inosinic
acid, and inosinic and guanylic acids are then
hydrolyzed by phosphomonoesterases to their
respective nucleosides. These nucleosides are
then cleaved by nucleoside phosphorylases to
generate the free purine bases, guanine, and
hypoxanthine. Hydrolytic deamination of guanine
forms xanthine, and oxidation of hypoxanthine
catalyzed by xanthine oxidase converts hypoxan-
thine to xanthine. Finally, xanthine oxidation by
xanthine oxidase leads to the formation of uric
acid (Fig. 3.4a, b). Thus, excessive tissue break-
down as one might observe clinically with tumor
28 3 Purine Biochemistry

Nucleic acid degradation via adenine nucleotides

Nucleic acid (DNA/RNA)

Nucleases

NH2 OH

N Adenylate deaminase N
N N
CH CH

N N
N N

P-R P-R
Inosinic acid
Adenylic acid

5˙- Nucleotidase

OH OH

N Purine nucleoside N
N phosphorylase N
CH CH

N N
N N
H
Hypoxanthine R
Inosine

Xanthine oxidase

OH OH

N N
N Xanthine oxidase N
CH OH

N N
HO N N
H HO H

Uric acid
xanthine

Fig. 3.4 (a, b) Nucleic acids (DNA and RNA) are
hydrolyzed by deoxyribonucleases or ribonucleases and
phosphodiesterases to 5¢-nucleotides. Adenosine mono-
phosphate is then converted to inosinic acid by adenylate
deaminase. Inosinic acid is subsequently converted to
inosine by 5¢-nucleotidases and to hypoxanthine by purine
nucleoside phosphorylase. Xanthine oxidase then oxidizes
hypoxanthine to xanthine and uric acid. Guanylic acid is
converted to guanosine by 5¢-nucleotidase, and guanosine
is then converted to its free base, guanine, by purine
nucleoside phosphorylase. Guanine deaminase converts
guanine to xanthine, and xanthine is oxidized by xanthine
oxidase to uric acid
Nucleic Acid Degradation 29

Nucleic acid degradation via guanylic acid

Nucleic acids (DNA/RNA)

Nucleases

OH OH

N N
N 5′ - Nucleotidase N
CH CH

N N
N H2N N
H2N
R
P-R
Guanosine
Guanylic acid
Purine
nucleoside
phosphorylase

OH OH

N N
N Guanine deaminase N
CH CH

N N
N H2N N
HO H H

Xanthine Guanine

Xanthine oxidase

OH

N
N
OH

N
HO N
H
Uric acid

Fig. 3.4 (continued)

30
destruction by chemotherapeutic agents often
leads to an excess production of uric acid. This
catabolic process may also be complicated by
excessive quantities of sparsely soluble uric acid
being presented to the kidney. The inability to
excrete excessive loads of uric acid may aggra-
vate the hyperuricemia associated with increased
rates of cell and tissue turnover.
De Novo Purine Nucleotide Synthesis
The de novo synthesis of purine nucleotides is
another key to understanding the biochemical
basis of gout. The precursors of the carbon and
nitrogen atoms in the purine are small molecules
that contribute to the complete biosynthesis of
the purine ring (Fig. 3.5a, b). Glycine contributes
carbon atoms 4 and 5 and nitrogen atom 7.
Formate provides carbon atoms 2 and 8, carbon
atom 6 arises from carbon dioxide, and nitrogen
atoms 3 and 9 come from the amide nitrogen of
glutamine. Nitrogen atom 1 comes from aspartic
acid. The complete synthesis of the purine nucle-
otide components of nucleic acids, adenosine
monophosphate and guanosine monophosphate,
requires the consumption of six high-energy
phosphates in the form of adenosine triphosphate
(ATP), and this requirement for high-energy
phosphate compounds is a sufficient rationale for
conserving purine synthesis. As will be discussed
subsequently, the purine salvage pathways con-
vert hypoxanthine, guanine, and adenine to their
respective nucleotides, thus conserving both the
purine-free bases synthesized by the de novo bio-
synthetic pathway without the utilization of addi-
tional ATP molecules.
The first irreversible reaction in purine syn-
thesis is the transfer of the amide group of
l-glutamine to phosphoribosylpyrophosphate
with the liberation of inorganic pyrophos-
phate. This reaction is catalyzed by the enzyme,
phosphoribosylpyrophosphate amidotransferase.
5-phospho-a-d-ribosyl pyrophosphate (PRPP)
has an a-configuration, and the ribosylamine
of phosphoribosylamine has a b-configuration
3 Purine Biochemistry
(Fig. 3.6). This inversion takes place during the
reaction to form 5-phospho-b-d-ribosylamine
(PRA), and the resultant amino group attached to
ribose forms the beginning of the purine ring. The
next step in de novo purine biosynthesis converts
phosphoribosylamine to 5¢-phosphoribosylg-
lycineamide (GAR) by attaching a glycyl group to
the amino group with the energy required for this
step supplied by ATP. The enzyme, phosphoribo-
sylglycineamide synthetase, catalyzes this reac-
tion. The next reaction adds a formyl group from
5, 10-methenyltetrahydrofolate to the free amino
group of the glycyl residue. It is catalyzed by
phosphoribosylglycineamide formyl transferase
and forms 5¢-phospho-ribosyl-N-formylglycine
(FGAR). Another nitrogen is then transferred
from the amide group of l-glutamine with the
energy for reaction provided by ATP, and this
converts FGAR to 5¢-phosphoribosyl-N-formylg-
lycinamidine (FGAM). This reaction is catalyzed
by phosphoribosyl-formylglycineamidine syn-
thetase. Another ATP is then consumed to catalyze
the closure of the imidazole ring by the enzyme,
phosphoribosylaminoimidazole synthetase, to form
5¢-phosphoribosyl-5-aminoimidazole (AIR). The
next enzyme in the pathway, phosphoribosylami-
noimidazole carboxylase, catalyzes the formation
of 5¢-phosphoribosyl-5-aminoimidazole-4-carbox-
ylate (CAIR) using carbon dioxide as the source
for the carboxylate group. Subsequently, the amino
group of l-aspartate is transferred to form 5¢-phos-
phoribosyl-5-aminoimidazole-4-(N-succino) car-
boxamide (succino-AICAR) utilizing ATP as the
energy to create the carboxamide. This reaction is
catalyzed by phosphoribosylaminoimidazole-suc-
cinocarboxamide synthetase. Adenylosuccinase
then cleaves the molecule into fumarate and
5¢-phosphoribosyl-5-aminoimidazole-4-carbox-
amide (AICAR). 10-formyl-tetrahydrofolate then
supplies the final carbon atom to the ring catalyzed
by phosphoribosylaminoimidazolecarboxamide
formyl transferase to form 5¢-phosphoribosyl-5-
formamidoimidazole-4-carboxamide (Formyl-
AICAR). Inosinocase removes water from the
preceding molecule to form the parent purine com-
pound, inosine-5¢-phosphate (IMP).
De Novo Purine Nucleotide Synthesis 31

De novo purine biosynthesis

2+ PP-ribose-P + AMP
A. Ribose 5-phosphate + ATP + Mg

2+
α-PP-ribose-P + glutamine + H2O + Mg β-Phosphoribosylamine + glutamic acid + PP

B. Phosphoribosylamine + glycine + ATP + Mg2+ 5’ - phosphoribosylglycineamide + ADP + Pi

5 10
Phosphoribosylglycineamide + N , N -methenyl-THFA + H2O Phosphoribosyl-α-N-
+
formylglycineamide + THFA + H

5’ -Phosphoribosylformylglycineamide + glutamine + ATP + H2O + Mg2+ 5’-

phosphoribosyl-α-N-formylglycineamidine + glutamic acid + ADP + Pi

5’ -phosphoribosylglycineamidine + ATP + Mg2+ + K+ 5’ -phosphoribosyl-5-aminoimidazole

+ ADP + Pi

5’ -phosphoribosylaminoimidazole + CO2 5’ - phosphoribosyl-5-amino-4-

imidazolecarboxylate

5’ -phosphoribosyl-5-amino-4-imidazolecarboxylate + aspartate + ATP + Mg2+ 5’ -

phosphoribosyl-5-amino-4-imidazolesuccinocarboxamixe + ADP + Pi

5’ -phosphoribosyl-amino-4-imidazolesuccinocarboxamide fumarate + 5”-

phosphoribosyl-5-amino-4-imidazolecarboxamide

10 +
5’ -phosphoribosyl-amino-4-imidazolecarboxamide + N -formyl-THFA + K 5’-
phosphoribosyl-5-formamido-4-imidazolecarboxamide
+ THFA

5’-phosphoribosyl-5-formamido-4-imidazolecarboxamide inosinic acid (IMP) + H2O

Biosynthesis of AMP and GMP

2+
Inosinic acid (IMP) + L-aspartate + GTP + Mg AMP-S + GDP + Pi

AMP-S AMP + fumarate

Inosinic acid (IMP) + NAD+ + H2O + k+

+
XMP + NADH + H

2+
XMP + glutamine + ATP + Mg GMP + glutamic acid + AMP + Pi

Fig. 3.5 (a) De novo purine biosynthesis. The second
thick arrow identifies the principal regulatory enzyme of
de novo purine biosynthesis, phosphoribosylpyrophos-
phate (PRPP) amidotransferase. It is the first irreversible
step in purine synthesis and is the site of feedback inhibi-
tion by various purine end products (AMP, GMP, and
6-mercaptopurine ribonucleotide). PRPP amidotrans-
ferase exists as an inactive enzyme form (molecular
weight of 270,000) and a catalytic species (molecular
weight of 133,000). PRPP converts the 270,000 enzyme
form to the catalytically active smaller form, whereas
purine ribonucleotides convert the small molecular weight
enzyme into the larger inactive form. The first thick arrow
indentifies the enzyme, PRPP synthetase, which is subject
to mutation in humans and may result in an increase in the
rate of purine synthesis. (b) The biosynthesis of adenosine
monophosphate and guanine monophosphate. Two addi-
tional high energy phosphates are utilized to generate
AMP and GMP from IMP. Adenosine monophosphate
and guanine monophosphate serve not only as precursors
of nucleic acids but also act as feedback inhibitors of
de novo purine biosynthesis. XMP stands for xanthosine
monophosphate
32 3 Purine Biochemistry

De novo purine biosynthesis: key reactions

H2O3POCH2
O

+ ATP

OH

OH OH

D-Ribose-5-phosphate

2+ PRPP Synthetase
Mg

H2O3POCH2
O

O O
+ L-glutamine
O-P-O-P-OH

OH OH
OH OH

Alpha-5-phospho-D-ribosyl-1-pyrophosphate (PRPP)

2+
PRPP amidotransferase
Mg

H2O3POCH2 NH2
O

OH OH

Beta-5-Phosphoribosyl-1-amine

Fig. 3.6 The rate of purine biosynthesis is controlled by
alterations in two enzymes, phosphoribosylpyrophosphate
synthetase and phosphoribosylpyrophosphate amidotrans-
ferase. Fine control of purine biosynthesis is mediated by
the latter enzyme through its response to changes in purine
nucleotides and the concentration of phosphoribosylpyro-
phosphate. Phosphoribosylpyrophosphate binds to the
enzyme, phosphoribosylpyrophosphate amidotransferase,
and induces activation of the enzyme by converting the
enzyme into small active monomers, whereas purine
nucleotides binding at a different site from where phos-
phoribosylpyrophosphate binds converts phosphoribo-
sylpyrophosphate amidotransferase into its large inactive
form. Variations in purine nucleotides, especially adenos-
ine diphosphate (ADP) and guanosine diphosphate (GDP),
also competitively inhibit phosphoribosylpyrophosphate
synthetase activity with respect to Mg-adenosine triphos-
phate concentrations. Similarly, 2,3-diphosphoglycerate
(2,3-DPG) competitively inhibits phosphoribosylpyro-
phosphate synthetase activity with respect to its substrate,
ribose-5-phosphate. The regulation of phosphoribosylpy-
rophosphate synthetase by purine nucleotides is less sen-
sitive than the inhibition of phosphoribosylpyrophosphate
amidotransferase by purine nucleotides
Biosynthesis of AMP and GMP 33

Phosphoribosylpyrophosphate

H2O3POCH2
O

O O

O P O P OH

OH OH
OH OH

Fig. 3.7 The rate of de novo purine nucleotide biosyn-
thesis is directly proportional to the intracellular concen-
tration of phosphoribosylpyrophosphate (PRPP), and this
metabolite is one of the key regulators of uric acid produc-
tion via the de novo purine biosynthetic pathway. Patients
with phosphoribosylpyrophosphate synthetase overactiv-
ity overproduce PRPP, and this increases the rate of
de novo purine biosynthesis and urate production. Patients
with hypoxanthine-guanine phosphoribosyltransferase
deficiency underutilize PRPP, and the resultant excess
PRPP activates the enzyme, PRPP amidotransferase, the
first irreversible step in de novo purine biosynthesis lead-
ing to an acceleration in uric acid production. Excessive
activity of the oxidative pentose phosphate pathway gen-
erates increased levels of ribose-5-phosphate, the immedi-
ate precursor of PRPP. Speculation states that carbohydrate
excess and increased lipogenesis lead to an increased rate
of pentose phosphate shunt activity, increased ribose-5-
phosphate, and PRPP production. Such a mechanism
could explain the hyperuricemia associated with hyper-
triglyceridemia and obesity. Glucose-6-phosphatase
deficiency and the resultant accumulation of glucose-6-
phosphate may stimulate the pentose phosphate pathway
leading to increased levels of ribose-5-phosphate and
PRPP. Such a mechanism may contribute to the hyperuri-
cemia observed in this type of glycogen storage disease

The Key Intermediate, PRPP contribute to the increased rate of purine synthe-
sis in such cells. Conversely, allopurinol, orotic
5-phosphoribosyl-1-pyrophosphate (PRPP) is acid, adenine, and 2,6-diaminopurine through
synthesized from ATP and ribose-5-phosphate their capacity to consume PRPP may reduce the
utilizing ATP as a source of energy and the intracellular concentrations of this substrate and
enzyme, ribose phosphate pyrophosphokinase reduce the rate of de novo purine biosynthesis by
(PRPP synthetase), as the catalyst to transfer diminishing the availability of PRPP for conver-
the pyrophosphate group from ATP to the one sion to PRA.
carbon of ribose-5-phosphate. PRPP has an
a-configuration (Fig. 3.7). Ribose-5-phosphate
arises from either the pentose phosphate path- Biosynthesis of AMP and GMP
way or ribose-1-phosphate. This key interme-
diate, PRPP, is a significant component of two Inosinic acid is the parent purine compound
critical reactions of purine synthesis: the conver- since it serves as the intermediate in the synthe-
sion of PRPP to phosphoribosylamine (PRA) sis of adenosine-5¢-monophosphate (AMP) and
and the conversion of free purine bases to ribo- guanosine-5¢-monophosphate (GMP) which are
nucleotides via the so-called salvage pathways. subsequently converted to nucleic acids. AMP is
When present in excess, this metabolite (PRPP) synthesized from IMP in two steps: the conversion
increases de novo purine biosynthesis through its of IMP to adenylosuccinate (N6-succinoadenosine
capacity to act as a substrate for the first irrevers- 5¢-phosphate) and the subsequent conversion of
ible step in purine synthesis, the conversion of adenylosuccinate to adenosine monophosphate
PRPP to PRA. PRPP levels are increased in cells (Fig. 3.5b).
deficient in hypoxanthine-guanine phosphoribo-
syltransferase activity [5], and these molecules IMP + L - aspartate + GTP ® AMP - S + GDP + Pi
34
This reaction is catalyzed by the enzyme, ade-
nylosuccinate synthetase, and requires magne-
sium as a cofactor. GTP is utilized as a source of
energy. The second step is catalyzed by the
enzyme, adenylosuccinase, that also catalyzes
the conversion of SAICAR to AICAR.
AMP - S « AMP + fumarate
The conversion of IMP to GMP also occurs in
two steps: the oxidation of IMP to xanthosine
monophosphate (XMP) and the subsequent ami-
nation of XMP to form GMP. The first step is
catalyzed by the enzyme, inosine 5¢-phosphate
dehydrogenase, and requires NAD+ as a hydro-
gen acceptor. The second step uses the amide
group of l-glutamine as the specific amino donor,
consumes ATP as a source of energy, and requires
magnesium as a cofactor. It is catalyzed by the
enzyme, guanosine-5¢-phosphate synthetase.
IMP + NAD + + H 2 O ® XMP + NADH + H +
XMP + L -glutamine + ATP
® GMP + glutamic acid + AMP + PPi
Nucleotide Interconversions
and Catabolism
Purine mononucleotides are converted to nucleo-
sides by the action of 5¢-nucleotidases or
nonspecific phosphatases.
Purine mononucleotide + H 2 O
® purine nucleoside + Pi
Purine nucleosides, except for adenosine, are
cleaved phosphorolytically to form a free purine
base and ribose-1-phosphate. The enzyme, nucle-
oside phosphorylase, is active with inosine or
guanosine as substrates and slightly effective
with xanthosine as the substrate.
Purine nucleoside + Pi → purine base + ribose-1-P
Adenosine is converted to inosine by the
enzyme, adenosine deaminase, and adenosine can
3 Purine Biochemistry
be converted to AMP by the enzyme, adenosine
kinase, that utilizes ATP as an energy source.
Adenosine + H 2 O ® inosine + NH 3
Adenosine + ATP ® AMP + ADP
Guanine can be converted to xanthine through
the activity of the enzyme, guanase.
Guanine + H 2 O ® xanthine + NH 3
Purine Salvage Pathways
Six ATP molecules (nine high-energy phosphate
groups if one includes the two ATP molecules
necessary to synthesize glutamine and for the
activation of formate) are consumed in the syn-
thesis of one molecule of inosinic acid, the parent
purine base, via the de novo purine pathway. This
enormous expenditure of energy would be waste-
ful if the free bases were simply excreted in the
urine. For this reason, salvage pathways or purine
reutilization pathways are available to preserve
the purine bases synthesized by the de novo path-
way. Four salvage pathways have been identified
of varying importance in the human. First, nucle-
oside phosphorylase catalyzes nucleoside forma-
tion from purine bases and ribose-1-phosphate.
The reaction equilibrium is toward nucleoside
formation rather than nucleoside degradation.
Salvaged nucleosides can then be phosphorylated
to the nucleotide by the activity of the enzyme,
purine kinase. Even though these two reactions
consume an ATP molecule, they require much
fewer high-energy phosphates than the de novo
purine pathway.
Purine base + ribose - 1 - phosphate
« purine nucleoside
Purine nucleoside + ATP
® purine nucleotide + ADP
The intermediate in the de novo pathway,
5-amino-4-imidazolecarboxamide (AIC) or
(ZMP)-5¢- monophosphate, can also be salvaged
by conversion to ZTP by the enzyme, PRPP
synthetase. This is the only reaction known to
favor the synthesis of a nucleoside triphosphate
Purine Salvage Pathways 35

Adenine phosphoribosyl transferase

NH2 NH2

Adenine phosphoribosyltransferase
N N
N N
PRPP + CH CH
2+
Mg
N N
N N
H
R-P
5′ - Nucleotidase

Fig. 3.8 Adenine phosphoribosyltransferase catalyzes
the salvage of adenine by its condensation with phospho-
ribosylpyrophosphate (PRPP) to form 5-adenosine
monophosphate (AMP). This enzyme is inhibited by
both its products, AMP and PPi. AMP is a competitive
inhibitor of the substrate, PRPP, but it is a noncompeti-
tive inhibitor of adenine. PPi is a noncompetitive inhibi-
tor of both substrates. The enzyme has an absolute
requirement for divalent cations (Mg2+) and may catalyze
the formation of nucleotides from specific adenine ana-
logs as well

utilizing an enzyme that usually catalyzes reac-
tions that favor the synthesis of PRPP. ZTP is
normally not found in human erythrocytes
except in the case of individuals with a complete
deficiency of the enzyme, hypoxanthine-gua-
nine phosphoribosyltransferase (Lesch-Nyhan
syndrome), in which elevated levels of ZTP
have been measured [6]. These patients also
excrete large quantities of 5-amino-4-carbox-
amide in their urine [7]. Since folate is required
for the conversion of this metabolite to IMP, this
metabolite is also increased in folate-deficient
patients.
The adenosine cycle may be physiologically
significant in the regulation of cellular energy
and for the synthesis of adenosine utilized for cell
receptors [8]. In this cycle, adenosine is formed
from adenosine monophosphate (AMP) through
the action of the enzyme, 5¢-nucleotidase, and
subsequently, adenosine is phosphorylated by the
activity of the enzyme, adenosine kinase, which
requires ATP as an energy source.
AMP ® adenosine + Pi
Adenosine + ATP ® AMP + ADP
The most significant purine salvage pathways
in the human are those catalyzed by the purine
phosphoribosyltransferases, adenine phosphori-
bosyltransferase (APRTase), and hypoxanthine-
guanine phosphoribosyltransferase (HGPRTase)
(Figs. 3.8 and 3.9). These reactions require mag-
nesium as a cofactor.
Purine base + PRPP
® purine mononucleotide + PPi
Two enzymes of this type exist in the human;
one converts adenine to AMP (adenine phosphori-
bosyltransferase), and the other converts
hypoxanthine or guanine to IMP or GMP, respec-
tively (hypoxanthine-guanine phosphoribosyl-
transferase). The latter enzyme also converts
6-thioguanine and allopurinol to their respective
ribonucleotides. The conversion of 6-thioguanine
or 6-mercaptopurine by this enzyme to their nucle-
otide forms is essential for the activity of these
antimetabolites. Thus, cells with a deficiency in
hypoxanthine-guanine phosphoribosyltransferase
are unaffected by these antimetabolites. In in vitro
studies, using cells in tissue culture can utilize this
property as a mechanism by which cells deficient
in this enzyme can be selected. Cells with an intact
enzyme are killed in the presence of these metabo-
lites, whereas cells deficient in this enzyme are
unable to convert the free base to its active nucle-
otide. Heritable deficiencies have been described
in both these enzymes, and alterations in the
enzyme, hypoxanthine-guanine phosphoribosyl-
transferase, are of significance to metabolic errors
in uric acid metabolism. In addition, patients
with adenine phosphoribosyltransferase deficiency
36 3 Purine Biochemistry

Ribose-5-P + ATP
3

5-Phosphoribosyl-1-Pyrophosphate (PRPP) + Glutamine

1 Fe
tion ed
ibi 5-Phosphoribosyl-1-amine ba
k inh c
ac

k
Glycine

inh
b
ed

ibi
Fe

tio
n
Formate

Nucleic acids Nucleic acid

Guanylic acid Inosinic acid Adenylic acid

7 7 7

PRPP
2 5 4
Guanosine Inosine Adenosine
P Adenine
PR

P 6
PR
PP

6
Guanine Hypoxanthine

8 2.8 dioxyadenine
Xanthine

8
Uric acid

Fig. 3.9 Summary of de novo purine synthesis and degradation

may mimic those with urate overproduction and
renal calculus formation since the 2,8-dihydroxy-
adenine stones formed in this disorder react to
some test reagents in a similar fashion to the way
urate stones react.
Phosphoribosylpyrophosphate
Synthetase
Three enzymes are of cardinal importance
to an understanding of hyperuricemia and
gout: phosphoribosylpyrophosphate synthetase
(PRPS), phosphoribosylpyrophosphate amido-
transferase, and hypoxanthine-guanine phos-
phoribosyltransferase. The enzyme, PRPS,
transfers the terminal pyrophosphate group of
ATP to the one carbon of ribose-5-phosphate and
is subject to allosteric regulation. The human
erythrocyte form of the enzyme has a molecular
weight of 65,000. It is constructed of two identical
subunits [9], and the enzyme has an absolute
requirement for inorganic phosphorus as an allos-
teric activator. One of its substrates, magnesium
ATP, causes aggregation of the enzyme into its
active, high molecular weight form (MW –
65,000–1,040,000) [10]. The enzyme possesses
three identifiable regulatory sites: a magnesium
ATP site, a ribose-5-phosphate site, and a nucle-
otide site. ADP acts as a competitive inhibitor of
magnesium ATP, and 2,3-diphosphoglycerate
(2,4-DPG) acts as a competitive inhibitor of
ribose-5-phosphate. A variety of nucleotides
including ATP, GTP, NAD, FAD, AMP, ADP,
GDP, IDP, ITP, TDP, and NADPH inhibit the
enzyme in a noncompetitive manner with respect
to its substrates. Nucleotide diphosphates and
triphosphates are the most potent inhibitors of the
nucleotide site. This enzyme resides on the X
chromosome [11], and as will be discussed subse-
quently, mutations in this enzyme are inherited as
X-linked recessive traits in the human (Fig. 3.10).
Phosphoribosylpyrophosphate Synthetase
Regulation of phosphoribosylpyrophosphate synthetase
MgATP
Adenosine diphosphate
(competitive inhibitor)
PRPP Synthetase
H2O3POCH2
O
OH
Fig. 3.10 Phosphoribosylpyrophosphate (PRPP) syn-
thetase is an allosteric enzyme that utilizes two substrates,
magnesium adenosine triphosphate (MgATP) and ribose-
5-phosphate (R-5-P), for the synthesis of PRPP. MgATP is
essential for the aggregation and activation of the enzyme,
and adenosine diphosphate (ADP) is a potent competitive
inhibitor of this substrate. ADP and GDP are noncompeti-
tive inhibitors of this enzyme. 2,3-diphosphoglycerate
(2,3-DPG) is a competitive inhibitor of PRPP synthetase
The product of PRPS activity, a-phosphori-
bosyl-1-pyrophosphate (PRPP), is an important
regulator of the first committed enzyme step in
de novo purine synthesis, the conversion of PRPP
to phosphoribosylamine by the enzyme, PRPP
amidotransferase. PRPP is also utilized as a sub-
strate in the purine salvage pathways, another
important purine biosynthetic regulatory step.
Phosphoribosylpyrophosphate levels are elevated
in cells deficient in hypoxanthine-guanine
37
Ribose-5-phosphate
2,3-Diphosphoglycerate
(competitive inhibitor)
O O
O-P-O-P-OH
OH
OH OH
Purine nucleotids - ADP and GDP
(noncompetitive inhibitors)
with respect to R-5-P. Magnesium and inorganic phospho-
rous are activators of the enzyme. PRPP is a substrate
used in the biosynthesis of purine, pyrimidine, and pyri-
dine nucleotides as well as certain synthetic compounds
(6-mercaptopurine, 6-thioguanine, allopurinol, and
azaadenine), and it is an important regulator of pyrimidine
and purine nucleotide synthesis via orotate phosphoribo-
syltransferase and PRPP amidotransferase activities
phosphoribosyltransferase, and in such settings,
purine biosynthesis is increased. The Km for
PRPP, the substrate of PRPP amidotransferase,
adenine phosphoribosyltransferase, and hypox-
anthine-guanine phosphoribosyltransferase mea-
sured in lymphoblasts is 0.30, 0.03, and
0.07 mmol/l, respectively. At physiological con-
centrations, these enzymes are incompletely sat-
urated with PRPP, the intracellular concentration
of which ranges between 1.0 and 5.0 umol/l [12].
38
Therefore, the increased PRPP concentrations
found in erythrocytes, lymphoblasts, and fibroblasts
from patients with increased PRPS activity are
accompanied by an increased rate of purine syn-
thesis [13]. The rate of purine synthesis can also be
reduced through the use of alternative substrates
for the salvage pathway such as allopurinol, orotic
acid, or 2,6-diaminopurine. In the clinical setting,
it is allopurinol that is utilized to reduce purine
biosynthesis and uric acid production.
Since the first description of human mutants
with PRPS overactivity [14], more than 30 fami-
lies with this exceedingly rare metabolic error in
purine synthesis have been documented [15–22].
Patients with this altered enzyme usually suffer
from gouty arthritis and uric acid lithiasis begin-
ning in early adulthood [15, 18]. The clinical pre-
sentation characterized by PRPS overactivity and
gouty arthritis is the adult phenotype; the infantile
phenotype is more severe and occurs in childhood.
In the latter phenotype, uric acid overproduction
together with growth and motor retardation and
sensorineural deafness [15–17, 19, 21, 22] are the
principal clinical findings. Since the genes for this
disorder are on the X chromosome, the disease is
transmitted to hemizygous males whose X chro-
mosome expresses the mutation. Heterozygous
females with the adult form of the disease are
asymptomatic [14, 18, 21, 23–26]; however,
female heterozygotes carrying the infantile phe-
notype may manifest clinical abnormalities albeit
less severe than in the affected hemizygotes [27].
Enzyme deficiencies are usually the classical
finding in those patients with inherited metabolic
abnormalities; however, PRPS overactivity is the
first inherited human disorder characterized by an
increase in enzyme activity [27]. Interestingly
enough, patients have also been documented with
a deficiency of this same enzyme that is restricted
to the erythrocyte and not present in the fibroblasts
of such patients [28, 29]. Patients with PRPS
deficiency present with hypouricemia, mental
retardation, megaloblastic bone marrow, and
increased excretion of orotic acid. Clinical disor-
ders representing PRPS overactivity and deficiency
are both associated with abnormalities of the ner-
vous system suggesting that the enzyme and its
products are likely to have a role in the development
3 Purine Biochemistry
and/or function of the nervous system. Recognition
of these disorders of overactivity and underactiv-
ity requires measurements of enzyme activity in
both erythrocytes and fibroblasts since PRPS
activity is usually normal or low in human eryth-
rocytes of patients with overactivity of the enzyme,
while it is elevated in fibroblasts from the same
patients [18]. As noted previously, those patients
with a deficiency of PRPS only express the lesion
in their erythrocytes [28, 29].
Evidence now supports the presence of two
major types of PRPS mutations: allosteric regula-
tory defects and pretranslational regulatory
defects. Just as the clinical expression of this dis-
order shows heterogeneity in its clinical manifes-
tations, the biochemical mechanisms of PRPS
overactivity are heterogeneous as well [30, 31]. A
variety of kinetic abnormalities of the enzyme
have been described. These allosteric regulatory
defects include enzymes with altered affinity for
the enzyme’s activator, phosphate, and enzymes
with an increased affinity for PRPP [16–18, 23,
25, 26]. The index cases of this PRPS overactivity
were shown to have an accelerated rate of PRPP
synthesis that was due to the insensitivity of the
enzyme to inhibition by guanosine diphosphate
(GDP), adenosine diphosphate (ADP), adenosine
monophosphate (AMP), and 2,3-diphosphoglyc-
erate (2,3-DPG) [14, 31–33]. In those patients
with allosteric regulatory defects, PRPS1 is found
to have point mutations in its cDNA encoding
enzymes with altered allosteric properties [34].
These widely dispersed point mutations in the
X-chromosome-linked PRPS1 gene lead to dis-
tinctive base substitutions and resultant amino
acid alterations in PRPS1 isoforms. Such altera-
tions cause changes in enzyme regulation by
purine nucleotide feedback inhibition as well as
enzyme activation by inorganic phosphate.
Thus, in the case of mutations causing insensi-
tivity to nucleotides, the enzyme is resistant to con-
trol by intracellular nucleotides and their dampening
effect on enzyme activity. Other individuals with
defects in this enzyme include those with an
increased affinity of phosphoribosylpyrophosphate
synthetase for its substrate, ribose-5-phosphate
[33]. In this setting, the enzyme catalyzes the syn-
thesis of PRPP more rapidly than normal for any
Phosphoribosylpyrophosphate Synthetase
concentration of ribose-5-phosphate below
enzyme-saturating concentrations. An additional
kindred has been shown to have a threefold increase
in erythrocyte PRPP synthetase activity as com-
pared to controls [17, 23]. This mutant enzyme
was shown to manifest increased activity at all
concentrations of its activator, inorganic phos-
phate, and responded normally to nucleotide end-
product inhibition. Further, the enzyme showed
normal affinities for its substrates. Other variants
of mutant PRPS have been shown to have both
regulatory and catalytic defects [17], and some
have been shown to have a defective response to
inhibition by ADP and the enzyme activator, inor-
ganic phosphate [35]. Analysis of these mutations
at the level of DNA is incomplete, but there is some
evidence that a single base transition accounts for
some of the phenotypic changes observed [36].
The second major PRPS1 enzyme defect (pre-
translational regulation) remains unknown at
present. Although the rate of transcription of the
PRPS1 gene is increased in these mutant forms,
there is no structural change in the PRPS1 gene
itself. Thus, there is an increased rate of tran-
scription of the gene, but no alteration in the
enzyme’s amino acid sequence. The only
identifiable enzyme alteration is an increase in its
maximal velocity. In addition, investigations of
PRPS1 DNA showed no changes in the region 5¢
to the consensus transcription initiation site. The
identification of normal base sequences in these
regions excludes any defect in promoter genes or
immediate PRPS1 flanking sequences [34, 37].
Speculation now suggests that a mutation may
exist in a different promoter region such as in an
intronic enhancer or suppressor, in a 3¢-flanking
DNA sequence, or in a trans-acting gene [34].
Thus, the actual mutation causing the increased
PRPS1 transcription remains to be identified.
One additional key point needs mention with
regard to the pretranslational regulatory defect.
Even though normal allosteric regulation of PRPS1
activity exists in this mutant and there are increased
purine nucleotide pools, the rate of PRPP synthe-
sis is sufficient to activate the enzyme, PRPP ami-
dotransferase, causing an increased rate of de novo
purine nucleotide synthesis [34, 38, 39]. Thus,
purine nucleotides inhibit both PRPS1 and PRPP
39
amidotransferase activity. The latter enzyme is
more susceptible to purine nucleotide inhibition
since PRPP activation is also antagonized. Despite
the existence of these feedback regulatory controls
of purine nucleotide synthesis, the pretranslational
mutant causing overexpression of PRPS1 is the
primary effector of purine nucleotide synthesis
and increased uric acid production.
At the present time, the following molecular
aspects of the enzyme, phosphoribosylpyrophos-
phate synthetase, have been characterized. Recently,
two PRPS enzymes (PRPS1 and PRPS2) have been
demonstrated in the rat [40], and subsequently two
enzymes have been identified in humans as well
[41]. From these and other studies, it has been
determined that PRPS1 maps to the long arm of the
X chromosome in the interval Xq22–q24 [42], and
PRPS2 maps to the short arm of the X chromosome
in the interval Xp22.2–p22.3 [42]. Both PRPS1
and PRPS2 specify proteins with 317 amino acids
[40, 43, 44]. Another PRPS enzyme has recently
been identified that is localized to testicular tissue
and has been termed, PRPS3 [45, 46]. This tissue-
specific enzyme has been mapped to the short arm
of chromosome 7 in the interval 7p15–p21.1 [47].
This enzyme shows greater than 90 % homology
with PRPS1 [43]. Recent studies examining the
physical and kinetic properties of PRPS1 and
PRPS2 from recombinant isoforms purified to
homogeneity have shown almost complete amino
acid sequence homology [48]. However, the physi-
cal and kinetic properties of these isoforms differ
significantly. PRPS1 is more heat labile than
PRPS2, and the latter isoform is less sensitive to
purine nucleotide inhibition. The PRPS2 isoform is
easier to dissociate into subunits that are inactive in
the absence of Mg2+ and ATP than PRPS1. The iso-
electric points of these two isoforms are also differ-
ent suggesting a charge difference. The pH optimum
of PRPS1 is 8.8, whereas it is 7.4 for PRPS1.
The mutational sites in PRPS1 cDNA have
been identified for two patients who manifest
altered feedback inhibition by purine nucleotides
[17, 27]. Both patients demonstrate a single base
substitution. One patient has an A to G transition
at nucleotide 341 that results in an asparagine to
serine transition in the enzyme protein. The other
patient shows a G to C transversion at nucleotide
40
547 that results in an aspartic acid to histidine
change at amino acid 182. When normal and
mutant PRPS1 cDNAs were cloned into a plas-
mid expression vector and introduced into an E.
coli strain in which expression of recombinant
hPRPS1 could be induced, the mutant phenotype
showed properties identical to those observed
with the patient’s enzyme [49]. Thus, the mutant
PRPS enzymes that have been examined demon-
strate only point mutations. Further work needs
to be done to evaluate the molecular basis of
the other types of mutations observed in this
enzyme.
PRPP Amidotransferase
The second significant reaction in purine biosyn-
thesis is the first committed step in purine synthe-
sis that converts phosphoribosylpyrophosphate
(PRPP) and l-glutamine to 5-phosphoribosylam-
ine and is catalyzed by the enzyme, PRPP amido-
transferase. The latter enzyme is of significance
not only because it represents the first irreversible
reaction in the de novo synthesis of purines but
also because it is subject to feedback regulation
by the purine nucleotides, IMP, AMP, and GMP,
in an allosteric fashion (Fig. 3.11). Thus, in the
absence of a normal complement of GMP, as
exists with a deficiency of hypoxanthine-guanine
phosphoribosyltransferase, there would be less
feedback inhibition of PRPP amidotransferase,
and there would be more PRPP for utilization by
the latter enzyme. The net result of the reduction
in feedback inhibitors is that the rate of de novo
purine pathway increases and uric acid is over-
produced. In contrast to the regulation of PRPP
synthetase, purine monophosphates have greater
inhibitory activity than diphosphates and triphos-
phates [50–52] on PRPP amidotransferase, and
phosphoribosylpyrophosphate synthetase is less
sensitive to purine nucleotide feedback inhibition
than PRPP amidotransferase [53]. Further, syner-
gism occurs between the various feedback inhibi-
tors of PRPP amidotransferase activity in contrast
to its absence in the case of PRPP synthetase [50,
52, 54]. It should also be recognized that the
branch points in the synthesis of AMP and GMP,
3 Purine Biochemistry
the conversion of IMP to adenylosuccinate and
then AMP and the conversion of IMP to xanthy-
late and GMP, are also subject to feedback inhibi-
tion. AMP inhibits the conversion of inosinic
acid to adenylosuccinate, and GMP inhibits the
conversion of inosinic acid to xanthylate. Thus,
the purine salvage pathways and PRPP synthetase
are key regulators of purine synthesis, and when
their activity and/or regulation are defective, an
overproduction of uric acid occurs.
Human glutamine phosphoribosylpyrophos-
phate amidotransferase, also known as PRPP
amidotransferase, has been shown to exist in a
small and large molecular weight form [55], and
the two forms purified from human placenta have
molecular weights of 133,000 and 270,000 [56].
The conversion of the large form to the small
form occurs in the presence of PRPP, and the lat-
ter is the active form of the enzyme. Purine ribo-
nucleotides acting as feedback inhibitors convert
the small form to the large inactive form. The
human enzyme has been determined in one
experiment to be localized to the pter → q21
region of chromosome 4 [57]. Although no
mutant forms of this enzyme have been charac-
terized in humans, there is evidence of mutants
existing in bacteria, Ehrlich ascites cell lines, and
Chinese hamster ovary cells [58–60]. The fact
that these mutants are resistant to feedback inhi-
bition suggest that human mutants of this same
type might exist. At this time, no human mutants
have been described; however, it is not unreason-
able to suspect that some overproducers of uric
acid could have alterations in this enzyme result-
ing in less feedback inhibition by nucleotides or
increased responsiveness to PRPP which could
result in increased purine production.
The most recent studies of PRPP amido-
transferase have focused on its catalytic and
inhibitory mechanisms using microbial enzymes
[61–74]. Even though these elegant structure-
function studies have, for the most part, been
accomplished using purified microbial enzymes,
they are pertinent to the human enzyme since the
cDNA of human amidophosphoribosyltransferase
and its derived amino acid sequence has a high
degree of identity with enzymes purified from
other species [66]. Of even greater significance to
PRPP Amidotransferase 41

Fig. 3.11 The rates of De novo purine biosynthesis: regulation

de novo purine biosynthesis
are regulated by
phosphoribosylpyrophosphate
(PRPP) and purine nucleotide H2O3POCH2
end products, adenosine O
monophosphate (AMP) and + Glutamine
O O
guanosine monophosphate
(GMP). Purine nucleotides
are negative feedback O-P-O-P-OH
regulators of both PRPP OH
OH
amidotransferase and PRPP OH OH
synthetase activities, whereas
PRPP is an allosteric activator
of PRPP amidotransferase. PRPP amidotransferase
Elevated concentrations of
PRPP (e.g. HGPRTase Mg2+
deficiency) overcome purine
nucleotide inhibition and
increase rates of de novo
purine biosynthesis.
Decreased PRPP
concentrations slow the rate
of de novo purine H2O3POCH2 NH2
biosynthesis O

OH OH

Inosine 5’-Phosphate

Adenosine 5’-phosphate Guanosine 5’-phosphate

the correlation between the microbial and human
enzymes is the conservation of the amino acids
essential for catalysis and feedback regulation
[61, 75]. On the basis of these and other studies,
the following structural and functional aspects
of PRPP amidotransferase have now been char-
acterized. The PRPP amidotransferase gene has
been mapped to the q12 region of chromosome 4
[75]. A propeptide consisting of 11 amino acids
must be removed from the human enzyme before
enzyme activity can occur. Mutations in certain
propeptide amino acid residues do not permit
the processing of the enzyme. The synthesis of
phosphoribosylamine by PRPP amidotransferase
occurs by two-half reactions at different sites
on the enzyme [72]. Glutamine is hydrolyzed to
glutamate and ammonia at the N-terminal glu-
taminase site on the enzyme. PRPP binding to
42
its C-terminal helical site is a requirement for the
activation of the glutaminase site. PRPP binding
lowers the Km for glutamine by 100-fold. These
changes serve to form an ammonia channel to pro-
vide the ammonia from glutamine for its reaction
with PRPP to form phosphoribosylamine. These
reaction mechanisms are generated through con-
formational changes in the amidotransferase such
that the distance between the PRPP and glutamine-
binding sites are drawn closer together [72]. The
mechanism for interdomain signaling between
the PRPP and glutamine sites has yet to be com-
pletely established, but the key amino acids for
substrate binding and the ammonia channel have
been defined [72]. Tyrosine is the key to the estab-
lishment of the interactions between the NH2-
terminal glutamine site and the COOH-terminal
PRPP site. Glutamine binding is regulated in part
by arginine and aspartic acid [73–75].
With regard to the feedback inhibitor sites on
PRPP amidotransferase, adenine and guanine
nucleotides as well as other less common nucle-
otides (6-mercaptopurine nucleotide) bind to an
allosteric site (A-site) and a catalytic site (C-site)
on the enzyme [62, 65, 67]. Feedback inhibitors
(adenosine monophosphate-AMP and guanosine
monophosphate-GMP) of de novo purine nucle-
otide biosynthesis may act in concert to cause
more than additive inhibition of the amidotrans-
ferase. Even though both nucleotides can interact
with either the A-site or the C-site, evidence
derived from microbial PRPP amidotransferase
has determined that GMP prefers binding to the
A-site and that AMP prefers binding to the C-site.
The A-site on the enzyme is localized adjacent to
the catalytic site in between the enzyme subunits.
Four intersubunit allosteric sites exist for each
amidotransferase tetramer. Nucleotide reactions
with the A-site or C-site keep the native enzyme
in an inactive conformation. Although nucleotide
feedback control is the major rate-limiting factor
of the de novo purine nucleotide biosynthetic
pathway, regulation of this pathway is also depen-
dent on another key enzyme, PRPP synthetase.
As will be discussed subsequently, it appears that
fine control of de novo purine biosynthesis is
regulated primarily by interactions with PRPP
amidotransferase.
3 Purine Biochemistry
It seems unlikely that human PRPP amido-
transferase mutants causing an overproduction of
urate will be identified since the enzyme reaction
requires complex substrate interactions as well as
conformational changes. Nonetheless, the possi-
bility exists that human enzyme mutants with
diminished feedback inhibition by purine nucle-
otides could occur. Another amidotransferase
mutant was isolated from E. coli grown in mini-
mal essential media and 6-diazonorleucine, an
inhibitor of PRPP amidotransferase [76]. This
bacterial mutant utilized ammonia as a substrate
rather than glutamine for de novo purine nucle-
otide synthesis when grown in the presence of
6-diazonorleucine, a glutamine analog and irre-
versible inhibitor of PRPP amidotransferase
activity. This mutant grew very slowly in mini-
mal essential media and clearly would not have
shown increased rates of purine synthesis. Thus,
no human PRPP amidotransferase mutants have
been characterized at this time, but there is a
remote possibility that they could exist.
Hypoxanthine-Guanine
Phosphoribosyltransferase (HPRTase)
Since the de novo purine nucleotide biosyn-
thetic pathway utilizes several small precursor
molecules (glycine, aspartic acid, glutamine,
10-formyl-H4-folate, and bicarbonate) and six
moles of adenosine triphosphate for the gen-
eration of each purine end product, recycling
of purine bases rather than excreting them con-
serves cellular energy and precursor molecules.
The salvage enzyme, hypoxanthine-guanine
phosphoribosyltransferase (HGPRTase), serves
this purpose by reutilizing hypoxanthine or gua-
nine. Its counterpart, adenine phosphoribosyl-
transferase (APRTase), performs a comparable
task by reusing the purine base, adenine. These
two enzymes are part of a family of related phos-
phoribosyltransferases that catalyze the synthesis
of pyrimidines, histidine, nicotinates, nicotin-
amides, quinolates, and tryptophan in a variety of
organisms. In most higher organisms, HGPRTase
has its highest activities in the testes and brain.
In the latter organ, it is primarily concentrated
Hypoxanthine-Guanine Phosphoribosyltransferase (HPRTase)
in the basal ganglia. Some have suggested that
there is an inverse relationship between the
de novo purine nucleotide pathway and the sal-
vage enzymes so that in those organs where the
de novo pathway is most active, the salvage path-
ways are least active. This appears to be the case
in the liver where the de novo pathway is most
active and the salvage enzymes are least active.
Similarly, in the brain where the de novo pathway
is nonexistent, the salvage enzymes have their
highest activity. HGPRTase also has higher activ-
ity in the gray matter of the brain than in white
matter [77–80]. Both these enzymes are localized
to the soluble cytoplasmic compartment of cells
even though some evidence suggests that there
may be a loose binding between these enzymes
and the cell membranes of erythrocytes and lym-
phocytes [81–83]. The activity of this enzyme is
also increased in tissues that have a rapid turn-
over such as embryonic cells [77, 84].
Hypoxanthine-guanine phosphoribosyltrans-
ferase catalyzes the transfer of phosphoribose
from dimagnesium PRPP to the nine positions of
hypoxanthine or guanine resulting in the forma-
tion of IMP or GMP. Adenine phosphoribo-
syltransferase transfers the same moiety
(phosphoribose) from dimagnesium PRPP to the
nine positions of adenine to form AMP.
Magnesium ions are competitive inhibitors of the
dimagnesium PRPP complex [85, 86]. Human
HGPRTase is reported to exist as a dimer or
tetramer depending on the ionic strength and pH
of its surrounding milieu. The monomers of the
dimer or tetramer are identical in composition
and contain 217 amino acids [87–89]. Each
monomer has a molecular weight of 24,470 [87,
89, 90]. The N-terminus of the original 218 amino
acid protein, methionine, is removed leaving ala-
nine as the N-terminus. The alanine N-terminus
is subsequently acetylated [87]. The enzyme is
composed of ten b strands and six a helices, and
the active site of the enzyme has been character-
ized as well as other structural components of the
normal and mutant enzymes [91, 92]. These stud-
ies also determined the crystal structure of the
enzyme in complex with GMP and that the reac-
tion mechanisms strongly favor the formation of
the nucleotide product. The Km values for guanine,
43
hypoxanthine, and PRPP from published reports
range between 4.0–21, 9.0–17, and 220–250 uM,
respectively [85, 93–95]. The human enzyme is
modified by posttranslational changes that
account for its electrophoretic heterogeneity [96–
99]. Several additional studies have utilized
mutant enzymes and analogs to characterize the
role of certain structural components of the
enzyme. The following articles should be con-
sulted for more structure-function relationships
[100–103]. A comparison of the cDNA from the
human, rat, Chinese hamster, and mouse HPRTase
shows a high degree of similarity approaching
70–90 % [104]. In fact, the primary structures of
the human hypoxanthine-guanine phosphoribo-
syltransferase and two bacterial phosphoribosyl-
transferases (E. coli PRPP amidotransferase and
S. typhimurium adenosine triphosphate phospho-
ribosyltransferase) show a common amino acid
domain between the E. coli and the human
enzyme but no shared domain with the S. typh-
imurium enzyme [105]. Similarly, another
20-amino-acid domain common to mouse,
human, and bacterial phosphoribosyltransferase
proteins has also been described [106, 107].
Analysis of these common amino acid spans led
to a prediction that a dinucleotide-binding fold
existed which could be related to substrate bind-
ing [105]. Subsequent data confirmed the pres-
ence of hypoxanthine/guanine and PRPP-binding
sites to this fold [106–112].
The cloning of the HGPRTase gene has pro-
vided additional information as to the gene, itself,
its pseudogenes, and the regulation of its expres-
sion [113]. The gene for hypoxanthine-guanine
phosphoribosyltransferase has been localized to
the X chromosome at Xq26–q27 [114–116], and
fine structure analysis has defined the order of the
various gene markers in the region of the
HGPRTase gene [117, 118]. In addition to the
locale for the principal gene, there are four
HGPRTase pseudogenes that have been deter-
mined to reside on chromosomes 5, 3, and 11
[119]. Two of the four pseudogenes reside on
chromosome 11, one is on chromosome 3, and
the other is in the region of 5p13–q11. These
pseudogenes are nonfunctional copies of the
functional gene. The HGPRTase gene contains
44
39.8 kb from its initiator methionine codon (ATG)
to its termination codon, TAA [120]. The gene
consists of nine exons. When the amino acid
sequences of human, rat, Chinese hamster, and
mouse HGPRTase are compared, only 16 amino
acids differences are found between the four spe-
cies [104]. The regions of the HGPRTase gene
necessary for the transcription of its DNA into
mRNA, the promoter region, have been deter-
mined. This region has the characteristics of a
housekeeping gene since it has guanosine-cyto-
sine-rich areas and no TATA or CCAAT sequences
[120]. These GC-rich regions are found surround-
ing promoter regions and have been called
“housekeeping genes” because they encode pro-
teins essential for cell viability. In the HGPRTase
gene, there are four copies of the GC-rich hexa-
nucleotide sequence, 5¢-GGCGG-3¢, on the 5¢
side of the first exon and three copies on the 3¢
side [120]. This sequence has been determined to
be a binding site for the transcription factor, Sp1,
in dihydrofolate reductase and may have the same
function in the enzyme, hypoxanthine-guanine
phosphoribosyltransferase [121]. Since these
GC-rich areas are located on both sides of exon
one, sequences of significance to the regulation
of the HGPRTase gene may exist in both these
locations as well. Multiple transcription start sites
have also been identified in association with this
gene [122, 123]. Other regulatory regions for the
HGPRTase gene have also been defined includ-
ing negative control elements, but the complete
regulatory aspects of the gene remain to be char-
acterized [124–126]. In addition to the fine struc-
ture of the HGPRTase gene, several other
parameters of this gene are of significance. Its
role in understanding X-chromosome inactiva-
tion, the mechanism by which it causes an
increase in de novo purine biosynthesis, the other
biochemical changes associated with mutations
in the HGPRTase gene, and the characteristics of
HGPRTase mutants all have contributed to the
knowledge base of human genetics.
The principal interest in the HGPRTase
enzyme has been the various mutant forms of this
phosphoribosyltransferase that have been
described and the diseases associated with them.
Although mutants of this enzyme have been
3 Purine Biochemistry
known to exist for many years in bacteria and cul-
tured mammalian cells [127–129], the first human
mutant of this enzyme was described in 1967.
This mutant was determined in association with a
clinical syndrome characterized by hyperurice-
mia, hyperuricaciduria, severe neurological
deficits including in some cases mental retarda-
tion [130], and soon thereafter, a second mutant
was described in adults with gouty arthritis [131].
These two human enzyme deficiencies were sub-
sequently described in many human tissues from
affected individuals including amniotic fluid
cells, cultured human fibroblasts, and lympho-
blasts. Initially, mutations in the enzyme were
identified by differences in their thermolability,
substrate affinity, electrophoretic mobility, and
decreased reactivity to anti-hypoxanthine guanine
phosphoribosyltransferase antibodies [94, 132–
139]. With the determination of the entire amino
acid sequence of the enzyme, peptide sequences
between normal and mutant enzymes could be
assessed, and with this methodology, structural
variations were observed in some mutants [108].
All these mutant detection methods are depen-
dent on the presence of enzyme protein, and since
over 70 % of Lesch-Nyhan patients have no
detectable enzyme protein, these methods failed
to provide any information concerning the type of
mutants in these patients [140]. Cloning of mutant
cDNA from affected individuals has revealed
significant heterogeneity in the characteristics of
the mutations including point mutations, substitu-
tions, deletions, and duplications spanning the
whole enzyme protein, splicing site mutations,
and conversions to stop codons [110, 141–151].
Many of these mutations have been catalogued
and characterized [152]. There is a clear spectrum
of clinical subsets of hypoxanthine-guanine phos-
phoribosyltransferase deficiency ranging from
patients with the classical Lesch-Nyhan syn-
drome who have choreoathetosis, self-mutilation,
spasticity, developmental retardation, muscle
hypotonia, and massive uricaciduria to those with
the Lesch-Nyhan syndrome without self-mutila-
tion, to those with late onset Lesch-Nyhan syn-
drome with slight neurological involvement, and
to patients with the Kelley-Seegmiller syndrome
(partial deficiency of HGPRTase) who have gouty
Hypoxanthine-Guanine Phosphoribosyltransferase (HPRTase)
arthritis, urate stones, uricaciduria, hyperurice-
mia, and renal disease. Unfortunately, with the
exception of finding partial enzyme activity in
patients with the Kelley-Seegmiller syndrome
and little or no enzyme activity in those with the
Lesch-Nyhan syndrome, no correlation has been
identified between the molecular abnormality and
the degree of the neurological deficit. To date,
well over 100 separate and distinct mutations
have been described for HGPRTase. Of some
interest, mutations affecting arginine at codon 51
when converted to glycine result in gouty arthritis
[109], whereas if the same amino acid is con-
verted to proline, the result is a patient with the
Lesch-Nyhan syndrome [141]. A variety of new
mutants have been identified since those summa-
rized in the 1998 edition of McKusick’s Mendelian
Inheritance in Man including data on the
identification of heterozygotes and the mutation
in a female with the Lesch-Nyhan syndrome
[153–168]. One issue that remains to be resolved
is the relationship between these various muta-
tions and the different clinical presentations of
HPRTase deficiencies.
In addition to the primary defect in the
enzyme, hypoxanthine-guanine phosphoribosyl-
transferase, several secondary biochemical alter-
ations have also been described in patients and
cells expressing this mutation. In patients with
either the Lesch-Nyhan or Kelley-Seegmiller
syndrome, the erythrocyte activity of the enzyme,
adenine phosphoribosyltransferase, is increased
[130, 169–173]. The mechanism for this altered
activity has been proposed to result from the
increased levels of erythrocyte PRPP which
has been determined to stabilize the enzyme,
adenine phosphoribosyltransferase [174–177].
Interestingly, adenine phosphoribosyltransferase
activity is completely within the normal range
in fibroblasts, lymphoblasts, and neuroblastoma
cells in specimens recovered from patients with
hypoxanthine-guanine phosphoribosyltrans-
ferase deficiencies [12, 178, 179]. Even though
the levels of PRPP are increased in these cells,
there is no concomitant increase in adenine phos-
phoribosyltransferase activity. Thus, the elevated
levels of PRPP do not stabilize the latter enzyme
in lymphoblasts, fibroblasts, and neuroblastoma
45
cells; it is only in the erythrocyte where this
mechanism appears to result in increased adenine
phosphoribosyltransferase activity.
Another enzyme, inosine monophosphate
(IMP) dehydrogenase, which catalyzes the con-
version of IMP to xanthosine monophosphate
(XMP) in the presence of DPN+ as a hydrogen
acceptor, is also found in elevated concentra-
tions in the erythrocytes of hypoxanthine-guanine
phosphoribosyltransferase-deficient patients
[173, 180]. The mechanism by which this enzyme
activity is increased has been proposed to be the
result of the high concentration of 2,3-diphospho-
glycerate in erythrocytes [181]. When the level of
this metabolite is reduced by prolonged dialysis,
IMP dehydrogenase activity is comparable to the
level of activity in normal erythrocytes [181]. In a
study of Lesch-Nyhan patients with no HGPRTase
activity, increased nicotinamide adenine dinucle-
otide (NAD) levels have been determined in
erythrocytes [182]. Elevated activities of nicotinic
acid phosphoribosyltransferase and NAD syn-
thetase were also found in these patients. The Km
for the substrates of these enzymes was within the
normal range, but the Vmax for these enzymes was
increased. Thus, the elevated NAD levels in eryth-
rocytes can be accounted for by the increased
activity of these biosynthetic enzymes. Finally,
monoamine oxidase, an enzyme that catalyzes
the degradation of biogenic amines, has been
found to have lower activity in skin fibroblasts
from patients with the Lesch-Nyhan syndrome
and in HGPRT-deficient neuroblastoma cells than
in control neuroblastoma cells or normal skin
fibroblasts [183–187]. Since the genes for mono-
amine oxidases A and B have been determined to
reside on the X chromosome, the relationship
between these enzymes and hypoxanthine-gua-
nine phosphoribosyltransferase remains to be
determined [188]. Thus, mutant hypoxanthine-
guanine phosphoribosyltransferases result in
changes in other enzymes. At this time, no patho-
genic relationships have been defined between
the primary mutation and these secondary
changes.
In addition to the characterization of mutant
HGPRTase and the secondary enzyme effects
in association with hypoxanthine-guanine
46
phosphoribosyltransferase deficiency, the mech-
anism for the overproduction of purines and uric
acid needs to be discussed. The deficiency in the
activity of hypoxanthine-guanine phosphoribo-
syltransferase leads to an increase in the avail-
ability of its substrates, hypoxanthine, guanine,
and PRPP, since the capacity of the enzyme to sal-
vage purine bases is diminished and fewer of its
substrate molecules are utilized. This decreased
reutilization of the free bases, hypoxanthine, and
guanine, for ribonucleotide synthesis to inosine
monophosphate (IMP) and guanosine mono-
phosphate (GMP), results in a diminished intra-
cellular concentration of these nucleotides, and
fewer nucleotides are available to exert feedback
inhibition on PRPP amidotransferase, the enzyme
catalyzing rate-limiting step in de novo purine bio-
synthesis. This mechanism for increased de novo
purine biosynthesis is a reasonable explanation
for the increased synthesis of IMP in hypox-
anthine-guanine phosphoribosyltransferase-
deficient human fibroblasts [189]. In addition,
comparative measurements of urinary hypox-
anthine and xanthine in hypoxanthine-guanine
phosphoribosyltransferase-deficient subjects
as compared to normal subjects and those with
primary gout and no known enzyme defect
show striking increases in uric acid, hypoxan-
thine, and xanthine in hypoxanthine-guanine
phosphoribosyltransferase-deficient subjects.
Data from the literature illustrate these changes;
urinary uric acid (mg 24 h−1 1.73 m−2), hypoxan-
thine (umol/g creatinine), and xanthine (umol/g
creatinine) were 1,906 ± 645, 544 ± 356, and
223 ± 167,respectively, in HPRTase-deficient
subjects as compared to levels of 418 ± 160,
29 ± 18, and 17 ± 12 in patients with primary
gout and 446 ± 86, 47 ± 14, and 29 ± 9 in normal
subjects [190]. A second mechanism resulting in
increased de novo purine biosynthesis is based on
the fact that PRPP, the other substrate for the sal-
vage enzyme, is present in excess since it is not
being utilized in the reaction catalyzed by hypox-
anthine-guanine phosphoribosyltransferase. This
excess PRPP drives de novo purine biosynthesis
since it is a substrate for the rate-limiting step
of purine synthesis, the conversion of PRPP to
phosphoribosylamine by the enzyme, PRPP ami-
3 Purine Biochemistry
dotransferase. This latter mechanism is probably
the major factor in the increased purine synthe-
sis observed in patients who are hypoxanthine-
guanine phosphoribosyltransferase-deficient.
A relative deficiency of the nucleotides inosine
diphosphate, inosine triphosphate, guanosine
diphosphate, and guanosine triphosphate may
contribute to the increased rate of purine synthe-
sis through an absence of their inhibition of the
enzyme, PRPP synthetase.
Since the HGPRTase gene has been localized
to the X chromosome, it has been used as a model
to understand the dosage compensation of
X-linked genes in male and female and the ran-
dom inactivation of female somatic cell X chro-
mosomes. There now exists sufficient evidence to
postulate that DNA methylation participates in
the regulation of X-chromosome inactivation.
The evidence can be summarized as follows.
Active X-chromosome DNA can provide
HGPRTase enzyme activity to an HGPRTase-
deficient recipient cell. Inactive X-chromosome
DNA cannot provide an HGPRTase-deficient
recipient cell with HGPRTase enzyme activity.
The use of 5-azacytidine to cause hypomethyla-
tion of cytosine in DNA is able to reactivate genes
of an inactive X chromosome, and altered pat-
terns of DNA methylation exist between active
and inactive X chromosomes [191–205].
Evidence that supports the role of DNA methyla-
tion in X-chromosome activation is found in the
differential methylation of the human HGPRTase
genes [192, 205–207]. On the first intron of the
HGPRTase gene, there is an unmethylated site
that is present on an active X chromosome, and
this same site is methylated when it is on an inac-
tive X chromosome [192, 193, 205]. Another
area of the gene demonstrates just the reverse,
methylation in the active and hypomethylation in
the inactive X chromosome [192, 193, 205]. In
the 5¢ region of the gene, reactivated X chromo-
somes are demethylated [193]. Since the mouse
gene for HPRTase provides evidence that the
changes in methylation occur after the X
chromosome has been inactivated, it is likely that
the methylation-demethylation process is not the
entire event related to X-chromosome inactivation,
but may be involved in the maintenance of the
Adenine Phosphoribosyltransferase
inactivation process [208]. X-chromosome inac-
tivation may be either a random or a nonrandom
process; in the former case, females who are
heterozygotes for an X-linked genetic trait have
two different cell types depending on which X
chromosome has been inactivated and are, there-
fore, mosaics. Since significant variation is
observed with respect to which X chromosome is
inactivated, this variation may account for the
different degrees of symptom expression related
to an X linked mutation. This mechanism might
be responsible for the occurrence of gout in
female patients who carry the X-linked HGPRTase
mutation [209]. A summary of the most recent
evidence suggests that DNA methylation plays a
major role in X-chromosome inactivation and
that the position and length of the methylated
regions as well as the chromatin structure may
interact to repress housekeeping promoters
on the inactive X chromosome [210–213].
Nonetheless, some genes on the X chromosome
escape inactivation, and the mechanism for this
escape is incompletely understood at this time
[214–216]. Alterations in X-chromosome inacti-
vation and escape mechanisms may have impli-
cations for carrier females and disease.
One final issue related to the HGPRTase gene
is completely unrelated to the subject matter of
this book but has relevance to the use of informa-
tion that the foregoing studies have provided to
the general scientific community. Since the gene
has been cloned, it has been used as a target for
potential mutagens. There are numerous publica-
tions showing the utility of this gene in the study
of mutagenesis and its role in the identification of
environmental and drug mutagens. Thus, knowl-
edge of the HGPRTase nucleotide and amino acid
sequence in normal individuals permits an analy-
sis of alterations caused by mutagens.
Adenine Phosphoribosyltransferase
There are several reasons why a deficiency in
adenine phosphoribosyltransferase (APRTase)
is discussed in a treatise on gout (Fig. 3.12).
First, APRTase-deficient patients form kidney
stones composed of the adenine metabolite,
47
2,8-dihydroxyadenine. These renal calculi have
often been confused with uric acid calculi, and
for this reason, autosomal recessive APRTase
deficiency is sometimes misidentified as a defect
in uric acid metabolism. The discussion that fol-
lows is designed to prevent this confusion.
Second, APRTase is deficient in some families
whose members have familial juvenile gouty
nephropathy [217, 218], and its pathogenic role
in this disorder remains incompletely defined.
Since this association may relate to alterations in
uric acid metabolism, a discussion of the bio-
chemistry of APRTase is provided to assist the
reader in understanding future studies that may
characterize this relationship more fully. Finally,
this enzyme is of significance to understanding
the feedback regulation of de novo purine bio-
synthesis since adenosine monophosphate is a
feedback inhibitor of PRPP amidotransferase. A
deficiency in the activity of the salvage enzyme,
adenine phosphoribosyltransferase, could affect
the rate of de novo purine biosynthesis by reduc-
ing the cellular levels of adenosine monophos-
phate, a negative feedback inhibitor of the first
committed enzyme in purine synthesis. As will
be discussed subsequently, this is not the case.
The salvage enzyme, adenine phosphoribosyl-
transferase (APRTase), catalyzes the conversion
of adenine and phosphoribosylpyrophosphate
(PRPP) to the mononucleotide, 5¢-adenosine
monophosphate (AMP), and inorganic pyrophos-
phate (PPi). In humans, this is the only system
available for salvaging the free purine base, ade-
nine. The Km for its substrate, adenine, using
human red blood cells as a source of the enzyme
ranges between 1.1 and 2.7 uM [219–222] and for
PRPP between 6 and 29 uM [219, 221–223]. The
latter substrate is Mg2+-dependent although other
metals may serve as substitutes but with much less
efficiency. Both end products of the reaction
inhibit substrate conversion by the enzyme to its
end products. Inhibition of APRTase activity by
PPi is noncompetitive with respect to both sub-
strates (adenine/PRPP), whereas inhibition by 5¢-
AMP is noncompetitive with respect to adenine
but competitive for PRPP [224, 225]. Several ade-
nine analogs can also act as substrates for APRTase
including 4-amino-5-imidazole-carboxamide
48 3 Purine Biochemistry

Fig. 3.12 The counterpart to Adenine metabolism in the presence and absence of adenine
hypoxanthine-guanine Phophoribosyl transferase
phosphoribosyltransferase
is adenine phosphoribosyl- NH2
NH2
transferase (APRTase), the
enzyme that recycles adenine
rather than excreting this N N
N Mg2+ N
purine metabolite. When
+ PRPP
adenine phosphoribosyltrans-
ferase deficiency exists, N
N N
adenine is oxidized by the N H
enzyme, xanthine oxidase, to R-P
form 8-hydroxyadenine and Adenine
2,8-dihydroxyadenine
(2,8-DHA). 2,8-DHA is Xanthine oxidase
nephrotoxic due to its
insolubility and may cause
NH2
renal failure but usually
results in the formation of
2,8-dihydroxyadenine kidney N
stones. 2,8-dihydroxyadenine N
is indistinguishable from uric OH
acid by routine tests, and the
N
stones formed from this N H
metabolite are also
radiolucent just as uric acid 8-Hydroxyadenine
stones are. Uric acid and
2,8-DHA can be
distinguished from each other
by specific tests Xanthine oxidase

NH2

N
N
OH

N
HO N H

2, 8-Dihydroxyadenine

(AIC), 2,6-diaminopurine (DAP), 4-aminopyra-
zole (3,4-d) pyrimidine, 8-azaadenine, 6,meth-
ylpurine, 6-methylaminopurine, 2-fluoroadenine,
and 4-caramoyl-imidazololium-5-olate [226–
228]. DAP and 8-azaadenine are used to select
for cells resistant to these agents and deficient in
APRTase by methods similar to those used for
the selection of HGPRTase-deficient cells. The
addition of antimetabolites to tissue culture media
along with cells permits the conversion of these
antimetabolites to their active form by normal
APRTase activity, and these products are then
lethal to the normal cell. Cells without the capac-
ity to convert these antimetabolites to their active
form survive and are selected for their absence of
APRTase activity. None of these analogs have a
higher affinity for APRTase than adenine [226].
Adenine phosphoribosyltransferase has been
purified to near homogeneity from human eryth-
rocytes [229], and its structure determined to be a
dimer with 179 amino acids per subunit [230].
The molecular weight of the enzyme has been
calculated to be 38,962 in total or 19,481 per sub-
unit. cDNA sequencing has predicted a polypep-
tide of 180 amino acids which is consistent with
the amino acid sequence determined from the
purified enzyme since the second amino acid,
alanine, is acetylated and becomes the N-terminal
Adenine Phosphoribosyltransferase
amino acid. The gene is composed of 5 exons
[231]. The human gene for APRTase has been
mapped to chromosome 16q24 [232–234], and
fine mapping has shown the location of the gene
to be distal to the haptoglobin (HP) gene and the
fragile site (FRA16D) so the resultant gene order
is HP-FRA16D-APRTase-qter [234]. Hamster or
mouse APRTase gene probes have been used to
isolate the human gene from a genomic lambda
bacteriophage library [235–237]. A BamHI frag-
ment has been used as a probe to isolate APRTase
cDNA clones from human cDNA libraries [237,
238]. The APRTase gene has been determined to
have five exons and four introns, and the amino
acid sequence obtained from the gene cDNA is
consistent with the sequence from peptide map-
ping studies [230]. Restriction-fragment-length
polymorphism (RFLP) sites have also been
identified, and the frequencies of these sites have
been determined for Caucasian and Japanese
populations [237–241]. The promoter region for
the APRTase gene like that for the HGPRTase
gene does not contain any CCAAT or TATA
sequences [242, 243]. There are also G- and
C-rich regions of the gene located in the promoter
region that may represent binding sites for Sp1 or
other components that assist in the binding of
RNA polymerase to DNA [242, 244]. Like the
HGPRTase gene, the APRTase gene has a rather
unique distribution of CpG dinucleotides that are
likely to be methylation sites that may control
gene expression [245, 246].
As with HPRTase-deficient patients, the
mutant forms of APRTase have been of greatest
interest to the geneticist and clinician. Two major
types of mutations have been identified through
clinical and biochemical studies: type I deficiency
(no APRTase enzyme activity in cell extracts)
and type II deficiency (partial APRTase enzyme
activity in cell extracts). The type I defect has
been described in patients from many ethnic
backgrounds [247–277], whereas the type II
alteration has only been identified, at this time, in
Japanese patients or those with Japanese heritage
[278–288]. In fact, the most common mutation in
the Japanese is a mutation of the trinucleotide
ATG (methionine) to ACG (threonine) at codon
136, and this mutation causes 68 % of the
disease-causing genes among the Japanese [278].
49
A survey of APRTase mutations in Japan, Korea,
and Taiwan gave a heterozygote frequency of 1.1
% for the Japanese and 0.53 % for the Koreans.
No heterozygotes were identified in the Taiwanese
[278]. On the basis of the presence of this muta-
tion in Okinawans and Koreans, it has been esti-
mated that the origin of this mutation occurred
prior to 300 BC [278]. Type I patients develop
symptoms of the disease at an earlier time than
type II patients. The biochemical abnormalities
associated with these mutations are principally
related to the resultant increase in the urine of
adenine and its metabolites, 8-hydroxyadenine
(8-HA) and 2,8-dihydroxyadenine (2,8-DHA)
[277]. Increased levels of these latter metabolites
arise because of the inability of cells to salvage
adenine and the subsequent oxidation of adenine
by xanthine oxidase to 8-HA and 2,8-DHA. The
ratio of these urinary purines has been determined
to be 1.0:0.03:1.5 for adenine, 8-HA, and 2,8-
DHA, respectively [277]. In patients on low-
purine diets, adenine compounds represent 20–30
% of the total urinary purine end products (uric
acid, oxypurines, and adenine metabolites)
excreted [250, 253, 263, 265, 266, 289].
Heterozygotes with a deficiency in this enzyme
have no alterations in adenine metabolite excre-
tion. Fast and relatively simple screening meth-
ods have been developed for the detection of
2,8-dihydroxyadenine in untreated urine samples
by capillary zone electrophoresis [290]. Using
this methodology, 2,8-dihydroxyadenine is sepa-
rated within 8 min, and its characteristic ultravio-
let spectra can be used to confirm its presence.
As indicated previously, type I APRTase
deficiency is manifested by a complete absence
of APRTase activity, whereas the type II lesion
is only a partial deficiency of the enzyme. The
latter defect is found almost exclusively in the
Japanese population [278–288], whereas the for-
mer has been described in patients from many
different countries including Japan [247–277]. In
the type I defect, enzyme activity in the erythro-
cyte is either very low or absent in homozygotes
[247–277], and heterozygotes of this type show
about 25 % of normal enzyme activity [219, 220,
223, 247–277, 291]. The proposed mechanism
for the absence or very low enzyme activity is
that either little or no enzyme is synthesized,
50
or the enzyme once synthesized is degraded
at a rapid rate. A variety of mutations in the
structural gene for APRTase could cause such
alterations, but detailed characterization of such
structural changes at the molecular level remains
to be described. In the heterozygotes with 25 %
enzyme activity and not the expected 50 % activ-
ity, it has been postulated that random aggrega-
tion of the two dimers making up the complete
APRTase enzyme occurs leading to three pos-
sible combinations. These would include a dimer
enzyme made up of two normal monomers, a
dimer containing one normal monomer and a
mutant monomer, and a dimer consisting of two
mutant monomers. If only the normal-normal
dimer is active, then only 25 % of the normal
APRTase activity would result in the other forms.
No explanation has yet been found for the occur-
rence of 50 % of the normal APRTase activity
in lymphoblasts and fibroblasts obtained from
heterozygotes for the type I deficiency. Possible
explanations include the fact that the hybrid
dimers are more stable in those cells, greater
quantities of the normal allele are present, or the
mutant allele is unstable [292]. Cells from type
I homozygotes fail to survive in azaserine (glu-
tamine analog)-alanosine-adenine medium but
have a normal survival in DAP medium [260,
281, 284, 293]. In contrast, cells from type I
heterozygotes survive in azaserine-alanosine-
adenine medium, whereas they do not in DAP
medium [258, 281, 284, 293].
In the type II defect, erythrocyte hemolysates
have approximately 25 % of the normal APRTase
activity, and T lymphocyte extracts show about
50 % of the normal activity [278–281, 288].
Patients homozygous for the type II defect cannot
be distinguished from type I heterozygotes using
only enzyme assays conducted on cell lysates
[280]. Cells from type II homozygotes are resis-
tant to the adenine analogs, 6-methylpurine and
DAP, indicating that although enzyme activity is
detected in these patients, the enzyme is nonfunc-
tional in the intact cell [281, 282]. In contrast,
cells manifesting the type I heterozygosity are
sensitive to these analogs. Further, intact erythro-
cytes from type II homozygotes incorporate
minimal amounts of radioactive adenine [280].
3 Purine Biochemistry
When one considers assays to distinguish the
heterozygotes of both types I and II, the heterozy-
gous types cannot be differentiated by their resis-
tance to adenine analogs, their uptake of
radioactive adenine, or the level of enzyme activ-
ity in cell lysates [279–284]. Both types of
heterozygotes generate DAP-resistant clones of
T lymphocytes, but no resistant clones arise in
individuals who do not carry any abnormality in
APRTase. The DAP-resistant clones from type I
heterozygotes have no detectable enzyme activ-
ity, whereas those from type II heterozygotes
show significant APRTase activity.
The properties of types I and II mutant
enzymes are quite different. As noted previously,
type I mutant enzymes from homozygotes show
APRTase activity and immunoreactive protein
values of less than 1 % of the normal enzyme.
APRTase activity from heterozygotes is about
25 % of normal; however, the immunoreactive
enzyme protein levels in heterozygotes range
from 22 to 100 %. In lymphoblasts from heterozy-
gotes, the corresponding values are 46 and 41 %,
respectively. In those with type II deficiency, the
enzyme has a reduced affinity for PRPP with a
normal affinity for adenine [282, 294]. The
mutant enzyme shows the kinetics of an allosteric
enzyme with respect to PRPP. A sigmoidal curve
is generated when its substrate (PRPP) concen-
tration is plotted as a function of enzyme satura-
tion. The Hill coefficient is nearly 2.0 for some
families who possess the mutant enzyme, whereas
it is 1.0 for the normal enzyme. In addition, the
S0.5 value for PRPP is 2.9 uM for the normal
enzyme and in the range of 47–82 uM in the
mutant enzyme. The enzyme from those with the
type II defect has altered heat stability when
compared to the normal enzyme [282, 294, 295].
Normal APRTase activity and type II mutant
enzyme can be distinguished using starch gel
electrophoresis since the mutant enzyme is found
closer to the anode than the normal enzyme [287,
296]. Type II heterozygotes show three bands on
starch gel electrophoresis as represented by the
wild, hybrid, and mutant. It is important to recog-
nize the fact that recent blood transfusions lead-
ing to admixtures of erythrocytes may provide
Adenine Phosphoribosyltransferase
misleading results in patients with these muta-
tions [289].
In summary, there are two different mutant
forms of the APRT enzyme that cannot be distin-
guished from each other by assaying erythrocyte
lysates alone. Patients and heterozygotes are only
distinguishable when several different assays are
used. These assays include (1) measurements of
APRTase activity in lysed and intact erythrocytes
and cultured lymphocytes [283, 297, 298], (2)
assessment of the sensitivity of cultured cells to
adenine analogs [281, 285, 293, 299], (3) analy-
sis of urinary adenine metabolites by high-per-
formance liquid chromatography or other
methods [270, 299, 300–302], and (4) assays for
adenine uptake using intact cells [260, 298–300].
Erythrocyte lysate assays for APRTase are used
to identify type I defects in homozygotes and
heterozygotes. Intact erythrocyte studies using
radioactive adenine to assay uptake differentiate
type I heterozygotes from homozygotes for the
type II defect since the former incorporate
significant quantities of the isotope, whereas the
latter only incorporate negligible amounts. Their
resistance to DAP or 6-methylpurine [303] dis-
tinguishes homozygous type II patients. The so-
called compound heterozygotes composed of
enzymes carrying the mutant phenotype for type
II defects and the type I defect showing no
enzyme activity (null allele) are only differenti-
ated by the use of analog-containing media.
As noted previously, APRTase deficiencies are
inherited as autosomal recessive disorders [191,
191, 194, 291, 297, 303], and the frequency of
heterozygotes has been estimated to range
between 0.4 and 1.1 % in various Caucasian pop-
ulations [190, 263, 291, 297, 304, 305].
Heterozygote frequency in the Japanese popula-
tions varies between 0.5 and 1.2 % [283, 299].
These estimates are higher than the actual
observed frequencies, and at this time, one can
only speculate as to why there is a variance
between the observed and estimated data.
Ascertainment may be one factor that accounts for
some of these differences. Asymptomatic patients
have been described, and such patients may not be
included in the ascertainment estimates. Confusion
has existed in the differentiation of uric acid
51
lithiasis from 2,8-dihydroxy adenine stones, and
misclassified patients may have been excluded.
Finally, some mutations may be lethal, and lethal
mutations may be excluded from ascertainment
calculations as well. Molecular studies of non-
Japanese and Japanese patients with this disorder
have shown that only three mutations exist in
Japanese patients. The most common mutation in
type II deficiency is a substitution of a threonine
(ACG) for methionine (ATG) at codon 136 desig-
nated as M136T. In type I deficiencies in this
same population, two mutations have been
identified, a TGG to TGA missense mutation in
codon 98 designated as W98X [288, 306–308]
and a four base pair duplication, CCGA, at codon
87 [288]. These three mutations represent 96 %
of the mutations observed in the Japanese with
the mutant, M136T, representing a little less than
70 % of the total. The M136T mutation appears
to have occurred within the codons for the PRPP-
binding region of the enzyme and could account
for the changes in the kinetic properties of this
enzyme (increased Km for PRPP) [202]. There is
sufficient evidence based on the relationships
between the M136T mutant and a TaqI polymor-
phic site in intron 2 to suggest that a crossover
has occurred between the mutation and SphI
polymorphic site [211]. The TaqI restriction-
fragment-length polymorphism (RFLP) site
results in a 2.1-kb and a 2.7-kb fragment when
the gene is exposed to TaqI. The frequency of the
alleles in the Caucasian population is 0.79 for the
smaller fragment and 0.21 for the larger frag-
ment, whereas in the Japanese population, the
allele frequency is about 0.50 [209]. The SphI
RFLP is 2.8 kb upstream from the TaqI site in
intron 2, and it results in an 8- and 12-kb frag-
ments with allele frequencies of about 0.80 and
0.20 in the Caucasian population and of about
0.40 and 0.60 in the Japanese population [81,
211]. In the Japanese population, all the M136T
mutants (194 alleles) have been associated with
2.7-kb TaqI fragment, and 42 of these alleles are
associated with the 8-kb SphI fragment and 6
with the 12-kb SphI fragment. These data along
with the population studies cited previously sug-
gest that a single ancestral mutation may well
account for the type II mutation [211, 278].
52
Similar molecular studies have been
performed to assess the basis of the type I non-
Japanese patients, and several different mutations
have been identified. The most common mutation
is a splicing defect localized to intron 4 [309,
310]. Insertion of a T nucleotide at the intron 4
splice donor site replaces an A nucleotide three
bases downstream from the splice site. A purine
nucleotide is necessary at that site for normal
splicing to occur [311]. Some of the patients with
this lesion are homozygous for the 2.1-kb TaqI
RFLP, whereas others are homozygous for the
8-kb SphI RFLP [309, 312]. Another patient has
been described with a transversion from G to T at
the intron 4 splice donor site that probably results
in defective splicing. In the Icelandic patients, a
single missense mutation results in the replace-
ment of an aspartic acid (GAC) by valine (GTC)
at codon 65 and has been designated D65V [310].
In this abbreviation, D is the conventional one-
letter symbol for aspartic acid and V is for valine.
All the patients described thus far with this muta-
tion have been found to be homozygous for the
2.1-kb Taq1 RFLP, and all the Icelandic patients
have been determined to be homozygous for the
8-kb SphI RFLP. The single English patient in
the group has been found to be heterozygous at
the SphI site [310, 313, 314]. Two other patients
showed an insertion of a T nucleotide in exon 2
that is likely to cause a frameshift after isoleucine
at codon 61 [310]. The remainder of the non-Jap-
anese patients have been shown to have princi-
pally deletions in exon 3 or exon 5 or single base
changes including R67Q (R = arginine, Q = glu-
tamine), R87X (R = arginine, X = any amino acid
to which arginine can be mutated), L110P
(L = leucine, P = proline), I112F (I = isoleucine,
F = phenylalanine), C153R (C = cysteine, R = argi-
nine), R89Q (R = arginine, Q = glutamine), and
M1V (M = methionine, V = valine) [310]. Most of
the adenine phosphoribosyltransferase mutants
have been reviewed in McKusick’s catalogue of
human inheritance, and compound heterozygotes
have been recently characterized in Japan [151,
315, 316].
Clinical investigations have recently described
an unusual patient who presented with 2,8-dihy-
droxyadenine urolithiasis and the Morquio syn-
drome [317]. The presence of these two genetic
3 Purine Biochemistry
disorders, N-acetylgalactosamine-6-sulfate sul-
fatase (GALNS) deficiency and adenine phos-
phoribosyltransferase deficiency, may be more
common than previously recorded since both
genes for these enzymes reside on the chromo-
some location 16q24.3 [317–320]. Morquio syn-
drome presents with a variety of organ
involvements, and such patients may have short
stature, dense calvaria, corneal opacities, hearing
loss, hepatomegaly, and different bony abnormal-
ities. The latter may include platyspondyly, odon-
toid hypoplasia, cervical subluxation, cervical
myelopathy, pectus carinatum, genu valgum, or
hip dysplasia. Fibroblasts and amniocytes (pre-
natal diagnosis) have a deficiency in galac-
tosamine-6-sulfatase, and leukocytes and
fibroblasts show metachromasia [321]. These
patients also have an increased urinary excretion
of keratin sulfate. Like APRTase deficiency,
Morquio syndrome is inherited as an autosomal
recessive. As noted previously, APRTase
deficiency presents primarily with renal calculi
or renal failure due to the deposition of the insol-
uble adenine metabolite, 2,8-dihydroxyadenine,
in the kidney. The mutation in this individual
with two genetic errors has been determined to be
the result of a deletion in the genes on chromo-
some 16 and a subsequent fusion between
sequences distal to the GALNS exon 2 and proxi-
mal to the APRT exon 3. The size of the deleted
region between GALNS intron 2 and APRT
intron 2 is approximately 100 kb [317].
Studies of the clinical biochemistry of
APRTase deficiency have shown that approxi-
mately 14 % of patients carrying the defect are
asymptomatic and only identified through family
studies in which a propositus has been docu-
mented to have the disorder [248, 253, 259, 266,
283, 322, 323]. The inability of patients with this
defect to salvage adenine and its subsequent oxi-
dation to hydroxylated adenine metabolites by
xanthine oxidase results in the generation of the
metabolites, 8-hydroxyadenine and 2,8-dihy-
droxyadenine. The latter metabolite is responsi-
ble for the pathologic consequences of the
disease. 2,8-DHA is insoluble at any pH and par-
ticularly at a near neutral pH (6.5) where its
solubility is 1.53 ± 0.04 mg/l [323]. At pH 5.0
(the approximate pH of urine), its solubility is
Adenine Phosphoribosyltransferase
2.68 ± 0.84 mg/l, and at an alkaline pH (7.8), its
solubility is little improved (4.97 ± 1.49 mg/l)
[323]. The urine contains unknown factors that
permit supersaturation of the urine to occur, and
levels of adenine metabolites between 40 and
90 mg/l have been determined [323].
The kidney is the primary target of the insolu-
ble adenine metabolite, and it is often deposited
in renal tubules eliciting an inflammatory
response consisting of lymphocyte infiltrates,
giant cell formation, and increased interstitial
connective tissue associated with atrophied
tubules. In addition to the deposition of 2,8-DHA
in the kidney tubules, renal calculi composed of
this same metabolite are often observed clini-
cally. The spectrum of stone formation ranges
from crystalluria to the formation of urinary tract
calculi and acute anuric renal failure secondary to
urinary tract obstruction. Yellow-brown, round
crystals of 2,8-DHA may be seen in the urine or
be suspected when diapers are stained with
brownish spots [314]. Stones recovered from
patients react in a fashion identical to uric acid
when tested using routine biochemical analyses.
Colorimetric analysis with phosphomolybdate,
murexide testing with nitric acid, and the alkaline
spectrum give identical reactions for 2,8-DHA
and uric acid. When a sample of 2,8-DHA on
filter paper is wet with liquid nitrogen and then
exposed to ultraviolet light, it is intensely phos-
phorescent [324]. Ultraviolet spectra in acid and
alkali, mass spectrometry, and high-performance
liquid chromatography are the usual techniques
used to provide absolute identification of this
metabolite and to differentiate it from uric acid
[299, 301, 302]. The principal treatment for
patients with APRTase deficiency is the hypoxan-
thine analog, allopurinol, which causes a redistri-
bution of the urinary metabolites since it inhibits
xanthine oxidase and blocks the conversion of
adenine to its hydroxylated metabolites.
Therefore, patients treated with allopurinol
excrete principally adenine rather than the toxic
metabolite 2,8-DHA. No alkalinization is required
to increase the solubility of the small quantities
of the hydroxylated adenine metabolites since
alkali does not alter the solubility of these com-
pounds. Two recent findings show promise for a
better understanding of the renal pathology in
53
APRTase deficiency [325–327]. Through the cre-
ation of mice that are homozygous for a null
APRTase allele, a mouse model for APRTase
deficiency has been developed [325, 326]. These
mice excrete adenine and 2,8-dihydroxyadenine
just as humans do with this disorder, and the
resultant renal histopathology is characterized by
renal tubular dilation, inflammation, necrosis,
and fibrosis. Birefringent crystalline deposits are
found in the kidney of these mice as are renal cal-
culi composed primarily of 2,8-DHA, the toxic
adenine metabolite. Treatment with allopurinol
improves the life expectancy of the affected mice
as well as the kidney function. Of interest, male
mice show significantly more renal damage than
females, and at this time, no sound explanation
for this difference has been determined [328].
Thus, this mouse model of nephrolithiasis, inter-
stitial nephritis, and chronic renal failure provides
a model for the investigation of interstitial nephri-
tis generated from renal calculi and more
specifically, a model that mimics human APRTase
deficiency.
Another recent clinical finding is that patients
with the autosomal dominant disorder, familial
juvenile hyperuricemic nephropathy (FJHN),
have been found to have reduced APRTase activ-
ity in their erythrocyte lysates [187, 329, 330].
This disorder is characterized by the early onset
of gout and/or hyperuricemia in affected females
and males. The molecular basis for this APRTase
deficiency has been identified as a single base
substitution in exon 3, codon 89, with the replace-
ment of the normal amino acid, arginine, by glu-
tamine. This mutation has been found in two
brothers with FJHN in one family, an affected
female in another family, and a mother and son
from a family with severe combined
immunodeficiency disease, and an unaffected
mother and her son in another family with FJHN.
Thus, a single base substitution in the APRTase
gene has been identified in three of nine families
with FJHN. A survey of 500 randomly selected
DNA samples did not identify this abnormality,
but it remains unclear as to whether this genetic
alteration has any clinical significance or whether
it is simply an incidental finding and bears no
relation to the underlying disorder in purine
metabolism.
54
The other issue related to purine metabolism
is the role of the enzyme, APRTase, in the control
of the first committed step in de novo purine bio-
synthesis. Since adenosine monophosphate
(AMP) is a product of the salvage enzyme,
APRTase, and this product is also a negative
feedback inhibitor of PRPP amidotransferase, the
absence of APRTase activity should lead to the
reduced formation of AMP and increased quanti-
ties of PRPP available for other reactions.
Reduced levels of AMP and increased availabil-
ity of PRPP could also increase purine synthesis
by the de novo pathway. The latter could occur
through the mechanism of either decreased feed-
back regulation of the first committed enzyme,
PRPP amidotransferase, or the use of the excess
PRPP as a substrate for the conversion of phos-
phoribosylpyrophosphate to phosphoribosylam-
ine. No patients with APRTase deficiencies have
been shown to excrete increased quantities of
uric acid, and this observation would suggest that
decreased quantities of AMP do not have a
significant role in the regulation of the de novo
pathway in these patients. Further, the increased
quantities of PRPP available as a result of its
underutilization for adenine salvage appear not to
drive purine synthesis more rapidly via the
de novo pathway. Thus, the deficiencies of ade-
nine phosphoribosyltransferase observed in
patients with familial juvenile hyperuricemic
nephropathy and their relationship to the defect
in uric acid metabolism in these families remain
to be determined. It would also appear that the
adenine salvage pathway plays no significant role
in the regulation of de novo purine biosynthesis.
Further, there is evidence that the increased level
of adenine phosphoribosyltransferase activity
observed in those patients with diminished or
absent hypoxanthine-guanine phosphoribosyl-
transferase activity may not be solely related to
stabilization of the former enzyme by phosphori-
bosylpyrophosphate. Erythrocyte APRTase activ-
ity and PRPP levels are elevated in patients with
purine nucleoside phosphorylase deficiency and
defective cell-mediated immunity [331, 332], and
erythrocyte APRTase activity is also elevated in
patients with the pyrimidine abnormality, heredi-
tary orotic aciduria [333, 334]. In the latter
3 Purine Biochemistry
genetic defect, the increased APRTase activity
has been determined to be related to the increased
synthesis of APRTase rather than diminished
degradation [334]. For these reasons, it may be
reasonable to reexamine the proposed role of
increased APRTase stabilization by PRPP.
Isotopes in the Evaluation of Uric Acid
Metabolism
Before leaving the biochemistry of purines, sev-
eral additional aspects should be discussed. Since
glycine supplies carbon atoms 4 and 5 and nitro-
gen atom 7 of the purine ring, this simple amino
acid can be used to assess the rate of purine syn-
thesis in vivo or in vitro. By measuring the rate of
incorporation of labeled glycine-1-C14 or glycine
alpha-N15 into uric acid or other purine end prod-
ucts, an estimation of the rate of purine synthesis
can be determined. Isotopes can also be utilized
to determine uric acid turnover rates, purine deg-
radation rates, and the rates of flow through
nucleotide pools. Studies using these isotope
methodologies were the first to suggest that
beyond measuring the quantity of uric acid in the
urine, the rate of purine synthesis could be shown
to be increased in patients with gout who excreted
more than the normal quantity of uric acid. A
variety of isotopes have been used to measure
purine production including glycine-2-C14, for-
mate-C14, 4-aminoimadazole-5-carboxamide-C14,
and ammonium-N15, whereas hypoxanthine-8-C14
and adenine-8-C14 have been utilized to measure
purine degradation and flow through the nucle-
otide pools. Radiolabeled adenine incorporated
into the adenine nucleotide pool permits the mea-
surement of adenine degradation through the
quantitation of radiolabeled products in the urine
[335, 336].
To summarize the significance of the de novo
purine biosynthetic pathway and its regulation in
humans with gout, accelerated production of uric
acid can occur on the basis of three fundamental
mechanisms: (1) increased concentrations of the
specific substrate, PRPP, available to the rate-
limiting step in purine synthesis catalyzed by the
enzyme, PRPP amidotransferase, (2) alterations
References
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decrease in their concentrations. Although the
activities of glutamine synthetase and glutami-
nase have been examined as putative contributors
to an increased rate of purine synthesis, no abnor-
malities have been identified, and it is unlikely
that alterations in l-glutamine, the other substrate
for PRPP amidotransferase, are responsible for
the gouty diathesis. As will be discussed in some
detail in the clinical chapters of this book, the
abnormalities in the enzymes, PRPP synthetase
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individuals with deficiencies in glucose-6-
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at this time. It may simply be an incidental finding
or it may have some pathogenetic significance
yet to be defined.
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 Uric Acid Metabolism in Humans
Overview
The metabolic alterations leading to an elevated
serum uric acid level are the precursors of the
clinical expression of hyperuricemia and gout,
and therefore, the key to understanding the patho-
genesis and management of gout lies with an
understanding of the mechanisms that can cause
these changes. Even though gout is a single clini-
cal entity, it is caused by a variety of different
mechanisms that may merit different treatment
regimens. The contributors to the pool of uric
acid in the human include preformed purines in
the diet that may be catabolized to uric acid, the
de novo biosynthesis of uric acid from small mol-
ecules, and the turnover and breakdown of tissue
nucleic acids to uric acid. There is constant
turnover of the uric acid pool since uric acid is
eliminated via the kidney, gastrointestinal tract,
and other minor routes such as tears, perspira-
tion, and saliva. A consideration of the routes of
urate generation and elimination provides a
framework for postulating the means by which
hyperuricemia could occur. The following poten-
tial mechanisms need to be considered. First, an
increased production of uric acid could occur via
the de novo pathway of biosynthesis. Second, an
increased catabolism of tissue purines and the
production of urate might be operating. Third,
excessive dietary intake of preformed purines
and their conversion to uric acid could cause
hyperuricemia. Fourth, there could be a decrease
in the elimination of uric acid via the kidney.
Fifth, a decreased elimination of uric acid via
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_4, © Springer-Verlag London 2013
4
extrarenal routes such as the gastrointestinal tract
could exist. In the human, only three of these
mechanisms are clearly associated with gout: the
increased production of uric acid via de novo bio-
synthesis, the increased production of uric acid as
a result of the breakdown of preformed tissue
nucleic acids, and the decreased elimination of
uric acid via the kidney.
Purine Biosynthesis
The ultimate rate of purine biosynthesis is the
result of complex interdependent relationships
between de novo biosynthesis, dietary purine
intake, purine degradation, and purine excretion.
Although attempts have been made to measure
the rate of purine synthesis in humans on purine-
restricted diets, these studies have produced vari-
able rates without providing a single standardized
rate for normal, healthy individuals. For this rea-
son, assessments of the rates of purine synthesis
have primarily relied upon the measurements of
urinary uric acid excretion which are reflections
of the rate of purine synthesis. On isocaloric,
purine-free diets, 24-h urinary uric acid excretion
values for normal males have been defined statis-
tically as 422 ± 75 mg [1, 2]. Since purine-free
diets are not very palatable and require about
a week to establish an equilibrium, such restric-
tive diets are rarely instituted to estimate purine
production in the clinical setting. Instead, it has
been established that normal individuals excrete
approximately 600–800 mg of uric acid in 24 h
69
70
on a regular diet. Values of 800–1,000 mg of uri-
nary uric acid/24 h are considered borderline, and
patients with such values deserve greater scrutiny
to determine whether they are truly urate overpro-
ducers. When values exceed 1,000 mg/24 h,
patients are definitely classified as overproducers
of uric acid. In patients with gout, urinary uric
acid excretion varies widely from patients who
have values as low as 100–200 mg/24 h to values
of more than 2 g/24 h. Low urinary uric acid lev-
els are observed in those who either have altered
renal function and retention of urates on the basis
of renal disease or have specific, yet to be
identified, renal defects in the excretion of uric
acid. The latter group of patients with diminished
urate excretion probably represents the largest
number of gouty patients. Like all laboratory val-
ues, urinary uric acid measurements should not
be viewed in isolation. Elevated urinary uric acid
levels in the absence of increased levels of serum
uric acid may not be a sign of overproduction of
urate but may indicate an increased renal clear-
ance of uric acid as might be observed in some
patients with hereditary renal hypouricemia.
Furthermore, normal urinary uric acid levels do
not exclude the overproduction of urate since
renal impairment may result in a larger fraction of
urate being shunted to extrarenal disposal sites.
Documented overexcretion of uric acid on
more than a single occasion may denote an
increased synthesis of purines by the de novo
pathway and indicates the need both to evaluate
such patients for the underlying cause of the
overproduction and to institute therapeutic
modalities for the prevention of the complica-
tions of this metabolic abnormality. It is esti-
mated that probably less than 5–10 % of patients
with primary gout are overproducers of urate.
Since this small percentage of patients is docu-
mented for those with primary gout, it excludes
those with secondary gout due to other disor-
ders such as malignancies, psoriasis, and other
diseases that may be associated with urate over-
production. The pathophysiological mecha-
nisms for primary and secondary gout are
discussed subsequently.
In addition to the measurements of urinary
uric acid excretion, a number of studies have
4 Uric Acid Metabolism in Humans
measured the incorporation of glycine-1-C14 to
assess the rate of purine synthesis. As noted pre-
viously, this small molecule is incorporated into
the purine ring and makes up carbon atoms 4 and
5 as well as nitrogen atom 7 of the completed
purine ring. In patients with gout who are urate
overexcretors and most normoexcretors, glycine
is overincorporated into urinary uric acid when
compared to normal, nongouty subjects. Further,
patients with gout incorporate glycine into uri-
nary uric acid more rapidly and to a greater extent
than normal subjects [3–6]. In some patients,
especially those who have lost weight, repeated
measurements of glycine incorporation into uri-
nary uric acid after weight reduction have shown
a decrease in the magnitude of the overincorpora-
tion [7]. Thus, the degree of overincorporation
can be reduced in some patients, and it has even
reverted to normal in one patient [8]. In gouty
patients with decreased renal function, the quan-
tity of uric acid excreted is likely to decline with
a resultant increase in the amount of uric acid
eliminated by the gastrointestinal tract. Unless
the changes in urate kinetics introduced by the
altered renal function are taken into consider-
ation, overincorporation of the radiolabel into
urinary uric acid may be disguised. If diminished
renal function is considered, then gouty subjects
who manifest glycine incorporation within the
normal range will show an increased incorpora-
tion when corrections are made for the decreased
renal function.
Miscible Pool of Urate
The dietary intake of preformed purines and uric
acid, de novo purine nucleotide biosynthesis cen-
tered in the liver and blood forming organs, and
the various catabolic pathways resulting in the
breakdown of nucleic acids and/or purine nucle-
otides and nucleosides represent the sources of
uric that contribute to the pool of uric acid
(Fig. 4.1). The miscible pool, by definition, is the
quantity of uric acid in the body by which isotopi-
cally labeled uric acid administered intravenously
is immediately diluted. The miscible pool does
not measure tissue resident urate deposits (tophi)
Miscible Pool of Urate
Pathogenesis of gout
De novo purine
Overproducers biosynthesis
Males: 480 − 1,050 mg (0 − 0.7 pools/day)
Females: 300 − 700 mg (0.6 − 0.7 pools/day)
Underexcretors Renal uric acid
excretion
Fig. 4.1 Serum uric acid levels are a function of endog-
enous and exogenous sources of this trihydroxy purine
and its rate of urinary excretion. The miscible pool or
freely exchangeable uric acid is a reflection of the serum
urate level. De novo purine biosynthesis is increased prin-
cipally in patients with heritable enzyme defects (hypox-
anthine-guanine phosphoribosyltransferase deficiency
which are often not freely exchangeable with the
body pool of urate. In males, the miscible (freely
exchangeable) pool has an average value of
1,200 mg [9, 10], and in females, values for this
pool range from 541 to 647 mg. If body weight is
considered, then the average pool size in males
is about 16.3 mg/kg of body weight [11].
In patients with gout, the miscible pool of
urate is significantly larger than it is in normal,
healthy subjects. In those without tophaceous
deposits, it ranges from 2,000 to 4,000 mg [10,
11], whereas in those with tophi, the pool size
may range from 18,000 to 31,000 mg [12].
All miscible pool measurements are based on
a one-compartment model with urate freely
exchangeable and exclude a second compartment
71
Dietray intake Cell and tissue
turnover
Miscible uric acid pool
Males: 800 − 1,500 mg
Females: 500 − 1,000 mg
Daily urate pool turnover
Intestinal Other sources
uricolysis (sweat, tears, etc.)
and phosphoribosylpyrophosphate synthetase overactiv-
ity). Increased purine nucleotide turnover is observed in
some malignant disorders and other metabolic dysfunc-
tions leading to an increase in the miscible pool of uric
acid and serum uric acid levels. The regulation of urinary
uric acid excretion also plays a significant role in the con-
trol of serum uric acid concentrations
where less freely exchangeable uric acid resides
as tissue deposits (tophi). Therefore, the values
obtained by the one-compartment miscible pool
methodology underestimate the actual pool size.
This concept has been confirmed by experiments
on tophi removed from patients who have been
administered 15N-labeled uric acid. These experi-
ments showed that only the peripheral layers of
the tophi were exchangeable with urate in the
soluble pool [12]. In fact, if a two-compartment
model is considered where the quantity of uric
acid in tissue deposits like tophi only slowly
exchange, if at all, with the soluble pool of uric
acid, the slowly exchangeable urate is estimated
to be 300-fold larger than the freely exchange-
able pool [13].
72
Urate Turnover Rate
The rate of disappearance of radiolabeled uric
acid from the miscible pool has been utilized to
calculate the turnover rate of uric acid even
though the one-compartment model has the limi-
tations noted previously. In nongouty subjects,
the mean turnover rate for uric acid has been
reported to be 693 ± 112 mg/24 h [11]. The turn-
over rates in gouty subjects, as one might guess,
are higher than those in normal subjects, and the
average turnover rate in one study has been
found to be 800 ± 130 mg/24 h [11]. However, in
some gouty subjects who have a miscible pool
within the normal range, the turnover rates have
also been found to be within the normal range.
Thus, in gouty patients with normal 24-h uric
acid excretion and no clinical evidence of tophi,
the uric acid turnover rates are likely to be
entirely normal or only slightly above the nor-
mal range. Usually, turnover rates are highest in
those subjects who overexcrete uric acid, and
such rates may reach levels of 2,000 mg/24 h in
some overexcretors, whereas normoexcretors
have a range of turnover rates from normal to
elevated [14].
Mechanisms of Hyperuricemia
and Gout
A number of studies have been performed to
measure the rate of purine biosynthesis using
labeled precursors of uric acid. The most accept-
able technique for the measurement of the rate of
uric acid biosynthesis de novo is to use 1-14C-
glycine in tracer amounts and to quantify the
radiolabel incorporated into urinary uric acid.
Various studies using this method have been aver-
aged and show that in normal subjects, the mean
value for incorporation of glycine into urinary
uric acid is 0.17 % in 7 days, whereas in gouty
subjects, the average incorporation is 0.28 % over
the same time period [15]. About one-half the
gouty patients who excrete less than 590 mg/day
have a cumulative incorporation into urinary uric
acid above the normal range [15].
4 Uric Acid Metabolism in Humans
Elevated PRPP Levels
In those patients with primary gout that excrete
more than 590 mg/day, the cumulative incorpo-
ration is always above the normal range [15]. As
noted previously, only a small number of patients
with primary gout, less than 5–10 %, overpro-
duce uric acid, and the mechanisms by which
this overproduction occurs have been defined in
two clinical settings, PRPP synthetase overac-
tivity and HGPRTase deficiency, and remain
undefined in others who overproduce uric acid
and have no recognizable enzyme abnormality.
The mechanism for the overproduction in PRPP
synthetase overactivity relates to the overpro-
duction of phosphoribosylpyrophosphate (PRPP)
which is the substrate for the rate-controlling
step in de novo purine biosynthesis, the conver-
sion of phosphoribosylpyrophosphate and
l-glutamine to phosphoribosylamine (PRA) by
the enzyme, PRPP amidotransferase (Fig. 4.2).
An excess of the substrate (PRPP) increases the
conversion of PRPP to PRA and subsequently
leads to an increase in the end product of
the purine pathway, uric acid. The mechanism
for urate overproduction in hypoxanthine-gua-
nine phosphoribosyltransferase (HGPRTase)
deficiency is the underutilization of PRPP as a
substrate for the conversion of either hypoxan-
thine or guanine to inosinic acid or guanosinic
acid, respectively, catalyzed by the enzyme,
hypoxanthine-guanine phosphoribosyltrans-
ferase. This leaves an excess of PRPP for use as
the substrate for PRPP amidotransferase and its
conversion to PRA (Fig. 4.3). This conversion
accelerates purine synthesis via the de novo
pathway. The evidence for this mechanism
comes from experiments showing an increased
production of uric acid as well as increased con-
centrations of PRPP in erythrocytes and
fibroblasts from patients with PRPP synthetase
overactivity [16–20]. Similarly, elevations in the
cellular levels of PRPP have also been deter-
mined in HGPRTase-deficient patients [20].
Cellular concentrations of PRPP are elevated in
some heterozygote carriers of HGPRTase
deficiencies who may, in some cases, develop
Decreased Hypoxanthine Reutilization
Regulation of phosphoribosylpyrophosphate synthetase
MgATP
Adenosine diphosphate
(competitive inhibitor)
PRPP
synthetase
H2O3POCH2
O
OH OH
Fig. 4.2 Phosphoribosylpyrophosphate synthetase super-
activity leads to an increased production of phosphoribo-
sylpyrophosphate, and the excess of this metabolite
activates the rate-limiting enzyme of de novo purine
nucleotide biosynthesis, phosphoribosylpyrophosphate
amidotransferase. These changes result in the overproduc-
tion of uric acid by the de novo pathway and cause an
increased excretion of uric acid via the kidney. The cause
gout. Since some heterozygotes for this enzyme
deficiency also have normal levels of PRPP
despite an increased excretion of uric acid and
hyperuricemia, erythrocyte PRPP levels may
not always reflect the levels of PRPP in other
tissues such as the primary sites of purine syn-
thesis (liver) or may indicate that other factors
contribute to the increased production of urate
in HGPRTase-deficient individuals. In some
individuals, elevated PRPP levels have been
documented in the absence of an enzyme defect,
and the mechanism responsible for this change
remains unidentified.
73
Ribose-5-Phosphate
2,3-Diphosphoglycerate
(competitive inhibitor)
O O
O-P-O-P-OH
OH OH
Purine nucleotides - ADP and GDP
(noncompetitive inhibitors)
of phosphoribosylpyrophosphate synthetase superactivity
has been attributed to defective regulation of this enzyme
by its allosteric effectors, catalytic overactivity, combined
regulatory and catalytic defects, or an increased affinity of
the substrate, ribose-5-phosphate, for the enzyme.
Catalytic overactivity is the most common defect, and the
cause for this mutation has yet to be determined
Decreased Hypoxanthine
Reutilization
It is known that decreased reutilization of
hypoxanthine to generate inosinic acid occurs
in patients with HGPRTase deficiency, and as a
consequence, more hypoxanthine is available
for oxidation to uric acid via xanthine oxidase
(Fig. 4.3). This mechanism produces more oxy-
purines including uric acid in those patients with
HGPRTase deficiency and contributes additional
oxypurines to the increased pool of urate gen-
erated by the accelerated urate production via
74 4 Uric Acid Metabolism in Humans

Purine salvage pathways

OH
OH
HGPRTASE
N
N N
N CH
CH
N
N
N
H2N N
R-P

Guanine
Inosinic acid
+ MgPRPP

OH
OH

N
N N
N CH
CH
N
N
N N H2N
HGPRTASE
R-P
Hypoxanthine
Guanylic acid

Xanthine oxidase

OH OH

N Xanthine oxidase N
N N
CH C OH

N N
N N
HO H HO H

Xanthine Uric acid

Fig. 4.3 In conjunction with the increased levels of
phosphoribosylpyrophosphate observed in hypoxanthine-
guanine phosphoribosyltransferase-deficient patients, the
hypoxanthine formed has no other metabolic route to fol-
low other than its oxidation to uric acid when it is not
converted to inosinic acid (IMP) by hypoxanthine-guanine
phosphoribosyltransferase activity. This mechanism
together with the increased rate of de novo purine nucle-
otide biosynthesis driven by the excess phosphoribosylpy-
rophosphate levels accounts for the hyperuricemia in these
patients

the de novo pathway. How the abnormality in remains to be determined. Other possibilities
hypoxanthine reutilization might contribute, if at exist to account for those urate overproducers
all, to the unidentified defect(s) in urate overpro- in whom no identifiable defect has been char-
ducers without an identified enzyme deficiency acterized. These include possible abnormalities
Accelerated ATP Degradation
in the feedback inhibition sites on the enzyme,
PRPP amidotransferase, and aberrations in the
pentosemonophosphate shunt producing more
ribose-5-phosphate for the conversion to PRPP,
the primary substrate for the first step of de novo
purine biosynthesis.
Glutamine Hypothesis
Although alterations in l-glutamine metabolism,
the other substrate for the rate limiting enzyme,
PRPP amidotransferase, have been proposed as
possible contributors to enhanced purine synthe-
sis, no evidence has been generated to support
this mechanism of purine overproduction.
Accelerated ATP Degradation
In secondary gout, quite different biochemi-
cal mechanisms cause urate overproduction.
These mechanisms include increased adenosine
triphosphate degradation, decreased adenosine
triphosphate synthesis, increased nucleic acid
turnover, and accelerated nucleotide degradation.
Hyperuricemia and gout are the primary long-
term complications of glucose-6-phosphatase
deficiency (glycogen storage disease, type I), and
the mechanism by which hyperuricemia occurs
in these patients has been shown to be the result
of an accelerated rate of adenosine triphosphate
turnover and degradation [21]. In glycogen
storage disease, hypoglycemia stimulates the
release of glucagon, and glucagon activates the
hepatic enzyme, glycogen phosphorylase, which
degrades glycogen to glucose-6-phosphate. The
absence of the enzyme, glucose-6-phosphatase,
prevents the further catabolism of this metabolite
except the small quantities that may be converted
to glucose by debrancher enzyme activity [22],
and the increasing formation of phosphorylated
sugars traps inorganic phosphate and depletes
ATP stores (Fig. 4.4). The depletion of ATP stores
leads to the formation of purine nucleoside mono-
phosphates which are then degraded to inosine,
hypoxanthine, xanthine, and uric acid (Fig. 4.5).
Experimental evidence confirms this mechanism
75
in that correction of hypoglycemia results in the
suppression of glucagon levels, a correction of
the hypoglycemia, and a reversal of the hyperuri-
cemia in individuals with glucose-6-phosphatase
deficiency [21, 23–30]. In contrast to these exper-
imental results, the infusion of glucagon increases
serum uric acid levels in patients with glycogen
storage disease, type I, as well as increasing the
urinary concentrations of oxypurines and uric
acid. Indeed, if labeled ATP is administered to
such individuals, glucagon causes an increase in
the urinary radiolabeled metabolites originating
from ATP. Further, the infusion of somatosta-
tin to suppress glucagon levels results not only
in the lowering of the glucagon levels but also
reductions in the serum urate, urinary uric acid,
and oxypurine levels. There is also a reduction
in the radiolabeled purine products if isotopically
labeled ATP has been infused. These experiments
serve to confirm the hypothesis that increased
serum uric acid and urinary oxypurines in gly-
cogen storage disease, type I, occur as a result of
ATP degradation. It is important to recognize that
there are several forms of type I glycogen storage
disease based on the hepatic microsomal glu-
cose-6-phosphatase complex [31]. The enzyme,
glucose-6-phosphatase, is located in the lumen
of the endoplasmic reticulum of hepatic cells in
association with a calcium-dependent regulatory
protein and transport proteins (T1, T2, and T3)
which transport glucose-6-phosphate, phosphate,
and glucose, respectively, across the endoplas-
mic reticulum membrane [31]. The T1 protein
transports glucose-6-phosphate to glucose-6-
phosphatase which then hydrolyzes the phos-
phorylated glucose, and the transport proteins,
T2 and T3, return the hydrolyzed phosphate and
glucose to the cytosol. Since some patients with
the clinical picture of glycogen storage disease
have completely normal glucose-6-phosphatase
activity, alternative explanations for the clini-
cal symptoms had to be defined. Recent studies
have characterized three additional subsets of the
type I glycogen storage disease [32]. Type Ia is
the classical form of glycogen storage disease
(von Gierke’s disease), type Ib is recognized as
a defect in the T1 protein or translocase, and type
Ic has been documented as a deficiency of the
76 4 Uric Acid Metabolism in Humans

Glycogenolysis

Glycogen

ATP Phosphorylase
Oligo-1,4-1,4 glucantransferase
Amylo-1,6-gucosidase

ADP

Glucose-1-phosphate

Phosphoglucomutase

Glucose-6-phosphatase

6-phosphogluconate Glucose-6-phosphate Glucose

Phosphohexose isomerase

Fructose-6-phosphate
ATP

Ribulose-5-phosphate Phosphofurctokinase

ADP AMP

Furctose-1,6-diphosphate

Ribose-5-phosphate
+
ATP
Uric acid
Lactate

PRPP + Glutamine PRA Inosinic acid Hypoxanthine

Fig. 4.4 In the absence of glucose-6-phosphatase (glycogen
storage disease type I), phosphate esters (glucose-6-phos-
phate) accumulate and inorganic phosphorous levels
decrease. Since inorganic phosphorus is a potent inhibitor
of adenosine monophosphate deaminase, this enzyme is
more active with the decrease in inorganic phosphorus
levels and catalyzes the breakdown of adenosine mono-
phosphate to uric acid (see Fig. 4.5). In the absence of
glucose-6-phosphatase, there is an increased conversion
of glucose-6-phosphate to fructose-6-phosphate and even-
tually to lactate. The latter small molecule inhibits the
excretion of urate by the kidney and results in an increase
in serum uric acid levels. Excess glusoce-6-phosphate may
also increase its conversion to 6-phospho-d-gluconolactone
and the eventual conversion to phosphoribosylpyrophos-
phate, an activator of de novo purine nucleotide biosynthe-
sis and an increased production of uric acid
Accelerated ATP Degradation 77

Adenine nucleotide catabolism

Adenosine kinase Adenylate kinase

Adenosin + ATP AMP + ATP 2 ADP

AMP deaminase

Inosine monophophate

Cytoplasmic 5’-nucleotidase

Inosine

Nucleoside phosphorylase

Hypoxanthine

Xanthine oxidase

Xanthine

Xanthine oxidase

Uric acid

Fig. 4.5 Adenine nucleotide catabolism is the final com-
mon pathway for the production of hyperuricemia in con-
ditions where increased adenosine triphosphate
degradation occurs. Such conditions include strenuous
muscle exercise, ethanol ingestion, glucose-6-phosphatase
deficiency (glycogen storage disease), hereditary fructose
intolerance (aldolase B deficiency), and fructose-1,
6-diphosphatase deficiency. Decreased adenosine triphos-
phate synthesis may also lead to hyperuricemia through
the acceleration of adenine nucleotide degradation in
conditions such as tissue hypoxia (severe illnesses) and
metabolic myopathies (glycogen storage disease types III,
V, and VII)
78
pyrophosphate transport protein (T2). There may
also be additional defects to be described includ-
ing those with a defect in the glucose transport
protein (T3) and possibly the regulatory protein
for glucose-6-phosphatase. With the exception
of type Ib which is often associated with altera-
tions in the number (neutropenia) and mobil-
ity of neutrophils, all these type I subsets have
similar clinical presentations, but they may vary
in their severity. Patients with type Ib may have
recurrent bacterial infections based on the afore-
mentioned alterations in the neutrophil. Similar
mechanisms for increased ATP degradation have
also been proposed as the cause for the hyperuri-
cemia observed in patients with hereditary fruc-
tose intolerance and fructose-1,6-diphosphatase
deficiency.
Several other types of glycogen storage dis-
eases have been shown to be associated with
hyperuricemia on the basis of alterations in ATP
metabolism. Glycogen storage diseases, type III
(debrancher enzyme deficiency), V (muscle phos-
phorylase deficiency), and VII (muscle phospho-
fructokinase deficiency), have all been studied to
characterize the mechanism by which hyperu-
ricemia occurs. Experiments using leg exercise
mediated via a bicycle ergometer to measure
the effects of exercise on purine metabolism in
such patients clearly document an increase in
plasma concentrations of ammonia, inosine, and
hypoxanthine after a modest degree of exercise
[33]. After a delay, the plasma urate concentra-
tion increases, and later, the urinary excretion of
inosine, hypoxanthine, and urate also increases.
These changes are the result of an accelerated
degradation of muscle purine nucleotides, and
the inosine and hypoxanthine produced in the
muscle then serve as substrates for the synthesis
of uric acid giving rise to the elevated plasma
urate levels and the increment in uric acid excre-
tion (Fig. 4.6). Blood cell hemolysis also occurs
in GSD, type VII, and may contribute to the hype-
ruricemia on the basis of an accelerated turnover
of nucleic acids. In addition to these glycog-
enoses, other less common disorders of muscle
metabolism have also been associated with hype-
ruricemia and accelerated ATP degradation with
exercise. These include reports of patients with
4 Uric Acid Metabolism in Humans
carnitine palmityl transferase deficiency, with
muscle phosphoglycerate mutase deficiency, and
a patient with a variant form of phosphofructoki-
nase deficiency [33–38]. Gouty arthritis has been
documented in 30% of the patients with glycogen
storage disease, type VII, as well as in a patient
with muscle phosphoglycerate mutase deficiency
and one with phosphofructokinase deficiency
[33]. Tophi have been observed in a patient with
phosphoglycerate mutase deficiency [37]. These
alterations in purine metabolism associated with
metabolic myopathies may not be recognized in
the absence of exercise testing and the measure-
ment of the metabolites, hypoxanthine, inosine,
lactate, and uric acid before, during, and after
exercise. Further, myogenic hyperuricemia and
gout may be a clue to an underlying disorder in
muscle metabolism if muscle pain and weak-
ness occur after exercise. Indeed, some patients
with primary muscle disease will give a his-
tory of pigmented urine due to unrecognized
myoglobinuria.
Ethyl alcohol ingestion has always been
associated with hyperuricemia and the gouty
diathesis; however, the pathogenesis of this asso-
ciation has not been well understood until rela-
tively recently. Experiments using radiolabeled
adenine administration to label the adenine pool
with the subsequent infusion of ethanol result in
an increase in urine radioactivity by 150 % and
in the excretion of urinary oxypurines by 400 %.
The proposed mechanism for this occurrence is
the oxidation of ethanol to acetaldehyde by the
enzyme, alcohol dehydrogenase, and, subse-
quently, the conversion of acetaldehyde to ace-
tate catalyzed by aldehyde dehydrogenase. Both
these oxidation reactions result in an increase in
NADH concentrations at the expense of NAD
and cause an increase in the ratio of NADH to
NAD. The change in that ratio alters the balance
between the redox pairs, lactate/pyruvate and
b-hydroxybutyrate/acetoacetate. The equilibrium
is shifted toward lactate and b-hydroxybutyrate,
metabolites that interfere with the excretion of
uric acid in the renal tubules. Acetate is then
converted to acetyl coenzyme A by the enzyme
acetyl-CoA synthetase which consumes ATP
in the process of synthesizing acetyl-AMP. The
Accelerated ATP Degradation 79

Nucleotide metabolism in muscle

Adenosine triphosphate (atp)

Glucose
Muscular oxidation, fatty
Activity acid oxidation,
and oxygen

Adenosine diphosphate (adp)

Adenylate kinase

Adenosine Adenosine monophosphate (amp) + atp

Amp deaminase

Inosinic acid (imp)

Adenosine
deaminase 5'-nucleotidase

Inosine + inorganic phosphorus

Purine nucleoside phosphorylase

Hypoxanthine (Hx)

Xanthine oxidase

Xanthine (X)

Xanthine oxidase

Uric acid (UA)

Fig. 4.6 Muscular activity utilizes adenosine triphos-
phate (ATP) as an energy source, and glucose oxidation
along with oxygen and inorganic phosphorus are require-
ments for the regeneration of ATP. Metabolic myopathies,
strenuous exercise, and other conditions that limit glucose
oxidation or fatty acid oxidation may lead to the degrada-
tion of ATP. Two routes are available for the catabolism of
adenosine monophosphate (AMP). The AMP generated
from the conversion of adenosine diphosphate (ADP) to
ATP and AMP may be converted to inosinic acid (IMP) by
AMP deaminase or to adenosine by 5¢-nucleotidase.
Subsequently, adenosine is converted to inosine by ade-
nosine deaminase and IMP is converted to hypoxanthine
by purine nucleoside phosphorylase. Hypoxanthine
released by muscle is then oxidized in the liver to xanthine
and uric acid by xanthine oxidase

AMP generated from ATP consumption may be converted to hypoxanthine, xanthine, and uric
either be recycled to ATP or degraded to IMP acid by the action of the enzyme, xanthine oxi-
and subsequently to inosine. Inosine may then dase (Figs. 4.5 and 4.7). Experiments utilizing
80 4 Uric Acid Metabolism in Humans

Fig. 4.7 The association Ethanol metabolism

between ethanol ingestion and
hyperuricemia has been
proposed to occur as a result
of an increased degradation of CH3CH2OH
adenosine triphosphate (ATP).
Ethanol is metabolized to NAD+
acetate by a series of
enzymatic reactions (alcohol Alcohol dehydrogenase
dehydrogenase, aldehyde
dehydrogenase, and acetyl- +
NADH+ + H
CoA synthetase). The
conversion of acetate to
acetyl-CoA consumes ATP CH3CHO
and results in the formation of
adenosine monophosphate NAD+
(AMP). The latter metabolite
may then be converted to ATP
Aldehyde dehydrogenase
or deaminated by AMP
+
deaminase to form inosinic NADH+ + H
acid (IMP). Subsequently,
IMP is converted to inosine _
CH3COO
by the enzyme, 5¢-nucleoti-
dase, and inosine is further ATP
converted to hypoxanthine by
purine nucleoside phosphory- Acetyl-coA synthetase
lase activity. Hypoxanthine is
then sequentially converted to PPi
xanthine and uric acid by NH2
xanthine oxidase. This
pathway is shown in Fig. 4.5.
This metabolic model has N
N _
been confirmed by the O O
infusion of acetate into human CH
subjects and documenting the H2C P O C CH3
N
increased ATP degradation N
O
and oxypurine excretion O
H H

H H
OH OH

Acetyl-coA synthetase

Acetyl-coA + Aenosine monophosphate

[14C] adenine in normal subjects have also docu-
mented increased ATP degradation and increased
oxypurine excretion [39]. Thus, ethanol induces
hyperuricemia and perhaps gout by increasing
ATP degradation and by inhibiting tubular secre-
tion of urate on the basis of the generation of lac-
tate and b-hydroxybutyrate.
The other clinical settings in which ATP
synthesis is decreased and in which hyperurice-
mia occurs are those associated with tissue
hypoxia resulting either from ischemia or hypox-
emia [40–44]. Elevated levels of hypoxanthine,
xanthine, and inosine have been measured in
patients with hypoxemia and are a reflection of
Increased Nucleic Acid Turnover
accelerated ATP degradation [43, 44]. Tissue
hypoxia and an impaired blood supply limit the
resynthesis of ATP. Thus, the flux of metabolites
is toward uric acid in these patients, and the level
of serum uric acid appears to be a biomarker of a
poor prognosis [43].
Increased Nucleic Acid Turnover
In addition to these examples of secondary hype-
ruricemia and gout, two other mechanisms have
been shown to cause these metabolic diseases:
increased nucleic acid turnover and accelerated
nucleotide degradation. Increased nucleic acid
turnover is a major component of lymphoprolif-
erative and myeloproliferative disorders, myeloid
metaplasia, pernicious anemia, certain hemo-
globinopathies, thalassemia and other chronic
hemolytic anemias, multiple myeloma, and poly-
cythemia (primary or secondary), and these dis-
eases may also be associated with hyperuricemia,
gout, and hyperuricaciduria. Increased turnover
of nucleic acids and bone marrow activity char-
acterize all these disorders, and hyperuricemia
is the common expression of these metabolic
abnormalities. Gout does occur in these condi-
tions but is much less common than the occur-
rence of hyperuricemia. The occurrence of gout
and/or hyperuricemia is of clinical significance
since they may herald the onset of the underlying
disease, and alterations in uric acid metabolism
can be an early clinical indicator of a hematopoi-
etic neoplasm. The mechanism for the derange-
ment in uric acid metabolism in neoplams is an
accelerated turnover of nucleic acid synthesis
since these malignancies utilize large quantities
of nucleotides. Excessive purine nucleotide uti-
lization leads to a reduction in tissue nucleotide
concentrations, to the subsequent relaxation of
feedback inhibition of PRPP amidotransferase
activity by nucleotides, and to an increased rate
of de novo purine biosynthesis (Fig. 4.8). These
foregoing changes in purine metabolism result
in hyperuricemia, hyperuricaciduria, and, at
times, gouty arthritis. Radiolabeled glycine has
been used to characterize the urinary purines in
certain of these disorders and has documented
81
maximal labeling of urinary uric acid on day
15 in polycythemia, on day 5–10 in secondary
polycythemia, and on days 3 and 12 in myeloid
metaplasia (two peaks) [45–48]. Additional stud-
ies of patients with myeloid metaplasia who have
been administered 1-14C-glycine show marked
early and greater labeling of urinary adenine,
guanine, and 7-methylguanine than of urinary
hypoxanthine, xanthine, and uric acid [49, 50].
Such results have suggested that turnover rates
for adenosine monophosphate, guanosine mono-
phosphate, and other nucleotides are more rapid
than normal. In disorders like polycythemia, uri-
nary uric acid labeling that peaks at 5–10 days
may reflect an augmented turnover of erythroid
cells. The peaks in labeling observed with myelo-
proliferative disorders at 12–15 days after the
administration of radiolabeled glycine most likely
indicate augmented turnover in myeloid cells. In
polycythemia vera, the erythrocytes manifest an
increased activity of the pentose phosphate path-
way, augmented generation of phosphoribosylpy-
rophosphate (PRPP), increased incorporation
of 14C-adenine into nucleotides, and increased
activity of adenine phosphoribosyltransferase.
If these erythroid precursor cells have an intact
de novo purine biosynthetic pathway, the excess
PRPP levels could increase the conversion of
PRPP to phosphoribosylamine (PRA), the first
irreversible step in purine synthesis leading to an
increased production of uric acid. It is important
to recognize that alterations in uric acid produc-
tion may first be detected after chemotherapeu-
tic agents have been used to treat the underlying
malignancy and the destruction of cells leads to
the release of massive quantities or nucleotides
for catabolism to uric acid. Similarly, patients
with untreated pernicious anemia may manifest
altered uric acid metabolism when treatment
begins and ineffective erythropoiesis ceases.
The hyperuricemia observed in association
with psoriasis is another example of how
increased nucleic acid turnover may contribute to
an increased pool of uric acid [51–54]. Studies of
this skin disease have focused on the increased
epidermal turnover that characterizes this disor-
der. Increased rates of epidermal turnover may
lead to an increased degradation of purines and
82 4 Uric Acid Metabolism in Humans

De novo purine biosynthesis: regulation

H2O3POCH2
O
+ Glutamine
O O

O-P-O-P-OH

OH OH
OH OH

PRPP amidotransferase

Mg2+

H2O3POCH2 NH2
O

OH OH

Inosine 5'-phosphate

Adenosine 5'-phosphate Guanosine 5'-phosphate

Fig. 4.8 The rate of de novo purine nucleotide biosynthe-
sis is subjected to end-product inhibition by purine nucle-
otides (AMP and GMP). Amino- and hydroxy-substituted
purine nucleotides at position 6 of the purine ring bind to
inhibitory sites different from the substrate of the enzyme,
phosphoribosylpyrophosphate (PRPP) amidotransferase.
Monophosphate nucleotides (AMP and GMP) are more
potent inhibitors of amidotransferase activity than diphos-
phate and triphosphate nucleotides (ADP, ATP, GDP, and
GTP). This is in contrast to the inhibition of phosphoribo-
sylpyrophosphate synthetase by purine nucleotides where
diphosphate and triphosphate nucleotides are more potent
inhibitors than monophosphate nucleotides. Combinations
of 6-amino and 6-hydroxy substituted purine monophos-
phates are synergistic with respect to their inhibition of
PRPP amidotransferase. Purine nucleotide end-product
inhibition of PRPP amidotransferase is overcome by ele-
vated concentrations of PRPP. Adenosine monosphos-
phate (AMP) also inhibits the conversion of inosinic acid
(IMP) to adenosine monophosphate (AMP)
Accelerated Nucleotide Degradation 83

Amp deaminase

NH2 OH

N N
N AMP deaminase N
CH CH
N
N N N

P-R P-R

Adenosine monophosphate GTP and Pi Inosine monophosphate

Fig. 4.9 A single patient with gout has been character-
ized with an alteration in the liver enzyme, adenosine
monophosphate (AMP) deaminase, leading to an acceler-
ation in nucleotide degradation and an increased produc-
tion of uric acid. AMP deaminase in this patient was
shown to be insensitive to guanosine triphosphate (GTP)
inhibition. This permits the breakdown of AMP to IMP
and then the further catabolism of IMP to uric acid (see
Fig. 4.5). In the normal state, AMP deaminase activity is
95 % inhibited by GTP

urate overproduction. However, in some studies, Accelerated Nucleotide Degradation

no correlation has been found between the amount
of skin involvement and serum uric acid concen-
trations [54–56], and some patients do not mani-
fest hyperuricemia. Hyperuricosuria has been
documented in many patients with psoriasis, and
clinical gout has been reported albeit rarely in
this disorder.
Finally, accelerated ATP degradation has been
documented after strenuous muscular exercise
[57–59]. Strenuous exercise in healthy normal
individuals leads to a depletion in muscle ATP
levels by almost one-half and results in a three-
fold elevation of plasma and urinary oxypurines
[57]. The mechanism by which this occurs is
through the rapid consumption of ATP during
muscle contractions which surpasses the capacity
to regenerate ATP due to the limited supply of
oxygen and glucose as well as the decreased fatty
acid oxidation necessary for its regeneration. The
latter metabolic setting leads to the conversion of
adenosine diphosphate (ADP) to adenosine
monophosphate (AMP) and then to adenosine,
inosine, hypoxanthine, xanthine, and uric acid
(Fig. 4.6). Although dehydration and hyperlacti-
cacidemia may contribute to the retention of urate
and an increase in the serum uric acid concentra-
tion, the primary mechanism for these changes in
urate metabolism during muscular exercise is
ATP degradation.
Accelerated nucleotide degradation, the other
proposed mechanism to account for enzyme
abnormalities in primary gout, has only been
identified in one patient with gout. Altered deam-
ination of adenosine monophosphate has been
described in a liver specimen obtained from a
male patient with familial gout. The activity of
adenosine monophosphate deaminase (AMPD1)
assayed in high speed supernatants of human
liver documented that enzyme activity was com-
pletely inhibited at 0.5 mmol/l GTP in healthy
adults, whereas a residual activity of 28 ± 2 %
(mean ± SEM of three determinations) was deter-
mined in the gouty liver specimen. This led the
authors to postulate that a reduction in the sensi-
tivity of AMP deaminase to GTP was the basis
for increased nucleotide degradation and gout
[60] (Fig. 4.9). The hypothesis formulated from
this single patient is that the increased deamina-
tion of adenosine monophosphate would provide
greater quantities of inosinic acid for conversion
to inosine, hypoxanthine, xanthine, and uric acid.
Recent publications have described additional
parameters of this enzyme that may be pertinent
to this single report of gout and AMP deaminase
deficiency. A patient with myoadenylate deami-
nase deficiency and exertional myalgias, elevated
creatine kinase, as well as elevated blood lactate
84 4 Uric Acid Metabolism in Humans

levels after ischemic forearm exercise has been Renal handling of uric acid
reported [61]. Is it possible that such patients
might present with hyperuricemia and possibly
gout on the basis of their exertional myalgias and
alterations in uric acid metabolism? Other studies
have shown that AMPD1 mRNA with exon 2
deleted encodes a functional AMPD1 peptide
[62]. This deletion is the result of alternative
splicing, and such alterations modulate the resid-
ual activity of AMPD1 in individuals with mutant 100 %
glomerular
alleles of this enzyme [63]. This is the only case filtration
of abnormal AMP deaminase reported in gout,
and it remains to be seen whether additional cases
will be shown to have this defect. The rescuing
process through alternative splicing may account
for the rarity of the expression of mutations and 98−100 %
clinical findings. reabsorption

Excessive Purine Intake

Certainly, dietary intake of excessive quantities

50 %
of nucleoproteins that can be converted to uric secretion
acid may contribute to an increased pool of uric
acid and hyperuricemia, but it is unlikely that
dietary indiscretions will be the sole factor caus-
ing hyperuricemia.

40−44 %
Elimination of Uric Acid reabsorption

The disposal of uric acid in the human occurs pri-

marily via the kidney and gastrointestinal tract;
minor extrarenal disposal routes also contribute
to the elimination of uric acid such as the saliva,
tears, and perspiration. The renal elimination of
uric acid in the human has been determined to
occur by a four-component system that includes
glomerular filtration, proximal tubular reabsorp-
tion, tubular secretion, and postsecretory reab-
sorption (Fig. 4.10). Of the uric acid presented to
the renal glomerulus, nearly 100 % is filtered,
and of that amount, about 98–100 % is reab-
sorbed by the proximal tubules. Subsequently, at
different segments of the proximal tubule, urate
is secreted [64]. The product of the plasma urate
concentration and the glomerular filtration rate is
a reasonable estimate of the filtered load of urate.
8−10 %
secretion
Fig. 4.10 The most significant components of the renal
handling of uric acid are located in the proximal tubules of
the kidney. Urine is completely filtered at the glomerulus and
almost completely reabsorbed in the proximal tubules. About
50 % of the reabsorbed urate is then secreted and a large frac-
tion (40–44 %) of the secreted urate is subjected to postsecre-
tory reabsorption. Thus, only 6–12 % of the filtered load of
urate is excreted in the urine. In the normal adult host on a
regular diet, this amounts to 600–800 mg of uric acid per day.
As noted in the text, excretion of quantities of uric acid above
this level usually are classified as overexcretors and may
often represent patients with abnormal purine metabolism
Renal Mechanisms of Hyperuricemia and Gout
The actual mechanisms of urate reabsorption and
secretion remain incompletely resolved in the
human, and their contribution to the urinary uric
acid excretion has yet to be accurately measured
in humans. A number of small molecules such as
b-hydroxybutyrate, lactate, acetoacetate, salicy-
late, and branched chain amino acids inhibit uri-
nary uric acid [65–68], and these alterations in
excretion have been documented to inhibit tubu-
lar secretion [68, 69]. These tubular mechanisms
play a significant role in the alterations in serum
uric acid observed in certain diseases in which
these small molecules are key metabolites. Thus,
renal mechanisms unrelated to gout may cause
hyperuricemia in certain patients and can result
in false conclusions regarding the gouty diathe-
sis. On the basis of many different studies
designed to examine the handling of urate by the
human kidney, the prevailing evidence that best
fits what is known to occur is almost complete
glomerular filtration of uric acid, almost complete
proximal tubular reabsorption with subsequent,
and perhaps overlapping, tubular secretion and
then postsecretory reabsorption.
Renal Mechanisms of Hyperuricemia
and Gout
The key abnormality observed in gouty subjects
who are not overproducers of uric acid is the
requirement of a higher plasma level of urate to
achieve a given clearance of urate when com-
pared to normal subjects. When urate excretion is
plotted as a function of different plasma urate
levels shows, the S-shaped curve representing the
data for gouty subjects is shifted to the right as
compared to the curve for normal subjects
(Fig. 4.11). These linear expressions of substrate-
velocity in normal and gouty subjects show that
gouty patients require serum urate values approx-
imately 1.7 mg/dl higher than normal subjects to
achieve the same uric acid excretion rates. These
values for gouty subjects are not the result of
prolonged hyperuricemia since patients with leu-
kemia and hyperuricemia have urate excretion
rates comparable to normal subjects or, in fact,
may have increased rates. Since this abnormal
85
9
8
7
6
UUR V (mg/min.)
5
4
3
2
1
0
4 6 8 10 12 14 16 18 20
Plasma uric acid (mg/100 ml)
Fig. 4.11 The data in the graph were collected from the
following published studies: Nugent and Tyler [70];
Seegmiller et al. [71]; Yu et al. [72]; Latham and Rodnan
[73]. The open symbols represent data from normal sub-
jects and the solid symbols from gouty subjects. Plasma
urate levels were either normal values under basal condi-
tions, after RNA feeding, or after infusions of lithium
urate. Data from Latham and Rodnan are represented by
squares, those from Yu are circles, those from Seegmiller
are inverted triangles, and those from Nugent are upright
triangles
substrate-velocity curve is postulated to be the
deficit in most patients with primary gout, the
fundamental question is what the underlying
cause for this abnormality in the handling of uric
acid by the kidney is. Several possibilities have
been proposed to account for this abnormality
including decreased glomerular filtration,
enhanced renal tubular reabsorption, and
decreased tubular secretion. Data are not avail-
able to confirm any of these possibilities.
Although some have suggested that increased
binding of urate is the cause for this renal defect
[74], there is little evidence to support this
hypothesis. On the basis of faulty assumptions
with regard to the pyrazinamide suppression test
which is now known to underestimate tubular
urate secretion [75–77], it was originally thought
that decreased tubular secretion accounted for the
cause of primary underexcretion of urate. Once it
was determined that postsecretory reabsorption
86
occurred in the human, it was suggested that
enhanced reabsorption of urate was the explana-
tion of the hyperuricemia and urate underexcre-
tion; however, little direct evidence for this
mechanism is available. More recent studies pro-
vide indirect evidence that decreased tubular
secretion is more likely to account for urate under-
excretion in gouty subjects. Such studies have
found that urate secretory rates in gouty subjects
who underexcrete uric acid are similar to those of
control subjects when plasma urate concentra-
tions are decreased [78]. Subsequently, it has been
shown that gouty underexcretors have a decreased
uricosuric response to probenecid and that the
tubular secretion of uric acid is not influenced by
plasma urate concentrations [79, 80]. These data
provide indirect evidence that a defect in urate
renal tubular secretion is responsible for the
underexcretion of urate in gouty subjects.
In addition to this renal disposal defect dis-
cussed previously in primary gout, there are
a number of other mechanisms that result in
decreased urate excretion and could contribute to
the defect in primary gout and to secondary hype-
ruricemia and perhaps secondary gout. These
include the following: (1) decreased glomerular
filtration rate, (2) increased tubular reabsorption,
(3) decreased tubular secretion, and (4) several
unknown mechanisms. In primary gout, although
altered protein binding of urate has been proposed
as a mechanism of renal-associated hyperurice-
mia and could result in a decreased urate filtration
in the face of a normal glomerular filtration rate,
there is little evidence to support abnormalities
in urate binding proteins as a cause for hyperu-
ricemia and gout in man. Reinterpretation of the
pyrazinamide suppression test which originally
did not include any allowance for postsecretory
urate reabsorption has suggested that enhanced
tubular reabsorption of urate could be the expla-
nation for the hyperuricemia in gouty underex-
cretors [75, 77, 81]. More recent evidence has
suggested that the site of the defect in the renal
excretion of urate in primary gout is a reduc-
tion in the renal tubular secretion of urate [75,
78]. This concept has been fostered by evidence
showing that plasma urate reduction resulted in
normalization of urate secretory rates to levels of
4 Uric Acid Metabolism in Humans
control subjects [78]. The published data show-
ing that when serum urate levels are decreased,
the underexcretion of urate returns to normal
excretion rates have been interpreted as support
for the concept of a defect in tubular secretion of
uric acid [82]. Other studies have utilized pyrazi-
namide to analyze postsecretory absorption along
with probenecid to measure secretory rates since
it inhibits postsecretory reabsorption. These stud-
ies documented a decreased uricosuric response
in gouty underexcretors [79, 80]. The tubular
urate secretory rate was unaffected by serum
urate levels. Despite all these studies, direct evi-
dence for a defect in renal tubular reabsorption or
secretion of urate in the human remains elusive.
Renal Mechanisms of Hyperuricemia
and Secondary Gout
For the most part, mechanisms leading to second-
ary hyperuricemia do not lead to gouty arthritis.
Exceptions to this generalization include some
cases of diuretic-induced enhanced reabsorption,
perhaps some cases of salicylate-induced decre-
ments in tubular secretion, and gout associated
with lead intoxication in which the renal mecha-
nism remains incompletely understood. There
are four mechanisms that account for secondary
hyperuricemia in association with decreased
urate excretion: (1) decreased glomerular
filtration rate, (2) increased tubular reabsorption
of urate, (3) decreased tubular secretion of urate,
and (4) unknown mechanisms of decreased renal
excretion of urate.
One of the most common causes of hyperuri-
cemia is observed in patients with chronic renal
disease and a decreased population of fully func-
tional nephrons. In order for the failing kidney to
maintain homeostasis with respect to uric acid
levels in the plasma, the urate excretion is aug-
mented for the reduced number of nephrons indi-
cating that glomerular filtration as well as urate
tubular reabsorptive and secretory rates is main-
tained until advanced renal disease supervenes.
At that stage, the declining glomerular filtration
rate gives way to a glomerulotubular imbalance
and hyperuricemia results [83]. For this reason
References
alone, it is imperative that serum uric acid mea-
surements be accompanied by simultaneous mea-
surements of blood urea nitrogen and serum
creatinine. In this way, the hyperuricemia associ-
ated with renal failure is indentified promptly,
and inappropriate treatment of the hyperuricemia
associated with renal failure is avoided. The
hyperuricemia of renal failure is probably the
most common cause of secondary hyperuricemia,
and this mechanism results from a decrement in
the glomerular filtration rate. Chronic renal fail-
ure is an exceedingly unusual cause for second-
ary gout.
Diuretic-induced hyperuricemia is probably
almost as common a cause of hyperuricemia as
renal failure and frequently is a common clinical
setting in which acute gout supervenes especially
in the aged female population. The primary mech-
anism for diuretic-induced hyperuricemia is the
contraction of the extracellular volume as a result
of the loss of water and salts causing an increased
reabsorption of urate as well as a decreased glom-
erular filtration rate [84–87]. Conditions other
than diuretic therapy can also result in hyperu-
ricemia by this same mechanism including dia-
betes insipidus and dehydration. Furosemide, a
loop diuretic, also causes lacticacidemia which
inhibits urate tubular secretion, and therefore,
two mechanisms are operative with this drug.
Thus, increased renal tubular reabsorption of
urate is the cause for the hyperuricemia observed
in clinical settings in which there is contraction
of the extracellular fluid compartment.
As noted previously, a number of organic
acids are secreted by the same mechanism as
urate and may competitively inhibit uric acid
secretion. The most well-defined organic acids
including acetoacetate, lactate, b-hydroxybu-
tyrate, branched chain keto acids, and low-dose
salicylate all cause hyperuricemia, and the mech-
anism is hypothesized to be the inhibition of
tubular secretion [65, 66, 88].
A number of other pharmacologic agents
including pyrazinamide, cyclosporin A, theo-
phylline, warfarin, catecholamines, b-adrenergic
blockers, methoxyflurane, levodopa, nicotinic
acid, and some nonsteroidal anti-inflammatory
drugs [89–98] also alter the renal clearance of
87
uric acid, but the exact mechanism by which
these agents alter this function remains incom-
pletely understood. Nonetheless, with the excep-
tion of several of the drugs cited, the alterations
in renal urate clearance caused by these agents
are of little clinical significance.
Lead is a heavy metal that has been shown to
cause “saturnine gout,” and intoxication with lead
leads to impaired urate excretion [99, 100], but
here again, the mechanism by which this occurs
is poorly understood. Of clinical significance
with respect to this chemical, secondary gout is a
complication of the hyperuricemia resulting from
chronic lead intoxication. For this reason, envi-
ronmental and occupational sources of lead expo-
sure are important to identify in the patient with
gouty arthritis.
In summary, an understanding of uric acid
metabolism provides the clinician with the ratio-
nale for comprehending the biochemical and
physiological basis of hyperuricemia and gout.
The vast majority of gouty patients seen by cli-
nicians are likely to have defective renal secre-
tion of urate as the underlying cause for their
gout, and a small percentage of such patients
will manifest an underlying biochemical error in
purine metabolism that will account for their
clinical presentation. The latter group of patients
requires a detailed genetic history, a careful
investigation of their uric acid metabolism to
identify the underlying cause, and treatment to
prevent complications of the overproduction of
urate.
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Ramos T, Vazquez OJ. Renal handling of uric acid in
normal subjects by means of the pyrazinamide and
probenecid tests. Nephron. 1983;35:183.
80. Levinson DJ, Sorenson LB. Renal handling of uric
acid in gouty and normal subjects: evidence for a
4-component system. Ann Rheum Dis. 1980;39:173.
81. Ross GR, Seegmiller JE. Hyperuricemia and gout.
N Engl J Med. 1979;300:1459.
82. Steele TH, Rieselbach RE. The contribution of resid-
ual nephrons within the chronically diseased kidney to
urate homeostasis in man. Am J Med. 1967;43:876.
83. Feinstein EI, Quion VH, Kaptein EM, Massry SG.
Severe hyperuricemia in patients with volume deple-
tion. Am J Nephrol. 1984;4:77.
84. Steele TH. Evidence for altered renal urate reabsorp-
tion during changes in volume of the extracellular
fluid. J Lab Clin Med. 1969;74:228.
85. Suki WN, Eknoyan G, Martinez-Maldonado M.
Tubular sites and mechanisms action of diuretics.
Annu Rev Pharmacol. 1973;13:91.
86. Steele TH, Oppenheimer S. Factors affecting urate
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Am J Med. 1969;47:564.
87. Goldfinger S, Klinenberg JR, Seegmiller JE. Renal
retention of uric acid induced by infusion of beta-hy-
droxybutyrate and acetoacetate. N Engl J Med.
1965;272:351.
4 Uric Acid Metabolism in Humans
88. Menon RK, Mikhailidis DP, Bell JL, Kernoff PB,
Daddona P. Warfarin administration increases uric
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1986;32:1557.
89. Sugino H, Kagoshima M, Katagiri S. Effects of some
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90. Palestine AG, Nussenblatt RB, Chan CC. Side effects
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95. Becker MA, Raivio KO, Meyer LJ, Seegmiller JE.
The effects of nicotinic acid on human purine metab-
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 Clinical Aspects of Gout
and Associated Disease States
Introduction
Deposition of a variety of microcrystals including
monosodium urate in the synovium and other soft
tissues causes acute and chronic arthritis. The
most common clinical disorders associated with
microcrystalline synovitis are gout and pseudog-
out. The latter two disorders may occur as sepa-
rate entities or may coexist. The definitive
diagnosis of gout depends on the identification of
specific microcrystals in synovial fluid aspirates
or tissue deposits (tophi).
Gout is the primary clinical expression of
many different underlying dysfunctions, and a
discussion of its clinical presentation should
address both the classical articular disease as well
as the heritable and acquired causes that predis-
pose individuals to gouty arthritis. Heritable and
acquired disorders that predispose an individual
to gout often have additional clinical findings that
assist the clinician in the identification of an
underlying cause for the gouty arthritis.
Primary gout is most often a disease of adult
males and includes those individuals who have as
their principal deficit an abnormality in purine
metabolism. Secondary gout occurs as a result of
an underlying disorder that leads to an alteration
in uric acid metabolism and is often associated
with drug administration (diuretics, cyclosporine)
or with disorders of increased nucleic acid turnover
(myeloproliferative diseases, multiple myeloma)
and affects both sexes. Those patients with pri-
mary gout resulting from heritable disorders, even
though they represent only a small percentage of
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_5, © Springer-Verlag London 2013
5
gouty patients, are important to recognize early
since the initiation of treatment may impede
not only the progression of the disease itself
but also some of its complications. Patients
with hyperuricemia and gout can be classified
into two broad groups: those with increased
purine biosynthesis or urate production and
those with decreased renal clearance of urate.
The key target organs affected by gout include
not only the skeletal system and soft tissues but
also the kidney. Although the terms primary
and secondary gout are often used to classify
gout, the recent literature has increased the
complexity of using these terms as a means of
classifying gout. It may be more reasonable to
classify and discuss gout in terms of the over-
production and underexcretion of uric acid
realizing that these two groupings may include
both primary or innate forms of gout as well as
secondary forms of gout.
Clinical Gout
Clinical gout in the human may include any one
or more of the following characteristics: ele-
vated serum uric acid concentrations; episodes
of an acute, painful mono-, oligo-, or polyar-
thritis; monosodium urate monohydrate crystals
observable in synovial fluid aspirates; soft tis-
sue deposits of monosodium urate monohydrate
(tophi) primarily, but not solely, in the vicinity of
joints; chronic arthritis with deformities mimick-
ing rheumatoid arthritis; kidney disease related
91
92 5 Clinical Aspects of Gout and Associated Disease States

to the deposition of urates or defective tubular

transport; and uric acid nephrolithiasis. Gout can
be separated into three principal stages: acute
gouty arthritis, intercritical gout, and chronic
tophaceous gout. Each of these clinical states
has typical presentations and treatment consider-
ations. Acute gouty arthritis has an abrupt onset
and manifests itself as an exquisitely painful joint
usually confined to the lower extremity. The joint
pain and inflammation typically progress rapidly,
and the patient may be crippled by an acute, pain-
ful arthritis within 4–6 h after the onset of joint
symptoms. As has been often said, the patient
may retire at night in perfect health only to be
awakened with an increasingly painful joint.
Classical gout is a distal monoarticular or oli-
goarticular arthritis often involving the first meta-
tarsophalangeal joint of the big toe (podagra).
This particular joint is involved in 90 % of patients
at some time during the life of their disease. In
addition to the great toe, the arthritis may involve
the instep, ankle, wrist, elbow, fingers, or knee.
Acute and chronic tophaceous gout rarely occurs
in other synovial joints but has been reported to
involve the hips, shoulders, sternoclavicular
joints, and sacroiliac and spinal joints [1–7].
Although involvement of the spine is usually
related to chronic tophaceous gout and is rarely a
component of acute gouty arthritis, back pain
may occur as a feature of gout and can present
infrequently as an acute process. Typically, acute
gout involves one joint but may involve as many
as three (oligoarticular) or more than seven (pol-
yarticular) joints. Only 10–15 % of affected indi-
viduals have polyarticular gout, and this form of Fig. 5.1 Acute gouty arthritis in the first metatarsopha-
gout has a predilection for postmenopausal langeal joint, a podagra. Also acute gout in the ankle joint.
females. It is also not unusual for acute gout to Gout may involve more than one joint simultaneously
involve a bursa with or without accompanying
joint involvement, and the olecranon bursa is the the presence of severe joint pain and fever may
most typical site affected (Figs. 5.1 and 5.2). suggest the presence of a septic joint. In fact, sep-
Joints affected by acute gout are extremely tic joints have been reported to occur in the pres-
painful (too painful to touch), swollen, hot to ence of an acute gouty episode. The pain in acute
palpation, and are red-blue in color at the peak gout is often so severe that the patient will not
of their inflammatory response. Fever and bear weight on the involved part and will even
chills may accompany the inflamed joints. The avoid the weight of bedclothes or a stocking over
inflammation often extends above and below the an involved joint. The skin over affected joints is
involved joint suggesting a cellulitis-like or tense, shiny, and dry. If the acute arthritis goes
superficial thrombophlebitis-like lesion. Further, untreated, the inflammatory response resolves in
Introduction
Fig. 5.2 Patient with long-standing chronic tophaceous gout. Urate-lowering therapy was unavailable because of renal
disease and an allergy to allopurinol, before febuxostat and pegloticase were available
Table 5.1 Common factors documented to precipitate
acute gout
Purine-rich diet
Rapid weight loss (ketosis)
Alcohol
Micro- or macrotrauma
Acute infections
Post-arthroscopy, cystoscopy, or gastroscopic studies
Myocardial infarction
Hemodialysis
Diuretic therapy
Intravenous nitroglycerin
Antihyperuricemic treatment without colchicine
Cyclosporine treatment
Postsurgery
3–12 days. As the redness and pain subside, there
is superficial desquamation of the overlying skin.
The patient is soon left with no residual symp-
toms or signs of the acute arthritis.
A number of events may serve to precipitate
acute episodes of gout (Table 5.1). Several gen-
eral rules can be drawn from these precipitating
factors. As a rule, it is best to accompany urate-
lowering drug therapy with low-dose colchicine
to prevent precipitating an acute attack of gout
during the time that the serum urate-lowering
drug is decreasing the urate pool. It may also be
93
reasonable to start urate-lowering drugs at a lower
dose and proceed gradually over days to the fully
recommended dose. If patients give a history of
specific foods as precipitating factors, then they
should be avoided or maintenance colchicine
used if such foods are eaten. Prophylactic colchi-
cine therapy should be used in gouty patients if
they are to undergo any surgical procedure. In the
postsurgical patient with suspected gouty arthri-
tis, arthrocentesis must be undertaken to exclude
infection.
Intercritical Gout
During an acute episode of gout, the clinical pic-
ture and synovial fluid analysis should lead to the
appropriate diagnosis, but in the asymptomatic
intercritical phase of gout, a clinical diagnosis
must be based, for the most part, on history alone.
Such a paucity of clinical signs and a poor histo-
rian may lead to an erroneous diagnosis [8, 9].
Recent studies have shown that arthrocentesis of
asymptomatic knees or first metatarsophalangeal
joints accompanied by synovial fluid analysis of
the aspirate using polarized light microscopy
with a first-order red compensator identified
monosodium urate (MSU) crystals in patients
94 5 Clinical Aspects of Gout and Associated Disease States

with asymptomatic gout who were not being

treated with hypouricemic agents [10]. Negatively
birefringent MSU crystals are usually not
observed in gouty patients receiving hypourice-
mic agents or who have low serum uric acid lev-
els. Crystals have also been demonstrated in
patients with gout in joints that have never been
the site of inflammation. Such crystals have also
been reported in joints of patients with hyperuri-
cemia and renal failure [11–13]. Several points
can be made regarding these studies. First, the
mean cell count in MSU crystal-containing syn-
ovial fluids (449 cells/mm3) is often significantly
higher than those synovial fluids without crystals
(64 cells/mm3), and those with crystals contain
more polymorphonuclear leukocytes than those
without crystals. Thus, low-grade inflammation
exists during the intercritical phase of the disease
in the joints that contain crystals. Second, sequen-
tial arthrocentesis showed that once hypourice-
mic drug therapy is initiated to reduce the serum
Fig. 5.3 Radiograph of patient in Fig. 5.1, earlier in her
uric acid levels, it takes months before the joint course. Note tophi in the soft tissues of the index and mid-
crystals disappear. Finally, in the two patients fingers
studied with hyperuricemia, renal failure, and
MSU crystals in their joints, the underlying kid- more severely than the joints of the feet. The dis-
ney disease was not defined, but the types of renal tribution of the joint involvement is asymmetric
disease investigated are of interest. One patient and often affects the big toe, olecranon bursa,
had sarcoidosis, two patients had polycystic kid- prepatellar bursa, or finger joints. On rudimentary
ney disease, one had glomerulonephritis, and in examination, severe tophaceous gout of the hands
five, no etiology could be determined. It would may resemble chronic rheumatoid arthritis.
be of some significance if the five patients with Grossly altered joints often have red shiny skin
MSU crystals had either polycystic kidney dis- over the involved joints, and areas of small whit-
ease or were young individuals with familial ish-yellow subcutaneous tissue deposits of urate
juvenile gouty nephropathy. Follow-up studies of may often be observed, especially if the joints are
patients with intrasynovial MSU crystals and no flexed. In some instances, large urate deposits
history of gout would help determine whether the drain white chalky material that is often mistaken
presence of crystals is a predictor of subsequent for a draining abscess. These draining tophi are
gout. seen most frequently at sites such as the olecra-
non bursa or big toe (Figs. 5.3, 5.4, and 5.5).
Accompanying these bone and joint changes,
Chronic (Tophaceous) Gouty Arthritis one may also see extra-articular urate deposits.
These extra-articular tophi often involve bursae
Chronic gouty arthritis occurs primarily in (especially the olecranon and prepatellar bursae),
patients who have deposits of urate in the bones ear cartilage, and tendons and soft tissue adjacent
adjacent to joints that cause a destructive arthrop- to joints. Tophaceous deposits in certain anatomi-
athy and secondary degenerative arthritis. Distal cal sites may also cause other rheumatic condi-
joints are the principal targets of the disease with tions. Deposits of urate in the wrist have caused
the proximal and distal finger joints often affected carpal tunnel syndrome, and deposits in the hip
Introduction
have lead to avascular necrosis of the femoral
head. Tophi may also be confused with rheuma-
toid nodules, especially when they are found on
the extensor surfaces of the forearm. Often, the
gouty tophus is grittier to palpation than the rheu-
matoid nodule; however, the presence of morning
stiffness and rheumatoid-like deformities of the
hands may require sterile aspiration, if feasible,
of a superficial whitish plaque to demonstrate
urate crystals by polarizing microscopy. Tophi
have been reported in visceral tissues as well
including the larynx, heart, and bronchi; deposi-
tions in disc spaces may cause paraplegia and
other neurological deficits [1–7]. It is important
to recognize that such visceral deposits of urate
may occur without any sign of peripheral tophi.
Tophi may also be present in Heberden’s nodes
Fig. 5.4 Radiograph of patient in Fig. 5.1, after 3 years
of untreated gout
Fig. 5.5 Draining tophus in
the olecranon bursa
95
and finger pads making the diagnosis somewhat
confusing [14].
Chronic gouty arthritis has a more rheuma-
toid-like presentation since the acute inflammatory
and severely painful monoarticular attacks of
acute gouty arthritis are replaced by morning
stiffness in the affected joints, swelling, and
deformity of multiple joints as well as polyarticu-
lar pain. Although this picture may mimic rheu-
matoid arthritis, these two disorders are rarely
seen together. Thus, the monoarticular presenta-
tion with severe inflammation of acute gout pro-
gresses over time to a polyarticular condition
with subacute inflammation (Figs. 5.1 and 5.6).
Organ transplantation and posttransplant ther-
apies to avoid organ rejection have been associ-
ated in their recipients with a marked increase in
hyperuricemia and tophaceous gout. The two
drugs most frequently associated with the induc-
tion of gout in these patients are diuretics and
cyclosporine. Diuretics reduce extracellular fluid
volume, which results in hyperuricemia, whereas
cyclosporine impairs the renal tubular secretion
of urate [15, 16]. Transplant gout represents a
specific clinical subset of tophaceous gout for the
following reasons. The use of cyclosporine and,
at times, diuretics has resulted in the occurrence
of gout as one of the most common complica-
tions of transplantation. Cyclosporine therapy
results in the rapid production of tophaceous gout
and is also associated with the deposition of urate
in unusual locations such as intramuscularly [17,
18]. Perhaps the most difficult problem is the
96
Fig. 5.6 Another patient similar to patient in Fig. 5.1, after many years of untreated gout, leading to chronic pain and
severe joint destruction. Acute gout in a large tophus as well
treatment of tophaceous gout in transplant recipi-
ents. Allopurinol, the best drug for the treatment
of tophaceous gout, causes the accumulation of
6-mercaptopurine, a drug often used to avoid
organ rejection. Such 6-mercaptopurine retention
may lead to myelosuppression and its complica-
tions [19]. Any reduction of 6-mercaptopurine
dosage to accommodate allopurinol therapy risks
the rejection of the graft. In addition to these drug
interactions, the use of colchicine to prevent
recurrent gouty episodes in transplant patients
often appears to precipitate colchicine myopathy,
especially when the drug is administered along
with cyclosporine [20–22]. Recent studies of the
uricosuric drug, benzbromarone, may provide the
means of treating transplant gout effectively and
without significant side effects [15, 23]. At the
time of this writing, this drug is not generally
available in the United States.
Differential Diagnosis
A variety of acute monoarticular and polyarticu-
lar inflammatory joint disorders may mimic acute
gout, but by in large, the most frequent arthritides
5 Clinical Aspects of Gout and Associated Disease States
that should be excluded from consideration are
bacterial arthritis (septic arthritis), calcium pyro-
phosphate crystal deposition disease (pseudog-
out), traumatic arthritis, or severe degenerative
arthritis. Chronic tophaceous gout is mistaken for
chronic rheumatoid-like arthritis, and often drain-
ing tophi, especially of the great toe, are treated
as draining abscesses. Both septic arthritis and
pseudogout may occasionally be accompanied by
acute gouty arthritis, and examination of the arth-
rocentesis specimen may reveal uric acid crystals
along with either bacteria or calcium pyrophos-
phate crystals. Thus, synovial fluid aspirates from
joints where infection or pseudogout are sus-
pected as the underlying process should be care-
fully examined with polarization microscopy for
negatively birefringent uric acid crystals.
Predisposing factors should be evaluated when
septic arthritis is considered in the differential
diagnosis. These include patients in the older age
group; joints damaged by arthritis, especially
rheumatoid arthritis; the presence of a prosthetic
joint; intravenous drug abuse; corticosteroid treat-
ment; and the immunocompromised host. In addi-
tion, patients with diabetes mellitus, Charcot’s
arthropathy, cancer, hemarthroses, and chronic
Differential Diagnosis
liver disease may also be at increased risk for sep-
tic arthritis. As is well known, patients with an
indwelling venous catheter or those undergoing
chronic hemodialysis are also at increased risk for
infection including septic arthritis.
The key to the diagnosis of bacterial arthritis
is the aspiration of the affected joint and a careful
analysis of the aspirate. Except for the culture
and Gram stain, the results of the synovial fluid
analysis often are similar, if not identical, to
those observed in both pseudogout and gout. The
synovial fluid white blood cell count is usually
above 50,000/mm3 with a predominance of poly-
morphonuclear leukocytes (neutrophils). Cell
counts of 100,000/mm3 or greater must be
assumed to be septic until proven otherwise.
Synovial fluid glucose levels are reduced, but
they are only valid if a matching serum sample is
drawn, and the aspiration of the joint is done 2 h
after a meal. Low levels of synovial fluid glucose
are related to glucose consumption by synovial
fluid cells, but similar levels are observed in
rheumatoid arthritis and crystal-induced arthri-
tis. None of these findings are diagnostic of
infection. Lactic acid in the synovial fluid may
also be elevated but is often normal in Gram-
negative infections. The Gram stain and synovial
fluid culture hold the key to the diagnosis of sep-
tic joints. For the most reliable results, the aspi-
rate should be immediately plated on blood agar,
chocolate agar, and in anaerobic culture media.
We prefer to do this at the bedside, but alterna-
tively, the aspirate may be deposited in blood
culture bottles at the bedside or can be taken to
the microbiology laboratory and plated on cul-
ture media immediately. Gram stains are produc-
tive of an organism about 50–70 % of the time.
Such stains will distinguish Gram-positive from
Gram-negative organisms but will not differenti-
ate staphylococci from streptococci. Blood cul-
tures should be done simultaneously with the
synovial fluid cultures, and if N. gonorrhoeae is
the suspected organism, cultures of the oral cav-
ity, skin lesions, penile discharge, and vaginal
cavity should be done as well. The presence of
crystals should not deter the clinician from con-
sidering infection as the primary cause for the
joint disease.
97
Almost 90 % of joint infections are caused
by Gram-positive organisms, whereas about
10–15 % are the result of Gram-negative infec-
tions. S. aureus, Streptococci, and Gram-negative
bacteria are the most common organisms
observed in septic joints. Gram-negative organ-
isms causing a septic arthritis include E. coli,
Pseudomonas aeruginosa, and Serratia marc-
escens. Staphylococci are the most common
organisms found in intravenous drug abusers,
but Gram-negative infections are also seen. Such
patients must be checked for HIV disease and
syphilis. Although both Gram-positive and Gram-
negative organisms occur in infected prosthetic
joints, low virulence S. epidermidis infections
are often encountered. Anaerobic organisms are
most frequently seen following trauma or bites.
Suspected joint infections require immediate
intravenous antibiotic therapy with revision of
the antibiotic regimen, if necessary, once specific
culture and sensitivity results are available.
Calcium pyrophosphate dihydrate (Ca2P2O7 ·
2H2O – CPPD) crystal deposition is a multifac-
eted disorder associated either with a heritable
condition, a metabolic disorder, joint trauma
including surgery, or no identifiable cause. Like
gout, CPPD crystal deposition disease presents
as a self-limiting inflammatory joint disorder. It
may often follow surgery and may follow a seri-
ous illness such as a stroke or myocardial infarc-
tion. The knee is the joint most often affected,
and the acute attack is similar in character to the
acute gouty episode except that it is often slightly
less painful. This disorder may be accompanied
by degenerative joint changes as determined by
clinical and radiographic examination. Flexion
contractions of the knee are common, and such
changes are unusual in gout. Patients may also
present with polyarticular involvement. In addi-
tion to knee involvement, wrists, metacarpopha-
langeal joints, hips, shoulders, ankles, and elbows
may also be affected. The disease may also have
other forms of presentation that mimic rheuma-
toid arthritis, osteoarthritis, and rarely ankylosing
spondylitis. Nonetheless, acute CPPD crystal
deposition disease, the mimicker of gout, has
been termed pseudogout for purposes of remind-
ing the examiner of its similarity to gout. The
98
most typical picture by X-ray is one of linear or
punctate calcification of the fibrocartilage of the
knee menisci, symphysis pubis, acetabular
labrum, triangular ligament of the wrist joint, and
rarely the annulus fibrosus of the spine. These
deposits have been termed chondrocalcinosis,
and they do not make the absolute diagnosis of
CPPD crystal deposition disease in the absence
of CPPD crystals observed in a synovial fluid
aspirate.
As with acute episodes of gout, CPPD crystal
deposition disease usually presents with a pain-
ful swollen joint associated with local warmth
and redness. It may also be polyarticular mim-
icking polyarticular gout. Peripheral blood leu-
kocytosis and fever may coexist with the acute
arthritis simulating an infected joint. If CPPD
crystal deposition disease becomes the definitive
diagnosis, then it is reasonable to exclude under-
lying diseases associated with CPPD crystals.
These disorders include hyperparathyroidism,
hemochromatosis, hypomagnesemia, and hypo-
phosphatasia. In patients where management of
these disorders could alter the prognosis, serum
calcium, serum parathormone, serum iron, serum
ferritin, alkaline phosphatase, and serum magne-
sium are measured to identify these underlying
diseases. Synovial fluid aspiration and wet syn-
ovial fluid preparations of the aspirate in CPPD
crystal deposition disease show variably sized
rhombic and/or needle-shaped crystals. Using a
polarized microscope with a red-plate compen-
sator, these CPPD crystals show weakly positive
birefringence. Identification of the latter crystals
together with an inflammatory joint or joints pro-
vides the diagnosis of CPPD crystal deposition
disease. In this setting, it is important to recognize
that CPPD crystals are observed in the face of an
infected joint, and the diagnosis and management
of the infection takes precedence over the treat-
ment of CPPD crystal deposition disease. CPPD
crystals disappear when wet preparations dry.
There are other clinical disorders that may be
associated with CPPD crystals and may infre-
quently mimic gout. Charcot joints secondary to
neuropathies associated with diabetes mellitus,
tabes dorsalis, syringomyelia, and other rarer neu-
rological disorders present with a swollen, warm,
5 Clinical Aspects of Gout and Associated Disease States
and erythematous joint. These acute neuropathic
joints usually involve nonweight-bearing joints
and may be painful despite the underlying neuro-
logical deficit. Chronic neuropathic arthropathies
may also mimic infectious processes and gout.
Over time affected joints present with large effu-
sions, are warm to the touch, but manifest little
or no redness. The tarsometatarsal and midfoot
are the most commonly affected joints in dia-
betics, whereas knees are usually the targets for
those with joint disease associated with tabes
dorsalis. Upper extremity joints are involved in
syringomyelia. Spontaneous fractures and infec-
tions often complicate neuropathic arthropathies.
Radiographic findings are not useful in making a
specific diagnosis. In acute neuropathic arthrop-
athies, soft tissue swelling and bone resorp-
tion are seen, whereas in chronic neuropathic
joints, the characteristic picture is one of severe
osteoarthritis. Synovial fluid analyses are usually
noninflammatory in nature with low white blood
cell counts and a normal differential count, but
joint fluids with findings similar to those in sep-
tic joints have been reported so infection must be
excluded. Trauma to such pain-free joints often
results in serosanguinous synovial fluids.
Traumatic arthritis is usually easy to diagnose
since there is a history of an acute injury. In cases
where there is an underlying fracture, the joint
may be painful and warm. Synovial fluid exami-
nation usually shows a normal total cell and dif-
ferential count, and no crystals are apparent on
careful analysis of a synovial fluid aspirate.
Cultures of the joint fluid are negative.
There are a number of additional acute arthri-
tides that may mimic a microcrystalline process
or a septic joint. These include Reiter’s syndrome,
psoriatic arthritis, acute rheumatic fever, and oth-
ers, but septic arthritis, pseudogout due to CPPD
crystals, and gouty arthritis remain as the major
diseases that need to be excluded when the joint
disease appears to be gout.
Chronic tophaceous gout should never be
diagnosed today, but surprisingly, patients with
deforming tophaceous gout of the hands may
infrequently present to physicians for care of
their deformity. In these cases, the hands usually
manifest deformities that may at first glance look
Diagnostic Criteria for Hyperuricemia and Gout
like the deformities seen in chronic rheumatoid
arthritis. However, flexing the joints easily dem-
onstrates the subcutaneous whitish to yellow uric
acid tophaceous deposits. Such deforming lesions
of the hands may also simulate psoriatic arthritis,
systemic lupus erythematosus, hemochromato-
sis, and multicentric reticulohistiocytosis. A sim-
ple, sterile aspiration of the whitish subcutaneous
lesions will demonstrate the uric acid crystal
when examined by polarized microscopy.
Another common misdiagnosis seen in
patients with chronic tophaceous gout is the treat-
ment of a draining tophaceous deposit as a septic
arthritis. This is a frequent occurrence in the
emergency room setting where a simple evalua-
tion of the discharge from the tophus would pro-
vide the true diagnosis. Of course, draining tophi
can become secondarily infected, but this is the
exception rather than the rule.
Diagnostic Criteria for Hyperuricemia
and Gout
The absolute criteria for the diagnosis of gout are
based on the documentation of uric acid crystals
in joint fluid with their characteristic strong nega-
tive birefringence using compensated polarized
light microscopy with a first-order red-plate com-
pensator. In this case, the needle-like uric acid
crystals are bright yellow when they are parallel
to the red compensator and blue when they are
perpendicular to it. A tophus aspirated under ster-
ile conditions may also reveal the characteristic
negatively birefringent uric acid crystals. Either
of these findings, uric acid crystals from the syn-
ovial fluid, or a tophus along with typical articu-
lar symptoms and signs provides an absolute
diagnosis of gout. Such crystals may be observed
to be present inside cells (intracellular) or outside
cells (extracellular). In patients with acute gouty
arthritis, synovial fluid aspirates show that the
major portion of crystals reside within cells.
There are other clinical, laboratory, and radio-
graphic findings that, if sufficient in number, may
permit the clinician to diagnose gout, but crystal
identification is still the preferable means by
which one can be certain of the diagnosis. These
99
12 additional criteria include: (1) monoarticular
arthritis, (2) peak inflammation of a joint within
24 h, (3) joint redness, (4) repetitive episodes of
acute arthritis, (5) asymmetric swelling of a joint,
(6) swelling and pain in the first metatarsopha-
langeal joint (podagra), (7) unilateral tarsal joint
inflammation, (8) suspected or proven tophus, (9)
elevated serum uric acid, (10) negative synovial
fluid culture during an acute episode of joint
inflammation, (11) asymmetrical joint swelling
in a single joint by X-ray, and (12) radiographic
demonstration of subcortical bone cysts without
erosion. If 6 of these 12 criteria are met or a
proven tophus has been found, then one can
strongly suspect that the joint disease is gout.
By definition hyperuricemia is present when
the solubility of uric acid in plasma is exceeded.
Age and sex have the most influence on the varia-
tions found in humans. If one evaluates the solu-
bility of uric acid in aqueous solutions with a
sodium ion concentration similar to plasma at a
temperature of 37 °C, these solutions are satu-
rated with uric acid at a concentration of 6.8 mg/
dl [24]. If one compares males and females in
large populations, uric acid concentrations at the
upper end of the reference range rise in both sexes
at puberty with values for females prior to meno-
pause about 1 mg/dl lower than the value for
males. In the postmenopausal female, uric acid
concentrations at the upper end of the reference
range increase approaching those of the male.
Thus, for adults, most investigators accept the
normal serum uric acid levels for males to be
7.0 mg/dl or less and for females, 6.0 mg/dl or
less. Values above this level in adults constitute
hyperuricemia. In children, the normal ranges for
serum uric acid vary with age, and these values
have been reviewed (see Reference 332 for a
complete listing of the publications dealing with
this subject). Reference ranges for uric acid con-
centrations should be obtained by the clinician
from the servicing laboratory, and the number of
observations required in defining these references
ranges should be large, age and sex specific, and
based on a specific method of measurement.
Since hyperuricemia may represent either a tran-
sient abnormality or a laboratory error, more than
a single uric acid measurement should be obtained
100
Table 5.2 Common causes of asymptomatic
hyperuricemia
Azotemia 20 %
Acidosis 20 %
Diuretics 20 %
Hypertension/obesity 18 %
Gout 12 %
Other conditions 10 %
before more expensive evaluations are under-
taken to identify the cause of this biochemical
abnormality.
In the absence of gouty arthritis, uric acid
tophi, urolithiasis, or urate nephropathy, elevated
serum uric acid levels are classified as asymp-
tomatic hyperuricemia. To determine whether or
not such a laboratory abnormality is secondary to
an underlying disease or the use of drugs affect-
ing urate metabolism, knowledge of those dis-
eases and drugs associated with changes in the
serum uric acid is essential. Common causes of
asymptomatic hyperuricemia have been delin-
eated, as have those conditions associated with
acute and chronic illnesses (Tables 5.1 and 5.2).
Careful evaluation of patients with persistent
hyperuricemia is necessary to exclude the pres-
ence of underlying disease and to determine fac-
tors such as urinary urate excretion that would
influence decisions to treat asymptomatic hype-
ruricemia. A family history of gout or renal cal-
culi is often helpful. Of course, the variations in
serum uric acid levels with age, sex, and race must
be considered before concluding that asymptom-
atic hyperuricemia exists. Hyperuricemia has
been documented in between 2 and 18 % of adult
populations evaluated [25]. Certain simple labo-
ratory tests may further distinguish the causes of
persistent asymptomatic hyperuricemia. These
include measurements of serum creatinine, uri-
nary ketones (diabetes mellitus and starvation),
blood lactate levels, blood gases and pH (beryl-
liosis and glycogen storage disease), and fasting
blood lipid levels (hyperlipoproteinemia). When
a reasonable suspicion of lead exposure exists, the
determination of blood and urinary lead levels are
indicated (see section “Saturnine gout”). The per-
sistence of significant hyperuricemia (10–13 mg/
dl) mandates that 24-h urinary uric acid concen-
trations be determined and the underlying defect
5 Clinical Aspects of Gout and Associated Disease States
in uric acid metabolism characterized so that the
various causes can be segregated (overproduction
and underexcretion).
A brief review of certain factors related to
acute and chronic disease processes and hyperu-
ricemia such as dehydration, moderate degrees of
ketosis, or alcohol ingestion is presented here,
and more extensive discussions are given subse-
quently [26, 27]. Appropriate treatment of these
acute disorders may result in a reversal of an ele-
vated serum uric acid level to normal. The patho-
genesis of the hyperuricemia of acute disease is
variable. A combination of increased nucleic acid
turnover, a compensatory increase in purine
nucleotide synthesis, and an increased produc-
tion of metabolites of purine degradation account
for the hyperuricemic state of acute leukemia.
Articular complaints in patients with leukemia
are not always the result of hyperuricemia [28].
The hyperuricemia associated with diabetic
ketoacidosis, exercise, starvation, and toxemia of
pregnancy is, for the most part, related to the
inhibitory effects of small organic molecules
(lactate, beta-hydroxybutyrate, and acetoacetate)
on the renal excretion of urate. The cause of the
hyperuricemia observed with acute myocardial
infarction is a decreased excretion of urate [29].
Decreased renal perfusion is the primary factor
implicated in the hyperuricemia of myocardial
infarction, but hypoxia and increased production
of uric acid secondary to the breakdown of tissue
nucleotides may also contribute to the hyperuri-
cemia observed in association with insults to the
myocardium, vigorous exercise, grand mal sei-
zures, severe respiratory acidosis, and congestive
heart failure [30–40] (Table 5.3).
Ethanol consumption has long been associated
with an increased prevalence of hyperuricemia
and gout, and populations with a high incidence
of gout often have increased numbers of alco-
hol imbibers [41, 42]. Ethanol-induced hyperu-
ricemia results from two different mechanisms.
Early studies have clearly shown that ethanol
ingestion resulted in elevated blood lactate levels
which were proposed as the cause for hyperuri-
cemia since lactate competitively inhibits uric
acid clearance by the proximal renal tubule [43].
Subsequently, it has been shown that ethanol is
converted to acetate through oxidative pathways.
Diagnostic Criteria for Hyperuricemia and Gout
Table 5.3 Acute pathologic processes associated with
hyperuricemia
Acute leukemia
Acute myocardial infarction
Diabetic ketoacidosis
Ethanol intoxication
Exercise
Grand mal seizures
Heat stress nephropathy
Infectious hepatitis
Infectious mononucleosis
Severe respiratory distress
Starvation with ketosis
Toxemia of pregnancy
Acute renal failure
Ethanol-induced acetate is then metabolized to
acetylcoenzyme A using high-energy phosphates
derived from adenosine triphosphate. The lat-
ter molecules are then converted to adenosine
monophosphate in the process [44]. Precisely
two moles of ATP are used for every mole of
ethanol oxidized. Since acetate infusions in man
markedly increase urinary oxypurine and plasma
hypoxanthine levels, there is strong support for
the concept that the adenosine monophosphate
generated during ethanol metabolism is degraded
to uric acid accounting for the hyperuricemia
observed with ethanol ingestion. It appears that
blood alcohol levels of less than 150 mg/dl are not
associated with hyperlacticacidemia, and in such
a setting, adenosine monophosphate degrada-
tion accounts for the hyperuricemia. When blood
alcohol levels exceed 200 mg/dl, uric acid excre-
tion is impaired and hyperlacticacidemia contrib-
utes to the ethanol-induced hyperuricemia.
In recent years, episodes of acute gout have
been observed in association with the adminis-
tration of intravenous nitroglycerin for unstable
angina [45]. Since intravenous nitroglycerin
preparations at the time contained significant
quantities of ethanol (Tridil containing 50 mg
of nitroglycerin per 10 ml of 30 % ethanol and
Nitrostat containing 5 % ethanol by volume),
reports of acute gouty arthritis observed during and
after intravenous nitroglycerin have been attributed
to ethanol-induced hyperuricemia with the subse-
quent occurrence of gouty arthritis [46]. Acute
renal failure, another cause of hyperuricemia,
101
denotes the sudden impairment of kidney func-
tion without regard to cause or mechanism. It may
be due to prerenal (diminished renal blood flow
from a variety of causes), postrenal (obstruction
to urine flow), or intrinsic renal disease involving
glomeruli, tubules, interstitium, vasculature, or a
combination of these sites. With the exception of
acute rhabdomyolysis, the hypercatabolic states
associated with lymphoproliferative or myelo-
proliferative disorders, or chemotherapy-induced
cell lysis, patients with acute renal failure all
manifest increased plasma uric acid levels. Such
increments are usually about 1–2 mg/dl above
normal. Such levels rarely exceed 15 mg/dl since
intestinal disposal of urate and urate hydroly-
sis by gut bacteria increase and usually prevent
greater increments in the serum levels. The incre-
ments in plasma urate observed in acute renal
failure result either from decreased renal perfu-
sion, diminished urate excretion by the kidney, or
a combination of the two. If the serum or plasma
urate level exceeds 20 mg/dl, then rhabdomyoly-
sis including muscle necrosis secondary to severe
status epilepticus, cell lysis, or a combination of
fasting and strenuous physical exercise are likely
to be the causes [31, 35]. The serum uric acid
concentration increases rapidly in acute renal
failure as renal function progressively deterio-
rates, and a marked catabolic state often occurs
with increased uric acid synthesis.
Hyperuricemia in rhabdomyolysis results
from the activation of 5¢-nucleotidase when mus-
cle cell ATP is significantly lowered which then
reduces the adenylate pool and increases inosine
synthesis and in turn uric acid production. As a
result of muscle cell necrosis, nucleoproteins are
released which are subsequently converted to uric
acid by the liver. Thus, rhabdomyolysis causes
increased nucleoprotein catabolism and uric acid
synthesis from inosine. The latter mechanism
may also be operative during vigorous exercise.
In patients combining weight reduction and
fasting, the acetoacetate and b-hydroxybutyrate
produced by fasting and the lactate generated by
physical exercise interfere with the secretion of
urate by the renal tubules and results in hyperuri-
cemia [32, 36]. Rarely, acute renal failure has
been observed in the management of solid tumors
as contrasted with its more common association
102
with leukemias and lymphomas treated with radi-
ation or chemotherapy. One such case has been
reported in a patient who received streptozotocin
treatment for an islet cell carcinoma of the pan-
creas [47]. The significance of this case is that uric
acid nephrolithiasis and acute renal failure
occurred in the absence of any apparent acute
tumor cell lysis accompanying the onset of oligu-
ria and in the presence of normal serum uric acid
levels. Streptozotocin, a nitrosourea derivative, is
known to be associated with a variety of renal
tubular dysfunctions including Fanconi syndrome
with hyperuricosuria and could have been respon-
sible for the induction of a defect in the renal tubu-
lar reabsorption of uric acid in this patient [47].
The mechanism for the hyperuricemia observed
after seizures (grand mal type) is related to the
production of lactic acid from intense muscular
activity and a subsequent decrease in the renal
tubular elimination of urate [40]. Correction of
carbon dioxide retention in severe respiratory aci-
dosis often results in the reduction of serum uric
acid levels and increased urinary uric acid excre-
tion. The mechanism for the hyperuricemia in heat
stress nephropathy, infectious hepatitis, and infec-
tious mononucleosis is less well defined [48].
In summary, a number of acute and chronic
illnesses are associated with elevated concentra-
tions of serum uric acid, and these conditions
must be excluded before embarking on a more
extensive analysis of the causes for this labora-
tory abnormality. The measurement of serum uric
acid should never be ordered as a sole parameter
and should always be evaluated in conjunction
with some measurement of renal function such as
serum creatinine or blood urea nitrogen. Such a
practice identifies renal disease as a cause for the
hyperuricemic state. Finally, a more extensive
discussion of drug-induced causes of hyperurice-
mia is included in the section “Drug-induced
hyperuricemia and gout”.
Urinary Uric Acid Measurements
Information from the medical history, physical
examination, and laboratory data may be sufficient
to establish the etiology of the hyperuricemic
5 Clinical Aspects of Gout and Associated Disease States
process without the need for a 24-h urinary uric
acid collection and analysis. As will become clear
from the following discussions, there are a num-
ber of disorders of uric acid metabolism that
require a more extensive evaluation in order to
make a prudent decision about the management
and treatment of the underlying alteration in
metabolism. A 24-h urinary uric acid measure-
ment is the key to assessing whether a patient is
an overproducer or underexcretor of uric acid;
such information is essential in some cases of
gout in order to identify the underlying disorder
and to initiate appropriate treatment.
Certain precautions are necessary to ensure
the proper 24-h urine collection for uric acid
measurements. Urine should not be refrigerated
during the collection since uric acid solubility
decreases at low temperatures and precipitation
of urate crystals may result in the underestima-
tion of urinary uric acid levels. A small quantity
of toluene (5 ml) used to be added to the urine
collection bottle to prevent bacterial growth and
uricolysis by bacteria. Today, a different noncarci-
nogenic preservative is added to prevent bacterial
growth. The uricase method for uric acid deter-
mination should be used since this methodology
avoids interference from urinary chromagens.
The recent use of X-ray contrast material should
also be avoided prior to the urine collection since
they may increase urinary excretion of uric acid
(see section “Uric acid nephrolithiasis”). Further,
radiocontrast materials can cause acute renal fail-
ure and hyperuricemia, even after relatively small
amounts of these substances have been adminis-
tered [49–54]. Finally, a careful history of the
drug usage including the use of nonprescription
drugs containing salicylates must be sought to
avoid erroneous measurements secondary to the
influence of drugs on uric acid excretion.
Overproduction of Uric Acid
Even though gout presents as a single clinical
entity, there are multiple causes of the disease.
Each of these separate causes may have special
and distinct clinical findings that help to identify
it and may denote the need for additional
Overproduction of Uric Acid
therapeutic initiatives. This section places empha-
sis on the clinical aspects of the different genetic
and acquired disorders leading to the overproduc-
tion of uric acid resulting in hyperuricemia and
gout (Table 5.2). Some of these inherited disor-
ders (Lesch-Nyhan syndrome, Kelley-Seegmiller
syndrome, phosphoribosylpyrophosphate syn-
thetase superactivity) can be classified as primary
gout, whereas others (glycogen storage diseases,
fatty oxidation deficiencies, tissue hypoxia, etha-
nol ingestion, blood diseases, malignancies, pso-
riasis, and dietary excesses) are clearly secondary
forms of hyperuricemia and gout. Disorders asso-
ciated with overproduction of uric acid probably
account for no more than 5–10 % of all the cases
of gout. It is important to recognize that the inher-
ited diseases have different modes of inheritance,
and these patterns of inheritance may assist in
determining the underlying genetic disease.
The principal mechanism for those disorders
characterized by increased production of uric
acid in primary hyperuricemia and gout is an
increased intracellular level of phosphoribosylpy-
rophosphate (PRPP). Such elevated intracellular
levels of PRPP enhance purine synthesis by
increasing the rate of conversion of PRPP to
phosphoribosylamine by the first enzyme in
de novo purine biosynthesis. Idiopathic forms of
gout include those individuals who overproduce
uric acid for which no mechanism has been char-
acterized. Secondary types of hyperuricemia and
gout with increased uric acid production include
those diseases in which increased ATP catabo-
lism or decreased ATP synthesis occur, and those
disorders associated with increased nucleic acid
turnover. Secondary hyperuricemia and gout may
also occur in those extremely rare instances in
which the patient ingests excessive quantities of
purines.
Lesch-Nyhan Syndrome
Despite the profound changes in uric acid metab-
olism observed in the Lesch-Nyhan syndrome,
the clinical presentation is not usually one of
gouty arthritis but is characterized by a severe
neurological disorder including self-mutilation,
103
choreoathetosis, spasticity, aggressive behavior,
and mental retardation. Affected patients mani-
fest the complete absence of the enzyme, hypox-
anthine-guanine phosphoribosyltransferase, and
this enzyme deficiency is inherited as an X-linked
recessive trait. On the basis of the pattern of
inheritance, this disorder affects primarily males,
but a few females have been reported who have
inherited separate mutations in this enzyme from
father and mother. All patients with the Lesch-
Nyhan syndrome manifest markedly excessive
uric acid production and may suffer from renal
calculi as the major complication of their altered
uric acid metabolism. These abnormalities of
purine metabolism may also cause hyperurice-
mia, uric acid crystalluria, and obstructive
uropathy.
Nonspecific signs of central nervous system
dysfunction may be present at birth in affected
infants, and the most common of these is general-
ized hypotonia. The first clear appearance of
specific neurological findings usually begins
between 3 and 6 months of age [55–59].
Established neurological dysfunction usually
makes itself known at age 1 or 2 years, and
affected children may be diagnosed with cerebral
palsy until self-mutilation makes its appearance.
Both signs of pyramidal and extrapyramidal tract
involvement may be observed. Athetoid move-
ments of the extremities that may become chore-
iform over time characterize the extrapyramidal
manifestations. Some patients are hypotonic and
develop hyperkinetic movements with dystonia
[60–62]. Hyperreflexia, ankle clonus, extensor
plantar responses, leg scissoring, and spasticity,
if present, are manifestations of pyramidal tract
involvement.
Dysarthria is also a prominent feature of the
Lesch-Nyhan syndrome, and its presence makes
communication with these patients most difficult.
Although patients may be able to communicate
single words, full sentences are almost always an
impossibility. This speech defect along with a
moderate degree of mental retardation makes
clinical management of these patients exceed-
ingly complex [57, 63]. A rare patient may have
normal intelligence, and so the absence of mental
retardation does not exclude the Lesch-Nyhan
104
syndrome [64]. Those patients with extensive
neurological disease are usually confined to a
wheelchair and are often incontinent. In addition
to these neurological deficits, growth may be
retarded in some affected individuals.
Several key symptoms of the Lesch-Nyhan
syndrome provide additional clues to the under-
lying diagnosis. Some infants may have episodic
irritability associated with red-orange crystals on
their diapers. Subsequently, urinary tract infec-
tions and obstructive uropathy may occur as a
manifestation of uric acid crystalluria and uric
acid nephrolithiasis. Hematuria and colicky
abdominal pain may occur in association with
these findings, but pure urate stones, themselves,
are radiolucent making their visualization impos-
sible on a simple flat plate of the abdomen.
Retrograde urography is necessary for their rec-
ognition as cyst-like structures. These urinary
tract features are the result of the massive excre-
tion of uric acid (25–140 mg/kg × day) as com-
pared to the normal value (18 mg/kg × day) [65].
Acute renal failure as a result of renal urate depo-
sition may also occur, and kidney stones may be
the only initial manifestation of this disorder.
Thus, although gouty arthritis is a rare sign of the
Lesch-Nyhan syndrome, the excessive uric acid
excretion leads to deleterious effects on the
kidney.
Along with these neurological and urinary
tract findings, the most distinguishing and unusual
feature of the Lesch-Nyhan syndrome is the com-
pulsion for self-injury that occurs in affected
patients. These patients manifest intermittent,
compulsive mutilation, principally of their lips,
buccal mucosa, fingers, and hands. Stress such as
hospitalization seems to exacerbate or increase
the self-injurious behavior. At times, no manifes-
tations of self-mutilation are present, and no cor-
relation with clinical findings has been defined to
account for these periods of freedom from their
self-mutilating behavior. Along with this aber-
rant behavior, Lesch-Nyhan patients also exhibit
a bizarre form of aggressiveness. They have been
known to strike others, spit at them, or kick them.
They may also destroy any implements that are
within their environment or use them as weapons
against other individuals or other objects. This
5 Clinical Aspects of Gout and Associated Disease States
aggressive and self-mutilating behavior is char-
acteristic of the Lesch-Nyhan syndrome and does
not occur in those individuals who have a partial
deficiency of the enzyme, hypoxanthine-guanine
phosphoribosyltransferase. Self-injurious behav-
ior is a problem in some autistic and non-autistic
retarded children, but it is most commonly a clin-
ical problem associated with the Lesch-Nyhan
syndrome and Tourette’s syndrome [66]. Recent
studies have documented a reduction in dopamine
transporters in the basal ganglia of Lesch-Nyhan
patients. Further, radiographic studies may pro-
vide a method for the recognition of these basal
ganglia alterations [67–69]. Although specific
therapy for self-injurious behavior is unavailable,
anticonvulsants and carbamazepine have offered
some relief for this symptomatology [70].
Hematologic abnormalities have also been
reported in the Lesch-Nyhan syndrome, but their
pathophysiology is unclear [71–73]. Usually
affected patients are anemic, and the anemia is
macrocytic, but hemolytic anemia has also been
reported [74]. Some patients have low folate lev-
els as a result of the consumption of this metabo-
lite by the increased rate of de novo purine
synthesis, but the megaloblastic anemia may be
unresponsive to folate treatment [75]. No other
hematologic abnormalities of clinical significance
have been reported. Thus, severe neurological
diseases characterized by choreoathetosis, spas-
ticity, and self-injurious behavior along with uri-
nary tract problems are the most typical clinical
findings in the Lesch-Nyhan syndrome
(Table 5.4).
Kelley-Seegmiller Syndrome
Although the Kelley-Seegmiller syndrome, a par-
tial deficiency of hypoxanthine-guanine phos-
phoribosyltransferase, is an uncommon cause of
gout, recognition of its clinical presentation can
lead to the prevention of its complications through
appropriate early treatment. Like the complete
deficiency of hypoxanthine-guanine phosphori-
bosyltransferase, it is also inherited as an X-linked
recessive trait. Its primary clinical parameters
involve the musculoskeletal system, urinary tract,
Overproduction of Uric Acid
Table 5.4 Classification of hyperuricemia and gout
I. Increased production of urate
A. Primary hyperuricemia and/or gout
1. Elevated PRPP
(a) Lesch-Nyhan syndrome
(b) Kelley-Seegmiller syndrome
(c) PRPP synthetase variants
2. Idiopathic
B. Secondary hyperuricemia and/or gout
1. Increased ATP catabolism
(a) GSD types I, III, V, and VII
(b) Muscle phosphoglycerate mutase (?)
(c) Tissue hypoxia
(d) Ethanol
2. Increased nucleic acid turnover
(a) Blood diseases
(b) Malignancies
(c) Psoriasis
3. Excessive purine intake
II. Decreased excretion of urate
A. Primary hyperuricemia and/or gout
1. Decreased filtered load (?)
2. Increased tubular reabsorption (?)
3. Decreased tubular secretion
B. Secondary hyperuricemia
1. Reduced glomerular filtration rate
(a) Chronic renal failure
2. Increased renal tubular reabsorption
(a) Dehydration
(b) Diabetes insipidus
(c) Diuretics
3. Decreased tubular secretion
(a) Disorders with increased ß-hydroxybutyrate
(b) Disorders with increased acetoacetate
(c) Starvation
(d) Diabetic ketoacidosis
(e) Branched chain ketoaciduria
(f) Disorders with hyperlacticacidemia
(g) Toxemia
(h) Acute alcoholism
(i) Tissue hypoxia
and kidney. In some patients, central nervous sys-
tem dysfunctions may also be apparent, but no
self-injurious behavior occurs. Affected patients
clearly suffer from recurrent and severe gouty
arthritis, and they may develop tophaceous depos-
its shortly after the onset of gouty arthritis.
Despite the presence of the mutant enzyme from
105
birth, the resultant altered urate metabolism usu-
ally does not give rise to gout until after the age
of 20. Tophaceous deposits in these patients may
develop in unusual locations. The rapid develop-
ment of tophi is a marker of the overproduction
of uric acid and the body’s inability to handle the
increased load of urate.
Kidney stones may be the first manifestation
of disordered urate metabolism, and uric acid
crystalluria and/or nephrolithiasis may occur
in the teens or early twenties. In some, kidney
stones have been passed in patients younger than
8 years of age [76]. Accompanying this manifes-
tation of urate overproduction are chronic urinary
tract infections and renal insufficiency. In fact,
acute renal failure has been reported as an ini-
tial event in patients with partial hypoxanthine-
guanine phosphoribosyltransferase deficiency
[77, 78]. Several patients have undergone neph-
rectomy as a result of severe infection. These
episodes of renal insufficiency and ultimate fail-
ure are treatable disorders in children and young
adults, if recognized early in the course of this
genetic disorder. The recognition of this enzyme
deficiency is absolutely essential if treatment is
to be successful.
Neurological dysfunction in these patients is
variable, and its manifestations are heteroge-
neous. The neurologic findings include nystag-
mus, hyperactive deep tendon reflexes, extensor
plantar responses, spastic movements, and dysto-
nia. Peripheral nervous system alterations may
result from compression neuropathies (carpal
tunnel syndrome) secondary to tophaceous
deposits. Mental retardation of a modest degree
is also seen in this disorder in some patients. The
majority of patients with partial deficiency of
hypoxanthine-guanine phosphoribosyltransferase
have no neurological deficits, and the reasons for
the appearance of central nervous system disease
in some must await the complete linkage of the
biochemical changes with the nervous system
symptoms and signs.
The clinical features of this enzyme deficiency
and its concomitant alterations in purine metabo-
lism are reflected in the changes in uric acid
metabolism. The serum uric acid concentrations
in most of the affected patients are in the range of
106
10 mg/dl, and most patients excrete more than
600 mg of uric acid per day in their urine. In addi-
tion, the uric acid to creatinine ratio in 24-h urine
specimens is usually greater than 2.
Just as some patients with a complete
deficiency of hypoxanthine-guanine phosphori-
bosyltransferase have a megaloblastic anemia,
some patients with a partial deficiency of the
same enzyme also manifest a megaloblastic ane-
mia often with an accompanying low serum folate
level. The pathogenesis of this finding remains to
be completely understood.
Finally, as one might suspect, patients with
the partial deficiency are also resistant to aza-
thioprine treatment because of their inability to
form the therapeutically active nucleotide. Thus,
if such patients require treatment with antime-
tabolites like azathioprine, alternative drugs
that do not require hypoxanthine-guanine phos-
phoribosyltransferase for their activity should
be selected. Even though these human mutants
probably represent less than 1 % of the patients
with gout, their identification and treatment will
reduce morbidity and mortality from this treat-
able disorder.
Phosphoribosylpyrophosphate
Synthetase Overactivity
Increased activity of the enzyme, phosphoribo-
sylpyrophosphate synthetase, has been described
in small number of kindreds and is characterized
by uric acid overproduction, gout, and urolithia-
sis, and in some families, neurodevelopmental
deficits have been documented [77–84]. Like
hypoxanthine-guanine phosphoribosyltransferase
deficiency, phosphoribosylpyrophosphate syn-
thetase superactivity is inherited as an X-linked
recessive trait [85, 86]. Even though phosphori-
bosylpyrophosphate synthetase superactivity is
inherited in this manner, heterozygous female
carriers of the mutation have been reported with
gout and sensineural deafness [81–83, 87]. There
are two somewhat different clinical expressions
of this enzyme abnormality. One phenotype is
characterized by an early age of onset in child-
hood, gross overproduction of uric acid (1.0–2.4
5 Clinical Aspects of Gout and Associated Disease States
g excreted/24 h), and neurodevelopmental abnor-
malities including ataxia, mental slowness,
sensineural deafness, hypotonia, and delayed
motor development. The neurological defect
identified most often in these patients is a high-
frequency deafness [81–83]. The mechanisms
causing these neurological deficits and their link-
age to purine biosynthesis are unknown. The
juvenile or early adult onset phenotype is also
characterized by uric acid overproduction, gout,
and/or uric acid nephrolithiasis, but no neurologi-
cal deficits have been found in these patients [81].
There is no definite single mutation that segre-
gates these two phenotypes except for the fact
that the childhood form signals a markedly exces-
sive rate of urate overproduction and usually
involves a mutant with a defect in regulation or
an abnormality in regulation combined with
another defect.
The biochemical mechanism leading to these
abnormalities in uric acid production results from
the overproduction of phosphoribosylpyrophos-
phate. Increased phosphoribosylpyrophosphate
levels, whether they result from underutilization
of this metabolite in purine salvage reactions or
by overproduction by phosphoribosylpyrophos-
phate synthetase activity, activate phosphoribo-
sylpyrophosphate amidotransferase and increase
de novo purine nucleotide biosynthesis and
excessive uric acid production.
The keys to suspecting this enzymatic abnor-
mality are the presence of a neurological deficit,
especially sensineural deafness, associated with
signs of uric acid overproduction such as topha-
ceous deposits or kidney stones. In fact, topha-
ceous gout has been described in an 8-year-old
boy with this abnormality [81]. In the absence of
neurological signs, it is difficult if not impossible
to differentiate this enzyme abnormality from
partial hypoxanthine-guanine phosphoribosyl-
transferase deficiency.
Idiopathic Gout
There are a small number of patients with primary
gout who are overproducers of uric acid but have
no identifiable genetic error in purine metabolism.
Overproduction of Uric Acid
There is the possibility that such patients may
have a mutation in the rate-limiting enzyme of
de novo purine biosynthesis, phosphoribosylpy-
rophosphate amidotransferase. Alterations in the
kinetic properties of this enzyme could also lead
to excessive rate of purine synthesis. Such abnor-
malities have been described in Ehrlich ascites
cell lines and bacterial species due to a decrease
in the sensitivity of these cells to inhibition of
purine nucleotides [88, 89]. No such mutants
have been identified to date in the human, but
mutations in the human amidotransferase may be
characterized in the future.
Secondary Hyperuricemia and Gout
due to Overproduction of Purines
As noted previously, secondary hyperuricemia
with increased urate production can be caused by
four different mechanisms: decreased synthesis
of ATP, increased ATP degradation, increased
nucleic acid turnover, or excessive ingestion of
purines. When the supply of inorganic phospho-
rus, oxygen, and nicotinamide adenine dinucle-
otide is limited, the synthesis of ATP in the
mitochondria may be decreased. Further, if
energy sources such as glucose or fatty acids are
restricted, ATP synthesis may also be diminished.
When the need for ATP exceeds the capacity of
the cell to synthesize ATP, then ATP degradation
occurs and adenosine diphosphate and adenosine
monophosphate are rapidly converted to inosine,
hypoxanthine, xanthine, and uric acid [90–92].
Some of the disorders associated with ATP
degradation are also associated with gout, while
others only produce hyperuricemia. Glycogen
storage diseases and hereditary fructose intoler-
ance have been documented as causes of both
gout and hyperuricemia. These disorders are dis-
cussed subsequently. Ethanol ingestion and fruc-
tose-induced hyperuricemia are discussed with
the drug-induced causes of hyperuricemia even
though the mechanism for the induction of hype-
ruricemia in these cases is via ATP degradation.
Fructose-1,6-bisphosphatase deficiency is an
autosomal recessive trait observed primarily in
newborns that present with hyperventilation,
107
convulsions, and coma [93, 94]. The laboratory
parameters of this disorder include hypoglyce-
mia, ketosis, and acidosis. In addition to elevated
blood levels of lactate, ketones, and alanine,
serum uric acid levels are also increased. This
hyperuricemia is reflected in the appearance of
excess uric acid in the urine [95–99]. Patients
with fructose-1,6-diphosphatase deficiency, like
hereditary fructose intolerance, manifest an
increase in serum uric acid levels after a fructose
load [100]. This enzyme deficiency must be dif-
ferentiated from other causes of lactic acidosis
such as pyruvate carboxylase deficiency, pyru-
vate dehydrogenase deficiency, and phosphoenol
pyruvate carboxykinase deficiency.
Decreased ATP synthesis is observed in two
conditions: tissue hypoxia and metabolic myopa-
thies. The latter disorders are discussed subse-
quently; tissue hypoxia on the basis of ischemia
or hypoxemia may result in massively elevated
serum uric acid levels [90, 101–104].
Hyperuricemia and elevated oxypurine levels
have been observed in cardiogenic shock, revers-
ible cardiac arrest, perinatal distress, and pulmo-
nary disorders [101, 105–117]. Gout has been
reported in rare cases of emphysema and chronic
obstructive pulmonary disease [118, 119]. The
coexistence of these two disorders probably rep-
resents the coincidental occurrence of two com-
mon disorders with the gout being aggravated by
an increased production of urate.
The other group of disorders associated with
impairment of ATP synthesis is the metabolic
myopathies. In these conditions, ATP is utilized
in muscular activity, but the source of carbohy-
drates or fatty acids is limited by deficiencies in
the generation of substrates for ATP synthesis.
As will be discussed subsequently, this group of
diseases causing myogenic hyperuricemia and, in
some instances, gout represents disorders of both
glycogen and fatty acid metabolism. The limited
capacity of these deficient individuals to provide
substrates for ATP synthesis leads to an acceler-
ated degradation of adenine nucleotides to inos-
ine, hypoxanthine, xanthine, and uric acid.
Increased nucleic acid turnover resulting in
hyperuricemia occurs in conditions where exces-
sive nucleic acid synthesis is required or when
108
there is a release of excessive quantities of nucleic
acids due to the lysis of cells. Excessive nucleic
acid synthesis is observed most often in hemato-
logical malignancies and results in altered purine
nucleotide concentrations. Excessive nucleic acid
synthesis in support of malignant cell growth
leads a decrease in cellular nucleotide content
with the resultant decrease in the feedback inhi-
bition of de novo purine biosynthesis and an
increase in de novo purine synthesis. Treatment
regimens for hematological malignancies or other
types of cancer can also cause cell destruction
with the resultant release of large quantities of
nucleotides. These excess nucleotides are subse-
quently converted to uric acid. There are a variety
of acquired disorders that have been reported in
association with gout and altered nucleotide turn-
over including hemolytic anemias, sickle cell dis-
ease, multiple myeloma, polycythemia, leukemia,
and myeloproliferative disorders [120–128].
Excessive ingestion of purines is an unusual
cause of hyperuricemia, but such dietary excesses
may be observed in individuals with unusual eat-
ing habits. In these individuals, dietary indiscre-
tions may either cause hyperuricemia by itself or
contribute to the hyperuricemia caused by other
mechanisms. Such dietary indiscretions usually
aggravate other causes of hyperuricemia and are
not the sole cause of this metabolic change.
Finally, there are two unusual and rare causes
of gout that have been reported in the literature
[129–132]. Both these enzyme abnormalities
lead to the overproduction of uric acid. In myo-
adenylate deaminase deficiency, patients experi-
ence muscle fatigue and myalgias after exercise.
The defect in this enzyme results in a deficiency
of ATP synthesis with subsequent ATP degrada-
tion to uric acid when exercise places increased
demands on ATP utilization that cannot be
achieved in those with this enzyme deficiency.
Since more than 200 patients have been described
with this muscle enzyme deficiency and roughly
2 % of muscle biopsy specimens submitted for
analysis have this enzyme deficiency, the single
case of gout reported in the literature probably
represents the occurrence of two common disor-
ders rather than a specific genetic error causing
gout [133].
5 Clinical Aspects of Gout and Associated Disease States
The other rare enzyme defect associated with
a single case report of gout is the accelerated
nucleotide degradation observed in a patient with
liver adenosine monophosphate deaminase
deficiency [129]. The conversion of adenosine
monophosphate to inosine monophosphate by the
enzyme adenosine deaminase is the rate-limiting
step for the degradation of adenine nucleotides,
and in this single case of gout, AMP deaminase
was determined to be insensitive to its physiolog-
ical inhibition by inorganic phosphorus and
guanosine triphosphate. Thus, AMP deaminase is
released from inhibition, and increased quantities
of adenosine monophosphate are converted to
inosinic acid and subsequently to uric acid. Since
liver biopsies are rarely, if ever, analyzed in
patients with gout, the frequency of this enzyme
abnormality in gouty subjects is unknown. This
enzyme and its alteration in purine metabolism
are discussed in greater detail in the section deal-
ing with uric acid metabolism in the human.
Glycogen Storage Diseases (GSD)
Although glycogen storage diseases are usually
recognized in childhood and treatment instituted
at that time, most patients survive into adulthood,
and some subsets of this disorder are first recog-
nized in adulthood [134–137]. Hyperuricemia
and/or gouty arthritis are frequently observed as
complications of glycogen storage disease types
I, III, V and VII, and their recognition necessi-
tates a careful analysis of the symptoms and signs
of these adult presentations if the true underly-
ing cause of this purine dysfunction is to be
identified.
In the adult, type I glycogen storage disease
(glucose-6-phosphatase deficiency) is often
manifested by musculoskeletal disease (gout,
short stature, osteopenia), hepatic and renal dys-
functions (altered liver function, enlarged liver,
hepatic adenomas, microalbuminuria, renal cal-
culi, and nephrocalcinosis), anemia, and hyper-
lipidemia. If type Ib GSD (glucose-6-phosphate
translocase deficiency) is the underlying prob-
lem, then neutropenia and recurrent bacterial
infections are also observed in conjunction with
Overproduction of Uric Acid
the findings associated with classical type I gly-
cogen storage disease [138]. Acute and chronic
tophaceous gout result from the increased degra-
dation of adenine nucleotides to uric acid
(Fig. 5.1) and the increased lactate production
that inhibits uric acid excretion by the kidney.
These two disorders (type I and 1b) are a major
cause of morbidity from gout especially if treat-
ment of these disorders has been ineffective for
any reason. Associated with this articular dis-
ease is an increased incidence of osteopenia
including bone fractures and osteonecrosis
[134]. The pathogenesis of these bone disorders
is incompletely understood, and they have not
been evaluated by modern quantitative method-
ologies [134, 139]
Renal problems are frequently found in asso-
ciation with these musculoskeletal disorders
including calculi that are usually composed of
calcium oxalate although stones formed from
uric acid may also be observed [140–143]. At the
present time, no biochemical rationale has been
proposed that links oxalate metabolism with
defective glycogen metabolism. Nephrocalcinosis,
glomerulosclerosis, and recurrent pyelonephritis
in the absence of structural abnormalities of the
urinary tract occur in more than half the patients
with GSD type I. Gross proteinuria (>1,000 mg/
day) and microalbuminuria are also often pres-
ent. These abnormalities of the kidney may or
may not be accompanied by a diminished creati-
nine clearance and hypertension. Allopurinol
treatment is recommended to impair the contri-
butions of hyperuricemia to the progression of
the renal disease. Renal tubular dysfunctions
may also be observed in patients with type 1 gly-
cogen storage disease including renal tubular
acidosis, hypercalciuria, and hypocitraturia
[143]. A Fanconi type syndrome with aminoaci-
duria, proteinuria (low molecular weight), phos-
phaturia, and bicarbonaturia has also been
described [144, 145].
Hepatomegaly is a uniform finding in patients
with type I GSD, and many of these patients may
also acquire multiple hepatic adenomas [146–
148]. These adenomas may rarely undergo malig-
nant degeneration, and for this reason are
important to identify. In addition to these organ
109
dysfunctions, serum triglycerides and cholesterol
levels are elevated due to the increased rate of
hepatic triglyceride synthesis and decreased
peripheral lipolysis [149]. These lipid abnormali-
ties give rise to pancreatitis and atheromatous
blood vessel disease.
In those patients with type Ib GSD, neutrope-
nia and frequent bacterial infections occur because
of impaired neutrophil function [150, 151]. These
recurrent bacterial infections require appropriate
antibacterial treatment and attention to personal
hygiene to prevent further infections including
the prevention of unnecessary exposures to other
infected individuals.
Recognition of the underlying disease process
and the institution of appropriate treatment
(allopurinol and high fluid intake) are likely to
prevent the morbidity related to renal calculi,
nephrocalcinosis, and recurrent gouty attacks.
The foregoing descriptions of symptoms and
signs unrelated to gouty arthritis can serve to alert
the clinician to an underlying disease. Although
the patient may be aware of the underlying GSD,
he or she may not make the connection between
nephrolithiasis, gout, and glycogen storage dis-
ease. For this reason, a detailed and careful history
is essential for the identification of the complicat-
ing disease process.
Type III GSD (debranching enzyme deficiency/
amylo-1,6-glucosidase deficiency) is clinically
similar to type I GSD in its childhood presenta-
tion with hepatomegaly, hyperlipidemia, hypogly-
cemia, and stunted growth as the most consistent
features. In adults, liver disease usually resolves
and hepatomegaly may remain as a feature, but it
is not a common finding. Weakness and muscle
wasting are the most predominant clinical findings
in adults with the disorder. Muscle atrophy is often
especially prominent in the legs and small mus-
cles of the hands, and electromyographic studies
show widespread evidence of myopathic changes
[152–158]. Electrocardiograms may show ven-
tricular hypertrophy [159–161]. Hepatic disease,
as noted previously, is not a prominent feature
of the adult disease although hepatic fibrosis is
often present.
Laboratory parameters may include moder-
ately increased levels of transaminases, elevated
110
serum triglyceride and cholesterol levels, and not
infrequently increased serum uric acid levels
[152, 153, 162]. Serum creatine phosphokinase
levels may or may not be elevated as a manifesta-
tion of the underlying muscle disease. A review
of the literature does not reveal any reported
patients who developed gout despite their ele-
vated serum urate levels. In many patients, lactate
and urate concentrations are within the normal
range and may account for the rarity of gouty
arthritis in this type of GSD. When type III GSD
patients exercise, an increase in the plasma con-
centrations of hypoxanthine and uric acid occurs
as compared to their concentrations in the non-
exercising patient [163]. Thus, hyperuricemia
may be especially prominent after exercise. Since
this disorder may be selective in its expression
involving liver and/or muscle, diagnostic studies
must include evaluations of the debranching
enzyme in both muscle and liver. This type of
GSD is often found in non-Ashkenazic Jews
from North Africa, and patients from this ethnic
background deserve special attention. The skel-
etal manifestations may lead to confusion with
Charcot-Marie-Tooth disease because of the
wasting of the small muscles of the hands and
feet as well as the peripheral limbs seen in both
diseases.
Type V GSD (muscle phosphorylase
deficiency) is clearly associated with hyperurice-
mia and gouty arthritis although in some cases,
the gout is thought to be coincidental [164, 165].
Type V GSD, although present from birth, mani-
fests a wide range of heterogeneity with respect
to its clinical findings, yet the enzyme defect per
se appears not to be linked with its varying clini-
cal presentations. The classical presentation is
one of exercise-induced muscle cramps with
pink- or burgundy-colored urine as a result of
rhabdomyolysis and myoglobinuria [166, 167].
As noted, the clinical dysfunctions may occur in
childhood, but more commonly, they manifest
themselves at age 20 or 30 and sometimes not
until late in life [168, 169]. Laboratory findings
include elevated levels of creatine phosphokinase
that can be significantly increased further with
exercise. Exercise also increases the levels of
blood ammonia, hypoxanthine, and uric acid
5 Clinical Aspects of Gout and Associated Disease States
[170, 171]. As a result of the muscle pain and
elevated creatine phosphokinase levels, this myo-
pathic disorder has been confused with polymyo-
sitis [172]. Although not a common cause of
hyperuricemia and gout, excessive adenine nucle-
otide degradation in muscle does occur in type V
GSD when intense or sustained exercise is under-
taken, and such occurrences suggest the need for
the evaluation of those suspected of this disorder
with exercise testing [163, 170].
Fewer than 50 cases of type VII GSD
(Tarui’s disease or muscle phosphofructokinase
deficiency) have been reported in the literature;
however, this myopathy is frequently associ-
ated with gouty arthritis and/or hyperuricemia
[173–177]. Although this disorder primarily
presents as a myopathy with fatigue and mus-
cle cramps associated with exercise along with
myoglobinuria, it may have significant variation
in its clinical characteristics. Late onset of this
myopathy may only have muscle weakness and
the complete absence of cramps and myoglobi-
nuria [174, 178, 179]. An infantile form of this
disease has also been reported which is fatal and
is of no concern to the subject matter discussed
herein [180, 181]. Tarui’s disease may be difficult
to distinguish from type V GSD since they both
present with myopathic symptoms associated
with exercise. Some aspects of the clinical pre-
sentation may assist in segregating these two
disorders. Tarui’s disease is often associated with
more severe muscle symptoms than type V GSD,
and the former patients may also complain of
nausea and vomiting accompanying acute epi-
sodes of muscle cramps. Hemolytic anemia with
hyperbilibubinemia, reticulocytosis, and reduced
erythrocyte 2,3-biphosphoglycerate levels is seen
in type VII GSD but not in type V GSD [182,
183]. In some patients with type VII GSD, hemo-
lysis may occur in the absence of any muscle
symptoms. The degree of hemolysis in type VII
GSD is mild, and leukopenia may accompany the
hemolysis if the patient has splenomegaly. The
mechanism for this hereditary nonspherocytic
hemolytic anemia is not completely resolved, but
it has been suggested that the accumulation of
red blood cell intermediate metabolites may alter
the erythrocyte membrane. Thus, if hemolytic
Overproduction of Uric Acid
anemia is present in type VII GSD, this compo-
nent may differentiate this disorder from type V
GSD in which no hemolysis has been recorded in
affected patients.
If one considers type III, V, and VII glyco-
gen storage diseases, the latter disorder (type
VII GSD) induces the most aggressive reduc-
tion in adenine nucleotides with its resultant
rise in serum uric acid levels. The magnitude of
the hyperuricemia is much greater than that
observed in types III and V GSD, and this may
account for the more frequent association of
gout with type VII GSD. Meals high in carbo-
hydrate are known to aggravate the exercise-
induced changes in muscle and their associated
symptoms [184]. The glucose provided by high
carbohydrate meals cannot be utilized due to
the deficiency of phosphofructokinase activity,
and this results in a decrease in blood fatty
acids, a key source of muscle fuel. In contrast to
this alteration in glucose metabolism, patients
with type V GSD can metabolize glucose, and
their exercise intolerance improves with high
carboyhydrate diets. Muscle biopsy in type VII
GSD shows a PAS-positive abnormal polysac-
charide [174, 175].
The diagnosis of type VII GSD requires the
demonstration of the enzymatic defect in muscle,
but exercise-induced muscle symptoms, hyperu-
ricemia, and/or gout should suggest to the astute
clinician that the underlying disease may be one
of the glycogen storage diseases affecting mus-
cle. Although adenine nucleotide catabolism and
the formation of inosine monophosphate, an
immediate precursor of uric acid, probably repre-
sent the primary source of the increased serum
urate levels, two other aspects of the disease may
contribute to the hyperuricemia. The low-grade
hemolysis and its accompanying turnover of red
blood cell nucleic acids may, when present, result
in increments in uric acid levels. In addition, the
accumulation of glucose-6-phosphate and fruc-
tose-6-phosphate resulting from the inability to
convert fructose-6-phosphate to fructose-1,6-bis-
phosphate may stimulate the pentose phosphate
shunt and generation of ribose-5-phosphate and
phosphoribosylpyrophosphate [185, 186]. The
latter compound is an immediate precursor of
111
phosphoribosylamine, the first step in de novo
purine biosynthesis.
There are a group of heritable myopathies that
must be differentiated from types V and VII
GSDs since they are characterized in their classi-
cal presentations by exercise intolerance, muscle
cramps, and myoglobinuria [166, 187]. These
metabolic myopathies can be divided into those
affecting glycogen metabolism, lipid metabo-
lism, or mitochondrial metabolism. Since purine
degradation, hyperuricemia, and/or gout have
only been recorded in some of these disorders, it
is unclear how common alterations in serum uric
acid levels and gouty arthritis may be in these
rare myopathies. For this reason, brief but not
detailed clinical descriptions of these disorders
are included.
Hyperuricemia or gout has been reported in
some patients with muscle phosphoglycerate
mutase deficiency and myoadenylate deaminase
deficiency, but how common these associations
are is unknown [131, 188]. Documentation of
excessive purine degradation in muscle has been
reported in these disorders so that it is likely that
hyperuricemia and perhaps gout would accom-
pany these diseases [132, 189].
As for the glycolytic metabolic abnormalities
that give rise to exercise intolerance, recurrent
myoglobinuria, myalgias, crampy muscle pain,
limb weakness with elevated creatine phosphoki-
nase levels, and rarely acute renal failure, their
clinical findings most often appear in the early
stages of exercise or associated with intense
physical exertion. Thus, the muscle symptoma-
tology of types V, VI, VII, VIII, IX, X, and XI
glycogen storage diseases occurs when the energy
source for muscle is primarily dependent on car-
bohydrates. At times, these patients may give a
history of a second burst of energy after their ini-
tial symptoms that probably relates to a shift in
the muscle energy source from carbohydrates to
fatty acids.
The clinical parameters of type V and VII
GSD have already been described, and only a
brief description of the other glycolytic disorders,
the fatty oxidation abnormalities, and the other
heritable disorders of exercise intolerance and
myoglobinuria are summarized here since the
112
extent of their association with hyperuricemia
and gout is unknown. Muscle-specific phospho-
rylase kinase deficiency is a rare autosomal reces-
sive trait presenting with muscle cramps and
myoglobinuria associated with exercise or mus-
cle weakness and atrophy [190–198]. Like other
muscle diseases, the presentation of this illness is
heterogeneous in that some patients may not have
muscle cramps, may have muscle cramps without
myoglobinuria, or may have muscle weakness
alone. Muscle biopsy shows a vacuolar myopathy
with glycogen accumulation [190, 193, 198].
Ischemic exercise shows an elevation in blood
ammonia but no abnormality in lactate. Since
there are different types of phosphorylase b
kinase deficiency affecting the liver only, muscle
and liver, muscle only, and heart muscle, it is
imperative that diagnostic studies include enzyme
analysis of these various tissues [197]. Enzyme
analyses of erythrocytes and/or leukocytes alone
may miss the enzyme deficit if muscle tissue is
not analyzed directly.
An X-linked form of glycogen storage disease
has been reported with muscle involvement and
gouty arthritis [199]. The clinical presentation of
this disorder in males is one of muscle weakness
in childhood, enlargement of the liver, growth
retardation, and a delay in sexual maturation.
Hyperuricemia and gouty arthritis have been
observed in adults with this disorder. Although
the precise enzyme deficit remains unknown,
the authors excluded deficiencies in glucose-6-
phosphatase, debrancher enzyme, phosphory-
lase, or phosphorylase kinase as the cause for the
disorder.
Phosphoglycerate kinase deficiency is an
X-linked recessive trait usually presenting in its
most complete form as a nonspherocytic hemo-
lytic anemia, mental retardation, seizures, muscle
cramps with exercise, myoglobinuria, and renal
failure. It is possible that the X-linked trait with
muscle involvement and gout described by
Keating and his colleagues represented a case of
phosphoglycerate kinase deficiency [199]. The
latter disorder has been termed type IX glycogen
storage disease, and electron microscopy of
muscle specimens shows elevated muscle glyco-
gen content [200]. The clinical and molecular
5 Clinical Aspects of Gout and Associated Disease States
Table 5.5 Heritable disorders of exercise intolerance
and myoglobinuria
Glycolytic abnormalities
Phosphorylase deficiency (type V GSD)
Phosphofructokinase deficiency (type VII GSD)
Phosphoglycerate kinase deficiency (type IX GSD)
Phosphoglycerate mutase deficiency (type X GSD)
Lactate dehydrogenase deficiency (type XI GSD)
Muscle-specific phosphorylase kinase deficiency
Fatty acid oxidation abnormalities
Carnitine palmitoyltransferase II deficiency
Long-chain acyl-CoA dehydrogenase deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Short-chain L-3-hydroxyacyl-CoA dehydrogenase
deficiency
Miscellaneous
Glucose-6-phosphate dehydrogenase deficiency
Myoadenylate deaminase deficiency
Duchenne and Becker muscular dystrophy
Familial recurrent myoglobinuria
expression of this heritable disorder is heteroge-
neous [201–206]. From the standpoint of clinical
heterogeneity, patients may present with hemo-
lytic anemia alone, myopathy alone, no central
nervous system changes, or without any symp-
toms at all. Phosphoglycerate kinase deficiency
may mimic types V or VII GSD in its presenta-
tion. Therefore, an X-linked recessive pattern of
inheritance by pedigree analysis may provide a
significant clue to the underlying cause of myo-
pathic symptoms. Ischemic forearm exercise test-
ing shows no elevation of venous lactate levels.
Phosphoglycerate kinase activity must be mea-
sured in muscle to make a definitive diagnosis
(Table 5.5).
Muscle phosphoglycerate mutase deficiency
is a rare autosomal recessive disorder associated
with exercise intolerance, muscle cramps with
exercise, myoglobinuria, and elevated creatine
phosphokinase levels [207–212]. Muscle biop-
sies from such patients show increased PAS stain-
ing and increased muscle glycogen content. For
purposes of classification, this disorder has been
called type X GSD. Studies of anaerobic glycoly-
sis have shown decreased lactate production in
this disorder, and in one middle-aged male with a
deficiency of this enzyme, gouty tophi have been
Overproduction of Uric Acid
observed [213]. It is not known whether the pres-
ence of gout in association with this heritable
myopathy is coincidental or the result of exercise
intolerance and hyperuricemia in a patient since
adolescence. The enzyme, phosphoglycerate
mutase, is a dimer composed of a slow-migrating
muscle isoenzyme and a fast-migrating brain
isoenzyme. In enzyme-deficient patients, assays
for enzyme activity in muscle may detect small
quantities of the brain isoenzyme and not the pre-
dominant muscle isoenzyme.
Lactate dehydrogenase-A deficiency is the
final error in glycolysis to be associated with
exertional muscle pain and myoglobinuria. It has
been classified as glycogen storage disease type
XI and is accompanied by an increase in serum
creatine phosphokinase levels [214–219]. This
enzyme deficiency is inherited as an autosomal
recessive trait, and in addition to its myopathic
features, erythematosquamous lesions of the skin
on the extensor surfaces of the limbs may be
observed [220–222]. In contrast to psoriasis,
these skin lesions are often worse in the summer.
As in other metabolic myopathies, acute renal
failure secondary to rhabdomyolysis is the most
serious complication of this heritable enzyme
deficiency.
Fatty Acid Oxidation Deficiencies
Heritable defects in fatty acid oxidation are
clearly associated with hyperuricemia, but so far
as can be determined, no cases of gouty arthritis
have been documented in the literature. All the
disorders discussed herein present with exercise
intolerance and recurrent myoglobinuria. In most
instances, the clinical symptoms of myalgias,
cramping, or stiffness of muscles appear after
prolonged exercise. The musculoskeletal symp-
toms are often accompanied by pigmenturia and
may rarely cause acute renal failure resulting
from rhabdomyolysis. During episodes of exer-
cise intolerance, creatine phosphokinase levels
are usually elevated, but they return to normal
levels on recovery. In muscles, carbohydrates
serve as the main energy source during the initial
phases of exercise, whereas 1–4 h of exercise,
113
fasting, emotional stress, cold exposure or an
infectious process may trigger symptoms in those
patients with defective fatty acid oxidation.
The principal fatty acid oxidation defect is the
hereditary deficiency of carnitine palmitoyltrans-
ferase II. The classical form of this disorder pri-
marily affects adult males even though there is a
severe, fatal infantile form [223–226]. This
enzyme deficiency is inherited as an autosomal
recessive trait, and the reason for the preponder-
ance of males with the disorder remains to be
determined. Renal failure secondary to myo-
globinuria is not an unusual finding in this dis-
ease and coupled with the fact that this enzyme
deficiency is a common metabolic cause of recur-
rent myoglobinuria makes its identification
imperative [227–235]. Although permanent mus-
cle weakness is rarely observed, it has been
reported with elevated creatine phosphokinase
levels and myopathic changes by electromyogra-
phy [236]. When patients with this disorder are
subjected to ischemic forearm testing in the fast-
ing state, plasma purine levels are determined to
be elevated. These findings clearly document the
increased ATP degradation and uric acid produc-
tion associated with heritable palmitoyltrans-
ferase deficiency [189]. In patients with adult
onset disease, tissue fibroblasts and leukocytes
may express the enzyme deficiency, and this
avoids the need for a muscle biopsy. The latter
procedure, if necessary for the demonstration of
the enzyme deficiency, may show an increase in
lipid droplets by oil red O staining. As noted,
ATP degradation products and hyperuricemia are
present in this disorder, but no reports of gout
have been documented in the literature.
As can be seen from the foregoing discussion,
a wide variety of genetic diseases are associated
with gout and urate overproduction. In addition,
there are a number of disorders in which ATP
metabolism is altered causing hyperuricemia and,
in some, gout (Table 5.3). These so-called over-
producer types of hyperuricemia and gout account
for about 5–10 % of the total cases of acute gout,
yet careful clinical analyses of patients with gout
may provide clues to an underlying heritable dis-
ease and prevent the morbidity related to unde-
tected family members.
114
Decreased Uric Acid Excretion
Introduction
In addition to the abnormalities in the production
of uric acid that cause hyperuricemia or gout,
alterations in the elimination of uric acid by the
kidney may also cause hyperuricemia and gout.
In general, urinary uric acid accounts for about
70 % of the uric acid eliminated in a day, whereas
the remainder is eliminated by intestinal uricoly-
sis and other minor routes such as tears and per-
spiration [237]. Theoretically, a decrease in
either intestinal uricolysis or renal excretion
could cause hyperuricemia, but in fact, altera-
tions in intestinal uricolysis do not cause hyperu-
ricemia [238].
To characterize the errors in renal excretion
leading to hyperuricemia or gout, the renal han-
dling of uric acid must be understood. The four-
component system of uric acid handling by the
kidney is the presently accepted model [239–
242]. At the glomerulus, uric acid is completely
filtered, and it is almost completely reabsorbed
by the proximal tubules. Proximal renal tubular
urate reabsorption occurs by an active transport
process [243, 244]. Subsequently, about 50 % of
the reabsorbed urate is secreted by the proximal
tubules, and the location of urate secretion
remains to be completely defined in the human.
Then, about 40 % of the secreted urate is reab-
sorbed by a postsecretory mechanism. Again, the
sites for urate secretion and presecretory reab-
sorption have not been localized in the human.
Evidence can be cited that different mechanisms
account for presecretory and postsecretory reab-
sorption [245, 246]. Despite the role that increased
purine synthesis and degradation may play in the
causation of hyperuricemia and gout, the most
common cause of these disorders is a decrease in
the excretion of uric acid. This may occur as a
primary phenomenon with no underlying acquired
disease or with a pharmacologic agent as the
cause or as a secondary phenomenon where the
development of hyperuricemia and gout occurs
as a result of another disease. Primary gout or pri-
mary underexcretor gout is observed in about 85
% of patients with gout [247].
5 Clinical Aspects of Gout and Associated Disease States
Primary Underexcretor Gout
Primary underexcretor gout is defined as a patient
with no identifiable underlying acquired disorder,
no pharmacologic treatment with agents known
to cause hyperuricemia or gout, underexcretion
of urinary uric acid (<250–300 mg/24 h on a
purine-free diet), and a lower uric acid clearance
rate than normal nongouty subjects [248–254].
The underexcretion of uric acid by gouty subjects
was further clarified when the urinary uric acid
excretion rate was plotted as a function of the
plasma urate concentration [249, 253, 255, 256].
In these experiments, the values for gouty sub-
jects were shifted to the right when compared
with nongouty subjects. The conclusion from
such changes is that gouty subjects require serum
uric acid concentrations 1.7 mg/dl higher than
nongouty subjects to achieve uric acid excretion
rates comparable to nongouty subjects. The same
alteration is found when the clearanceurate/clear-
anceinulin is evaluated in gouty and nongouty sub-
jects [248, 253, 256]. When the plasma urate
concentration is increased by exogenous RNA or
by urate infusions and the clearance of urate is
evaluated, gouty subjects require a higher plasma
urate concentration to achieve a clearance identi-
cal to nongouty subjects [251, 257]. Even though
the mechanism to account for these differences in
the handling of uric acid by the kidney remain
unknown, primary underexcretor gout most likely
represents an abnormality (perhaps inherited) in
the renal tubular transport of uric acid.
Secondary Hyperuricemia and Gout due
to the Underexcretion of Uric Acid
In addition to patients with primary underexcre-
tor hyperuricemia and gout, there are a number of
clinical settings in which renal function changes
impair the excretion of uric acid as a result of the
effects of an underlying disease or the use of a
medication. For example, the reduced nephron
population in chronic renal disease and the decline
of glomerular filtration rates cause a reduction
in the fractional excretion of urate [258]. Thus,
the hyperuricemia of renal failure results from
Decreased Uric Acid Excretion
a decreased glomerular filtration rate. Diuretic-
induced hyperuricemia and gout are primarily
caused by increased salt and water loss with a
resultant volume contraction and increased urate
reabsorption by the proximal tubules [259–261].
This disorder is discussed further in the section
“Drug-induced hyperuricemia and gout.” Finally,
decreased renal tubular secretion of uric acid and
secondary hyperuricemia occur when various
organic acids compete with urate tubular secre-
tory sites and inhibit uric acid secretion. Such
secondary renal hyperuricemia has been docu-
mented in association with elevated blood lev-
els of lactate, ß-hydroxybutyrate, acetoacetate,
branched chain keto acids, and with low serum
concentrations of salicylates [262–265].
Urate Nephropathy
Even though it is clear that the skeletal system is
the major pathologic recipient of abnormal purine
metabolism and gout, the classic studies of
Talbott and Terplan have also established that the
kidney is also a target organ in gout [266]. If one
considers human purine metabolism, the kidney
is the primary excretory route for the uric acid
generated from biosynthetic and degradative
pathways as well as from the catabolism of
ingested purines and nucleic acids. About two-
thirds of the daily production of uric acid is
filtered at the glomerulus and subsequently sub-
jected to transtubular reabsorption and secretion.
A relatively small amount is then eliminated by
the kidney. The most recent models of the han-
dling of uric acid by the kidney indicate that four
stages are involved in the excretion of urate:
glomerular filtration, tubule reabsorption, tubular
secretion, and postsecretory reabsorption
(Fig. 5.1). To emphasize this key renal role in the
excretion of urate, the intestinal tract excretes
only about one-third of the daily production of
uric acid, and the kidney excretes the remaining
two-thirds. Uric acid in the intestine is degraded
by microbial uricase so that very little uric acid,
per se, is actually eliminated by the bowel. The
role of the kidney becomes even more significant
if the low pH of the urine and the poor solubility
115
of uric acid at such low levels are considered.
Thus, clinical settings where the quantity of uric
acid presented to the kidney is excessive and
exceeds the capacity of renal tubules, renal pelvis
or ureters to handle this increased urate load, uric
acid may precipitate. The kidney is also the site
of uric acid deposits in some diseases associated
directly with gout and in other diseases in which
uric acid deposits occur as the result of massive
tissue destruction and urate production that
exceeds the kidney’s capacity to excrete it. Thus,
urate nephropathy is defined as the deposition of
microtophi within the kidney parenchyma and is
most frequently observed in conditions where
there is marked overproduction of uric acid like
the Lesch-Nyhan syndrome.
Although older studies have documented urate
nephropathy as a cause of death in gout, more
recent studies have questioned the common
occurrence of this pathologic abnormality [266–
268]. It is not appropriate to maintain the concept
that the development of irreversible kidney dys-
function is the primary cause of death in 10–25 %
of patients with gout as the older literature has
cited [266, 269, 270]. The change in the fre-
quency of this end-stage renal lesion and the
cause of death in gout are most likely related to
an earlier recognition of those entities causing
urate deposition in the kidney and the use of uri-
cosuric and hypouricemic agents to protect the
kidney from the formation of renal urate depos-
its. Further, the early recognition and effective
treatment of coexistent disorders such as hyper-
tension, ischemic heart disease, preexistent renal
disease, and rarely chronic lead exposure have
served to decrease the incidence of renal disease
[268, 271–274]. Several population studies have
confirmed the fact that hyperuricemia has only a
modest effect on the deterioration of renal func-
tion. In the Framingham study, only 2 % of the
240 patients evaluated with serum uric acid levels
greater than 7 mg/dl had clinical evidence of
renal disease to which hyperuricemia might have
contributed [275]. A subsequent study of 1,356
men aged 60–69 with asymptomatic hyperurice-
mia or gout showed relatively modest elevations
in their serum creatinine over a 10-year period,
and no deaths could be attributed to renal disease
116
caused by hyperuricemia [276, 277]. Finally, the
Normative Aging Study of 1,658 male veterans
with asymptomatic hyperuricemia evaluated over
a 15-year period showed less than 1 % of the par-
ticipants to have serum creatinine levels of 2 mg/
dl or more [278]. On the basis of these studies,
hyperuricemia per se appears in many clinical
settings to have little or no deleterious effect on
the kidney.
Despite these findings supporting the rarity of
kidney-related deaths in those with hyperurice-
mia, urate nephropathy does occur in certain
clinical settings associated with gout, and there
are changes in kidney function and pathology
that occur in these situations. Intermittent or per-
sistent albuminuria may occur in 20–40 % of
patients with gout, and glomerular filtration rates
are often decreased [248, 279, 280]. Further,
there is often loss of the capacity to generate a
maximally concentrated urine. These findings
may be present even when hypertensive patients
are excluded from consideration. Of course, these
laboratory abnormalities are nonspecific and
offer no clue to their underlying causation. The
gross examination of kidneys from patients with
gout may show small white specks with a granu-
lar feel at the corticomedullary junction, and the
renal pelvis may contain uric acid calculi. If
pyelonephritis has been superimposed, the kid-
neys may be small and contracted. The classic
pathologic finding in gout is the tophus that is
represented by a monosodium urate deposit sur-
rounded by chronic inflammatory cells (lympho-
cytes, macrophages, and plasma cells) and foreign
body giant cells. In order to preserve urate crys-
tals in tissues, proper fixation and staining are
necessary. Fixing tissues in absolute alcohol
rather than using aqueous fixation that dissolves
the crystals preserves crystalline deposits. If tis-
sues are then viewed by polarizing microscopy,
the crystals are intensely anisotropic. With the de
Galantha silver stain after alcohol fixation, urate
crystals appear brown-black, whereas with hema-
toxylin-eosin staining after formalin fixation, the
crystals are a deep blue color [281]. Without
proper fixation or with aqueous fixation, only
clefts may be observed where crystals have been
deposited. The most characteristic locations
5 Clinical Aspects of Gout and Associated Disease States
for such crystalline deposits are the papillae,
renal pyramids, and the medullary interstitium.
Pathological examination may also show glom-
eruli hyalinization, vascular changes of hyperten-
sion, interstitial fibrosis, tubular atrophy, and
other nonspecific changes. To confirm the chemi-
cal structure of the renal crystalline deposits,
X-ray diffraction analyses of kidneys from gouty
patients have been examined [282]. Monosodium
urate monohydrate crystals were detected in
patients with gouty arthritis, and in addition,
some gouty patients showed calcium oxalate
monohydrate crystals. The latter finding again
demonstrates the poorly understood linkage
between uric acid metabolism and calcium
oxalate crystals and calculi. In contrast to these
findings, evaluation of patients at autopsy with
acute leukemia and increased nucleic acid turn-
over, the crystals were composed of uric acid.
Some investigators have indicated that the glom-
erular changes are distinctive for gout and differ-
ent from those of nephrosclerosis and diabetic
glomerulosclerosis, whereas others do not agree
with this conclusion [281, 283, 284]. Despite the
identification of uric acid crystals in pathological
specimens from the kidney, several studies docu-
ment the difficulties in making the diagnosis of
gout based on postmortem findings [285, 286]. In
one postmortem study of individuals succumbing
to renal insufficiency, only four patients had a
history of acute gouty arthritis, whereas 17
patients manifested renal medullary microtophi
[285]. In another postmortem study, 26 % of the
individuals had medullary microtophi with no
underlying cause discernable [286]. In contrast to
these studies of medullary microtophi, investiga-
tions of kidney biopsies, and postmortem exami-
nations of patients with familial juvenile gouty
nephropathy, a disease to be discussed subse-
quently, only occasional crystals have been
observed [287, 288]. These studies all support the
notion that urate microtophi are not diagnostic of
gout per se, and they raise the question as to
whether chronic hyperuricemia causes significant
renal damage. As a practical matter, patients with
serum uric acid levels in excess of 10 mg/dl in
females or 13 mg/dl in males should be carefully
evaluated and treated, if necessary, to prevent
Decreased Uric Acid Excretion
renal damage. It is imperative that measurements
of uric acid be accompanied by laboratory evalu-
ations of renal function since serum uric acid val-
ues rise in the face of impaired renal function. In
prepubertal children, the serum uric acid may
remain in the normal range despite gross over-
production of uric acid since the renal clearance
is high in children. In those patients in whom
elevated levels of uric acid are of concern, the
inherited abnormalities in purine metabolism,
hypoxanthine-guanine phosphoribosyltransferase
deficiency, and phosphoribosylpyrophosphate
synthetase superactivity must be excluded.
Acute Uric Acid Nephropathy
Acute uric acid nephropathy is usually not asso-
ciated with gout due to overproduction of uric
acid, but it is frequently observed in clinical set-
tings where treatment regimens cause massive
tissue destruction, nucleic acid catabolism, and
the presentation of large quantities of urate to
the kidney. As a result, the collecting tubules,
renal pelvis, and ureters become obstructed with
uric acid crystals. A variety of conditions with
increased turnover of nucleic acids and uric acid
formation can result in the precipitation of uric
acid crystals in the collecting ducts and ureters
leading to acute obstruction of urine outflow and
renal failure. Acute uric acid nephropathy is the
result of uric acid overproduction and overex-
cretion. It is commonly observed in association
with malignancies and rapid cell destruction
such as myeloproliferative disease, lymphomas,
leukemias, polycythemia, megaloblastic ane-
mias, hemolytic anemias, epileptic seizures, and
thalassemia [289–298]. Other disorders that
have been reported in association with hyperuri-
cemic acute renal failure include metastatic
seminoma, metastatic medulloblastoma, ductal
carcinoma of breast cancer, gout, heritable
deficiencies of hypoxanthine-guanine phospho-
ribosyltransferase, and gout with markedly
acidic urine [294, 299–302]. In malignancies,
acute renal failure usually arises in course of
chemotherapy or radiation if the patient is not
hydrated and pretreated with allopurinol. One
117
report indicates that NSAID therapy may be a
risk factor for this disorder since it has the capac-
ity to alter vascular tone through the impairment
of vasodilatory substances [303]. In addition to
the hyperuricemia, this syndrome may be accom-
panied by hyperphosphatemia, hyperkalemia,
and hypocalcemia [297].
The diagnosis should be suspected in those
clinical settings known to be associated with the
syndrome, the presence of a serum uric acid level
in the range of 10–30 mg/dl in the adult, and olig-
uria or anuria. Urinalysis may or may not reveal
the presence of uric acid crystals. The ratio of
uric acid to creatinine in the urine usually exceeds
1.0, whereas in other causes of renal failure, it is
less than one [304]. The management of this dis-
order requires its early recognition, the use of
allopurinol prophylaxis, the judicious use of
sodium bicarbonate to alkalinize the urine, and
increase urate solubility. Fluid loading to main-
tain a urine output in the range of 2–3 l/day and
the use of loop diuretics are helpful in the treat-
ment of this syndrome. If diuresis cannot be
established, then hemodialysis must be initiated
to remove the toxic metabolites.
Finally, there are four disease associated with
gout for which the mechanism(s) of the hyperuri-
cemia remains incompletely understood. Both
autosomal dominant polycystic kidney disease
and medullary cystic disease have been reported
in association with gout and uric acid calculi, but
the frequency of this association is probably quite
low. Familial juvenile gouty nephropathy is an
unusual kidney disease that is seen with gout and
renal failure, yet urate microtophi are exceed-
ingly rare in this disease. This disorder may
become a more prominent cause of gout as more
physicians realize that this familial nephropathy
may not express gout as an early manifestation of
the disease. Gout may be observed in family
members before the propositus with renal failure
expresses the articular symptoms of gout.
Nephrogenic diabetes insipidus and some other
types of diabetes insipidus may present with
hyperuricemia, and the mechanism by which this
occurs is thought to be through changes in the
urinary collecting system caused by the increased
volume of urine excreted in this disorder.
118
Autosomal Dominant Polycystic Kidney
Disease (ADPKD)
Autosomal dominant polycystic kidney disease is
a relatively common heritable kidney disease that
may not be apparent clinically until the fourth or
fifth decade of life [305]. Further, only about 50
% of the recipients of the disease progress to
renal failure [306]. Surprisingly, ADPKD is one
of the causes of chronic renal failure that is asso-
ciated with gouty arthritis [266, 307, 308].
Furthermore, this heritable nephropathy is asso-
ciated with nephrolithiasis, and the renal calculi
are composed of uric acid and/or calcium oxalate
[309, 310]. The frequency of the occurrence of
polycystic kidney disease, renal calculi, and gout
is not known, and kidney transplantation for
polycystic kidneys with the use of cyclosporine
to prevent organ rejection may prevent an accu-
rate ascertainment of this association. Nonetheless,
the presence of gouty arthritis and/or uric acid
nephrolithiasis in a patient with impaired renal
function should alert the clinician to the possibil-
ity that polycystic kidney disease may be the
underlying condition. Certain clinical parameters
may increase the chances that polycystic kidneys
are present. Nocturia and inability to concentrate
the urine maximally are, in some patients, early
signs of the disease [311, 312]. A careful abdom-
inal examination may reveal a palpable mass.
Pain and hematuria are also frequent clinical
signs of the presence of polycystic kidneys. The
character of the pain is variable as is the cause. In
most cases, no cause for the aching or heaviness
in the flank is identifiable, but in some cases,
bleeding into the cyst or perinephric tissues may
precipitate complaints of a painful abdomen or
back. The pain is usually more severe with peri-
nephric hemorrhages and may be stabbing in
character. Since kidney infection and renal cal-
culi are often components of ADPKD, pain of
more than several days duration must be care-
fully evaluated. Renal malignancy is a rare com-
plication and should be suspected when weight
loss, fever, and anemia are also present. Gross or
microscopic hematuria may result from a variety
of causes including cyst rupture into the kidney
pelvis, renal stones, infected cysts, or rarely
5 Clinical Aspects of Gout and Associated Disease States
malignancy. Examination of the urine for casts
and crystals is critical to exclude the presence of
red blood cell casts and the rare occurrence of
glomerulonephritis as well as the presence of cal-
cium oxalate stones. If pain persists, is severe,
and none of the above conditions are shown to
exist, it may simply be the result of an enlarge-
ment of one or more of the renal cysts. Cyst aspi-
ration and the use of a sclerosing agent may
improve this clinical problem [313]. Care must
be taken to prevent any deterioration in kidney
function as a result of these painful conditions.
This makes careful evaluations of such painful
episodes a prerequisite to preventing the progres-
sion of renal failure.
A comprehensive review documents the high
frequency of urinary tract infections as a compli-
cation of ADPKD, especially in females [314].
Both parenchymal and cyst infections are possi-
ble in this disorder, and cyst infections are often
more difficult to diagnose because of the absence
of systemic signs (fever, bacteremia, leukocyto-
sis, and pyuria) of infection. Cyst infection is
often unilateral, unaccompanied by pyelonephri-
tis or bacteriuria/bacteremia, and may only mani-
fest itself by tenderness or pain on palpation over
the infected cyst. Pinpointing the offending
organism may also be difficult and, at times, may
require aspiration and culture of the cyst contents.
Removal of any renal pelvic calculi is imperative
since infections may persist if stones are not
removed. Infected cysts may also be imperme-
able to some lipid-soluble antibiotics making the
use of nonpolar, lipid-soluble antibiotics a neces-
sity. As noted previously, calcium oxalate and
uric acid stones also occur in about 20 % of
patients with ADPKD and may complicate the
treatment of infections [310].
Another common complication of ADPKD is
the development of hepatic cysts that occur in
more than 50 % of patients, especially with
increasing age [315]. Women are more prone to
such cysts, especially in the post-pregnancy state
or in the course of estrogen therapy [316]. These
facts suggest that hormone therapy such as the
use of birth control medications must be carefully
considered in patients with ADPKD. Despite the
gross hepatic enlargement that may occur in
Decreased Uric Acid Excretion
polycystic kidney disease, liver function is usu-
ally in the normal range except in those rare situ-
ations in which hepatic venous obstruction occurs
or another hepatic disorder coexists [317, 318]. If
the liver enlargement becomes a burden to the
patient as a result of pain or abdominal disten-
sion, hepatic cysts can be drained percutaneously
or partial hepatectomy performed [319]. Other
gastrointestinal manifestations include pancreatic
and splenic cysts, but these are infrequent com-
plications. The occurrence of diverticulosis may
be a complication of ADPKD, but whether it is a
part of the kidney disease or a coincidental finding
has not been established [320, 321].
The most serious complications of ADPKD
are those involving the vascular system.
Hypertension that most often precedes the onset
of renal failure is a significant risk factor for the
progression of the renal insufficiency and its car-
diovascular alterations [322, 323]. Recognition
of elevated blood pressure is most important in
males with genetic mutations in chromosome 16
(PKD1 – polycystic kidney disease 1) since the
male gender and PKD1 gene mutations increase
the risk of the progression to renal insufficiency
[323–325]. Other cardiac manifestations includ-
ing mitral and aortic valve lesions, coronary
artery, and abdominal aortic aneurysms have also
been reported in association with ADPKD, but
their presence may or may not be directly linked
to the kidney disease. They may be related to the
hypertension or, in fact, coincidental findings
[326–331]. Of this group of vascular complica-
tions, cerebral aneurysms are the most serious
and life-threatening problems [332–335]. They
occur in about 5 % of patients with ADPKD. To
avoid the disastrous consequences of aneurysmal
rupture, rigorous control of hypertension in all
patients and screening of patients with a family
history of cerebral aneurysms or those with cen-
tral nervous system symptomatology should be
undertaken. It should also be noted that an auto-
somal recessive form of polycystic kidney dis-
ease exists, but it has not been reported in
association with gout [336, 337]. Although this
form of cystic disease may permit survival beyond
the first two decades of life, most patients die in
the newborn period. This short survival time may
119
explain the absence of gout and uric acid stones
in this patient group.
In summary, the presence of flank masses by
palpation and hypertension in association with
pain, hematuria, urinary tract infection, nephro-
lithiasis, or obstructive uropathy and a history of
gout should alert the clinician to the possible
existence of polycystic kidney disease. The key
to the diagnosis in most cases is a family history
of kidney disease and, in some cases, early death
from kidney failure. Since about 10 % of those
undergoing chronic renal dialysis have ADPKD,
dialysis may be a starting point to identify poly-
cystic kidney disease in other affected family
members. As can be seen from the complex pre-
sentations of ADPKD, the management and
ongoing care of such patients is not simple. In
fact, the management of the articular disease is
probably the least challenging aspect of the
underlying disorder.
Since cystic disease occurs as an acquired dis-
order in those patients undergoing hemodialysis
or peritoneal dialysis, it is important to exclude
this possibility when evaluating the incidence of
ADPKD in dialysis populations [338, 339]. To
differentiate the presence of simple cysts and
avoid false-negative results, criteria have been
established for the diagnosis of ADPKD by ultra-
sonography used in conjunction with DNA test-
ing [306, 340, 341]. These criteria propose that
the adult over 60 years of age is required to have
at least four cysts in each kidney for the diagnosis
of ADPKD, whereas those between the ages of
39 and 59 years require only two cysts per kid-
ney. In those younger than 30 years of age, diag-
nosis requires at least two cysts in one kidney for
diagnosis.
Medullary Cystic Disease (MCD)
Medullary cystic disease is another autosomal
dominant trait manifesting kidney disease that
has been reported in association with gout [266].
The frequency of the latter association is unknown.
The disease is difficult to identify in clinical
settings until its azotemic phase since flank
pain, hematuria, hypertension, and nephrolithiasis
120
infrequently accompany the disorder. The kidneys
are not enlarged or palpable. Cysts are present
at the corticomedullary margin, deep medulla,
and papilla. Tubular atrophy, glomerular hyalini-
zation, basement membrane thickening, and
patchy interstitial fibrosis are also associated
with these cysts. Sparse infiltration with chronic
inflammatory cells is also observed [342–345].
Like ADPKD, an early sign of medullary cystic
disease is a loss of maximal concentrating capac-
ity. Salt wasting, hyponatremia, and extracellular
fluid contraction are often transient manifesta-
tions of this disease, but here again, a family his-
tory of kidney disease may be first clue to the
presence of MCD. Further, clinical signs may not
be recognized until azotemia occurs. Since the
frequency of gout in patients with MCD may
be very low, such underlying pathology should
be excluded when one is presented with a patient
with renal failure and gout. Thus, MCD, ADPKD,
and familial juvenile gouty nephropathy are
autosomal dominant traits that need to be con-
sidered when patients present with gout and a
family history of renal insufficiency. Of course,
all the inherited X-linked recessive traits associ-
ated with gout may also present with renal fail-
ure, and such patients must also be carefully
assessed to determine the true underlying cause
of their gout.
Familial Juvenile Gouty Nephropathy
(FJGN)
Hyperuricemia is a common feature of renal fail-
ure from any cause, but gout in association with
chronic renal disease is unusual except in asso-
ciation with specific renal diseases [346, 347].
Renal failure may complicate the Lesch-Nyhan
syndrome, the Kelley-Seegmiller syndrome, and
phosphoribosylpyrophosphate synthetase super-
activity. This complication usually occurs when
these disorders are unrecognized or have compli-
cations secondary to renal calculi or infection.
The usual clinical parameters of these genetic
disorders have been discussed previously. Several
additional heritable disorders need discussion
here. Gout, renal disease, and hyperuricemia have
5 Clinical Aspects of Gout and Associated Disease States
been identified in a number of families, and more
recently this constellation of findings has been
given the name familial juvenile gouty nephropa-
thy [348–369]. This heritable renal disease is also
inherited as an autosomal dominant trait and may
be misdiagnosed as a familial nephropathy before
the appearance of gouty arthritis in a member of
a family under evaluation. The disease often
manifests itself as progressive renal failure. Since
clinical gout and hypertension are inconsistent
features of the disease, some clinicians have
omitted gout from the name and use the term
familial juvenile hyperuricemic nephropathy
[348, 366, 367, 370]. The onset of this disease is
usually in the adolescent years or in early adult-
hood, but clinical gout has been reported in a
9-year-old female [359]. As is clearly apparent,
gout in a female at this young age is distinctly
unusual, and such an occurrence should alert cli-
nicians to the possible presence of FJGN or one
of the other heritable disorders causing gout.
Thus, the occurrence of gout at or before puberty
and especially in a female is a clinical marker for
FJGN. Hyperuricemia out of proportion to the
degree of renal failure should also raise the pos-
sibility of FJGN. Characteristically, the renal dis-
ease progresses rapidly, and end-stage renal
disease usually occurs in the third or fourth
decade of life. Hypertension is not an early com-
ponent or consistent feature of the disease, but
when it occurs, the renal disease is aggravated.
Aggressive treatment of the hypertension and
hyperuricemia is essential if the deleterious
effects of these abnormalities on the progression
of the renal disease are to be impeded.
Renal biopsies from patients with FJGN are
most interesting because they rarely, if ever, show
deposition of urate crystals in the renal tissue.
Such biopsies do show severe tubulointerstitial
nephropathy with sclerotic glomeruli and peri-
glomerular fibrosis. A patchy distribution of
tubular atrophy is also seen along with interstitial
fibrosis and chronic inflammatory cell infiltrates.
Basement membranes of the tubular cells may be
thickened as well [361, 363, 365, 369, 371].
In addition to the characteristic progres-
sive renal insufficiency with its exaggerated
hyperuricemic response, a significantly decreased
Decreased Uric Acid Excretion
fractional excretion of uric acid (FEurate) is pres-
ent, and this abnormality may precede the onset
of the renal disease [367]. The mean clearance of
uric acid relative to creatinine (FEurate) in those
patients with FJGN is usually less than 5 %,
whereas normal values for this measurement
usually range between 7 and 12 %. This fact
emphasizes the need to evaluate carefully every
member of an affected family since early recog-
nition and treatment of this disorder can prevent
the progression of the renal disease. One addi-
tional parameter of this disease is the occurrence
in some families of neonatal death or death in
utero [213]. Although the frequency of this pos-
sible complication of FJGN is unknown and the
cause for it is also presently unknown, the pos-
sible mating of two FJGN heterozygotes leading
to the occurrence of a lethal homozygote cannot
be excluded at this time.
One final parameter of this disorder is of great
significance and emphasizes the need for the rec-
ognition of this disease. Recent data have deter-
mined that FJGN is the most common disorder
studied by the Purine Research Laboratory at
Guy’s Hospital in London [358]. It accounts for
32 % of the cases of defective purine metabolism
evaluated in this laboratory over the past decade.
If one adds to this percentage, the frequency of
hypoxanthine-guanine phosphoribosyltransferase
deficiency, these two diseases, FJGN and
HGPRTase deficiency, make up more than 50 %
of the cases evaluated by this group. Like
HGPRTase deficiency, FJGN appears to have a
worldwide distribution since reports of the disor-
der have been recorded in Asia, Australia, Europe,
and the United States.
In summary, the autosomal dominant trait,
familial juvenile gouty nephropathy, should be
considered in any case of documented familial
renal disease, and the occurrence of gout in any
individual, male or female, of less than 30 years
of age should alert the clinician to the possibility
of this progressive renal disease associated with
gout. The molecular cause for this disorder
remains unknown; however, several hypotheses
have been proposed as potential contributors to
its pathogenesis. These include the presence of
an unrecognized metabolite capable of inhibiting
121
urate secretion, a possible structural defect related
to interstitial nephritis, thickened tubular base-
ment membrane and atrophic tubules, or a defect
in the basolateral or brush-border membrane pro-
teins regulating urate transport. Recent studies
have identified a urate transporter in rats [372–
374]. Although the interactions between urate
transport and other organic anions in the human
are complex and variations in transport mecha-
nisms among various animal species make
extrapolations to the human difficult, the cloning
of this urate transporter in rats may provide a
stepping stone to the understanding of human
urate transport and perhaps the abnormality
responsible for FJGN. Studies of this transport
system might also provide clues to the more com-
mon lesion in urate underexcretors documented
in primary gout. In the absence of a molecular
probe for FJGN, clinicians must diagnose the dis-
ease from clinical findings in association with
relatively sophisticated renal excretory studies
measuring the decrease in the fractional excre-
tion of urate. The latter studies must exclude a
variety of other causes of decreased fractional
excretion of urate including drugs, toxic sub-
stances, severe respiratory acidosis, diabetic
ketoacidosis, metabolic alkalosis, and lead intox-
ication [263, 375–379].
Nephrogenic Diabetes Insipidus (NDI)
Nephrogenic diabetes insipidus is a rare cause of
gout since it has only been reported in three
patients from different families [380, 381].
Hyperuricemia has been reported in transient
nephrogenic diabetes insipidus in association
with pregnancy and hepatic failure, central dia-
betes insipidus, and nephrogenic diabetes insipi-
dus unrelated to pregnancy [381–385]. In
nephrogenic diabetes insipidus, the presence of a
lowered urate to creatinine clearance in associa-
tion with a normal 24-h urinary uric acid level
has suggested that the hyperuricemia in this
disorder is the result of renal handling of urate
[381]. This may result from the dilated renal col-
lecting system characteristically observed in this
X-linked recessive trait or the high filtration
122
fraction known to occur in this disease. The rarity
of gout may be due to better diagnostic methods
and earlier recognition of the disorder. Diabetes
insipidus has been discussed as a clinical entity
associated with gouty arthritis, but its occurrence
in the modern literature is almost never reported.
The diagnosis of diabetes insipidus is made by
documenting the abnormally large volumes of
dilute urine (>50 ml/kg body weight in 24 h) with
a urine specific gravity of less than 1.010 or an
osmolality of less than 300 mOsmol/kg body
weight [386]. The presence of a serum sodium
concentration of greater than 143 meq/l and a
low specific gravity (<1.010) is highly suggestive
of diabetes insipidus if there is no history of a
high sodium intake. The absolute diagnosis of
NDI is confirmed by the failure to concentrate
the urine in the presence of high plasma vaso-
pressin concentrations and after the parental
administration of vasopressin or desmopressin
[387]. The chronic excretion of large volumes of
urine in untreated patients causes hydronephro-
sis, hydroureter, and megacystis, all of which
may contribute to the hyperuricemic state [388].
Female carriers of X-linked NDI may be com-
pletely asymptomatic or have varying degrees of
polyuria and polydipsia [389, 390].
The differential diagnosis of NDI includes
a deficiency of the synthesis of the antidiuretic
hormone, arginine vasopressin, in the supraop-
tic nuclei or a deficiency in the secretion of the
hormone by the posterior pituitary. The cause
for these so-called neurogenic types of diabetes
insipidus may either be genetic (autosomal domi-
nant inheritance of a mutant prepro-arginine-
vasopressin-neurophysin II gene) or acquired.
The acquired forms include defects due to trauma,
malignancies, infections, granulomatous disease,
autoimmune disorders, or vascular abnormali-
ties. Acquired forms of NDI may also result from
lithium treatment, hypokalemia, cystic renal
disease, or urinary tract obstruction. Primary
polydipsia is the result of psychiatric illness and
altered thirst mechanisms. It can arise as a result
of compulsive water drinking or other mental
aberrations. If there is a high water intake and a
plasma osmolality of greater than 295 mOsmol/
kg body weight or a serum sodium of greater than
5 Clinical Aspects of Gout and Associated Disease States
143 meq/l, primary polydipsia can be excluded as
a consideration.
In summary, gouty arthritis has rarely been
reported in association with diabetes insipidus;
however, hyperuricemia is not an uncommon
association with this disorder.
Uric Acid Nephrolithiasis
Introduction
Of the three types of renal afflictions (urate neph-
ropathy, acute uric acid nephropathy, and uric
acid nephrolithiasis) associated with gout, renal
calculi are probably the most common. Since uric
acid lithiasis may occur in a variety of heritable
and acquired disorders, patients with such calculi
must be carefully evaluated to determine the
underlying cause and to institute the proper pre-
ventative measures. This is especially important
in the absence of a stone for chemical analysis or
in the presence of a radiolucent filling defect by
radiographic examination. In these clinical set-
tings, the following considerations must be taken
into account. Pure uric acid stones are far less
common than either pure or mixed stones com-
posed of calcium oxalate or calcium phosphate.
Uric acid stones may be composed of pure uric
acid or occur in combination with calcium
oxalate, calcium phosphate, or magnesium phos-
phate. Pure uric acid stones are radiolucent (non-
opaque) and not visible on plain X-rays, whereas
their combination with calcium salts may make
them visible on plain X-rays. Chemical analysis
is used to determine the primary component of
any stone. In the United States, about 5–10 % of
all the reported kidney stones are composed of
uric acid [391–397]. In other areas of the world,
the frequency of uric acid stones is much higher.
For example, the prevalence of uric acid stones is
38 % in Iran, and in West Algeria, uric acid stones
account for 31 % of the calculi seen in children
[398, 399]. In addition to this propensity for the
frequency of urate stones to be increased in hot
climates, the prevalence of such stones appears to
be increased in workers exposed to heat stress in
their occupations [400]. Thus, climate, chronic
Uric Acid Nephrolithiasis
dehydration, and ethnic factors must be consid-
ered when evaluating uric acid nephrolithiasis.
At physiological pHs (7.4), uric acid is almost
completely ionized and is in its soluble form, as
it exists in normal plasma. At low pH values,
uric acid is quite insoluble. As the pH drops
from 7.4, a greater proportion of the molecule is
converted to its non-ionized form. Free (non-
ionized) uric acid is much less soluble than its
ionized counterpart. At the pKa point of uric
acid (pH – 5.75), there are equal parts of ionized
and non-ionized forms of the molecule. At a pH
of 5.2, only about 20 % of uric acid is ionized.
On the basis of these properties, the lower the
urine pH, the less soluble uric acid becomes,
and the more likely for it to precipitate. A num-
ber of studies have confirmed these parameters
by measuring urine pH in uric acid stone form-
ers. In patients with gout and uric acid stones,
the urine pH was less than 5.0 in 48 %, whereas
in the matched controls, only 15 % had a urine
pH below 5.0 [401]. In idiopathic uric acid
nephrolithiasis, a disorder shown to have nor-
mal plasma and urinary uric acid levels, low
urine pH has been documented as a primary
contributor to stone formation [402–404].
Additional evidence for the role of urinary pH in
the formation of uric acid stones comes from
patients with chronic acidosis or chronic diar-
rhea. The classic example is observed in patients
with an ileostomy who manifest increased uri-
nary uric acid excretion, a decreased urinary
pH, and a decreased volume of urine. Such
patients are at increased risk for the formation
of uric acid lithiasis [405, 406]. In addition to
low urinary pH, dehydration from any cause
resulting in a low urine volume with increased
urinary uric acid concentrations and a low uri-
nary pH may create a setting for uric acid stone
formation.
Probably the most significant parameter caus-
ing the generation of uric acid stones is an
increased urinary uric acid concentration (hyper-
uricosuria). Adult males usually excrete about
800 mg of uric acid in a 24-h urine on a standard
diet, whereas females excrete between 700 and
750 mg/24 h. Data on the frequency of uric acid
nephrolithiasis show that in those patients with
123
Table 5.6 Uric acid nephrolithiasis
Heritable causes
Lesch-Nyhan syndrome (X-linked recessive trait)
Kelley-Seegmiller syndrome (X-linked recessive trait)
Phosphoribosylpyrophosphate synthetase
superactivity (X-linked recessive trait)
Polycystic kidney disease (autosomal dominant trait)
Heritable uric acid lithiasis (autosomal dominant trait)
Glycogen storage disease type I (autosomal recessive
trait)
Cystinuria (autosomal recessive trait)
Hemoglobinopathies (autosomal recessive trait)
Thalassemias (autosomal recessive trait)
Hereditary renal hypouricemia (autosomal recessive
trait)
Acquired causes
Myeloproliferative disorders
Lymphoproliferative disorders
Multiple myeloma
Polycythemia
Pernicious anemia
Uricosuric induced
Simulators of uric acid lithiasis
Iatrogenic xanthine lithiasis
Oxypurinol calculi
2, 8-Dihydroxyadenine lithiasis
Hereditary xanthinuria
Hyperuricosuric calcium oxalate lithiasis
levels of urinary uric acid of less than 300 mg/
day, the prevalence of uric acid stones is 11 %,
whereas this prevalence figure increases to 50 %
when the urinary uric acid is more than 1,000 mg/
day [407]. Data similar to these have also been
reported from studies of patients with the inher-
ited disorders of purine metabolism, HGPRTase
deficiency, and PRPP synthetase superactivity. In
both these genetic errors, the urinary uric acid
concentration usually exceeds 1,000 mg/day
[408–410]. Thus, low urinary pH and increased
urinary uric acid concentrations are the most fre-
quent predisposing factors leading to uric acid
nephrolithiasis. For discussion of the clinical dis-
orders associated with renal calculi, the causes of
kidney stones have been divided into heritable
and acquired diseases associated with uric acid
stones and those kidney stones that may mimic
uric acid stones. This classification is summa-
rized in Table 5.6.
124
Heritable Causes of Uric Acid
Nephrolithiasis
Any disorder associated with uric acid calculi
demands the early identification of the underly-
ing cause so that the morbidity and, at times, the
mortality from the kidney stones and their com-
plications can be prevented. This is especially
true for infants and children suffering from the
Lesch-Nyhan syndrome, a disorder in which uric
acid stones are quite common. Patients with this
disease are often difficult to manage and may be
confused with cerebral palsy patients. They are
often uncooperative and their central nervous
system disease makes their surgical management
even more difficult. In fact, the author lost a
patient who required nephrectomy secondary to
kidney stones and a treatment-resistant kidney
infection. The post-nephrectomy course was
hampered by the movement disorder and the
inability to control the patient’s attempts to dam-
age the operative site with its drain. The patient
eventually succumbed to an overwhelming
infection.
In children with the Lesch-Nyhan syndrome,
urinary uric acid excretion ranges between 40
and 70 mg of uric acid per kilogram of body
weight per day [411, 412]. Gouty arthritis cannot
be used as a marker for the presence of this
X-linked disorder since gout is rare in the Lesch-
Nyhan syndrome. Further, hyperuricemia may
not be a manifestation of the disease since chil-
dren have a high renal clearance of this metabo-
lite. If renal failure is not present, uric acid
excretion relative to creatinine is usually elevated
to levels twice or four times normal [348, 358]. In
the presence of renal failure, these findings may
be masked [358, 413]. In this setting, the serum
uric acid is usually markedly elevated in the range
of 13–17 mg/dl. Renal ultrasonography is a use-
ful noninvasive tool that may detect crystal neph-
ropathy. Of course, the absolute diagnosis must
be determined by enzyme analysis. Urolithiasis
and crystal nephropathy with or without renal
failure are also observed in other inherited disor-
ders such as adenine phosphoribosyltransferase
deficiency with 2,8-dihydroxyadenine stone for-
mation, xanthine dehydrogenase deficiency with
5 Clinical Aspects of Gout and Associated Disease States
xanthine stones, phosphoribosylpyrophosphate
synthetase superactivity with uric acid stones,
and glycogen storage disease with either uric acid
or calcium oxalate stones. Even if the diagnosis is
known and the patient is receiving allopurinol
therapy, the possibility of iatrogenic xanthine or
oxypurinol calculi also needs to be considered
[414–416]. In the two other inherited X-linked
recessive traits, Kelley-Seegmiller syndrome
(partial hypoxanthine-guanine phosphoribosyl-
transferase deficiency) and phosphoribosylpyro-
phosphate synthetase superactivity, uric acid
calculi have also been reported. More than three-
quarters of the patients with Kelley-Seegmiller
syndrome have a history of renal stones. Although
renal calculi also occur in the PRPP synthetase
defect, data for the frequency of stone in this
enzyme abnormality are lacking. Nonetheless, if
the serum uric acid is greater than 10–13 mg/dl or
the urinary uric acid excretion is greater 1,000 mg/
day, an error in purine metabolism or a disorder
causing an increased turnover of nucleic acids
must be excluded. Lower levels of these parame-
ters do not exclude the presence of a heritable
disorder in purine metabolism.
Uric acid calculi may or may not be associated
with gout. In some cases, the kidney stone may
precede the onset of acute gouty arthritis. For
example, a urinary calculus may be the first sign
of the Kelley-Seegmiller syndrome or phosphori-
bosylpyrophosphate synthetase superactivity.
Kidney stones or painful crystalluria may also be
the presenting sign of the Lesch-Nyhan syn-
drome, and in this disorder, gout is rare.
Even though HGPRTase deficiency and PRPP
synthetase superactivity are probably the most
common heritable diseases associated with gout
and uric acid calculi, several other inherited dis-
eases have been documented as causes of gout
and/or uric acid calculi. About 20 % of the
patients with autosomal dominant polycystic kid-
ney disease (ADPKD) develop renal stones com-
posed of either uric acid or calcium oxalate [310,
417–420]. Calcifications within the kidney paren-
chyma may also be observed in ADPKD and
must be differentiated from stones within the uri-
nary collecting system. The best method for
accomplishing this differentiation is by computed
Uric Acid Nephrolithiasis
tomography (CT) scanning of the kidneys [340].
Like all disorders associated with nephrolithiasis,
it is essential to identify stones that are not passed
and may result in urinary tract infection, obstruc-
tive uropathy, and deterioration of kidney func-
tion. CT scanning or magnetic resonance imaging
is useful for identifying and excluding retained
stones.
Renal disease including stone formation is
also common in adult glycogen storage disease
[421, 422]. Contrary to common opinion, most
renal calculi in this disorder are composed of cal-
cium oxalate, but uric acid stones have also been
reported. Alterations in uric acid metabolism
occur in glycogen storage disease as a result of
the decreased renal urate clearance due to lacti-
cacidemia and ketonemia as well as the increased
production of uric acid secondary to ATP degra-
dation and increased pentose phosphate shunt
activity [90, 423–425]. Distal renal tubular acido-
sis, hypocitraturia, nephrocalcinosis, and hyper-
calcemia have also been described in glycogen
storage disease, and these abnormalities may also
contribute to stone formation [143].
Even though pure cystine stones are the most
common renal calculi observed in homozygous
cystinuria, a few individuals with this relatively
rare autosomal recessive disorder of renal tubule
and gastrointestinal amino acid transport may
also develop calcium oxalate or uric acid stones
[426, 427]. The occurrence of hyperuricemia,
normal renal function, and cystinuria has been
reported in the older literature [428–431]. The
presence of uric acid nephrolithiasis in cystinuric
patients has also been cited in a review of the dis-
eases associated with uric acid stones [432].
The primary clinical expression of cystinuria
is the formation of renal/bladder stones and their
complications including urinary tract infections
and urine outflow obstruction. Urinary excretion
of cystine as well as arginine, lysine, and orni-
thine in various patterns is increased. The genetic
defect in the renal tubule has been localized to a
human gene whose protein, a type II membrane
glycoprotein, is a carrier protein for the reabsorp-
tion of cystine and other dibasic amino acids
across the proximal brush border membrane
[433, 434]. The cystine transport gene has been
125
localized to different chromosomes depending on
the amino acid excretion pattern [435–437].
Recent publications have also documented an
increase in uric acid excretion in some cystinuric
patients [438]. In this series of patients, hypercal-
ciuria and hypocitraturia have also been demon-
strated in 22 and 44 % of the patients, respectively.
The “abnormality” of uric acid excretion is of
interest for several reasons. These data confirm
an association between increased urinary uric
acid and stone formation as will be discussed
subsequently in calcium oxalate stone formers. It
also emphasizes the concept that acid urines,
known to occur in both gout and cystinuria, pro-
vide a setting for the formation of stones in meta-
bolic abnormalities other than those associated
with errors of purine metabolism. In a more spec-
ulative realm, there is the possibility that altera-
tions in renal transport proteins such as those
mutated in cystinuria may affect other renal trans-
port mechanisms including those responsible for
uric acid transport. In summary, cystinuria is a
very rare cause of uric acid stones, and this asso-
ciation may be related to defects in transport
proteins.
One report of uric acid nephrolithiasis has
been observed in three independent families in
the absence of hyperuricemia and gout [439].
This form of uric acid lithiasis is inherited as an
autosomal dominant trait and is not reported to be
associated with any other abnormalities. No fur-
ther reports of this familial form of uric acid stone
formation have appeared in the literature. Rarely,
uric acid nephrolithiasis has been observed in
specific hemoglobinopathies and thalassemias,
especially in the presence of severe hemolysis.
Finally, in contrast to these disorders associ-
ated with uric acid overproduction, hypouricemia
and defective urate reabsorption are components
of hereditary renal hypouricemia, and the latter
disorder often gives rise to uric acid kidney
stones. Neither this disease nor cystinuria is
accompanied by gouty arthritis. Hereditary renal
hypouricemia is a rare autosomal recessive trait
with a defect in postsecretory reabsorption of
urate producing hypouricemia, increased renal
clearance of urate, hyperuricosuria, and/or hyper-
calciuria. In 25 % of the homozygotes with this
126
disorder, calcium oxalate or uric acid stones have
been reported [440–444]. In other reported cases
where hypouricemia exists in the absence of any
pattern of inheritance, calcium oxalate stones
have recovered [445]. These cases show quite
different dysfunctions in tubular transport, and
only one of the patients has been documented to
have a defect in presecretory urate reabsorption.
Interestingly, the latter patient had multiple
myeloma associated with type 2 renal tubular aci-
dosis. The other patients described in this publi-
cation could be classified as idiopathic renal
hypercalciuria [446]. Thus, some patients with
hypouricemia may present with calcium oxalate
stones but do not fit into the true definition of
hereditary renal hypouricemia even though they
have an increased clearance of uric acid.
One useful key to the recognition of patients at
the greatest risk for uric acid stones is the quanti-
tation of urinary uric acid since those with stones
usually excrete more than 900–1,000 mg of uric
acid/day. Some patients with hereditary renal
hypouricemia also manifest hypercalciuria [440,
444, 447, 448]. The mechanism for this hypercal-
ciuria has been shown to be due to increased
intestinal reabsorption in some, but in others, the
cause for the hypercalciuria remains unknown
[440, 444]. The degree of hypercalciuria in sev-
eral patients has also been shown to lead to a
decreased bone density and osteoporosis [447,
449]. There has been a suggestion that the mas-
sive increase in urate clearance may lead to acute
uric acid nephropathy with associated renal
parenchymal deposition of urate, but absolute
proof of such lesions in hereditary renal hypouri-
cemia is lacking [450, 451].
The key to the diagnosis of hereditary renal
hypouricemia lies initially with the identification
of a low serum urate level that is less than 2.5 mg/
dl in adult males and less than 2.1 mg/dl in adult
females [452–455]. Such low serum urate levels,
as noted previously, could be the result of either a
low production of uric acid or an excessively high
rate of urate clearance. In the case of hereditary
renal hypouricemia, it is the latter process that
leads to the low serum urate levels. In normal
individuals, the fractional urate clearance (clear-
anceurate/glomerular filtration rate) ranges between
5 Clinical Aspects of Gout and Associated Disease States
7 and 12 %, whereas in those with hereditary
renal hypouricemia, this value is increased to lev-
els between 30 and 90 %. Even though the inter-
pretation of data acquired using pyrazinamide to
localize the renal tubular transport of urate is
imprecise, both pyrazinamide and probenecid
tests have been used to determine the defects in
renal tubular transport. As discussed previously,
normal renal handling of uric acid by the kidney
includes 100 % filtration at the glomerulus,
98–100 % reabsorption in the proximal tubules,
50 % distal proximal tubular secretion, 40–45 %
postsecretory reabsorption, and 5–10 % secre-
tion. On the basis of these analyses of human
renal urate transport, five different defects of
urate transport have been postulated: a complete
transport deficiency (no uric acid secretion or
reabsorption), a complete urate reabsorption
deficiency, a presecretory reabsorption defect, a
postsecretory defect, and secretory superactivity.
These postulated defects express themselves to
variable degrees as a result of individual varia-
tion, overlapping renal tubular functions, and
probably the existence of partial deficiencies in
transport proteins. When FCurate values and the
alterations in pyrazinamide and probenecid are
tabulated from the reports of hereditary renal
hypouricemia documented in the literature, the
following tubular transport deficiencies have
been identified. More than half the subjects
reported can be classified as having defective pre-
secretory urate reabsorption [440, 447, 448, 456–
462]. Other reported cases of hypouricemia and
renal transport defects fit the pattern of different
transport abnormalities [449, 459, 462–464].
To differentiate hereditary renal hypouricemia
from a variety of other genetic and acquired dis-
orders is not a simple task since there are a large
number of conditions that can give rise to hypou-
ricemia (Table 5.4). Since there are fewer than 50
cases of hereditary renal hypouricemia in the
world’s literature, more frequent causes of hypou-
ricemia need to be excluded initially. Probably
the most common cause of hypouricemia is
related to the use of pharmacologic agents that
affect renal tubular urate transport. Salicylates
(aspirin) are known to have a paradoxical effect
on uric acid excretion since this drug causes uric
Uric Acid Nephrolithiasis
acid retention by inhibiting uric acid secretion at
low doses (serum salicylate levels of 5–10 mg/
dl), whereas at high doses (serum salicylate lev-
els of >15 mg/dl), the drug inhibits uric acid reab-
sorption and causes uricosuria [262, 465]. Some
radiocontrast agents (iapanoic acid, megulamine
iodipamide, and sodium diatrizoate) have urico-
suric properties and can also lower serum uric
acid levels [466, 467]. Glyceryl guaiacolate also
causes hypouricemia [453, 468]. The less com-
monly used uricosuric drugs such as probenecid,
sulfinpyrazone, and phenylbutazone may also
reduce serum uric acid levels. Dicoumarol and
outdated tetracycline also reduce serum uric acid
levels; the latter drug causes a Faconi-like syn-
drome [469]. Thiazides and loop diuretics, known
commonly for their capacity to cause hyperurice-
mia, increase the fractional excretion of urate
acutely, whereas when the volume of extracellu-
lar fluid is contracted from their use, diuretics
decrease the fractional excretion of uric acid.
Mannitol, when used as an osmotic diuretic, also
causes uricosuria and hypouricemia. More
recently, the angiotensin II receptor antagonist,
losartan, has been shown to be a potent uricosuric
[470–474]. In fact, losartan is a more potent
inhibitor of urate reabsorption than probenecid
on the basis of its high affinity for a human urate/
anion renal tubular exchanger. Finally, high-dose
ascorbic acid (>4 g/day) causes hypouricemia.
There are some rare heritable enzymatic
deficiencies that also cause hypouricemia.
Classical xanthinuria type 1 arises as a result of
a mutation in the xanthine dehydrogenase gene,
and such a mutation leads to the inability of the
human host to convert hypoxanthine and xanthine
to uric acid. This heritable disorder is discussed
briefly here and in more detail in the subsection
dealing with those disorders that simulate uric
acid nephrolithiasis. Patients with xanthinuria
may be totally asymptomatic or present with uro-
lithiasis and its complications [475–483]. Renal
damage may be severe leading to chronic renal
failure in some patients while in others, the sever-
ity of the kidney problem has resulted in nephrec-
tomy and terminal uremia [484–490]. In addition
to xanthine stones that are nonopaque by plain
X-rays unless they contain calcium oxalate,
127
arthralgias and arthritis similar to gouty arthritis
have been reported in some cases of xanthinu-
ria [477, 484, 489, 491–494]. It has been pos-
tulated that this is a crystal-induced arthropathy
since animal studies have documented that xan-
thine crystals can cause an inflammatory arthri-
tis [484]. In some cases of xanthinuria, muscle
inflammatory responses have been documented
in association with muscle aches and pains [484,
489, 493–497]. The significance of this recessive
trait, hereditary xanthinuria, is that it may present
with a migratory arthritis and a radiolucent kid-
ney stone under clinical circumstances mimicking
the Lesch-Nyhan syndrome, adenine phospho-
ribosyltransferase deficiency with its radiolu-
cent 2,8-dihydroxyadenine stones, and in a few
other disorders. For this reason, identification of
the chemical constituents of any kidney stone is
critical for diagnosing the underlying disorder.
Xanthine, uric acid, and 2,8-dihydroxyadenine
stones all give a purple color in the murexide test
[498]. Thus, the murexide test may provide a clue
to an underlying defect in purine metabolism, but
an ultraviolet spectrum at pH 2.0 and 10.0, col-
umn chromatography, infrared or mass spectrom-
etry, or X-ray crystallography are necessary for
the precise identification of xanthine and these
other causes of stones.
One child with hypouricemia and mental retar-
dation has been reported [499–501]. Presumably,
this child acquired the hypouricemic state as a
result of a decreased level of PRPP accompa-
nied by a significant decrease in de novo purine
nucleotide biosynthesis. The remainder of the
inherited hypouricemic disorders is those asso-
ciated with the Fanconi syndrome and defec-
tive proximal renal tubular urate reabsorption.
These hypouricemic disorders include Wilson’s
disease, galactosemia, hereditary fructose intol-
erance, cystinosis, and the Hartnup syndrome
[502–509].
There are a number of acquired causes of
hypouricemia that need to be excluded before
hereditary renal hypouricemia can be invoked as
the cause for the hypouricemia in an isolated patient
without a family history of an inherited renal tubu-
lar disorder. Malignancies including pulmonary
neoplasms, lymphomas (Hodgkin’s disease), and
128
multiple myeloma are often associated with
hypouricemia and a Fanconi-like renal tubular
disorder [510–515]. Hypouricemia may also be a
marker for the inappropriate secretion of antidi-
uretic hormone (ADH) and the resultant expan-
sion of the extracellular volume [516–518]. In
addition to its role as a marker of the possible
presence of an underlying malignancy, the degree
of hypouricemia appears to correlate with the
activity of the disease in Hodgkin’s lymphoma
[510, 511, 519]. The remaining disorders causing
renal hypouricemia are the renal tubular lesions
of heavy metal intoxication and liver disease with
jaundice [520–523]. A search of the literature
does not reveal any cases of nephrolithiasis in
renal hypouricemia except for those observed in
hereditary renal hypouricemia.
In this group of heritable diseases associated
with nephrolithiasis, the pattern of inheritance is
variable and may assist in identifying the under-
lying disease. X-linked inheritance is observed
with the Lesch-Nyhan syndrome, Kelley-
Seegmiller syndrome, and phosphoribosylpyro-
phosphate synthetase superactivity, whereas
autosomal dominant inheritance occurs with
polycystic kidney disease, heritable uric acid lith-
iasis, and medullary cystic disease. The latter dis-
ease can present with kidney stones, but such an
occurrence is rare. Finally, a variety of autosomal
recessive diseases including glycogen storage
disease, thalassemia, hemoglobinopathies, hered-
itary renal hypouricemia, and cystinuria may also
be associated with uric acid lithiasis.
Acquired Causes of Uric Acid
Nephrolithiasis
Acquired disorders of uric acid lithiasis are prob-
ably of greater significance to recognize in the
pediatric population than in adults. Children are
susceptible to urolithiasis in association with
hematological malignancies either as a result of
chemotherapy or as an initial event due to
increased nucleic acid turnover [524–527]. Uric
acid nephrolithiasis may also occur in children
due to nonmalignant conditions [528]. In adults,
reports of uric acid nephrolithiasis in association
5 Clinical Aspects of Gout and Associated Disease States
with hematological and chronic hemolytic ane-
mias are documented in the older literature, but
the recent literature is marked by the absence of
such case reports [407, 432, 529]. The lack of
reports in the modern literature probably results
from an earlier recognition of hematological dis-
orders and the use of allopurinol to prevent acute
uric acid nephropathy and nephrolithiasis.
In some instances, uric acid stones may com-
plicate non-hematological cancers and are asso-
ciated either with increased tumor cell turnover
or the lysis of tumor cells induced by therapeutic
agents [530]. When primary and secondary gout
are considered, the incidence of renal calculi in
primary gout (no underlying disease other than
gout) is only 22 %, whereas this percentage is
roughly doubled in secondary gout (gout second-
ary to another disorder or drug use) [407]. Thus,
the causes of secondary gout with the potential
for uric acid nephrolithiasis include myeloprolif-
erative and lymphoproliferative disorders, multi-
ple myeloma, secondary polycythemia, pernicious
anemia, chronic hemolytic anemias, certain
hemoglobinopathies, polycythemia vera, myeloid
metaplasia, Gaucher disease, chronic myelocytic
anemia, and thalassemias [125, 398, 530].
Several unusual and rare causes of uric acid
nephrolithiasis exist in addition to those associ-
ated with hematological diseases. Uric acid lithia-
sis has been reported in association with the
uncommon occurrence of a calculus forming in
patients with functioning renal transplants [531,
532]. A variety of causes may contribute to this
clinical problem including excessive purine intake
and cyclosporine treatment [532, 533]. Uric acid
calculi in this clinical setting represent only one
type of calculus seen in renal transplant patients
since stones composed of other substances have
been reported in renal transplant patients with
hyperparathyroidism, hyperoxaluria, and even
adenine phosphoribosyltransferase deficiency
[534, 535]. Another rare cause of uric acid neph-
rolithiasis has been observed in some patients who
have abused laxatives and, as a result, acquired
hypokalemia, extracellular volume depletion, sys-
temic alkalosis, and elevated angiotensin levels
[536, 537]. This complication is seen most fre-
quently in females and should be suspected when
Uric Acid Nephrolithiasis
an ammonium urate calculus is found in conjunc-
tion with a sterile urine. Urine specimens in these
cases may test positive for phenolphthalein.
Finally, a single case of Prader-Willi syndrome
has been reported with uric acid urolithiasis
[538]. According to the authors of this case
report, the stone resulted from the hyperphagia
that occurs in Prader-Willi syndrome. The latter
syndrome is characterized by hypotonia in
infancy, hyperphagia, mental retardation, hypog-
onadotrophic hypogonadism, and small hands
and feet. Despite the relatively common occur-
rence of this genetic syndrome, this is the only
report of a uric acid calculus associated with this
or other hyperphagic syndromes [539–541]. Even
though this is an inherited genetic disorder, it is
discussed under acquired disorders since the
cause for the uric acid stone is overeating.
Nephrolithiasis Mimicking Uric
Acid Stones
A variety of renal calculi composed of non-urate
metabolites may mimic uric acid stones due to
their nonopaque appearance on plain radiographs
or as filling defects on excretory urograms, and at
times, non-urate stones occur in patients with dis-
orders that may resemble dysfunctions similar to
those observed with alterations in uric acid
metabolism. The differential diagnosis of such
filling defects includes uric acid calculi, xanthine
calculi, 2,8-dihydroxyadenine stones, indinavir-
associated lithiasis, blood clots (especially in
those with hemophilia), renal cysts, inflammatory
processes, and renal carcinoma [542]. Since
unexplained filling defects observed radiographi-
cally in the renal pelvis and elsewhere are nondi-
agnostic, CT scanning has been recommended as
a tool for diagnosing nonopaque calculi [543,
544]. The principal simulators of uric acid calculi
are stones composed of xanthine, 2,8-dihydroxy-
adenine, and oxypurinol.
Iatrogenic Xanthinuria and Xanthine
Lithiasis
Xanthine calculi have been described in patients
with disorders requiring allopurinol therapy, and
129
sophisticated stone analyses are necessary to
characterize the chemical composition of the
stone [545–548]. The use of allopurinol to con-
trol gross endogenous uric acid overproduction
causes significant elevations in plasma xanthine
levels. The latter state may be greatly exagger-
ated when HGPRTase is deficient, and the host is
unable to reutilize hypoxanthine. The renal clear-
ance of xanthine approaches and may exceed the
glomerular filtration rate resulting in an elevated
urinary xanthine concentration that may exceed
the limited solubility of this metabolite in urine
[475, 495, 549]. In fact, the urinary concentration
of xanthine may approach or exceed 1 mmol/
mmol of creatinine in patients treated aggres-
sively for urate overproduction or malignancies
as a result of the markedly elevated serum xan-
thine concentrations and the high renal clearance
of xanthine. Normally, the urinary xanthine con-
centration is less than 0.01 mmol/mmol of creati-
nine. The calculated solubility of xanthine in the
urine at pH 5.0 and 7.0 is 5 and 13 mg/dl (~ 0.03–
0.07 mmol/dl), respectively, and these values can
often be exceeded during allopurinol therapy in
certain clinical settings [550]. For these reasons,
xanthine crystalluria, xanthine stones, and acute
renal failure may occur in patients treated with
allopurinol, and these complications are most
likely to be observed in the Lesch-Nyhan syn-
drome, the Kelley-Seegmiller syndrome, and in
patients being treated aggressively with
allopurinol to protect them from excessive tissue
nucleic acid breakdown and increased uric acid
production during chemotherapy or radiotherapy
of malignancies [545, 548, 551–556].
Except for the characteristics of the stones
themselves, the remainder of the parameters of
allopurinol-induced xanthine stone formation is
defined by laboratory findings. Xanthine stones
are usually brown or orange brown in color and
can easily be transected. The cut surface is lami-
nated and may contain a core of calcium oxalate
[476–478, 489]. They may be detected by renal
ultrasonography [416]. Since the renal clear-
ance of oxypurine is so high, the serum oxypu-
rine concentration may only rise to 0.5–2.0 mg/
dl, whereas the normal plasma oxypurine
concentrations are in the range of 0.1–0.3 mg/dl
130
[550, 557–560]. The ratio of xanthine to hypox-
anthine during allopurinol therapy is roughly
2:1 [561]. The serum uric acid in the course of
maximal allopurinol therapy may be reduced to
2–3 mg/dl in the presence of normal renal func-
tion. The urinary excretion of oxypurines is often
the key to identifying the potential for crystalline
deposits of xanthine or the formation of xanthine
stones. Urinary oxypurines in patients receiving
allopurinol are usually in the range of 50 to over
100 mg/day in contrast to the normal urinary con-
centration of less than 20 mg/day. In patients who
develop acute renal failure, urinary xanthine con-
centrations may be as high as 152 mg/mmol of
creatinine (~ 1.5 g/g of creatinine), whereas the
normal urinary xanthine concentration usually
less than 1.5 mg/mmol of creatinine (15 mg/g of
creatinine).
An animal model of xanthine crystalluria has
been used to evaluate the course of renal damage
in pigs fed a high purine diet in the form of gua-
nine along with allopurinol [562]. This model
demonstrated the extensive renal tubular damage
associated with the deposition of xanthine crys-
tals in the pig kidney. The crystalline deposits
were found predominantly in the distal renal
tubules and collecting ducts and caused wide-
spread tubular epithelial damage including inter-
stitial edema and inflammation. Such renal
inflammatory lesions and scarring may well be
the precursor of permanent renal damage such as
in the case in those patients who manifest renal
insufficiency during the course of allopurinol
therapy.
The differential diagnosis of allopurinol-in-
duced xanthinuria includes a number of disorders
associated with the renal handling of urate as
well as hereditary xanthinuria. Clues to the pres-
ence of these disorders include the presence of
hypouricemia and the use of allopurinol. However,
reduced levels of serum uric acid may not be
observed in the face of renal failure when
allopurinol is prescribed. Thus, iatrogenic xanthi-
nuria with stone formation is probably best diag-
nosed by ultrasonography and the measurement
of urinary purine metabolites. A variety of sensi-
tive methods are available for the identification of
hypoxanthine and xanthine in the plasma and
5 Clinical Aspects of Gout and Associated Disease States
urine [485, 563–570]. To assure the validity of
the results, a second method of xanthine analysis
is usually performed. One simple method for
assuring that a peak is truly xanthine is to rerun
the sample after digestion of the xanthine with an
excess of xanthine oxidase. Another method is to
run the sample using two different separation
systems for the detection of the metabolite.
The clinical management of xanthine stones is
similar to the management of any other kidney
stone. In cases where the overproduction of urate
requires high doses of allopurinol to control,
allopurinol dose reduction and alternative means
to regulate urate production such as diet and/or
alternative drugs should be considered.
Hereditary Xanthinuria
Hereditary xanthinuria is a rare autosomal reces-
sive trait that may affect the kidney and/or mus-
culoskeletal system. There are two subtypes of
this disorder that have been identified by differ-
ences in their capacity to oxidize allopurinol
[571]. Subsequently, these variations have been
expanded to include the ability or inability to oxi-
dize pyrazinamide [572, 573]. Type I xanthinuria
represents a deficiency of xanthine dehydroge-
nase (XDH) with normal activity of aldehyde
oxidase (AOX) and sulfite oxidase. The absence
of XDH results in the inability to oxidize hypox-
anthine and xanthine to uric acid [571–573]. This
deficiency also results in the inability to oxidize
pyrazinoic acid to 5-hydroxypyrazinoic acid.
Since type I-deficient patients have aldehyde oxi-
dase activity, allopurinol is converted to oxy-
purinol, thiopurinol to oxythiopurinol, and
pyrazinamide to 5-hydroxypyrazinamide [571–
576]. Type II xanthinuria results from a deficiency
of both xanthine dehydrogenase and aldehyde
oxidase. These enzyme deficiencies block the
oxidation of N-methylnicotinamide to 2- to
4-pyridonecarboxamides, allopurinol to oxy-
purinol, and pyrazinamide to 5-hydroxypyrazin-
amide [480, 495, 570, 571, 577, 578]. Roughly,
50 % of the patients with classical xanthinuria
will also manifest a deficiency in aldehyde
oxidase.
The principal clinical manifestations of classi-
cal xanthinuria are related to the formation of
Uric Acid Nephrolithiasis
xanthine stones or acute renal failure secondary
to xanthine crystalluria. About 40 % of the
patients with classical xanthinuria are diagnosed
on the basis of urolithiasis or its associated com-
plications such as renal colic, urinary tract infec-
tions, hematuria, or other clinical difficulties
associated with crystalluria. Another 20 % of the
cases are completely asymptomatic and often
discovered through family studies by the pres-
ence of hypouricemia. Although urolithiasis and
crystalluria may occur at any age from birth
through the eighth decade, most of the cases are
first observed in infants who express the disease
by nonspecific signs such as irritability, insom-
nia, vomiting, and poor weight gain [479]. Like
the Lesch-Nyhan syndrome and APRTase
deficiency, hereditary xanthinuria may lead to
serious renal disease and even requiring nephrec-
tomy. Indeed, some patients may die from uremia
[481, 485–490]. Children may also present with
significant signs of kidney damage such as
clubbed calices or hydronephrosis. Renal tubular
acidosis and hypercalciuria have also been
reported in association with xanthinuria [482].
Approximately 10 % of xanthinurics may have
either articular symptoms or myalgias. Pain,
tightness, and stiffness in the distal upper and
lower limbs are the usual complaints of adults
with this presentation [477, 484, 489, 493, 497,
579, 580]. In some of those patients with muscle
symptoms, xanthine and hypoxanthine crystals
have been observed as crystal deposits in skeletal
muscle biopsy specimens [581, 582]. There is
speculation that muscle exercise induces lactic
acid production, a fall in tissue pH, and the depo-
sition of oxypurines as a result of the insolubility
of these metabolites in an acid environment.
Recurrent migratory polyarthritis is also
observed in a small number of patients with xan-
thinuria [477, 484, 489, 491–493]. Since xan-
thine crystals can cause arthritis in animal
models, it has been hypothesized that crystal
deposition may cause the synovitis observed in
humans with xanthinuria [484]. However, to
date, no hypoxanthine or xanthine crystals have
been found in synovial fluid or tissues from xan-
thinuric patients. There also appears to be an
increased frequency of duodenal ulcers in
131
patients with hereditary xanthinuria for reasons
that are not clear at this time [484, 566, 571,
583–586]. Other diseases observed in associa-
tion with hereditary xanthinuria appear to be
coincidental findings.
The absolute diagnosis of hereditary xanthi-
nuria requires an in vitro assay for xanthine dehy-
drogenase/xanthine oxidase activity in duodenal
or jejunal mucosa biopsies. Liver biopsies may
also be assayed for enzyme activity, but the inher-
ent dangers in closed liver biopsies obviate the
use of the liver as a source of the enzyme unless
laparotomy is planned or other reasons necessi-
tate liver biopsy. Sample preparations and assay
conditions are discussed along with references to
detailed assays in other resources [587]. Analysis
of muscle tissue from affected patients may be
suggestive of the underlying condition on the
basis of their elevated concentrations of hypox-
anthine and xanthine [484, 493, 580, 582].
Control values for hypoxanthine were less than
30 ng/mg dry weight of muscle, and values from
affected muscle were 8–12 times higher than the
control value. Control values for xanthine were
less than 50 ng/mg dry weight of muscle, whereas
in affected muscle, the values were six to nine
times higher than the controls.
Since the enzyme, xanthine dehydrogenase/
xanthine oxidase, converts hypoxanthine and
xanthine to uric acid, in its absence, plasma and
urinary uric acid levels are low and often are
undetectable. Plasma levels of oxypurines vary
between 0.01 and 0.07 mg/dl in healthy individu-
als. Urinary oxypurine concentrations vary
depending on the purine dietary intake, but males
in the United Kingdom evaluated on a low purine
diet have been reported to excrete between 4 and
10 mg/24 h of hypoxanthine and a similar quan-
tity of xanthine [587]. In xanthinuria, plasma
xanthine concentrations are elevated to levels
between 0.15 and 0.61 mg/dl, whereas plasma
hypoxanthine concentrations are less than
0.068 mg/dl [479, 485, 566, 567, 569, 576].
Urinary excretion of oxypurines in hereditary
xanthinuria is dominated by xanthine in ratio of
4:1 (xanthine/hypoxanthine), and the total oxy-
purine concentration in the urine ranges between
300 and 450 mg/24 h.
132
The differential diagnosis of hereditary xan-
thinuria depends in large part on what parameter
is selected for comparison with other diseases. If
stone formation is the clinical marker, then a
large variety of causes of urolithiasis must be
considered. However, if the stone is radiolucent,
then the differential diagnosis can be restricted to
causes related to stones composed of uric acid,
xanthine, cystine, or 2,8-dihydroxyadenine. It is
important to recognize that about 85 % of stones
contain calcium so that completely radiolucent
stones are the exception rather than the rule.
Perhaps the best method for differentiating these
disorders is to measure the serum uric acid levels
and the urinary uric acid levels. If hyporuricemia
is present (serum uric acid levels of less than
2.5 mg/dl) and is selected as the clinical marker
for comparison, two mechanisms can be evalu-
ated to assess its causation: decreased uric acid
production and increased excretion of urinary
uric acid. Further, low urinary uric acid levels
identify those patients with decreased uric acid
production such as hereditary xanthinuria, severe
liver disease, phosphoribosylpyrophosphate syn-
thetase deficiency, and allopurinol/oxipurinol
administration (iatrogenic xanthinuria) [453, 499,
588–590]. A complete classification of hypouri-
cemia is tabulated in Table 5.7. Population sur-
veys have determined the frequency of
hypouricemia to be in the range of 0.5–1.0 %
[453, 455, 591–594]. The frequency of hypouri-
cemia appears to be significantly lower in the
Japanese population [595, 596]. These popula-
tion surveys document the low frequency of
hypouricemia and the fact that most hypourice-
mic patients manifest urate hypersecretion in
contrast to those with hyposecretion. Further,
hypouricemia is frequently associated with the
use of medications.
2,8-Dihydroxyadenine Lithiasis
Not all radiolucent stones are composed of uric
acid and 2,8-dihydroxyadenine (2,8-DHA), and
xanthine stones are also nonopaque and may be
difficult on clinical grounds alone to differentiate
from uric acid stones. 2,8-Dihydroxyadenine cal-
culi have often been misdiagnosed as uric acid
stones on the basis of their chemical analysis or
5 Clinical Aspects of Gout and Associated Disease States
their radiolucency [597, 598]. The unusual
occurrence of a radiopaque 2,8-dihydroxyade-
nine stone emphasizes the need to investigate
stone composition by sophisticated analyses
[599]. 2,8-DHA urolithiasis results from a com-
plete or partial deficiency of the purine salvage
enzyme, adenine phosphoribosyltransferase
(APRTase). This deficiency is characterized by
a spectrum of clinical findings related to the
excretion of the insoluble metabolite, 2,8-dihy-
droxyadenine, by the kidney. Despite the neph-
rotoxicity of 2,8-DHA, roughly 15 % of patients
with this defect remain completely asymptom-
atic. When crystals or stones of 2,8-DHA are
formed, urinary tract infections, hematuria, dys-
uria, colicky pain, obstructive uropathy, or, in a
few clinical settings, acute anuric renal failure
may occur [600]. Unfortunately, if unrecog-
nized in a timely fashion and untreated, some
patients will develop chronic renal insufficiency
requiring chronic dialysis and/or renal trans-
plantation [601–605]. The presence of radiolu-
cent renal calculi and chemical analyses of
kidney stones have led to the misdiagnosis of
uric acid stones [601, 602, 606–608]. This con-
fusion resulted primarily because simple chemi-
cal analyses such as the phosphomolybdate and
murexide tests, the ultraviolet spectrum in alka-
line solutions, and thermogravimetric analyses
give identical results for uric acid and 2,8-dihy-
droxyadenine [601, 602, 609–612]. However,
these stones can be distinguished from uric acid
by performing an ultraviolet spectrum of the
stone components in both alkali and acid solu-
tions, by using infrared analysis, by mass spec-
trometry, or by X-ray crystallography [605, 606,
609, 610, 613].
APRTase deficiency is inherited as an auto-
somal recessive trait, and heterozygotes are usu-
ally completely asymptomatic [614–619]. Two
homozygote subsets of this disorder can be dis-
tinguished by enzymatic analysis. Type I
deficiency is characterized by a complete absence
of adenine phosphoribosyltransferase activity in
erythrocyte lysates, whereas patients with type II
deficiency have about 10–25 % of normal activity
in their lysates. Patients with type I deficiency
have been identified worldwide, whereas those
Uric Acid Nephrolithiasis 133

Table 5.7 Causes of hyperuricemia 8-hydroxyadenine, and 2,8-dihydroxyadenine is

I. Decreased uric acid production 1.0:0.03:1.5, respectively. These urinary purines
A. Hereditary xanthinuria are excreted because of the inability to salvage
B. Severe liver disease adenine by the enzyme, adenine phosphoribo-
C. Phosphoribosylpyrophosphate synthetase deficiency syltransferase. In the absence of this enzyme,
D. Allopurinol/oxipurinol administration adenine is converted by xanthine oxidase to
II. Increased excretion of uric acid 8-hydroxyadenine and 2,8-dihydroxyadenine.
A. Inborn error of membrane urate transport The latter compound can be analyzed by the
1. Hereditary renal hypouricemia methods cited previously or by high performance
B. Acquired renal hypouricemia
liquid chromatography [565, 620, 621]. Affected
1. Inappropriate ADH secretion
individuals vary in their capacity to solubi-
2. Multiple myeloma
lize 2,8-dihydroxyadenine in their urine, and in
3. Lymphomas (Hodgkin’s disease)
some, the urine may be supersaturated with this
4. Pulmonary neoplasms
C. Fanconi syndrome
metabolite. An increased capacity to solubilize
1. Idiopathic this metabolite may explain the asymptomatic
2. Wilson’s disease subjects with adenine phosphoribosyltransferase
3. Cystinosis deficiency.
4. Type I glycogen storage disease Treatment of this metabolic error can be
5. Galactosemia undertaken by restricting purine intake in the
6. Hereditary fructose intolerance diet, prescribing a high fluid intake, and using
7. Heavy metal intoxication allopurinol at 10 mg/kg body weight in a child or
8. Outdated tetracycline use 300 mg/day in an adult. Allopurinol dose reduc-
9. Liver disease and jaundice tion is essential in patients with renal insufficiency,
10. Neoplasms and plasma oxypurinol levels should be moni-
D. Drugs tored to avoid the toxicity of this allopurinol
1. Benzbromarone metabolite. Since 40 % of the cases of APRTase
2. Calcium ipodate
deficiency are reported in children, and such
3. Dicoumerol
affected subjects may develop chronic renal
4. Estrogens
insufficiency, it is critical to consider this disease
5. Ethyl biscoumacetate
in any child presenting with crystalluria, radiolu-
6. Glyceryl guaiacholate
7. Iodopyracet
cent stones, or renal failure. Although APRTase
8. Iopanoic acid deficiency is a rare cause of nephrolithiasis in the
9. Phenylbutazone adult, it has been identified in patients in their
10. Probenecid seventh decade.
11. Salicylates
12. Sodium diatrizoate Oxipurinol Calculi
13. Sulfinpyrazone Disorders with hyperuricosuria are often treated
14. Carbamazepine with the hypoxanthine analog, allopurinol
15. Beta-lactamases (4-hydroxypyrazolo (3,4d)-pyrimidine), to
reduce the serum and urinary uric acid levels
[557, 558]. Allopurinol not only inhibits xan-
with type II deficiency have been confined to thine oxidase activity to prevent the conversion
those of Japanese ancestry. of hypoxanthine and xanthine to uric acid, but
Laboratory analyses of affected patients dem- allopurinol itself is also converted by xanthine
onstrate that there is no alteration in serum or uri- oxidase to a less soluble metabolite, oxipurinol
nary uric acid levels. The urine contains adenine (4,6-dihydroxypyrazolo (3,4d) pyrimidine)
and two of its metabolites: 8-hydroxyadenine [622]. Since oxipurinol is an analog of xanthine,
and 2,8-dihydroxyadenine. The ratio of adenine, it shares certain of its chemical properties with
134
xanthine [549]. Oxipurinol is much less soluble
than its parent compound, allopurinol. At 37 °C,
allopurinol has a solubility of 0.75 mg/ml in
water, whereas oxipurinol has a solubility of
0.35 mg/ml under the same conditions [623]. On
the basis of its relative insolubility, oxipurinol
crystalluria and stone formation have been
observed under certain circumstances. In one
patient with purine overproduction who was
treated with both oxipurinol and allopurinol,
oxipurinol lithiasis has been reported [624]. A
second case of oxipurinol lithiasis has been
reported in a woman with a long history of
regional enteritis and recurrent uric acid stones
[625]. This patient was initially treated with
600 mg of allopurinol, and subsequently the
dose was increased to 900 mg a day. At a dose of
300 mg of allopurinol a day, this patient excreted
in her urine 47 mg of xanthine and 243 mg of
oxipurinol over a 24-h time period. On 900 mg
of allopurinol, these same urinary outputs
increased to 145 mg of xanthine and 440 mg of
oxipurinol for a 24-h time period. Chemical
analysis of the nonopaque calculus passed by
this patient documented its major component to
be oxipurinol with a minor fraction being
xanthine.
Uncommon Cause of Nonopaque Stones
One uncommon cause of uric acid calculi and
non-urate radiopaque stones deserves mention.
Indinavir sulfate, an effective protease inhibitor
of human immunodeficiency virus type 1, has
been recognized as a cause of radiolucent stone
formation [626–629]. These calculi, like uric acid
stones, are not visible on plain radiographs, and
CT scans are also nondiagnostic [626]. Excretory
urograms and/or renal ultrasound must be used to
visualize these stones. Indinavir stones are
observed in about 10–20 % of patients taking this
medication, and a history of AIDS is an impor-
tant historical clue to the possibility of such a
stone. Infrared spectrophotometry provides a
structural analysis of indinavir calculi that is
compatible with indinavir monohydrate [627].
Some reports have indicated that HIV-positive
hemophiliacs are at increased risk for indinavir-
associated nephrolithiasis [629].
5 Clinical Aspects of Gout and Associated Disease States
Hyperuricosuric Calcium Oxalate
Nephrolithiasis
Several additional problems may lead to confu-
sion when the diagnosis of a renal calculus is
entertained. First, gouty subjects also have an
increased frequency of calcium oxalate stones
as well as other stone constituents [626, 627].
Second, other radiolucent stones (xanthine and
2,8-dihydroxyadenine) may be confused with
nonopaque uric acid stones, and third, the use
of uricosuric agents or hypouricemic drugs
may give rise to uric acid stones or in the case
of allopurinol, xanthine, or oxipurinol stones.
Finally, hyperuricosuric calcium oxalate nephro-
lithiasis occurs in recurrent calcium stone form-
ers, and the increased urinary uric acid levels may
lead to confusion with an abnormality in purine
metabolism and gout.
Calcium oxalate is the most common constitu-
ent of kidney stones, and it would not be surpris-
ing to find stones containing this metabolite in
patients with gout. In fact, a survey of gouty
patients showed that 80 % of stones are com-
posed of pure uric acid, whereas 12 % of the
stones contained only calcium oxalate [407].
Mixed stones composed of uric acid and calcium
oxalate have been observed as have stones com-
posed of uric acid and calcium phosphate and
uric acid and magnesium ammonium phosphate.
In calcium stone formers, there is a poorly under-
stood link between uric acid excretion and stone
formation in that the higher the urinary uric acid
excretion, the more likely stone formation will
occur. If the data related to calcium stone formers
are analyzed roughly 26 % manifest hyperurico-
suria and 12 % have hypercalciuria [628].
Analyses of such patients show that in part, the
increased urinary uric acid excretion in affected
individuals is related to a high purine intake;
however, in other cases, the urinary uric acid
excretion remained at higher than normal levels
even after 7 days on a purine-free diet [629].
Thus, both excessive dietary purines and uric acid
overproduction from endogenous purine synthe-
sis play a role in the generation of increased uri-
nary uric acid levels. Further, patients with
hyperuricosuric calcium oxalate nephrolithiasis
have more serious disease as measured by the
Drug-Induced Hyperuricemia and Gout
rate of cystoscopy and other surgical procedures,
and it appears that their stone formation peaks at
age 40–45 in contrast to other stone formers
whose disease peaks at age 25–30 years [630]. It
appears to be a predominantly a disease of males
which may account for the increased intake of
purines in the diet. The most critical evidence
linking uric acid metabolism with recurrent cal-
cium oxalate stone formation is the capacity of
allopurinol to reduce new stone formation [628,
631–634]. Since allopurinol has no effect on cal-
cium oxalate crystal growth or nucleation, these
studies conclude that the mechanism of allopurinol
action must be through a reduction in urate excre-
tion. Further, in those patients who have hyper-
calciuria in association with hyperuricosuria, the
use of allopurinol together with thiazide treat-
ment has been shown to be effective in reducing
stone formation. For patients who cannot tolerate
allopurinol, it has been shown that potassium cit-
rate therapy reduces the rate of stone recurrence
[635]. The rationale for this treatment is the fact
that citrate lowers calcium oxalate supersatura-
tion and may block urate-induced crystallization
of calcium oxalate [636]. The most compelling
issue related to this disorder is at what level of
urinary uric acid should treatment be initiated.
Urinary uric acid levels of 800 mg/day or greater
in men and levels of 600 mg/day in women are
probably reasonable measurement points when
allopurinol therapy should be considered. If
dietary indiscretions are suspected as contribu-
tors to the disease process, suggesting a reduction
in high purine-containing foods might be useful.
There have been studies to suggest that uric
acid promotes the crystallization of calcium
oxalate from urine, but these studies have been
refuted by others [637, 638]. Thus, the relation-
ship between uric acid and calcium oxalate stone
formation remains unresolved.
Drug-Induced Hyperuricemia
and Gout
A wide variety of pharmacologic agents can
cause hyperuricemia and, in some, gouty arthri-
tis. The principal mechanism of hyperuricemia
135
induced by drugs is by an alteration in the renal
tubular excretion of urate, but some drugs are
known to increase the formation of uric acid. The
most important drugs causing hyperuricemia
include diuretics, salicylates, pyrazinamide, nic-
otinic acid, ethambutol, ethanol, fructose, cyto-
toxic agents, and cyclosporine.
Diuretics
Diuretics represent a significant cause of hyperu-
ricemia and gout because of their common usage
in clinical therapeutics. The most frequently
implicated agents are furosemide, ethacrynic
acid, and benzothiadiazines. Some diuretics such
as spironolactone, amiloride, triamterene, and
organomercurials do not result in hyperuricemia.
Two primary mechanisms contribute to the hype-
ruricemic response: volume contraction of the
extracellular fluid leading to an increase in solute
(urate) reabsorption or decreased tubular urate
secretion [261, 639–644].
The clinical features of diuretic-induced gout
do not differ from other causes of gout, but epide-
miological studies have characterized diuretics as a
risk factor for the development of gout [645–653].
Diuretics have also been documented as a
significant contributing factor to gouty arthritis in
females [645, 647–650, 653]. Most females who
have gout are postmenopausal, and many have an
underlying disease such as renal insufficiency and/
or hypertension. Both females and males who
develop gout may be receiving diuretics and
cyclosporine after kidney transplantation. In con-
trast to the increased frequency of diuretic use in
females who develop gout, males most often have
chronic alcohol abuse as an associated condition
[652]. In those females who develop gout in the
premenopausal state, anorexia nervosa may be the
underlying disease and may be associated with
diuretic abuse [646]. One must recognize that in
this setting, the patient may try to deceive the phy-
sician by denying the use of diuretics or other drugs
to lose weight. Postmenopausal diuretic-induced
gout occurs frequently at age 50 or above, whereas
gout observed in association with renal allografts
is most often seen in younger patients. Thus, in
136
diuretic-induced gout, there is often another medi-
cal condition that results in the impairment of urate
excretion. If necessary, diuretic-induced hyperuri-
cemia can easily be treated and controlled with
uricosuric agents [654]. It is not reasonable to treat
diuretic-induced hyperuricemia unless there is a
rationale for such treatment such as recurrent acute
gouty arthritis or renal insufficiency. If for some
reason uricosuric agents are contraindicated,
allopurinol can be used [655, 656].
Salicylates
Salicylates have a paradoxical effect on the han-
dling of uric acid by the kidney. At doses of less
than 2.5 g/day, salicylates cause the retention of
uric acid, whereas at doses greater than this, they
are uricosuric [657–659]. In fact, salicylates at
high doses were used as uricosurics prior to the
marketing and use of probenecid/Benemid [660].
The pathophysiological effects of salicylates on
uric acid metabolism have been investigated in
some detail. At low doses of salicylate (<1.2 g/
day), serum uric acid levels are increased by 1.0–
2.0 mg/dl [659]. Uric acid retention has been
shown to have its maximal effect at plasma sali-
cylate concentrations of 5 mg/dl, whereas urico-
suria occurs at plasma concentrations greater
than 10 mg/dl [262]. The most precise measure-
ment for assessing the effect of salicylate on the
renal tubular handling of urate has been shown to
be the concentration of free salicylate in the renal
tubular urine [262]. An excretion rate of free sali-
cylate of less than 0.5 mg/min is uricoretentive
whereas at rates above this level, salicylates are
uricosuric. It has been proposed that low-dose
salicylates block the renal tubular secretion of
urate whereas at high doses, it inhibits both renal
tubular secretion and reabsorption. In addition to
these renal tubular effects of salicylates, it is
important to recognize that salicylates at any dose
abrogate the uricosuric effects of probenecid and
sulfinpyrazone [661].
Even though salicylates may increase serum
urate concentrations, this effect does not appear
to be a significant precipitating factor for gout. If
one considers the large number of elderly adults
consuming low-dose aspirin to prevent vascular
5 Clinical Aspects of Gout and Associated Disease States
occlusion, there does not appear to be a significant
increase in the frequency of gouty arthritis in this
population.
Ethanol
Chronic alcohol use, hyperuricemia, and gout
have been known to be interrelated since the rec-
ognition of gout as a metabolic disease. The cause
for ethanol-induced hyperuricemia is multifacto-
rial. Hyperlacticacidemia leading to a suppres-
sion of renal urate excretion, fasting causing
ketonemia and urate retention, increased muscle
activity causing lactate production, and the inges-
tion beer with its high purine content may all
contribute to the hyperuricemic state induced by
alcohol [662–665]. Despite the frequent associa-
tion of alcohol consumption and hyperuricemia,
alcohol use infrequently results in gouty arthritis
[647, 652, 653, 666].
Cytotoxic Agents
Therapeutic agents that lead to the destruction of
cells will routinely cause hyperuricemia unless
the host is protected by allopurinol prior to treat-
ment with such cytotoxic agents. The neoplastic
diseases prone to this complication have been
discussed previously in the section “Acute uric
acid nephropathy.” These cytotoxic agents cause
the release of cellular nucleic acids and purine
nucleotides that are subsequently metabolized to
uric acid. The latter metabolite, if produced in
sufficient quantity, may markedly increase serum
uric acid levels and may also cause acute uric
acid nephropathy. The onset of gout may coin-
cide with the initiation of chemotherapy or radia-
tion therapy [530]. As discussed in the Chap. 4,
“Nephrolithiasis,” renal calculi are not uncom-
mon in patients with gout secondary to myelo-
proliferative disorders.
Allopurinol-Induced Gout
It is not uncommon for an acute gouty episode to
occur in the course of the initiation of allopurinol
Drug-Induced Hyperuricemia and Gout
treatment. The precipitation of acute gout in this
setting is the result of a rapid change in the serum
uric acid concentration along with a dramatic
alteration in the uric acid pool. Gouty attacks
have been reported to occur with serum uric acid
levels as low as 2 mg/dl in association with a
significantly decreased urinary uric acid excre-
tion [558]. This fact serves to emphasize that an
elevated serum uric acid is not necessary for the
clinician to entertain the diagnosis of acute gouty
arthritis. In fact, either a rapid increase or decrease
in the serum uric acid level may trigger an attack
of acute gout. Since allopurinol may cause acute
gout, it is reasonable to make the patient aware of
this possibility and to use lower doses of
allopurinol at the start of therapy while progress-
ing to the full dose of 300 mg/day. The use of
colchicine in low dosage (0.5–1.0 mg/day) may
also prevent acute gouty episodes during the ini-
tiation of hypouricemic therapy.
Antituberculous Drugs
The resurgence of tuberculosis emphasizes the
importance of understanding the role of ethamb-
utol and pyrazinamide in altering the renal han-
dling of uric acid. Both these drugs continue to be
used in the treatment of tuberculosis. Pyrazinamide
has been recognized as a potent uricoretentive
drug since 1956 [667]. Not only does this drug
cause hyperuricemia via a renal mechanism, but
it may also induce acute gouty attacks [667–669].
The mechanism by which pyrazinamide alters
uric acid metabolism is thought to be by impair-
ing both secretion and reabsorption with the net
result being a reduction in the renal clearance of
uric acid [257, 670, 671]. From these and other
studies, it became clear that the deaminated
pyrazinamide metabolite, pyrazinoic acid, was
the primary mediator of the hyperuricemic effect
[671, 672]. Pyrazinamide-induced hyperuricemia
does not respond to uricosuric therapy, but it can
easily be controlled with allopurinol [672–674].
Acetylsalicylic acid at low dosage and p-amin-
osalicylic acid can reverse the uricoretentive
effects of pyrazinamide [675, 676].
Subsequent to these observations, ethambutol
was also shown to cause hyperuricemia [677].
137
The exact mechanism for the hyperuricemic effect
caused by ethambutol has yet to be determined
[678]. It has been established that hyperlacticaci-
demia and volume contraction do not explain its
hyperuricemic effect. The increment in serum
uric acid concentration and the decrease in renal
clearance of uric acid occur by mechanisms that
are different from similar changes in uric acid
metabolism induced by diuretics, ethanol, pyrazi-
namide, and acetylsalicylic acid [678].
Cyclosporine
Since the early 1960s, hyperuricemia and gout
have been observed as a complication of
cyclosporine therapy for immunosuppression
after organ transplantation [679–683]. In clinical
studies of cyclosporine therapy, hyperuricemia
occurs in 80–90 % of patients being treated with
this immunosuppressant, and roughly 10–20 %
of these patients develop acute gouty arthritis
[16, 684–686]. As discussed previously in the
discussion of chronic tophaceous gout,
cyclosporine-induced gout is an accelerated form
of gout with tophi occurring over a relatively
short time period and in unusual sites [14, 684].
Clearly, cyclosporine causes a decrease in
renal urate clearance, but the exact mechanism for
this decrement remains incompletely understood
and may be a multifactorial cause. Alterations
in glomerular filtration rates, renal tubular func-
tions, or renal vasculature all have been impli-
cated in the nephrotoxicity of this drug leading
to hyperuricemia [15, 687–691]. Hypertension,
renal insufficiency, and diuretic use may also
contribute to the changes in uric acid metabolism
caused by cyclosporine. Tophaceous deposits
should be sought in unusual locations including
soft tissues, intraspinal sites, and the spine itself
[18, 692, 693].
The management of cyclosporine-induced gout
in transplant recipients is complex and difficult.
Allopurinol prevents the accumulation of uric
acid, but its use in patients receiving 6-mercap-
topurine or its derivatives causes the accumulation
of 6-mercaptopurine by preventing its metabolism
via xanthine oxidase to an innocuous metabolite,
thiouric acid [694]. The accumulation of either
138
6-mercaptopurine or azathioprine potentiates the
suppression of the myeloid cells in the bone mar-
row [19]. Another complication of allopurinol
therapy is that renal insufficiency leads to the
accumulation of allopurinol itself, and this drug
is relatively insoluble at high concentrations.
Reduction in azathioprine or 6-mercaptopurine
dosages to accommodate the use of allopurinol
in the treatment of cyclosporine-induced hype-
ruricemia may reduce their immunosuppressive
effects leading to graft rejection [695, 696].
Even though no absolute methods for the man-
agement of cyclosporine-induced gout have been
determined, several alternative drugs have been
used with some success. ACTH injections have
been used, but they have a tendency to induce
rebound attacks of gout after the effect of injec-
tions have ceased. The inosine dehydrogenase
inhibitor, mycophenolate, has been used in place
of azathioprine in kidney transplant recipients
with a resultant modest reduction in the hyperuri-
cemia and the capacity to use full doses of
allopurinol [697].
Probably the most effective agent for the man-
agement of cyclosporine-induced hyperuricemia
and gout is the uricosuric drug, benzbromarone,
since it is effective in those patients with renal
insufficiency [698]. There are two disadvantages
to the use of this drug. First, it is not available
on a general basis in the United Kingdom or
the United States, and second, it is ineffective if
the creatinine clearance is less than 20 ml/min.
Several publications have attested to the efficacy
of benzbromarone or its iodinated counterpart,
benziodarone, in the treatment of cyclosporine-
induced hyperuricemia and gout [15, 23, 699,
700]. Both these drugs were effective in normal-
izing serum uric acid levels without significant
complications. In this small number of published
reports (less than 100 patients), a few patients
have developed uric acid calculi of the kidney,
and one case of drug-induced hepatitis requir-
ing liver transplantation has been reported after
benzarone use [699, 701, 702]. Less serious
side effects of the drug include gastrointesti-
nal disturbances and hypersensitivity rashes. In
comparison to probenecid, benzbromarone in a
dose of 100 mg/day is equivalent to 1.0 g/day of
5 Clinical Aspects of Gout and Associated Disease States
probenecid [703]. Like other uricosuric agents,
the uricosuric effect of benzbromarone is antago-
nized by pyrazinamide and salicylates, but the
salicylate effect does not completely abrogate the
uricosuric effect [704]. Benziodarone, the iodine-
containing uricosuric drug, is used infrequently
since it alters human thyroid function [705].
Another less commonly used drug to counteract
cyclosporine-induced hyperuricemia is the enzyme,
urate oxidase, derived from a variety of extracts
including Aspergillus flavus, Arthrobacter proto-
formiae, and Candida utilis [706–710]. Although
the initial studies of this enzyme used purified
urate oxidase, subsequent studies used urate oxi-
dase covalently attached to polyethylene glycol to
reduce antibody formation in the host [711–713].
At the present time, a recombinant urate oxidase is
being tested and may be made available soon for a
wider distribution and use [714].
The mechanism by which this enzyme acts is
through the conversion of uric acid to the highly
water-soluble metabolite, allantoin and carbon
dioxide. This mode of therapy requires an intrave-
nous or intramuscular injection and is useful in
the treatment and pretreatment of patients at risk
for the tumor lysis syndrome [715, 716]. Even
though in most cases urate oxidase therapy is a
safe and efficient means of treating cyclosporine-
induced hyperuricemia and gout as well as other
causes of gout, it is not without side effects.
Anaphylactoid reactions, hypersensitivity skin
rashes, bronchospasm, and hemolytic anemia
have been reported with its use. Additional studies
may deem this agent as an attractive option for the
management of severe gouty arthritis in patients
with renal insufficiency, in those at risk for tumor
lysis syndrome, and in transplant recipients.
One additional issue related to transplant
recipients and gout needs to be discussed. In
some patients, maintenance colchicine therapy
has been used to prevent the recurrence of gouty
attacks or to abrogate the onset of gout in the face
of treatments known to trigger acute gout. Such
regimens are often not the best way to prevent
acute gout in renal transplant recipients since
colchicine often induces a myopathy [20, 21,
717]. The onset of muscle weakness (usually
painless), distal sensory changes, and elevated
Drug-Induced Hyperuricemia and Gout
creatine phosphokinase levels is especially likely
to occur in patients with renal insufficiency
treated with colchicine and cyclosporine [20, 22].
The measurement of creatinine clearance has
been proposed as a means of analyzing the risk of
colchicine myotoxicity [718]. This investigation
determined that patients at the highest risk for
colchicine-induced myotoxicity had a creatinine
clearance of less than 50 ml/min.
Thus, cyclosporine-induced hyperuricemia
and gout occur frequently and are difficult to treat
since the pharmacologic options may interfere
with the therapy to prevent graft rejection. It
appears that newer agents available in Europe
such as benzbromarone and urate oxidase may
offer safer and more effective therapy for this
complicated drug-induced disease.
Nicotinic Acid
Nicotinic acid has been used as a hypolipidemic
drug since it reduces the levels of plasma total
cholesterol, plasma triglyceride, and very low
density lipoprotein cholesterol and increases the
high density lipoprotein cholesterol level [719].
Unfortunately, in patients with type II diabetes
mellitus, it increases insulin resistance and blood
sugar concentrations [720]. In addition to this
relative contraindication to its clinical use, it also
causes flushing, gastric irritation, hepatotoxicity,
and hyperuricemia [721–725]. The primary effect
of this agent on uric acid metabolism is to
decrease the clearance of uric acid by the kidney
[721, 726]. In an attempt to localize the site of
action of nicotinic acid on the renal tubular han-
dling of uric acid and characterize any drug-drug
interactions, the effect of nicotinic acid on
sulfinpyrazone, iopanoic acid, and acetylsalicylic
acid has been evaluated [721]. Acetylsalicylic
acid does not reverse the nicotinic acid-induced
hyperuricemia in contrast to its reversal of pyrazi-
noic acid’s effect on the kidney. Nicotinic acid
inhibits the uricosuric effects of sulfinpyrazone
and iopanoic acid. The latter action indicates the
necessity for allopurinol use if nicotinic acid-in-
duced hyperuricemia needs to be treated. In addi-
tion to the alteration in the renal tubular handling
139
of uric acid, some investigators have proposed
that nicotinic acid and its amide derivative, nico-
tinamide, may also increase purine biosynthesis
[727–729]. Other evidence has been presented to
document a decrease in phosphoribosylpyrophos-
phate levels associated with nicotinic acid admin-
istration [721, 730].
In summary, nicotinic acid clearly induces
hyperuricemia and may occasionally precipitate
an attack of acute gout. The present literature
suggests that it should not be commonly used
since effective drugs such as the statins and fibric
acid derivatives are available.
Fructose-Induced Hyperuricemia
Fructose-induced hyperuricemia is of significance
since its mechanism of action on uric acid metab-
olism is well characterized, and the possible
connection between fructose ingestion, hyperu-
ricemia, and gout in the heterozygous carriers of
phosphofructoaldolase deficiency [731–736]. The
initial report of the effects of intravenous fruc-
tose clearly demonstrated that 0.5 g of fructose
per kilogram of body weight results in hyperuri-
cemia and hyperuricosuria both in patients with
hereditary fructose intolerance and in normal
children [734]. Subsequent reports have shown
that 200 mg of fructose/kg body weight admin-
istered intravenously also induces hyperuricemia
in healthy children and adults [733]. Even doses
of fructose as low as 160 mg/kg body weight/h
will cause hyperuricemia in critically ill patients
[737]. Other investigators have demonstrated that
measurements of urinary uric acid as a function
of urinary creatinine (mg of uric acid per mg
creatinine) may be a more precise indicator of
the changes in uric acid metabolism induced by
fructose than serum uric acid levels per se [738,
739]. In addition to increased urinary uric acid
concentrations, fructose also induces an increase
in uric acid precursors (inosine, hypoxanthine,
and xanthine) in the urine [735, 740, 741]. The
association of the heterozygous state for aldolase
B (fructose 1,6-bisphosphate aldolase) deficiency
and gout is discussed in detail in the chapter on
genetics. Suffice it to say that some evidence sug-
140
gests that familial gout may be associated with the
carriers of the mutant gene for hereditary fructose
intolerance since a number of such heterozygotes
were shown to have gouty arthritis.
The mechanism for the increments in serum
and urinary uric acid in hereditary fructose intol-
erance is via the degradation of adenine nucle-
otides to uric acid [742, 743]. Studies of the
liver after fructose infusions have demonstrated
a decrease in adenosine triphosphate (ATP), a
decrease in inorganic phosphorus, and an increase
in fructose-1-phosphate. The decrease in ATP is
the result of its use in the conversion of fructose
to fructose-1-phosphate, and the decrease in inor-
ganic phosphorus results from the rephosphory-
lation of ADP in the mitochondria. In hereditary
fructose intolerance, the accumulation of fruc-
tose-1-phosphate results from the absence of
the enzyme, aldolase B, and the inability to split
fructose-1-phosphate into d-glyceraldehyde and
dihydroxyacetone phosphate. These changes in
the liver have been documented by 31P magnetic
resonance spectroscopy [731, 732, 744–746].
These changes in metabolite concentrations are
diminished in the presence of hepatocellular
disease as a result of the decreased capacity to
phosphorylate fructose [747, 748]. In comparing
patients with chronic hepatitis and healthy adults,
the alterations in phosphomonoesters in healthy
adults after the infusion of 0.5 g of fructose/kg
body weight increased in 15 min to 338 ± 76 %
of the preadministration value in contrast to an
identical analysis of patients with chronic hepa-
titis where the increase was only 151 ± 49 % of
the preadministered value. In addition to the
decrease in ATP concentration after fructose infu-
sions, the concentration of GTP also decreases
[749]. A similar depletion of high-energy phos-
phate also occurs after fructose infusion in the
kidney and small intestine [750–752]. Thus,
the fructose-induced catabolism of ATP, ADP,
and AMP begins by the conversion of fructose
to fructose-1-phosphate with the generation of
ADP. Adenosine diphosphate is then converted to
ATP by adenylate kinase with the generation of
AMP. The latter metabolite is converted to inos-
ine monophosphate by AMP deaminase. Then,
inosine monophosphate is converted to inosine
by cytoplasmic 5¢-nucleotidase, or alternatively,
5 Clinical Aspects of Gout and Associated Disease States
AMP is converted by the same nucleotidase
to adenosine that is subsequently converted to
inosine by adenosine deaminase. Inosine is then
converted to hypoxanthine by nucleoside phos-
phorylase. Xanthine oxidase acts on the latter
substrate and its immediate product, xanthine, to
convert these metabolites to uric acid. These reac-
tions are significantly enhanced by the release of
AMP deaminase inhibition by the fall in inor-
ganic phosphorus levels and GTP concentrations
induced by fructose infusions [749]. As a result
of the catabolism of adenine nucleotides and the
decreased concentration of nucleotides causing
feedback inhibition of the enzyme, phosphoribo-
sylpyrophosphate (PRPP) amidotransferase, the
rate-limiting enzyme in de novo purine biosynthe-
sis, the rate of purine synthesis is also increased
[753, 754]. In isolated rat hepatocytes, fructose
induces a transient (60 min) increase in PRPP
and ribose-5-phosphate concentrations [755].
Although there is speculation that this change
relates to an increased PRPP synthetase activity,
the complete mechanism has as yet to be defined.
Another contributor to fructose-induced hyperu-
ricemia is the elevated blood lactate concentra-
tions observed after fructose infusions. The latter
metabolite blocks urate excretion and results in
hyperuricemia [265, 739, 756].
In summary, fructose infusion triggers the
catabolism of adenine nucleotides that lead to the
generation of uric acid. This metabolic change is
especially prominent in patients with hereditary
fructose intolerance. Further, such metabolic
changes may be a factor in the association of gout
with patients who carry the mutant gene for
hereditary fructose intolerance.
Megaloblastic Anemia
Hyperuricemia, hyperuricosuria, and acute gouty
arthritis have been observed during the treatment
of megaloblastic anemias [757–760]. A variety
of markers of increased purine production have
been investigated in patients during vitamin
replacement therapy in pernicious anemia, and
the increase in purines appears to be correlated
with the peak reticulocyte count on days 5–7 of
the treatment program [761].
Saturnine Gout (Lead-Induced Gout)
The mechanism of these changes in uric acid
metabolism is related in part to the increased
synthesis of purine nucleotides via the elevated
activity of adenine phosphoribosyltransferase,
hypoxanthine-guanine phosphoribosyltrans-
ferase, and PRPP synthetase as well as the increase
in the urinary excretion of aminoimidazolecar-
boxamide, an intermediate in the de novo purine
biosynthetic pathway, and increased levels of uri-
nary oxypurines [761–763]. Another somewhat
confusing observation is the occurrence of mac-
rocytes and megaloblastosis in the bone marrow
of patients with the Lesch-Nyhan syndrome and
the Kelley-Seegmiller syndrome [72, 764–768].
The increased rate of de novo purine biosynthe-
sis and the reduction in the serum folate concen-
trations due to its increased usage to form the
purine ring undoubtedly contribute to the mega-
loblastosis, but the megaloblastic anemia appears
not to respond to folate therapy [767, 768]. Why
these divergent facts occur remains puzzling, but
factors other than folate must play a role in the
megaloblastic anemia of some Lesch-Nyhan syn-
drome patients.
Summary of Drug-Induced
Hyperuricemia and Gout
From the foregoing facts, it is clear that many
pharmacologic agents can cause hyperuricemia,
and in some patients, several of the drugs dis-
cussed may also precipitate attacks of acute gouty
arthritis. The marked overuse of allopurinol for
the treatment of hyperuricemia and the clinical
myth that all hyperuricemic patients need to be
treated should lead the clinician to consider drug-
induced causes of hyperuricemia and gout. The
use of alternative pharmacologic agents and the
control of alcohol intake could reduce the inci-
dence of these abnormalities in purine
metabolism.
Saturnine Gout (Lead-Induced Gout)
The association between lead exposure and
the occurrence of gout has been documented
from the early 1800s. The clearest documented
141
examples of lead-induced gout or so-called satur-
nine gout have been reported from Queensland,
Australia, and the southern part of the United
States [769, 770]. The sources of lead in these
two examples are quite different, but they empha-
size an unusual source of lead in one case and a
long delay in the expression of gout in the other.
In semitropical Queensland, the lead source was
fences painted with a lead-based paint in proxim-
ity to children’s play areas. Lead intoxication
resulted from the ingestion of flakes of lead from
the paint. In the southern part of the United States,
the source of the lead was the solder and old car
radiators used in the construction of illicit stills
for the purpose of distilling and refining alcohol.
The product of this distillation process has been
given the name moonshine, and the gouty arthri-
tis associated with the use of this product has
been called Dixie gout. Lead-containing paints
are still in use today, but the primary exposures to
lead-containing paint occur most frequently in
rundown inner city housing where children are
exposed to the flakes of the old paint that contain
lead [771]. Other potential exposures to lead in
children include parental sources of lead from
employment in an industry using lead and living
near industrial sites that emit lead [772–774].
Industrial lead exposures occur mainly in the
manufacture of automobile batteries, the produc-
tion of alloys like solder, manufacture of plastics
and ammunition, scrap metal salvaging, lead
smelting, and the manufacture and use of various
lead-containing pigments. A complete list of haz-
ardous exposure to lead in industrial settings has
been published [775].
In the southern part of the United States, ele-
vated blood lead levels have been documented
in individuals drinking illegally distilled alcohol
[776–784]. This modern-day association
between gout and illicitly distilled alcohol also
has a counterpart in history since fortified
English wines from the years of 1770 and 1820
contained lead concentrations of 320–1,900
ug/l, values above allowable lead concentrations
[784]. These findings may reflect the many car-
toons from the era depicting Englishmen with
their bandaged foot on a footstool with a bottle
of wine on a nearby table. Lead-tainted bever-
ages date back centuries since Sir George Baker
142
first reported lead colic from the ingestion of
contaminated cider in 1767 [785]. Such events
continue to be recorded in the literature [786,
787]. It has been suggested that the popularity
of so-called moonshine whiskey is its low cost
to the consumer, but the major reason for its use
is the sweet taste imparted by the lead, which
attracts these advocates of home brew. Thus, in
the southern regions of the United States and
elsewhere, solder used in homemade stills, lead-
glazed receptacles used to process grapes, and
even lead crystal wine glasses can be ready
sources of lead and lead poisoning [788, 789].
Other potential exposures that might cause lead
poisoning include exposures occurring in con-
struction workers, deleaders, house painters,
firing range users, and do-it-yourself home ren-
ovators [790]. Indeed, in the 1800s, Garrod
observed that 25 % of his patients with gout
were either painters or artisans who had lead
poisoning [791].
From a clinical standpoint, Queensland and
Dixie (moonshine) gout present with somewhat
different clinical findings. Chronic lead nephrop-
athy is a characteristic feature of Queensland
gout, and death from chronic renal failure was a
common occurrence in Queensland in the early
1900s [769]. The studies of this Australian type
of lead intoxication demonstrated a clear associa-
tion between contracted granular kidneys found
at autopsy in affected patients and an increased
lead concentration in bone. This finding offered
suggestive proof that lead was the cause of the
nephropathy. Subsequently, the use of EDTA
chelation of lead demonstrated an increased lead
excretion in the urine of these patients, and
despite the absence of any symptoms or signs of
recent lead exposure, these results documented
the past exposure of these patients to lead [792].
Of those with chronic lead nephropathy and no
persistent signs of lead poisoning, 50 % devel-
oped gouty arthritis [793]. In contrast to these
findings, a history of childhood lead intoxication
leading to chronic renal disease and ultimately
death from the kidney disease has not been
observed in children with lead poisoning in the
United States. This leads to the idea that there
may be additional factors contributing to the renal
5 Clinical Aspects of Gout and Associated Disease States
disease in Queensland. In Queensland, the kid-
ney disease precedes the onset of gout, whereas
renal disease usually does not predate the gout in
the southern part of the United States. Dixie gout
affects primarily black males from rural areas,
whereas in Queensland gout, there is almost an
equal distribution between the sexes, and the
females with gout often contract their disease
prior to the menopause. In addition, there is no
significant history of alcohol use in the Queensland
patients [794–796].
To date, there remains a degree of controversy
regarding the role of lead in the generation of kid-
ney disease. In all the cases of saturnine gout, the
following characteristics have been documented.
The serum uric acid levels usually exceed those
observed in other forms of chronic disease [770,
792]. The renal clearance of uric acid is reduced
in saturnine gout, and some evidence has been
presented to suggest that this change is the result
of increased renal tubular reabsorption [792].
Prevailing published data indicate that the renal
disease in Dixie gout is less severe than the
kidney disease observed in Queensland gout.
Tophaceous deposits have reported to be unusual
in saturnine gout, but other studies have not
confirmed this finding [795, 797]. Although lead
nephropathy exists as an entity with nonspecific
renal pathology, its pathogenesis and associated
clinical findings remain incompletely resolved;
additional work may resolve the remaining
dilemmas [798–814].
No consistent historical feature or clinical
finding except for the history of lead exposure is
characteristic of saturnine gout. Since the most
recent studies of gout document a marked vari-
ability in the occurrence of lead-induced gout, it
is unclear from the literature when gouty patients
should be screened for this disorder [782, 795,
803–805, 815, 816]. It is reasonable to ask every
patient with gout about exposure to lead in the
home or at work. If a positive history of lead
exposure is obtained, then further investigation of
the body stores of lead is indicated. Patients with
renal disease of no apparent cause and gout cer-
tainly require a careful evaluation for the pres-
ence of underlying lead intoxication as a cause
for the abnormal kidney findings.
Saturnine Gout (Lead-Induced Gout)
Laboratory evaluations of patients at risk for
lead exposure should include analyses for the
detection of both acute and chronic lead intoxica-
tion. The total body burden of lead is distributed
throughout the body and includes a rapidly
exchangeable pool in the blood and a more stable
pool in the skeleton [817]. The rapidly exchange-
able blood pool of lead represents only 2 % of the
total body burden of lead, whereas the skeletal
pool stores more than 90 % of the body lead in its
stable pool. Thus, blood lead concentrations mea-
sure the lead recently absorbed by the body, and
such concentrations do not reflect the total body
burden of lead. Measurements of skeletal lead
concentrations provide an assessment of cumula-
tive lead absorption from past exposures. Blood
lead concentrations and zinc protoporphyrin con-
centrations are the two most commonly used tests
for biologic monitoring and to measure current
lead absorption [818–820]. Presently, a blood
lead level of <40 ug/dl is the standard for protect-
ing workers from excessive lead exposure even
though most adults have a blood lead level of <15
ug/dl and many have levels of <10 ug/dl. It is
important to recognize that lead-induced neph-
ropathy and saturnine gout do not occur after
short-term exposures to lead but are caused by
chronic, long-term exposures. The other tests
used by some to monitor exposure are the free
erythrocyte porphyrin (FEP) or zinc protopor-
phyrin (ZPP) levels. In adults, the FEP or ZPP
levels are usually less than 35 ug/dl. Levels higher
than this are usually correlated with blood lead
levels of greater than 50 ug/dl. Since elevated
ZPP levels are also observed in iron deficiency
anemia, they are not specific for lead exposure.
The anemia of lead poisoning is normocytic, nor-
mochromic, whereas iron deficiency anemia is
usually a macrocytic, hypochromic anemia.
Collections of blood for lead analyses require
special lead-free glass tubes.
In cases where lead intoxication and saturnine
gout are suspected, it is necessary to determine
the total body burden of lead. Two methods have
been used to make this determination: EDTA
mobilization and K x-ray fluorescence. In the
case of the EDTA mobilization test, the total body
burden of lead is assessed as the urinary excretion
143
of lead. The excretion of 500–600 ug of lead in a
24-h urine collection in a lead-free container is
considered abnormal [793, 795]. There are ques-
tions concerning the effect of the EDTA mobili-
zation test as to the deposition of the mobilized
lead in the human [821–823]. Even though EDTA
mobilization tests continue to be used, the possi-
ble redistribution of lead to the brain during such
tests has raised issues about the overall safety of
this procedure, and newer pharmacologic agents
for mobilizing lead and X-ray fluorescence are
likely to replace this older test for the measure-
ment of total body lead burden. A number of pub-
lished investigations of K x-ray fluorescence have
documented the use of this technology for the
assessment of bone lead accumulation [799, 824–
831]. Noninvasive X-ray fluorescence appears to
be an accurate method for determining cumula-
tive lead exposure and may be further refined to
assess future health effects of the stable pool of
lead in bone.
Finally, once lead intoxication has been
detected or the total body burden of lead is found
to be elevated, the issue becomes the treatment of
this condition. The key to any treatment program
is to remove the individual from continued expo-
sure to lead. This may obviate the need to take
any further steps to remove lead from the body.
Nonetheless, this initial therapeutic step may be
difficult to accomplish in moonshine users, but as
an alternative in this population of patients, the
continuous monitoring of body stores of lead
may be easier to accomplish. Once the individual
has been removed from lead exposure, chelation
therapy may be necessary to reduce the body bur-
den of lead. The need for chelation therapy is
based on the blood lead concentration, the total
body burden of lead, clinical symptoms, labora-
tory abnormalities, and the duration of the expo-
sure. Urinary excretion of lead should be
measured before and after chelation therapy to
assess the quantity of lead released from the body
stores. In addition to EDTA as a chelating agent,
new, nontoxic drugs are now available that can be
administered by mouth [832–850]. The dose of
these newer agents for both adults and children
are provided in the various published studies
[832, 834–840, 844, 847]. While chelation is
144
ongoing, the patient should be carefully moni-
tored for potential side effects of drugs used in
the treatment protocol.
In summary, saturnine gout with or without
nephropathy may be a cause of gouty arthritis,
especially in moonshine users and in patients
from industrial settings where lead is being used.
Lead-associated gout is not a common cause of
gout, but in specific patients, it is valuable to ask
about exposure to lead. The suspicion of satur-
nine gout demands specific testing for the body
burden of lead and treatment plans to reduce this
burden.
Gaucher Disease (Glucocerebrosidase
Deficiency)
Gaucher disease, a lysosomal glycolipid storage
disorder resulting from mutations in the lyso-
somal hydolase, has recently been shown to be
associated with gouty arthritis [851]. Since the
actual cause of the defect in purine metabolism
remains unresolved at this time, the reason for
this abnormality in uric acid metabolism cannot
be classified into an overproduction or underex-
cretion defect. In the past, Gaucher disease has
been reported in association with gout when it
was observed in the presence of a myeloprolifer-
ative disorder [125, 852]. The occurrence of gout,
Gaucher disease, and lymphoproliferative disor-
ders is consistent with the apparent increased
frequency of such lymphoproliferative disorders
in Gaucher disease. Even though there are more
than 100 citations in the literature documenting
the association between Gaucher disease and
malignancies, proof of the significance of these
observations remains to be determined [853–866].
Large splenic infarcts can give rise to an acute
abdomen with metabolic acidosis and hyperuri-
cemia, but such an occurrence would not account
for the recent report of Gaucher disease and gout
[851, 867]. As indicated by the recent report of
Gaucher disease and gout, the Ashkenazic Jewish
population is especially prone to Gaucher disease
[868–870]. At the present time, the mechanism(s)
for the occurrence of the recent report of gout in
association with Gaucher disease are not known.
Further concepts about the pathogenesis of gout
5 Clinical Aspects of Gout and Associated Disease States
in Gaucher disease must await additional docu-
mentation of this association and more detailed
study of the affected individuals in this report.
Gout in Females
Hyperuricemia and gout are unusual in females,
and when these clinical and laboratory findings
are observed in women, they deserve special
attention in order to define any underlying condi-
tion. In population studies in the United States
elsewhere, the percentage of females with gout
varies from publication to publication, but on the
average, females represent about 5–10 % of any
large series of gouty patients [125, 871–877]. For
purposes of this discussion, it is useful to classify
hyperuricemia and gout in the female into four
categories: juvenile, premenopausal, pregnancy,
and postmenopausal forms.
Juvenile Hyperuricemia and Gout
Juvenile gout was reviewed in the 1970s prior to
the complete assessment of some genetic disor-
ders like familial juvenile gouty nephropathy
(FJGN), so the small group of females reported,
two of whom had renal disease, are hard to char-
acterize metabolically by today’s standards [352].
Subsequent to this review, a number of clinical
disorders have been documented that must be
considered in juveniles who develop gout.
Unfortunately, the frequency of these rare forms
of hyperuricemia or gout has not been determined
since the total numbers of affected females are
quite small, but gout occurs very infrequently in
this age group. Nonetheless, two disorders,
HGPRTase deficiency and FJGN, are known to
affect females and have been documented to
account for roughly 50 % of the cases referred to
the Purine Research Laboratory in London [358].
Familial juvenile gouty nephropathy represented
about 32 % of the total cases seen by this group.
The latter disease is important to recognize since
early recognition and treatment may forestall the
progression of the associated renal disease. Since
gout is not a consistent manifestation of this dis-
order, some investigators have elected to use the
Gout in Females
term, familial juvenile hyperuricemic nephropa-
thy, to describe the disease. We have elected to
use the term, familial juvenile gouty nephropa-
thy, to emphasize that this disease may mimic
other forms of familial nephropathies and search-
ing pedigrees for a history of gouty arthritis may
reveal a useful marker for FJGN as the underly-
ing disease. Thus, a family history of renal dis-
ease, a low fractional excretion of uric acid, and
hyperuricemia may suggest that the underlying
disease is FJGN, and a history of gout in the fam-
ily provides stronger evidence for FJGN. Such
patients may or may not be hypertensive, and
urate crystals are not often found in kidney biop-
sies from such individuals. Less common herita-
ble diseases that can be associated with gout are
the autosomal recessive disorders such as glyco-
gen storage diseases and muscle phosphoglycer-
ate mutase deficiency as well as autosomal
dominant disorders such as autosomal dominant
polycystic kidney disease and medullary cystic
disease of the kidney. Only in very rare instances
does the Lesch-Nyhan syndrome occur in females
when the affected female has inherited a mutated
gene from each parent. Gout has been reported in
female carriers of HGPRTase deficiency and
PRPP synthetase superactivity [82, 83, 878]. The
carriers of X-linked recessive disorders are more
likely to express clinical gout at an age beyond
their juvenile years. Although hyperuricemia and
gout are complications of organ transplantation
in the adult, gout was not thought to be a compli-
cation of transplantation in the pediatric age
group until recently. Gout has now been reported
in three males and two females below the age of
18 years who underwent renal transplantation
[686]. Cyclosporine and diuretic therapy appear
to be the causative agents in these cases. Thus,
drug-induced gout does occur in juveniles of both
sexes.
Hyperuricemia may be present in juvenile
females, but its presence is characterized by a
large number of underlying causes, and they will
not be discussed in detail here. However, several
points should be made concerning juvenile hype-
ruricemia in the female. First, the renal retention
of nitrogenous wastes due to renal disease must
be excluded as a cause of the hyperuricemia.
Therefore, if an arthritis package of tests is
145
ordered, serum creatinine and/or blood urea
nitrogen must also be measured to ensure the
absence of renal dysfunction as the cause for the
hyperuricemia. Second, a variety of inherited dis-
orders may manifest hyperuricemia including
glycogen storage diseases, carnitine palmitoyl-
transferase II deficiency, cystinuria, and fatty
acid oxidation deficiencies. Third, hyperurice-
mia secondary to an increased turnover of
nucleic acids may account for the origin of the
elevated uric acid levels. Fourth, unusual causes
of hyperuricemia must also be considered includ-
ing hypothyroidism, lead nephropathy, infectious
mononucleosis, and others.
Premenopausal Hyperuricemia
and Gout
Since most gouty episodes occur in postmeno-
pausal females, gout is rare in the post-juvenile,
premenopausal female. As noted previously,
female carriers of HGPRTase deficiency and
PRPP synthetase superactivity have both been
reported to develop clinical gout. Indeed, exces-
sive urate production has been documented in
heterozygous female carriers of HGPRTase
deficiency when sophisticated isotopic analyses
of purine synthesis have been measured [879].
Autosomal dominant nephropathies associated
with hyperuricemia and gout such as familial
juvenile gouty nephropathy, polycystic kidney
disease, and medullary cystic disease of the kid-
ney are also observed in females in this age group.
Drug-induced gout is also certainly seen in
females in their premenopausal years. The most
prominent expression of gout is observed in those
females undergoing organ transplantation and
subsequent treatment with cyclosporine and
diuretics. Even though the use of diuretics is most
often associated with transplantation, diuretics
used for other reasons have also been observed to
trigger gout in the premenopausal female. Chronic
lead intoxication and saturnine gout have also
been reported in females in this age group.
Finally, gout secondary to myeloproliferative dis-
orders is more common in women than primary
gout [125, 530]. Renal calculi and tophaceous
deposits are frequent in females with blood
146
dyscrasias and may antedate the first episode of
gout [880]. This is one cause of gout in this age
group that must be carefully evaluated in any
female with gout so that early intervention can
occur if such a disorder is identified.
An unusual cause of hyperuricemia and gout
has been reported in a few females abusing laxa-
tives [536]. These patients presented with gener-
alized weakness, hypokalemia, and systemic
alkalosis. Two of the patients had hyperuricemia
while two had recurrent episodes of gout. This
disorder is self-sustaining since laxative-induced
hypokalemia reduces intestinal motility and trig-
gers further laxative use and abuse. Hyperuricemia
also occurs with a higher frequency in certain
ethnic groups [881–886]. Females in these ethnic
groups may also have a higher incidence of gouty
arthritis than other females of similar age. The
pathogenetic mechanisms have not been com-
pletely defined for the alteration in uric acid
metabolism in these ethnic groups (Filipinos,
Polynesians, Micronesians, and Aborigines), but
dietary habits, plasma factors, and/or renal dys-
function may contribute to the increased fre-
quency of hyperuricemia and gout in these
groups.
Hyperuricemia and Gout in Pregnancy
Gout is an extremely unusual and rare occurrence
in pregnant females, but gout has been docu-
mented during and after pregnancy in the older
literature [887–894]. It is difficult to discuss the
pathogenesis of gout in these reports since these
cases were described before genetic causes of
gout were identified. Nonetheless, it appears from
the reported cases and some textbooks that gouty
arthritis in pregnant females is probably in most
cases secondary to another disease associated
with elevated serum uric acid levels or multifac-
torial in its etiology [895].
Hyperuricemia is much more common during
pregnancy than gout since it is a marker for preec-
lampsia, a condition occurring not infrequently
during pregnancy. Despite its occurrence in
preeclampsia, the mechanism(s) for the altered
uric acid metabolism in this condition remains
5 Clinical Aspects of Gout and Associated Disease States
unknown [896–902]. Even though the mecha-
nism remains unknown, hyperuricemia is a use-
ful marker for preeclampsia. In addition to
preeclampsia, there are other more unusual clini-
cal settings in which hyperuricemia occurs. Acute
fatty liver of pregnancy (Sheehan’s syndrome) is
a rare complication of pregnancy associated with
vomiting, abdominal pain, and hyperuricemia
[903]. This disorder may be confused with tox-
emia of pregnancy, and early diagnosis is para-
mount if one is to avoid encephalopathy, liver and
kidney failure, and a fatal outcome. Another dis-
order that may also be confused with a toxemia-
like syndrome is the occurrence of transient
vasopressin-resistant diabetes insipidus in asso-
ciation with elevated liver function tests,
decreased renal function, and hyperuricemia
[383]. Some of the cases with this constellation
of findings have been associated with hepatitis.
The mechanism for the hyperuricemia in this dis-
order may be related to the changes in uric acid
metabolism observed in diabetes insipidus [381–
385]. Finally, hyperuricemia has been observed
in one case of acute uric acid nephropathy during
pregnancy [300]. The diagnosis in this case was
made on the basis of the marked hyperuricemia
and an elevated uric acid to creatinine ratio as has
been discussed previously in the section “Renal
disease and gout.” Conventional treatment of this
disorder leads to the reversal of the renal failure
and resulted in a healthy newborn.
In summary, gout is an extremely rare compli-
cation of pregnancy. If gouty arthritis does mani-
fest itself during pregnancy, an underlying disease
is likely to have triggered this abnormality in uric
acid metabolism leading to gout. Hyperuricemia
is a more common finding, and preeclampsia is
probably the most frequent cause. Nonetheless,
diuretic use, hepatic dysfunction, and even endo-
crine disturbances may result in elevated serum
uric acid levels in pregnant females.
Postmenopausal Hyperuricemia
and Gout
Most of the female patients with gouty arthritis
have been reported during the postmenopausal
Associated Disorders
years [645, 904–906]. Perhaps contributing to the
increased incidence of gout in this age group is
the fact that serum uric acid levels approach or
are equal to those in males [275, 455, 907–910].
A large percentage of postmenopausal females
with gout are being treated with diuretics [645,
880]. Although the clinical characteristics of gout
in the female vary from report to report, the fol-
lowing differences between males and females
have been noted in some publications. Most
reports identify the female as having the onset of
their disease about a decade later than males with
gout [904, 906]. Some investigators have found
that renal insufficiency is more common in
females with gout than males [645, 880]. A more
universal finding is the increased incidence of
hematologic malignancies in females compared
to males [880]. This cause of gout is important to
identify early so that treatment of the underlying
marrow disease can be initiated. Such patients
may present with renal calculi and tophi, and
these complications may precede the onset of
articular disease [880]. Although the joint
involvement is similar in males and females with
gout, a few investigations have suggested that the
involvement of finger and ankle joints is more
common in females than in males [906, 911]. In
both the premenopausal and postmenopausal
female with gout, it is reasonable to assume that
any underlying condition leading to hyperurice-
mia such as psoriasis, infectious mononucleosis,
and sickle cell disease may be sufficient to cause
gouty arthritis [912–914].
In summary, gout is most common in post-
menopausal females as compared with the pre-
menopausal and juvenile female. Even though
underlying diseases, especially renal insufficiency,
may be an accompanying disorder, diuretic use
and malignant disease represent the most impor-
tant conditions that need to be excluded in the
postmenopausal female with gout.
Associated Disorders
There are a number of disorders that occur fre-
quently in association with hyperuricemia and
gout. Assessment of these associated disorders
147
reveals no simple relationships exist between
obesity, hyperlipidemia, hypertension, diabetes
mellitus, and atherosclerosis despite their fre-
quent coexistence with hyperuricemia and gout.
Obesity
Obesity has been recognized as a condition asso-
ciated with hyperuricemia both from population
studies and from investigations of the metabolic
consequences of obesity [915–920]. In addition
to the correlation between obesity and hyperuri-
cemia, surveys of gouty patients have also found
a higher percentage of obesity than in control
subjects [875, 876, 921]. Further, excess weight
gain has been shown to increase the risk of gout
among patients with hyperuricemia [652]. As a
corollary to these studies, weight loss has been
documented to reduce gouty episodes and lower
serum uric acid levels [922].
There remains controversy over the role of
hyperuricemia as a risk factor for cardiovascular
disease despite the fact that some studies suggest
a positive correlation between hyperuricemia and
cardiovascular disease [923–926]. This point is
discussed further in the section “Atherosclerosis.”
However, there appears to be a correlation
between obesity, hyperuricemia, and other car-
diovascular risk factors such as hypertension and
hyperlipidemia. For this reason, it is reasonable
to initiate therapies aimed at the control of excess
weight, hypertension, and elevated blood lipids
in hyperuricemic subjects.
Modern studies have investigated obesity and
hyperuricemia using modern tools such as CT
scanning to evaluate fat distribution [927–929].
The results of these investigations define differ-
ent mechanisms for the hyperuricemia depending
on the body distribution of fat [929]. Clearly,
these mechanistic studies need further evaluation
to determine how the distribution of fat affects
uric acid metabolism. There have also been cor-
relations made between the adipocyte hormone,
leptin, and serum uric acid levels [930]. Future
studies may uncover relationships between uric
acid metabolism, leptin concentration, hyperin-
sulinemia, and fat distribution [931–934]. Since
148
more than 5 % of the national health expenditure
in the United States is related to the costs of obe-
sity and its complications, ongoing studies aimed
at understanding and defining risk factors of obe-
sity and its related disorders are of great
significance [935].
Hyperlipidemia
Documentation of a hyperlipidemic state is
important for several reasons. First, the older lit-
erature indicates that a strikingly high percentage
of patients with gout (72–84 %) have hypertrig-
lyceridemia [936–941]. Further, many patients
with hypertriglyceridemia have hyperuricemia as
well [937]. More recent studies have described
the lipoprotein phenotypes in patients with pri-
mary gout [942]. Less than 15 % of these gouty
subjects manifested types IIa and IIb hyperlipo-
proteinemia (hypercholesterolemia, low density
lipoproteins, and combined hyperlipidemia –
LDL plus very low density lipoproteins), whereas
most (almost 70 %) manifest type IV hyperlipi-
demia (endogenous hyperlipemia – VLDL).
Other studies have shown decreases in high den-
sity lipoprotein cholesterol and alterations in very
low density apolipoprotein C-III [943–946]. All
these studies document the occurrence of hyper-
lipemia in association with hyperuricemia and
gout, but they often do not evaluate either the
newer clinical subsets and mutants causing hyper-
lipemia or the clinical subsets of gout.
Second, the identification of lipid abnormali-
ties and their treatment are a preventive measure
that often decrease morbidity from atherosclero-
sis and prolong life. The results of preventive
treatment and the documented association
between gout and hyperlipidemias provide a rea-
sonable rationale for screening for both heritable
and acquired disorders of lipid metabolism.
Third, a recent paper has documented a deficit
in renal function in patients with chronic gout
who were using nonsteroidal anti-inflammatory
drugs (NSAIDS) for the treatment of their gout
[947]. These studies showed that low creatinine
clearance in their gouty subjects was related to
age, hypertension, hypertriglyceridemia, and the
5 Clinical Aspects of Gout and Associated Disease States
presence of previous renal disease. Removal of
NSAIDS from their treatment protocol and the
control of their serum uric acid levels resulted in
a significant improvement in their creatinine
clearance of greater than 10 ml/min. Thus, these
results suggest that the control of vascular risk
factors may improve renal function.
A few studies have documented the occur-
rence of hypercholesterolemia in those with
hyperuricemia and gout, but no linkage has been
established between hypercholesterolemia and
hyperuricemia or gout [938, 939, 948–951].
Even though the frequency of hypertriglyceri-
demia in patients with hyperuricemia and gout is
probably related to lifestyle factors (obesity, diet,
diabetes mellitus, and alcohol intake) and drugs
(diuretics, estrogen therapy, or beta-adrenergic
blockers), the importance of hyperlipidemia to
the overall health of the patient makes its recog-
nition and treatment of significance to those car-
ing for gouty patients [952, 953]. For this reason,
as well as the high frequency of hypertriglyceri-
demia in those with hyperuricemia or gout, a
brief review of both inherited and acquired causes
of hypertriglyceridemia is discussed. An addi-
tional rationale for such a discussion is the fact
that hypertriglyceridemia is a common ailment
affecting 10 % of males in the age group between
35 and 39 [954].
Even though no mechanisms have been clearly
defined for the association between purine and
triglyceride metabolism, hypertriglyceridemia is
more frequent than gout. The latter has a preva-
lence of 0.2–0.3 per 100 individuals as contrasted
with 1 per 100 for hypertriglyceridemia. The her-
itable lipid abnormalities associated with elevated
triglyceride levels include familial combined
hyperlipidemia and its variant, familial lipopro-
tein lipase deficiency, familial apolipoprotein
C-II deficiency, familial inhibitor of lipoprotein
lipase, monogenic hypertriglyceridemia (type V
hyperlipoproteinemia), lecithin/cholesterol acyl-
transferase deficiency, fish-eye disease, type III
hyperlipoproteinemia (dysbetalipoproteinemia),
and the DNA polymorphisms of apo A-I, apo
C-III, and apo A-IV. The acquired disorders are
discussed with type III hyperlipoproteinemia
with which they are associated.
Associated Disorders
Familial Combined Hyperlipidemia
Familial combined hyperlipidemia occurs in
about 1–2 % of the population in North America
and Europe. It may occur as a single entity or in
combination with hypertension, obesity, or insu-
lin resistance [955–961]. This disorder is the
most common genetic hyperlipidemia identified
in survivors of myocardial infarctions, but to
date, its complete genetic composition remains
unknown [957]. It is also said to cause 10–20 %
of the cases of premature coronary heart disease
[962]. The pattern of inheritance is compatible
with an autosomal dominant trait [957]. Its clini-
cal presentation is most effectively defined by
evaluating patients with premature coronary
artery disease. Xanthomas are rare, and the lipo-
protein patterns may change in an affected indi-
vidual over time. Lipoprotein patterns may also
vary within family members. No single genetic
marker has been characterized for familial com-
bined hyperlipidemia, but some inroads have
been made into its genetic identity [963–969].
In familial combined hyperlipidemia, the
plasma triglyceride levels are elevated ranging
between 200 and 400 mg/dl or even higher. The
LDL cholesterol levels are usually higher than
100 mg/dl, and total serum apo B levels are often
higher than 85 mg/dl. The latter apolipoprotein is
often used as a marker for this disorder.
Familial Lipoprotein Lipase Deficiency
Familial lipoprotein lipase deficiency, familial
apolipoprotein C-II deficiency, and familial lipo-
protein lipase inhibitor are rare genetic causes of
hypertriglyceridemia. The first two disorders are
inherited as autosomal recessive traits, whereas
familial inhibitor of lipoprotein lipase appears to
be inherited as an autosomal dominant trait. The
full-blown clinical picture of familial lipoprotein
lipase deficiency includes abdominal pain due to
pancreatitis, hepatosplenomegaly, eruptive xan-
thomas, and lactescent plasma. As noted, this dis-
order is very rare, but in some populations, it may
occur at a higher frequency [970, 971].
Heterozygotes with familial lipoprotein lipase
deficiency may or may not have elevated plasma
triglyceride levels, but hypertriglyceridemia may
occur in patients when secondary factors are
149
present and superimposed on other diseases such
as diabetes mellitus, estrogen therapy, lipid-rais-
ing drugs, or alcohol use [972].
Familial Apolipoprotein C-II Deficiency
Apolipoprotein C-II is a cofactor for the activa-
tion of lipoprotein lipase, and like familial lipo-
protein lipase deficiency, a defect in this cofactor
for lipase activation alters the hydrolysis of trig-
lycerides and the transfer of fatty acids to tissues.
The clinical hallmark of apolipoprotein C-II
deficiency is pancreatitis associated with marked
chylomicronemia and triglyceridemia [973].
Since this disease simulates familial lipoprotein
lipase deficiency (hyperlipoproteinemia type I),
it has also been referred to as hyperlipoproteine-
mia type IB.
Familial Lipoprotein Lipase Inhibitor
Little is known about familial lipoprotein lipase
inhibitor since only a single family has been
investigated [974]. Clinically, affected patients
have markedly elevated triglyceride levels
(>2,000 mg/dl), eruptive xanthoma, and abdomi-
nal pain with pancreatitis. The inhibitor from
affected patients blocks adipose tissue lipopro-
tein lipase activity and postheparin lipase.
Monogenic Hypertriglyceridemia
Monogenic hypertriglyceridemia (type V hyper-
lipoproteinemia) may present with moderate or
severe elevations in triglyceride levels. For pur-
poses of classification, patients with chylomi-
cronemia are separated into those with elevated
VLDL levels (type V) and those with no eleva-
tion in their VLDL levels along with the absence
of postheparin plasma lipoprotein lipase activity
[975]. Type V hyperlipoproteinemic patients usu-
ally present with hypertriglyceridemia and have
chylomicronemia after an overnight fast, whereas
type IV hyperlipoproteinemic patients have
hypertriglyceridemia but do not have chylomi-
crons in their plasma in the fasting state.
Except for a very few cases, familial hyper-
triglyceridemia is usually a manifestation of a
primary disorder in association with a secondary
cause of hyperlipidemia [953, 976–981].
Secondary causes for hypertriglyceridemia
150
include obesity, alcohol intake, and diabetes mel-
litus [976]. Drugs including diuretics, beta-adren-
ergic blockers, estrogens, and isotretinoin
(accutane) treatment may elevate triglycerides. In
the case of accutane, about 25 % of patients
treated with this agent develop hyperlipidemia.
As inferred previously, hypertriglyceridemia may
exist without any accompanying acquired disor-
der, but the nature of the primary cause remains
unknown [978]. In some studies examining type
V hyperlipoproteinemic patients and their first-
degree relatives, no increase in atherosclerosis
has been observed [976, 982].
Type III Hyperlipoproteinemia
Type III hyperlipoproteinemia or dysbetalipopro-
teinemia is an inherited disorder in which patients
manifest elevated concentrations of both plasma
cholesterol and triglycerides along with choles-
terol-rich remnants (ß-VLDL) derived from chy-
lomicrons secreted by the intestine and VLDL
secreted by the liver [983, 984]. Subsequent stud-
ies documented the role of apo-E, a protein that
normally mediates the interaction of apo-E-con-
taining lipoprotein and binding to lipoprotein
receptors. Mutant apo-E in type III hyperlipopro-
teinemia alters binding to lipoprotein receptors
[985–987].
The most common mutant form of apo-E is
apo-E-2, and this mutant results in type III hyper-
lipoproteinemia with a single amino acid substi-
tution of cysteine for arginine at residue 158 in
apo-E. Other rare variants have also been
described [985, 988, 989]. Overt hyperlipopro-
teinemia occurs rarely in patients with mutant
apo-E-2 or its variants, and most patients with
homozygous apo-E-2 are normolipodemic or
even hypolipidemic. This low frequency of overt
hyperlipidemia indicates that additional genetic
or environmental factors are necessary for the
full expression of type III hyperlipoproteinemia.
The secondary environmental factors most often
implicated are hypothyroidism, glucose intoler-
ance, obesity, aging, estrogen deficiency,
increased intake of dietary cholesterol, alcohol
intake, and some drugs [984, 990–998]. For the
most part, these secondary factors in type III
hyperlipoproteinemia cause a reduction in LDL
5 Clinical Aspects of Gout and Associated Disease States
receptors or a decrease in receptor-mediated lipo-
protein uptake as in hypothyroidism [999]. The
decrease in LDL receptor number observed in
heterozygotes with familial hypercholesterolemia
along with a mutant apo-E allele has also been
shown to trigger the expression of type III hyper-
lipoproteinemia [1000]. Dietary alterations that
increase cholesterol and plasma lipoproteins and
downregulate LDL receptors may also increase
type III hyperlipoproteinemia expression
[992–995].
The secondary genetic parameters that have
been shown to contribute to the expression of
type III hyperlipoproteinemia include those dis-
orders with an overproduction of lipoproteins or
elevated levels of cholesteryl ester transfer pro-
tein [1001–1003]. Thus, autosomal recessive
forms of type III hyperlipoproteinemia are repre-
sented by a mutant apo-E together with a second-
ary acquired or genetic factor.
Type III hyperlipoproteinemia may also occur
as an autosomal dominant trait. The mutants
identified as mediators of the dominant form of
type III hyperlipoproteinemia all affect the bind-
ing of apo-E to LDL receptors [989, 1004, 1005].
These mutants include alterations in amino acid
sequences in the receptor-binding domain of
apo-E (residues 136–150). Mutations identified
at this time are 142Arg → Cys, 145Arg → Cys,
146Lys → Gln, 146Lys → Glu substitutions, or a
seven amino acid insertion at residues 121–127.
In addition to defective receptor binding, the
142Arg → Cys and the seven amino acid inser-
tion mutants show a preference for triglyceride-
rich lipoproteins [1006, 1007]. Further, residues
136–150 have an increased affinity for heparin
binding which is important for lipolytic process-
ing and lipoprotein remnant uptake [1008, 1009].
Thus, mutants altered in their capacity to bind to
LDL receptors or heparin binding sites with a
preference for triglycerides regulate the dominant
inheritance of type III hyperlipoproteinemia.
These abnormalities lead to defective uptake and
processing of triglycerides.
The clinical findings in patients with type III
hyperlipoproteinemia usually include an adult
onset of the disease with xanthomas, premature
coronary artery, and peripheral vascular disease
Associated Disorders
as well as asymptomatic hyperuricemia. The geo-
graphic locations of the xanthomas are of special
significance since palmar xanthoma occurring in
the palmar creases is pathognomonic of type III
hyperlipoproteinemia [1010, 1011]. About one-
half the patients with untreated type III hyperli-
poproteinemia manifest this diagnostic sign,
whereas other xanthomas (tuberous and tubero-
eruptive) are also encountered on the elbows,
knees, buttocks, and knuckles. The latter are non-
diagnostic of type III hyperlipoproteinemia since
they are also observed in other hyperlipidemias.
Peripheral vascular disease is almost as common
as coronary artery disease in type III patients, and
vascular disease is observed in about 50 % of
such patients [984, 1012–1015]. Asymptomatic
hyperuricemia has been reported in about 50 %
of patients with this disorder, but only a small
percentage of such patients (4 %) develop gout
[984]. As can be determined from this discussion,
the diagnosis of type III hyperlipoproteinemia is
not a straightforward process since the disease
expression is variable. The following diagnostic
parameters are the most useful: serum triglycer-
ide and cholesterol levels in the range of 400 mg/
dl, the presence of ß-VLDL, xanthomas (espe-
cially palmar crease xanthomas), premature vas-
cular disease, and the occurrence of the apo E-2/2
phenotype.
Lecithin/Cholesterol Acyltransferase
(LCAT) Deficiency
Both lecithin/cholesterol acyltransferase
deficiency and fish-eye disease manifest hyper-
triglyceridemia and are inherited as autosomal
recessive traits [1016–1022]. In familial LCAT
deficiency, there is an absence of lecithin/choles-
terol acyltransferase activity in the plasma. The
clinical manifestations of the disorder include cor-
neal opacities, normochromic anemia, bone mar-
row foam cells, proteinuria with red blood cell,
and hyaline casts, and in some patients, athero-
sclerosis with tendon and planar xanthomas are
observed. Serum uric acid levels are elevated in
some patients, and one reported patient had gout.
An abnormal pattern of lipoproteins is present
including elevated plasma triglycerides,
unesterified cholesterol, and phosphatidylcholine.
151
Low concentrations of plasma cholesteryl esters
and lysophosphatidylcholine are characteristic of
the disorder [1023]. It is important to recognize
that not all patients with LCAT deficiency have
hypertriglyceridemia.
Fish-Eye Disease
Fish-eye disease also represents a deficiency
(partial) in LCAT activity, but these patients only
manifest corneal opacities with no other associ-
ated findings. Most patients with this disorder
have elevated plasma triglycerides, low HDL
cholesterol levels, and normal plasma cholesteryl
ester levels [1020, 1024, 1025].
DNA Polymorphisms
Finally, a number of investigations have been
directed toward an evaluation of genetic markers
to determine whether such determinants are
capable of identifying those patients at risk for
atherosclerosis [1026–1045]. Although no simple
means for the detection of DNA polymorphisms
that confer susceptibility to hyperlipidemia and
coronary artery disease exist at the present time,
such investigations are eventually likely to define
a panel of DNA polymorphisms that will be use-
ful for the characterization of patients at increased
risk for coronary artery disease.
As noted at the outset of this section
“Hyperlipidemias”, the pathogenesis of the inter-
actions between hypertriglyceridemia and hyper-
uricemia remains unresolved. Some investigators
have shown that no change occurs in the serum
uric acid level, urinary uric acid level, or oxypu-
rine excretion when serum triglyceride levels are
dramatically increased [1046]. Other investiga-
tors have documented an inverse correlation
between serum triglyceride levels and fractional
urate excretion as well as a positive correlation
between serum triglyceride and serum uric acid
levels [1047–1050]. In summary, there is an
established interrelationship between uric acid
metabolism and hyperlipidemia, usually hyper-
triglyceridemia, but the cause for these interac-
tions is unknown. It seems reasonable to assess
fasting lipids (12 h fast) in patients with hyperuri-
cemia and patients with gout. This concept is rein-
forced by the role that treatment and disease-related
152
prevention play in those with an identifiable
abnormality if their plasma lipids are lowered.
Analyses of the complex lipid abnormalities are
not a simple task; however, the clinical
identification of xanthomas (especially palmar
crease xanthomas) and lenticular opacities can
easily characterize some of the inherited hyper-
lipidemias. In addition, appropriate attention to
secondary causes of hyperlipidemias is usually
easy to recognize clinically and can be treated in
a straightforward manner.
Glucose Intolerance
There are two separate components that relate to
glucose intolerance and alterations in uric acid
metabolism. The first is the multifaceted meta-
bolic syndrome X or insulin resistance syndrome
that is associated with insulin resistance, hyperin-
sulinemia, dyslipidemia, essential hypertension,
visceral obesity, glucose intolerance or noninsu-
lin-dependant diabetes mellitus, abnormalities in
blood coagulation (elevated levels of plasmino-
gen activator inhibitor type 1 and fibrinogen),
microalbuminuria, and hyperuricemia [1051–
1058]. Some investigators have added polycystic
ovaries as a component of this syndrome as well.
The lipid abnormalities in syndrome X overlap
with the dyslipidemia observed in some patients
with hyperuricemia and gout. In syndrome X, the
lipid abnormalities include elevated serum trig-
lycerides, small LDL particles, low high density
lipoprotein (HDL) cholesterol, and hypercholes-
terolemia. These lipid parameters along with
hypertension and the prothrombotic state increase
the risks for coronary artery disease. Since there
is no question about the association between
insulin resistance and hyperuricemia, the patho-
genesis of this abnormality in uric acid metabo-
lism and its relation to insulin needs to be
investigated [1055, 1059]. As might be expected,
the pathogenesis of hyperuricemia in syndrome
X is multifaceted. It has been related to diuretic
use, obesity, enhanced renal sodium retention,
and hypertriglyceridemia [1057, 1060–1062].
Weight reduction definitely lowers serum uric
acid and serum triglyceride levels [1057, 1062].
5 Clinical Aspects of Gout and Associated Disease States
Thus, a complete understanding of the mecha-
nism causing hyperuricemia in syndrome X
remains unresolved, but it appears to be a multi-
factorial problem.
Two unusual findings reported in association
with syndrome X deserve brief mention. First, a
review of the patients with gonadal dysgenesis
(Turner syndrome) has documented an increased
frequency of syndrome X including hyperurice-
mia in these patients [1063]. As would be
expected, these patients have an increased inci-
dence of diabetes mellitus (NIDDM and IDDM)
as well as hypertension, stroke, and ischemic
heart disease. The other unusual clinical finding
in syndrome X is the case of a 64-year-old female
with severe tophaceous gout [1064]. This patient
also suffered from NIDDM, obesity, hyperten-
sion, and dyslipidemia, all components of syn-
drome X. This rare association between gout and
syndrome X emphasizes the need to recognize
the clinical diversity associated with hyperurice-
mia and gout.
The second component is the relationship
between hyperuricemia, gout, and diabetes mel-
litus. Despite continued interest in these relation-
ships, there is little evidence in support of any
pathophysiological process relating modest
degrees of hyperglycemia to uric acid levels in
diabetes mellitus [916, 1065, 1066]. Of course,
diabetic ketoacidosis is associated with hyperuri-
cemia, and the pathogenesis of this metabolic
derangement relates to the capacity of ketoacids
to inhibit renal tubular urate secretion [263].
Hypertension
Clearly, hypertension and gout are linked since
the older literature documents the fact that
25–50 % of gouty subjects have hypertension
[1067, 1068]. Hyperuricemia has also been
reported in about one-third of the patients with
untreated hypertension [1069–1071]. More recent
studies confirm the association between hyper-
tension and hyperuricemia; the frequency of this
association in these studies was about 60 %
[1072]. Since hypertension, obesity, insulin resis-
tance, and hypertriglyceridemia often coexist,
Associated Disorders
diagnostic studies should identify these addi-
tional risk factors as well [1073–1077]. Some
other studies have emphasized the role of hyperu-
ricemia as a marker of renal disease in hyperten-
sive patients [1078–1084]. Hyperuricemia
observed in association with hypertension is often
the result of decreased renal urate excretion, and
some investigators have proposed that intrarenal
ischemia caused by vascular contraction and
increased lactate production may contribute to a
decrease in urate secretion by the anion-exchange
tubular transport mechanism [1078]. As a corol-
lary to the pathogenesis of hypertension-related
hyperuricemia, reduction in serum urate levels in
the hypertensive gouty subject may prevent addi-
tional impairment of kidney function.
Atherosclerosis
Cerebrovascular and cardiovascular disease are
major causes of death in gouty patients treated
with antihyperuricemic drugs, but it is clear that
hyperuricemia by itself is not an independent risk
factor for atherosclerosis, cerebrovascular dis-
ease, or coronary artery disease [1085–1089].
Even though hyperuricemia as an independent
risk factor of atherosclerosis remains controver-
sial, obesity, hyperlipidemia, and hypertension,
frequent components of the clinical presentation
of gout, are known risk factors for atherosclerosis
and its accompanying disorders [1090].
Thus, of the associated disorders discussed
herein, it is reasonable to screen gouty patients
for lipid disorders and to treat obesity and hyper-
tension aggressively to prevent vascular disease
including any deterioration in renal function.
Evaluating hyperuricemia in patients with gout is
discussed in the section “Asymptomatic
hyperuricemia.”
Critical Illnesses
There is now a large body of evidence to con-
tradict the thesis that uric acid is a metaboli-
cally inert end product of purine metabolism
and to support the premise that this ubiquitous
153
compound is a potent antioxidant capable of free
radical scavenging [1091–1102]. The literature
now has determined that uric acid is capable of
scavenging singlet oxygen, hypochlorous acid,
and other radicals, and its plasma concentration
(300 uM/dl or greater–5.0 mg/dl or greater) is
significantly greater than ascorbate, another major
plasma antioxidant [1091, 1097]. Uric acid has
been shown to be produced by the microvascular
endothelium and blocks the oxidative inactiva-
tion of cyclooxygenase and angiotensin-convert-
ing enzyme [1099]. This latter activity protects
coronary-sized vessels from vasoconstriction
and permits vasodilation in the face of oxida-
tive stress. These properties of uric acid may be
related to the role of uric acid in cardiovascular
disease [1099]. Such concepts are further sup-
ported by animal studies showing vasorelaxation
of the rat thoracic aorta after uric acid scavenges
peroxynitrite [1103]. Further, oxidized LDL
(low density lipoprotein) has been shown to be
associated with coronary artery disease [1104].
Even though the evidence linking atherosclero-
sis, uric acid, and oxidized LDL is incomplete,
these possible interrelationships add confusion
to the role of hyperuricemia in atherosclerosis.
It is clear that resident vascular cells, oxidative
stress, and inflammation stimulate the formation
of oxidized LDL. Resident vascular cells pro-
duced so-called minimally modified LDL [1105].
This altered LDL stimulates vascular cells to pro-
duce monocyte chemotactic protein 1 as well as
granulocyte and macrophage colony stimulating
factors [1106]. These reactions stimulate further
peroxidation of LDL, and such oxidative stress
generates completely oxidized LDL. Receptors
on the macrophage internalize the oxidized LDL
to create foam cells, primary components of ath-
erosclerotic lesions [1107, 1108]. Since oxidized
LDL cellular uptake is not regulated by feed-
back inhibition, massive quantities of cholesterol
are ingested by these macrophages to become
foam cells. Oxidized LDL is chemotactic for
monocytes and enhances monocyte binding to
endothelium [1109, 1110]. Once these lipid-laden
macrophages/monocytes enter the subendothelial
space, their egress is inhibited by oxidized LDL
[1111]. The cytotoxicity of oxidized LDL also
154
damages vascular cells leading to the release of
lysosomal enzymes. These alterations cause the
progression of atherosclerotic lesions [1112,
1113]. As further proof of the role of oxidized
LDL in atherosclerosis, antibodies against oxi-
dized LDL react with atherosclerotic lesions
in blood vessels but not with normal arteries in
the absence of atherosclerotic lesions [1114]. In
addition, autoantibodies to oxidized LDL are at
higher concentrations in patients with carotid
atherosclerosis than in age-matched normal con-
trol subjects [1115]. Similarly, immunoreactive
oxidized LDL plasma concentrations are elevated
in patients with acute myocardial infarctions as
compared to normal control subjects [1116].
Despite all this evidence linking the reduced
oxidation of LDL and atherosclerosis, the role of
uric acid as an antioxidant and as a factor causing
reduced atherosclerosis remains an incomplete
story. A number of investigations support the
antioxidant activity of uric acid against lipopro-
tein oxidation, but whether this is the sole or
major factor acting to reduce the severity of ath-
erosclerosis remains an open question [1117–
1120]. As the mechanism(s) of atherosclerosis
become better understood, a reevaluation of the
role that uric acid plays in this pathological pro-
cess is necessary.
Finally, in contrast to these hypothesized pro-
tective roles of uric acid in atherosclerosis,
marked hyperuricemia is related to tissue hypoxia
in severely ill patients and often indicates a poor
prognosis [101, 1121]. Subsequent studies have
questioned the use of uric acid levels as well as
adenosine, inosine, hypoxanthine, and lactic acid
levels as specific markers of prognosis even
though such metabolic changes were increased as
clinical deterioration progressed [1122].
Nonetheless, the hypothesis that tissue hypoxia
results in increased production of uric acid via
the depletion and catabolism of adenosine
triphosphate remains valid. In addition, patients
with hypoxia also have a decreased uric acid
excretion. Some investigations have also sug-
gested that the hyperuricemia observed in severe
illnesses may only reflect the degree of renal dys-
function [1123]. Some have even suggested that
allopurinol treatment may prevent deterioration
5 Clinical Aspects of Gout and Associated Disease States
of renal function and enhance hypoxanthine sal-
vage as a result of xanthine oxidase inhibition by
allopurinol [1121]. Clearly, the role of hyperuri-
cemia as a marker of serious illness and as a
prognostic factor remains incompletely under-
stood and somewhat controversial. Its role as an
antioxidant and its capacity to reduce atheroscle-
rosis are also incompletely resolved issues.
In summary, although there are no direct
mechanistic associations between uric acid
metabolism and obesity, glucose intolerance,
hyperlipidemia, atherosclerosis, hypertension,
and critical illnesses, sufficient evidence exists
to evaluate some of these associations in patients
with hyperuricemia and/or gout. At the present
time, it appears reasonable for physicians caring
for patients with gout to treat obesity with weight
reduction, to evaluate and manage hypertension
aggressively to protect renal function deteriora-
tion, and to evaluate and treat these same patients
for any identifiable dyslipidemias. It must be
clear from this discussion that gout is the clini-
cal expression of many different underlying
disorders.
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95:2611.
1117. Abuja PM. Ascorbate prevents prooxidant effects
of urate in oxidation of human low density lipopro-
tein. FEBS Lett. 1999;446:305.
1118. Schlotte V, Sevanian A, Hochstein P, Weithmann
KU. Effect of uric acid and chemical analogues on
oxidation of human low density lipoprotein in vitro.
Free Radic Biol Med. 1998;25:839.
1119. Nieto FJ, Iribarren C, Gross MD, et al. Uric acid
serum antioxidant capacity: a reaction to athero-
sclerosis? Atherosclerosis. 2000;148:131.
1120. Hasegawa T, Kuroda M. A new role of uric acid as
an antioxidant in human plasma. Rinsho Byori.
1989;37:1020.
1121. Boda D. Role of hyperuricemia in critically ill
patients especially newborns. Acta Paediatr Hung.
1984;25:23.
1122. Jabs CM, Sigurdsson GH, Neglen P. Plasma levels
of high-energy compounds compared with severity
of illness in critically ill patients in the intensive
care unit. Surgery. 1998;124:65.
1123. MacKinnon KL, Molnar Z, Lowe D, et al. Measures
of total free radical activity in critically ill patients.
Clin Biochem. 1999;32:263.
 Diagnostic Procedures
in the Management of Gout
Introduction
The objective of this chapter is to provide the
reader with the methodologies used to investigate
abnormalities in purine synthesis and metabo-
lism. As one might suspect, there are many pub-
lished variations of specific methods, and no
attempt has been made to include all these differ-
ences. Methodologies that have become some-
what universal in their usage have been selected
for inclusion. Further, an attempt has been made
to include only those methodologies that have
primary significance to the clinician-investigator
who is faced with the task of the diagnosis and
management of patients who may have abnor-
malities in purine metabolism.
Hyperuricemia
The chemical properties of the uric acid of great-
est significance to the production of disease are
its capacity to form crystals and its relative insol-
ubility in nonalkaline solutions. Crystal forma-
tion leads to the initiation of an acute inflammatory
response in synovial joints and ultimately an
acute arthritis. The insolubility of uric acid often
leads to the formation of kidney stones in the host
who is excreting large quantities of uric acid and
also may result in the deposition of urates in tis-
sue sites such as tophaceous deposits. In water, a
saturated solution of uric acid at 37 °C is
0.38 mM, which corresponds to a concentration
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_6, © Springer-Verlag London 2013
6
of 6.45 mg %. The monosodium salt of uric acid
is slightly more soluble in water than the free
acid, and the free acid has two ionization con-
stants (pKa1 = 5.75 and pKa2 = 10.3). As the pH
approaches the second pKa, the molecule is more
soluble, and therefore, alkalinity enhances the
solubility of uric acid. Solubility in plasma is
somewhat greater than in water, and supersatura-
tion occurs at 7.0 mg %. As calculated from
Allen’s data by Loeb [1, 2], uric acid has a solu-
bility of 6.8 mg % at 37 °C in the presence of
sodium ions (140 mM). On the basis of these cal-
culations, supersaturation of the plasma occurs at
concentrations of uric acid above 7.0 mg %.
Thus, the physicochemical definition of hyperu-
ricemia is a plasma concentration above 7.0 mg
%. There are data in the literature that higher
concentrations of monosodium urate in plasma
can be attained in supersaturated solutions [3–5],
but such supersaturated solutions are usually
unstable and over time monosodium urate pre-
cipitates. The factor or factors governing the
enhanced solubility of urate in plasma remain
incompletely understood, even though some
plasma macromolecules including albumin, low-
density beta-lipoprotein, beta-2 macroglobulin,
and an alpha-1, alpha-2-globulin have been pro-
posed and their affinity for urate characterized in
some cases [6–12]. In summary, there are macro-
molecules that bind urate in plasma; however, the
binding of urate to plasma proteins at 37 °C is
likely to be of little physiological or clinical
significance.
187
188
Synovial Fluid Analysis
Arthrocentesis and synovial fluid analysis are
procedures essential for making an absolute diag-
nosis of either a septic joint or a crystal-induced
arthritis. In addition, synovial fluid culture and
sensitivity must be done in cases where septic
arthritis is suspected. Except for synovial fluid
analysis including culture, there is no reliable
means of differentiating septic arthritis from
crystal-induced arthritis. As a general rule, it is
reasonable to culture all synovial fluids recovered
from patients with an acute arthritis to exclude
infection.
Any synovial fluid analysis that has a white
blood cell count of greater than 100,000 cells/
mm3 represents a possible septic joint until proven
otherwise by culture results. In contrast, a syn-
ovial fluid count of less than 50,000 white blood
cells/mm3, although less suspicious of infection,
does not exclude a septic joint from consider-
ation. Immunocompromised hosts, especially
those undergoing treatment to avoid organ rejec-
tion or to suppress systemic connective tissue
diseases, are often unable to mount a sufficient
neutrophil response to an infection or crystal-
induced inflammatory response. The identification
of monosodium urate crystals in synovial fluid
with accompanying findings supportive of gout
provides the clinician with an absolute criterion
for the diagnosis of gout. Nonetheless, such crys-
tals may also be associated with an infectious
process or calcium pyrophosphate dihydrate
(CPPD) crystals.
Arthrocentesis Techniques
The technique for joint aspiration is straightfor-
ward when the aspiration of a relatively large
joint (ankle, knee, wrist) is the objective. Smaller
joints (finger) and hips or shoulders may be more
difficult to aspirate. If one lacks experience with
joint aspirations, the task should be assigned to
an experienced rheumatologist or orthopedist.
Initially, the aspiration site should be cleansed
6 Diagnostic Procedures in the Management of Gout
with soap and water and subsequently swabbed
with iodine and alcohol. One should determine
that the patient is not sensitive to iodine before
treating the skin with iodine. Alcohol cleansing
alone can be used in patients with iodine sensitiv-
ity. The skin over the site of aspiration may be
anesthetized either with Xylocaine or ethyl chlo-
ride spray. Deep infiltration with Xylocaine
should be avoided to prevent injecting anesthetic
into the synovial fluid and thereby altering the
results of the subsequent synovial fluid analysis.
Small-sized needles may be used for Xylocaine
infiltration (25 gauge), but 16- to 18-gauge nee-
dles should be used for the aspiration of synovial
fluid. The syringe should be wet with sodium
heparin to avoid clotting of the aspirated fluid.
Although the author prefers to use heparin as an
anticoagulant, EDTA (ethylenediaminetetraa-
cetic acid) or sodium citrate solutions can also be
used. Anticoagulants to avoid are powdered
oxalate and lithium heparin, since these prepara-
tions form crystals that lend confusion to the
analysis [13–15]. Talc from surgical gloves may
also give rise to Maltese crosses in synovial fluid
leading to confusion when the fluid is examined
for true crystals [16].
For diagnostic aspirations, only 1–5 ml of
fluid is required. If one elects to perform a com-
plete aspiration for relief of tension in the joint, a
hemostat attached to the hub of the needle per-
mits an easy exchange of syringes should that be
necessary. In knee aspirations, fluid can be pushed
toward the needle by compressing the side oppo-
site from the site of needle entry. The knee may
be aspirated from a lateral or medial site.
Loculated accumulations of pus, especially in
gonococcal infections, may be encountered, and
both lateral and medial approaches to the knee
may be necessary in such settings to enter these
loculated accumulations of pus. The wrist is usu-
ally aspirated from its dorsal surface at the site of
the radiocarpal joint. After identifying the joint
space, the ankle may be aspirated anterior to the
malleolus. The shoulder may be aspirated using
either an anterior or posterior approach. The ante-
rior approach is done by inserting the needle just
Synovial Fluid Analysis
lateral to the coracoid process with the needle
pointing toward the glenohumeral joint. The pos-
terior approach to the shoulder joint is accom-
plished by inserting the needle about 1 in. below
the posterolateral boundary of the acromion pro-
cess. Finger joints are best aspirated using a dor-
solateral approach to the joint. Several excellent
books and CDs are available to guide the clini-
cian in joint aspirations, and these informative
sources may be consulted for further information
on joint aspirations [17–19].
If one uses sterile techniques during joint aspi-
rations, there are rarely any complications from
this procedure. The most common complications,
when they occur, are pain, hemarthroses, and
infections. With respect to pain, adequate local
anesthesia and avoidance of pain-sensitive joint
structures are sufficient to prevent significant dis-
comfort during the procedure. Occasionally,
patients may faint during or after the procedure,
so it is essential to have somebody stay with the
patient when he or she arises after the completion
of the joint tap. If the patient is known to have a
significant bleeding diathesis, it is necessary to
perform arthrocentesis after treating the coagula-
tion disorder. Infections relating to arthrocentesis
are rare. It is inappropriate to aspirate a joint at a
site where cutaneous infections or skin lesions
exist, because infectious agents from such lesions
may be carried into the synovial cavity during
aspiration and result in a septic joint.
A recent randomized controlled trial of dry
taps indicated that failed arthrocentesis was most
frequently the result of the presence of extremely
viscous synovial fluid, adipose tissue, or lipoma
arborescens [20]. Lipoma arborescens (thickened
synovium infiltrated with fat) and fluid viscosity
may also be a problem with dry taps in chronic
synovial effusions. The observations in these
studies suggest that a lateral approach for knee
aspirations may be more rewarding than a medial
approach. There is also objective evidence that a
delay in synovial fluid analysis may alter the
findings even if the fluid is stored at 4 °C prior to
analysis [21]. Even if the delay is a relatively
short period of time (5–6 h), the synovial fluid
189
white blood cell count decreases by about 1,000–
4,000 cells/mm3, and after 24 h, the number of
CPPD crystals decreases significantly and they
become more difficult to recognize. Artifactual
crystals also form in the synovial fluid over time
[21]. Finally, although monosodium urate crystals
remain present in synovial fluid samples for
8 weeks, they are fewer in number, less birefrin-
gent, and smaller in size than in the original sam-
ple. Another comparable difficulty in the
collection and analysis of synovial fluid is the
delay in processing specimens for culture. For
this reason, it is often useful to use blood culture
bottles at the bedside for the immediate culture of
specimens. In both adults and children, cultures
may be positive in only 50–70 % of cases, and
processing synovial fluid samples for culture at
the bedside may increase the chances of recover-
ing an organism [22–25].
Synovial Fluid Culture
In acute synovitis, where gout and septic arthritis
are the primary clinical considerations, four syn-
ovial fluid diagnostic tests are often required: cul-
ture and sensitivity of the fluid, synovial fluid
smears for Gram stain and white blood cell dif-
ferential counts, total white blood cell count, and
wet preparations for crystal analyses. In both
adults and children, cultures of synovial fluid
may not be positive in 100 % of cases, and pro-
cessing specimens at the bedside may increase
the chances of recovering an organism. In fact, in
one recent publication, 70 % of children with
clinical findings indicative of septic arthritis had
negative synovial fluid cultures [26]. Certain
clinical settings increase the risk of infection such
as the elderly patient or a child, the presence of a
prosthetic joint, prior arthrocentesis, prior corti-
costeroid injection, and certain medical condi-
tions. The latter include diabetes mellitus,
rheumatoid arthritis, systemic lupus erythemato-
sus, sickle cell disease, chronic liver disease,
intravenous drug abuse, and the administration of
immunosuppressive drugs.
190
Since a delay in processing synovial fluid
specimens for culture decreases the yield of posi-
tive cultures, the use of aerobic and anaerobic
blood culture bottles at the bedside for the imme-
diate culture of specimens is a good practice. N.
gonorrhoeae are especially difficult to culture
from synovial fluid, and most physicians elect to
plant aspirates from those suspected of infection
with this organism on chocolate agar or Thayer-
Martin culture media at the bedside. Once the
specimen is plated on culture media, it should be
grown in 10 % CO2 for at least 10 days at 37 °C.
Joint infections due to anaerobic bacteria are
exceedingly unusual, but certain clinical settings
increase the chance of such infections. Penetrating
trauma, surgical procedures, prosthetic joints,
and a compromised host are the most common
predisposing risk factors for anaerobic infections.
When this class of bacteria is suspected, culture
media appropriate for anaerobic organisms
should be used.
Synovial Fluid Gram Stain
Gram stains of the synovial fluid may provide an
early clue to the underlying infectious agent and
permit the institution of antibiotic therapy before
culture results are available. Gram stains usually
reveal an organism in 50–70 % of cases, and they
can easily distinguish Gram-positive from Gram-
negative bacteria. Unfortunately, Gram stains
cannot distinguish staphylococcal from strepto-
coccal infections and cannot, by themselves,
determine whether an infectious arthritis is com-
plicated by a crystal-induced arthritis.
It is essential to clean all glass slides and
cover slips prior to their use to avoid visualizing
artifacts in the Gram stained specimens or in wet
preparations of synovial fluid for crystal exami-
nation. The application of acetone to slides and
cover slips and subsequent drying in a dust-free
environment removes most contaminating mate-
rial. Initiating antibiotic therapy on the basis of
Gram stain results serves to forestall the amount
of joint destruction and its resultant alterations
6 Diagnostic Procedures in the Management of Gout
in joint functions caused by the infectious
process.
Synovial Fluid White Blood Cell Counts
Synovial fluid white blood cell counts of 2,000
cells/mm3 or less are usually considered
noninflammatory, but total white blood cell counts
in this range are observed in some systemic
articular disorders such as systemic lupus erythe-
matosus, enteric arthritis, systemic sclerosis,
osteoarthritis, and rarely crystal-induced synovi-
tis [27–29]. Other articular diseases may also
present with noninflammatory total white blood
cell counts in their synovial fluid including hyper-
trophic pulmonary osteoarthropathy, sickle cell
disease, hypothyroidism, amyloidosis, neuro-
pathic arthropathy, and hyperlipoproteinemia. It
is also imperative to remember that individuals
who are immunocompromised may express low
total white blood cell counts when infection or
crystal-induced arthritis is the underlying cause
of their joint inflammation.
At the other extreme, synovial fluid total white
blood cell counts in the range of 50,000–100,000
cells/mm3 are the usual findings in septic arthritis
or crystal-induced arthritis [30]. However, this
degree of synovial fluid leukocytosis may also be
observed in rheumatoid arthritis and other non-
septic arthritis. Nonetheless, data from a series of
synovial fluid tests confirm the sensitivity and
specificity of synovial fluid white blood cell
counts and the percentage of neutrophils as keys
to discriminating between inflammatory and
noninflammatory diseases of the joints [31].
Thus, although synovial fluid levels of protein,
glucose, lactic acid dehydrogenase, and other
chemical analyses of the fluid may be helpful, the
total white blood cell count, differential cell
count, and culture are the most critical tests for
characterizing infectious and crystal-induced
arthritides.
Two critical issues need to be recognized
regarding white blood cell counts. First, the
proper diluent for synovial fluid cell counts is
Synovial Fluid Analysis
normal saline and not acetic acid, the diluent used
for peripheral blood cell counts. If acetic acid is
used as the diluent for synovial fluid, clots of
mucin and other components of the fluid occur
and white blood cells are trapped in this precipi-
tated material. When such acetic acid-treated
fluids are subjected to automated cell counters,
cell clumping and other debris dramatically
reduce total white blood cell counts. The author
has experienced this laboratory error a number of
times, especially when inexperienced night staff
are operating the laboratory.
Second, the color and turbidity of a fluid often
suggests an underlying infection but is not always
a foolproof sign. Certainly, purulent-appearing
fluid with a green, yellow, or white color is most
likely to indicate an infection with the variation
in color imparted by the type of infecting organ-
ism. Several cases of acute gouty arthritis have
been reported with thick, white synovial fluid on
aspiration [32, 33]. Such milky effusions appear
to be most common in alcohol abusers, and such
effusions have been found to result from massive
accumulations of uric acid crystals. The large
number of crystals interferes with either the accu-
mulation of leukocytes or their accurate count-
ing. In fact, one reported patient with such a
milky effusion had a total white blood cell count
of 6,750 WBC/mm3 with 91 % neutrophils.
Interestingly, not all chalky-white synovial fluids
represent purulent effusions or crystal-induced
inflammation. Lipid-laden synovial fluids are
orange-white in color, and large numbers of rice
bodies in synovial fluid may mimic pus. Lipid-
laden fluids are usually observed in patients with
chronic, long-standing effusions. Thus, not all
purulent-appearing fluids represent infection.
Synovial Fluid Differential Cell Count
Using clean cover slips and glass slides, a thin
smear of synovial fluid is made to examine the
differential white cell count after staining the
smear with Wright’s stain. If the total cell count
is low, a concentrated sediment of fluid can be
191
used. Centrifuging the synovial fluid specimen at
3,000 rpm for 10 min may form such a cell pellet.
After decanting the supernatant, the cell pellet
may be resuspended in several drops of the super-
nate. The cell concentrate can then be used both
for preparing smears for differential counts and
for crystal examination using a wet cell
preparation.
In most septic joints, the synovial fluid dif-
ferential cell count reveals more than 95 %
neutrophils. Crystal-induced arthritis usually
has a slightly lower percentage of neutrophils.
As a general rule, infected synovial fluids show
neutrophil percentages of 75 or more, and
crystal-induced inflammatory fluids have 50 % or
more neutrophils in their differential count.
Synovial Fluid Wet Preparations
for Crystal Identification
The most significant test in the evaluation of an
acute inflammatory process in a joint other than
synovial fluid Gram stains and cultures is the
search for crystals by light and compensated
polarized microscopy [34, 35]. Specimens should
be examined promptly after the wet preparation
is prepared, and the need for a careful and tech-
nologically sound examination of such prepara-
tions cannot be overemphasized [36–38].
To prepare a wet preparation, two drops of
synovial fluid are placed on a clean glass slide
and covered with a clean cover slip. The edges of
this wet preparation are then sealed with clear
nail polish or Permount. Sealing prevents the dry-
ing of the specimen and the movement of the
contents to be examined. Wet preparations from
pelleted cells and repeated synovial fluid analy-
ses may be necessary for the identification of
crystals [39]. Light microscopy appears to iden-
tify calcium pyrophosphate dihydrate (CPPD)
crystals more readily than compensated polarized
microscopy since only 20 % of CPPD crystals are
birefringent [40].
Crystals can be visualized by light, phase, and
compensated polarized microscopy, but the latter
192 6 Diagnostic Procedures in the Management of Gout

method is the most definitive way to identify

monosodium urate crystals. In addition to the
characteristics of crystals seen by compensated
polarized microscopy, crystal morphology is
helpful in distinguishing CPPD from MSU crys-
tals. MSU crystals are linear and needle shaped
with pointed ends, whereas CPPD crystals are
linear and rhomboid in shape with blunt ends.
These crystals may be found both in intracellular
and extracellular locations. As one might expect,
uricase dissolves MSU crystals but not CPPD
crystals. Recently, a commercial staining method
(Diff Quik) has been useful for the identification
of MSU and CPPD crystals when preparations
are examined both by compensated polarized
microscopy and transmitted light microscopy
[41]. In the absence of a first-order red plate
compensator, birefringent material can be visual-
ized as white colored objects on a black micro-
scopic field when the second polarizing lens is
rotated 90° from the first polarizer and the sam-
ple for examination is placed between the two
polarizers. Such dark field examinations are use-
ful for a preliminary search for birefringent mate-
rial, but the absence of the color changes in Fig. 6.1 Monosodium urate crystals visualized using
crystals seen with a first-order red compensator polarized light microscopy. Crystals are needle shaped,
strongly birefringent, and have a negative sign of birefrin-
in place makes a positive identification of the gence, appearing yellow when parallel to the axis of the
crystal type impossible. With a first-order red red plate, and blue when perpendicular. The upper panel
compensator in place and a rose-colored back- shows crystals under plane polarized light. The lower
ground, MSU crystals have a bright yellow color panel shows crystals under plane polarized light using a
red plate to identify the sign of birefringence
when the crystals are parallel to the axis of the
line of slow vibration of the compensator and
blue when perpendicular to the line of slow viewing many synovial fluid specimens. In addi-
vibration. On the basis of these findings, MSU tion to MSU and CPPD crystals, hydroxyapatite,
crystals have strong negative birefringence. In calcium hydrogen phosphate dihydrate, calcium
contrast, CPPD crystals are blue when they are oxalate, cholesterol, lipid inclusions, and immu-
parallel to the axis of the line of slow vibration of noglobulin cryoprecipitates may occur in various
the compensator and yellow when they are at forms of synovitis and may be seen by compen-
right angles to this axis. CPPD crystals show sated polarized microscopy as birefringent objects
weak positive birefringence and, in many cases, [42–49]. Further, many artifacts are also birefrin-
may show no birefringence (Figs. 6.1 and 6.2). gent and lead to confusion in the interpretation of
Since other birefringent crystals and refractile synovial fluid specimens. The most common
artifacts can be observed using compensated refractile artifacts include the anticoagulants, lith-
polarized microscopy, there is no substitution for ium heparin and calcium oxalate, talc from surgi-
training with someone who is experienced in crys- cal gloves, and corticosteroid crystals [14, 15, 50,
tal identification and for increasing one’s skills by 51]. The latter crystals may remain in a joint for
Synovial Fluid Analysis
Fig. 6.2 Calcium pyrophosphate dehydrate crystals.
Using polarized light microscopy. These crystals are usu-
ally rhomboid, weakly birefringent, and have a positive
sign of birefringence, opposite to urate crystals. The panel
prolonged periods of time (months) or be intro-
duced into the joint by withdrawing synovial
fluid with a needle that has been used for thera-
peutic steroid injections. Less common refractile
components found in the synovial fluid include
debris from methyl methacrylate or polyethylene
used for prosthetic joint replacement, nail polish
used to seal wet preparations, fibers from lens
cleaning paper, and crystals contained in immer-
sion oil used for microscopy [52].
Additional Clinical Data Concerning
Synovial Fluid
Although the foregoing discussion details the role
of the clinical laboratory in the use of synovianal-
ysis for the diagnosis of acute monarticular arthri-
tis, there are several additional facets that need
193
on the right is under polarized light alone, and the two
panels on the left are seen with polarized light and a red
plate
emphasis with regard to crystal-induced disorders.
It is now well established that asymptomatic gouty
patients may have MSU or CPPD crystals in
noninflamed joints during the intercritical phase
of their disease. MSU crystals in such joints are
most frequently recovered from the knee or first
metatarsophalangeal joint and may also be recov-
ered from joints that have never been the site of
an acute episode of gout. Such crystals are more
likely to be recovered from noninflamed joints of
those patients who have not been treated with
hypouricemic drugs and who maintain a degree
of hyperuricemia [53–55]. MSU crystals have
also been identified in the noninflamed joints of
patients with renal failure and hyperuricemia [43,
49]. Thus, the presence of MSU crystals in syn-
ovial fluid from a noninflamed joint does not
make an absolute diagnosis of intercritical gout
[56]. It is also worth reemphasizing the fact that
194
MSU crystals may be observed in the presence of
a septic joint as well as in the presence of other
crystals [57, 58].
Gout rarely complicates systemic connective
tissue disorders, but it has been reported in
patients with systemic sclerosis and in both
females and males with systemic lupus erythe-
matosus [59–65]. The coexistence of gout and
systemic connective tissue diseases may lead to
an erroneous diagnosis if a synovial fluid analysis
is not performed and a search for crystals under-
taken. Errors in diagnosis may be particularly
prominent when immunosuppressive agents are
used in the treatment of systemic connective tis-
sue diseases and serve to suppress the acute syno-
vitis associated with gout. In cases where gout
complicates lupus, hyperuricemia, kidney dis-
ease, and diuretic use may provide clues to avoid
misinterpreting the synovitis as the arthritis of
SLE [64].
Until recently, there was a commonly held
belief that gout was unusual in blacks; however,
recent surveys have disposed of this notion
[66–70]. These studies document that gout is not
that unusual in blacks and that many associated
factors such as hypertension, diuretic use, renal
disease, and alcohol abuse are observed as comor-
bid conditions in blacks with gout.
Finally, there are ongoing attempts to develop
sensitive, rapid, and specific tests for the diagno-
sis of bacterial arthritis. Such investigations have
also been linked to hypotheses suggesting that
bacteria may have a role in certain systemic
arthritides such as rheumatoid arthritis and the
spondyloarthropathies. These tests have primar-
ily been aimed at discriminating between the
components of the inflammatory responses
observed in septic arthritis versus those in crystal-
induced arthritis or in defining specific bacterial
products not observed in crystal-induced arthri-
tis. Measurements of cytokines and acute phase
reactants in the synovial fluid have not been able
to define specific differences between septic
arthritides and crystal-induced arthritis [71].
Although extensive investigations of synovial
fluid lactic acid levels have been reported, the
inability of these tests to differentiate nonseptic
joint disorders from bacterial arthritides limits
6 Diagnostic Procedures in the Management of Gout
their usefulness [72–74]. Probably the most
promising technique for excluding infection
resides in the use of polymerase chain reactions
and DNA amplification of synovial fluid samples
to identify and characterize infectious organisms
[75–81]. However, at the present time, none of
these techniques including those based on bacte-
rial DNA provides foolproof characterization of
specific organisms. Nonetheless, as more becomes
known about the molecular structure of various
bacterial species, bacterial DNA analyses of syn-
ovial fluid aspirates may provide a rapid, specific,
and sensitive means of excluding bacterial
arthritides.
In summary, aspiration of synovial fluid and
its subsequent culture and analysis represents on
the most useful diagnostic tests for distinguishing
various articular diseases. When the diagnosis of
a swollen joint is in question, clinicians should
not hesitate to tap the joint and examine the con-
tents of the aspirate. Although general rules
always have significant exceptions, a synovial
fluid white blood cell count between 50,000 and
100,000 cells/mm3 with 90 % or more neutrophils
in its differential cell count often indicates either
the presence of an infection or a crystal-induced
arthritis. Bedside culturing of synovial fluid aspi-
rates increases the likelihood of recovering the
offending organism, and infection must always
be a consideration when the arthritis is associated
either with another disease or a host prone to
infectious complications. A paucity of white
blood cells in a synovial specimen does not
exclude the diagnosis of gout [82]. Careful prep-
aration of slides for crystal analysis and search-
ing a number of microscopic fields by
compensated polarized microscopy usually docu-
ments the presence of crystals when they are
present.
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2. Loeb JN. The influence of temperature on the solubility
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 Roentgenographic Findings
and Musculoskeletal Ultrasound
Introduction
The diagnosis of gout is based primarily on the
medical history and clinical findings. Radiological
examinations of patients with gout should most
frequently be utilized either to exclude other
diagnoses or to identify tissue urate deposits. The
latter findings assist the clinician in the
identification of those patients that require inter-
vention with hypouricemic agents. The three pri-
mary radiographic manifestations of gout are:
joint and/or bursal effusions with soft tissue
swelling, bony erosions, extra-articular tophi,
and uric acid stones. Less common findings
include the rare finding of avascular necrosis due
to tophaceous deposits interfering with blood
supply to bone, enlarged kidneys secondary to
polycystic kidney disease, enlarged liver shadows
due to alcoholism or glycogen storage disease,
and massive hydronephrosis, hydroureter, and
dilation of the bladder in nephrogenic diabetes
insipidus associated with hyperuricemia and
gout. In addition, urate crystal deposits may be
visualized by both musculoskeletal ultrasound
and dual-energy computerized tomography, and
these techniques will be discussed after some
consideration of the use of ordinary radiography.
The absence of physicians skilled in arthro-
centesis or the unwillingness to refer patients to
those with such skills, and often, the lack of an
appropriate microscope for visualizing uric acid
crystals under polarizing light may lead to
unsound clinical judgments. It is important to
recognize that gout is only one of many disorders
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_7, © Springer-Verlag London 2013
7
that may show an elevated serum uric acid level,
and therefore a precise and unequivocal diagno-
sis of gout is essential as the first step in the man-
agement of gout. The gold standard for the
diagnosis of gout has become the identification
of monosodium urate (MSU) crystals obtained
from an inflamed joint or a tophus (see Chap. 6).
For these reasons, there has been a real need for a
noninvasive means to identify uric acid crystal
deposits without the need for synovial fluid
aspirations.
Soft Tissue Swelling and Joint
Effusions
Acute gouty arthritis is manifested by an intense
inflammatory reaction of the involved joint or
joints with associated soft tissue swelling and
often an effusion in the affected joint(s).
Although X-rays of the involved joints are not
likely to change the clinical impression and will
not exclude the presence of intra-articular sep-
sis, an X-ray of the involved joint may exclude
complicating disorders such as fractures, osteo-
myelitis, or chondrocalcinosis. Clinical exami-
nation is able to detect large effusions of involved
joints, and often a positive bulge sign can iden-
tify small effusions in joints. Arthrocentesis is
essential to exclude infection and to identify
urate microcrystals. The failure of an attempt at
arthrocentesis can be due to several factors
including a medial patellofemoral compartment
fat pad, the presence of lipoma arborescens, a
199
200 7 Roentgenographic Findings and Musculoskeletal Ultrasound
medial plica, viscous synovial fluid, or needle
blockage by rice bodies or other debris [1]. In
obese patients, fat deposits may simulate small
effusions and can also be a reason for the failure
to withdraw synovial fluid [1]. These causes for
the apparent absence of joint fluid on arthrocen-
tesis have been confirmed by magnetic resonance
imaging supplemented by intravenous gadoli-
nium contrast [1].
If clinical suspicions mandate the need for
arthrocentesis, and fluid cannot be detected with
certainty on physical examination, a magnetic res-
onance image can define the precise anatomical
location of an effusion for purposes of directing
the physician in the performance of the aspira-
tion. This need for an MRI occurs very infre-
quently but may arise in patients where infection
is a strong consideration, and the identification of
the infectious agent is necessary to initiate treat-
ment promptly. It is often most advantageous to
perform a synovial aspiration of the lateral knee
compartment and to have an assistant compress
the areas of the knee opposite from the point of
aspiration.
Distal peripheral joints in an asymmetric pat-
tern represent the usual distribution of acute
gouty arthritis. The characteristic joints involved
are the ankle, the first metatarsophalangeal, inter-
phalangeal, carpal, and elbow joints [2, 3]. The
olecranon and prepatellar bursae are often
inflamed and manifest associated soft tissue
swelling with bursal effusions. Acute gouty
arthritis may also involve the knees that may
show marginal erosions of the femorotibial or
patellofemoral joints. In the early stages of gout,
joint space width is preserved in the presence of
bony erosions, whereas the late stages of the dis-
ease show nonuniform articular cartilage narrow-
ing in association with degenerative joint disease.
Rarely, gouty arthritis may involve the spine,
hips, or sacroiliac joints. These sites are almost
never involved in the acute process but are more
likely to show changes consistent with chronic
tophaceous gout. In chronic tophaceous gout
associated with repetitive acute gouty episodes,
osteopenia is observed from disuse of the
involved joint and the effect of inflammatory
mediators on bone.
Bony Erosions
Cyst-like lesions (tophi) containing aggregated,
radiolucent deposits of uric acid occur adjacent
to the margins of the articular cortex and erode
the underlying bone in gout. They may also local-
ize to juxtachondral areas and simulate the ero-
sions observed in other inflammatory arthritides
such as rheumatoid arthritis. These lesions, simi-
lar to the cystic changes observed in rheumatoid
arthritis, are not usually associated with para-
articular osteoporosis caused by the inflammatory
rheumatoid pannus. In contrast, the gouty tophus
is a sharply marginated, punched-out defect in
the joint margins of the small bones of the hands
and feet. These tophi often have thin sclerotic
margins with the characteristic overhanging mar-
gin of bone [4]. The marginal deposition of urate
tophi also causes periosteal new bone formation
localized to the outer margin of the tophus. Such
changes often appear as an elevated overhanging
edge. This overhanging edge is frequently
observed in association with the gouty tophus but
may also be seen in sarcoidosis and psoriatic
arthritis. Frequently, tophaceous deposits are also
associated with osteoarthritis of the distal inter-
phalangeal joints that is consistent with the idea
that tophi are found in areas of tissue damage.
Although tophi can be observed in many differ-
ent sites, anteroposterior views of the hands and
feet are the most rewarding X-rays for the delin-
eation of tophi. In untreated patients with gout,
these tophaceous deposits enlarge, destroy more
bone, and in a few instances, where extensive
bony destruction has occurred, may appear like a
tumor that has invaded bone (Fig. 7.1).
Tophi may also be identified in X-rays as soft
tissue masses, frequently localized to the olecra-
non bursa. Such masses may or may not contain
punctate deposits of opaque calcium interspersed
throughout the tophus. In addition to the cystic
lesions of subchondral bone, tophi extending into
soft tissue may show increased density as com-
pared with the adjacent soft tissues. Upon occa-
sion, tophaceous deposits extend through the
overlying skin and drain granular material.
Unfortunately, these draining tophi are some-
times mistaken for infectious processes, and
Uric Acid Calculus
Fig. 7.1 Tophi causing erosions in early gout. Note the
lucent areas in the distal metatarsal bone and the proximal
phalanx of the great toe
clinicians may treat such lesions as the result of a
spreading osteomyelitis with associated abscess
formation. Examination of the exudate using
polarizing microscopy serves to identify easily
the cause for the lesion.
Extra-articular Tophi
Tophaceous deposits may occur in juxtaposition
to tendons and ligaments and cause weakening of
those structures eventually leading to rupture.
Furthermore, the deposition of urate in confined
spaces such as the carpal tunnel may give rise to
an entrapment neuropathy [5, 6].
Uric Acid Calculus
Uric acid nephrolithiasis occurs commonly in
several clinical settings. Patients with the onset
of gouty arthritis between the ages of 16 and 35
who may or may not have a family history of gout
are at the highest risk for a genetic form of gout
associated with urate overproduction and the pro-
pensity to form urate stones. In the unusual cir-
cumstance of patients who have not been hydrated
or pretreated with allopurinol and undergoing
radiotherapy or chemotherapy, an increased risk
for urinary tract obstruction due to the excretion
201
of large quantities of urate secondary to tumor
lysis and breakdown of purine precursors is pres-
ent. Such patients are prone to acute renal failure
resulting from the accumulation of urate sludge.
Finally, infants may present with acute renal fail-
ure as a result of underlying enzyme deficiencies
predisposing them to stone formation, obstruc-
tive nephropathy, and postrenal failure. Although
postrenal failure is the least common cause of
acute renal failure when compared to prerenal
and intrinsic causes of failure, the potential for
curing postrenal failure by removing an obstruc-
tion mandates that radiographic studies be done
to evaluate the presence of urinary tract outflow
obstruction. Since more than 80 % of urinary cal-
culi contain calcium, a simple plain film of the
abdomen (KUB) is the first radiologic diagnos-
tic procedure to be performed in such settings.
However, this procedure is of little use in patients
who have disorders of purine metabolism since
stones in these diseases are usually radiolucent.
The second procedure of choice used to be intra-
venous urography. In the case of uric acid calculi,
this procedure will demonstrate a filling defect in
the pelvocalyceal system denoting the presence
of radiolucent uric acid stones or other opaque
structures. This procedure has now been largely
replaced by ultrasonography, a technique that
avoids the risks associated with the use of con-
trast media even though such risks are relatively
low [7]. Such risks include a spectrum of minor
to severe reactions such as nausea, vomiting,
urticaria, nephrotoxicity, pulmonary edema, con-
gestive heart failure, bronchospasm, and anaphy-
laxis. Ultrasonography may reveal the presence
of hydronephrosis as the sole manifestation of
obstructive uropathy or may also show the calcu-
lus itself. Since most kidney stones are located at
the ureteropelvic or ureterovesical junction, ultra-
sound evaluations must be carefully performed to
include examinations of these locations. Partial
obstructions by a stone or forniceal ruptures may
result in an unrecognized presence of a stone
since ultrasonography may miss a kidney abnor-
mality in the absence of hydronephrosis. In such
cases, if a stone is strongly suspected, evaluation
by intravenous urography should be undertaken.
Nonetheless, ultrasonography as a noninvasive
202 7 Roentgenographic Findings and Musculoskeletal Ultrasound
procedure has been extremely useful for the
assessment of infants who present with acute
renal failure and have been subsequently shown
to have obstructive uropathy due to stones. It is
important to recognize that not all urate stones
are radiolucent since they may contain flecks of
calcium that gives a speckled radiodense appear-
ance. Furthermore, there are other renal calculi
that are radiolucent including stones composed
of xanthine, 2,8-dihydroxyadenine, cystine, and
oxipurinol. Oxipurinol stones arise as a result of
the inappropriate use of allopurinol and are usu-
ally iatrogenic.
Avascular Necrosis
Rarely tophi in the right location can contribute
to the obstruction of the blood supply to a bone
and result in the occurrence of avascular necrosis
(osteonecrosis). In gout, osteonecrosis is com-
monly localized to the head of the femur [8]. This
disorder progresses through five stages that have
been defined radiographically [9]. Stage 0 repre-
sents the patient who is asymptomatic and has a
normal plain radiograph of the hips but has
necrotic marrow or bone defined by high signal
intensity in both T1 and T2 magnetic resonance
images. Stage 1 represents the patient with clini-
cal manifestations (pain in the affected joint) and
a normal plain radiograph of the joint. Stage 2
represents the patient who has an abnormal plain
X-ray of the involved joint showing areas of
osteopenia and osteosclerosis. Stage 3 represents
patients with early bone collapse on a plain film
of the involved joint and may have the so-called
crescent sign delineating an area of dead bone as
a translucent subcortical area of bone. Stage 4
represents patients with clearly identified bone
collapse manifested as flattening of the articular
surface with or without joint incongruity. If avas-
cular necrosis is suspected in a patient, a plain
roentgenogram of the involved joint or a neutral
anteroposterior and frog leg views of the hips
should be obtained [10, 11]. Bone scintigraphy
can also be used to assess the uptake of the radio-
pharmaceutical in the same joint on both sides of
the body [10]. As noted previously, an MRI is the
most sensitive and specific method for the diag-
nosis of osteonecrosis. The MRI can distinguish
normal marrow and bone from unrepaired dead
bone with marrow replaced by debris along with
areas of repair [11–13]. The high signal intensity
of necrotic bone and marrow together with the
dark striations of subchondral bone gives the
characteristic serpiginous pattern of the MRI in
this condition. It should be noted that osteonecro-
sis can be seen in other disorders associated with
gout such as sickle cell disease, leukemia, lym-
phoma, organ transplantation (drug therapy), and
alcohol abuse.
Chondrocalcinosis
Since pseudogout and gout are at times difficult
to differentiate from each other and the two con-
ditions can occur simultaneously [14–17], chon-
drocalcinosis, the radiographic hallmark of
pseudogout, is helpful although not diagnostic in
cases where a microcrystalline arthritis is sus-
pected. The presence of chondrocalcinosis is of
no diagnostic significance to patients with gout
except for the possible concurrent occurrence of
pseudogout. The presence of punctate and linear
densities in articular hyaline or fibrocartilage is
the characteristic finding in chondrocalcinosis.
The typical locations for calcification include the
articular cartilage and menisci of the knee, the
articular cartilage of the hip joint, the fibrocartilage
of the symphysis pubis, the articular disc of the
wrist, and the annulus fibrosus of the interverte-
bral discs, and X-rays of these structures often
reveal the presence of chondrocalcinosis. The
presence of chondrocalcinosis does not indicate
the presence of calcium pyrophosphate dihydrate
(CPPD) crystals that must be identified in a joint
aspirate using compensated polarized light
microscopy. This microscopic examination will
identify CPPD crystals by their characteristic
shape and their weakly positive birefringence.
Studies have indicated that anteroposterior pro-
jections of both knees, posteroanterior views of
the hands, and anteroposterior projections of the
pelvis will identify 80–90 % of the cases of chon-
drocalcinosis. In tissues where the deposits are
Dual-Energy Computed Tomography (DECT)
faint, fine detail radiographs of thin bones and
magnification of thick bones may be useful.
Finally, gout and pseudogout can occur together,
and radiographic signs of one do not exclude the
other.
Musculoskeletal Ultrasound
Musculoskeletal Ultrasound is a procedure that
is now widely used in rheumatology practice. It
is a noninvasive technique that may be used to
visualize articular and other connective tissue
structures as well as an aid to guide the aspiration
of joint fluid and the injection of glucocorticoids
into joints, bursae, and tendon sheaths. It is use-
ful for visualizing the deposits of monosodium
urate in tissues through its features that appear
to be specific for urate deposits. The features of
urate deposits include the hyperechoic enhance-
ment of the outer surface of hyaline cartilage or
the double contour sign, the so-called “soft” and
“hard” tophi, and the hyperechoic spots within
the synovial fluid. Tophi in tissues are hyper-
echoic, heterogeneous, and have poorly defined
contours. They are surrounded by an anechoic
halo (Figs. 7.2 and 7.3). This technique provides
Fig. 7.2 Extended image in the longitudinal plane (P
proximal, D distal) of the distal upper arm and elbow
(outer curve), showing multiple grouped heterogeneous
hypoechoic tophi (TH) at the insertion site (arrowheads)
of the triceps tendon (T) on the olecranon (arrows). Open
203
a convenient, noninvasive method of identify-
ing urate deposits in and around joints and also
may be used to demonstrate the disappearance of
tophi in response to therapy [18–20].
Dual-Energy Computed Tomography
(DECT)
Dual-energy computed tomography (DECT) rep-
resents another technique that permits specific
and quantitative visualization of urate deposits in
the human host [21–23]. DECT is a reliable, non-
invasive method that can surpass the clinical
examination in the detection of uric acid depos-
its. The recent use of dual-energy computed
tomography (DECT) scans that are color-coded
to identify uric acid crystal deposits may provide
another noninvasive technique for the early rec-
ognition of such tissue crystal deposits [21–24].
Although the dimensions of DECT’s sensitivity
for the identification of MSU deposits have yet
to be completely defined, early studies have
confirmed its use in the accurate diagnosis of
gout and for the quantitative evaluation of the
body burden of MSU deposits. Dual-energy com-
puted tomography scans are likely over time to
arrow demonstrates the continuity of tophi with the ole-
cranon bursa. The contours of the bone surface of the pos-
terior humerus are marked with open arrowheads.
Subcutaneous tissue is marked with an asterisk. The mus-
cle belly of the triceps is marked with an M
204 7 Roentgenographic Findings and Musculoskeletal Ultrasound
Fig. 7.3 Extended image of the posterior proximal fore-
arm in the longitudinal plane (P proximal, D distal) show-
ing multiple grouped hyperechoic heterogeneous tophi
with imprecise contours (dotted lines between s). The
replace the need for an invasive arthrocentesis or
tophus needling that are essential for the
identification of MSU crystals. It is also likely to
be a more accurate method to monitor the
response of gouty patients to treatment regimens
designed to reduce and eliminate MSU deposits
rather than using clinical observation alone.
Dual-energy (DE) computed tomography
(CT) using a Siemens SOMATOM definition
dual source CT scanner has been able to acquire
images that demonstrate clearly uric acid and cal-
cium crystal deposition [24–27]. Clearly, addi-
tional and larger studies are needed to determine
the sensitivity, specificity, and the lower limits for
the detection of uric acid crystals.
One additional parameter of DECT is its
capacity to detect urinary tract stones composed
of uric acid [28–30]. These additional parameters
will undoubtedly have an enormous impact not
only for uric acid overproducers and their pro-
pensity to form stones but also for those with
genetic defects in purine metabolism leading to
uric acid stone formation.
To summarize these early DECT studies to
detect uric acid deposits, one can conclude that
DECT is an effective tool for diagnosing gout
and demonstrating uric acid crystals. It can also
differentiate atypical forms of inflammatory
arthritis from gouty arthritis by showing the
absence of uric acid crystals. Finally, most
bright line underneath is the cortical bone of the ulna
(arrows). A hypoechoic peripheral echo pattern encom-
passes the tophi (arrowheads)
important to this discussion, DECT not only
permits an accurate, noninvasive diagnosis of
gout but also provides a technique for monitoring
the progression of gout and the effectiveness of
hypouricemic treatments. At this stage of knowl-
edge, it would seem reasonable to perform DECT
examinations to determine the extent of uric acid
deposits in gouty patients and to monitor treat-
ment in patients who demonstrate crystal depos-
its and avoid the loss of joint functions. DECT
examinations of hands, feet, and elbows would
be a useful selection of body parts to examine for
crystal deposition.
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3. Resnick D. The radiographic manifestations of gouty
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8. Mielants H, Veys EM, DeBussere A, et al. Avascular
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12. Jergesen HE, Lang P, Moseley M, et al. Magnetic
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17. Smith JR, Phelps P. Septic arthritis, gout, pseudogout
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19. Thiele RG. Role of ultrasound and other advanced
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20. Thiele RG, Schlesinger N. Diagnosis of gout by ultra-
sound. Rheumatology. 2007;46:1116–21.
21. Nicolaou S, Yong-Hing CJ, Galea-Soler S, et al.
Dual-energy CT as a potential new diagnostic tool in
the management of gout in the acute setting. Am
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 Mechanisms of the Acute Attack
of Gout and Its Resolution
Overview
The hallmarks of an acute inflammatory response
in the synovial joint space are the presence of
swelling, redness, warmth, pain, and loss of full
function of the involved joint. These external
findings are reflected in the joint space by the
recruitment and emigration of polymorphonu-
clear leukocytes from the intravascular compart-
ment into the joint space and the accompanying
vascular leakage via the postcapillary venules of
proteinaceous fluids containing proinflammatory
mediators. This complex process requires the
production and release of both cell- and plasma-
derived mediators as well as endothelial cell and
neutrophil responses to cause the transmigration
of inflammatory cells from the intravascular com-
partment to the synovial compartment and the
subsequent generation of the crystal-induced
inflammation associated with acute gout.
Acute gouty arthritis is the model for all types
of crystal-induced synovitis, and many differ-
ent factors contribute to the inflammatory and
anti-inflammatory events that result from the
precipitation of monosodium urate (MSU) crys-
tals, the subsequent intra-articular inflammatory
response, and the eventual resolution of the
acute inflammatory process. Specific interre-
lated events are essential to the pathogenesis of
acute gouty arthritis including the formation and
precipitation of urate crystals, the generation
and release of neutrophil chemoattractants and
proinflammatory mediators from both humoral
and cellular sources, the transmigration of
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_8, © Springer-Verlag London 2013
8
inflammatory cells from the postcapillary venules
of the synovial membrane into the synovial cav-
ity, the phagocytosis of MSU crystals, and the
eventual propagation of those factors inducing
the resolution of the acute gouty episode as well
as other mechanisms that may contribute to the
cessation of the acute inflammatory response.
Each of the foregoing processes is complex
and only partially characterized in gout. In gen-
eral, only the biomarkers recovered from the syn-
ovial fluid can be assayed during an acute episode
of gout since the molecular pathology of the
human synovial membrane in the course of an
acute attack of gout is almost never available for
analysis. However, the injection of MSU crystals
into an artificially constructed or actual joint
space using animal models of acute gouty arthri-
tis provides information on the pathogenesis of
acute gout in the human. In fact, the dog model
shows that edema, vasodilation, and neutrophil
migration are the earliest events in crystal-in-
duced synovitis [1]. One may assume that similar
changes occur in the human during the early
stages of an acute attack of gout.
In addition to the gross changes associated
with the inflammatory response to MSU crystals,
molecular alterations also occur at the level of a
single cell (neutrophil or macrophage) to induce
and regulate a variety of cellular processes. These
include those changes required by the cell to
phagocytose and completely engulf the MSU
crystal or the apoptotic neutrophil, to alter the
shape of the cells necessary to accomplish these
tasks, to trigger and regulate the intracellular
207
208 8 Mechanisms of the Acute Attack of Gout and Its Resolution
changes essential for the transportation of the
phagocytosed components to intracellular sites
for degradation, and to generate anti-inflammatory
agents necessary for the resolution of the acute
process.
Although few studies have examined the
resolution of acute gouty arthritis, the molecular
events involved in the spontaneous resolution of
the acute inflammatory response associated with
gout are likely to be of great significance to the
physiological management of acute gout. This
resolution process includes the clearance of neu-
trophils from the synovial space, the suppression
of the activity of proinflammatory mediators,
the release of anti-inflammatory mediators, and
the return of the synovial membrane vascula-
ture to its normal tone and blood flow. A num-
ber of molecular events are likely to participate
in this process including neutrophil apoptosis,
receptor desensitizations, the generation of anti-
inflammatory mediators, and other regulatory
processes. The molecular pathways and require-
ments for the resolution of an acute inflammatory
reaction like acute gout are likely to be as com-
plex and interdependent as the generation of an
acute inflammatory response.
The principal reasons for providing a detailed
molecular description of these inflammatory-
provoking processes as well as the putative
resolution events is to identify more clearly the
mechanisms that initiate, sustain, and eventu-
ally resolve the acute gouty episode. A variety
of endogenous and exogenous anti-inflammatory
agents have been described, and their mechanisms
of action offer a means of understanding the reso-
lution of inflammatory responses. Through an
understanding of the molecular pathogenesis of
acute gout and its resolution, one may be able to
delineate possible mechanisms for the preven-
tion of acute episodes of gout or to define ways to
shorten the duration of the acute episode. There are
many complex processes that are part of the initia-
tion, propagation, and resolution of an acute gouty
episode. Cell migration, phagocytosis, apoptosis,
and internal cell regulatory mechanisms, and the
control of these and other processes are incom-
pletely characterized and can only be described as
fragmented pieces of a large puzzle.
Many areas of investigation are necessary
to arrive at a complete picture of the diverse
and complex processes necessary to address
the acute gouty episode and its resolution. The
identification of possible sites for pharmacologic
intervention of these pathological responses may
also reveal more specific targets for modifying
the acute process. Further, knowledge obtained
from the detailed study of gout will also iden-
tify parameters of pertinence to other forms of
crystal-induced arthritis and acute inflammatory
reactions.
Since major advances have been made in
defining the molecular details of an acute
inflammatory response, the complexity of these
processes have increased dramatically. To iden-
tify putative target sites for pharmacologic agents
designed to alter this acute reaction and to develop
more rational types of therapy, the intricacy of
the attraction and migration of cellular compo-
nents of the inflammatory response as well as the
generation of inflammatory mediators and the
expression of cell receptors for them must also be
fully characterized. Moreover, the handling of
ligands associated with the inflammatory process
and the internal signaling to transduce their mes-
sages provides a molecular picture of their mech-
anisms of action and also identifies potential
pharmacologic targets for the inhibition or
enhancement of these activities. In addition to
describing the role of cells and mediators in the
generation of an inflammatory response, little
attention has been given to the mechanism by
which the acute gouty episode resolves on its
own without any therapy. In this discussion, some
of the components that might propagate this reso-
lution of acute gout are also discussed.
Synovial Membrane
The synovial membrane is a delicate structure
that lines synovial joints, bursa, and tendon
sheaths, and its intimal layer of cells is only one
to three cell layers thick. This delicate, undulat-
ing membrane present in synovial joints is made
up of the so-called synovial membrane intima
which overlies a subsynovial layer of fibroblasts
Synovial Membrane
and adipocytes intermixed with collagen fibers
and proteoglycans [2]. Vascular endothelial cells
with basement membranes, unmyelinated nerve
endings, and lymphatic channels are also found
in the subsynovial tissue, but these components
are mostly absent from the synovial membrane
intima.
Ultrastructural studies of the synovial mem-
brane intima have demonstrated the presence of
two principal cell types: type A and type B syn-
ovial lining cells [3–6]. The type A cell has an
appearance similar to a tissue macrophage with
highly developed Golgi complexes, smooth-
walled vacuoles, mitochondria with an electron-
dense matrix and irregular cristae, and filopodia.
The nucleus of this macrophage-like cell is dense,
rich in heterochromatin, and surrounded by abun-
dant cytoplasm containing a paucity of rough
endoplasmic reticulum and ribosomes. Studies
have documented the bone marrow derivation of
type A cells using mouse radiation chimeras [7].
The membrane properties of these type A cells
such as the presence of nonspecific esterase, Ia
surface antigens, and rosette formation with IgG-
coated sheep red blood cells also provide further
credence for their monocytic origin [8]. On the
basis of their origin from monocytes, these type
A phagocytic synovial macrophages may pro-
duce IL-8 and LTB4, potent chemoattractants.
Type A synovial membrane lining cells (mac-
rophage-like synoviocytes) also stain with mono-
clonal antibodies for annexin-1, the proposed
mediator of the anti-inflammatory activity of glu-
cocorticoids [9]. Annexin-11 staining has also
been identified in perivascular tissues and
endothelial cells. The latter cells stain strongly
for annexin-IV and annexin-VI. The type B syn-
ovial membrane cell (fibroblast-like synoviocyte)
has a pale nucleus with an abundance of rough
endoplasmic reticulum, a few ribosomes in its
cytoplasm, and a paucity of cytoplasmic Golgi
complexes and vacuoles. The type B synovial
membrane cell has the ultrastructural appearance
of a connective tissue fibroblast, and these cells
are derived from mesenchyme [10, 11]. Some
investigators have described the presence of a
type C synovial membrane cell resident in the
intima with ultrastructural components of both
209
the type A and B cell [4]. The two primary syn-
ovial cell types (A and B) can be differentiated by
cytochemical staining to identify nonspecific
esterase activity in type A cell membranes,
whereas uridine diphosphoglucose dehydroge-
nase and prolyl hydroxylase activities are used to
detect type B synovial membrane cells [12, 13].
The absence of leukocyte and endothelial cell
antigens by immunohistochemical staining
confirms these cell types. There are a number of
publications that have dealt with changes in these
synovial membrane lining cells derived from
synovial membranes recovered from patients
with various pathological disorders, but no such
studies have been done in patients with acute
gouty arthritis and few studies have investigated
normal synovial membrane for the components
cited in the following references [14–22]. Thus,
the synovial membrane lining cells in acute gouty
arthritis remain to be completely characterized.
The synovial membrane has three principal
functions: the production of joint lubricant, the
removal of debris, and the repair of joint damage.
The type 8 cell is constructed for biosynthetic
activities and is the source of hyaluronic acid that
is responsible for the friction-free motion of hya-
line articular cartilage. It also produces the col-
lagen for joint remodeling. The vascular adhesion
molecule-1 (VCAM-1) has also been detected on
type 8 synoviocytes as well as in the vascular
wall outside the endothelial cell layer [23]. In
addition, the ligand for LFA-1 (leukocyte func-
tion antigen) and intercellular adhesion mole-
cule-1 (ICAM-1) have also been demonstrated on
synovial cells [24]. As noted, the synovial mem-
brane intimal fibroblasts produce hyaluronan,
fibronectin, type IV collagen, laminin, and chon-
droitin-6-sulfate-bearing proteoglycans [12, 25–
28]. Synovial fibroblasts (type 8 cells) also
express high levels of complement decay-accel-
erating factor (OAF) [12, 29–32]. Type B syn-
ovial cells may also synthesize lubricant,
phospholipids, unique carbohydrates, and the
potent chemoattractant, IL-8 [33–35].
The type A cell is constructed for the removal
of both cellular and particulate debris. It is also
likely to be involved in the phagocytosis of urate
and CPPD crystals. The synovial membrane is
210 8 Mechanisms of the Acute Attack of Gout and Its Resolution

also the site of fenestrated blood vessels as well Table 8.1 Principal cellular distribution and expression
as nerves and lymphatic channels. The type A of cell adhesion molecules
synovial lining cells have not been cultured Adhesion molecules and ligands M G EC p
in vitro so their functions have been inferred from L-selectin (CD62L) + +1 +1
studies of blood mononuclear cells from which P-selectin (CD62P)
these type A synovial cells are derived. E-selectin (CD62E) +1
Studies have shown that normal and diseased GlyCAM-1 CD62L ligand +
human synovium can be engrafted into subcu- PSGL-1 CD62P ligand + +
ESL-1 CD62E ligand + +
taneous pouches in the ears of severe combined
Integrin LFA-1 (CD11a/CD18) + +
immunodeficient mice [36]. These xenografts
Integrin Mac-1 (CD11b/CD18) + +
retain the identical cell composition of the nor-
Integrin CD11c/CD18 + +
mal synovium including endothelial cells. Such
Integrin CD11d/CD18 + +
synovial grafts also respond to cytokines (tumor Integrin ligand ICAM-1(CD54) + +1
necrosis factor-alpha) and express intercellu- Integrin ligand ICAM-2 (CD102) + + +
lar adhesion molecule-1 (ICAM-1) as well as Integrin ligand ICAM-3 (CD50) + +
vascular adhesion molecule-1 (VCAM-1) and Integrin ligand VCAM-1 (CD106) + +1
E-selectin. The expression of the latter two mole- Integrin ligand VLA-4 (CD49d) +
cules decreases over time. These grafts composed PECAM (CD31) + + + +
of human synovium may permit a more inte- G granulocyte, M monocyte/macrophage, EC endothelial
grated view of the early stages of monosodium cell, P platelet
urate crystal-induced inflammatory responses. 1. Endothelial cells must be activated to express these
components
As indicated above, the synovium is enriched
with capillaries and postcapillary venules. The
superficial vessels are fenestrated, whereas the endothelial cells. At this point, the neutrophils
deeper vessels in the subsynovial layer have con- are prepared to migrate across the blood vessel
tinuous endothelium. A few studies have exam- wall and into the tissue parenchyma. This com-
ined the fine structure and functions of the synovial plex process of neutrophil adherence requires
membrane, but investigations of the molecular both non-chemotactic cytokines (tumor necrosis
biology and detailed biochemical analyses have factor, interleukin-1, and gamma interferon) and
lagged behind those of other tissues since access chemoattractants (C5a, PAF, LTB4, and IL-8).
to the human synovium in acute inflammatory The distribution and expression of the cell adhe-
processes is prohibited [37–43]. Thin-walled lym- sion molecules on endothelial cells, monocytes,
phatics have also been identified close to the deep platelets, and neutrophils are summarized in
synovial membrane capillaries and venules [44]. Table 8.1. To begin their emigration, neutrophils
The synovial membrane capillaries and venules use selectin receptors to form loose attachments
are lined with endothelial cells that are of great with endothelial cells and to start rolling along
significance to an inflammatory process since the endothelium. Subsequently, neutrophils are
these microvessels regulate the trafficking of anchored tightly to the endothelium by b2 integ-
inflammatory cells. Endothelial cells and their rins before embarking on their migration through
functions of significance to the inflammatory pro- venule walls to the inflammatory site.
cesses are described in a subsequent section. There are a number of cell surface adhesive
Circulating neutrophils emigrating from the molecules that play an essential role in the migra-
intravascular compartment to make contact with tion of neutrophils into the joint cavity during
endothelial cells and then gain access to the site an inflammatory reaction. The so-called inter-
of inflammation must first be marginated from the cellular adhesion molecules (ICAMs) are pres-
flowing blood. After margination occurs and when ent on endothelial cells and fibroblasts and are
the neutrophils are rolling along the endothelial upregulated in inflammatory processes [45–47].
surface, they then become firmly adherent to In addition, selectins and integrins mediate the
Monosodium Urate Crystallization
interactions between endothelial cells and leuko-
cytes [48–61]. A number of recent publications
have now documented the expression of cell
adhesion molecules in the normal synovium [23,
62–66]. Such investigations have documented
the expression of both selectin and integrin mol-
ecules in normal human synovial membranes and
provide evidence for the mechanisms by which
inflammatory cells migrate from intravascular
compartments to sites of inflammation. The func-
tion and significance of selectins and integrins in
the inflammatory process are discussed in some
detail in a subsequent section. The subsynovial
vascular channels also permit the migration of
precursors of the type A synovial phagocyte from
the bone marrow and peripheral blood to proceed
to their final residence in the synovial membrane.
In this same subsynovial compartment, unmyeli-
nated nerves exist that provide the sensory inner-
vation of the synovial membrane and contain a
neuropeptide, substance P, that has been found in
the synovial fluid [67, 68]. Rare mast cells also
reside in the synovium, and the rat experimen-
tal model of monosodium urate crystal-induced
inflammation has been attenuated by pretreat-
ment with antihistamine drugs [69]. These lat-
ter drugs have little of no effect on acute gouty
arthritis in the human.
In summary, the delicate synovial membrane
contains all the structures necessary for the prop-
agation of the acute inflammatory process associ-
ated with gout and some of the factors involved in
protecting the joint from the deposition of crys-
tals. The intimal cells of the synovium may syn-
thesize and release proinflammatory cytokines
that mediate the early stages of the intrasynovial
reaction to urate crystals. In fact, the type A cell
may ingest crystals and form, over time, a tophus
that could also be the source of the intrasynovial
cavity deposition of monosodium urate crystals
in acute gouty episodes. It is also likely that the
cells of the synovial membrane synthesize and
release proinflammatory cytokines that mediate
the early stages of the intrasynovial reaction to
crystals. As will be discussed in detail subse-
quently, the synovial membrane also contributes
to those parameters that result in the limitation
and resolution of the acute gouty episode.
211
Monosodium Urate Crystallization
Central to the acute attack of gouty arthritis is
the formation and precipitation of uric acid
crystals in the synovial joint cavity. That micro-
crystals of monosodium urate are essential to the
inflammatory process has been known since 1899
when acute gouty episodes and characteristic
tophi were produced by the injection of sodium
urate into animals [70–72]. After a hiatus of more
than a half-century, microcrystals of urate were
documented in synovial aspirates from patients
with acute gouty arthritis, and their usefulness
in the diagnosis of acute gout was confirmed
[73]. It is now clear that negatively birefringent,
needle-shaped monosodium urate crystals have
been identified in the synovial aspirates of most
patients with acute gouty arthritis, and the pres-
ence of such crystals is the only absolute criterion
for the diagnosis of acute gout.
The mechanism(s) that results in the precipita-
tion of uric acid in the synovial space is incom-
pletely understood; however, a sudden change in
the serum urate level, either an increase or a
decrease, is almost always associated with the
onset of an acute episode of gouty arthritis in the
susceptible individual [74]. Hyperuricemia is fre-
quently a precondition to the precipitation of
urate crystals but is not always present since
patients undergoing therapy with hypouricemic
agents (allopurinol) to lower their serum uric acid
levels may also develop acute gout. Further,
hyperuricemia is not always an essential precur-
sor of acute gout since patients with normal
serum uric acid levels (below the saturation con-
centration of 6.8 mg %) can and do develop acute
gout. Hyperuricemia may also be present in indi-
viduals who may never experience an episode of
gout. The latter is the case with those patients
who have certain types of chronic renal disease
and hyperuricemia but not gout [75]. These facts
lead to two conclusions. First, hyperuricemia
may be helpful in the differential diagnosis of an
acute synovitis, but an elevated serum uric acid
level alone is not diagnostic of acute gouty arthri-
tis. Second, supersaturation of the synovial fluid
with uric acid is only one of the factors that may
contribute to the onset of acute gout. Obviously,
212 8 Mechanisms of the Acute Attack of Gout and Its Resolution
decreased solubility of uric acid in the synovial
fluid could contribute to the precipitation of
monosodium urate crystals. Plasma and synovial
fluid uric acid concentrations are usually compa-
rable in patients with gout, but plasma has been
determined to be a better solvent for monosodium
urate than synovial fluid [76–78].
In addition, low intra-articular temperatures
may also contribute to the insolubility of uric acid.
In fact, there is a temperature gradient between
the central body temperature, the more proximal
joints, and the peripheral joints. This temperature
gradient has been confirmed by the direct mea-
surement of intra-articular temperatures [79–81].
For example, in the knee joint, the temperature
has a range between 30.5 and 32.8 °C, whereas
the ankle joint has a lower temperature (29 °C)
[79–81]. The solubility of uric acid in normal
human plasma (maximum equilibrium concentra-
tion) in the presence of 140 mM Na+ is 6.8 mg %
at 37 °C, whereas the solubility falls dramatically
to half that value (3.3 mg %) at 25 °C [82]. This
differential in joint temperatures from the more
central joints to the peripheral joints may contrib-
ute to the crystallization of urate and the propen-
sity for acute gouty arthritis to affect peripheral
joints more frequently than more central joints.
However, this explanation does not hold for all
types of crystals since pseudogout, a disorder due
to the precipitation of calcium pyrophosphate
dihydrate crystals, is observed more frequently
in the knee joint than the toe joint. There is also
speculation that the increased temperature gener-
ated by the inflammatory response in microcrys-
talline processes may enhance the solubility of
precipitated urate and in that way, contribute to
the resolution of the acute episode [82]. The pro-
pensity for the first metatarsophalangeal joint to
be afflicted with gout (podagra) may result from
the constant microtrauma to which this joint is
subjected and may have little to do with the tem-
perature of the joint.
The disruption of tissue continuity as occurs
in the presence of diseased tissues may also con-
tribute to the acute gouty episode since gout is
known to occur in Heberden’s nodes and erosive
osteoarthritis [83–85]. Experiments performed
in vitro have documented the enhanced forma-
tion of urate crystals in the presence of gamma
globulin and insoluble type I collagen fibers
[86]. Further, synovial fluid from gouty patients
added to supersaturated solutions of sodium
urate under physiological conditions significantly
increases urate nucleation, but synovial fluids
from patients with degenerative joint disease
only increase nucleation to a moderate degree
and fluids from rheumatoid patients have little
effect on urate nucleation [87]. These facts lead
to the conclusion that both synovial fluid compo-
nents and physical properties contribute to
changes in urate solubility and the formation of
microcrystals.
The interaction between monosodium urate
and macromolecules has also been investigated.
The sites of urate deposition contain large quanti-
ties of polysaccharides [88]. In fact, total serum
glycosaminoglycans have been reported to be
three times their normal level in patients with
gout [89]. Chondroitin sulfate concentrations
have also been shown to influence in vitro urate
crystal formation and crystal growth in synovial
fluids, and cartilage is known to have an affinity
for absorbing urate in vitro [90, 91]. Urate is also
more soluble in aggregated than non-aggregated
proteoglycans [92]. In summary, although many
connective tissue components may contribute to
the crystallization of uric acid, no single element
has been identified as the key to this initial pro-
cess essential to the development of acute gouty
arthritis.
In addition to the influence of connective tis-
sue components on the solubility of urate, plasma
proteins have also been implicated in the crystal-
lization and processing of urate, but little evi-
dence supports the interaction between plasma
proteins and serum uric acid under physiological
conditions. The older literature described a
deficiency in urate binding to an ornithine-con-
taining plasma protein that migrated as an
a1-globulin in gouty kindreds [93]. The same
group of investigators had postulated a role for
this plasma protein in the maintenance of uric
acid solubility [94], but little information con-
cerning this urate-binding protein is available in
Inflammasome: Innate Immunity; Inflammation in Gout Is Mediated by the Innate Immune System
the modern literature. In fact, some investigations
have failed to detect alterations in urate binding
in patients with gout [95].
Monosodium urate crystals isolated from the
synovial fluid and tophi of gouty patients are
coated with immunoglobulins [96, 97]. The prin-
cipal immunoglobulin coating these crystals is
IgG, and its binding to urate crystals occurs
through the F(ab), antigen-binding fragment of
the immunoglobulin, leaving the Fe crystalliz-
able fragment of immunoglobulin G (IgG) free
for interaction with the Fe receptor present on
phagocytes. In some cases, it has been shown that
the immunoglobulin coating uric acid crystals is
a polyclonal IgG antibody specific for urate crys-
tals [98]. These IgG antibodies isolated from syn-
ovial fluid aspirates of patients with gout
accelerate crystal formation in supersaturated
urate solutions in vitro. In contrast to this effect,
IgG antibodies isolated from patients with
osteoarthritis, rheumatoid arthritis, or pseudog-
out do not have this property. In fact, IgG anti-
bodies from gouty synovial fluid have a
concentration-dependent effect on monosodium
urate monohydrate nucleation. The higher the
concentration of the IgG antibodies specific for
urate, the greater the number of crystals formed.
Investigations that are more recent have shown
that the hydrophilic surfaces of the urate crystal
also react with human serum albumin through
protein carboxylate groups [99]. Thus, proteins
are clearly absorbed to the negatively charged
surface of the urate crystal and appear to serve
the purpose of enhancing the capacity of such
crystals to be phagocytosed. In addition, IgG
antibodies specific for urate crystals may enhance
crystallization since these immunoglobulin mol-
ecules have a structure like the surface of the
urate crystal that serves as a nucleating matrix.
Despite all these factors that may contribute to
the precipitation of uric acid and the formation of
crystals, no single factor has been determined as
the key to the initiation of crystal formation.
Thus, a variety of factors in the surrounding
milieu are likely to be responsible for MSU crys-
tal formation including some components that
may protect the host from crystal deposition.
213
Inflammasome: Innate Immunity;
Inflammation in Gout Is Mediated
by the Innate Immune System
Introduction
The inflammatory reaction in gout is mediated by
the innate immune system. The innate immune
system is a primitive defense mechanism evolved
to protect from noxious agents, especially infec-
tious agents including bacteria, viruses, and fun-
gal organisms. It responds to dangerous substances
and organisms, and is immediately available to
the host. It differs from the adaptive immune sys-
tem, which depends on the development of anti-
bodies and specific lymphocytes that then protect
against infections and other insults.
Around the turn of this century, the term
“autoinflammatory” was applied to several dis-
ease states that differed from autoimmune dis-
eases in that they were apparently unprovoked
inflammatory states that were not associated with
autoimmunity and were not associated with any
obvious infectious organisms. Several disorders
prompted this concept, initially several periodic
fever syndromes including familial Mediterranean
fever, the TNF receptor-associated periodic syn-
drome (TRAPS), each of which are associated
with periodic fever, serositis, arthritis, and skin
rash, without any evidence for autoimmunity,
such as is seen with diseases such as systemic
lupus erythematosus, which can cause similar
manifestations.
Another group of diseases that supported this
concept are three syndromes that were found to be
associated with mutations in the gene, NLRP3/
CIAS1, that encodes a protein previously called
cryopyrin, now NLRP3, an activator of interleu-
kin-1b, IL-1b (Fig. 8.1 and 8.2). These syndromes
vary in their manifestations and severity of illness,
depending on the location of their mutations within
the NLRP3 gene, and all include periodic fever,
rashes, and in the more severe forms, bone and
joint, and neurologic disease. Subsequently, the
concept of autoinflammatory disease has been
extended to include many both rare and common
diseases extending beyond the periodic fever
214 8 Mechanisms of the Acute Attack of Gout and Its Resolution

DAMP/
PAMP NLRP1 inflammasome
K
+ DAMP/PAMP
ATP Pannexin-1 NLRP1 PYD NACHT LRR
Crystalline/
P2X7
particulate
ligands CARD FIIND

1 CASP1 CARD
CYTOPLASM

2 p20 p10
3
Reactive oxygen NLRP3 inflammasome
species Lysosomal
R rupture NLRP3 PYD NACHT LRR
LR

LR
R

ASC PYD
NACHT
NACHT

NLARP3

CARD
D
PY

PY CASP1 CARD p20 p10

D

D ASC
PY

PY
D
D
CARD

CARD
D

IPAF inflammasome
CAR
CAR

IPAF CARD NACHT LRR

CASP
CASP
NUCLEUS

CASP1 CASP1 CARD

Cathepsin B
NLRP3 inflammasome inhibitor p20 p10
assembly (Ca-074-me) ASC?
NAIP?

CASP AIM2 inflammasome

Activated
CASP Caspase-1 AIM2 PYD HIN
ASC PYD
IL-1ß
Pro-IL-1ß
“Priming” by CARD
proinflammatory stimuli
CASP1 CARD p20 p10
e.g. TLRs, TNF, IL-1ß

Fig. 8.2 Minimal NLRP1, NLRP3, IPAF, and AIM2

IL-1ß
Fig. 8.1 NLRP3 inflammasome activation. Three major
models for NLRP3 inflammasome activation are favored
in the field, which may not be exclusive: (1) The NLRP3
agonist, ATP, triggers P2X7-dependent pore formation by
the pannexin-1 hemichannel, allowing extracellular
NLRP3 agonists to enter the cytosol and directly engage
NLRP3. (2) Crystalline or particulate NLRP3 agonists are
engulfed, and their physical characteristics lead to lyso-
somal rupture. The NLRP3 inflammasome senses lyso-
somal content in the cytoplasm, for example, via
cathepsin-B-dependent processing of a direct NLRP3
ligand. (3) All danger-associated molecular patterns
(DAMPs) and pathogen-associated molecular patterns
(PAMPs), including ATP and particulate/crystalline acti-
vators, trigger the generation of reactive oxygen species
(ROS). A ROS-dependent pathway triggers NLRP3 inflam-
masome complex formation. Caspase-1 clustering induces
autoactivation and caspase-1-dependent maturation and
secretion of proinflammatory cytokines, such as interleu-
kin-1b (IL-1b) and IL-18
inflammasomes For simplicity, the unoligomerized
inflammasome complexes are depicted. Removal of the
CARD domain and processing of the caspase domain of
caspase-1 by autocleavage at the indicated sites results in
the formation of the active caspase-1 p10/p20 tetramer. It
should be noted that although human NLRP1 contains a
PYD, mouse NLRP1 proteins do not harbor functional
PYDs. Human NLRP1 can also recruit a second caspase,
caspase-5, to the complex (not shown). Maximal caspase-1
activation in response to IPAF agonists can require ASC
or NAIP, depending on the stimulus. The interaction of
these proteins with the IPAF inflammasome activation is
currently unclear. Domains: CARD, caspase recruitment
domain; FIIND, domain with function to find; HIN, HIN-
200/IF120x domain; LRR, leucine-rich repeat; NACHT,
nucleotide-binding and oligomerization domain; PYD,
pyrin domain (From Schroder and Tschopp [100].
Reproduced with permission)
syndromes. While several of the periodic fever
syndromes involve genetic mutations of the NLRP3
gene, a protein which associates with other pro-
teins to form the NLRP3 inflammasome, others
Inflammasome: Innate Immunity; Inflammation in Gout Is Mediated by the Innate Immune System
have mutations in other proteins that activate
inflammasomes, and others disease have known
mutations in other proteins, and in some, the defect
is unknown. In addition to the inflammasome dis-
orders, five other categories have been proposed.
These include: NF-kB activation disorders, pro-
tein-misfolding disorders, complement disorders,
cytokine-signaling diseases, and macrophage acti-
vation syndromes [101, 102].
Finally, a substantial body of evidence has
shown that certain particulate matter induces
inflammatory reactions through activation of the
NALP3 inflammasome. These include monoso-
dium urate and calcium pyrophosphate dehydrate
(CPPD) crystals, as well as asbestos and silica.
Studies with urate and CPPD crystals in normal
mouse macrophages demonstrate caspase activation
and IL-1b release, and this response is abrogated in
Nlrp3 knockout mice [103]. Studies by others have
shown that urate-induced inflammation was reduced
in mice deficient in the inflammasone component,
Asc or in the IL-1 receptor, or in the IL-1 receptor
component, MyD88, but the inflammatory response
was not reduced in mice deficient in each of several
toll-like receptors [104].
Recent investigations have determined that crys-
talline structures like monosodium urate (MSU),
calcium pyrophosphate dihydrate (CPPD), silica,
and asbestos create an inflammatory response
through their capacity to interact with the innate
immune system that identifies certain foreign sub-
stances in a manner similar to the mechanism by
which it detects invading microbes [105–115]. The
innate immune system is a more primitive system
relative to the adaptive immune system, and it gen-
erates a nonspecific response when recognizing
and responding to dangerous signals like MSU or
CPPD crystals. Once these dangerous substances
are recognized by their receptors, a complex
protein scaffolding called an inflammasome is
constructed, and its formation leads to the attrac-
tion of a caspase enzyme that converts inactive
pro-IL-1 to its active proinflammatory cytokine
IL-1b. Once the latter cytokine is released from
the cell cytoplasm into the extracellular milieu, it
acts as a major mediator of inflammatory reactions
including the recruitment of neutrophils along with
the production of other proinflammatory cytokines
215
and the induction of the components necessary to
respond to the attack on the host’s tissues cre-
ated by the crystals. In order to detect and mount
a response to such dangerous substances, the
human host has developed both extracellular and
intracellular sensors that identify microbial and
viral components by generating pattern-recogni-
tion receptors (PRRs) called pathogen-associated
molecular patterns (PAMPs) [105–107, 109–118].
In the case of MSU or CPPD crystals, the sensor
has been called danger-associated molecular pat-
terns (DAMPs), and these crystal stimuli have
been demonstrated to cause the activation of the
NALP3, now called the NLRP3, inflammasome
that is involved in the inflammatory response
to these crystals [119]. Several types of innate
immune signaling receptors have been identified
[120]. Toll-like receptors (TLRs) and C-type lectin
receptors are transmembrane molecules localized
to the plasma membrane and to the membranes of
lysosomes, endosomes, and endoplasmic reticu-
lum. Receptors found in the cell cytosol include
the retinoic acid-inducible gene-I-like helicases or
RIG-I-like receptors (RLRs), and the nucleotide-
binding domain leucine-rich repeat-containing
receptors or Nod (nucleotide oligomerization
domain)-like receptors (NLRs) [121–126]. These
innate immune-signaling receptors have diverse
functional capacities in that they can recognize
molecules associated with microbes, molecules
related to tissue damage, molecules not synthe-
sized by the host such as lipopolysaccharide, and
molecules related to diseases such as monosodium
urate (MSU) crystals in gout, calcium pyrophos-
phate dihydrate (CPPD) crystals in pseudogout,
silica in silicosis, and asbestos in asbestosis.
The sensors of the danger to the host in the
case of uric acid crystals interact with intracellu-
lar innate immune receptors that trigger the
construction of a complex protein called the
inflammasome. The nucleotide-binding domain
leucine-rich repeat-containing receptors or NLRs
form a group of intracellular innate immune
receptors of which over 20 have now been
identified in humans. These NLRs in man have
certain common features related to their
C-terminus but differ in their N-terminal domain.
A standardized nomenclature for the NLR family
216 8 Mechanisms of the Acute Attack of Gout and Its Resolution
has now been established and is used in most of
the recent publications related to inflammasomes
[127]. What is significant to this discussion of the
microcrystalline disorder, gout, is the fact that
NLRs not only sense microbial, viral, and fungal
components but may also sense nonmicrobial
danger signals and are dependent on the forma-
tion of large (~ 700 kDa) multiprotein, cytoplas-
mic scaffoldings called inflammasomes. These
protein complexes promote the recruitment of
caspase-1 and cause the conversion of pro-IL-1b
to its active, proinflammatory form, IL-1b. The
NLR family member of significance to gout is the
NLPR3 inflammasome that has also been
described by other nomenclature in the early lit-
erature (CIASI, PYPAF 1, cryopyrin, or NALP3).
The two commonly used terms for this molecular
complex are NALP3 and NLRP3 that stand for
NACHT-LRR-PYD3 or NLR family pyrin family
containing 3. In any event, the overall structure of
this complex (NLRP3) is PYD-NACHT-NAD-
LRR. The NLR family members (NLRP1,
NLRP3, and NLRC3) lead to the activation of
caspases, and therefore, they have been classified
as inflammasomes [128, 129]. In its inactive state,
the NLRP3 inflammasome prevents the associa-
tion of ASC (apoptosis-associated speck-like
protein containing a CARD) or CARDINAL with
the PYD domain of NLRP3 because of the pre-
sumed self-association of the LRR domain. When
NLRP3 is activated by nucleotides (ATP, deoxy-
ATP, GTP, or uric acid crystals), the molecule
unfolds permitting the association of ASC with
NLRP3 [130].
Aspartic acid-specific cysteine proteases are
major players in the inflammatory response.
Inflammatory initiators (caspase-1, caspase-4,
and caspase-5) and especially caspase-1 is
responsible for the processing of pro-IL-1b to its
active molecule, IL-1b. Procaspase-1 conversion
is induced by macromolecular oligomerization of
the proenzyme onto the complex called the
inflammasome [125, 128, 131–134]. This process
is mediated by the recruitment domains in pro-
caspase-1 and inflammasome adaptor proteins
like ASC [135, 136]. Although the mechanisms
involved in NLRP3 activation, procaspase-1 con-
version to caspase-1, and IL-1b transport out of
the cell cytoplasm are incompletely understood
at this time, these processes are beginning to be
unraveled [137]. It is likely that when these pro-
cesses are completely understood, additional tar-
gets will become available to prevent the
inflammatory reaction engendered by NLRP3.
Interleukin-1b and Interleukin-18
Interleukin-1 is a multifunctional cytokine whose
two active forms, IL-1a and IL-1b, have similar
functions that include the upregulated expression
of adhesion molecules, the generation of other
proinflammatory cytokines like IL-6, arachidonic
acid metabolites, and chemokines with the capac-
ity to recruit neutrophils [138]. IL-1 also causes
angiogenesis, fibroblast proliferation, and fever. It
is a pleiotropic molecule acting on many cell types
including leukocytes, endothelial cells, adipose
tissue, hepatocytes, and other cell types [138].
When IL-1 is administered to humans, significant
local pain, erythema, and swelling occur at the
subcutaneous injection site heralding an inflammatory
reaction [139, 140]. A number of other physical
findings associated with IL-1 exposure also occur
including chills, fever, and hypotension [139, 141–
143]. IL-1b injection also causes a significant
increase in cortisol release [143, 144]. Many excel-
lent, recent reviews of the functions of IL-1 and
another cytokine produced and released by cas-
pase-1 activity, interleukin (IL-18), have been
published and may be evaluated for additional
parameters of these inflammasome-mediated
activities [138, 145–153].
The principle sources of IL-18 are mac-
rophages and dendritic cells [147]. IL-18 or
interferon-g (IFN-g)-inducing factor was first
described two decades ago and was considered
an immunomodulatory cytokine because of its
properties as an inducer of IFN-g [147]. IL-18
or interferon-g (IFN-g)-inducing factor was first
described two decades ago and was considered
an immunoregulatory cytokine because of its
properties as an inducer of IFN-g [154]. IL-18 is
a potent proinflammatory cytokine that mediates
the production of some inflammatory cytokines,
chemokines, nitric oxide, and IFN-g, a product
Inflammasome: Innate Immunity; Inflammation in Gout Is Mediated by the Innate Immune System
that activates macrophages [155]. It also induces
the production of IL-1b from monocytes and
macrophages, and IL-6 by LPS-treated periph-
eral blood mononuclear cells [156, 157]. It can
also produce chemokines for the recruitment of
monocytes and macrophages such as macrophage
inflammatory protein-1 alpha (MIP-1 alpha) and
monocyte chemotactic protein-1 (MCP-1) when
exposed to peripheral blood mononuclear cells
as well as the adhesion molecule, ICAM-1 [158].
IL-18 differs from IL-1 and TNF-a since it does
not produce fever in humans [159, 160]. It also
differs from IL-1 and TNF-a since it does not
lead to the induction of cyclooxygenase-2 and,
therefore, does not produce PGE2 [145, 161].
In addition to its proinflammatory properties,
IL-18 is a key immunomodulating molecule
[162–170]. As noted previously, IL-1b is a potent
proinflammatory molecule that manifests a broad
array of effects including an increased expression
of cytokines like TNF-a, MIP-a, and IFN-g as
well as proinflammatory mediators like cycloox-
ygenase-2, phospholipase A2, inducible nitric
oxide synthase, and endothelin, adhesion mol-
ecules like ICAM-1, VCAM-1, and ELAM1,
hepatic acute phase reactants like CRP, xanthine
oxidase, lysozyme, and other inflammatory and
tissue remodeling components [138]. As a result
of its increased expression when IL-1 is injected,
it causes the following biological effects: fever,
hypotension, lactic acidosis, hyperglycemia,
neutrophilia, increased corticosterone synthesis,
increased release of arachidonic acid prostanoids
and eicosanoids, increased neutrophils in the joint
spaces when injected into joints, and many other
components associated with inflammation [138].
Mechanisms of NLRP3 Activation
Several hypotheses based on data derived from
the study of NLRP3 activators have been pro-
posed for the mechanisms of NLRP3 activation
including a decrease in intracellular potassium
concentrations, ligand-receptor interactions that
allow the DAMP to bind to a LRR receptor site
causing a change in molecular conformation of
the NLRP3 and resulting in its activation, ATP-
217
mediated macrophage production of reactive
oxygen species (ROS) via ROS-dependent PI3K
activation and caspase-1 activation with the resul-
tant processing of pro-IL-1 beta, and phagosomal
destabilization leading to lysosomal disruption
and NLRP3 activation [71, 110, 118, 131,
171–188]. Although the mechanisms for NLRP3
activation are incompletely understood, there are
some data in support of these hypotheses.
However, knowledge of the complete activation
process remains incomplete at this time.
There is a good case to be made that the leak-
age of intracellular K+ from cells is a necessary
component for NLRP3 activation. It is well char-
acterized that ATP, asbestos, and MSU all acti-
vate NLRP3, but they also cause an efflux of
potassium at the same time [110, 131, 179]. In
support of the fact that K+ efflux is essential for
NLRP3 activation are the data showing that phys-
iological levels of potassium block the activation
of NLRP3 [131, 176]. However, the mechanisms
of NLRP3 activation are still incomplete regard-
ing how this potassium efflux works to cause
inflammasome activation. Another mechanism
that has some validity is NLRP3 activation by
reactive oxygen species [110, 118, 131, 179].
Human monocytes have been shown to release
ATP, and these cells are related to macrophages
that are known to phagocytose MSU crystals
[189–192]. The evidence used to support this
concept is the fact that ROS inhibition reduces
the formation of mature IL-1 beta when cells are
exposed to ATP, MSU crystals, asbestos, or silica
[118, 179]. Several studies have supported the
concept that lysosomes and/or their contents may
cleave certain substrates and contribute to the
activation of NLRP3 and IL-1b production [173].
The lysosomal protease, cathepsin B, when inhib-
ited partially decreases IL-1 beta generation and
release [170, 171, 173, 174, 187, 193]. In addi-
tion, cathepsin B-deficient macrophages also
show a reduction of IL-1b production when
treated with NLRP3 activators. A cathepsin
B inhibitor also has been shown to block cas-
pase-1 activation by the lethal toxin of anthrax in
another NLRP system [194].
Recent investigations have shown that NALP1
is activated by a two-step mechanism and requires
218 8 Mechanisms of the Acute Attack of Gout and Its Resolution
muranyl dipeptide (MDP) and subsequently
a ribonucleoside triphosphate to cause caspase-1
activation of NALP1 [184]. The postulate pro-
posed in this study was that the synthetic MDP
molecule, muramyl dipeptide, comprised of
L-alanyl and d-isoglutamine (MDP-LD) induces
a conformational change in NALP1. This step
permits NALP1 to bind ribonucleotide triphos-
phates in the second step. This latter step causes
oligomerization of the NALP1 with the subse-
quent generation and release of IL-1 beta.
MSU crystals added to cultured monocytes
from controls released both IL-1 and caspase-1,
but this response was significantly decreased in
monocytes obtained from mice with mutations in
their NALP3 molecule or ASC. When MSU crys-
tals were injected into the peritoneal cavity of
control and mutant mice with ASC mutations, the
inflammatory response was significantly reduced
in the mutant mice as compared to the control
mice [108]. Finally, mice lacking a receptor for
IL-1 also showed a diminished inflammatory
response [105]. All the foregoing studies indi-
cated that IL-1 and the inflammasome play a key
role in the generation of an inflammatory response
to MSU crystals, and discovery of its mechanisms
of action should be a key objective of future
studies.
The proof of the principle that the inflammatory
reaction induced by MSU crystals activates IL-1
through the inflammasome lies in the demonstra-
tion that three IL-1 inhibitors have been shown to
have anti-inflammatory effects on acute gouty
arthritis, and these results are described in the
chapter on therapy (Chap. 9).
Neutrophil Chemoattractants
Overview
Neutrophil chemotaxis is a critical element of the
acute inflammatory response in gout. The recruit-
ment of neutrophils must be sufficient to address
the capture and ingestion of the inflammation-
provoking urate crystals but insufficient to cause
permanent tissue damage from the release of toxic
metabolites from the neutrophil. Thus, the pro-
cess of neutrophil chemotaxis must be rigorously
regulated. A variety of neutrophil chemoattrac-
tants have been described in the human, but the
contributions of each of these neutrophil chemot-
actic agents in acute gout remains incompletely
defined. The chemoattractants commonly impli-
cated in acute gout include the complement cas-
cade product, C5a, the product of phospholipase
A2 stimulation, leukotriene B4 (LTB4), the phos-
phocholine lipid, platelet-activating factor (PAF),
and the potent peptide neutrophil chemoattrac-
tant, interleukin-8 (IL-8) [1, 195]. A number of
neutrophil chemoattractants with structures simi-
lar to IL-8 have also been characterized and des-
ignated as chemokines, a term derived from the
words, chemotactic cytokines. Growth-regulating
oncogenes (GRO-a, GRO-J3, and GRO-y)
or melanocyte growth-stimulating activity
(MSGA), neutrophil-activating peptide-2 (NAP-
2), epithelial cell-derived neutrophil-activating
peptide (ENA-78), and granulocyte chemotactic
peptide (GCP-2) are also chemokines that act as
chemoattractants for neutrophils, but no descrip-
tion of their role in acute gout exists [196].
The origin of the crystals that initiate the
inflammatory reaction in acute gout is unknown,
but several sources are possible. Urate crystal
deposits, so-called synovial membrane tophi,
have been identified and could be a possible
source of crystals initiating an acute gouty
episode. Such monosodium urate crystals might
simply precipitate from the synovial fluid as
a result of an elevated concentration of urate
exceeding its solubility in this compartment.
These crystals might also have their origin in
the cartilagenous deposits (tophi) in joint carti-
lage. Urate crystals, once precipitated, then must
make contact with a phagocytic cell to generate
chemoattractants such as IL-8 or LTB4 or activate
the classical or alternative complement pathway
to generate the complement-derived chemotactic
factor, C5a. Phagocytic cells capable of gener-
ating chemotactic agents in the synovial space
include the small number of neutrophils and/or
monocytes resident in the normal synovial fluid,
the monocyte-derived type A synovial membrane
cell, or the type 8 fibroblast-like synovial mem-
brane cell. Acute gouty episodes can occur in
Neutrophil Chemoattractants
the virtual absence of neutrophils in the synovial
fluid, and such data suggest that synovial mem-
brane cells may also play a key role in the gen-
eration of inflammatory mediators under certain
conditions.
The chemoattractants, C5a (a product of the
complement cascade), platelet-activating factor
(PAF, a product of activated endothelial cells),
leukotriene B4 (LTB4, a product of stimulated
phospholipid metabolism in inflammatory cells),
and the chemokine, interleukin-8 (IL-8), are the
most likely contributors to the chemotaxis of
neutrophils in acute gout [197]. Although the
sentinel neutrophil chemoattractant in gouty
arthritis has not been positively identified, IL-8
has been characterized as the principal neutrophil
chemoattractant in acute gout. Further support
for the role of certain chemoattractants has been
derived from the detection of IL-8 and LT84 in
the synovial fluid of patients with acute gout.
Although scientific rationales can be cited to sug-
gest that other neutrophil chemoattractants might
be involved in acute gout, no other chemotaxins
have been measured in the synovial effusions in
acute gouty arthritis.
The availability of many different chemoat-
tractants (LTB4, IL-8, C5a, PAF, and perhaps oth-
ers) raises the question as to why such redundancy
exists. Different explanations have been offered to
justify this redundancy. First, different chemoat-
tractants arise from different cellular sources
and the redundancy of these agents assures that
no matter what tissue is affected, the recruitment
of neutrophils to the inflammatory site will be
effective and prompt. Second, IL-8 is secreted
by many different tissues and inflammatory cells
after such cells and/or tissues are activated by
proinflammatory stimuli. This may explain the
principal role of this chemokine in gout since
different cells associated with the synovial mem-
brane and joint space fluid are able to secrete this
chemoattractant agent in response to monoso-
dium urate crystals. Third, neutrophil chemoat-
tractants can integrate different chemoattractants
in a variety of ways including responses to the
vector sum of the orienting signals, prioritizing
chemoattractant signals based on the memory
of their signals, or by agonist combinations to
219
enhance the chemoattractant effect [197]. This
chemotactic-mediated integration of neutrophil
chemotaxis is, in large part, regulated by chemot-
actic receptors on the neutrophil plasma mem-
brane. Fourth, some chemoattractants can block
the effect of another chemotactic agent by their
ability to desensitize the receptor of the other
chemoattractant. This phenomenon has been
termed heterologous desensitization, and the
chemoattractant, C5a, is an especially competent
effector of this form of receptor downregulation.
This process is in contrast to homologous desensi-
tization which occurs when a ligand desensitizes
its own receptor. A full discussion of desensiti-
zation is provided subsequently since this pro-
cess may contribute to the resolution of uric acid
crystal-induced inflammation. Finally, chemoat-
tractant receptors stimulate a variety of differ-
ent cellular functions such as degranulation and
release of lysosomal enzymes, upregulation of
adhesion molecules, and initiation of a respiratory
burst. An example of these differential effects of
chemoattractants is illustrated by the fact that the
neutrophil respiratory burst is only dependent on
the IL-8 receptor, CXCR-1, whereas the intracel-
lular elevation of calcium and the phosphorylation
of mitogen-activated protein kinase are mediated
by both IL-8 receptors (CXCR-1 and CXCR-2).
These latter receptor-mediated effects regulate or
trigger specific cellular functions [198].
Proteinases and Neutrophil Migration
Even though the effect of proteinases on neu-
trophil migration remains controversial, there
is some evidence that the neutrophil granule
enzymes such as elastase (present in azurophil
granules), gelatinase (present in specific and
gelatinase granules), and cathepsin G (present
in azurophil granules) play a role in the regu-
lation of neutrophil migration in a variety of
ways. Elastase regulates the quantity of the vita-
min d-binding protein (DBP) or Gc-globulin, a
multifunctional 56-kDa protein that enhances
C5a chemotactic activity. Elastase performs this
function by mediating the shedding of the DBP
binding site, a cell-surface chondroitin sulfate
220 8 Mechanisms of the Acute Attack of Gout and Its Resolution
proteoglycan. Cathepsin G or elastase result in the
proteolysis of the P-selectin glycoprotein ligand-1
(PSGL-1) and causes the downregulation of neu-
trophil adhesion to P-selectin. The proteolysis of
P-selectin counterreceptor decreases adhesion of
the neutrophil and, subsequently, enhances the
migration of these inflammatory cells to the site
of tissue injury. The role of various proteinases in
the migration of neutrophils has also been inves-
tigated using proteinase inhibitors. These studies
demonstrate a reduction in neutrophil chemotaxis
and/or migration in the presence of proteinase
inhibitors. In contrast to these findings and the
absence of direct evidence for the role of protei-
nases in neutrophil migration, elastase-deficient
mice clearly demonstrate that neither neutrophil
elastase, matrix metalloproteinase-9, nor cathep-
sin G are essential for neutrophil transendothelial
migration [199]. These data may indicate differ-
ences between the human and murine systems or
the lack of identification of the true proteinases
supporting neutrophil chemotaxis and migra-
tion. Thus, the cellular sources of chemoattrac-
tants, their role in biological functions other than
chemotaxis, and their effect on chemoattractant
receptors are factors that must be considered in
assessing neutrophil chemoattraction.
Since the chemoattractants C5a, LTB4, and
IL-8, and perhaps PAF, are likely participants
in neutrophil chemotaxis in gout, each of these
mediators is discussed in greater detail here.
Except for the investigations of the C5a recep-
tor and heterologous receptor desensitization by
C5a, little has been published concerning the rote
of the C5a chemotaxin in gout since IL-8 appears
to be the major chemoattractant in that disorder.
Nonetheless, since the generation of C5a is not
cell dependent, and since it induces the synthesis
and secretion of the proinflammatory cytokines,
IL-1, IL-6, IL-8, and TNF, the activation of C5a
by monosodium urate crystals could be the early
reaction triggering the release of inflammatory
mediators associated with acute gout [200].
Furthermore, the fact that C5a can regulate neu-
trophil chemotaxis via heterologous receptor
desensitization may provide this complement fac-
tor with the capacity to modify neutrophil migra-
tion to inflammatory sites and may be involved in
the resolution of the acute gouty episode. Thus,
an elevated concentration of C5a in the synovial
fluid of resolving gouty arthritis might provide
evidence of the role of this chemoattractant in the
modification of the acute episode.
The Complement Fragments:
C5a and C5a des Arg
Human C5a is a cationic glycoprotein containing
74 amino acids with a carbohydrate moiety
attached to an asparagine residue shown in bold
in the amino acid structure. Its amino acid
sequence is shown below. The carbohydrate moi-
ety is an oligosaccharide containing glucosamine,
sialic acid, mannose, and galactose.
Thr-Leu-Gin-Lys-Lys-lle-Giu-Giu-lle-
Aia-Aia-Lys-Tyr-Lys-His-Ser-Vai-Val-
Lys-Lys-Cys-Cys-Tyr-Asp-Giy-Aia-
Cys-Vai-Asn-Asn-Asp-Giu-Thr-
Cys·Giu-Gln-Arg-Aia-Aia-Arg-lle-
Ser-Leu-Giy-Pro-Arg-Cys-lle-Lys-
Aia-Phe-Thr-Giu-Cys-Cys-Vai-Vai-
Aia-Ser-Gin-Leu-Arg-Aia-Asn-lle-
Ser-His-Lys-Asp-Met-Gin-Leu-Giy-
Arg
C5a des Arg has a structure identical to C5a
except for the absence of a carboxy-terminal
arginyl residue. This modified C5a molecule is
generated by the action of carboxypeptidase on
the native molecule. The neutrophil chemotactic
activity of C5a has been documented in several
experimental systems and has the capacity to
attract human neutrophils at concentrations as
low as 0.1 nM. C5a concentrations greater than
1 nM can cause desensitization of the C5a recep-
tor and decrease neutrophil chemotaxis. The C5a
derivative, C5a des Arg, is formed through the
action of serum carboxypeptidase N which con-
verts C5a to C5a des Arg. The latter metabolite is
much less potent as a neutrophil chemotaxin
(about 10–20 times less), but it shows compara-
ble neutrophil chemoattractant activity when
combined with its cochemotaxin, Gc-globulin or
vitamin d-binding protein [201]. C5a also trig-
gers actions other than neutrophil chemotaxis
such as the secretion of lysosomal enzymes,
Neutrophil Chemoattractants
eicosanoids, PAF, and IL-6, the increased
expression of cell adhesion molecules, and the
increased production of superoxide anion.
Monosodium urate crystals are known to acti-
vate both the classical and alternative complement
pathway. These crystals mediate, either in a
C-reactive protein-dependent or in an IgG-
dependent manner, the depletion of plasma com-
plement with the production of many polypeptides
including C1r, C1s, fibronectin, C1q, fibrinogen,
lysosomal enzymes, IgG, and apoproteins. What
part the 74 amino acid protein C5a, a neutrophil
chemoattractant, plays in the neutrophil emigra-
tion in acute gout remains incompletely resolved
and somewhat controversial. The levels of com-
plement in the joint fluid from patients with acute
gout have been found to be normal using a hemo-
lytic assay for the measurement of complement.
Further, heating urate crystals to temperatures
where their capacity to activate complement is lost
has no effect on the ability of such heated crystals
to initiate an inflammatory response. Additional
evidence that complement fragments may not play
a central role in the mediation of the inflammatory
response to urate crystals has been generated from
animal experiments. Cobra venom factor, a sub-
stance known to deplete complement components
when injected into joints, has no effect on the leu-
kocyte response to urate crystals injected into the
same joints. Whether the initial chemotactic factor
production results from the activation of the syn-
ovial fluid complement cascade with the genera-
tion of C5a, the synthesis and release of LTB4 from
synovial lining cells, the release of a-chemokines
by the synovial lining cells, or a combination of
these and other events remains to be firmly estab-
lished. Nonetheless, the process of neutrophil
chemotaxis is likely to be amplified once neutro-
phils arrive in the synovial cavity. In addition, C5
can be converted to the potent chemotaxin, C5a, or
its less potent derivative, C5a-des-arg, by C5 con-
vertase formed on the urate crystal surface.
C5a Receptor (C5aR)
The C5a receptor belongs to the large family
of human G protein-coupled receptors, and it
221
contains an extracellular amino terminal domain,
seven transmembrane-spanning domains, and an
intracellular carboxy-terminal domain for the
coupling of a G protein (a heterotrimeric GTP-
binding or hydrolyzing protein). The seven trans-
membrane-spanning domains, because of their
coiled appearance, have led to the use of the term
“serpentine receptor” since the G protein-coupled
receptors resemble a coiled snake. When C5a, the
receptor ligand, binds to C5aR, it causes a change
in the receptor conformation that results in the
activation of C5aR and catalyzes the exchange of
guanosine triphosphate (GTP) for guanosine
diphosphate (GDP) on the alpha subunit of the
heterotrimeric (a, b, and g) protein. This interac-
tion causes the dissociation of the a subunit from
the bg dimer, and the free bg dimer then activates
the effector channels for the transduction of
the C5a messages necessary for the stimulation
of chemotaxis, granule enzyme release, and
superoxide anion production. C5a triggers the
initiation of a number of intracellular processes
including the activation of phospholipase C and
phosphatidylinositol 3-kinase as well as the
secretion of TNF-a, IL-1, and IL-8. The human
receptor for C5a has been cloned and sequenced
[197, 198]. The eDNA sequence for the C5a
receptor encodes a structure with seven trans-
membrane domains, a long intracellular carboxy-
terminus, three cytoplasmic loops, an extracellular
amino terminus, and three extracellular loops.
Additional structural and functional characteris-
tics of this receptor can be found on the website
for G protein-coupled receptors (www.gpcs.
org/7tm/). Recent evidence has documented the
role of the NH2-terminal domain to the binding
of C5a to C5aR, but work continues to under-
stand fully the binding of C5a to its receptor and
the transduction of its message [202]. Studies of
this receptor have identified some binding, acti-
vation, and transduction sites. Tyrosine-sulfated
residues at position 11 and 14 of the NH2-
terminus of the receptor have been shown to
mediate the initial docking of C5a to its receptor
but appear not to mediate its receptor activation
site. This sulfation reaction occurs as a posttrans-
lational modification of C5aR and is essential for
C5a binding to C5aR. The gene for the C5aR has
222 8 Mechanisms of the Acute Attack of Gout and Its Resolution
been localized to the chromosome site, 19q13.3-
q13.4. The C5aR has a protein structure contain-
ing 350 amino acids and has a molecular weight
of 39,320. About 50,000–100,000 C5a molecules
bind per cell with a Kd of approximately 2 nM.
Although C5a has been shown to play an
important role in some forms of inflammatory
arthritis, its role in gout has not been fully evalu-
ated [203]. Recent studies have investigated the
presence of the C5a receptor on human synovio-
cytes. In synoviocytes recovered from patients
with rheumatoid arthritis and osteoarthritis,
mRNA for C5aR has been identified and its
expression determined to be on the surface of
synoviocytes from synovial membranes of
patients with osteoarthritis and rheumatoid arthri-
tis. When C5a and lipopolysaccharide are added
to cultured synoviocytes, tumor necrosis factor-
alpha is released. These studies merit a reexami-
nation of the role of C5a and its receptor in acute
inflammatory forms of arthritis like gout.
Platelet-Activating Factor (PAF)
Platelet-activating factor (1-ortho-alkyl-2-acetyl-
sn-glycero-3-phosphocholine) and leukotriene
84 (LTB4) are the two lipid chemoattractants
for neutrophils. Although other fatty alcohols
may occur in the sn-1 position of PAF, the major
metabolite in humans is constructed with a hexa-
decanol in the sn-1 position. The molecular
structure of PAF is as shown below (Fig. 8.3).
Changes in the ether linkage of alkyl group at
the sn-1 position of the glycerol backbone, the
short chain acyl residue at the sn-2 position, or
the phosphocholine head group at the sn-3 posi-
tion, all reduce the biological potency of the
native molecule. PAF and receptors for this lipid
have been identified by several groups. Other
chemical substances related to PAF have also
been isolated including a molecule identical to
the hexadecanol derivative but containing alkyl
chains of different lengths in the sn-1 position.
Investigations have detected PAF species with
alkyl derivatives including 17:0, 18:0, and 18:1
groups in the sn-1 position. In addition to these
cell products, inflammatory platelet-activating
Platelet-activating factor
H3C—O—(CH2)15—CH3
O
H3C-C—O.CH O
H2C—O –P—O—CH2—CH2—N(CH3)3
O-
Fig. 8.3 The structure of PAF (1-O-alkyl-2-acetyl-sn-
glycero-3-phosphocholine) usually contains hexadecanol
in the sn-1 position, and changing the length of this fatty
alcohol diminishes the potency of the molecule. The ace-
tate at position sn-2 is essential for PAF activity since its
removal abolishes the biologic activity of the molecule.
The polar head group at position sn-3 is also critical for
the function of the molecule since its alteration decreases
the potency of the molecule. The actual stereochemistry
for binding to PAF receptors is not illustrated in this
diagram
factor-like molecules are derived from oxidized
low-density lipoproteins [204]. Although the
role of these oxidized lipoproteins has not been
explored in gout or other inflammatory synovit-
ides, low-density lipoproteins and other lipopro-
teins have been isolated from the synovial fluid
in some articular diseases. Since lipoproteins
are altered in some patients with gouty arthritis
and oxidized low-density lipoproteins induce
5-lipoxygenase activity in leukocytes, this mech-
anism for the production of monocyte chemoat-
tractant protein-1 as well as LTB4 may contribute
to the generation of these proinflammatory medi-
ators in acute gout. Further, these oxidized, PAF-
Iike molecules stimulate monocytes, leukocytes,
and platelets; cause monocyte and neutrophil
chemotaxis; and enhance leukocyte adhesion to
endothelium [205]. Like authentic PAF, these
oxidized lipoproteins act via leukocyte PAF
receptor. PAF may also be referred to as AGEPC
(alkyl glycerol ether phosphoryl choline) or PAF-
acether in the literature, but PAF is the term most
widely accepted.
In support of the fact that PAF may have a role
in the pathogenesis of acute gout, PAF has been
identified as a constituent of synovial fluid
Neutrophil Chemoattractants
leukocytes and some inflammatory joint diseases
in animal models [205].
Furthermore, PAF has been recovered in the
synovial fluid from inflammatory arthritides. The
most compelling evidence related to the associa-
tion between gout and PAF comes from an ani-
mal models of acute uric acid crystal-induced
arthritis that has been evaluated using uric acid
crystals and an inhibitor of the PAF receptor.
Pretreatment with a PAF receptor antagonist
before the injection of urate crystals significantly
reduced the following inflammatory parameters
as compared to controls (no antagonist present):
synovial fluid volume, the number of cells in the
synovial fluid and synovial membrane, and the
concentration of PGE2 and IL-6 in synovial fluid.
Another interesting facet that could relate to syn-
ovial joint inflammation in gout is the synthesis
of PAF by monocyte-derived macrophages when
stimulated by serum-opsonized zymosan. From
such data, one might infer that monocyte-derived
synoviocytes could phagocytose uric acid crys-
tals and produce PAF. These investigations pro-
vide a rationale for the discussion of PAF as
a putative mediator in the pathogenesis of acute
gout. The principal sources of PAF are neutro-
phils, monocytes, eosinophils, and endothelial
cells. In some cases, PAF is not released from its
cell source but remains on the plasma membrane
of the cell [206]. This is an especially prominent
state in endothelial cells since cell surface PAF
signals neutrophil adhesion. The quantity of
membrane-associated PAF is dependent on the
experimental conditions.
Platelet-activating factor is not stored in cells
and is synthesized only in activated cells. Two
pathways can lead to the synthesis of PAF: the
remodeling pathway and the de novo pathway
(Figs. 8.4, 8.5, and 8.6). The former pathway is
well characterized, accounts for the generation of
PAF for immune and inflammatory responses,
and is the major biosynthetic pathway for PAF
synthesis in neutrophils, endothelial cells, and
monocytes/macrophages. The first step in the
remodeling pathway is catalyzed by a cytosolic
phospholipase A2 that hydrolyzes the sn-2 fatty
acid from alkyl-choline phosphoglycerides to
form an intermediate, 1–0-alkyl-sn-glycero-3-
223
phosphocholine (lyso-PAF). Usually, this first
step is designated as phospholipase A2 acting on
1-0-alkyl-2-arachidonoyl glycerophosphocholine
to form lyso-PAF and free arachidonate. The lat-
ter compound can then be converted to various
arachidonate metabolites. The second step in the
remodeling pathway is catalyzed by the enzyme,
acetylcoenzyme A: lyso-PAF acetyltransferase.
This enzyme catalyzes the addition of an acetyl
group to the sn-2 position of lyso-PAF to form
1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine
or PAF. The enzymatic activity of both cytosolic
phospholipase A2 and lyso-PAF-acetyltrans-
ferase is regulated by phosphorylation-dephos-
phorylation reactions [207]. The cytosolic
phospholipase A2 is regulated by a G protein-
coupled pathway that causes the activation of
protein kinase C and subsequently, the phospho-
rylation of PLA2 by mitogen-activated protein
kinase.
Cytosolic phospholipase A2 activity is asso-
ciated with increments in intracellular calcium
concentrations and by phosphorylation of mul-
tiple serines in the enzyme. The calcium ions
interact with the amino terminal C2-domain of
the cytosolic phospholipase A2 and phosphory-
lation may occur at serine-505, serine-515, and/
or serine-727. The phosphorylation of serine-505
is mediated by mitogen-activated protein kinases
(MAPK), phosphorylation of serine-515 by cal-
cium-/calmodulin-dependent protein kinase II
(CAMK II), and phosphorylation of serine-727
by MAPK-interacting kinase Mnk1 or another
related kinase [208]. The mechanism by which
cytosolic phospholipase A2a increases its
enzyme activity remains unresolved, but a con-
formational change in the enzyme has been sug-
gested [209]. In the neutrophil, it has been clearly
shown that p38 mitogen-activated protein kinase
phosphorylates acetyltransferase and increases its
enzymatic activity. A coenzyme A-independent
transacylase also plays a role in PAF synthesis
[210]. This pathway causes the generation of free
arachidonate and lyso-phosphatidylethanolamine
from the PLA2 substrate, arachidonate-contain-
ing plasmalogen phosphatidylethanolamine.
Lyso-phosphatidylethanolamine then acts as an
acceptor of the free arachidonate derived from the
224 8 Mechanisms of the Acute Attack of Gout and Its Resolution

Fig. 8.4 The synthesis Remodeling pathway A

of platelet-activating factor
(PAF) by the remodeling
pathway A occurs in two
steps. The first step is H2C –O -CH2 —R
catalyzed by phospholipase
A2 which hydrolyzes the sn-2 20:4 — CH O
fatty acid from alkyl-choline
phosphoglycerides to form +
H2C — O — PH —CH2 —N(CH2)2
an intermediate, 1-O-alkyl-
sn-glycero-3-phosphocholine
(lyso-PAF). The second step O-
is catalyzed by the enzyme,
acetylcoenzyme A: lyso-PAF 1-0-alkyl-2-arachidonyl glycerophosphocholine
acetyltransferase, which
converts lyso-PAF to PAF
(1-O-alkyl-2-acetyl-sn- Phospholipase A2
glycero-3-phosphocholine).
The degradation of PAF is
catalyzed by an intracellular
PAF acetylhydrolase that Arachidonic acid + H2C —— O —CH2 — CHR
converts PAF to lyso-PAF.
The lyso-PAF molecule is
then reacylated with a long HO—CH O
chain fatty acid by the
activity of an acyltransferase. +
H2C — O —P—CH2 —N(CH3)3
Thus, the remodeling
pathway designated as
pathway A results in PAF O-
synthesis by the activity
of phospholipase A2 Lyso-platele-activating factor
catalyzing the conversion
of 1-O-alkyl-2-arachidonoyl +
glycerophosphocholine to ACETYL CoA
lyso-PAF and free
arachidonic acid. The latter
serves as a substrate for
eicosanoid production. The Lyso-PAF-acetyltransferase
lyso-PAF is then acetylated
through the activity of a
specific enzyme, lyso-PAF
acetyltransferase, and acetyl
coenzyme A donates the
acetyl group. The enzyme, O
lyso-PAF is the rate-limiting H2C — O —CH2 —CHR
enzyme for the pathway
H3C — C— O——— CH O

+
H2C — O —— P —— CH2 —— N(CH3)3

O-
Platelet-activating factor
Neutrophil Chemoattractants
Remodeling pathway B
H2C – O — CH CHR
HO— CH
O
H2C — O — P — O — CH2CH2NH2
O-
PLA2
Coenzyme A-indpendent transacylase (CoA-IT)
H2C — O — CH CHR
20:4 — CH O
H2C — O — P — O — CH2CH2NH2
O-
O H2C — O — CH2R
CH3— C—— O— CH
O
H3C — O — P — O — CH2CH2N(CH3)3
O-
Fig. 8.5 The other remodeling pathway B uses phos-
phatidylethanolamine as the source of arachidonic acid by
phospholipase A2 hydrolysis rather than phosphatidylcho-
line. The increased concentrations of 1-O-alk-1¢-enyl-2-
lyso-sn-glycero-3-phosphoethanolamine and the presence
of the enzyme, coenzyme A-independent transacylase
(CoA-IT) provides evidence for the hydrolysis of arachi-
donate-containing plasmalogen phosphatidylethanolamine
by phospholipase A2 and the stimulation by lyso-phos-
phatidylethanolamine of the transfer of arachidonate from
phosphatidylcholine to lysophosphatidylethanolamine
catalyzed by the transacylase enzyme with the formation
of lyso-PAF. The latter molecule is then converted to PAF
225
H2C — o —CH2R
20:4 — CH
+
H2C — O — P -CH2CH2N(CH3)3
O-
PLA2
H2C — O — CH2R
HO— CH
O
+
H2C — O — P — O — CH2CH2N(CH3)3
O-
Lyso-PAF-acetyltransferase
+
by the activity of the enzyme, lyso-PAF acetyltransferase.
The major storage compound for arachidonate in human
neutrophils is the ethanolamine plasmalogen, 1-O-alk-1’-
enyl-2-acyl-sn-glycero-3-phosphoethanolamine.
Stimulated neutrophils trigger phospholipase A2 activity
and cause the hydrolysis of glycerol-3-phosphoethano-
lamines containing arachidonic acid. The products of this
hydrolysis are alkenyl-lyso-GPE and free arachidonic
acid. Alkenyl-lyso-GPE is a substrate for arachidonate
derived from 1-O-arachidonoyl-GPC. This reaction is
catalyzed by CoA-independent transacylase and leads to
the formation of lyso-PAF which is then converted to PAF
by the enzyme acetyl-CoA:lyso-PAF-acetyltransferase
226 8 Mechanisms of the Acute Attack of Gout and Its Resolution

De novo pathway

H2C — OR O

HO — CH + CH2C — SCoA

H2C — O — P — OH

O-
1-Alkyl-2-lyso-sn-glycero-3-phosphate Acetyl-CoA

De novo acetyltransferase
H2C — O — R
O

+ CoASH
CH3C—— O —CH

H2C—— O —P

1-Alkyl-2-acetyl-sn-glycero-3-phosphate Coenzyme A

Phosphohydrolase

H2C —— O— R
O
H2PO4
CH3C — O—— CH +

H2COH

1-Alkyl-2-acetyl-sn-glycerol Phosphate

Cholinephosphotransferase
+

+
CDP-CH2CH2N(CH3)3

PAF

+ CDP

Fig. 8.6 The de novo biosynthetic pathway primarily has
been characterized as a less significant source of PAF than
the remodeling pathways. It is found to operate in the
kidney and central nervous system. The immediate pre-
cursors of PAF in this pathway are the 1-akyl-2-acetyl-sn-
glycerols that arise from the acetylation-dephosphorylation
reactions catalyzed by acetylCoA:1-alkyl-2-lyso-sn-glyc-
ero-3-phosphate acetyltransferase and by 1-alkyl-2-acetyl-
sn-glycero-3-phosphate phosphohydrolase. In this de novo
pathway, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate with
its cofactor, acetyl CoA, is converted to 1-O-alkyl-2-
acetyl-sn-glycero-3-phosphate and coenzyme A by the
enzyme, de novo alkylglycerophosphate acetyltransferase.
In the second step, 1-O-alkyl-2-acetyl-sn-glycero-3-
phosphate is converted to 1-O-alkyl-2-acetyl-sn-glycerol
and phosphate by the enzyme alkylacetylglycero-P phos-
phohydrolase. The last step is the conversion of 1-O-alkyl-
2-acetyl-sn-glycerol and cytidine diphosphocholine to
PAF and phosphate catalyzed by the enzyme CDP-
choline:alkylacetylglycerol cholinephosphotransferase
PAF Receptor
PLA2 substrate, 1–0-alkyl-2-arachidonoyl glyc-
erophosphocholine and catalyzed by the enzyme,
coenzyme A-independent transacylase (CoA-IT).
Both these biosynthetic pathways require phos-
pholipase A2. The de novo pathway is utilized
mainly in the kidney and brain. This pathway
consists of three steps. Initially, 1-0-alkyl-
sn-glycero-3-phosphate is acetylated by the
enzyme, 1-0-alkyl-sn-glycero-3-phosphate:acetyl
CoA:acetyltransferase. The product of this reac-
tion is then transformed by a specific phospho-
hydrolase to 1-0-alkyl-2-acetyl-sn-glycerol. The
latter metabolite is then converted by a dithiothre-
itol-insensitive CDP-cholinephosphotransferase
to PAF. In contrast to the remodeling pathway,
the regulation of this de novo pathway is only
dependent on the availability of substrates.
PAF Receptor
Like the C5a receptor, the PAF receptor is a G
protein-coupled receptor containing seven trans-
membrane domains, three extracellular loops, an
extracellular amino terminus, and an intracellular
carboxy-terminus. The human gene for this
receptor has been cloned, and it encodes a protein
containing 342 amino acids and has a molecular
weight of 39,200. The nucleotide sequence for
this gene has been mapped to human chromo-
some 1p35-p34.3. Extensive investigations con-
tinue to identify and characterize the ligand
binding sites for PAF responsible for desensitiza-
tion. The effects of PAF receptor desensitization
will be discussed subsequently, but the complete
picture of the regulation and activation of this
receptor remains to be completely characterized.
Biological Functions of PAF
PAF stimulates a variety of different functions in
human neutrophils including !32 integrin activa-
tion, chemotaxis, degranulation, oxygen radical
generation, and changes in cell shape. PAF also
primes neutrophils to enhance the response of
this cell to other agonists. PAF is more effective
in its capacity to prime cells, change their shape,
227
and activate b2 integrins than it is as an effector
of chemotaxis, degranulation, or reactive oxygen
generation. PAF concentrations necessary for
neutrophil degranulation and oxygen generation
are usually in the range of 100 nM, whereas con-
centrations for neutrophil priming, chemotaxis,
and b2 integrin activation are in the range of the
Kd for the high-affinity receptor for PAF (0.2–1.0
nM). PAF, as wm be discussed subsequently,
primes neutrophils for enhanced superoxide gen-
eration when such primed cells are stimulated by
other agonists. PAF also primes neutrophils for
aggregation, granule enzyme release, and actin
polymerization, and it also stimulates the synthe-
sis of the chemoattractant, LTB4, and stimulates
its own (PAF) synthesis in neutrophils [211, 212].
The link between the action of PAF on arachi-
donic acid metabolism and the production of the
potent chemoattractant, LTB4, demonstrates the
redundancy in the generation of chemotactic
agents. PAF is probably most efficient as a medi-
ator of cell adhesion-dependent functions. LFA-1
(lymphocyte function antigen) and MAC-1, the
integrin adhesive molecules enhancing the bind-
ing of neutrophils to endothelial cells are upregu-
lated by PAF [213–215]. It also mediates
neutrophil aggregation and adhesion to specific
matrix proteins [216]. The increment in the sur-
face expression of these PAF-induced integrins is
caused by the recruitment of integrins via neutro-
phil exocytosis. To reemphasize the interdepen-
dencies that occur in the inflammatory response
has been shown to potentiate PAF-stimulated
neutrophil degranulation .
Finally, PAF has been shown to induce neutro-
phil chemotaxis. It is clear from the investiga-
tions cited and other studies that the C16:0
molecule is more potent than the C18:0 or C18:1
molecules. Neutrophil chemotaxis by PAF is
mediated specific receptors on the neutrophil
plasma membrane. These PAF-specific binding
sites on neutrophils have been confirmed using
PAF-specific receptor antagonists. Since LTB4
and interleukin-8 (IL-8) are also potent neutro-
phil chemoattractants and are found in the syn-
ovial fluid of patients with acute gout, it is
reasonable to compare the potency of LTB4, ll-8,
and PAF neutrophil chemoattractants [101].
228 8 Mechanisms of the Acute Attack of Gout and Its Resolution
The only published data comparing the potency
of these three chemoattractants comes from the
pediatric literature and uses newborn neutrophils
as the target. These studies show a rank order of
potency of lL-8 > lTB4 > PAF and combining
these three chemoattractants increases chemot-
axis over the average of each agent alone. The
latter increments were due to either the combina-
tion of IL-8 and PAF or LT84 and IL-8. Although
no data exist for the adult human neutrophil
responses to these chemoattractants, it is reason-
able to assume that the rank order of potency for
adult neutrophils would be similar to newborn
neutrophils.
The significance of PAF to acute gouty arthri-
tis is its biological role as a mediator that increases
microvascular permeability, that stimulates the
adherence of neutrophils to endothelial cells and
that may cause the chemotaxis and migration of
neutrophils to endothelial cell monolayers. In
those endothelial cells stimulate to synthesize
PAF, this mediator is transferred to the surface of
the cell where it causes neutrophil adhesion and
triggers the induction of the activation-dependent
upregulation of the adhesion molecules, b2 inte-
grins (CD11/CD18, CD11a/CD18, CD11b/
CD18), in neutrophil plasma membrane and sub-
endothelial matrix. In addition to regulating these
key leukocyte-endothelial cell interactions, PAF
also stimulates the degranulation and generation
of active oxygen metabolites from human neutro-
phils. These functional responses occur at con-
centrations much higher than the subnanomolar
concentrations necessary for the induction of
neutrophil adhesion to endothelial cells. Even
though PAF is a weak agonist for the generation
of oxygen radicals, it primes cells for other stim-
ulants of this response. Thus, PAF plays two key
roles in its interaction with endothelial cells and
neutrophils: neutrophil chemotaxis and activa-
tion of endothelial cell receptors for neutrophils.
Several additional facets are significant as to the
generation and biological effects of PAF. Both
tumor necrosis factor and interleukin-1a, two
potent proinflammatory mediators, have the
capacity to stimulate various cells to produce
PAF. Thus, these mediators may augment the
inflammatory process via their production of
PAF. Furthermore, PAF binding to its receptor
activates phosphatidylinositol-specific phospho-
lipase C that causes an increment in intracellular
calcium and the formation of diacylglycerol. The
increase in calcium causes the activation of pro-
tein kinase C and the catabolism of phosphatidyl-
choline to form diacylglycerol and phosphatidic
acid [217]. Such phospholipid changes also lead
to the production of arachidonic acid and the pro-
duction of proinflammatory arachidonate
metabolites.
Regulation of PAF: Acetylhydrolase
To counter the activation of cytosolic PLA2
and lyso-PAF acetyltransferase and their genera-
tion of the proinflammatory mediator, PAF, the
rapid hydrolysis of PAF and PAF-Iike bioactive
lipids is catalyzed by PAF acetylhydrolases.
Thus, PAF acetylhydolases downregulate the
proinflammatory signals generated by PAF and
PAF-like lipids, and in a sense, this enzyme
serves as an anti-inflammatory agent. PAF acetyl-
hydolases with their anti-inflammatory properties
could serve as a modulator of acute gouty arthri-
tis [218]. Two forms of PAF acetylhydrolase
exist: plasma (secreted) PAF acetylhydrolase and
intracellular PAF acetylhydrolase. The principal
sources of plasma PAF acetylhydrolases are mac-
rophage-containing tissues [218]. In addition, the
differentiation of peripheral blood monocytes
into macrophages in culture causes an increase in
intracellular PAF acetylhydrolase activity, and
such changes may have significance with respect
to the monocyte-derived type A synoviocyte.
During differentiation of monocytes and HL-60
cells, PAF acetylhydrolase is secreted. Thus, PAF
may induce the synthesis and release of PAF
acetylhydrolase and, in this way, serve as a feed-
back mechanism to protect the host from exces-
sive PAF activity. The active site amino acids
critical for plasma PAF acetylhydrolase activity
has been identified as Ser-273, Asp-296, and His-
351. The human promoter region for plasma PAF
acetylhydrolase has also been identified and the
transcriptional activator for the gene character-
ized. Intracellular PAF acetylhydrolases also play
PAF Receptor
a regulatory role in the accumulation of PAF,
especially in macrophages. Several intracellular
PAF acetylhydrolases have been cloned and char-
acterized [219]. At this time, some intracellular
PAF acetylhydrolases appear to have activity
against both PAF and PAF-Iike molecules,
whereas others are specific only for PAF. In sum-
mary, PAF acetylhydrolases probably play a key
role in the expression and regulation of the bio-
logical effects of PAF. This may be especially
significant if the type A monocyte-derived
synoviocyte is shown to express and secrete
this enzyme. Furthermore, any effect of acety-
lhydrolases might have on acute gouty arthritis
and its resolution will be dependent on the role,
if any, PAF plays in the propagation of acute
gout.
Leukotriene B4 (LTB4)
Leukotriene B4 is a powerful neutrophil chemo-
attractant derived from the lipoxygenation of
arachidonic acid. As its structure shows, LTB4
belongs to the lipid class of chemoattractants.
Leukotriene B4
OH OH
COOH
LTB4 Biological Functions
In addition to its role as a neutrophil chemoat-
tractant and aggregator, LTB4 also causes mono-
cyte adhesion to endothelial cells, neutrophil
degranulation, cation fluxes, and the release of
lysosomal enzymes and reactive oxygen species.
A less well-characterized effect of LTB4 is the
induction of monocyte chemoattractant protein-1
(MCP-1) in human monocytes. MCP-1 induction
by this mechanism is mediated via the LTB4
receptor, BLT1. This receptor-mediated effect
also requires the activation of the ERK1/2 or JNK
mitogen-activated protein kinase to cause a dose-
and time-dependent increment in MCP-1 tran-
scription. NF-kappa B expression may also be
229
involved in the increase in MCP-1 expression.
Another monocyte-related function of LTB4 is to
trigger an increase in monocyte adhesion to
endothelial cells as a component of the recruit-
ment of monocytes to inflammatory sites.
Although some studies have reported an upregu-
lation of surface b2-integrin expression on mono-
cytes, recent investigations examining human
monocytes under flow conditions determined that
no change in the levels of b1- and b2- integrins
occurred in response to LTB4. Under physiologi-
cal flow conditions, LTB4 caused no change in
integrin expression on human monocytes but did
cause an increased avidity of b1- and b2-integrin
for their counterligand. Such changes enhanced
the recruitment of monocytes.
Of significance to gout, monosodium urate
crystals incubated with human neutrophils and
arachidonic acid produce LTB4. If such assays
are dependent on endogenous supplies of arachi-
donic acid, neutrophils also produce LTB4 but at
lower levels than when exogenous arachidonic
acid is in the incubation [102]. The genera-
tion of LTB4 has been shown to result from the
capacity of monosodium urate crystals to induce
phospholipase A2 activity and the synthesis of
phospholipase A2-activating protein/5-lipoxyge-
nase-activating protein (FLAP).
A diversity of pathways are activated by LTB4
to regulate its biological functions. The genera-
tion of pseudopods and their extension on migrat-
ing cells is essential for their chemotactic activity,
and the rate of pseudopod extension is dependent
on the LTB4 concentrations presented to the cell.
Such changes are regulated by the activation of
RhoA and its effector kinase, ROCK. These same
effects occur with other chemoattractants includ-
ing IL-8, C5a, PAF, and fMLP. The inhibition of
pseudopod formation and extension is mediated,
in part, by compounds that block phosphati-
dylinositol 3-kinase activity. The dependence of
the rate of pseudopod extension on the concentra-
tion of a chemoattractant like LTB4 as well as
other chemoattractants such as IL-8, PAF, C5a,
and fMLP at equimolar concentrations suggests
that the polymerization of cytoskeletal F-actin is
regulated by a common rate-limiting step or
steps. LTB 4 also induces the release of human
230 8 Mechanisms of the Acute Attack of Gout and Its Resolution
neutrophil granules as measured by the release of
elastase. Elastase release is dependent on p38
MAP kinase activity. Studies using neutrophils
obtained from mice demonstrate that the release
of primary granules such as myeloperoxidase and
elastase are regulated by the Rho GTPase, Rac 2.
These observations have not been confirmed
using human neutrophils. LTB4 clearly activates
human neutrophils, and at the same time, this
chemoattractant delays apoptosis [220, 221].
Although the pathways for such activation and
apoptosis retardation remain to be completely
characterized, they appear to be regulated sepa-
rately. A key role for neutrophils and mac-
rophages in gout is their capacity to phagocytose
immunoglobulin-coated uric acid crystals, and
LTB4 has been shown to augment FcyR-mediated
phagocytosis by both macrophages and neutro-
phils. These observations are supported by the
fact that human neutrophils treated with different
leukotriene inhibitors exhibit a reduction in their
capacity for phagocytosis. LTB4 also activates
the protein tyrosine kinase, Syk, a molecule
essential for phagocytosis via the Fey receptor
[222]. It accomplishes its actions by causing an
increment in intracellular calcium, and this acti-
vates a number of kinases including protein
kinase C, mitogen-activated protein kinase, phos-
phatidylinositol 3-kinase, and protein tyrosine
kinase [223].
Another property of LTB4 is its capacity to act
as a feedback inhibitor of LTB4 under specific
conditions. Exogenous LTB4 inhibits the pro-
duction of LTB4 by neutrophils when cells are
exposed to the mediator prior to initiating the
phagocytosis of opsonized zymosan. It also
inhibits the synthesis and release of 5-hydroxy-
6,8,11,14-eicosatetraenoic acid as well as the
release of arachidonic acid by phagocytosing
neutrophils. Furthermore, exogenously deliv-
ered LTB4 metabolites, 20-hydroxy-LTB4 and
3(S)-hydroxy-LTB4, also reduce LTB4 synthe-
sis and release by neutrophils phagocytosing
opsonized zymosan. These inhibitory functions
are all blocked when an LTB4 receptor inhibi-
tor is present. In addition, this reduction in the
production of LTB4 by exogenous LTB4 and its
metabolites appears to be specific since other
receptor-mediated chemotaxis of neutrophils such
as the presence of fMLP has no effect on LTB4
production. This feedback inhibition appears to
be a mechanism for limiting LTB4 production
and preventing the harmful effects of excessive
LTB4. Finally, LTB4 activates other neutrophil
functions of significance to the inflammatory
response including the upregulation of the com-
plement receptor, the generation of superoxide,
and the increase in cell calcium levels [224]. In
summary, the biological roles of LTB4 are criti-
cal for inflammatory reactions including acute
gout, and its function as a recruiter of monocytes
may point to its putative action in the resolution
of acute gouty episodes.
LTB4 Biosynthesis via Phospholipase/
Lipoxygenase and Its Release
Leukotriene B4 (5S,12R-dihydroxy-6,14-cis-8-
,10-trans-eicosatetraenoic acid), a potent lipid
mediator, requires for its synthesis the activation
of cells with the release of arachidonic acid by
the activity of cytosolic phospholipase A2 and
the subsequent activation of 5-lipoxygenase. 5-li-
poxygenase in association with 5-lipoxygenase-
activating protein (FLAP) converts arachidonic
acid into the unstable, reactive epoxide, LTA4.
The unstable allylic epoxide intermediate, LTA4
is then hydrolyzed by the activity of LTA4 hydro-
lase to form the dihydroxy acid, LTB4 [225].
Phospholipase A2 enzymes are the rate-limiting
steps for several pathways leading to the synthe-
sis of biologically active lipids. These enzymes
catalyze the hydrolysis of the sn-2 position of
membrane glycerophospholipids and lead to the
release of fatty acids and lysophospholipids.
Among the fatty acids released by these enzymes,
arachidonic acid is an especially important
product since it is subsequently converted enzy-
matically to mediators like prostaglandins and
leukotrienes. Even the other products of phos-
pholipid A2 activity, lysophospholipids, are
themselves biologically active and can be con-
verted to the active proinflammatory mediator,
platelet-activating factor. Specific phospholipases
may also be involved in the generation of
PAF Receptor
mediators that are keys to the resolution of acute
inflammatory responses.
LTA4 Hydrolase
The final step in the biosynthesis of LTB4 is cata-
lyzed by a zinc metalloenzyme with anion-depen-
dent aminopeptidase activity called LTA4
hydrolase. This enzyme has been cloned and
characterized from human sources. The gene for
this approximately 69-kDa enzyme has been
mapped to chromosome 12q22. This gene con-
tains 19 exons and has a promoter region upstream
of its transcription initiation site. In most studies,
LTA4 hydrolase has been isolated from the solu-
ble protein fraction of cells, but one notable
exception is the alveolar macrophage. As is obvi-
ous, no data are available regarding the location
of these enzymes in the synovial membrane mac-
rophage-like cells. In the alveolar macrophage,
despite the preponderance of LTA4 hydrolase in
the nucleus, smaller quantities of this enzyme
exist in the cytoplasm. In the neutrophil, LTA4
hydrolase remains in the soluble fraction regard-
less of the cell’s state of activity. Since LTA4
hydrolase is found in both the cytoplasm and
nucleus of alveolar macrophages, the idea that
LTA4 hydrolase migrates from the cytoplasm to
the nucleus may or may not be a reasonable
assumption. If that concept is reasonable, then
import sites must exist on the enzyme. It has been
proposed that either basic amino acid clusters or
armadillo repeats on the LTA4 hydrolase might be
responsible for the import of this enzyme to the
nucleus. The details of the import of LTA4 hydro-
lase to the nucleus of macrophages such as those
residents of the alveolus remain to be resolved,
and additional characterizations of the enzyme
can be found in the following citations [226].
A few characteristics of the enzyme bear
emphasis. First, the enzyme is a metalloenzyme
that contains one zinc atom per enzyme molecule,
and chelation of this metallic atom by 1,10-
phenanthroline generates an apoenzyme without
activity. Second, the enzyme has a very selective
substrate specificity since the double bond geom-
etry of its substrates limits its capacity to catalyze
231
the conversion of substrates to specific products.
Only LTA4, LTA 3, and LTA5 are substrates for
the enzyme, and the latter two compounds are
relatively poor substrates. These leukotriene
epoxides inactivate leukotriene hydrolase during
the formation of LTB4 or the products of other
substrates by a mechanism characterized as
suicide inactivation. The latter mechanism is
characterized in greater detail in the following
citations. LTA4 hydrolase has dual catalytic
activities: epoxide hydrolase and aminopepti-
dase. The enzymatic catalytic sites are separate
but overlapping sites. As noted, the epoxide
hydrolase transforms LTA4 to LTB 4, and the
aminopeptidase cleaves a variety of peptides yet
its endogenous substrate(s) remain unknown.
The active sites of these catalytic activities (epox-
ide hydrolase and aminopeptidase) have been
identified and characterized.
Transcellular Metabolism and LTB4
Production
Finally, LTA4 transcellular metabolism occurs in
cells that do not contain the enzyme, 5-lipoxyge-
nase, but do contain the widely distributed, LTA4
hydrolase, These data implicate the latter enzyme
as a significant regulator of the inflammatory
response. The absence of 5-lipoxygenase and the
presence of LTA4 hydrolase in endothelial cells
and platelets demonstrates the capacity of these
cells to contribute LTB4, LTC4, and even lipoxins
to neutrophil-dependent inflammation by using
the LT secreted by endothelial cells or platelets to
synthesize LTB 4 via LTA4 hydrolase. Of impor-
tance to the inflammatory reactions observed in
joint disease is the interaction between neutro-
phils and endothelial cells. Neutrophils release
LTA4 at a level greater than 50 % of the total
quantity synthesized. This quantity of released
LTA4 results in the additional formation of LTB4
and the omega-oxidized metabolites of LTB4,
20-hydroxy- and 20-carboxy-leukotriene B4.
Furthermore, such interactions may also result
in the synthesis of LTC4, LTD4, and LTE4.
Such transcellular metabolism between neutro-
phils and endothelial cells may contribute to the
232 8 Mechanisms of the Acute Attack of Gout and Its Resolution
maintenance of an elevated gradient of LTB4
for the recruitment of additional neutrophils.
LTB4 at high concentrations may also cause
the generation of superoxide, induce neutrophil
degranulation, and enhance neutrophil adher-
ence to vascular endothelium. Both LTC4 and
LTD4 significantly modify microvascular per-
meability. Such transcellular metabolism is not
confined to the leukotrienes since other reactive
intermediates may also be transferred and uti-
lized for eicosanoid biosynthesis. Thus, transcel-
lular metabolism represents another route for the
host to generate LTB4 and other proinflammatory
mediators. In addition, transcellular metabolism,
as will be discussed subsequently, also leads to
the synthesis of anti-inflammatory eicosanoids.
Furthermore, it emphasizes the significance of
the enzyme, LTA4 hydrolase, to the inflammatory
process. This enzyme, because of its central role
in the generation of LTB4, also becomes a rea-
sonable target for inhibitors that block its bio-
synthetic capacities. Recently, investigations of
the structure of leukotriene hydrolase complexed
to several different inhibitors have provided the
basis for understanding inhibitor-leukotriene
hydrolase interactions and for designing inhibi-
tors based on such structural interactions. A vari-
ety of potent inhibitors have now been developed
and tested for their specificity.
A few additional concepts are worthy of com-
ment here. The mechanism by which leukotriene
hydrolase is inactivated by its substrate and iso-
mers has been characterized. Such data may be
useful in the design of leukotriene inhibitors.
Colchicine, a drug often used in the treatment of
acute gout, has been shown to block phospholi-
pase A2 activity and the processing of arachi-
donic acid by 5-lipoxygenase. This agent that
disrupts microtubules may, via its alteration in
arachidonic acid metabolism, contribute to its
anti-inflammatory effects. It is important to rec-
ognize that not all the lipoxygenase enzymes
translocate to the nuclear envelope, and this doc-
uments the fact that not all lipoxygenases are
localized to the same cellular compartments. In
the foregoing citation investigating a mouse mac-
rophage cell, RAW 267.4, 15-lipoxygenase was
not translocated to the nuclear envelope. These
studies also demonstrate the complexity of trans-
location and the present inability to identify
specific protein sequences responsible for this
translocation or lack thereof. The status of 15-li-
poxygenase compartmentalization has not been
determined in human macrophages. Recently, an
increased risk of myocardial infarction and stroke
has been determined to be associated with a sin-
gle-nucleotide polymorphism at the locus of the
arachidonate 5-lipoxygenase-activating protein
(ALOX5AP) gene at the chromosomal locus
13q12-13 [227]. These patients with this poly-
morphism produce increased quantities of LTB4.
Since cardiovascular disease, gout, and hyperten-
sion often coexist, this polymorphism might also
identify patients with gout who may be at
increased risk for cardiovascular and cerebrovas-
cular events. Thus, both 5-lipoxygenase and leu-
kotriene hydrolase activities are essential for an
acute inflammatory reaction and their inhibition
can modify such responses.
Phospholipase Classification
and Functions
Since the release of arachidonic acid, the precur-
sor of proinflammatory and anti-inflammatory
mediators, is a key to the synthesis of these
mediators, the enzymes regulating the release of
this metabolite play a central role in the devel-
opment of acute gout and its resolution. These
enzymes are classified here and will be discussed
subsequently for their role in shifting from an
acute inflammatory response to the initiation of
the resolution phase of an inflammatory reac-
tion. The phospholipase A2 family of enzymes
includes plasma, secreted, and intracellular
forms of phospholipase with a unique substrate
affinity for platelet-activating factor. Thus, the
latter phospholipases (PAF acetylhydrolases)
serve to downregulate the proinflammatory sig-
nals derived from PAF. Investigations into the
role of phospholipase A2 enzymes are ongoing,
and at this time, this family of enzymes can be
separated into three principal groups: cytosolic
PLA2 (cPLA2), intracellular PLA2 (iPLA2), and
secretory PLA2 (sPLA2) [228]. There are ten
PAF Receptor
secretory phospholipase A2 enzymes that have
been identified at this time, and they have been
classified into ten groups: group IB, group IIA,
group IIC, group IID, group IIE, group IIF, group
III, group V, group X, and group XIIA [229]. At
least four cytosolic PLA2s have been identified.
The four cytosolic enzymes have been termed
cPLA2a, cPLA2b, cPLA2g, and cPLA2d. These
phospholipases are classified as group IV phos-
pholipases. Finally, the calcium-independent
phospholipase A2 enzymes are classified as
group VI. The group VIA PLA2 in the human
has been mapped to chromosome 22q13.1, and
this gene encodes five splice variants classified
as group VIA-1 (GPVIA-1), group VIA-2
(GPVIA-2), group VIA-3 (GPVIA-3), group
VIA-ankyrin-1 (GPVIA-ankyrin-1), and group
VIA-ankyrin-2 (GPVIA-ankyrin-2). Additional
calcium-independent PLA2s continue to be char-
acterized with functions related to energy mobi-
lization and storage for the maintenance of lipid
homeostasis [230].
Having characterized the various phospholi-
pases, the question remains as to what specific
functions these multiple enzymes carry out. This
has been a difficult problem since most cells con-
tain more than one PLA2 and the use of inhibi-
tors and antisense molecules to determine their
functions often lack specificity. The present dis-
cussion will be limited to those phospholipases
that are known to play an essential role in the
activation and resolution of inflammatory pro-
cesses like gout. It is also entirely possible that
additional phospholipases will be found to con-
tribute to this process in the future. At present,
the group IV calcium-dependent cytosolic PLA2a
is the principal phospholipase with a preference
for the hydrolysis of glycerophospholipids con-
taining an arachidonyl residue at their sn2 posi-
tion. This phospholipase is induced by cell stimuli
and the resultant activation of such cells causes a
calcium-dependent translocation of the enzyme
from the cytoplasm to perinuclear and nuclear
membranes. Such translocation places this phos-
pholipase in the location of the arachidonic acid-
metabolizing enzymes like cylcooxygenases and
lipoxygenases [231]. In addition to the control of
cPLA2a by increments in intracellular calcium,
233
activation of cPLA2a is regulated by phosphory-
lation. This phospholipase can be phosphorylated
at Ser 505, Ser-515, or Ser-727. Phosphorylation
of Ser-505 is mediated by mitogen-activated pro-
tein kinase, whereas calcium-/calmodulin-depen-
dent protein kinase II catalyzes the phosphorylation
of Ser-515. Cytosolic PLA2a may also be phos-
phorylated at Ser-727 by MNK1-related protein
kinase. The basis for the phosphorylation of these
different serines is dependent on the cell type and
the stimulus, but phosphorylation increases the
enzyme activity regardless of the mechanism of
phosphorylation. The amino acid residues critical
for the catalytic activities of cPLA2a are Arg-
200, Ser-288, Asp-549, and Arg-566. These same
amino acids are conserved in all the cPLA2s.
Further details relating to these cytosolic phos-
pholipases can be found in a recent review.
Recently, cytosolic phospholipase A2g, although
it does not show a preference for arachidonic acid
release, causes spontaneous and stimulus induced
(ll-1) arachidonic acid release. Critical for its
activity is Ser-82 and its C-terminal prenylation
site. The arachidonate released by this phospholi-
pase has been shown to produce COX-1 and
COX-2 products.
Other studies have begun to explore the role of
phospholipase A2s in phagocytosis. Using mouse
macrophage-like P38801 cells, it has been deter-
mined that zymosan-induced arachidonic acid
release may be mediated, in part, by calcium-in-
dependent phospholipase A2. It has been pro-
posed that this cPLA2 pathway is likely to be
protein kinase (PK) dependent. Recently, the
receptor for the Fc portion of the immunoglobu-
lin molecule found on neutrophils, monocytes/
macrophages, and other cells has been shown to
couple with calcium-independent PLA2b in
U937 cells and to release arachidonic acid lead-
ing to the subsequent generation of prostaglandin
E2 and leukotriene B4. The activation of iPLA2
in this setting was PKC dependent.
Investigations have also focused on the role of
phospholipases in apoptosis, a cellular function
active in the resolution of an acute gouty episode.
A host of publications have addressed the inter-
action between apoptosis and phospholipases,
but the entire details of this process remain
234 8 Mechanisms of the Acute Attack of Gout and Its Resolution
incomplete. What is clear from the foregoing
citations is that the connections between phos-
pholipases and apoptotic pathways are still under
investigation, but it is reasonably well established
that cytosolic phospholipase plays a role in some
of the apoptotic pathways. In general, TNFa-
induced cell death appears to be mediated by
cytoplasmic PLA2 since caspase-3 causes
a cleavage of cPLA2 at Asp-525 producing an
inactive N-terminal cPLA2 fragment This inac-
tive cPLA2 fragment localizes to the membrane
fraction of the cell and competes with native
cPLA2. It acts as a dominant negative mutant and
prevents A23187 and IL·1 from releasing arachi-
donic acid in significant quantities. This cPLA2
fragment also selectively reduces the catalytic
activity of other PLA2s such as sPLA2 IIA and
iPLA2. Recent data also suggest that iPLA2 is
also cleaved by caspases at Asp-183. This iPLA2
fragment accelerates membrane phospholipid
remodeling including the translocation of
phosphatidylserine, an activity associated with
apoptosis. Further investigations are necessary to
define the pathways relating PLA2s to the apop-
totic process and what signals trigger these
events.
In summary, cPLA2 is the major enzyme
responsible for the generation of arachidonic
acid used for the synthesis of inflammatory
mediators like PGE2 and LTB4. The activity of
cPLA2 IVA is regulated positively by increases
in intracellular calcium and by serine phosphory-
lation. The release of arachidonic acid during
phagocytosis by cell lines appears to be regulated
by calcium-independent PLA2, and arachidonic
acid release as well as the onset of apoptosis
require cPLA2 or iPLA2 depending on whether
FAS or TNF-a are inducing apoptosis. Secretory
PLA2s also have a diversity of functions includ-
ing the production of lipid mediators such as
eicosanoids and lysophospholipids that contrib-
ute to the inflammatory process as well as tissue
repair and the removal of apoptotic cells. These
secretory PLA2 (sPLA2) enzymes are of low
molecular weight (14–18 vs. 85 kDa for cPLA2s),
require millimolar levels of calcium for their
activity, are cysteine rich, and are globular in
structure. This group of secretory PLA2s have
been detected at increased levels in some
inflammatory disorders and in the synovial fluid
of some inflammatory arthritides [232]. Secretory
PLA2-IIA, sPLA2-V, and sPLA2-X all have
a deliterious effect on pulmonary surfactant.
Group II phospholipase A2s also manifest potent
bacteriocidal properties via their degradation of
bacterial phospholipids. Despite the role of these
phospholipases in inflammatory reactions, few
investigations of these enzymes have been con-
ducted in patients with acute and resolving gout.
The design of specific inhibitors of these enzymes
may provide tools for regulating the acute
inflammatory response in gout. Furthermore, the
key role both cPLA2 and iPLA2 play in the
chemotaxis of monocytes to the monocyte
chemoattractant protein-1 emphasize the impor-
tance of these enzymes to the resolution of acute
gout [233]. Thus, phospholipase A2 activity not
only provides arachidonic acid for further metab-
olism to the potent chemoattractant, LTB4, but
also may play a key role in other proinflammatory
and anti-inflammatory responses essential for the
propagation and resolution of an acute gouty
episode.
Arachidonic acid released by PLA2 activity is
then converted to the unstable epoxide, LTA4 by
5-lipoxygenase with the help of 5-lipoxygenase-
activating protein (FLAP). 5-Lipoxygenase cata-
lyzes the hydroperoxidation of arachidonic acid
to form 5-(S)-hydroperoxy-6,8,11,14-eicosatet-
raenoic acid (5-HPETE) followed by a dehydrase
reaction to form the unstable epoxide, LTA4. It is
now clear that all the key enzymes in eicosanoid
biosynthesis (cPLA2, cyclooxygenase, and lipox-
ygenase) are translocated to the nuclear envelope
where eicosanoid biosynthesis occurs [234]. In
addition to these enzymes, the 18-kDa mem-
brane-bound protein, 5-lipoxygenase-activating
protein (FLAP), required for 5-lipoxygenase
activity and the in vivo formation of leukotrienes,
is also localized to the nuclear envelope. The lat-
ter site is where arachidonic acid metabolism
occurs. These studies demonstrate that FLAP
remains localized to the nucleus in polymorpho-
nuclear leukocytes, peripheral blood monocytes,
and alveolar macrophages, whereas the 5-lipoxy-
genase, cytosolic phospholipase A2, prostaglandin
PAF Receptor
endoperoxide H synthase, and prostacyclin syn-
thase require translocation to the nuclear enve-
lope for the synthesis of their metabolites in
activated cells. Investigations are now focused on
determining and characterizing the import and
export sequences that regulate the translocation
of these enzymes [235]. The identification of
these translocation signals, especially those con-
trolling import, might be useful if specific inhibi-
tors could be designed to abrogate their capacity
to translocate. Although the mechanisms remain
incompletely resolved, recent investigations have
demonstrated that cyclic AMP-elevating agents
and protein kinase A activators inhibit leukot-
riene biosynthesis and 5-lipoxygenase transloca-
tion in stimulated cells [236, 237]. Further studies
related to enzyme translocation and the subse-
quent synthesis of prostaglandins and leukot-
rienes may reveal ways in which the synthesis of
these inflammatory mediators can be downregu-
lated by therapeutic agents.
Interleukin-8 (IL-8)
Interleukin-8, proposed as the primary chemoat-
tractant in acute gout, is a 72-amino acid poly-
peptide with sulfide bridges between cysteines 7
and 34 and between cysteines 9 and 50. Its amino
acid sequence is quite different from the 74-amino
acid peptide that comprises the other peptide
chemoattractant, C5a. A comparison of these two
polypeptide sequences is shown below. Of course,
these polypeptide chemoattractants are not struc-
turally related in any way to the lipid chemoat-
tractants, LTB4 and PAF.
Amino Acid Structure of IL-8
Ser-Aia-Lys-Giu-Leu-Arg-Cys-Gin-
Cys-llelys-Thr-Tyr-Ser-Lys-Pro-
Phe-His-Pro-lysPhe-lle-Lys-Giu-
Leu-Arg-Val-lle-Giu-SerGly-Pro-
His-Cys-Aia-Asn-Thr-Glu-lle-lle
Vai-Lys-Leu-Ser-Asp-Giy-Arg-Giu-
Leu-Cys
Leu-Asp-Pro-Lys-Giu-Asn-Trp-Vai-Gin-Arg
Vai-Vai-Giu-Lys-Phe-Leu-Lys-Arg-
Aia-GiuAsn-Ser
235
Amino Acid Structure of CSa
Thr-Leu-Gin-Lys-Lys-lle-Giu-Giu-lle-Aia
Aia-Lys-Tyr-Lys-His-Ser-Vai-Vai-Lys-
LysCys-Cys-Tyr-Asp-Giy-Aia-Cys-
Vai-Asn-AsnAsp-Giu-Thr-Cys-Giu-
Gln-Arg-Aia-Aia-Arglle-Ser-Leu-
Giy-Pro-Arg-Cys-lle-Lys-AiaPhe-
Thr-Giu-Cys-Cys-Vai-Vai-Aia-Ser-
GinLeu-Arg-Aia-Asn-lle-Ser-His-
Lys-Asp-MetGln-Leu-Giy-Arg
Interleukin-8 is a member of the a- and
b-chemokine superfamily. The a-chemokine
family includes IL-8, GROa (growth-related
oncogene a), GROb, GROg, NAP-2 (neutrophil-
activating peptide-2), ENA-78 (epithelial cell-
derived neutrophil-activating peptide), GCP-2
(granulocyte chemotactic protein), PBP (plate-
let basic protein), CTAP-III (connective tissue
activating protein-Ill), and bTG (beta thrombo-
globulin). Some of these chemokines contain
a unique amino acid triad (glutamic acid-leucine-
arginine) at their amino terminus preceding the
first cysteine residue of the primary structure.
This amino acid sequence is visualized in bold
type in the amino acid structure shown above.
Chemokine receptors with this ELR (Giu-Leu-
Arg) motif induce the recruitment of human
neutrophils in vivo. There are seven human
chemokines with the ELR motif: interleukin-8,
growth-regulated oncogene a (GROa), growth-
regulated oncogene b (GROb), growth-regulated
oncogene g (GROg), neutrophil-activating pep-
tide-2 (NAP-2), epithelial cell-derived neutrophil-
activating peptide-78 (ENA-78), and granulocyte
chemoattractant protein-2 (GCP-2). This struc-
tural element termed the ELR motif indicates an
enhanced neutrophil binding capacity as well as
the capacity to induce neutrophil migration and
angiogenesis [237, 238]. Some a-chemokines
lack the ELR motif, and for this reason, they do
not attract mature neutrophils. Such non-neutro-
phil chemoattractants include platelet factor-4
(PF-4), interferon-gamma (IFN-g)-inducible pro-
tein-10 (IP-10), monokine induced by interferon-
gamma (MIG), stromal cell-derived factor-1
(SDF-1), and interferon-inducible T cell alpha
chemoattractant (I-TAC). All the alpha- and beta-
chemokines have conserved cysteines that form
236 8 Mechanisms of the Acute Attack of Gout and Its Resolution
disulfide bonds. The a-chemokines induce both
neutrophil activation and migration [239]. The
alpha-chemokines are 8- to 10-kDa proteins with
the positions of the first two cysteines separated
by an amino acid, and for this reason, they are
designated as CXC chemokines based on their
cysteine spacing [239]. In the beta-chemokines,
the conserved cysteines are adjacent to each other
and designated as CC chemokines. There are addi-
tional chemokines designated as C and CX3C,
but they have no relevance to this discussion. In
modern terminology, the following nomenclature
has been used for these ligands: GROa = CXCL1,
GR0b = CXCL2, GROg = CXCL3, ENA-
78 = CXCL5, GCP-2 = CXCL6, NAP-2 = CXCL7,
and IL-8 = CXCL8. Of some interest to this dis-
cussion are some of the CC chemokines that
relate to monocyte/macrophage activities such
as monocyte chemoattractant protein (MCP)-1,
and macrophage inflammatory protein (MIP)-a
and MIP-13. These ligands have been identified
by the following nomenclature: CCL2 = MCP-1,
CCL3 = MIP-1a, and CCL4 = MIP-1b.
The beta-chemokines attract monocytes as
well as eosinophils, basophils, and lymphocytes
and are potent inhibitors of angiogenesis. The
monocyte chemoattractants in the b-chemokine
family may have a role in the late phases of
the acute gouty episode. The CC or beta-
chemokines include the monocyte chemotactic
proteins (MCP-1, MCP-2, MCP-3, and MCP-4),
RANTES (regulated on activation normal T cell
expressed and secreted), HCC-1 (hemofiltrate
CC chemokine-1), eotaxin (eosinophil chemoat-
tractant), MIP-1a (macrophage inflammatory
protein-1a), MIP-1. MIP-1g, TARC (thymus-
and activation-related hemokine), 1–309, 6
chemokine (chemokine with six cysteines), MIP-
3b (macrophage inflammatory protein-3 ). MDC
(macrophage-derived hemokine), and MIP-3a/
LARC (liver- and activated-related chemokine)/
Exodus-1. In addition to their chemoattractant
capacity for monocytes, CC chemokines are also
chemotaxins for T cells, B cells, dendritic cells,
eosinophils, basophils, and natural killer cells.
None of the latter cells play a prominent part in
acute gout.
Cell Sources
Interleukin-8 continues to be the most widely
investigated alpha-chemokine and is a very
potent neutrophil chemoattractant. A variety of
cells can produce IL-8 including endothelial
cells, fibroblasts, monocytes, macrophages,
some epithelial cells, mitogen-stimulated T cells,
and neutrophils. Synovial type B fibroblast-like
cells can also synthesize IL-8, and the type A
synovial cell derived from monocytes may also
have the capacity to generate IL-8 as well since
it is derived from monocytes [240]. The diversity
of cells capable of IL-8 synthesis and release
(macrophages, neutrophils, fibroblasts, and
endothelial cells) provides a basis for speculat-
ing that one of the initial events in acute gout
may be the production of IL-8 by the interaction
between a monosodium urate crystal and one of
these cells in the synovium or synovial fluid. It
has also been shown that IL-8 occurs in a precur-
sor form containing 77 amino acids rather than
the mature, 72 amino acid form. Recent studies
have documented the cleavage of the 77 amino
acid form by human hepatic cathepsin L to form
the mature 72 amino acid form of IL-8 [241].
This converting enzyme is also the secretory
product of human fibroblasts, and the mature
IL-8 form is a much more potent chemoattrac-
tant then the 77 amino acid form. Animal studies
have employed 99mTc-labeled interleukin-8 to
detect pulmonary infections and colitis. Such
techniques may be useful in detecting hidden
sites of inflammation but lack the specificity for
differentiating bacterial versus crystal-induced
inflammation.
IL-8 Gene
The gene that codes for IL-8 has been mapped to
chromosome 4q12-21. It contains four exons and
three introns and has a structure similar to other
neutrophil chemoattractants like GRO and giP-10.
Both IL-1 and TNF, proinflammatory cytokines
present in inflamed joints, can induce the synthe-
sis of IL-8 mRNA. In addition to inducing IL-8
PAF Receptor
mRNA, IL-1 appears to result in a more stable
IL-8 mRNA than in its absence. An AU-rich
sequence in the IL-8 gene contributes to the post-
translational regulation of IL-8 and increased
quantities of these sequences in the 3¢-untrans-
lated regions of the gene result in lower levels of
IL-8 mRNA [242].
IL-8, MSU Crystals, and Gout
A body of in vitro and in vivo evidence exists to
document the role of MSU crystals in the pro-
duction of IL-8. Peripheral blood monocytes and
cultured synovial lining cells (fibroblast-like)
incubated in vitro with MSU crystals cause the
release of IL-8. The IL-8 release from MSU
crystal-stimulated synovial fibroblast-like cells
occurs in a dose- and time-dependent manner.
IL-8 has also been measured in synovial fluid
aspirates recovered from patients with acute gout
and compared with aspirates from those with
uncomplicated osteoarthritis. The latter speci-
mens showed no leukocytosis in contrast to those
aspirates from gouty subjects. Synovial fluid
gouty aspirates had mean IL-8 levels of 8.4 ng/
ml as compared to 1.5 ng/ml in the aspirates from
patients with osteoarthritis (p value = 0.006). The
role of IL-8 has also been confirmed in animal
models of MSU crystal-induced synovitis and
cytokine responses of synovial cells [243]. IL-8
has also been measured in the synovial fluid of
other inflammatory forms of synovitis reinforc-
ing its role in the generation of inflammatory
responses.
There are no data regarding the role of other
a-chemokine neutrophil chemoattractants such as
the ELR ± C-X-C chemokines other than IL-8 in
acute gouty arthritis. ENA-78 has been identified
in synovial tissues, but its role in gout has not
been determined. Other a-chemokine neutrophil
chemoattractants have been found in synovial
fluids and joint tissues from nongouty articular
disorders, but their role in gout remains undefined
[244]. There is some evidence from in vitro stud-
ies suggesting that the a-chemokines may have
a coordinated effect on neutrophil migration, may
237
substitute for IL-8 activities when its action is
blocked, and may have different potencies
depending on many factors.
The most acceptable mechanism for the
transendothelial emigration of neutrophils, if
not via fenestrae, is for these cells to migrate
between endothelial cells at the vascular-
endothelial (VE)-cadherin junctions. Both
in vivo and in vitro studies have demonstrated
that antibodies against VE-cadherin increased
neutrophil transmigration. Neutrophils also
have the capacity to degrade VE-cadherin and
13-catenin, major proteins of these cell junc-
tions. Furthermore, elastase inhibitors block
this degradation, and the presence of elastase
inhibitors such as a 1-proteinase inhibitor can
block the activity of neutrophil elastase. In addi-
tion, neutrophil oxygen metabolites can inacti-
vate this elastase inhibitor permitting elastase
to induce the proteolysis of VE-cadherin junc-
tions. More recent studies have shown that
neutrophil elastase is bound to the neutrophil
membrane and is catalytically active but resis-
tant to inhibition by circulating antiproteases.
Additional evidence also demonstrates that neu-
trophil migration is regulated by an endothelial
cell-dependent process causing the phospho-
rylation of myosin light chain kinase with the
resultant retraction of adjacent endothelial cells
and gap formation. These reactions are calcium-
and calmodulin-dependent processes and are
inhibited by calcium chelation or calmodulin
inhibition.
In normal human synovium, two adhesion
molecules that have a prominent role in the
early steps of the transendothelial migration of
neutrophils have been identified: selectins and
integrins. Both so-called E-selectin expressed on
endothelial cells and intercellular adhesion mol-
ecule (ICAM-1) have been localized to synovial
venules. E-selectin was a prominent component
of the superficial venules, whereas ICAM-1 had
a more prominent expression on large venules
located in the deeper layers of the synovium.
The biological role of these adhesion mole-
cules and others are discussed in greater detail
subsequently.
238 8 Mechanisms of the Acute Attack of Gout and Its Resolution
Adhesion Molecules
An Overview of Selectins and Integrins
The migration of neutrophils from the intravas-
cular space to the intrasynovial space is essential
for the development of the inflammatory response
associated with acute gouty arthritis. A complex
set of molecular interactions moderated by adhe-
sive proteins and leukocyte activation regulate
these initial events and the subsequent tight bind-
ing of neutrophils to the endothelium. The initial
step in this process is the tethering and rolling
of neutrophils along the surface of endothelial
cells lining the postcapillary venules. The selec-
tin family of cell adhesion molecules and their
glycoconjugated ligands initiates this rolling
and tethering process. E (endothelium)-selectin
(CD62E) is expressed on activated endothe-
lial cells, and P(platelet)-selectin (CD62P) is
expressed on platelets and endothelial cells.
L(leukocyte)-selectin (CD62L) is expressed on
most leukocytes. P-selectin resides in storage
granules (a-granules) in platelets and endothelial
cells (Weibei-Palade bodies) and are mobilized
to the cell surface by various secretagogues such
as thrombin, histamine, and others. E-selectin is
induced by inflammatory cytokines such as TNF-
a, IL-113. and others. L-selectin is constitutively
expressed on myeloid cells and lymphocytes, and
its main function is to participate in lymphocyte
recirculation and the migration of neutrophils
into inflamed tissue sites. The tethering of neu-
trophils to endothelial cell surfaces is regulated
by interactions between P-selectin, E-selectin,
and L-selectin and their respective ligands.
Neutrophils roll along the surface of endothe-
lial cells and recognize chemokines such as IL-8
on the endothelial cell surface. Recognition of
the chemokines, PAF, LTB 4 as well as selec-
tins and their ligands by the rolling neutrophil
triggers the activation of integrins, and binding
then occurs between leukocyte integrins and the
immunoglobin superfamily to cause firm attach-
ment of neutrophils to the endothelium [245].
This cascade of molecular events (tethering, roll-
ing, chemokine recognition, integrin activation,
and firm neutrophil-endothelium attachment)
provides the setting for neutrophil transmigration
to the inflammatory site.
Selectin Structures
The structure of all three selectins is similar.
Selectins function like lectins and bind to car-
bohydrate ligands. Each selectin molecule has
an NH2 extracellular terminus composed of
120 amino acids that is similar to a domain in
the C-type animallectins. This amino terminal
domain is linked to an amino acid sequence of
variable length (35–40 amino acids) that has been
designated as the epidermal growth factor (EGF)
domain due to its similarity to repeat sequences
in the EGF molecule. These EGF domains con-
tain six cysteines in positions comparable to
those in EGF. Attached to this EGF domain are
repetitive amino acid sequences (short consensus
repeats-SCRs) that resemble complement regula-
tory proteins and have been designated as com-
plement binding (CB) elements. These repetitive
elements in the CB domain are about 60 amino
acids long, and the number of CB domains varies
depending on the selectin. For example, human
L-selectin contains two such domains, whereas
human P-selectin has nine and E-selectin has
six such domains. The membrane region of each
selectin is anchored by a short transmembrane
domain linked to a short cytoplasmic tail. The
structure of the cytoplasmic tail varies depend-
ing on the selectin analyzed. The cytoplasmic
tail of human P-selectin contains 35 amino acids,
whereas E-selectin contains 32 amino acids, and
L-selectin contains only 17 amino acids. Each
selectin molecule has a separate binding part-
ner or ligand with the construct of a glycopro-
tein. With the exception of E-selectin ligand-1
(ESL-1), the ligand for E-selectin, the two other
selectin ligands are sialomucins or have a sialo-
mucin domain. E-selectin and P-selectin expres-
sion require activation of endothelial cells.
Therefore, in the absence of proinflammatory
mediators, adhesion molecules on the endothe-
lium are absent. The necessity for the induc-
tion of endothelial activation before interactions
between leukocytes and the blood vessel intima
Adhesion Molecules
protects the endothelium from attracting neutro-
phils in the absence of inflammation.
Ligands or binding partners for selectins are
carbohydrates that bind to the lectin domain of
the selectins. Lectin receptors are different from
the usual agonist-receptor recognition site since
they represent triads composed of a receptor,
a ligand, and a carrier. The ligands for selectins
are oligosaccharides, and the carriers are the scaf-
folding on which these oligosaccharides are
assembled and modified for their binding to the
lectin domains. The physiological ligands for the
selectins are glycoproteins with attached oligo-
saccharides that are subject to posttranslational
modifications.
P-Selectin Glycoprotein Ligand-1
P-selectin glycoprotein ligand-1(PSGL-1) is the
high affinity counterligand for P-selectin and is
the principle ligand for P-selectin on human neu-
trophils and other leukocytes including T cells.
PSGL-1 is a membrane polypeptide localized to
neutrophil surface microvilli containing a serine-
threonine-proline-rich extracellular domain, a
transmembrane domain, and a cytoplasmic tail.
Leukocytes express a homodimer of two identi-
cal 120 kDa subunits with a tyrosine sulfation
motif on the N-terminus of the extracellular
domain and a distal polypeptide with 15 deca-
meric sequence repeats. The serine and threonine
residues in the molecule are potential 0-glycosy-
lation sites generated by glucosaminyltransferase
enzymes. PSGL-1 like other selectin ligands is a
sialomucin and has been cloned from a human
HL-60 cell line. Even though L-selectin binding
occurs initially, it is short-lived and P-selectin
binding causes a slower rolling velocity and a
longer contact between neutrophils and endothe-
lial cells. Although sufficient evidence exists for
the demonstration of E-selectin binding to
PSGL-1, such interactions may be the result of
leukocyte-leukocyte effects and secondary to
tethering rather than a direct interaction between
E-selectin and PSGL-1.
The rolling of neutrophils is blocked by
monoclonal antibodies against epitopes on the
239
N-terminus of the PSGL-1 polypeptide. Further,
removing a short peptide (10 amino acids) from
the N-terminus of PSGL-1 disrupts the binding
between the ligand and P-selectin. Other key
components of PSGL-1 for binding to P-selectin
have been identified by site-directed mutagene-
sis of PSGL-1 or removal of the extracellular
domain of PSGL-1 enzymatically using 0-sia-
lylglycoprotease. Recent publications suggest
that PSGL-1 contributes significantly to neutro-
phil adhesions to vascular endothelium via all
three selectins. The identification of PSGL-1 as
a critical ligand for the tethering and rolling of
leukocytes for all three selectins has been char-
acterized only in mice, but the description of the
structural requirements of L-selectin binding to
neutrophils and their role in primary leukocyte-
endothelial interactions between circulating and
adherent leukocytes indicate that future prog-
ress will resolve the binding of ligands to their
selectins [246].
L-Selectin
L-selectin, present on the microvillus-like projec-
tions on the surface of leukocytes, is constitu-
tively expressed on myeloid cells, and the
tethering and rolling mediated by it is much more
rapid than that directed by P- and E-selectin. This
tethering and rolling function of selectins through
contact with their ligands is a major area of con-
tinuing investigation aimed at understanding the
physical and topographical forces required for
the association-dissociation reactions between
selectins and their ligands [247]. Since this inter-
action only slows the rolling of leukocytes, it is
clear that the bonds between selectins and their
counterligands must be only temporary and eas-
ily broken. For the most part, selectin ligands
have been characterized most completely in
murine cells, and it is unclear in every case what
the composition of the human homologues is.
Furthermore, little is known about the ligands for
selectins on the synovial membrane venules. The
principal ligands for L-selectin have been investi-
gated extensively in mice and humans in relation
to the homing of lymphocytes to the high endothelial
240 8 Mechanisms of the Acute Attack of Gout and Its Resolution
venules in peripheral lymph nodes [248]. The
most well-defined L-selectin ligands include
GlyCAM-1 (glycosylation-dependent cell adhe-
sion molecule-1), MadCAM-1 (mucosal addressin
cell adhesion molecule-1), podocalyxin-like pro-
tein, endoglycan, and Sgp 200 [249].
GlyCAM-1 is a transmembrane glycosylated
protein molecule with an 0-linked sugar and sia-
lyl groups. This molecule has been cloned from
human cells, has been localized to chromosome
12q13.2, and supports the rolling of lymphocytes
on endothelial cells [250]. Mucosal addressin cell
adhesion molecule-1, another L-selectin ligand,
has been primarily characterized in high endothe-
lial venules from lymph nodes. The human gene
for MadCAM-1 has been cloned and character-
ize.. It has been localized to chromosome 19 at
p13.3 near the genes for intercellular adhesion
molecule-1 and -3 that are ligands for integrins.
The gene has five exons, and each exon encodes
a separate domain of the complete molecule (sig-
nal peptide, two immunoglobin domains, and a
mucin domain). Exon five encodes the transmem-
brane domain, the cytoplasmic domain, and a
3¢-untranslated region. Little is known about the
other L-selectin ligands except for their role in
immune reactions. The complex structure to these
ligands for the selectins and their possible varia-
tions provides diversity for the recognition of dif-
ferent cells and mediating their capture by
endothelial cells.
Unique L-Selectin Properties
L-selectin is a somewhat unique member of the
selectin family of adhesion molecules since it has
two additional properties. It may cause shedding
of membrane L-selectin, and it also mediates sec-
ondary neutrophil capture. L-selectin mediates
the accumulation of neutrophils along the vascu-
lar endothelium in response to inflammation by
invoking both neutrophil-endothelium and neu-
trophil-neutrophil interactions. Perhaps of greater
significance to the cell adhesion process is that
neutrophil activation causes L-selectin shedding,
and this activity regulates leukocyte recruitment
[251]. Endothelial activation by inflammatory
mediators such as chemoattractants (IL-8, LTB4,
and C5a) and activating factors (tumor necro-
sis factor and granulocyte-macrophage colony
stimulating factor) also induces the shedding of
L-selectin from the neutrophil membranes. Most
of these activators have been identified in the
synovial fluid recovered from patients with acute
gouty arthritis. The transmembrane metallopro-
teinase, tumor necrosis factor TNF-a convert-
ing enzyme (TACE), is responsible for releasing
soluble TNF-a, L-selectin, transforming growth
factor-a, and TNF receptor from cells. TACE or
ADAM-17 (a disintegrin and metalloproteinase)
is a zinc metalloproteinase that is membrane-
associated and has an extracellular domain, a
transmembrane domain, and an intracellular
C-terminal domain. Blocking this receptor and
membrane-shedding process indicates the key
role played by TACE activity in the inflammatory
process. TACE inhibitors decrease the roll-
ing velocity of neutrophils, upregulate Mac-1,
increase binding to ICAM-1, and increase the
firm adhesion of neutrophils to endothelial cells
[252]. As a corollary, L-selectin shedding limits
neutrophil recruitment to inflammatory sites by
decreasing the functions noted to be altered by
TACE inhibitors. L-selectin shedding decreases
leukocyte binding and subsequent transmigra-
tion since it decreases signaling to rolling leuko-
cytes, decreases b2-integrin adhesive responses,
and alters the accessibility to endothelial activa-
tion signals [253]. Data show that calmodulin is
associated with L-selectin in resting leukocytes
and the dissociation of these molecules leads to
L-selectin shedding. Speculation suggests that
changes in intracellular calcium concentrations
and phosphorylation of L-selectin may trigger
this dissociation [254]. Of relevance to acute gout,
neutrophils shed L-selectin during their transend-
othelial migration into inflamed lung tissue, and
such studies suggest that L-selectin may also par-
ticipate in the transmigration of neutrophils into
the synovial joint space. Furthermore, painful
stimuli cause L-selectin shedding and reduce neu-
trophil migration into inflamed joints in a rat model
of arthritis. Increased concentrations of soluble
L-selectin also decrease inflammation(cytokine)-
mediated leukocyte adherence and vascular
Adhesion Molecules
leakage in vivo. These studies document the
key role L-selectin shedding plays in regulating
neutrophil emigration to sites of inflammation.
Furthermore, such data support the development
of pharmacologic agents that can act as selec-
tin antagonists or increase L-selectin shedding.
Some of the human genes for L-selectin ligands
have been cloned and characterized.
Since the cell membrane shedding process has
a key role in the regulation of cell interactions,
the role of the soluble mediators such as the non-
chemotactic cytokines and chemoattractants
deserves further discussion. Tumor necrosis fac-
tor-a and its receptor when shed are no longer
able to activate the expression of selectins and
integrins on cells and to promote the production
of PAF, IL-8, and ICAM-1. IL-1 is also able to
mediate some of these cell changes. The soluble
chemoattractant molecules, as noted previously,
have a key role in activating neutrophils and
endothelial cells and the subsequent expression
of adhesion molecules. Although there is
significant redundancy in the chemotactic agents
that may be active in regulating the migration of
neutrophils to sites of inflammation, the presen-
tation of activators and chemotaxins in their cor-
rect sequence is necessary for neutrophil
migration. For example, IL-8 and C5a can cause
desensitization of cells to their actions through
their own receptors, and they can also desensitize
cells to each other by acting through each other’s
receptors as well as through the PAF receptor.
Such functions document the complexity of
chemoattractant activity and the necessity for
concentration- and time-dependent regulation of
their actions and emphasize the regulation that
must exist between the sequence of neutrophil
and endothelial cell activation, the expression of
adhesion molecules, and the interactions between
various cell receptors. Such processes and their
regulation also suggest molecular mechanisms
for altering the recruitment of neutrophils and
interrupting the inflammatory process.
Before discussing the tight adhesion of neu-
trophils to endothelial cells mediated by cell
membrane integrins, the role of soluble adhesion
molecules as biomarkers and regulators of the
inflammatory process needs to be documented
241
since their measurement represents a noninvasive
means of defining what proinflammatory media-
tors are active in specific diseases and what stage
of the process is evolving. Evaluating such data
avoids direct, invasive assays of the synovial
membrane microvasculature.
Although few of the soluble cytokines have
been measured in acute gout, many of these
mediators have been assayed in articular disor-
ders. Since most of these cytokines are adhesion
molecules residing on cell surfaces, the mecha-
nisms by which they become circulating, soluble
mediators is of significance to the underlying
pathology as well as to the development of pos-
sible pharmacologic agents to alter the progression
of the process. For the most part, these soluble
adhesive molecules arise either by secretion or by
proteolytic action against these surface-expressed
molecules. In addition, some soluble adhesion
molecules arise from variations in mRNA splic-
ing that result in the synthesis of molecules with-
out a transmembrane domain. Other soluble
cytokines (E-selectin, VCAM-1, ICAM-1, and
ICAM-3) have a molecular size consistent with
the absence of transmembrane and cytoplasmic
domains, but they are also generated by prote-
olytic mechanisms. The most well-characterized
proteolytic shedding mechanism is the cleavage
of tumor necrosis factor-a by tumor necrosis fac-
tor-a converting enzyme (TACE/ADAM-17)
[255]. This metalloproteinase-disintegrin also
releases the tumor necrosis factor p75 receptor,
transforming growth factor, interleukin-1 recep-
tor, p55 tumor necrosis factor-a receptor, and
l-selectin. TACE is a membrane-anchored trans-
membrane protein that contains a proenzyme
domain, a catalytic domain (zinc-dependent met-
alloproteinase), a cysteine-rich sequence of 197
amino acids, a transmembrane domain, and a
cytoplasmic tail. Calmodulin appears to act as a
negative regulator of TACE activity [256]. The
latent TACE proenzyme can be activated to its
active form by oxidizing a cysteine residue in the
TACE inhibitory peptide that masks the zinc atom
in the catalytic domain [256]. Tumor necrosis
factor-a has been shown to induce the release of
its receptors and also triggers the release of reac-
tive oxygen species. Thus, TNF and reactive
242 8 Mechanisms of the Acute Attack of Gout and Its Resolution
oxygen species can activate TACE to release sol-
uble mediators. In addition, nitric oxide can also
activate this enzyme. Monosodium urate crystals
are potent stimuli for the generation of interleu-
kin-1 (IL-1) and TNF-a production by mono-
cytes and macrophages, and phagocytosis of
such crystals induces the generation of reactive
oxygen species [257]. Further, soluble TNF and
its receptors have been found in the serum and
synovial fluid of patients with inflammatory
forms of arthritis including gout. Although little
is known about the role of nitric oxide in gout,
this mediator has been documented as a modula-
tor of leukocyte transmigration in inflammatory
joint disorders.
The significance of either proinflammatory or
anti-inflammatory soluble mediators in an acute
inflammatory process such as gout has yet to be
completely characterized, but recent findings indi-
cate that these soluble cytokines are likely to have
an important role as regulators of inflammation.
For example, soluble TNF and its soluble recep-
tors may bind to each other and prevent excessive
TNF activity which might be harmful to the host.
The competition between cellular receptors for
TNF and soluble TNF receptors could prevent the
injurious effects of excessive TNF activities act-
ing via cellular receptors. The second significant
point regarding soluble cellular adhesion mole-
cules is the observation that such molecules may
have a different role as soluble agents in contrast
to their membrane bound actions. At this time,
only vascular adhesion molecule 1 (VCAM-1)
and E-selectin as soluble components have been
shown to express such variations. In case of both
these soluble adhesion molecules, monocyte
chemotaxis is one biological function generated
by these soluble mediators. Although monocyte
chemotaxis via this mechanism has only been
shown to occur with these soluble adhesion mol-
ecules isolated from the synovial fluid obtained
from patients with rheumatoid arthritis, a simi-
lar effect might also take place in the late stages
of acute gout when monocytes begin to appear
in the synovial fluid. The stimulation of mono-
cytes by soluble E-selectin demonstrated a time-
dependent increase in tyrosine phosphorylation
of cellular proteins via the Src kinases and the
mitogen-activated protein kinases (MAPK).
These findings also provide a basis for the devel-
opment of therapeutic agents designed to prevent
cellular receptor binding or to mimic/inhibit
biological functions generated by these soluble
adhesion molecules.
On the basis of the foregoing facts, it may be
reasonable to reexamine some of the other solu-
ble mediators found in synovial fluid to deter-
mine if there are any additional biological
functions performed by these molecules. In addi-
tion to the soluble adhesion molecules cited
above, intercellular adhesion molecule-1
(ICAM-1), vascular cellular adhesion molecule-1
(VCAM-1), soluble interleukin-6 (IL-6) receptor
as well as other mediators such as IL-6, IL-4,
IL-113, and IL-10 have been detected in synovial
fluid and serum from patients with inflammatory
arthritides [258]. Recent publications have also
documented the use of soluble cytokine receptors
as therapeutic agents and as regulators of joint
inflammation.
Another unique property of L-selectin is its
ability to mediate secondary capture of leuko-
cytes. Primary capture in this setting refers to the
initial rolling of leukocytes along endothelium,
whereas secondary capture defines a process
where freely flowing leukocytes interact with
rolling leukocytes and subsequently attach to the
endothelium. The ligand for L-selectin in this
leukocyte-leukocyte interaction is P-selectin gly-
coprotein ligand-1. Although primary leukocyte
capture is the predominant mechanism causing
leukocyte rolling, a low rate of secondary capture
does occur in venules.
E-Selectin
The major ligand for E-selectin is E-selectin
ligand-1 (ESL-1). E-selectin like P-selectin is
expressed on activated endothelial cells. ESL-1
binding to E-selectin requires N-glycans [259].
ESL-1 has been cloned and characterized from
mice. A protein designated as MG160 has been
isolated and cloned from the Golgi apparatus
and is homologous to fibroblast growth factor
and the E-selectin ligand, ESL-1. Mouse ESL-1
Adhesion Molecules
has also been localized to the Golgi apparatus,
and its role in this cell organelle is incompletely
understood. In addition to E-selectin, L-selectin
has been proposed as an E-selectin counterrecep-
tor as has P-selectin glycoprotein ligand-1[260].
As noted previously, the selectin-mediated bind-
ing to selectin ligands results in the tethering and
rolling of neutrophils along the endothelium.
Such initial interactions between neutrophils
and endothelium result in weak and reversible
recognition of selectin ligands. The transition
from neutrophil rolling to firm adhesion to the
endothelium is mediated by a change from selec-
tin-dependent adhesion to CD18 [132]-integrin-
dependent firm adhesion between neutrophils
and the endothelium.
Integrins
After the selectins initiate neutrophil tethering,
firm adhesion of these cells to the endothelium
is mediated by integrins. Integrin is a term origi-
nally coined to describe membrane receptors that
integrate the extracellular matrix or cells with
the intracellular cytoskeleton. Since this original
terminology was defined, integrin functions have
been extended to include cell differentiation,
motility, growth, and cell polarity. Of significance
to acute gouty arthritis is the fact that this glyco-
protein family regulates neutrophil trafficking.
The principal interest in integrins as they relate
to the inflammatory response is their capacity
both to cause firm adhesion of neutrophils to the
endothelium in preparation for their migration
from the blood vessel to the inflammatory site
but also to transduce messages regulating neutro-
phil shape and ligand binding affinity. The rate
at which cells migrate depends on the integrin
levels of expression induced by the inflammatory
mediators that cause the transport of b2-integrins
from the peroxidase negative granules of neu-
trophils and monocytes to the cell surface. The
substratum ligand levels for integrins and integ-
rin-binding affinities also contribute significantly
to the rate of cell migration. All integrins consist
of one alpha subunit and one beta subunit, and as
such, they are heterodimers.
243
Integrins are transmembrane glycoprotein
receptors that mediate cell-matrix or cell-cell
adhesion. They are heterodimers consisting of an
a and b subunit in a 1:1 stoichiometric ratio which
are bound noncovalently to each other. In 2000,
19 known a subunits and 8b subunits were
reported in mammals, and these subunits can
form at least 25 ab heterodimers. Since this dis-
cussion focuses primarily on neutrophils the
emphasis is on b1, b2, and b3 integrins that are
expressed by these cells [261]. The b2 integrin
subunit is the key structure regulating neutrophil
binding to endothelium, and the trivial names for
these integrin subunits are Mac-1 (macrophage
antigen-1), LFA-1 (lymphocyte-function-associ-
ated antigen-1), and GP150,95. The common
designations for these molecules are aMb2
(Mac-1), aL b2 (LFA-1), and axb2 (GP150,95),
and the CD nomenclature is as follows: CD11a
(aL). CD11b (aM), CD11c (ax), and CD18 (b2).
The human a subunits have been localized in
a cluster on chromosome 16p13.1-p11. The
human gene for the b2 subunit has been localized
to chromosome 21q22.3 [262].
Integrin Structure
The structure of the human b2 chain (Mr of
95,000) and the alpha subunits (aL, aM, and ax)
have all been determined. The a subunits vary in
their molecular weight with human aL having a
Mr of 177,000, aM with an Mr of 165,000, and ax
with an Mr of 150,000. Although alpha-4 beta-1
integrin has been documented as a functional inte-
grin on murine and rodent neutrophils as well as
on human neutrophils treated with LTB4, C5a, or
TNF-a, its presence on human neutrophils is con-
troversial because the antibody utilized to identify
this integrin on human neutrophils is nonspecific.
The a subunit contains at its extracellular
N-terminus a seven blade 13-propeller structure
attached to a b barrel or four to six 13-sandwich
domains and an I domain between the second and
third propeller blades. The cytoplasmic tail of the
a subunits contains a GFFKR peptide sequence
(glycine-phenylalanine-phenylalanine-lysine-
arginine) and a phosphorylation site. Models of
244 8 Mechanisms of the Acute Attack of Gout and Its Resolution
these structural elements have been constructed.
The b2 subunits also contain an 1-like domain
near their N-terminus and a cysteine-rich peptide
in their extracellular domain. A phosphorylation
site is also present on their intracellular cyto-
plasmic tail. The configuration of these al3 het-
erodimers changes in response to ligand binding
as has been characterized by binding studies and
in models of such binding sites [263]. Structure-
function studies of specific al3 heterodimers
are ongoing, but several conclusions have been
drawn from published analyses. First, the domain
of the b2 subunit is the primary element involved
in ligand binding via their metal ion-dependent
adhesion site (MIDAS) motifs [264]. Second, the
divalent cation binding sites on the ab heterodi-
mers have a critical role in ligand binding, and
these sites may either promote or inhibit ligand
binding [265, 266]. Finally, the molecular varia-
tions in the integrins may be increased by changes
in gene splicing, posttranslational modifications,
and molecular alterations induced by reactions
with other cells or intracellular molecules.
The complete molecular characterization of
neutrophil firm adhesion remains to be defined,
but many of the component, parts of this complex
series of steps that mediate the transmigration of
neutrophils are understood. The selectin-medi-
ated tethering of leukocytes places these cells in
a setting in which neutrophils are activated to
express the b2 integrins, Mac-1 and LFA-1. The
sequence of events responsible for generating
firm adhesion to post-capillary venules includes
the activation of neutrophils to mobilize and clus-
ter ab heterodimers (Mac-1 and LFA-1) adhesive
molecules on neutrophil membrane and a subse-
quent change in the conformation of these mem-
brane-expressed molecules to increase their
avidity for their opposing ligand, intercellular
adhesion molecule-1 (ICAM-1). The latter adhe-
sion molecule is an immunoglobin-like molecule
whose expression on endothelial cells is mark-
edly increased by inflammatory cytokines. The
loose adhesion of neutrophils to endothelial cells
by reversible bonds between the selectins and
their counterligands does not require neutrophil
activation. In contrast to selectin-mediated teth-
ering, tight adhesion to the endothelium mediated
by b2 integrins requires signaling and activation
of neutrophils. A variety of complement peptides
(principally C5a), chemokines (primarily IL-8),
lipid factors, and other inflammatory mediators
such as IL-1, GM-CSF, PAF, and TNF-a can
serve as activators of neutrophils. The process of
activating neutrophils involves a complex series
of cell and mediator interactions that lead to neu-
trophil activation and adhesion. Interleukin-1 and
tumor necrosis factor activate endothelial cells.
These activated endothelial cells then produce
PAF in response to the aforementioned mediators
as well as granulocyte-macrophage colony-stim-
ulating factor (GM-CSF), IL-1, and IL-8. These
molecules (IL-1, PAF, GM-CSF, and IL-8) then
activate neutrophils and leukocyte adhesion. IL-1
and TNF activate endothelial cells to produce
mediators such as GM-CSF, IL-1, PAF, and IL-8
that in turn activate neutrophils.
Neutrophil activation by the foregoing media-
tors causes neutrophil degranulation and the
translocation of receptors for adhesion molecules
on the endothelium as well as enzymes from
specific intracellular neutrophil granules to the
cell surface [267]. Integrins are rapidly mobilized
by the degranulation step from secondary and
tertiary granules of neutrophils and are expressed
at seven to tenfold greater levels on the cell sur-
face than they are in the quiescent neutrophil.
The neutrophil compartments that store pre-
formed integrins (Mac-1 and LFA-1) include
secretory vesicles, specific granules, and
gelatinase-containing granules [268]. Recently,
increased ceramide levels in neutrophils have
been shown to induce cells to degranulate and to
increase the expression of integrins on the neu-
trophil plasma membrane [269]. Thus, TNF and
chemoattractants cause neutrophil degranulation
and translocation of the b2 integrins to the neu-
trophil plasma membrane, and the function of
these molecules remains quiescent until integrins
are activated by intracellular and extracellular
signals that cause a conformational alteration in
the molecule to expose its ligand binding sites.
There are several factors that enhance the binding
of integrins to their counterligands including a lipid
molecule given the name, integrin-modulating
factor and a cytoplasmic protein, cytohesin-1
Adhesion Molecules
[270]. These enhancing molecules and other
mediators developed by so-called outside-in cell
signaling pathways are responsible for the b2
integrin avidity for. its counterligand and for
spreading of the neutrophil on the endothelial
cell surface in preparation for its transmigration.
Such changes are mediated by interactions
between neutrophil integrins and the cell’s
cytoskeleton [271].
Ligands for Integrins
Tight adhesions between endothelial cells and
neutrophils are dependent on the binding of these
neutrophil integrins with their ligands. The prin-
ciple ligands for LFA-1 and Mac-1 are the
endothelial ligands designated as intercellular
adhesion molecules (ICAMs). These ICAMs
belong to the immunoglobulin gene superfamily
(lgSF). ICAM-1 (CD54) contains five extracel-
lular immunoglobulin domains, a hydrophobic
transmembrane domain, and a short cytoplasmic
tail at its C terminal end. ICAM-2 (CD102) has a
structure similar to ICAM-1 except that it con-
tains only two extracellular immunoglobulin
domains in contrast to the five in ICAM-1.
ICAM-3 is another member of the immunoglob-
ulin gene superfamily with a structure similar to
ICAM-1 since it has five extracellular immuno-
globulin domains. TNF, IL-1 and other mediators
markedly increase the expression of ICAM-1
during inflammatory states. Another related mol-
ecule, vascular cell adhesion molecule-1 (VCAM-
1) is an inducible endothelial cell immunoglobulin
superfamily member and an effective ligand for
integrin a9b1. VCAM-1 interaction with a9b1 inte-
grin supports the adhesion of neutrophils to TNF-
a-activated endothelial cells. However, the
primary role of this cell surface glycop-
rotein(VCAM-1) is to mediate the adhesion of
monocytes and lymphocytes to cytokine-acti-
vated endothelial cells. Vascular cell adhesion
molecule-1 is a cell surface glycoprotein contain-
ing 9 exons and spanning approximately 25 kb of
DNA and a binding site domain 1. Integrin aLb2
binds to domain 1 of the ICAM-1 molecule, and
integrin aMb2 binds to domain 3 of ICAM-1
245
[272]. ICAM-3 has now been recognized as the
preferred counterligand for leukocyte aLb2 integ-
rin and is found on the surface of neutrophils as
well [273]. ICAM-3 binding occurs in the region
where aLb2 integrin causes neutrophil aggrega-
tion and induces changes in the neutrophil
cytoskeleton to enhance adhesion. After these
interactions between Mac-1, LFA-1, and integ-
rins, neutrophils are tightly adherent to venule
endothelial cells and ready for their migration
through the venule wall to the inflammatory site.
The genes for ICAM-1, ICAM-2, and ICAM-3
have been mapped to chromosome 19p13.3-
p13.2, chromosome 17q23-25, and chromosome
19p13.3-p13.2, respectively. The gene for
VCAM-1 has been mapped to chromosome
1p32-p31.
The selectin family of adhesion molecules
regulates the initial step of the interaction between
neutrophils and endothelium, and the second step
culminating in the firm arrest of neutrophils
requires interactions between neutrophil integrins
and the endothelial immunoglobulin superfamily.
Inflammatory mediators including chemoattrac-
tants and TNF-a stimulate an increase in b2 inte-
grins on the surface of the neutrophil. Two types
of adhesion occur via b2 integrins. One type
involves the recruitment of neutrophils from the
flowing blood stream to neutrophils already bound
to the endothelium of the vessel wall [274]. These
neutrophil-neutrophil interactions have been
called neutrophil homotypic adhesions, and they
are dependent upon interactions between LFA-1
(CD11a/CD18) and intercellular adhesion mole-
cute-3. ICAM-3 is expressed at high concentra-
tions on the surface of neutrophils, monocytes,
and lymphocytes, and this molecule differs
significantly in its transmembrane and cytoplas-
mic domains from ICAM-1 and ICAM-2.
ICAM-3 is also a counterreceptor for the recently
characterized aDb2 integrin. ICAM-3 expression
on neutrophils exceeds the expression of ICAM-1
and can activate neutrophils to a proadhesive
state in the absence of stimuli to recruit b2 inte-
grins from intracellular storage sites. Activation
of neutrophils via ICAM-3 causes a reorganiza-
tion of the neutrophil cytoskeleton and the syn-
thesis and secretion of chemokines (IL-8). Such
246 8 Mechanisms of the Acute Attack of Gout and Its Resolution
neutrophil-neutrophil-mediated interactions along
with IL-8 secretion amplify the recruitment of
neutrophils and the magnitude of the inflammatory
response. Furthermore, the binding between
LFA-1 and ICAM-3 is much weaker than the
binding between LFA-1 and ICAM-1, and such
differences may favor neutrophil-endothelial cell
interactions. Interleukin-8-stimulated neutrophils
cause a redistribution of ICAM-3 and moesin, a
molecule linking plasma membrane proteins and
actin cytoskeleton, to the distal portion of neutro-
phil uropods (a projection of the neutrophil in the
rear of the migrating cell). Thus, ICAM-3 may
play a key role in the recruitment and amplification
of the migration of neutrophils to an inflamed site.
The ligand, vascular cell adhesion molecule-1
(VCAM-1), has also been identified on human
endothelial cells and is induced by TNF-a and
IL-1, inflammatory mediators present in acute
gout [275]. Integrins a4b1and a9b1 on neutrophils
bind to this endothelial ligand. These integrins
and their endothelial ligand, VCAM-1, represent
a b2-integrin independent neutrophil adhesion
mechanism that can contribute to neutrophil-en-
dothelial cell adhesion and neutrophil transmi-
gration through the endothelium. This pathway
may be of significance to an arthritic disorder like
gout since neutrophils expressing a4-integrin
have been identified in rats with adjuvant arthri-
tis. The complete role of VCAM-1 and the b1-
integrins in human articular inflammatory
conditions remains to be determined.
The second type of adhesion occurring via the
b2-integrins involves interactions between LFA-1
(aLb2) and Mac-1 (aMb2) integrins and their ligands,
ICAM-1 and ICAM-2 [276]. Chemoattractants
like LTB4 and IL-8 activate b2 integrins (CD11a/
CD18 and CD11b/CD18) and result in the sequen-
tial binding of these integrins to ICAM-1 and
ICAM-2 on endothelial cells. LFA-1 is involved
primarily in the capture of neutrophils and the
establishment of sustained contact of neutrophils
with endothelium. Subsequently, Mac-1 interac-
tion with ICAM-1 and ICAM-2 causes the stable
adhesion of neutrophils to the endothelium. The
chemoattractants, IL-8 and LTB4, induce optimal
rates of LFA-1-dependent adhesion at subnano-
molar concentrations. Furthermore, LFA-1 adhe-
sions to endothelium are brief and begin to decay
after 1 min in experimental systems, whereas
Mac-1 adhesions are more sustained. In this
experimental system, Mac-1 translocates to the
uropod, whereas LFA-1 remains bound to lamel-
lipodal regions. In TNF-a-activated endothelial
cells, Mac-1 accumulates at the region of contact
between the neutrophil and the endothelial cell,
and as the neutrophil spreads on the endothelial
cell, Mac-1 translocates to the leading edge of
the neutrophil. Thus, Mac-1 moves from the con-
tact area between neutrophil and endothelial cell
to the leading edge of the migrating neutrophil
as it moves to make its way across the endothe-
lium. The LFA-1 affinity for endothelial ligands
is normally induced by allosteric activation of
CD18 and amplified by chemotactic signals.
Phosphatidylinositol 3-kinase activity is a key to
the mobility of active CD18 and the formation of
high avidity patches of CD18. During the change
from inactive binding to an active ligand-binding
state, integrins cluster and alter their conforma-
tion. As can be determined by these changes in
neutrophil-endothelial binding both inside-out
signaling and outside-in signaling are required
for optimal binding. Chemoattractants activate b2
integrins. This b2 integrin activation and ligand
binding is mediated by inside-out signaling. Once
ligand occupancy occurs then signal transduction
into the cell takes place via outside-in signaling.
The latter process governs endothelial gap for-
mation and increased endothelial permeability,
and the transmembrane signaling by neutrophils
causes an elevation of endothelial cell free cal-
cium, a rearrangement of their actin filaments,
a conformational change in their cytoskeleton,
endothelial cell contraction, and gap formation
[277]. Vascular permeability factor/vascular
endothelial cell growth factor (VPFNEGF) and
its generation by neutrophils is a key mediator
of inflammation and neutrophil transmigration.
This permeability factor promotes the produc-
tion of fenestrations that are known to exist in
the capillaries of the synovium. VEGF, present
in the specific granule fraction of neutrophils,
is secreted by human neutrophils stimulated by
TNF-a [278]. The permeability of endothelial
cells is associated with changes in the endothe-
lial cytoskeleton. Such changes are calcium-
dependent and lead to endothelial cell contraction
Oxygen Radical Generation
and intercellular gap formation Tyrosine kinase is
required for the changes in cell shape accompa-
nying the formation of gaps, the reorganization
of actin filaments, and the formation of F actin
are likely to participate in these changes in cell
shape.
Since the absence of the cytoplasmic domain
of ICAM-1 inhibits neutrophil transmigration
but adhesion remains intact, signals generated by
ICAM-1 are of importance to neutrophil migra-
tion. Furthermore, the migration of neutrophils on
the surface of endothelial cells towards endothe-
lial junctions is inhibited by the presence of p38
mitogen-activated protein kinase inhibitors. These
inhibitors also block endothelial cytoskeleton
changes and stiffening of these cells. The means
by which ICAM-1 ligation mediates signals to the
endothelial cell is not fully understood, but some
aspects are known. ICAM-1 is associated with
an actin-binding protein, a-actinin. The cyto-
plasmic domain of ICAM-1 can bind phosphati-
dylinositol 4,5-bisphosphate and ezrin/radixin/
moesin proteins. Finally, neutrophil adhesion
induces increments in endothelial cell calcium,
and chelation of such calcium increments in the
endothelial cell does not alter neutrophil adhe-
sion but inhibits neutrophil transmigration across
endothelial cells [279]. Future investigations will
identify more fully the endothelial cell signaling
pathways and their specific role in the functions
related to neutrophil migration.
One final principal regarding the function of
integrins has significance to their role in neutro-
phil transmigration as well as the identification
of possible therapeutic targets to impede
inflammatory reactions. In addition to their
capacity to mediate cell migration in response to
tissue injury, integrins also act as signal transmit-
ters capable of transducing information in both
directions across the plasma membrane of cells.
These bidirectional message transduction routes
have been characterized as outside-in or inside-
out signaling. The outside-in pathway appears to
control the cell shape of the neutrophil and other
cytoskeletal alterations as well as triggering the
synthesis of different biochemical mediators to
signal these changes. Prominent effectors of out-
side-in signaling include tyrosine kinases, phos-
phatidylinositol 3-kinase, and mitogen-activated
247
protein kinase (MAPK). Inside-out signaling or
the integrin activation pathway regulates ligand
binding and may increase the affinity or avidity
of the receptor for its ligand. Such complex sig-
naling pathways mediated by leukocyte integrins
have been reviewed in recent publications, but the
complete picture of integrin signaling remains an
area of active research. The significance of these
integrin signaling functions has been demon-
strated through the use of antagonists and mono-
clonal antibodies against integrin molecules,
and such studies have documented a variety of
functional defects in cells treated with these inte-
grin modifiers. The goal of investigations using
integrin antagonists is to develop therapeutic
agents that could modify the inflammatory reac-
tion and its progress by altering the transmigra-
tion of inflammatory cells. Since the pathological
changes induced by urate crystals are in some
part repaired by inflammatory responses in the
tissues, the dose of therapeutic integrin antago-
nists would have to be carefully adjusted to
maintain tissue repair while still modifying the
inflammatory response.
In conclusion, several regulators of neutrophil-
endothelial cell adhesion have a significant role
in the modulation of neutrophil migration. There
are some observations in mouse mutants deficient
in adhesive molecules that b2 integrins and selec-
tins collaborate to produce the ideal conditions
for firm adhesion of neutrophils to endothelial
cells. In mice with a deficiency of CD18, leuko-
cyte rolling velocities are significantly increased,
and such data support a role for CD18 in the
regulation of leukocyte rolling velocity [280–
282]. Thus, in murine species, b2 integrins may
decrease leukocyte rolling velocities before leu-
kocytes rolling on endothelial cells establish firm
adhesions.
Oxygen Radical Generation
NADPH oxidase and the generation of reactive
oxygen radicals During phagocytosis by neutro-
phils, there is a burst of oxygen consumption.
This burst of oxygen consumption is related to
the generation of oxygen radicals by the enzyme
complex, NADPH oxidase and the resultant
248 8 Mechanisms of the Acute Attack of Gout and Its Resolution
superoxide ( O -2 ) production via this enzyme
which is necessary for the destruction of a vari-
ety of microorganisms. The significance of this
enzyme’s activity is documented by the suscep-
tibility of patients with chronic granulomatous
disease to infections because their NADPH
oxidase is inactive. Since oxidants generated
by NADPH oxidase may also induce damage
to nearby tissues, its ·enzyme activity must be
tightly regulated to avoid such damage. In fact,
the translocation of the enzyme’s components
and its activation prior to the closure of the pha-
gosome may account for the local production of
oxidants capable of causing local tissue destruc-
tion. Further, when neutrophils attempt to ingest
an antibody- or complement-coated surface too
large to phagocytose, reactive oxygen species
may be released in a process known as frustrated
phagocytosis. These oxygen-derived molecules
can amplify Fey receptor signaling and thereby
increase the phagocytic capacity of the neutro-
phil. Furthermore, an imbalance between pro-
tein tyrosine phosphatase (CD45) and protein
tyrosine kinase in favor of decreased phospho-
rylation causes a decrease in calcium mobiliza-
tion, the respiratory burst, and phagolysosome
degranulation. Evidence suggests that the imbal-
ance between tyrosine kinases and tyrosine phos-
phatases is, in part, created by oxidant-mediated
inactivation of tyrosine phosphatases. The mech-
anism by which oxidants inactivate tyrosine
phosphatase activity appears to be via cysteine
residues in the catalytic site of the enzyme. Thus,
reactive oxygen intermediates, especially hydro-
gen peroxide, amplify FcgR-mediated phago-
cytosis in both neutrophils and monocytes by
increasing receptor-mediated tyrosine phospho-
rylation of FcgR-Iinked ITAMs.
To avoid the generation of oxygen radicals in
resting neutrophils, the components necessary
for neutrophil activation and the generation of
oxygen radicals are localized in separate subcel-
lular compartments. The p40phox, p47phox, and
p67phox occur in the cytosol of neutrophils as
a complex, and p22phox and gp91phox are localized
to the membranes of secretory vesicles and
specific granules. The following equations repre-
sent the biochemical mechanisms by which
superoxide and hydrogen peroxide are produced
from the NADPH oxidase complex residing on
the plasma and phagolysosomal membranes and
using NADPH as an electron donor.
2O 2 + NADPH ® O -2 + NADP + + H +
Most of the superoxide produced by this
membrane-localized reaction reacts with itself by
a dismutation reaction in a spontaneous manner
to form hydrogen peroxide. As diagramed below,
this dismutation reaction is catalyzed by the
enzyme, superoxide dismutase.
2O -2 + 2H + ® H 2 O 2
In addition to these oxidants, a variety of other
superoxide-dependent reactive oxygen species
may also be produced including singlet oxygen,
hydroxyl radical, hypochlorous acid, chloramine,
nitric oxide, and peroxynitrite.
Under quiescent circumstances in neutrophils,
the enzyme complex is dormant and its compo-
nent parts are stored in different cellular compart-
ments to maintain their inactivity. Six oxidase
subunits are necessary to construct the complete
enzyme, and they are designated by their appar-
ent molecular mass in kilodaltons. The term phox
is an eponym for phagocyte oxidase and is also
used to designate these component parts. The
membrane-localized components are made up of
a b-type cytochrome constructed as a heterodi-
mer containing a 91 kDa glycosylated protein
(g91-phox) and a nonglycosylated 22 kDa sub-
unit (p22-phox). The cytoplasmic components
consist of p47-phox, p40-phox, p67-phox, and
the low molecular weight GTPase, Rac1 or Rac2
[283]. The p47-phox, p67-phox, and p40-phox
exist as a complex in neutrophil cytoplasm [284].
The gene for p47-phox has been localized to
chromosome 7q11.23, and the gene for p67-phox
has been mapped to chromosome 1q25. The gene
for the membrane-localized gp91-phox is located
on the x chromosome at p21.1, and the gene for
p22-phox has been mapped to chromosome
16q24.
The component essential for electron trans-
port from cytoplasmic NADPH to oxygen is
Oxygen Radical Generation
gp91-phox, and the other membrane subunit,
p22-phox, is a regulatory molecule necessary for
the activation· of the oxidase and the recruitment
of other cytosolic subunits. The gp91-phox sub-
unit contains a NADPH binding site, a noncova-
lently bound flavin adenine dinucleotide (FAD),
and two non-identical heme groups integrated by
two histidine residues. A variety of soluble and
particulate material can stimulate the assembly
and activation of NADPH oxidase in phagocytic
cells including chemokines, opsonized microor-
ganisms, arachidonic acid metabolites, and cal-
cium. The assembly of a functional NADPH
oxidase and its activation include a variety of sig-
nal transductions induced by membrane receptor
binding as well as the signals and changes neces-
sary for NADPH oxidase assembly. Receptor
binding triggers the generation of two significant
second messengers, diacylglycerol and inositol
1,4,5-triphosphate. These phospholipid deriva-
tives cause the release of calcium from its intrac-
ellular stores and activate protein kinase C. This
enzyme along with tyrosine kinases, serine
kinases, threonine kinases and mitogen-activated
kinases may all change the phosphorylation of
neutrophil proteins. Guanine nucleotide-binding
proteins as well as GTPases are also involved in
the regulation of phagocytosis.
NADPH Oxidase Assembly
The key to the assembly of an active NADPH
oxidase resides in the cytoplasmic p47-phox.
Exposure of neutrophils to a wide variety of stim-
uli leads to the translocation and integration of
the cytosolic subunits with the membrane sub-
units of NADPH oxidase [285]. P47-phox is
inhibited in resting cells through the intramolecu-
lar binding of two SH3 groups in the N-terminal
portion of a polybasic sequence of the C-terminus
of this molecule. Protein kinase C, Akt, or MAP
kinases can phosphorylate this region of the intra-
molecular binding, block the autoinhibition of
the molecule, and open binding sites in the
exposed N-terminal SH3 domains for interaction
with the proline-rich domain of membrane-local-
ized p22-phox [286]. This interaction of p47-
249
phox, of course, links these molecules with
cytochrome b558. Phosphatidylinositol kinases
and phosphatases are required or membrane
localization of the cytoplasmic PHOX constitu-
ents. The conformational changes in the p47-
phox upon activation also lead to the interaction
between the phox homology (PX) domain of
p47-phox and the activated PI3K [287]. P47-
phox binds predominantly to phosphatidylinosi-
tol 3,4-bisphosphate. The present suggestion is
that these interactions lead to membrane localiza-
tion of p47-phox. It is clear that the cytosolic pro-
teins, p47-phox and p67-phox form a complex
with p40-phox in the cytoplasm of the neutrophil.
Phosphorylation of p47-phox at a critical serine
residue assists in the formation of a p47-phox,
p40-phox, and p67-phox complex. The other crit-
ical component for the formation of active
NADPH oxidase is Rac2. Stimulation by the ini-
tiation of phagocytosis leads to the dissociation
of the RhoGTPase, Rac2, from its inhibitor
RhoGDI, and Rac2 then interacts with the cell
membrane via its prenylated C-terminus. The
binding of Rac2 to the membrane-localized
flavocytochrome b558 forms a binding site for
p67-phox. P67-phox also contains a so-called
activation domain in residues 187–210 that inter-
acts with gp91-phox and regulates the electron
flow from NADPH to FAD [288]. The role of the
cytoplasmic components of NADPH oxidase in
the final construct is incompletely resolved, but
p40-phox increases the affinity of p47-phox for
cytochrome in in vitro systems. In any event, the
p40-phox SH3 domain interacts with the proline-
rich domain of p47-phox and its PC domain
interacts with the PDI domain of p67-phox. The
p40-phox is not necessary for NADPH oxidase
activity when the components are reconstituted
in vitro, and genetically altered p40-phox does
not lead to chronic granulomatous disease. Rac2
is essential for reconstituted NADPH oxidase
activity in vitro and in vivo. Rac translocates to
the cell membrane independent of p47-phox,
p67-phox, p40-phox, and gp91-phox. All these
subcomponents of NADPH oxidase and their
functions are the subject of recent reviews, and
additional details can be acquired from this pub-
lication [289, 290].
250 8 Mechanisms of the Acute Attack of Gout and Its Resolution
As can be inferred from the foregoing discus-
sion, NADPH oxidase is found on the surface of
the cell’s plasma membrane but when phagocyto-
sis occurs, the cell’s external plasma membrane
becomes shifted to the internal portion of the
phagosome via membrane invagination and can
release its oxidants directly on the ingested for-
eign body. In the resting neutrophil, a small por-
tion of the oxidase (10 %) is localized at the
plasma membrane and remainder (90 %) is local-
ized in the secretory vesicles and specific gran-
ules. In contrast to the neutrophil, NADPH
oxidase resides exclusively on the cell plasma
membrane in the macrophage.
Oxidants and Oxidant-Mediated
Destructive Responses
Since this discussion is concerned with the inges-
tion and destruction of uric acid crystals and at
times, a complicating infectious organism, a more
complete discussion of reactive oxygen species
and oxygen-independent mechanisms of micro-
bicidal activity is warranted. Some of the oxi-
dants suspected of causing oxidation are either
unlikely to have a major role as oxidants or may
be very short-lived and difficult to detect. The
most prominent oxidants produced by neutro-
phils is superoxide, and most of the oxygen con-
sumed by the oxygen burst of phagocytes ends up
as hydrogen peroxide.
When two superoxide molecules interact with
each other spontaneous dismutation occurs. One
superoxide molecule is oxidized, and the other
reduced with the resultant formation of oxygen
and hydrogen peroxide. This reaction occurs pre-
dominantly at pHs of less than 5.0, but as the pH
rises, the reaction to form hydrogen peroxide is
more dependent on superoxide dismutase. The
latter enzyme may be provided by ingested
microorganisms. Phagosomal pH is also regu-
lated by NADPH oxidase through the transfer of
reducing equivalents across the cell membrane to
oxygen, and the subsequent acidification of the
cytoplasm. The neutrophil phagosome undergoes
a biphasic response with respect to its pH.
Although incompletely understood, the initial or
alkaline phase causes a transient increase in pH
to 7.8–8.0. The second phase causes a decrease in
pH to 6.0 over time through the activities of a
Na+/H+ antiport, H± ATPase, and an H+ conduc-
tance channel. It has been postulated that the ini-
tial increase in phagolysosomal pH results from
the consumption of hydrogen ions by the reaction
catalyzed by superoxide dismutase. This reaction
generates hydrogen peroxide by the following
reaction:
2O 2 + 2H + ¾¾¾¾¾¾
superoxide dismutase
® H 2 O2
Phagosomal acidification is not only an essen-
tial component of neutrophil microbicidal
responses but also provides the acid environment
for the acid hydrolases resident in the lysosomes.
Further, these oxidants may inactivate enzymes
that have an oxidant-sensitive reactive group
required for catalysis.
The generation of the strong oxidant, hydroxy
radical, has been the subject of much speculation
since the original papers by Fenton and the eluci-
dation of the Haber-Weiss reaction. These chemi-
cal reactions are as follows:
Fenton Reaction
H 2 O 2 + Fe 2 + ® Fe3+ + OH - + • OH
Haber-Weiss Reaction
H 2 O 2 + O 2- ® O 2 + OH - + • OH
Now it is known that small amounts of • OH
are formed in neutrophils by the MPO-H2O2-Cl−
system. Although very small amounts of
hydroxyl radical are formed, its reaction with
carbon dioxide to form the HCO3. radical may
create a microbicide. Singlet oxygen, 1O2, is also
formed in neutrophils via the myeloperoxidase-
H2O2-chloride system. There is also evidence
that ozone can be generated by oxidation of
water by singlet oxygen to produce ozone (O3)
and hydrogen peroxide. Ozone is highly reactive
and has a relatively long half-life (t1/2 = 1 min in
water at 37 °C. The production of ozone by neu-
trophils requires antibody (IgG), singlet oxygen,
and water [291].
Oxygen Radical Generation
Myeloperoxidase
A key to the microbicidal system of phagocytes
is myeloperoxidase (MPO) that together with
hydrogen peroxide, and a halide, especially chlo-
ride, form hypochlorous acid and subsequently
chlorine, chloramines, hydroxyl radicals, singlet
oxygen, and ozone. MPO resides in the azuro-
phil granules of granulocytes and in the primary
lysosomes of the monocyte. MPO granules in the
monocyte are fewer than in the neutrophil. There
is heterogeneity amongst the MPO enzymes found
in neutrophil granules. The human gene for MPO
has been cloned and localized to chromosome
17q12-24. The enzyme is enzymatically altered
during its processing from its initial translation to
its mature 140 kDa protein. Mature MPO consists
of a pair of a subunits (59 kDa) and two smaller
b subunits (13 kDa). The light subunits contain
112 amino acids and the heavy subunits have
467 amino acids. The heavy subunits are linked
by disulfide bonds via cysteine 319, mannose-
rich carbohydrates, and two hemes that are cova-
lently bound to the heavy subunit. The reduction
and alkylation of MPO creates a hemi-myeloper-
oxidase consisting of a heavy (a) and light (b)
subunit. This hemi-myeloperoxidase retains its
enzymatic and bactericidal activities. MPO is a
basic protein with an isoelectric point of greater
than 10, and on the basis of this chemical property,
it has the propensity to bind to negatively charged
molecules. As has been known for many years,
MPO is found in cytoplasmic granules and is dis-
charged into phagosomes. Although myeloperoxi-
dase may find its way into the extracellular milieu
(frustrated phagocytosis and an unclosed phago-
some), it can be removed from the extracellular
compartment via a mannose receptor-mediated
process by macrophages. When bacteria associ-
ated with myeloperoxidase or eosinophil peroxi-
dase are taken up by macrophages, the destruction
of microorganisms is enhanced. After many puta-
tive hypotheses, in the late 1960s, it was shown
that MPO, H2O2, and iodide, bromine, chloride,
or thiocyanate ions formed a potent antimicrobial
system in neutrophils.
The mechanism of action of MPO is to form
initially compound I in the presence of hydrogen
251
peroxide and ferric iron (Fe2+) [209]. Compound
I then reacts with a halide to form hypohalous
acid with the generation of ferrous iron (Fe3+).
Compound I can also be formed through the reac-
tion of MPO and hypochlorous acid (HOCI).
Compound II is formed when an excess of hydro-
gen peroxide is present, and this compound can-
not form hypochlorous acid. Superoxide reacts
with both MPO and compound II. In the latter
case, superoxide reduces compound II to its
active form (compound I) with the capacity to
form HOCI again. How effective the superoxide-
mediated conversion of compound II to com-
pound I is unresolved since other reducing agents
appear to be more efficient than superoxide.
Superoxide can react directly with myeloperoxi-
dase to form compound III, and this conversion is
slower than the reaction of myeloperoxidase and
hydrogen peroxide. The conversion of native
MPO to compound III is not as rapid as the con-
version of MPO and hydrogen peroxide despite
the presence of compound III in neutrophils and
its reactivity with many compounds.
Despite all these possible reactions to form
various compounds, the significance of MPO is
its antimicrobial activity via its production of
hypochlorous acid and the monochloramines
[292]. As can be determined from the foregoing
citations, a vast array of oxidant-mediated reac-
tions can occur leading to changes in bacteria and
subsequently microbial destruction. Such changes
cause alterations in microbial membrane trans-
port, disruption of membrane electron transport,
destruction of membrane nucleotide energy
pools, suppression of bacterial DNA synthesis,
and oxidation of iron and sulfur necessary for
microbial viability. There is now extensive evi-
dence that microbicidal activity is MPO-
dependent, and the presence of 3-chlorotyrosine
and 3,5-dichlorotyrosine in bacterial proteins
inside phagosomes provides documentation of
these MPO-dependent mechanisms [293–296].
Nitric Oxide and Bacterial Killing
Another oxidant-dependent system in the human
is the generation of nitric oxide (NO) from the
252 8 Mechanisms of the Acute Attack of Gout and Its Resolution
oxidation of L-arginine to L-citrulline. The reaction
is catalyzed by nitric oxide synthase and
requires molecular oxygen. Human neutrophils
and macrophages contain an inducible nitric oxide
synthase. Nitric oxide reacts with superoxide to
form peroxynitrite ion (ONO−2). Peroxynitrite ion
can be converted to peroxynitrous acid (ONO2H)
at acid pHs, and this compound then converts to a
strong oxidant. Both these compounds have
microbicidal properties [297]. Despite the forma-
tion of these reactive nitrogen intermediates,
a question remains as to their role in phagosome-
related bacterial killing [298].
Oxidants and Uric Acid Destruction
Even though bacterial infections sometimes
accompany acute gouty arthritis, the main prem-
ise for discussing oxidants is to determine how
the host disposes of ingested uric acid crystals.
The older literature confirms that humans can
metabolize uric acid despite the absence of
uricase. In addition to these experiments showing
uricolysis in the intact human host, studies have
also shown that verdoperoxidase (MPO) is capa-
ble of oxidizing uric acid. In these experiments,
MPO and hydrogen peroxide yielded urea and
allantoin.
An additional problem arises in the manage-
ment of gout relating to the clearance of uric acid
crystals and bacteria, if infection triggers the
acute gouty episode. There is a need to clear such
foreign agents before initiating potent therapeutic
initiatives that may obviate the ingestion and deg-
radation of the crystals or bacteria. To make such
agents more appropriate for use, the development
of synovial fluid markers are needed to determine
reasonably and accurately the stage of the
inflammatory reaction. A most effective marker
would be one that indicates with some degree of
certainty the point at which there is a shift from
an acute process to a resolving one. The use of
such markers would provide an opportunity to
use agents such as 15d-PGJ2 or TGF-13, as well
as natural molecules that enhance the resolution
of an inflammatory response.
More recent investigations with peroxidase
and hydrogen peroxide used to oxidize uric acid
demonstrated the following products of this reac-
tion: urea, carbon dioxide, alloxan, alloxan
monohydrate, allantoin, 5-hydroxyhydantoin-5-
carboxamide and parabanic acid. Thus, oxidation
by myeloperoxidase and hydrogen peroxide not
only kills microbes but also breaks down uric
acid into soluble products for disposal and
excretion.
Although oxygen-independent mechanisms
exist that also contribute to the microbicidal
activity of phagocytes, these phagocyte resident
molecules are of no relevance to the disposal of
uric acid. They may, however, contribute to the
bactericidal activity of these phagocytes. Since
septic arthritis may accompany acute gout in
some patients, a brief overview of these oxy-
gen-independent mechanisms is provided. The
major oxygen-independent bactericidal proteins
in neutrophils include cathepsin G, cationic
antimicrobial protein (CAP37 or azurocidin),
proteinase 3, elastase, bactericidal/permeabil-
ity-increasing protein (BPI or CAP57), defensins
(HNP-1, HNP-2, HNP-3, and HNP-4), and
lysozyme. These bactericidal proteins reside,
for the most part, in the neutrophil azurocidin
granules, but some (lysozyme) are also found in
specific granules of the neutrophil. They also
have a spectrum of antibacterial activity against
gram-positive and gram-negative organisms.
The defensins have the broadest spectrum of
activity since gram-positive and gram-negative
bacteria as well as many fungi and some viruses
are susceptible to its activity. CAP37, protei-
nase 3, elastase, and bactericidal/permeability-
increasing protein are effective against
gram-negative bacteria. The effects of some of
these proteins are also dependent on intrapha-
gosomal pH. However, studies of the intrapha-
gosomal pH have provided data showing a delay
in the acidification of this structure. These data
may be subject to error if the chlorination of a
probe is used to measure pH. Despite these
variable results, it does appear that intraphago-
somal pH decreases during and after phago-
cytosis.
Proinflammatory Mediators
Proinflammatory Mediators
Non-chemotactic, Proinflammatory Cell
Mediators
The key components of an acute inflammatory
response in the synovial space are the recruitment
and emigration of polymorphonuclear leukocytes
from the blood into the joint space as well as the
accompanying vascular leakage via the postcap-
illary venules. This complex process requires the
production and release of both cellular and
plasma mediators as well as endothelial cell and
neutrophil responses to generate the crystal-
induced inflammatory reactions observed in gout.
The inflammatory properties of urate crystals
have been documented as mediators of an acute
synovitis as well as an inflammatory response in
skin and subcutaneous tissues. Cytokines and
synovial fluid-derived mediators that cause the
inflammatory response are produced in the syn-
ovial compartment along with neutrophil
chemoattractants. Since a variety of cells includ-
ing neutrophils, synoviocytes, endothelial cells,
and others as well as plasma may produce media-
tors of inflammation, the exact sequence and
temporal pattern of mediator synthesis and release
in gouty arthritis remains incompletely defined.
However, the proinflammatory mediators respon-
sible for the symptoms and signs of acute gout
can be postulated on the basis of their biological
properties as well as what molecules have been
isolated from the synovial fluid in acute gouty
arthritis.
Vasoactive Arachidonic Acid
Metabolites
Vasoactive prostaglandins (prostaglandin E2
[PGE2] and prostaglandin I2 [PGI2]) as well as the
potent neutrophil chemoattractant, leukotriene
B4 [LTB4], and hydroxyeicosatetraenoic acids
are synthesized by synovial cells and other
inflammatory cells found in the synovial fluid
during acute gouty episodes. In addition, MSU
crystals do not need to induce membranolysis to
253
activate inflammatory cells since interactions
between the plasma membranes of cells and crys-
tals may trigger cellular activation and the release
of prostaglandins [299]. Thus, prostaglandins
and leukotrienes are likely to play a role in the
earliest manifestations of acute gouty arthritis
and probably account, in part, for the vasodila-
tory response and the pain of acute gouty
episodes.
Interleukins Interleukins have also been
detected in synovial fluid and are produced by
synovial and cellular components known to be
involved in acute gouty arthritis. Two forms
of interleukin-1 exist, IL-1a and IL-1b, and
they have identical biological functions. These
interleukin molecules are significant media-
tors of the inflammatory response in acute gout.
Interleukin-1, an endogenous pyrogen, stimulates
the production of PGE2 by synovial fibroblasts
and induces the synthesis of other cytokines
including interleukin-6, a mediator of acute phase
reactants like fibrinogen, C-reactive protein, and
serum amyloid A as well as the potent neutrophil
chemoattractant, interleukin-8. A key role for the
acute phase reactant, serum amyloid A (SAA),
has recently been described in acute inflammatory
processes [300]. SAA, at a concentration of 100
ug/ml, induces a 75- to 400-fold increase in
TNF-a, IL-113. and IL-8 over basal levels. Thus,
SAA may be one of the early mediators of IL-8
release, and the latter molecule is a potent neu-
trophil chemoattractant and a major mediator of
the neutrophil influx observed in gouty synovi-
tis. IL-8 also enhances exocytosis, stimulates the
respiratory burst, and increases the expression
of membrane adhesion receptors in neutrophils.
Thus, these three interleukins (IL-1, IL-6, and
IL-8) are likely contributors to the early manifes-
tations of acute gout with interleukin-1 providing
the vasodilatory effects through its capacity to
generate PGE2 and its pyrogenic effect leading to
the low-grade fever sometimes observed during
acute gout. Interleukin-6 undoubtedly also con-
tributes to the generation of acute phase reactants
like C-reactive protein which is elevated during
the acute gouty episode and interleukin-8 which
is the principal neutrophil chemotaxin in gout.
254 8 Mechanisms of the Acute Attack of Gout and Its Resolution
Bradykinin
Bradykinin is also a likely contributor to the
localized heat, redness, and pain of acute gout.
Synovial fluid contains components of the con-
tact system (Hageman factor, prekallikrein, high-
molecular-weight kininogen, and coagulation
factor XI) from which bradykinin is derived.
Since the injection of monosodium urate crystals
into a dog joint causes the rapid generation of
joint pain and heat peaking within 10 min, and
bradykinin is a more potent vasoactive agent than
high doses of prostaglandin E1 (0.1 M) or hista-
mine (0.01 M), bradykinin may be a key media-
tor of the early stages of acute gout. In fact,
intra-articular injections of MSU crystals in
a patient with the gouty diathesis triggered an
acute episode of gout in association with a rapid
increase in the synovial fluid concentration of
bradykinin.
The mechanism for the generation and release
of bradykinin from high-molecular-weight
kininogen is well understood. The negatively
charged surface of monosodium urate crystals
binds Hageman factor (HF/factor XII) through
the positively charged amino acids in its heavy
chain and is subsequently activated, and this
interaction initiates further interactions between
factor XII, prekallikrein, and high-molecular-
weight kininogen [301]. This process is known
as contact activation. Factor XII migrates as a
beta globulin by electrophoresis, and cleavage of
this molecule and the generation of activated HF
(factor XIIa) occurs from exposure to plasma kal-
likrein or through spontaneous autoactivation on
negatively charged surfaces like uric acid [302].
The structure of Hageman factor has been eluci-
dated from purified human sources and its direct
amino acid sequence characterized. It consists of
596 amino acids and is activated to factor XIIa
by the cleavage of a bond between arginine-353
and valine-354 resulting in a heavy chain of 353
amino acids and a light chain of 243 amino acids.
The heavy chain contains the site for binding
to negatively charged surfaces. Activated factor
XIIa catalyzes the conversion of prekallikrein
to kallikrein. Plasma prekallikrein migrates
as a gamma globulin, has a molecular weight
of 88,000, and has been purified from human
plasma. The structure of the circulating molecule
is a single polypeptide chain consisting of 619
amino acids, and cleavage of this molecule at an
arginine-isoleucine bond results in the generation
of a disulfide-bonded molecule consisting of a
heavy chain of 371 amino acids from the amino
terminus of the molecule and a light chain of
248 amino acids from the carboxy-terminus. The
active site of the molecule is localized in the light
chain, and the binding site for high-molecular-
weight kininogen is on the heavy chain [303].
Plasma kallikrein cleaves high-molecular-weight
kininogen, a single-chain glycoprotein with Mr
of 120,000 Da to generate the vasodilatory nona-
peptide, bradykinin.
In summary, the initial event in this sequence
of events is the activation of Hageman factor
which then interacts with prekallikrein bound to
kininogen that serves as a substrate for factor
XIIa leading to the generation of the active pro-
tease, kallikrein. The latter then cleaves kinino-
gen to form the vasoactive peptide, bradykinin.
This small peptide increases vascular permeabil-
ity, dilates blood vessels, and mediates pain
responses. Kallikrein also acts as a stimulus for
neutrophil degranulation. A recent publication
has indicated that bradykinin formation from
autoactivated factor XII on the surface of endothe-
lial cells occurs placing this vasoactive mediator
close to its target, the blood vessel [304]. Contact
activation appears not to be a component of the
inflammatory response of gouty arthritis since
gout has been reported in patients with a
deficiency of the Hageman factor. However, a
poorly characterized tissue pathway may also
generate bradykinin. Thus, bradykinin functions
to cause venular dilation and activation of phos-
pholipase A2 to increase arachidonic acid metab-
olism and the release of prostaglandins.
Tumor Necrosis Factor
Tumor necrosis factor (TNF) is a pleiotropic
17-kDa protein produced primarily by monocytes
Monosodium Urate Crystal-Induced Inflammation
and macrophages, but other cell types including
neutrophils also produce it. This mediator has
been documented in synovial fluids associated
with acute inflammatory processes and has been
shown to be released from cultured monocytes
and synovial lining cells by monosodium urate
crystals. Its biological functions include the
induction of human neutrophil degranulation,
and it is now well established that the p55 TNF
receptor is responsible for the respiratory burst of
neutrophils. This mediator also stimulates the
release of secretory phospholipase A2 (sPLA2),
the enzyme that regulates the synthesis of eico-
sanoids and platelet-activating factor (PAF), and
this action results in the rapid release of prostacy-
clin (PGI2), another vasoactive substance. In
addition, TNF also has a direct action on the
endothelial cell adhesion molecules, ICAM-1
(intracellular adhesion molecule) and VCAM-1
(vascular cell adhesion molecule), that in turn
play a role in the interactions between leukocytes
and endothelium. These cell adhesion molecules
are an essential part of the mechanisms involved
in the migration of neutrophils through blood
vessel walls during inflammatory processes.
Monosodium Urate Crystal-Induced
Inflammation
Proinflammatory Mediators and MSU
Crystals
The deposition of monosodium urate crystals and
their interaction with neutrophils are central to
the inflammatory process associated with acute
gouty arthritis. Such neutrophil-MSU crystal
interactions not only lead to the production of
proinflammatory mediators but also trigger the
activation of the biochemical pathways that regu-
late these reactions. Such crystals can generate
complement peptides, kinins, histamine, vasoac-
tive prostaglandins, platelet-activating factor as
well as cytokines such as IL-1, TNF-a, IL-8, IL-6,
oxygen free radicals, and phospholipase
A2-activating protein (FLAP) [102, 104, 124]. In
addition to neutrophii-MSU crystal interactions,
255
monocytes and synovial membrane lining cells
may also trigger the release of proinflammatory
mediators when challenged by MSU crystals.
Such interactions between monocytes and MSU
crystals cause the release of IL-8, IL-1, IL-6, and
tumor necrosis factor-a [103, 104, 123].
Interactions are also likely to occur between the
type A (monocyte-derived) synovial lining cell
and uric acid crystals, but these cells have not
been isolated and cultured in vitro so that their
molecular and functional capacities remain
incompletely defined.
A large body of data exists relating to human
fibroblast-like synovial lining cells including
receptors on these cells, their transduction path-
ways, and the effects of therapeutic agents on
these cells. However, the publications describing
these parameters have been primarily restricted
to synovial cells recovered from patients with
rheumatoid arthritis and osteoarthritis. Since
these synoviocytes may have structural and func-
tional differences from normal synoviocytes, it is
probably inappropriate to assume that patients
with gout will have completely identical charac-
teristics to those synoviocytes recovered from
patients with nongouty forms of arthritis.
Despite these shortcomings, uric acid crystals
do activate fibroblast-like synoviocytes in culture
and stimulate the production of proinflammatory
cytokines (IL-6, IL-8, TNF-a, and IL-1) [104,
125]. These same human cells challenged with
MSU crystals also release matrix metallopro-
teinase, collagenase as well as arachidonic acid
metabolites including prostaglandins. MSU
crystals also produce neutral proteases from
human synovial fibroblast-like cells. In addition
to the direct action of MSU crystals on human
synoviocytes, other proinflammatory cytokines
as well as MSU-induced neutrophil metabo-
lites that have the capacity to modulate the
inflammatory response can interact with human
fibroblast-like synoviocytes. Thus, the presence
of proinflammatory cytokines or modulators of
synoviocyte-mediated inflammatory events in the
synovial fluid have the potential to regulate syn-
ovial fibroblast responses associated with acute
gouty episodes and their subsequent resolution.
256 8 Mechanisms of the Acute Attack of Gout and Its Resolution
Regulation of Synovial
Fibroblast-Like Cells
As noted previously, IL-1 and TNF-a are the main
proinflammatory cytokines generated in acute
gout, and these cytokines regulate a number of
type B synoviocyte functions. Tumor necrosis
factor-a induces the expression of vascular cell
adhesion molecule (VCAM) on human syn-
ovial fibroblasts and triggers the synthesis and/
or expression of PGE2, IL-6, hyaluronic acid,
interleukin-1, granulocyte colony-stimulating
factor (G-CSF), granulocyte-macrophage col-
ony-stimulating factor (GM-CSF), macrophage
colony-stimulating factor (M-CSF), intercel-
lular adhesion molecule (ICAM)-1, monocyte
chemoattractant protein-1 (MCP-1), collagenase,
and interleukin-10. TNF-a also regulates the
expression of the constitutive gene for I kappa b
kinase-1 (IKK-1) in human fibroblast-like syn-
oviocytes [305]. This kinase plays a central role in
the regulation of nuclear factor-kappa B (NF-kB)
that controls expression of genes of significance
to the inflammatory response. Interleukin-1,
another key effector of human fibroblast-like syn-
oviocyte function, stimulates the synthesis and/or
expression of many proinflammatory components
similar to those affected by TNF-a such as colla-
genase, PGE2, GM-CSF, IL-6, G-CSF, M-CSF,
IL-10, IL-10R, and MCP-1 [306]. Interleukin-1
also regulates the expression of stromelysin-
1(MMP-3) and tissue inhibitor of metallopro-
teinases (TIMP-1). Like TNF-a, interleukin-1
also regulates I kappa B kinase activity. Further,
IL-1 and TNF-a act synergistically to induce the
synthesis and release of IL-6. Interleukin-1 and
bradykinin also act synergistically to increase the
synthesis and release of PGE2.
No detailed studies of “normal” synovial
fibroblast-like cells have been undertaken, but
numerous investigations have been published
with respect to the functions and responses of
human synovial fibroblast-like cells recovered
from patients with rheumatoid arthritis, osteoar-
thritis, and musculoskeletal trauma. Many of
these publications have focused on rheumatoid
synoviocytes and have documented many diverse
findings related to these cells. Without any nor-
mal standard to compare with these cells, it is
inappropriate to conclude that such findings can
be assumed to occur in synovial fibroblast-like
cells in patients with gout. On the other hand, the
findings in synovial fibroblast-like cells from
patients with osteoarthritis and musculoskeletal
trauma are not likely to retain fixed lesions in
their structure and function. Thus, some of the
data cited in the literature is based on findings
from synovial fibroblast-like cells recovered from
patients with osteoarthritis and musculoskeletal
trauma and may of may not reflect those responses
present in the “normal” synovial fibroblast.
MAP Kinase and MSU Crystal-Induced
Neutrophil Activation
The most complex and significant aspect of
crystal-induced reactions is the identification
and characterization of the pathways leading to
neutrophil activation, the mechanisms by which
activation is regulated, and the cellular functions
that are mediated by such activation. Particulate
phagocytosis and proinflammatory cytokines
such FMLP and TNF-a have been identified
as activators of p38 mitogen-activated protein
kinase (MAPK), but a complete picture of this
pathway and its functional role remains to be
determined. Evidence supports a role for MAP
kinases in chemoattractant-induced degranula-
tion responses, the assembly of NADPH oxidase
and the subsequent activation of the respiratory
burst, the synthesis and expression of IL-8 activ-
ity, and neutrophil apoptosis [307]. The regula-
tion of human neutrophil IL-8 synthesis requires
p38 MAP kinase for the TNF-a-mediated produc-
tion of IL-8. Since TNF-a induces the activation
and nuclear translocation of the transcription fac-
tor, NF-kB, and the IL-8 gene has NF-kB binding
sites essential for the transcriptional activation
response to TNF-a, it seems reasonable to pro-
pose that TNF-a appears to activate MAP kinase
which then activates NF-kB to cause IL-8 gene
expression. Thus, MAP kinase is a key regulator
of gene expression [308]. Even though the MAP
kinase and other pathways regulate neutrophil
functions known to be triggered by MSU crys-
tals, the direct relationship of these pathways to
such crystals has not been defined.
Monosodium Urate Crystal-Induced Inflammation
Phospholipase D and MSU Crystals
MSU and CPPD crystals also generate messages
via phospholipase-specific phospholipase D. This
enzyme hydrolyzes phosphatidylcholine and
forms phosphatidic acid, a significant lipid medi-
ator, and the water soluble product, choline. One
product of this enzyme reaction, phosphatidic
acid (PA), may also be converted to other second
messengers such as 1,2-diacylglycerol and lyso-
phosphatidic acid. Mammalian cells contain two
separate genes for phospholipase D designated
phospholipase D1 (PLD1) and phospholipase D2
(PLD2). Two splice variants of PLD1 have also
been identified and designated as PLD1a and
PLD1b. Another oleate-activated phospholipase
D isoform has also been identified, but it has yet
to be cloned and characterized further.
Phospholipase D activity has been implicated
in a variety of cellular functions including cell
secretion, superoxide generation, and immune
responses. As indicated previously, MSU crystals
trigger a number of reactions essential for neutro-
phil functions. First, MSU crystals increase the
intracellular free calcium ion concentration that
causes the hydrolysis of phosphatidylinositol
4,5-biphosphate by a specific phospholipase C
with the resultant formation of inositol [1, 4,]
triphosphate. Second, the product of phospholi-
pase D, phosphatidic acid, can be further metabo-
lized to diacylglycerol (DAG), and these two
lipid second messengers (DAG and PA) interact
directly with NADPH oxidase components to
cause the assembly of this enzyme and its subse-
quent activation [309]. These same metabolites
also regulate phosphatidic acid-activated protein
kinase and protein kinase C isoforms. Third,
phosphatidic acid has also been shown to regu-
late a specific tyrosine kinase (Fgr), but the func-
tional role of this tyrosine kinase is incompletely
characterized. Even though the role of the tyrosine
kinase, Fgr, is not known, MSU crystals are
known to induce tyrosine phosphorylation and
perhaps this enzyme is involved [310]. Fourth,
phospholipase D activity appears to result in a
prolonged survival of neutrophils by delaying
apoptosis [311]. Studies of the latter phenomenon
show that MSU crystals inhibit both spontaneous
and TNF-a-induced apoptosis. The pathways for
257
the regulation of TNF-a-induced apoptosis by
CPPD crystals have begun to be characterized,
but pathways for the delay of apoptosis by MSU
crystals have yet to be completely defined. Fifth,
phospholipase D activity and ADP-ribosylation
factor 1 (ARF1) are associated with lysosomal
membranes in neutrophils and HL-60 neutrophil-
like cells. ARF1 is able to restore lysosomal
secretion. More recent investigations have postu-
lated that ADP-ribosylation factor 6 (ARF6) is
the key metabolite in receptor-mediated NADPH
oxidase activation in a PLD-dependent manner.
The role of other ARF isomers in phagocyte
function remains to be determined, but it has
recently been shown that ARF has a major role in
the signaling between the fMLP receptor and
NADPH oxidase [312]. Thus, phospholipase D
has a regulatory role in the assembly and activa-
tion of NADPH oxidase as well as an incom-
pletely characterized role in lysosomal enzyme
secretion. Further, phospholipase D is directly or
indirectly associated with the generation of sec-
ond messengers such as calcium, phosphatidic
acid, and diacylglycerol that control specific neu-
trophil functions.
Since the phospholipase D of human neutro-
phils is activated by MSU crystals and plays a role
in neutrophil functions triggered by MSU crys-
tals, factors regulating phospholipase D activity
are of significance. The key regulators of PLD
activity are small GTPases such as ADP-
ribosylation factor 1 and its isomers as well as
Rho proteins and Ral 1. Recent data have also
shown that phospholipase D1 is phosphorylated
by a casein-kinase-2-like serine kinase. This
casein kinase-2-mediated phosphorylation of
phospholipase D1 occurs on cell membranes and
is probably responsible for the localization of the
enzyme (PLD1), its substrates, and its regulators,
to the cellular membranes. Since PLD via its
immediate and more distal products (phosphatidic
acid, diacylglycerol, and lysophosphatidic acid)
regulate the respiratory burst, ligand-induced
secretion, prostaglandin synthesis and release,
cytokine release, and cytoskeletal rearrangements,
this enzyme has been and will continue to be a
target for potential therapeutic agents with PLD
inhibitory activity. Neutrophils are also stimulated
by protein kinase C isoforms such as PKC-a and
258 8 Mechanisms of the Acute Attack of Gout and Its Resolution
PKCb11 [313]. Thus, phospholipase D and its
products play a key role in mediating certain neu-
trophil functions as well as generating second
messengers for neutrophil-associated responses
MSU Crystals and Other Phospholipids
Metabolizing Enzymes
Both MSU and CPPO crystals also activate phos-
phatidylinositol 3-kinase activity, and such acti-
vation is a key to a transduction pathway for
neutrophil respiratory bursts and degranulation
responses. MSU crystals also stimulate phospho-
lipase A2 activity with the resultant production of
proinflammatory eicosanoids. Investigations have
also shown that MSU crystals induce the synthe-
sis of PLA2-activating protein (FLAP), a modu-
lator of arachidonic acid-mediated inflammatory
responses. Recent studies have demonstrated that
PLA2 and phosphatidic acid cause the fusion of
neutrophil granules and plasma membranes.
Thus, phospholipid metabolism, especially that
mediated by phospholipases A2 and D, may play
a central role in neutrophil degranulation.
Furthermore, U73122, a specific inhibitor of
phospholipase C, inhibits MSU crystal-induced
superoxide generation and neutrophil degranula-
tion. It has been postulated that PLC gamma2 is
the PLC isoform involved in this signal transduc-
tion pathway. Unopsonized MSU crystals can
also activate neutrophils by inducing pertussis
toxin-insensitive phosphatidylinositol bisphos-
phate (PIP2) hydrolysis with the generation of
inositol [1, 4,] triphosphate and the mobilization
of calcium. This pathway modulates superoxide
generation and release.
Other Pathways Stimulated by MSU
Crystals
Two additional MSU crystal-induced reactions
have been characterized. First, MSU crystals
stimulate the phosphorylation of SAM68 (sarc-
associated in mitosis 68 kDa). This component is
involved in the signal transduction and activation
of RNA and may regulate specific patterns of
chemokine and cytokine synthesis triggered by
MSU crystals. MSU crystals also induce CD18
(b2 integrin)-independent and selectin-indepen-
dent adhesion of neutrophils to endothelial cells.
Thus, ARF nucleotide binding site opener
(ARNO) and perhaps cytohesion-1, another gua-
nine nucleotide exchange factor, support the con-
version of nucleotide-bound ARF and in this way
activate phospolipase D. This activation sequence
then activates protein kinase C causing the cou-
pling of FcyRI to phospholipase D1. The exact
relationships between ARNO, cytohesion-1,
ARF1, ARF6, PKC-a, and MSU crystal-induced
neutrophil phagocytosis remains to be completely
resolved. Recent studies have shown that the gua-
nine exchange factor, ARNO, is stimulated by the
chemotactic factor, fMLP, in HL-60 cells, and it
is likely that similar reactions will occur with
other chemotactic factors such as IL-8.
Another pathway of interest is the protein
tyrosine phosphatase MEG2 (megakaryo-
cyte 2) that regulates secretory vesicles in
hematopoietic cells and is also associated with
diphosphate > phosphatidylinositol 3,4,5-triphos-
phate > phosphatidylinositol 4-phosphate) and is
stimulated by opsonized zymosan and phorbol
12-myristate 13-acetate. This enzyme, protein
tyrosine phosphatase MEG2, is unaffected by
the chemoattractant, fMLP. On this basis, there
is speculation that protein tyrosine phosphatase
MEG2 may regulate, in some manner, phagocy-
tosis, but the complete signaling pathway and its
ultimate role in neutrophil function remains to be
determined.
Tec kinases represent a large group of non-
receptor tyrosine kinases that may be involved in
the transduction of cell surface receptor mes-
sages. The structure of these cytoplasmic tyrosine
kinases includes proline-rich regions and pleck-
strin homology (PH) domains for their regulation
and activation. The PH domain is able to bind
phospholipids and heterotrimeric G proteins.
These Tec kinases are activated by interaction
with many cell-surface receptors, integrins, and
G protein-coupled receptors [314]. The interac-
tions with cell-surface receptors have recently
been shown to include chemotactic agents.
Since Tec kinase activation is blocked by
Monosodium Urate Crystal-Induced Inflammation
phosphatidylinositol 3-kinase inhibitors, the
product of this enzyme, phosphatidylinositol
3,4,5-triphosphate, may be critical for Tec kinase
activation. This is consistent with data showing
the binding of such phosphoinositides to the PH
region of some Tec kinases. In addition to their
role in neutrophil chemotactic activity, Tec
kinases may signal the activation of MAP kinases,
actin rearrangement, and transcription activities.
All these MSU crystal-induced reactions as
well as other transduction pathways described in
the neutrophil may be potential sites for interac-
tion with modulators that can modify the biologi-
cal effects of these pathways. Although excellent
pharmacologic agents are already available for
the treatment of acute gout, newer agents may
offer better treatment regimens for the patient
intolerant to presently available drugs or those
patients with contraindications to the standard
drugs used to treat gout. Of course, there is always
the possibility that newer drugs might be more
potent or more rapidly acting agents than those
therapeutic agents presently available.
MSU Crystal-Induced Proinflammatory
Mediators
In addition to oxidants and the exocytosis of
phagolysosomal contents such as lysosomal
enzymes, MSU crystals can generate a number of
proinflammatory mediators including complement
peptides, kinins, histamine, vasoactive prosta-
glandins, platelet-activating factor, and cytokines
such as IL-1, TNF-a, IL-8, IL-6, and phospho-
lipase A2-activating protein (FLAP) via MSU
crystal-neutrophil interactions. The deposition of
monosodium urate crystals and their interaction
with neutrophils are central to the inflammatory
process associated with acute gouty arthritis. Such
neutrophil-MSU crystal interactions not only lead
to the production of proinflammatory products
but also trigger the activation and regulation of the
biochemical pathways that regulate these reac-
tions. The proinflammatory products generated by
MSU crystal-neutrophil interactions include lyso-
somal enzymes, interleukin-1, interleukin-8, oxy-
gen free radicals, and eicosanoids. In addition to
259
neutrophii-MSU crystal interactions, monocytes
and synovial lining cells also trigger the release
of inflammatory mediators when challenged by
MSU crystals. Such interactions between mono-
cytes/synovial lining cells cause the release of
IL-8, IL-1, IL-6, and tumor necrosis factor-a.
MSU Crystals and Cell Membrane
Interactions
MSU crystals are rapidly phagocytosed by neu-
trophils and engulfed by phagolysosomes. Since
lysosomes contain proteolytic enzymes capable
of digesting the proteins coating crystals, the neg-
ative surface of crystals can hydrogen bond with
the phospholipid head groups of the lysosomal
membranes [314]. Monosodium urate crystals
that are weakly acidic appear to hydrogen bond
with the phosphate esters of phospholipids and
cause the perforation of the organelle with the
resultant release of lysosomal enzymes and cell
cytoplasmic contents. Studies of serum proteins
absorbed to MSU crystals clearly demonstrate
why immunoglobin-coated crystals do not cause
membranolysis of the plasma membrane of neu-
trophils since protein-coated crystals have a pro-
tective effect on plasma membranes via these
absorbed proteins. MSU crystal-induced neutro-
phil membranolysis and cytolysis raises the ques-
tion of the fate of the urate crystals released by
this process. There are at least two enzymes, per-
oxidase and cytochrome oxidase, that have the
capacity to digest uric acid. Probably the major
route for MSU crystal destruction is via the per-
oxidative presence of a monosodium urate tophus
in the synovial membrane may delineate another
possible site for the removal and storage of crys-
tals [42]. Finally, free uric acid crystals are often
observed in the synovial fluid long after the acute
episode of gout has subsided. Why these free
urate crystals do not evoke an acute inflammatory
response is presently unknown, but perhaps it is
the absence of an immunoglobin coating and the
inability to interact with Fe receptors.
In summary, the phagocytosis of IgG-coated
uric acid crystals is an exceedingly complex
process and remains incompletely characterized.
260 8 Mechanisms of the Acute Attack of Gout and Its Resolution
It involves a complex set of molecular interactions
by the neutrophil to surround the crystal and even-
tually ingest it fully. Such a response necessitates
the use of actin filaments to guide the changes in
the cell protrusions in association with contractile
proteins, and to surround the crystal completely
involves fusion and fission of the membranes. The
key components for the ingestion and disposal
of uric acid crystals are dependent on NADPH
oxidase, myeloperoxidase, and hydrogen per-
oxide. These oxidant-producing systems lead to
the breakdown of the purine ring and the genera-
tion of more soluble molecules such as allantoin
and urea once the phagosome has fused with
the lysosome and the release of such oxidants is
initiated. If bacterial infections accompany the
acute episode of gout, the killing of bacteria is, in
part, dependent on these same systems. It seems
unlikely that therapeutic agents to alter these pro-
cesses would lead to significant improvements in
the treatment of gout. Nonetheless, an increment
in the disposal of apoptotic neutrophils and their
ingested uric acid crystals might enhance the res-
olution of the acute gouty episode. Thus, a dis-
cussion of apoptosis, the key process involved in
the phagocytosis of such dying cells, is described
in the succeeding sections.
Neutrophil and Macrophage
Apoptosis
Overview
Apoptosis is a term used to describe a morpho-
logical process characterizing cell death by a par-
ticular series of events quite different from cell
necrosis. The apoptotic cell appears shrunken
with membrane blebbing, has nuclear chromatin
condensation and DNA fragmentation into
nucleosome-length fragments, and these changes
in cell membranes cause phosphatidylserine and
oxidized phospholipids to take their place on the
external surface of the cell. The term, apoptosis,
comes from the Greek meaning “to fall away
from.” This apoptotic phenomenon is a carefully
orchestrated and genetically controlled event of
significance to the inflammatory process observed
in gout and other inflammatory disorders since it
is the key to the resolution of inflammation and
fibrosis. Even though apoptosis occurs as an
abnormal balance between cell survival and cell
death in some diseases, it is, for the most part,
considered as a process of physiologic cell death.
The absence of inflammatory responses in asso-
ciation with apoptosis distinguishes it from
necrosis and other forms of cell death. Caspases
are cysteine proteases that play a central role in
the execution of the apoptotic process [315]. Two
major pathways can be utilized by neutrophils
and macrophages to activate caspases and cause
cell death. The first pathway or so-called death
receptor pathway is an extrinsic route to cell
death by the interaction of certain cytokines of
the TNF/nerve growth factor family with their
cognate receptors (TNFR, CD95R, and TNF-
related apoptosis-inducing ligand receptor). Once
these interactions take place, an adaptor molecule
(TNF receptor-associated death domain or FAS-
associated protein with a death domain) binds to
the receptor, and these complexes can bind and
activate specific caspases directly The second
pathway is an intrinsic one and is mediated by the
release of cytochrome c from the cell mitochon-
dria into the cytoplasm. Cytosolic cytochrome c
interacts with apoptotic protease-activating fac-
tor 1 (Apaf-1) to result in the oligomerization of
Apaf, and this complex then recruits caspase-9.
Once this so-called apoptosome (Apaf 1 and pro-
caspase-9) is activated, it can then interact with
and activate other caspases. The third pathway
that can activate caspases is of no significance to
this discussion since it involves the use of gran-
zyme B from the granules of cytotoxic T cells/
natural killer cells which are not involved in the
acute gouty attack. The key to the destructive
processes associated with apoptosis are the
cysteine proteases called caspases.
Endogenous and Exogenous
Anti-inflammatory Agents
Overview
Immune and inflammatory reactions represent
physiological mechanisms by which the human
host responds to tissue and organ-damaging
Endogenous and Exogenous Anti-inflammatory Agents
stimuli. Since excessive expression or inappro-
priate activation of these reactions may cause cell
and tissue damage, homeostatic mechanisms
exist to protect the host from such damaging
effects and to regulate tightly the expression of
these inflammatory and immune responses. Acute
episodes of gout are known to resolve without
treatment suggesting the presence of endogenous
anti-inflammatory mechanisms. The literature
supports the view that the human host has the
capacity to turn off acute inflammatory processes
and to cause their resolution [316, 317]. Uric acid
crystals and in some settings, accompanying bac-
terial pathogens, are the stimuli that trigger the
acute inflammatory response in acute gout. The
critical elements of the proinflammatory mecha-
nisms associated with these stimuli are primarily
the gene transcription factors, nuclear factor-
kappa S (NF-KB), activator protein-1 (AP-1),
and STATs (signal transducers and activators of
transcription (STATs) [318]. These transcription
factors regulate a wide variety of genes associ-
ated with inflammatory and immune responses
including proinflammatory cytokines, cytokine
receptors, chemotactic proteins, and adhesion
molecules. The presence of sites for TNF-a,
IL-1b, IL-8, macrophage chemotactic protein-1
(MCP-1), granulocyte-macrophage colony stim-
ulating factor (GM-CSF), intercellular adhesion
molecule-1 (ICAM-1), vascular adhesion mole-
cule-1 (VCAM-1), E-selectin, and others on the
promoter or regulatory motifs of these transcrip-
tion factors emphasize the key role of transcrip-
tion factors in the regulation of inflammation.
Several different approaches have also been
utilized to understand how an inflammatory
response can be modulated to cause its resolu-
tion. Homeostatic mechanisms that regulate the
response of the human host to inflammatory
stimuli identify the pathways utilized to suppress
inflammation as well as the key components of
such pathways. As has been discussed, receptor
desensitization to proinflammatory agonists is an
effective mechanism by which inflammatory
responses can be suppressed. In addition, the
nuclear factor-kappa B represents an ideal target
for inhibition since it activates inflammatory gene
expression. Several different mechanisms have
been shown to suppress inflammatory responses
261
including blocking the activation of the transcrip-
tion factor, nuclear factor KB (NF-KB), that reg-
ulates proinflammatory cytokines, chemokines,
and cell adhesion molecules [319]. The activa-
tion of NF-KB requires phosphorylation and pro-
teolytic degradation of its inhibitor, IKB, with the
subsequent release of NF-KB, its translocation to
the nucleus, and its binding to DNA sequences in
the promoters of the target genes to initiate their
transcription. The proteolytic degradation of IKB
occurs via the proteasome pathway, and the inhi-
bition of this pathway would, in turn, stabilize
IKB and maintain its capacity to bind to NF-KB
in the cytoplasm preventing NF-KB activation.
Since proteasome inhibitors have been utilized as
NF-kB activation inhibitors, a brief review of this
mechanism follows. However, these small, non-
selective NF-KB inhibitors may activate NF-KB
in some cells and may also inhibit other activities
unrelated to the inflammatory response [320].
The nonspecific nature of these proteasome
inhibitors suggests that their use may be limited
in their capacity to impair acute inflammatory
responses.
Antisense technologies represent a more
potent means of investigating gene function for
the future design of more specific treatment
approaches for diseases like gout through their
capacity to block the expression of mRNAs
associated with inflammation. Such initiatives
are entirely dependent on functional genomics
since a specific treatment must be based on the
inhibition of a specific mRNA. The major groups
of sequence-specific nucleic acids designed to
block mRNA expression include antisense oli-
gonucleotides (ODNs), ribozymes, DNAzymes,
and RNA interference (RNAi). Such antisense
technologies must be delivered efficiently to a
cell, have stability and resistance to nuclease
activity, have little, if any, activity against sites
other than the specific target mRNA, must be
nontoxic to the cell, and must reduce the target
mRNA specifically. Here again, such antisense
technology as well as antigene strategies using
DNA triplex technology (vide infra) may be lim-
ited in their use in acute gout since fulfilling all
the criteria for an effective and efficient anti-
sense or antigene strategy may be difficult to
achieve.
262 8 Mechanisms of the Acute Attack of Gout and Its Resolution
The most promising technology using nucleic
acids is gene silencing via RNA interference.
Since many organisms use double-stranded RNA
to silence genes during their developmental
phases and to protect cells from viral invasion,
transposon jumping, and for silencing introduced
transgenes, this naturally occurring system and
its effector, small interfering RNA (siRNA), has
been utilized to administer exogenous siRNAs to
cause gene-specific silencing or to provide vec-
tor-induced expressions of siRNAs in cells as a
means of gene silencing. Although RNAi has yet
to reach its full potential, improved virus- and
plasmid-based delivery systems are likely to per-
mit the delivery of siRNAs to appropriate tissue
sites at the right time and to characterize the role
of specific genes in the expression of acute gouty
arthritis. Such information may provide better
targets for anti-inflammatory agents.
Anti-inflammatory eicosanoids such as lipox-
ins (lipoxygenase interaction products.), cyclo-
pentenone prostaglandins derived from PGD2
and its metabolites, and the resolvins derived
from eicosapentaenoic acid (C20:5) and docosa-
hexaenoic acid (C22:6) in the presence of acety-
lated COX-2 and 5-lipoxygenase activity, both
represent endogenously generated eicosanoids
that are involved in the resolution of inflammatory
responses. These endogenously synthesized anti-
inflammatory agents also emphasize the role
transcellular biosynthesis plays in the downregu-
lation of the inflammatory process. Stimulating
the generation of these anti-inflammatory eico-
sanoids is a physiological means of suppressing
inflammatory responses, and the development of
analogs of these suppressive molecules with sim-
ilar biological activity could be used, in the
future, as therapeutic agents.
Another means of modulating an acute
inflammatory response is to enhance apoptosis, a
process that clears cellular debris from an
inflamed site. For the most part, these apoptosis-
enhancing mechanisms rely primarily on imped-
ing the activation of NF-KB and its induction of
antiapoptotic molecules. This can be accom-
plished by altering the capacity of IKB to release
NF-KB and its subsequent activation, by impair-
ing the interactions between receptor-interacting
protein (RIP) and IKKy and their role in Nt = −KB
activation, or by causing the destruction of cal-
pastatin and permitting calpain to activate apop-
tosis. These mechanisms are reviewed in the
following discussions.
Finally, a variety of anti-inflammatory drugs
have the capacity to alter NF-KB activation. In
addition to the nonsteroidal anti-inflammatory
drugs (NSAIDS), glucocorticoids also have a
significant role in modulating the inflammatory
response since they have the capacity both
to counteract the synthesis and release of
proinflammatory mediators and to cause the pro-
duction of anti-inflammatory cytokines like IL-10,
IL-4, TGF-b, and annexin-1. Glucocorticoids
and the compounds that are induced by them
represent a major negative feedback mechanism
to prevent the overexpression and activation of
proinflammatory cytokines and other components
that may result in organ and tissue damage.
Anti-inflammatory Eicosanoids
Overview
Acute gouty arthritis is an intense inflammatory
disorder primarily mediated by the precipitation
of monosodium urate crystals in the intrasynovial
space and the recruitment of neutrophils and their
proinflammatory products to the involved joint.
The initial phase of this inflammatory process
is regulated by the generation of chemotactic
signals for neutrophils and the expression of
chemotactic cell-surface receptors. This segment
of the discussion places emphasis not on the
proinflammatory aspects but on those factors at
play during the resolution of this inflammatory
response. A characteristic of acute gout not often
discussed as a result of the availability of effective
drugs for the treatment and suppression of acute
gouty episodes is the fact that the human host is
able to resolve over time the acute inflammatory
response of gout in the absence of any treatment.
This reparative or resolution process provides
strong evidence for the presence of endogenous
molecular system(s) with the capacity to coun-
teract proinflammatory mediators and to generate
Lipoxin Biosynthesis
proresolution mediators. Such anti-inflammatory
processes must account for the downregulation of
the synthesis and release of neutrophil chemoat-
tractants, the generation and clearance of apop-
totic neutrophils in a nonphlogistic manner, the
upregulation of the synthesis and release of mono-
cyte/macrophage chemotactic agents, the phago-
cytosis of apoptotic neutrophils by macrophages,
and the eventual disappearance of the phagocytic
macrophages from the intrasynovial space via the
lymphatics. As might be predicted from the tasks
necessary for resolution, this reparative phase
is just as complex as the generation of an acute
inflammatory reaction. If one examines the list of
endogenous anti-inflammatory agents the resolu-
tion factors are multiple, often redundant in their
functions, and will probably result in as complex
a process as the expression of molecules engaged
in acute inflammation.
Like proinflammatory reactions, proresolution
responses have different effects, in some cases,
depending on the cells and tissues targeted. In
addition, although animal models may be excel-
lent tools for examining the role of mediators in
inflammatory settings, there is no guarantee that
identical findings will always be determined in
humans. The conversion to a proresolution state
is mediated principally by a shift from the
proinflammatory prostaglandins and leukotrienes
to the proresolution lipoxins and cyclooxygenase-
2-derived mediators from eicosapentaenoic acid
(EPA) and docosahexaenoic acid termed resolvins,
docosatrienes, and neuroprotectins. Additional
endogenous anti-inflammatory factors may also
contribute to this resolution process such as heme
oxygenase-1, IL-10, and others, but the principal
proresolution mediators identified to date are
those derived from the prostaglandin and omega-3
polyunsaturated fatty acid pathways [321].
Two factors, prostaglandin E2 and phospholi-
pases, appear to mediate the resolution of
inflammation by the induction of 15-lipoxyge-
nase activity and the synthesis and release of
LXA4as well as by the alteration in phospholi-
pase isoforms leading to the expression of secre-
tory PLA2s types IIA and V and cytoplasmic
PLA2 (type IV) in conjunction with an increase
in cyclooxygenase-2 activity. Prostaglandin E2 is
263
a molecule exhibiting both proinflammatory and
anti-inflammatory effects and regulates the shift
from the eicosanoid biosynthesis of LTB4 and
5-lipoxygenase-derived products to the induction
of 15-lipoxygenase activity and the release LXA4.
PGE2 also upregulates the macrophage produc-
tion of IL-10, another anti-inflammatory media-
tor [322]. The presence of four PGE receptors
(EP1 EP2, EP3, and EP4) that subtend different
signal transduction pathways may contribute to
this shift to the 15-lipoxygenase pathway. The
EP2 and EP4 receptors stimulate adenylate
cyclase and increase the intracellular levels of
cyclic AMP, whereas the EP1 receptor activates
phospholipase C and phosphatidylinositol turn-
over. The EP3 is more complex since it has mul-
tiple isoforms as a result of EP3 gene splicing.
Nonetheless, PGE2 via its capacity to increase
intracellular cyclic AMP stimulates phosphory-
lated CREB-1-mediated activation of 15-lipoxy-
genase transcription.
Accompanying these changes induced by
PGE2 there is an alteration in the activities of
phospholipase A2 isoforms from a predomi-
nance of the type VI calcium-independent PLA2
in the acute inflammatory response to the expres-
sion of types IIA and V secretory phospholipase
A2s and subsequently the expression of type IV
cytosolic phospholipase A2 in the resolution
phase. In parallel with this transition to the reso-
lution phase, there is an increased expression of
cyclooxygenase-2 [602]. The calcium-indepen-
dent PLA2 is responsible for the generation of
the proinflammatory mediators PGE2, LTB4,
IL-1b, and PAF, whereas the type IV PLA2 in
conjunction with COX-2 generates PGD2 and
15-deoxy-D12¢14-PGJ2, mediators that have
anti-inflammatory activities.
Lipoxin Biosynthesis
The lipoxins are lipid mediators derived from
cell-cell interactions and the activity of either 15-
and 5-lipoxygenase or 5- and 12-lipoxygenase
[323]. The term, lipoxins, is derived from lipoxy-
genase interaction products and indicates the
endogenous production of these molecules from
264 8 Mechanisms of the Acute Attack of Gout and Its Resolution
lipoxygenases. In contrast to the proinflammatory
lipid mediators generated from arachidonic acid
via cyclooxygenase-1 and cyclooxygenase-2 to
form prostaglandins or via 5-lipoxygenase to
form leukotrienes, the lipoxins are produced by
transcellular biosynthesis and are endogenous
stop signals for inflammatory responses. The lat-
ter lipids are trihydroxytetraene-containing mol-
ecules synthesized in the vascular lumen by the
interaction between platelets and leukocytes or in
tissues via endothelial cell and leukocyte
interaction.
The first lipoxin biosynthetic pathway was
identified in monocytes and epithelial cells and
catalyzed the insertion of oxygen into arachi-
donic acid mediated by 15-lipoxygenase to
form 15S-hydroperoxyeicosatetraenoic acid or
its reduced form, 15S-hydroxyeicosatetraenoic
acid (15S-HETE). The latter compound then
serves as a substrate for neutrophil 5-lipoxy-
genase to form 5,6-epoxytetraene. The latter
compound is unstable and leads to the genera-
tion of trihydroxytetraenes via leukocyte epox-
ide hydrolases. Two trihydroxytetraenes result
from this biosynthetic pathway: lipoxin A4
(5S, 6R, 15S-trihydroxy-7,9,13-trans-11-cis-
eicosatetraenoic acid or lipoxin A4) and lipoxin
B4 (5S, 14R, 15S-trihydroxy-6,0,12- trans-8-cis-
eicosatetraenoic acid or LXB4).
A second pathway for the synthesis of lipox-
ins is through the generation of leukotriene
from arachidonic acid catalyzed by neutrophil
5-lipoxygenase. LTA4 taken up by platelets and
interacts with platelet 12-lipoxygenase leading
to the formation of 5S,6S,15S-epoxytetraene
and subsequently to and LXA4 and LXB4. The
third major pathway for lipoxin synthesis is
perhaps the most interesting since it involves
another anti-inflammatory agent, aspirin. In the
presence of aspirin, cyclooxygenase-2 (COX-2)
in endothelial cells, epithelial cells or mono-
cytes is acetylated and blocks the formation of
proinflammatory prostaglandins. This inhibi-
tory activity shifts the conversion of arachi-
donic acid from prostaglandin synthesis to
15R-hydroxyeicosatetraenoic acid. Leukocyte
5-lipoxygenase then converts 5-HETE to
5S,6S,15R-epoxytetraene and subsequently to
Table 8.2 Major endogenous anti-inflammatory factors
Annexin-1 and annexin-derived peptides
Lipoxins and 15-epi-lipoxins Interleukin-10
Resolvins, docasatrienes, and neuroprotectins
Anti-inflammins
PGD2 and PGA1
Inosine monophosphate
PAF acetylhydrolase (PAF-AH) Epoxyeicosatrienoic
acids (EET) Nitric oxide, peroxynitrite
TGF-a (Transforming growth factor-a) IL-1 receptor
antagonist (IL-1ra)
IL-13
IL-4
High-density lipoproteins
Heme oxygenase-1 and carbon monoxide
15-epi-LXA and 15-epi-LXB4. These are the
15R-enantiomers of LXA4 LXB4, and the lat-
ter lipoxins have been given the acronym, ATL,
for aspirin-triggered lipoxins. These lipox-
ins are rapidly synthesized, often enhanced by
proinflammatory cytokines and their upregula-
tion of 5-lipoxygenase or cyclooxygenase, and
are rapidly inactivated by oxireductases after
their local effect has occurred [324].
Lipoxins have documented to be present in
inflammatory disorders, and a variety of anti-
inflammatory actions have been determined for
these molecules and their stable analogs using
both in vitro and in vivo systems. Such in vitro
and in vivo effects are summarized in Table 8.2.
The in vivo studies of lipoxins have addressed
primarily organ-specific changes and do not
include any evaluations of the synovial mem-
brane, but it is likely that such lipoxin-induced
changes may well be relevant to gout. The data
in clearly demonstrate that LXs, ATLs, and their
nontoxic analogs inhibit leukocyte trafficking
via an alteration in chemotaxis, cell adhesion,
and neutrophil transmigration. They also enhance
the phagocytic clearance of apoptotic cells. Such
in vitro and in vivo data document the role of
these agents in resolving inflammatory responses
and emphasize the broad therapeutic effects of
aspirin. In summary, lipoxins have been identified
as endogenous regulators of inflammation since
they appear to act as brakes for the inflammatory
response.
Lipoxin Biosynthesis
Anti-inflammatory Effects of Lipoxins
The anti-inflammatory effects of lipoxins are
summarized in Table 8.2 and such data empha-
size the broad spectrum of effects mediated by
these molecules. A few of these effects deserve
further discussion. As noted previously, another
interesting offshoot of the inflammation regula-
tory aspects of lipoxins is the induction of
15-epi-lipoxin A4. by aspirin [325]. Aspirin is
well known to acetylate the active site of cycloox-
ygenase-2 in endothelial and epithelial cells
[326]. Such COX-2 acetylation leads to the syn-
thesis of (15R) hydroxy-eicosatetraenoic acid
(15R-HETE). The latter molecule is then con-
verted to 15-epi-lipoxin by leukocyte 5-lipoxyge-
nase by a transcellular mechanism. Such a
mechanism appears to be present in humans since
aspirin causes an increase in urinary 15-epi-
lipoxin levels in humans [213]. This latter metab-
olite (15-epi-lipoxin) causes an increase in the
plasma levels of nitrite. This increment results
from both constitutive nitric oxide synthase
(eNOS) and inducible nitric oxide synthase
(iNOS) [214]. Aspirin has also been found to
reduce the inflammatory response in correlation
with an increase in plasma nitric oxide in rats
with carrageenin-induced pleurisy. Since nitric
oxide appears to have a biphasic effect, the level
of NO may have a significant role on its regula-
tory effects. At low levels of NO produced by
eNOS, NF-kappa B is activated, whereas at high
levels of NO typical of iNOS induction,
NF-kappaB is inhibited. Thus, the use of stable
analogs of 15-epi-lipoxin holds promise as a way
to cause anti-inflammation when such agents are
under strictly controlled delivery [214].
Of some interest to this discussion of lipoxins
and the resolution of the inflammatory response
is the fact that LXA4, at very low concentrations,
decreases LTB4-and fMLP-mediated calcium
mobilization, and such interference with cal-
cium mobilization impedes neutrophil chemot-
axis, transmigration, adhesion, degranulation,
and superoxide generation. Of even greater
interest to the resolution of gout is the fact that
lipoxins and their stable analogs stimulate non-
phlogistic phagocytosis of apoptotic neutrophils
265
by mononcyte-derived macrophages LXA4-
triggered phagocytosis has been shown to be
optimal at 10–9 M concentrations (EC50 = ~ 0.5
× 10 − 9 M), and this concentration is consistent
with the EC50 for LXA4 of 8.3 × 10−10 observed
in the THP-1 cell line derived from acute mono-
cytic leukemia cells. Thus, lipoxin(LX), aspirin-
triggered lipoxin (ATL), 15-epi-lipoxin B4
(15-epi-LXB4), and a stable synthetic analog
of lipoxin, 15(R/S)-methyl-LXA4, all promote
macrophage phagocytosis of apoptotic human
neutrophils in vivo.
This macrophage phagocytic process is not
dependent on phosphatidylserine membrane
expression but depends on the expression of avb3-
CD36 complex. This adds significance to the
redundancy of receptors utilized for the inges-
tion of apoptotic cells by the macrophage. Now
two receptors for lipoxins have been described :
FPRL-1 and FPRL-2. Incubation of macrophages
with apoptotic neutrophils also causes a sixfold
increase in the release of TGFb, another anti-
inflammatory mediator. Furthermore, PKC, Pl3-
kinase, and phosphatase inhibition decreases
macrophage phagocytosis of apoptotic neutro-
phils. Finally, the fact that in some instances,
lipoxins suppress neutrophil chemotaxis, yet
they activate monocyte chemotaxis gives rise
to the question as to how such differences in
chemotaxis occur. One explanation offered for
these opposite actions on the monocyte and neu-
trophil is the possibility that they utilize different
receptors. This receives support from the fact that
FPRL-2 is not present on the neutrophil but is
expressed on the monocyte/macrophage. Recent
investigations have characterized some of the
anti-inflammatory effects of LXA4. on human
synovial fibroblasts and determined their action
occurred via the LXA4receptor. In these stud-
ies, IL-1b and TGF-b2 upregulated the expres-
sion of LXA4R mRNA. In addition, the effects
of LXA4 were inhibited by antibodies against its
receptors.
Another role for the arachidonic acid
metabolite, 15-hydroperoxyeicosatetraenoic acid
(15-HPETE) has recently been described [215].
These studies suggest that 15-HPETE appears
to destabilize TNFmRNA by interacting with
266 8 Mechanisms of the Acute Attack of Gout and Its Resolution
a protein_bound to the AU-rich element of
TNFmRNA. In summary, the existence of anti-
inflammatory molecules with the potential for
modulating the inflammatory response in humans
is confirmed by the foregoing studies. Neutrophils
clearly are programmed for cell death based on
their short lifespan, but this short lifespan may be
prolonged by proinflammatory substances and
antiapoptotic molecules. The balance between
proapoptotic and antiapoptotic proteins is the key
to the route the neutrophil takes either for sur-
vival or death. It is likely that the induction of
proapoptotic proteins or the design of nontoxic,
stable analogs of these proapoptotic proteins will
be useful as agents to enhance the clearance of
neutrophils from the inflamed site and may be of
benefit shortening the acute episode of gout.
Proinflammatory to Anti-inflammatory
Switch
There are two phases to the inflammatory
response with respect to lipid mediators as defined
by the murine air pouch model of inflammation.
All these experiments support the theory that
15d-PGJ2 and perhaps other PGD2 metabolites
have anti-inflammatory effects on the cellular
responses known to be associated with resolving
gout. Additional experiments using animal mod-
els of acute crystal-induced gout need to be com-
pleted so that chondrocyte and synoviocyte
responses can be evaluated in the presence of
15d-PGJ2 injected into crystal-induced (MSU)
inflammation in animal joints.
Resolvin Biosynthesis (Fig. 8.7a, b)
The trivial name, resolvin, arises from the fact that
they are resolution phase interaction products. The
compounds derived from eicosapentaenoic acid
are designated as the E series of resolvins, whereas
the resolvins derived from docosahexaenoic acid
are designated as the D series of resolvins. The
biosynthesis of the so-called resolvins occurs in
the presence of omega-3 fatty acids such as eicos-
apentaenoic acid (C20:5) and docosahexaenoic
acid (C22:6) and aspirin. As has been shown
arachidonic acid is metabolized by aspirin-acety-
lated cyclooxygenase/lipoxygenase interactions
to the epi-lipoxins. When eicosapentaenoic acid
(EPA) or docosahexaenoic acid (DHA) are substi-
tuted for arachidonic acid, DHA is converted to
17R-hydroxydocosahexaenoic acid (17R-H(p)
DHA) and subsequently reduced to its correspond-
ing alcohol. The action of leukocyte 5-lipoxyge-
naseleadstothegenerationof7(8)-epoxy-17R-DHA
or 4(5)-epoxy-17R-HDHA. These two precursors
lead to the formation of four different resolvins:
7S, 8, 17R-triHDHA and 7S, 16, 17R-triHDHA
(resolving D1 and D2, respectively) from
7(8)-epoxy-17R-DHA and 4S, 11, 17R-triHDHA
and 4S, 5, 17R-triDHA (resolvins D3 and D4,
respectively) from 4(5)-epoxy-17R-HDHA. In the
case of human endothelial cells treated with aspi-
rin in the presence of EPA, the latter molecule is
then converted to 18R-hydroxyeicosapentaenoic
acid and 15R-hydroxyeicosapentaenoic acid.
These molecules are further metabolized to gener-
ate 15R-LX5 and 5,12,18R-hydroxyeicosapen-
taenoic acid. The latter compound has been given
the common name, resolvin E1. A number of
recent publications have reviewed these biosyn-
thetic pathways and the properties of their prod-
ucts [316, 327].
Resolvin Receptors (Fig. 8.8)
The specific receptors for the resolvins are desig-
nated as resolvin D receptors (ResoDR1), resol-
vin E receptors (ResoER1), and neuroprotectin D
receptors (NPDR). The characterization of such
receptors is in its early stages, but the definition
of such receptors holds the promise of the devel-
opment of stable agonists that would trigger the
synthesis of resolvins and enhance the resolution
of an acute inflammatory process. The resolvins
and protectins are a new family of lipid mediators
derived from omega-3 polyunsaturated fatty acids
that promote the resolution of inflammatory reac-
tions. These publications document the potent
anti-inflammatory activities of these resolvins
and protectins, and the design of stable analogs
of these endogenous anti-inflammatory agents as
Lipoxin Biosynthesis 267

well as their transductive pathways offers the
possibility of acquiring potent anti-inflammatory
therapeutic drugs.
In summary, the resolution of an acute
inflammatory process is a complex, multifaceted
process that requires three critical parameters:
the suppression of neutrophil recruitment, the
disposal of apoptotic cells including other dead
cells and cellular debris, and the suppression of
antiapoptotic mechanisms. Lipoxins and their
stable analogs inhibit neutrophil infiltration from
the vascular compartment to inflamed sites as
well as blocking the expression of proinflammatory
mediators such as IL-1b, TNF-a, and IL-8. Both
resolvin D and E also have the capacity to sup-
press neutrophil recruitment to inflammatory
sites. In addition, annexin 1, a protein induced by
glucocorticoids, and its N-terminal peptides also
diminish neutrophil extravasation and suppress
the inflammatory response. An intriguing aspect
of these anti-inflammatory molecules is that one
receptor, ALXR, is utilized by both annexin 1
and lipoxin A4 as well as other endogenous pro-
teins that regulate the pathways engaged by these
anti-inflammatory vectors. Interestingly, the
resolvin receptors await complete characteriza-

a COOH

Eicosapentaenoic acid

HOOC

Fig. 8.7 (a, b) In addition to O(O)H

arachidonic acid, omega-3 18-Hydroperoxyiecosapentaenoic acid
fatty acids such as
COOH
docosahexaenoic acid (DHA)
and eicosapentaenoic acid
(EPA) are converted by
acetylated COX-2 to potent
anti-inflammatory agents
designated as resolvins.
Human neutrophils via this
reaction yield 17R-DHA, and OH
O
endothelial cells by the same
reaction yield 18R-EPE. The
following nomenclature has
been adopted for these 5s, 6R-epoxy, 18R-hydroxy-eicosapentaenoic acid
trihydroxy products: 7S, 8, COOH
17R-triHDHA is resolvin D1; HO
7S, 16, 17R-triHDHA is
resolvin D2; 4S, 11,
17R-trihydroxyHDHA is
resolvin D3; 4S, 5,
17R-trihydroxyHDHA is OH
resolvin D4; and 5S, 12R,
18R-trihydroxy-EPE is
resolvin E1. 4(5),
17R-HDHA is OH
4(5)-epoxy-17R-HDHA 5S,12R,18R-trihydroxyeicosapentaenoic acid
268 8 Mechanisms of the Acute Attack of Gout and Its Resolution

b
COOH

Docosahexaenoic acid

HOOC

O(O)H
17R-H(p) DHA

COOH

4(5)-17R-H DHA

HO
COOH COOH

OH

OH OH
OH

HO

4S, 5,17R-triHDHA 4S, 11,17R-triHDHA

Fig. 8.7 (continued)

Lipoxin Biosynthesis 269

Specialized Pro-Resolving Mediators

Stop PMN transmigration and Non-phlogistic monocyte recrutment

chemotaxis, brake eosinophils
SPM Uptake and removal of apoptotic PMN and
General Actions Block prostaglandins and leukotrienes microbial particles by macrophages
Reduce cytokine release and function Enhance anti-microbial defense mechanisms
(TNFα) and clearance at mucosal surfaces

Precursors Arachidonic acid Eicosapentaenoic acid Docosahexaenoic acid

(AA) (EPA) (DHA)

E- Series D- Series Protectins/

Families Lipoxins Resolvins Resolvins Neuroprotectins

HO COOH
OH OH
HO OH
COOH COOH
HO OH OH COOH
OH OH

OH COOH HO HO OH
LXA RvE1 RvD1 RvD2 PD1/
NPD1
PMN-medicated tissue damage DC IL-12 production
Pain signals DC migration Adhesion receptors PMN adhesion to NF-KB and COX-2 expression
Angiogenesis and Phosphorylation signals ROS generation & endothelial cells Renal fibrosis
cell proliferation inhibit NF-κB reportor Pro-Inflammatory Nitric oxide and prostacyclin T-cell migration
l/R injury gene activation cytokines (TNFα, IL-8) in endothelial cells TLR-mediated Mφ activation
SPM PMN transmigration
ROS extracellular release Block PMN chemotaxis Microbial kiling and TNF and IFNγ release
Specific Actions Adhesion PGE2 production
Mucosal clearance of clearance Protection of retinal
Pro-inflammatory cytokines PMN by CD55 Neovascularization pigment epithelial cells
(TNFα, IL-12) PMN detachment Microglial cell Neuroprotective actions
DC-lymphocyte interactions cytokine expression
LXA4 production CCR5 expression on T-cells
(immune synapse)
ROS intracellular
Phagocytosis and IL-10
production Microbial killing

Fig. 8.8 The genus of specialized proresolving media-
tors: structures and actions. The SPM genus is defined by
reduction or limiting further PMN infiltration and reduc-
tion of lipid mediators and cytokines. SPM also stimulate
the nonphlogistic recruitment of mononuclear cells and
the stimulation of macrophages to phagocytose apoptotic
PMN microbes and microbial particles. The family pre-
cursors are substrates for their respective conversion to
lipoxins, E-series resolvins, D-series resolvins, and protec-
tins. The main structures of key SPM genus members are
depicted; the complete stereochemistry of each has been
determined, and their physical properties and bioactions
have been confirmed by total organic synthesis (Source:
Serhan [328]. Copyright © 2010 American Society for
Investigative Pathology Terms and Conditions)

tion and their relationship to the AXL receptor
remains to be defined.
The clearance of leukocytes and macrophages
from inflamed sites may occur by several routes.
Leukocytes can emigrate from an inflamed site
back to the systemic circulation [329]. Cells
from inflammatory sites may also migrate to
lymph nodes via the lymphatic drainage system.
Finally, cells may be cleared by phagocytosis
after cell death by necrosis or apoptosis. The lat-
ter process is the most efficient means of clearing
cells and limiting tissue damage since it is a non-
phlogistic process. Cells such as neutrophils in
an inflammatory site must undergo apoptosis
and subsequent phagocytosis by macrophages if
clearance in a nonphlogistic manner is to occur.
A variety of mechanisms have been described for
the recognition of apoptotic neutrophils, the sup-
pression of proinflammatory cytokines as well as
the release of immunosuppressive cytokines like
IL-10 and TGF-b1 by macrophages, and apop-
totic cells contribute to the anti-inflammatory
effects of these processes. As noted previously,
glucocorticoids and lipoxins can increase the
capacity of macrophages to ingest apoptotic cells.
Apoptosis is also of significance to the switch
from proinflammatory to anti-inflammatory
processes as well as to the enhancement of the
expression of death receptors and the induction
of apoptosis. PGE2 via its capacity to increase
cellular cyclic AMP can suppress the capacity of
macrophages to ingest apoptotic neutrophils, yet
lipoxin and annexin 1 can induce apoptosis and
enhance the ingestion of apoptotic neutrophils
270 8 Mechanisms of the Acute Attack of Gout and Its Resolution
by macrophages [330]. Although incompletely
resolved, elevated prostaglandin levels such as
PGE 2 appear to be involved in the switch from
the generation of proinflammatory eicosanoids
to the synthesis of proresolving eicosanoids like
lipoxin. The following mechanism, as noted pre-
viously, has been proposed as a means by which
prostaglandins and phospholipases regulate this
switch. Type VI calcium-independent phospho-
lipase A2 triggers the synthesis of PGE2, PAF,
LTB4, and IL-1b, the proinflammatory mediators
that are observed in the early phases of an acute
inflammatory response. During the resolution of
an inflammatory response, type IIa and type V
secretory PLA2 and type IV cytoplasmic PLA2
are the predominant isoforms expressed. These
PLA2 isoforms are either not detectable or mini-
mally detectable at the onset of an inflammatory
reaction. These studies were performed on rats
that had the inflammation-provoking substance,
carageenin, injected into their pleural cavity to
create an inflammatory pleuritis. Pleural exu-
dates were then examined for their distribution of
phospholipases using the cells recovered from the
exudate as the phospholipase source. Although
only this pleuritis model has been evaluated, it
is presumed that this experimental system would
hold for other inflammatory reactions. Since cor-
ticosteroids regulate inflammatory responses, the
level of corticosterone was measured during the
onset and resolution of this carageenin-induced
pleuritis. In carageenin-induced pleuritis, cor-
ticosterone levels were the highest at the outset
but declined to normal levels and below dur-
ing the resolution phase. Interestingly, experi-
mental data show that dexamethasone has little
effect on the suppression of IL-1b-stimulated
type VI calcium-independent PLA2, whereas
dexamethasone reduces the type IV cytosolic
PLA2 increments triggered by IL-1b. These
data suggest that type VI calcium-independent
PLA2 appears to be resistant to glucocorticoid
PLA2 suppression and that the expression of
PLA2 is regulated by endogenous glucocorti-
coids. It has also been postulated that the inhi-
bition of secretory and cytoplasmic PLA2 leads
to the expression of calcium-independent PLA2
as the primary provider of arachidonic acid for
the synthesis of proinflammatory mediators.
Calcium-independent PLA2 is also necessary for
IgG-mediated phagocytosis and for the process-
ing of IL-1b. In the resolution phase of rat car-
ageenin-induced pleuritis, sPLA2 types IIa and
IV are expressed at 36 and 48 h after the onset
of inflammation, and they synthesize lipoxins
and PAF. Lipoxins suppress leukocyte functions
including inflammatory cell infiltration, whereas
PAF enhances phagocytosis of apoptotic neutro-
phils by macrophages. Finally, in the late phase
of carageenin-induced pleuritis, lipoxins and
PAF trigger the expression of type IV cytoplas-
mic PLA2 and cyclooxygenase-2. This leads to
the synthesis of PGD2 and its cyclopentenone
prostaglandins to enhance resolution).
It is reasonable to assume that a complete pic-
ture of the changes in phospholipases and the
resultant genesis of anti-inflammatory agents
does not exist at this time. Nonetheless, several
components of importance to these changes have
been identified. Endogenous glucocorticoids
appear to have a role since the early phases of
inflammation are regulated by type VI calcium-
independent phospholipase A2 which is resistant
to suppression by glucocorticoids, and once
endogenous glucocorticoid levels are reduced to
normal, type IIa and type IV secretory phospholi-
pases come into play. The signal for the activa-
tion of these secretory PLA2s remains to be
identified, but the cytoplasmic type IV phospho-
lipase is triggered by lipoxins. Two additional
factors may have a role in this switching process:
PAF acetylhydrolase and nitric oxide/apoptosis.
PAF Acetylhydolase
and Anti-inflammation
Human plasma PAF acetylhydrolase (AH) is
composed of 441 amino acids and has been
mapped in the human to chromosome 6p12-21.1.
During the differentiation of monocytes to mac-
rophages, the latter cells synthesize and release
PAF-AH [331]. Although PAF-AH shows both
apoptotic and antiapoptotic activity, PAF-AH
Lipoxin Biosynthesis
regulates inflammation by diminishing the
proinflammatory stimuli of PAF and deficiencies
in PAF-AH give rise to several inflammatory
states. Although additional insight into the role
of PAF-AH is needed, the fact that macrophages
derived from monocytes synthesize and release
of PAF-AH suggests a role for this enzyme in
modifying PAF and its proinflammatory actions.
Apoptosis and Anti-inflammation
The other significant pathways regulating the
resolution of inflammatory responses are closely
linked to the apoptotic cell response. Two
major routes can be manipulated to suppress
inflammation: pathways that induce apoptosis
and pathways that suppress the expression of
antiapoptotic genes. Two pathways are known
to trigger apoptosis: the extrinsic pathway or the
death receptor pathway and the intrinsic path-
way or the mitochondrial death pathway. The
extrinsic pathway is triggered by the activation of
transmembrane death receptors secondary to the
binding of CD95, Fas, and tumor necrosis factor-
a to them. The binding of these receptors leads
to the activation of caspase-8 and/or caspase-10.
These caspases cleave procaspase-3 to generate
caspase-3 leading ultimately to apoptosis. The
caspases are proteolytic enzymes activated by
proapoptotic stimuli. C-FLIP (FADD-Iike ICE
(caspase-8) inhibitory protein, ARC (apoptosis
repressor with caspase recruitment domain), and
IAP (inhibitors of apoptosis) may impede the
progress of apoptosis and emphasize the need
to block their activity. The mitochondrial death
pathway is dependent upon the release of cyto-
chrome-c from the mitochondrial intermembrane
area to the cytoplasm of the cell. The mecha-
nism by which cytochrome-c is released from
the mitochondria is not completely resolved but
a number of mechanisms have been proposed.
Furthermore, staurosporine, actinomycin D,
peroxide, and ultraviolet radiation may also dis-
rupt the mitochondrial membrane and cause the
release of cytochrome-c. Once released from the
mitochondrial membrane, cytochrome-c binds the
271
apoptotic protease-activating factor 1 (APAF-1)
and with the addition of deoxyadenosine triphos-
phate/adenosine triphosphate (dATP/ATP) forms
the apoptosome. The latter heptameric complex
activates caspase-9 which then activates the
effector caspases (caspase-3, caspase-6, and cas-
pase-7). This pathway can also be interrupted by
inhibitors and emphasizes the need to shut down
all the proapoptotic molecules.
Two parameters have been described
that have pertinence to the resolution of
inflammation: the regulation of the pro apop-
totic and antiapoptotic pathways by NF-KB
and the role of epi-lipoxins and nitric oxide in
the anti-inflammatory response. Several factors
are of significance with respect to NF-KB. The
inhibition of NF-KB DNA binding in the late
phase of an inflammatory response impedes
the resolution of inflammation. COX-2 inhibi-
tion also impedes the resolution. An analysis of
leukocyte gene expression in the early phase (6
h) and the late phase (48 h) of a carageenin-
induced pleuritis demonstrated the presence
of proinflammatory cytokines (lymphotoxin
TNF-a, and the antiapoptotic protein, Bcl2) in
the early phase, whereas anti-anti-inflammatory
cytokines (TGF-and the proapoptotic Bcl2
homolog, Bax) are expressed in the late phase.
Recent evidence implicates the IKKa subunit
of the IKK complex as a negative regulator of
inflammation [332]. IKKa suppresses NF-kB
activity by increasing the turnover of the RelA
and c-Rel subunits of the NF-kB and their
removal from proinflammatory gene promoters.
In addition, p50-p50 homodimers appear to be
the principal NF-kB activity in the late phase
of inflammation. This p50-p50 homodimer is
known to suppress proinflammatory gene tran-
scription. To confirm these experimental data,
inhibition of NF-kB at the time of resolution
of inflammation has been shown to prolong
the inflammatory response and prevent apopto-
sis. These data also suggest that studies of the
IKKa subunit of NF-kB and its regulation are
likely to reveal approaches to the induction of
the resolution of inflammation and the means
by which apoptosis can be induced.
272 8 Mechanisms of the Acute Attack of Gout and Its Resolution
Nitric Oxide and Anti-inflammation
Finally, a series of investigations have related
nitric oxide, NF-kB activity, and aspirin.. Aspirin
acetylates COX-2 residing in either endothelial
cells or leukocytes which then leads to the syn-
thesis of 15-epi-lipoxin A4. The latter compound
then induces nitric oxide synthesis via constitu-
tive endothelial nitric oxide synthase and induc-
ible nitric oxide synthase. The nitric oxide
production triggered by aspirin then impairs leu-
kocyte-endothelium interactions causing an anti-
inflammatory effect. Investigations have also
shown that nitric oxide has a biphasic effect on
NF-kB activity. At low levels of nitric oxide gen-
erated by endothelial nitric oxide synthase,
NF-kB activity is activated, whereas at higher
levels triggered by inducible nitric oxide syn-
thase, NF-kB activity is inhibited. It has also been
shown that under some circumstances, endothe-
lial nitric oxide synthase causes the expression of
inducible nitric oxide synthase via soluble gua-
nylate cyclase. The existence of this nitric oxide
guanylate cyclase pathway has been confirmed in
human mesangial cells. These same investiga-
tions showed that IL-1- or TNF-a-triggered nitric
oxide production inhibited by NG-nitro-L-
arginine methyl ester (L-NAME) causes a
significant reduction in inducible nitric oxide
synthase expression. Such experiments demon-
strate the dependence of iNOS on eNOS activity,
and such findings are reversed by providing a
nitric oxide donor.
Evidence for the effects of lipoxins and aspi-
rin-triggered epi-lipoxins on leukocyte properties
and leukocyte-endothelial interactions have also
been described. These anti-inflammatory lipox-
ins impair leukocyte-endothelial cell interactions,
diminish leukocyte diapedesis, and block leuko-
cyte chemotaxis. A variety of publications have
documented the role of lipoxins and their stable
analogs as well as 15-epi-lipoxin A4 on cell adhe-
sion molecules [333]. It has also been shown that
inhibitors of lipoxin receptors or 15-epi-lipoxin
A4 synthesis significantly impair the inhibition
of the effects of aspirin on neutrophil-endothelial
cell interactions. It remains to be determined
whether lipoxins alter cell adhesion directly or
via the generation of nitric oxide. Nonetheless,
nitric oxide does regulate components like
P-selectin and CD11/CD18 expression that
clearly affect inflammatory responses, and it may
account, in some part, for the anti-inflammatory
effects of aspirin and aspirin-triggered lipoxins.
In addition to its role in impairing leukocyte
transmigration, nitric oxide can also modulate
apoptosis. The general concept proposed at this
time is that low levels of nitric oxide produced by
the neuronal and endothelial cell isoforms of
nitric oxide synthases are cytoprotective, whereas
high levels of nitric oxide such as those produced
by inducible nitric oxide synthase cause apopto-
sis. The latter concept has some experimental
support since endogenous- and exogenous-
derived nitric oxide from inducible nitric oxide
synthase induce apoptosis in murine macrophage
cell lines. Human macrophages also undergo
apoptosis when exposed to exogenous donors of
nitric oxide. There are, however, some conflicting
reports as to apoptosis induced by nitric oxide
including the role of peroxynitrite formed from
the interaction between nitric oxide and the
superoxide anion [334]. Nonetheless, experi-
ments indicate that activated macrophages can
induce apoptosis by the release of nitric oxide.
In general, it is now proposed that low concen-
trations of nitric oxide activating soluble guany-
late cyclase with the formation of cyclic GMP
protects the cell from apoptosis. In contrast to
this, rabbit macrophages exposed to high concen-
trations of nitric oxide become apoptotic by
a guanylate cyclase-independent pathway that is
not altered by cyclic GMP-dependent kinases or
cyclic GMP analogs. Superoxide dismutase
antagonizes peroxynitrite-induced apoptosis in
these experiments, and therefore, the balance
between superoxide and nitric oxide may be
a significant regulator of apoptosis. Thus, nitric
oxide generation and inducible nitric oxide syn-
thase play a key role in the regulating apoptosis.
Finally, a brief discussion of the soluble epox-
ide hydrolases is warranted since this enzyme
family converts biologically active compounds
like epoxyeicosatrienoic acids (EETs), hydroxye-
icosatrienoic acids (HETEs), and epoxyoctade-
cenoic acids (EpOMEs) to their respective diols.
Lipoxin Biosynthesis
These EETs possess anti-inflammatory activity
and inhibiting their further metabolism via epox-
ide hydrolases may serve to preserve these anti-
inflammatory effects. There is now experimental
evidence that soluble epoxide hydrolases inhibited
by either 12-(3-adamantane-1-yl-ureido)-dode-
canoic acid butyl ester (AUDA-BE) or 1-ada-
mantane-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)
urea (compound 950) diminishes levels of
proinflammatory cytokines and nitric oxide
metabolites but enhances the formation of lipox-
ins. Such inhibitors may also alter the expression
of NF-kB and IkB kinase via the persistence of
epoxyeicosatrienoic acids. These studies have
been extended by evaluating the changes in
tobacco smoke-induced inflammation in rats in
the presence and absence of the soluble epoxide
hydrolase inhibitor, 12-(3-adamantane-1-yl-
ureido)-dodecanoic acid n-butyl ester. When
either the inhibitor or the inhibitor plus EETs was
injected subcutaneously to mice prior to smoke
exposure, there was a significantly reduced num-
ber of bronchoalveolar lavage cells including
a reduction in neutrophils and macrophages when
compared to controls receiving no inhibitor/EETs
[335]. These investigations also showed that the
12-(3-adamantane-1-yl-ureido)-dodecanoic acid
n-butyl ester was rapidly converted to 12-(3-ada-
mantane-1-yl-ureido)-dodecanoic acid in vivo by
an esterase, and the latter compound appeared to
be the active ingredient. Furthermore, the combi-
nation of this inhibitor and epoxyeicosatrienoic
acids reduced the effect on bronchoalveolar
lavage cell accumulation more than the inhibitor
alone. Such data provide further evidence of the
anti-inflammatory actions of EETs.
The foregoing summary provides a bird’s eye
view of the complexity of the resolution of
inflammatory responses. In addition to this, the
role of glucocorticoids in the suppression of
inflammation is also. discussed subsequently in
another section. As will be seen, glucocorticoid-
induced anti-inflammatory effects mediated by
annexin 1 continue to provide significant insights
into the suppression of inflammation. It is
expected that investigations of the resolution of
inflammation and its regulation will continue to
provide useful information and will also generate
273
cellular and tissue targets for the development of
agents to control this phase of inflammation.
This discussion also describes in some detail
the pathophysiological responses that have been
or might be observed in acute and resolving gout.
Although not all the parameters discussed have
been definitively determined in gout, it is clear
that MSU crystal deposition, neutrophil chemot-
axis, neutrophil-MSU phagocytosis, and the gen-
eration of the inflammatory mediators necessary
to accomplish the ingestion of MSU crystals are
essential for the clearance of these inflammatory-
provoking foreign crystals. Much of the attention
concerning the management of inflammatory
conditions has focused on agents that block the
signaling controlled by NF-kB expression. This
approach is based on a large group of studies show-
ing that many anti-inflammatory agents inhibit
NF-kB. Such inhibitors of NF-kB include aspi-
rin, sodium salicylate, NSAIDS, glucocorticoids,
antioxidants, proteasome inhibitors, antisense
oligodeoxynucleotides, green tea polyphenols,
curcumin, resveratrol, and some cell-penetrating
peptides. Aspirin and sodium salicylate bind to
and block the ATP binding site of IKKb, the
phosphorylator of IkB and its subsequent degra-
dation. Thus, NF-kB is no longer constrained by
its inhibitor, IkB. Some NSAIDS inhibit NF-kB
activation, whereas others do not. Even acet-
aminophen blocks the binding of NF-kB to DNA
in certain cells under specific conditions.
A variety of mechanisms have been published
with respect to the way in which glucocorticoids
impair NF-KB activation and the expression of
the genes it regulates. These include the increased
synthesis of IkBa (the inhibitor of NF-kB),
a direct interaction between NF-kB and the glu-
cocorticoid receptor, the inhibition of RNA poly-
merase II phosphorylation, the sequestration of
RelA (a component of NF-KB), and the recruit-
ment of histone deacetylase 2 [336]. The effects
of glucocorticoids are discussed in greater detail
in a separate section subsequently. Selected anti-
oxidants also impair NF-kB activation. The inhi-
bition of prosteasome-dependent degradation of
the natural inhibitor of NF-kB, IkB, results in
the inability of NF-kB to free itself from its
inhibitor and translocate to the nucleus. Several
274 8 Mechanisms of the Acute Attack of Gout and Its Resolution
proteasome inhibitors have been characterized
as effective NF-kB inhibitors via this mecha-
nism. Both antisense oligodeoxynucleotides and
decoy oligodeoxynucleotides have also been
found to impair NF-kB-mediated gene expres-
sion [337]. In addition, natural dietary com-
pounds including green tea polyphenols,
resveratrol, curcumin, and capsaicin also impair
NF-kB expression, usually by blocking IKK
activity [338]. Despite the clear evidence that
NF-kB inhibition provides a means of suppress-
ing inflammatory responses, the lack of target
specificity raises some problems with the use of
such agents. For example, the inhibition of
cyclooxygenase activity is clearly beneficial in
the treatment of inflammation, but the nonse-
lective activity of these inhibitors may be haz-
ardous to the gastrointestinal tract, kidney, or
cardiovascular system. However, the joint cav-
ity represents an excellent site for the activity
of such agents to prevent inflammation since
compounds can be designed to act only at the
local site and have a delayed rate of absorption.
The use of natural substances also avoids the
issue of the immunogenicity of therapeutic
agents.
Drugs
The dependence of proinflammatory gene expres-
sion on transcription factors like NF-kB has led
to an evaluation of the role of anti-inflammatory
drugs as modulators of NF-kB. Aspirin and
sodium salicylate at relatively high doses (mM)
impede the degradation of IkB, and by this mech-
anism, they inhibit the activation of IKK. These
agents bind to IKKb but not to IKKa to inhibit its
kinase activity. The use of aspirin inhibits IL-1-
and TNF-induced NF-kB activation as well as
the expression of IL-6 and IL-8 in synovial
fibroblasts.
A variety of nonsteroidal anti-inflammatory
drugs (NSAIDs) all inhibit IkBa kinase causing
a decrease in its degradation and a decrease in
NF-kB-regulated genes.
A few additional anti-inflammatory and anti-
arthritic medications are also inhibitors of NF-kB
activation. Sulfasalazine has been shown to be
a specific inhibitor of NF-kB activation but its
two metabolites, sulfapyridine and 5-aminosali-
cylic acid (5-ASA), do not have any effect on
NF-kB activation. Sulfasalazine also blocks
TNF-, endotoxin-, and phorbol ester-induced
NF-kB activation. Some evidence also exists to
show that gold compounds may also impede
NF-kB activation. Since reactive oxygen species
(ROS) can activate NF-kB, antioxidants such as
dithiocarbamates and N-acetylcysteine have been
evaluated as suppressors of NF-kB activation.
Both dithiocarbamate and N-acetylcysteine sup-
press NF-kB activation. These data support the
concept that NF-KB activation is a key to the
generation and expression of proinflammatory
genes, and the inhibition of this process repre-
sents a significant means of suppressing
inflammatory reactions.
Glucocorticoid
Overview
Although receptor desensitization and lipoxin
generation are natural mechanisms for the
induction of anti-inflammatory responses with
the subsequent resolution of acute arthritic
attacks in gout, the mechanisms by which
anti-inflammatory drugs affect inflammatory
responses may also provide additional ratio-
nales for suppressing inflammation. One
of the most efficient means of suppressing
inflammatory responses is through the use of
glucocorticoids. These drugs upregulate lipoco-
rtin-1 and p11/calpactin binding protein which
act to suppress the release of arachidonic acid,
a precursor of many proinflammatory mediators.
Glucocorticoids also induce secretory leukocyte
protease inhibitor (SLP1), b-adrenergic recep-
tors, and interleukin-1 type II receptor (IL-IRA).
Glucocorticoid-dependent induction processes
take 24–48 h to develop, and for this reason, they
are likely to regulate the late stages of an acute
inflammatory reaction. Of greater pertinence
to the regulation of immediate inflammatory
responses are the glucocorticoid-dependent
Glucocorticoid
mechanisms that negatively control gene tran-
scription. Such mechanisms include DNA bind-
ing-dependent transrepression, transrepression
without DNA binding, and gene regulation via
posttranscriptional and translational mecha-
nisms [339]. Although glucocorticoid-mediated
induction of proteins may contribute to the late
anti-inflammatory effects of glucocorticoids,
glucocorticoid-mediated actions may also occur
by nongenomic actions such as the activation
of mitogen-activated protein kinases, adenylate
cyclase, protein kinase C, and heterotrimeric
guanosine-binding proteins (G proteins). Many
glucocorticoid-mediated anti-inflammatory
changes may also act by decreasing gene expres-
sion. In fact, the major anti-inflammatory action
of glucocorticoids occurs via the inhibition of
proinflammatory transcription factors such as
activator protein (AP-1), signal transducers and
activators of transcription (STATs), nuclear fac-
tor of activated T cells (NF-AT), and nuclear
factor (NF)-kappa B. In general, multiple mecha-
nisms for positive and negative regulation of
glucocorticoid-mediated gene expression exist,
and as will discussed in detail subsequently, the
specific sites to which the glucocorticoid-gluco-
corticoid receptor complex binds can either acti-
vate (transactivation) or repress (transrepression)
gene transcription.
Mode of Action
Glucocorticoids cause their effect on cells in the
following manner. Lipophilic glucocorticoids
diffuse across the cell membrane and react with
intracellular cytoplasmic glucocorticoid recep-
tors (GRs). In the resting state, the glucocorti-
coid receptors are associated with proteins like
heat shock proteins that enhance their stability
and block their nuclear localization sequences.
However, when GR binds to its ligand, it dis-
sociates from hsp (heat shock protein) 90 with
the resultant exposure of nuclear localiza-
tion sequences. Glucocorticoid receptors are
encoded by a single gene, but two variants have
been described: an alpha and beta form. These
two homologous isoforms of the glucocorticoid
275
receptor (GR) are generated by alternative splic-
ing of the human GR gene in its ninth exon at
the site of the GR pre-mRNA [340]. The GRa
and GRb receptors diverge in their structure at
their carboxyl terminus. The last 50 amino acids
in the GRa are replaced by a nonhomologous,
15 amino acid sequence in GRb. The GRa
when bound to a glucocorticoid molecule results
in the translocation of the GRa from the cyto-
plasm to the nucleus. In the nucleus, this hor-
mone-receptor complex binds to specific DNA
response elements in the promoter region of the
glucocorticoid-responsive genes to enhance the
transcription of anti-inflammatory genes. The
direct binding of activated glucocorticoid recep-
tor alpha to the glucocorticoid response elements
(GREs) present on inducible anti-inflammatory
genes is called transactivation. The other mech-
anism by which the GRa receptor regulates
proinflammatory gene expression is by a process
termed transrepression. By this mechanism, acti-
vated GRa has a direct interaction with different
proinflammatory transcription factors like AP-1
and NF-kB to transrepress transcription factor-
inducible inflammatory gene activation. The
GRb receptor behaves quite differently from the
GRa since GRb, in contrast to the GRa, reacts
weakly with heat shock proteins, is transcription-
ally inactive and does not bind glucocorticoids.
In addition, GRb has a longer half-life than
GRa and has been related to glucocorticoid-
resistant states in several inflammatory cell types
and diseases, and its expression is enhanced by
proinflammatory cytokines such as TNF-a, IL-1,
a combination of IL-2 and IL-4, and IL-13. The
prevailing hypothesis is that GRa and GRb form
a heterodimer complex, and this heterodimer
inhibits GRa nucleus shuttling in response to
steroids. Although the role of the GRb receptor
still remains controversial, a significant data base
exists in support of the concept that GRb plays an
important role in the inhibition of GRa expres-
sion [341, 342]. Therefore, evidence supports
the fact that the human glucocorticoid receptor
beta is a natural dominant negative inhibitor of
human glucocorticoid receptor alpha-induced
transactivation of glucocorticoid-responsive
genes. The N-terminal domain of this receptor
276 8 Mechanisms of the Acute Attack of Gout and Its Resolution
contains serines and threonines where kinases
may phosphorylate the receptor [343]. Such
phosphorylation may alter nuclear export and
import, glucocorticoid binding affinity, recep-
tor stability, or transactivating capacity. The
glucocorticoid receptor-ligand complex binds
to specific sequences in the nuclear DNA pro-
moter region called glucocorticoid response
elements (GREs). Glucocorticoid-ligand com-
plexes bind as homodimers to nuclear DNA.
These GREs located in the promoter region
are known to regulate steroid-sensitive genes,
and activated glucocorticoid receptors regulate the
transcription of genes either directly or indirectly.
Several points should be recognized concern-
ing the functions of glucocorticoid-mediated
gene regulation. First, glucocorticoid-mediated
positive regulation of gene transcription or trans-
activation controls the side effects of steroid
treatment, whereas the regulation of anti-
inflammatory effects of steroids occurs via pro-
cesses of negative regulation of gene transcription
or transrepression. Second, as noted previously,
two forms of the human glucocorticoid receptor
have been described. The human GRa isoform
contains 777 amino acids, whereas a somewhat
smaller, dominant negative, and non-hormone
binding human GRb has also been characterized.
Third, both GR transactivation and GR transre-
pression appear to occur via multiple different
mechanisms. For example, genes that are posi-
tively regulated by GREs may activate transcrip-
tion when homodimers of GR bind cooperatively
to GRE sites. Another mechanism of positive
transactivation occurs when GR and another tran-
scription factor both bind to DNA and activate
transcription from composite binding sites. An
additional mechanism involves the interaction of
GR with a second transcription factor, and
together they activate transcription without the
requirement that DNA bind to GRE. Fourth, GR
transactivation regulates genes involved in gluco-
neogenesis including tyrosine aminotransferase,
alanine aminotransferase, and phosphoenolpyru-
vate carboxykinase. It is presently believed that
the genes responsible for the side effects of glu-
cocorticoid therapy are also regulated by GR
transactivation.
The primary purposes of the following discus-
sion are twofold: to characterize the mechanisms
for the activation and repression of inflammatory
genes and to delineate the mechanisms by which
glucocorticoids cause the suppression of acute
inflammatory responses like gout. Fulfilling these
two objectives not only identifies targets for the
development of anti-inflammatory drugs but also
characterizes putative pharmacological interven-
tion sites with the possibility of developing addi-
tional drugs with enhanced potency and fewer
side effects than the drugs available today.
Glucocorticoids can regulate genes through direct
transcriptional control, indirect transcriptional
regulation by interfering with other transcription
factors, and by posttranscriptional effects. Like
transactivation, negative regulation of transcrip-
tion (transrepression) can occur via many differ-
ent mechanisms, and models for glucocorticoid
receptor transcriptional modulation have been
generated and supported by investigative findings.
In the first model, homodimers of the glucocorti-
coid receptor repress transcription by interacting
negatively with glucocorticoid response ele-
ments. Such negative GRE sites are not common
and regulate only a few genes. In the second
model, a composite site exists for GR and factors
required for gene transcription. Such competitive
binding prevents transcriptional factors from
binding to GRE. This setting occurs when the
cyclic AMP response element binding protein
(CREB) cannot bind to GRE because it has over-
lapping sites with GR binding sites. In the third
model, GR interacts with a second transcription
factor and prevents gene transcription by a
method that does not require GR binding to DNA.
In the last model, both GR and· a second tran-
scription factor repress transcription through
composite DNA binding sites. This model
requires binding of both GR and the second tran-
scription factor to DNA. In summary, glucocorti-
coids regulate inflammation by transrepression of
transcription factors such as activator protein-1,
nuclear factor-kappa S, and nuclear factor-AT.
Thus, the primary but not the only means by
which glucocorticoids repress inflammation is by
interfering with transcription factors. Since
inflammatory response genes are primarily regu-
Glucocorticoid
lated by NF-kB and AP-1 then it is the interfer-
ence with these transcription factors by
glucocorticoids that causes the repression of
the inflammatory response. As the mechanisms
by which inflammatory genes are expressed and
repressed are discussed in the following
paragraphs, the relationships between glucocorti-
coids and these mechanisms will be characterized
if they apply.
At this time, the mechanisms by which glu-
cocorticoids suppress inflammation are com-
plex and continue to be evaluated, yet these
agents remain as the most common drugs used
to modify inflammatory responses. Even though
the anti-inflammatory effects of glucocorticoids
are complex and data regarding their mecha-
nisms of action are incomplete, multiple ways
for such anti-inflammatory effects to occur have
been described. The glucocorticoid effects on
inflammatory disorders are mediated by the inter-
actions between the ligand glucocorticoid and the
glucocorticoid receptor a and that complex then
serves as a transcription factor. There are three
ways in which such glucocorticoid-glucocorti-
coid receptor complexes mediate their effects:
activation or inhibition of transcription by RNA
polymerase II, interactions between the recep-
tor complex and other transcription factors such
as NF-kB or AP-1, and nongenomic pathways
whose activity is generated via membrane-associ-
ated receptors and their second messengers [344].
Another regulatory component of the glucocorti-
coid receptor is its posttranslational modifications
based on serine phosphorylations mediated by
cyclin-dependent kinases and mitogen-activated
protein kinases [345]. In fact, ubiquitin-related
modifiers interacting with the glucocorticoid
receptor may increase the transcriptional activ-
ity of the receptor. Glucocorticoids can result
in the expression of anti-inflammatory proteins
such as lipocortin, IL-1 receptor antagonist, and
the anti-inflammatory mediator, IL-10, by induc-
ing the transcription of genes near the glucocor-
ticoid response elements, by the recruitment of
co-activators such as CREB-binding protein/
p300, or by the action of RNA polymerase.
Glucocorticoids also inhibit the expression of
many proinflammatory cytokines such as IL-1,
277
TNF-a, chemokines, and leukocyte adhesion
molecules by blocking the effects of activated
glucocorticoid receptors on transcription factors
like NF-kB and AP-1. In addition, glucocorti-
coids inhibit histone acetyltransferase activity and
recruit histone deacetylase [346]. This inhibitory
and recruitment activity prevents the unwind-
ing of DNA and access to transcription factors.
Another way in which glucocorticoids cause anti-
inflammatory effects is via its interference with
the phosphorylation of the C-terminal domain
of RNA polymerase II, and thereby, reducing its
interaction with NF-kappa B-regulated promoter
regions and subsequent gene expression [347].
Finally, there is evidence in some cell types, espe-
cially lymphocytes and monocytes, that dexam-
ethasone triggers the synthesis of the NF-kappa
B inhibitor, I-kappa S-a [348].
Histone Acetylation and Glucocorticoids
The major mechanism by which inflammatory
genes are repressed is by altering histone acetyla-
tion. The cell chromatin in the nucleus of the cell
contains a complex of DNA, histones, and non-
histone proteins. Genes are repressed when DNA
is bound tightly to core histone proteins (H2A,
H28, H3, and H4), and the RNA polymerase II
enzyme cannot bind to DNA and generate
mRNAs. Histone core proteins contain lysine
molecules in their long N-terminal tail that can be
acetylated by the enzyme histone acetyltrans-
ferase. Acetylation of histones causes the tightly
bound DNA to unwind and allows the RNA poly-
merase II along with transcription factors to bind
to DNA Such acetylation reduces the charge on
histones and results in an activated form of chro-
matin ready for transcription factor binding. The
proinflammatory transcription factors like
NF-kappaB bind to specific DNA sequences and
then interact with coactivator molecules. The
principal coactivator molecules are cyclic ade-
nosine monophosphate response element-binding
protein (p300/CREB) and p300/CBP-associated
factor (PCAF). These coactivator molecules are
switches that control gene transcription, and they
have intrinsic histone acetyltransferase activity to
278 8 Mechanisms of the Acute Attack of Gout and Its Resolution
transform the chromatin structure from a closed
conformation to an open, activated form [349].
Thus, histone acetylation and coactivator associa-
tions result in the unwinding of DNA, the binding
of TATA box-binding protein (TBP), and the
binding of coactivators to the TBP. TBP brings
together the TATA box that identifies the start site
of gene transcription and the coactivator factors
and their related proteins as well as RNA poly-
merase II. The acetylation of histones, therefore,
initiates the expression of inflammatory genes.
Histone deacetylases (HDACs) cause the deacety-
lation of acetylated histones and result in the
repression of genes. It is also known that differ-
ent HDACs, of which there are 12, interact with
different histone acetylation patterns. It is also
well known that the inhibition of HDAC activity
causes an increase in histone acetyltransferase
activity and increased inflammatory gene expres-
sion. In addition to these HDAC activities that
suppress gene expression, other means of gene
repression exist including the modification of
core histones by methylation, phosphorylation,
ubiquitination, inhibition of mRNA stabilizers,
and inhibition of activators of transcription fac-
tors such the c-Jun N-terminal kinase and p38
MAP kinase. Glucocorticoid receptors may either
bind directly to activators and inhibit histone
acetyltransferase activity or may recruit histone
deacetylases to reverse histone acetylation and
suppress the expression of proinflammatory
genes. As noted, there are also other mechanisms
that play a role in the expression and repression
of proinflammatory genes including the induc-
tion and expression of anti-inflammatory genes
that lead to the release of anti-inflammatory
molecules.
Annexins and Glucocorticoids
At this juncture, the significant role of a gluco-
corticoid-inducible protein is discussed since it
plays a major role in the anti-inflammatory effects
of glucocorticoids. The first anti-inflammatory
agents to be identified in humans and animals
were natural and synthetic glucocorticoids. This
early work was extended by the discovery of a
glucocorticoid-inducible 37 kDa protein origi-
nally designated as lipocortin but now called
annexin 1 (ANXA1). This inducible protein
inhibits phospholipase A2 activity and as a result,
suppresses prostaglandin biosynthesis in per-
fused lungs and activated macrophages. A
significant impetus to the increase in its role in
inflammation resulted from the cloning of the
glucocorticoid-inducible protein, annexin, and
its capacity to inhibit acute inflammatory
responses.
In general, annexins are a family of intracel-
lular proteins with a unique structure of their cal-
cium binding sites permitting them to interact
with negatively charged phospholipids [350].
Although annexins are mainly components of the
intracellular milieu including elevated concentra-
tions in the cytosol of neutrophils, the adherence
of neutrophils to the endothelium results in the
export of annexin 1 to the cell surface. How
annexin 1 is transported to its extracellular sites
remains incompletely resolved, but several dif-
ferent concepts have been proposed [351].
Annexin 1 is stored in the gelatinase granules of
the human neutrophil and is transported to the
cell surface when neutrophils adhere to endothe-
lium. Glucocorticoids induce annexin 1 expres-
sion and/or the secretion of annexin.
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 Management of Hyperuricemia
and Gout
Overview
Management plans for the treatment of gout have
to be designed to meet the requirements of each
individual patient and to control both gout and its
associated disorders. The objectives of such plans
are as follows: (1) to initiate the resolution of an
acute episode of gout by using the appropriate
anti-inflammatory drugs, (2) to assess by history,
physical examination, and laboratory analyses
any underlying pathophysiological abnormalities
associated with hyperuricemia or gout, (3) to
treat any pathophysiological abnormalities com-
plicating the gouty diathesis such as hyperlipi-
demia, hypertension, obesity, and others, (4) to
prevent, when possible, any abnormality associ-
ated with the deposition of monosodium urate
such as tophaceous deposits, nephrolithiasis, and
renal damage, and (5) to educate patients as to the
management parameters for which they have the
primary responsibility (diet, alcohol use, etc.)
and to describe the potential side effects and
proper use of the prescribed drugs used for the
treatment.
There are two important principles with
respect to these management plans that need
emphasis. First, a distinct difference exists
between those pharmacologic agents used in the
treatment of acute gout and those drugs used as
uricosuric agents (e.g., probenecid) or xanthine
oxidase inhibitors (e.g., allopurinol). Drugs like
colchicine, NSAIDs, corticosteroids, and others
are anti-inflammatory agents with little or no
therapeutic effect on the control of hyperurice-
D.S. Newcombe, Gout,
DOI 10.1007/978-1-4471-4264-5_9, © Springer-Verlag London 2013
9
mia. Corticosteroids may have a modest uricosu-
ric effect but are never used to regulate uric acid
metabolism or to reduce the serum uric acid level.
In contrast to anti-inflammatory drugs, agents
used to control hyperuricemia and hyperuricaci-
duria have absolutely no anti-inflammatory activ-
ity and, in fact, may trigger an episode of acute
gout associated with the changes in the uric acid
pool induced by this drug. Furthermore, the con-
trol of acute gout with anti-inflammatory drugs is
absolutely required for the well-being of the
patient, whereas the reduction in the serum uric
acid level may not always be required.
Second, prescribing uric acid-lowering ther-
apy requires that the patient is in a quiescent
(intercritical) phase of their gout (inactive gouty
arthritis) and that a careful and thorough history
has been taken, a complete physical examination
has been performed, and appropriate laboratory
analyses have been undertaken to evaluate the
possible underlying disorders that might be asso-
ciated with gout. Individuals who overproduce
uric acid and have genetic abnormalities in purine
metabolism (PRPP synthetase overactivity and
hypoxanthine-guanine phosphoribosyltransferase
deficiency) merit treatment with urate-lowering
drugs. In addition, patients with uric acid nephro-
lithiasis and uric acid-induced renal disease who
require hypouricemic therapy should also be
treated with inhibitors of uric acid synthesis,
rather than uricosuric agents, since the latter may
increase the risks of nephrolithiasis. Certainly,
patients with antimetabolite-sensitive tumors
deserve pretreatment with allopurinol to prevent
291
292
urinary tract obstruction resulting from purine
breakdown and the precipitation of uric acid in
the renal tubules. Finally, patients with a solitary
kidney also deserve a careful clinical evaluation
if they suffer from acute or chronic gout since
their treatment regimens may need adjustment
based on the function of the solitary kidney.
Any approach to identify the cause(s) of hype-
ruricemia must include a determination as to
whether or not treatment should be instituted to
reverse this biochemical derangement. Even
though a solid scientific basis exists from which
rational therapeutic decisions can be made, phy-
sicians frequently mismanage hyperuricemia. In
general, hyperuricemia should only be treated
when urate-induced tissue damage has occurred
or is likely to occur from persistent, untreated
hyperuricemia. An approach based on mecha-
nisms of altered urate metabolism is presented
here. The significance of the two foregoing prin-
ciples concerning anti-inflammatory drugs and
hypouricemic agents requires careful consider-
ation by attending physicians, and for this reason
the discussion of such principles is expanded in
the following text.
Management of Asymptomatic
Hyperuricemia
In the case of non-drug-related hyperuricemia,
there are relatively few indications for the treat-
ment of asymptomatic hyperuricemia (Table 9.1),
and the clinical settings in which treatment is
necessary are rare. A history of renal calculi,
composed of either uric acid or calcium oxalate,
is a clear indication for the introduction of
allopurinol therapy to reduce the recurrence of
calculi. With respect to calcium oxalate calculi,
an increased uric acid excretion (>1 g/day) is
generally accepted as the urinary uric acid level
requiring the institution of allopurinol treatment
since the recurrence of calcium oxalate stones
decreases with such a treatment regimen.
Certainly, allopurinol therapy is indicated in indi-
viduals who express any of the heritable enzyme
deficiencies associated with abnormalities of
purine metabolism and overproduction of uric
9 Management of Hyperuricemia and Gout
Table 9.1 Allopurinol treatment of asymptomatic hype-
ruricemia: indications
Heritable enzyme deficiencies
Hypoxanthine-guanine phosphoribosyltransferase
PRPP synthetase overactivity
Glycogen storage disease (?)
Renal calculus
Calcium oxalate
Uric acid
Increased risk for renal calculus or tophaceous deposits
Urinary uric acid excretion of more than 1,000 g/day
Serum uric acid greater than 8–10 mg/dl
Single functioning kidney
Prophylaxis for cytotoxic chemotherapy or
radiotherapy
Secondary hyperuricemia
Urinary uric acid greater than 1,000 mg/day
Serum uric acid of 8 mg/dl or more
Renal disease (?)
acid since these patients are at higher risk for the
development of renal calculi and/or tophaceous
gout. Urinary uric acid excretion greater than
1,000 mg/day places these patients at risk for the
development of these complications, and
allopurinol significantly reduces the risk of such
complications (Table 9.1).
The issue of whether individuals with chronic
renal disease need treatment to reduce elevated
serum uric acid levels remains controversial.
Chronic renal disease is almost always associated
with hyperuricemia, but the serum uric acid levels
are usually less than 10 mg/dl, and the renal dis-
ease usually progresses very slowly. There is little
evidence to suggest that treatment with allopurinol
slows the rate of kidney deterioration in these
patients [1]. Nonetheless, in patients with a soli-
tary functioning kidney and marked changes in
uric acid metabolism (serum uric acid greater than
10 mg/dl and a urinary uric acid level of greater
than 1,000 mg/day), hypouricemic therapy may
be warranted. As one might suspect, there are no
hard and fast rules for these treatment regimens,
and there are exceptions to these recommenda-
tions. In addition, the levels of serum uric acid
considered to be indicative of the need for treat-
ment have been selected in an arbitrary fashion
and may vary from physician to physician. Their
Management of Asymptomatic Hyperuricemia
selection is not based on experimentally derived
data.
Drug-induced hyperuricemia is probably the
most common cause of elevated serum uric acid
levels observed in patients if one excludes those
with chronic renal disease and an associated
diminished excretion of nitrogenous waste prod-
ucts. Asymptomatic hyperuricemia induced by
drugs, especially diuretics, rarely requires treat-
ment to control the serum uric acid levels with
several important exceptions that are discussed
subsequently. The mechanisms by which diuretics
cause hyperuricemia are variable. Volume con-
traction secondary to diuresis may stimulate prox-
imal renal tubular reabsorption of urate leading to
elevated serum uric acid levels [2, 3]. Both furo-
semide and diazoxide induce hyperlacticacidemia
which reduces renal tubular excretion of urate
resulting in an elevation of serum urate levels [4,
5]. Furosemide and its congeners are bound to
plasma proteins and are not filtered to a significant
degree at the glomerulus. They are secreted into
the renal tubular fluid of the proximal tubules by
an organic transport system, and probenecid, a
uricosuric agent, blocks furosemide activity by
preventing its entry to the tubular fluid.
Hypertension and gout frequently occur
together, and patients with gout are at higher risk
for the development of hypertensive disease and
its complications than the general population [6–
8]. Since diuretics are often used for the treatment
of hypertension, gouty episodes in patients with
established gout may be aggravated by diuretic
therapy for hypertension, and hypertensive
patients may experience a new episode of acute
gout in association with the use of diuretics.
Recent studies have defined predictive factors for
the onset of gout in hypertensive populations to
include an increased consumption of alcohol,
obesity, male sex, and the use of loop diuretics
[9]. Of interest is the fact that thiazide diuretics
are more commonly prescribed for hypertension
than loop diuretics, but the latter drugs are more
frequently associated with gout in the hyperten-
sive patient than thiazides. Further, the associa-
tion of gout and the use of loop diuretics have
been shown to be related to reduced renal func-
tion since the increased frequency of gout has
293
been observed equally in patients both with no
renal impairment and those with decreased renal
function. Chlorthalodine is a more potent antihy-
pertensive than hydrochlorothiazide, and it also
causes elevations of the serum uric acid levels.
Patients with asymptomatic, drug-induced
hyperuricemia and an associated impairment of
renal function present a special set of problems.
First, it is difficult to determine what fraction of
the retained urate is related to renal dysfunction
and what quantity can be attributed to a drug-in-
duced alteration in the renal handling of urate.
Second, it is often difficult to distinguish between
urate-induced renal disease and non-urate-in-
duced nephropathy. Third, there are no carefully
controlled studies of the effects of antihyperuri-
cemic drugs on the course of chronic renal
disease.
Thus, whether the combination of diuretic-in-
duced hyperuricemia and an underlying nonurate
nephropathy should be treated in a different man-
ner from diuretic-induced hyperuricemia in the
absence of renal disease remains an unresolved
problem. Controlled studies need to be done to
determine what effects the additional burden of
diuretic-induced hyperuricemia might have on
the kidneys with a compromised capacity to
excrete urate. In the absence of such data, the
case for treatment is made on the basis of an
accelerated loss of residual renal function from
the hyperuricemic state and the concept that treat-
ment will retain the residual function. Those
opposing treatment argue that the potential risks
of hypouricemic drugs far outweigh their benefits.
Such arguments are reinforced by long-term fol-
low-up studies of diuretic-induced hyperuricemia
that show little evidence of progressive renal dys-
function [10–12]. Nonetheless, some physicians
consider treatment of hyperuricemia when the
serum urate levels are in the range of 8–10 mg/dl
in patients without hemoconcentration. An iden-
tical therapeutic regimen should be utilized for
patients with drug-induced hyperuricemia and an
associated urate nephropathy. A serum urate level
of 10–13 mg/dl or greater may justify hypourice-
mic drug treatment.
There are several special problems that arise in
the management of drug-induced asymptomatic
294
hyperuricemia. Patients with only a single func-
tioning kidney and drug-induced hyperuricemia
should probably be treated early and adequately
with antihyperuricemic drugs. Any complicating
clinical issue such as dehydration or urinary tract
infections in which the renal excretion of urate is
impaired should also be treated aggressively to
prevent deterioration of renal function. Drug-
induced hyperuricemia in an asymptomatic
patient with a family history of severe gout prob-
ably should be treated promptly to reduce serum
urate levels. Either a uricosuric agent or a xan-
thine oxidase inhibitor would be an appropriate
drug in the absence of renal disease; a xanthine
oxidase inhibitor is the drug of choice when renal
dysfunction exists. If drug-induced serum urate
levels are in the 9- to 10-mg/dl range or greater in
the male or female, a careful evaluation must be
undertaken to detect underlying disorders that
may be contributing to the altered uric acid
metabolism.
In asymptomatic hyperuricemic patients being
treated with nondiuretic-hyperuricemic drugs,
the mechanism inducing hyperuricemia is more
complex. Salicylates at low doses (<1.2 g/day)
cause urate retention by the kidney, but at higher
doses (2–4 g/day), salicylates are uricosuric
[13–15]. Low-dose salicylates rarely cause incre-
ments in serum urate concentrations greater than
1 mg/dl, but the use of salicylates in conjunction
with uricosuric agents abolishes the effect of the
latter drug [16, 17].
Pyrazinamide-induced hyperuricemia is
unresponsive to uricosuric drugs, but high doses
of salicylates (2–4 g/day) reverse the hyperuri-
cemia caused by this drug [18, 19]. Nicotinic
acid in doses of 3–6 g/day causes hyperuricemia
and inhibits the uricosuric effect of both
sulfinpyrazone (Anturane) and iopanoic acid (a
radiocontrast dye) [20]. For the latter reason,
nicotinic acid-induced hyperuricemia is usually
treated with allopurinol when therapy is indi-
cated. Rarely is treatment needed for such a con-
dition. Ethambutol (12–19 mg/kg body wt/day)
is likely to increase serum uric acid concentra-
tions, and elevated serum urate levels respond
either to uricosuric agents or xanthine oxidase
inhibitors [21].
9 Management of Hyperuricemia and Gout
The use of cytotoxic agents in the treatment of
neoplasia is also an important indication for
allopurinol pretreatment in order to avoid the
occurrence of uric acid nephropathy.
Symptomatic Drug-Induced
Hyperuricemia
A general scheme for the management of drug-
induced, symptomatic hyperuricemia includes
the identification of the offending drug, institu-
tion of a treatment regimen appropriate for gouty
arthritis, if present, and the use of antihyperurice-
mic agents to normalize the serum uric acid con-
centration when tophi, calculi, and/or gouty
nephropathy are present.
Drug-induced hyperuricemia is of course most
easily managed by substituting a drug that does
not cause hyperuricemia. In certain cases, the
offending drug is unnecessary and can be discon-
tinued altogether. For example, some patients use
aspirin, aspirin-containing drugs, or over-the-
counter NSAIDs for nonspecific illnesses on a
chronic basis, and this habit can frequently be
interrupted by the physician. Acute gouty arthri-
tis as a complication of drug-induced hyperurice-
mia is managed by pharmacologic agents that
reduce the acute intra-articular inflammatory
response. Tophi as a complication of drug-
induced hyperuricemia are relatively rare (see
the chapter on clinical gout and the subsection
entitled cyclosporine), but their presence is an
absolute indication for antihyperuricemic ther-
apy. In the absence of a simple, noninvasive
means for the detection of urate nephropathy and
clinical data that clearly define the effects of
hyperuricemia on renal function, recommenda-
tions regarding the use of antihypertensive drugs
to prevent renal insufficiency remain empirical.
Most attention should be devoted to the treatment
of any underlying medical condition predispos-
ing to renal dysfunction. Thus, the aggressive
management of hypertension, obesity, hyper-
lipidemia, and diabetes mellitus should take
precedence over the use of antihyperuricemic
drugs. Nonetheless, when serum uric acid levels
exceed 8–10 mg/dl, allopurinol is sometimes
Treatment of Acute Gouty Arthritis
used to prevent deterioration of renal function,
although as noted above, there is little evidence
to support this assumption. Allopurinol dosage
should at first be lowered when serum creatinine
levels are persistently elevated; such adjustments
in dose prevent the retention of allopurinol and
its oxidation product, oxypurinol [22, 23].
However, the dose of allopurinol should be
adjusted upward sufficient to bring the serum
urate levels to <6 mg/dl in order to prevent
sodium urate crystal deposition. Both allopurinol
and oxypurinol are relatively insoluble and may
be deposited in the kidney parenchyma [24].
Hyperuricemia Associated with the
Treatment of Neoplastic Disease
Drug-induced hyperuricemia associated with an
increased production of uric acid represents a
common problem for patients undergoing treat-
ment for neoplastic disorders. Acute uric acid
nephropathy is a serious complication of antine-
oplastic treatment regimens resulting from cell
destruction, purine catabolism, and the subse-
quent excretion of excessive quantities of urate
by the kidney. For this reason, it is customary to
initiate allopurinol therapy in those patients who
are scheduled to undergo chemotherapy or radio-
therapy for tumors. Allopurinol therapy, if possi-
ble, should precede the use of antineoplastic
therapy and should always be accompanied by
fluid hydration to ensure adequate solubility of
uric acid as well as the pyrazolopyrimidines
(allopurinol and its metabolites). To induce a
rapid inhibition of xanthine oxidase, allopurinol
should be administered at a dose of 300 mg/m2/
day in the first 48 h and followed by a dose of
300 mg daily. Twice-a-day dosage is the usual
method for dividing the total dose; a practical
regimen for most antineoplastic treatment settings
is to administer allopurinol 300 mg twice a day
for the initial period and follow this by a dose of
150 mg twice a day. Hydration may be accom-
plished either by mouth or by the intravenous
route. Three to 5 l of fluid over the normal
daily intake is an appropriate therapeutic goal.
Urine alkalinization with sodium bicarbonate or
295
acetazolamide (Diamox) also increases the solu-
bility of urate and allopurinol and its metabolites,
but alkalinization is usually not necessary in the
setting of antineoplastic treatment unless acute
uric acid nephropathy occurs. Acetazolamide is
associated with a rebound acidosis, which is the
reason why preference is given to sodium bicar-
bonate for urine alkalinization [25]. If acute uric
acid nephropathy does occur, one must first deter-
mine whether the patient is anuric or not. In the
anuric patient, hemodialysis is the most effective
means of treatment [26]. Ureteral lavage with
alkaline solutions and surgery to remove the urate
sludge are indicated only if the ureters are
obstructed. Conservative management including
measures to increase urine flow, solubilize urates,
and reduce uric acid production should be uti-
lized in patients who are able to maintain an ade-
quate urine output. This conservative regimen
necessitates careful monitoring of the volume of
urine excreted, urinary pH, plasma electrolytes,
arterial pH, and ketones when underlying chronic
pulmonary disease, renal disease, or diabetes
mellitus are present. Inhibition of carbonic anhy-
drase with acetazolamide to increase bicarbonate
excretion by the kidney is contraindicated when
arterial pH values are less than 7.2 or lactic acid
contributes to the acidosis. Since allopurinol
blocks the degradation of 6-mercaptopurine, aza-
thioprine, and other purine analogs and increases
the toxicity of these antimetabolites, their dose
should be reduced by one-third or more to avoid
the toxic potentiation of the antimetabolite effects
caused by allopurinol [27]. Further, careful moni-
toring of the patient on such a dual regimen has to
be undertaken to diagnose bone marrow suppres-
sion and secondary infections as a result of the
increased toxicity of these antimetabolites.
Treatment of Acute Gouty Arthritis
In this section, we will discuss the pharmacology
and the therapeutic uses of agents used to manage
gout. The drugs used to treat the acute attacks of
gout are discussed first. These include colchicine,
NSAIDs, glucocorticoids, and finally the emerg-
ing use of IL-1 inhibitors. Next, the management
296
of the chronic phase of gout is considered, that is,
the treatment of hyperuricemia, the factor that
underlies the acute attack and the chronic
inflammation and tissue destruction which occur
in gout. The important underlying principle is
that the pathologic consequences of gout arise
from the supersaturation of the body fluids with
monosodium urate that leads to precipitation of
monosodium urate crystals in tissues. It cannot
be emphasized too strongly that adequate preven-
tion of gout requires that the concentration of uric
acid in the blood, which is nearly all in the form
of urate monoanion, must be reduced below the
saturation level of 6.8 mg/dl (357 meq/l) in order
to prevent the precipitation of sodium urate in tis-
sues. Effective treatment of gout can only be
achieved when this condition is met. From a prac-
tical point of view, physicians should aim to
reduce the serum levels of uric acid to less than
6.0 mg/dl. Failure to adhere to this principle is
responsible for the widespread failure of the
management of gout in clinical practice, both by
the specialist and the generalist.
Colchicine Use in Acute
and Chronic Gout
Treatment Schedules
Colchicine is effective in the treatment of acute
gouty arthritis and can act prophylactically to
reduce the number of recurrent episodes of gouty
arthritis. In the past, responses to this drug have
been used as a diagnostic test for gout, but the
therapeutic response of pseudogout and other
articular disorders (sarcoidosis, hydroxyapatite
deposition, and familial Mediterranean fever) to
colchicine treatment has decreased the validity of
this pharmacologic test as a diagnostic tool
[28–39]. The standard dosage schedule for the
treatment of acute gout with colchicine has been
to administer one 0.5 or 0.6 mg tablet by mouth
every hour to a maximum of 6–8 mg in adults.
However, administration of colchicine according
to this schedule produces significant gastrointes-
tinal symptoms of nausea, vomiting, and diarrhea
9 Management of Hyperuricemia and Gout
H3CO
H3CO
O
OCH3
O
H OCH3
N
H3C H
Fig. 9.1 The chemical structure of colchicine. This alka-
loid was originally obtained from the plant Colchicum
autumnale
in nearly all patients. More recently, a study has
been published that compares the standard colchi-
cine schedule with a lower dose consisting of
1.2 mg followed by 0.6 mg 1 h later [40].
Observations at 24 h after initiating these treat-
ments demonstrated that the therapeutic responses
of both groups of patients were equivalent. This
study leads to the conclusion that the high-dose
schedule is inappropriate because of its toxicity
and that similar responses are obtained on the
lower-dose schedule with significantly fewer
toxic side effects. However, responses were only
reported after the first 24 h of treatment, and it
has not been shown that the responses to high-
and low-dose therapy are similar throughout the
entire duration of the acute attack, and more study
of this issue is needed (Fig. 9.1).
Even low doses of colchicine may be associ-
ated with significant gastrointestinal toxicity in
some patients, and alternative forms of treatment
may be needed, as discussed below. In addition,
patients with gout and an associated serious intes-
tinal disorder, such as Crohn’s disease, should be
treated with alternative drugs to prevent these
gastrointestinal side effects. Acute gouty arthritis
may become less responsive to colchicine after
joint symptoms have been present for 48–72 h, as
is the case with other forms of treatment.
It should be kept in mind that when an acute
arthritis occurs, even in a patient with a history of
gout, alternative diagnoses to gout may be pres-
ent, especially septic arthritis. Therefore, aspira-
tion of the joint is often indicated, both to
document the diagnosis of gout by crystal
identification and culture to exclude infection.
Colchicine Use in Acute and Chronic Gout
Mechanism of Action
Colchicine is a lipid soluble drug that crosses cell
membranes easily; its structure and pharmaco-
logic properties are shown in Fig. 9.1 and
Table 9.2. Any discussion of the mechanism of
action of colchicine must correlate plasma and
tissue levels of the drug attained in clinical usage
with concentrations of colchicine shown to have
pharmacologic activity against specific cellular
functions such as inflammatory cell chemotaxis
and chemotactic peptide generation [41–44]. To
date, only these two functions in addition to
changes in neutrophil tyrosine phosphorylation
have been shown to be impaired by colchicine
concentrations in the range found in the plasma
after oral or intravenous dosages [41–45]. Other
cellular functions proposed as mechanisms by
which colchicine is effective in acute gouty
arthritis require higher concentrations than those
attainable in vivo with pharmacologic doses of
the drug (Table 9.3) [46–52]. Colchicine clearly
diminishes the inflammatory response to urate
crystals in vivo [52]. In vitro, the drug also binds
avidly to neutrophil microtubules and inhibits
stimulus-induced lysosomal enzyme release
[53–55]. Since both the release of chemotactic
peptides and chemotaxis are proposed as the pri-
mary pharmacologic targets of colchicine, stud-
ies of the mechanism of action of colchicine have
been focused on these parameters. Investigations
have shown that a glycoprotein with chemotactic
properties for neutrophils and mononuclear leu-
kocytes is synthesized by neutrophils exposed to
monosodium urate crystals, and colchicine inhib-
its the production and release of this glycoprotein
[56]. Neutrophils treated with colchicine (10−5 M)
also show a significant decrease in their capacity
to synthesize and release leukotrienes B4 and
other lipoxygenase products such as hydroxyei-
cosatetraenoic acids [57]. Since LTB4 is a potent
neutrophil chemotaxin, some authors have sug-
gested that colchicine alters the production of
leukotrienes B4 in the intact neutrophil which
subsequently decreases the chemotaxis of neutro-
phils to the site of monosodium urate crystals
[57]. Although the concentrations of colchicine
297
Table 9.2 Pharmacologic properties of colchicine
Colchicine does not alter serum urate levels
Colchicine does not alter urinary uric acid levels
Colchicine binds to tubulin in microtubules
Colchicine (in vitro) inhibits chemotaxis and neutrophil
adhesion
Colchicine (in vitro) impairs lysosome degranulation
and cell motility
Colchicine blocks the release of a chemotactic
substance
Colchicine under certain conditions may impair
neutrophil phagocytosis
Colchicine does not bind to plasma proteins
Table 9.3 Colchicine concentrations required for the
inhibition of specific cell functions
Function I Inhibitory concentration
Leukocyte locomotion 40,000 ug % (10−3 M)
Lysosomal degranulation 100–500 ug % (10−5 M)
Kinin release 400 ug % (10−5 M)
Cell metabolism during 50–100 ug %
phagocytosis (2 × 10−6 M)
Release of chemotactic 0.4–40 ug %
peptide (10−6–10−8 M)
Chemotaxis 0.4–4 ug % (10−7–10−8 M)
required to demonstrate these effects may be
above those achieved in serum, leukocytes may
concentrate colchicine intracellularly, allowing
these effects to occur. Since urate crystals are
now thought to initiate acute gout by activating
the NLRP inflammasome, colchicine may either
impair the uptake of urate crystals by the
inflammatory cells, neutrophils and macrophages,
and synovial cells. Whether there are direct
effects of colchicine on the inflammasome itself
remains unclear (Tables 9.2 and 9.3).
Although polymorphonuclear neutrophils and
inflammatory mediators such as lysosomal
enzymes, oxygen-derived free radicals, interleu-
kin-1, crystal-induced chemotactic factor, and
5-lipoxygenase products contribute to the acute
intrasynovial response to uric acid and calcium
pyrophosphate dehydrate (CPPD) crystals, the
actual mechanism by which colchicine alters
acute crystal-induced arthritis still remains
incompletely understood.
298
It is also noteworthy that studies over the past
few years have led to the concept that crystal-
induced arthropathies, gout and pseudogout,
belong to the category of disorders called
autoinflammatory diseases. These diseases differ
from autoimmune diseases in that inflammation
employs the innate immune system, as opposed
to the adaptive immune system. Adaptive immu-
nity requires antibody and T cell-specific activ-
ity such as that seen in autoimmune diseases,
systemic lupus erythematosus and rheumatoid
arthritis, whereas the innate immune system is
independent of these mechanisms. Over the past
several years, an increasing number of
inflammatory diseases are now considered to be
disorders which employ the innate immune sys-
tem. It is also intriguing that colchicine is an
effective therapy for autoinflammatory diseases
that are based on unrelated principles. Colchicine
is effective in the treatment of gout and pseudog-
out, both of which are induced by microcrystals,
as well as in familial Mediterranean fever, a dis-
ease related to genetic defects in the protein
pyrin, which induces recurrent bouts of fever,
arthritis, and serositis. The explanation for the
effectiveness of colchicine in these apparently
disparate diseases remains unexplained at this
time [58].
Zero time plasma colchicine level is 1.79 ± 0.7
ug % (4.5 × 10−8 M) after 2 mg of colchicine is
administered intravenously. Highest mean colchi-
cine level is 0.323 ± 0.7 ug % (7 × 10−9 M) after
1 mg of colchicine is administered orally.
Recent investigations have demonstrated that
exposure of neutrophils to monosodium urate or
CPPD crystals causes a rapid increase in the cyto-
plasmic concentration of free calcium, the forma-
tion of 1,4,5-triphosphate, the activation of
phosphatidylcholine-specific phospholipase D,
and the tyrosine phosphorylation of a 70-kD pro-
tein [59–62]. Colchicine specifically inhibits this
phosphorylation reaction at 10−7–10−6 M concen-
trations that are similar to colchicine concentra-
tions observed in patients receiving therapeutic
doses of the drug [63, 64]. Interestingly, the
colchicine concentrations and the reaction times
for the inhibition of tyrosine phosphorylation are
almost identical to those required for the inhibi-
9 Management of Hyperuricemia and Gout
tion of microtubule assembly and for the promo-
tion of concanavalin cap formation in human
neutrophils [65–70]. Some other anti-
inflammatory drugs with some similarities to the
structure of colchicine, the NSAIDs, do not affect
crystal-induced tyrosine phosphorylation. This
crystal-induced reaction is presently somewhat
specific for CPPD and monosodium urate (MSU)
crystals since other particulates including unop-
sonized zymosan, latex beads, heat-killed staphy-
lococcus, and silica crystals cause qualitatively
different responses. It appears from these studies
that MSU and CPPD crystals activate kinases or
phosphatases associated with microtubules or
tubulin causing a characteristic tyrosine phos-
phorylation that is modulated by colchicine. As
discussed elsewhere, a major mechanism for the
induction of inflammation by sodium urate and
other crystalline materials, calcium pyrophos-
phate dehydrate, and silica is now thought to
reside in the activation of the inflammasome
NLRP3.
Pharmacokinetics of Colchicine
In healthy subjects, colchicine is rapidly absorbed
from the gastrointestinal tract after oral adminis-
tration and reaches peak plasma concentrations
within one-half to two hours. Absorption in the
gut presumably takes place in the jejunum and
ileum since large doses of colchicine alter func-
tions known to be carried out by these segments
of the small bowel such as vitamin B12 absorption
[71, 72]. The pharmacokinetic properties of
colchicine include a short half-life, a large appar-
ent volume of distribution (2.19 ± 0.8 l/kg body
weight), and little or no plasma protein binding
(Table 9.2) [53]. Urinary and pulmonary excre-
tions do not explain the short half-life of colchi-
cine, and the large volume of distribution, which
is greater than the extracellular volume, suggests
a high affinity of the drug for tissues. In fact, data
show that polymorphonuclear leukocytes con-
centrate colchicine, and these cells are also an
essential element of the inflammatory response to
monosodium urate crystals [63]. After 3 mg of
colchicine intravenously, healthy volunteers
Colchicine Use in Acute and Chronic Gout
Table 9.4 Colchicine kinetics and metabolism
Oral colchicine is absorbed via the gastrointestinal tract
Average peak plasma levels are 0.32 ug/dl after oral
colchicine (1 mg)
Peak plasma concentrations are attained in 0.5–2 h
Intravenous colchicine has a half-life of 20 min
Intravenous colchicine (3 mg) reaches a peak level in
white blood cells of 43 ug/dl after 10 min
Oral colchicine (1 mg) gives a serum colchicine level
of 0.03–0.24 ug/dl
Colchicine is excreted in the bile, feces, and urine
manifest a peak concentration of colchicine of 43
ug/dl at 10 min, and significant levels of colchi-
cine are still measurable in leukocytes (11 ug/dl)
from these individuals after 72 h [63]. These leu-
kocyte concentrations of colchicine exceed
plasma concentrations and are comparable to the
drug concentrations necessary to inhibit those
specific leukocyte functions accounting for the
drug’s mechanism of action in acute gout.
Colchicine is also released slowly from rat peri-
toneal mast cells, rat peritoneal macrophages,
and human synovial cells [73–76]. Its primary
excretory route in the human is the kidney, but
the lung accounts for an unknown fraction of
excreted drug [52, 77]. The kinetics and metabo-
lism of colchicine are shown in Table 9.4. The
recent observations concerning the inhibition of
tyrosine phosphorylation by colchicine may char-
acterize the biochemical basis for the activity of
this ancient drug [62]. In patients with chronic
liver disease, colchicine levels in the plasma are
measured at higher initial levels than normal, but
the drug disappears from the plasma more rap-
idly than normal [64]. Further, in those patients
without associated renal dysfunction, significantly
increased quantities of colchicine are excreted in
the urine. In patients with severe renal disease,
the rate of plasma colchicine disappearance is
slower than normal, and the quantity of drug
excreted by the kidney is markedly decreased
[64, 78]. Surprisingly, patients with gout and
moderate renal dysfunction have patterns of
plasma colchicine disappearance similar to
patients with severe renal disease but excrete nor-
mal quantities of the drug in their urine [64]
(Table 9.4).
299
Table 9.5 Colchicine toxicity
Full therapeutic doses of colchicine are toxic to the GI
tract in 80 % of its recipients
Crampy abdominal pain, hyperperistalsis, diarrhea,
nausea, and vomiting are common side effects
Chronic colchicine use may lead to bone marrow
depression, peripheral neuritis, and hair loss
Other toxic effects of chronic use include amenorrhea,
dysmenorrhea, oligospermia, and azoospermia
Overdoses may lead to hemorrhagic gastroenteritis,
metabolic acidosis, electrolyte disturbances, renal
failure, shock, Gram-negative septicemia,
hepatocellular failure, and CNS dysfunctions
Colchicine Toxicity
Life-threatening toxic reactions of the central
nervous system, bone marrow, muscle, and liver
are the most likely to occur in patients with renal
or hepatic dysfunction who are taking colchicine
[79–82]. Excretion of colchicine and its metabo-
lites is impaired with renal and hepatic disease,
and the drug should be avoided in these clinical
settings [83, 84]. Alopecia, bone marrow sup-
pression, and transient mental confusion have
rarely been reported during colchicine therapy;
usually they are associated with toxic responses
to the drug [52, 79, 85, 86]. Although colchicine-
induced myopathy has been described as a result
of drug overdoses, recent clinical data suggest
that colchicine myoneuropathy may be a rela-
tively common complication of gouty patients
with diminished renal function [86–88]. Such
myoneuropathies may be observed when modest
doses (1–1.5 mg) of colchicine are being used
[88] (Table 9.5).
The clinical findings of this myopathy include
proximal muscle weakness that at times is associ-
ated with a mild peripheral neuropathy [88].
Laboratory findings demonstrate an increase in
serum creatinine (>1.6 mg/dl), significant eleva-
tions of creatine kinase activity (>150 I.U./l), and
an abnormal electromyographic pattern [88].
Muscle biopsy specimens show a distinctive lys-
osomal, vacuolar myopathy with vacuoles
identified as lysosomal by their acid phosphatase
reactivity [88]. Peripheral nerve biopsies show a
loss of myelinated axons [88]. Reduction or dis-
continuance of colchicine results in a dramatic
300
Table 9.6 Colchicine contraindications
Inflammatory bowel disease
Pregnancy
Nursing mothers
Hepatic dysfunction
Decreased renal function
reversal of the muscular weakness that correlates
with a return to normal of the elevated creatine
kinase activity. The toxic responses to colchicine
are summarized in Table 9.5.
A recent case report raises concerns regarding
the use of colchicine in renal transplant recipients
who are being treated with immunosuppressive
drugs like cyclosporine and azathioprine [89]. In
this reported patient, a severe neuromyopathy
developed in association with markedly elevated
creatine kinase (phosphokinase) activity (600
I.U./l), aldolase activity (45 I.U./l), SGOT activ-
ity (929 I.U./l), and SGPT activity (288 I.U./l).
An EMG showed prominent fibrillations, posi-
tive sharp waves, pronounced high-frequency
discharges, early recruitment, and myopathic
units. Nerve conduction velocity tests were con-
sistent with a sensorimotor polyneuropathy, and
muscle biopsy showed the pathognomic features
of a colchicine-induced neuromyositis. The
mechanisms by which this patient developed
colchicine myopathy are unknown, but the
authors speculate on the possible interactions
between cyclosporine and colchicine as the prime
mediators responsible for the neuromyopathy
and the associated hepatic dysfunctions observed
in this patient. Another unusual toxic effect of
colchicine has been described in a patient receiv-
ing 1 mg of colchicine daily in conjunction with
cyclosporine-induced gout [90]. This patient
experienced a reversible azoospermia.
The generally accepted contraindications to
colchicine usage are shown in Tables 9.6 and 9.7.
Tests using d-xylose as a measure of intestinal
absorption may be inaccurate in patients taking
colchicine since the drug reduces xylose absorp-
tion [71] (Tables 9.6 and 9.7). Colchicine should be
used in reduced doses in the presence of even mild
to moderately reduced renal function and generally
should be used with caution and in reduced doses
9 Management of Hyperuricemia and Gout
Table 9.7 Relative contraindications to colchicine therapy
Neutropenia
Renal failure
Hepatocellular disease
Gastrointestinal disease (mucosal lesions)
Agranulocytosis
Aplastic anemia
Infertility (azoospermia)
Myopathy
Elderly patients with cardiovascular, renal, or
gastrointestinal diseases
if the creatinine clearance is 30 ml/min and avoided
completely when the estimated glomerular filtration
rate is less than 30 ml/min. Colchicine should not
be used in the presence of other drugs which are
metabolized by the cytochrome P450 3A4 path-
way. These include clarithromycin, cyclosporine,
certain calcium channel blockers, and ketocon-
azole and related drugs.
Intravenous colchicine is rapid and an effec-
tive treatment of acute gout that avoids the gas-
trointestinal toxicity of oral colchicine, but
serious toxic reactions and death have been
reported in association with intravenous colchi-
cine therapy [83]. Toxic reactions to intravenous
colchicine are also observed more frequently in
patients with renal and/or hepatic disease and in
those patients who have been receiving oral
colchicine as maintenance therapy. Local reac-
tions to intravenous colchicine include skin
necrosis and phlebitis at the site of local injec-
tion, and median nerve neuritis has been reported
secondary to the extravasation of colchicine into
soft tissues [91]. Because of its toxic potential,
intravenous colchicine has fallen into disuse, and
intravenous preparations of colchicine are no lon-
ger available in the United States.
As previously used, intravenous colchicine was
usually administered in 20 ml of saline (0.9 %)
containing 2 mg of the drug. Repeat doses of 1 mg
may be given every 6 h to a total dose of 4 mg. We
believe that intravenous colchicine should rarely,
if ever, be used for the management of gout. When
intravenous colchicine therapy is used, the patient
should be monitored in the hospital to avoid drug
overdoses, and elderly patients should never
receive more than 2 mg intravenously for a single
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
attack of gout. Extreme care should be exercised
to avoid intravenous colchicine in patients already
receiving maintenance colchicine. As noted previ-
ously, colchicine is excreted slowly, and cells that
have been exposed to colchicine are more sensi-
tive to its effects since the drug persists in cells for
long time periods.
The relative contraindications to colchicine
treatment are shown in Table 9.6.
In summary, oral colchicine may be used in low
doses to treat acute gouty arthritis without serious
gastrointestinal toxicity. Colchicine may also be
used in low dosage, 0.5 mg once or twice a day, to
protect patients undergoing surgical procedures
from precipitating a postsurgical episode of gout.
It may be used in low doses also for acute gouty
episodes [40]. This colchicine dosage regimen has
been used in a randomized, placebo-controlled
trial where the low-dose colchicine group utilized
1.8 mg of colchicine over 1 h (1.2 mg of colchi-
cine initially and 0.6 mg 1 h later) to treat acute
gouty attacks within the first 12 h of its onset. This
experimental group was compared with a high-
dose colchicine group (4.8 mg of colchicine over 6
h). The high-dose group manifested a significant
degree of diarrhea and vomiting (77 and 17 %,
respectively), whereas in the low-dose group, diar-
rhea occurred in only 23 % and no one in the group
vomited. Thus, low-dose colchicine may be used
to treat acute gouty episodes, but there remains the
issue of diarrhea in about one-quarter of the recipi-
ents of the drug. Such data do not resolve the issue
of colchicine’s toxicity to the gastrointestinal tract
and the selection of patients to avoid such compli-
cations. It also has some serious drug-drug inter-
actions, especially with cyclosporine usage, that
make it a dangerous choice for kidney transplant
patients with gout.
Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)
The second category of drugs that is useful for
the treatment of acute gouty arthritis is that of
NSAIDs. These drugs have the common mecha-
nism of action of inhibiting eicosanoid synthesis
by the cyclooxygenase enzymes. Inhibition of
301
cyclooxygenase accounts for the therapeutic and
the toxic effects of these agents. The NSAIDs are
in wide use as analgesic and anti-inflammatory
drugs for a large number of inflammatory condi-
tions. These drugs are also highly effective in
relieving the severe pain and swelling of acute
gouty arthritis. We will begin with a general dis-
cussion of the mechanism of action and clinical
uses of the NSAIDs as a class and then discuss
two drugs, indomethacin and naproxen, in detail
since these two agents are most commonly used
for treatment of acute gout, and controlled clini-
cal trials have demonstrated their effectiveness in
gout. However, comparison studies have shown
that several other NSAIDs are effective in acute
gout.
Eicosanoids are the products of several differ-
ent enzymes. They are derived from 20-carbon
polyunsaturated fatty acids, primarily arachi-
donic acid. These fatty acids are major constitu-
ents of phospholipids in all cell membranes. The
prostaglandins and thromboxanes are the prod-
ucts of the action of cyclooxygenases on arachi-
donic acid, and the cyclooxygenases are the
enzymes that are inhibited by the NSAIDs
(Fig. 9.2). There are two enzymes (cyclooxyge-
nase-1 [COX-1] and cyclooxygenase-2 [COX-2])
responsible for the conversion of arachidonic
acid to the prostaglandin endoperoxides (PGG2
and PGH2) The eicosanoid products of COX-1
are generally considered to mediate protective
functions of prostaglandins, and COX-2 produces
mediators of inflammatory reactions. This has led
to the hypothesis that specific inhibitors of COX-2
would be effective inhibitors of inflammation,
without producing toxicity by inhibiting the
COX-1 enzyme that mediates the protective func-
tions of prostaglandins and thromboxanes.
Subsequently, specific cyclooxygenase-2 inhibi-
tors were developed that block the elevated levels
of prostaglandins in inflammatory states [92–97].
The significance of COX-2 to inflammatory
responses lays in the fact that exposure of cells to
inflammatory stimuli causes an increased expres-
sion of cyclooxygenase-2 [98–100]. It has also
been shown that COX-1 is involved in the release
of prostaglandins for physiological processes and
is expressed in many different tissues, whereas
302 9 Management of Hyperuricemia and Gout

Membrane phospholipids

Phospholipase A2
Diverse physical,chemical,
inflammatory, and mitogenic stimuli

Arachidonic Coxibs
acid

Prostaglandin G2 COX Prostaglandin G2

Prostaglandin G/H Prostaglandin G/H
synthase 1 synthase 2
(cyclooxygenase-1) Prostaglandin H2 HOX (cyclooxygenase-2)
Prostaglandin H2

Tissue-specific isomerases

Prostanoids Prostacyclin Thromboxane A2 Prostaglandin D2 Prostaglandin E2 Prostaglandin F2α

Receptors IP TPa, TPβ DP1, DP2 EP1, EP2, EP3, EP4 FPα, FPβ

Platelets,
Brain, kidney, Uterus, airways,
Endothelium, vascular smooth- Mast cells,
vascular smooth- vascular smooth-
kidney, muscle cells, brain,
muscle cells, muscle cells,
platelets, brain macrophages, airways
platelets eye
kidney

Fig. 9.2 Production and actions of prostaglandins and
thromboxane. Arachidonic acid, a 20-carbon fatty acid
containing four double bonds, is liberated from the sn2
position in membrane phospholipids by phospholipase
A2, which is activated by diverse stimuli. Arachidonic
acid is converted by cytosolic prostaglandin G/H syn-
thases, which have both cyclooxygenase (COX) and
hydroperoxidase (HOX) activity, to the unstable interme-
diate prostaglandin H2. The synthases are colloquially
termed cyclooxygenases and exist in two forms, cycloox-
ygenase-1 and cyclooxygenase-2. Coxibs selectively
inhibit cyclooxygenase-2. Prostaglandin H2 is converted
by tissue-specific isomerases to multiple prostanoids.
These bioactive lipids activate specific cell-membrane
receptors of the superfamily of G-protein–coupled recep-
tors. Some of the tissues in which individual prostanoids
exert prominent effects are indicated. IP denotes prostacy-
clin receptor, TP thromboxane receptor, DP prostaglandin
D2 receptor, EP prostaglandin E2 receptor, FP prostaglan-
din F2a receptor (Reprinted from N Engl J Med with
permission)

COX-2 is induced by inflammatory mediators competitive inhibitors of cyclooxygenases. All

acting on cells involved in inflammatory responses
(neutrophils, macrophages, endothelial cells, and
fibroblasts) [101]. Furthermore, glucocorticoids,
potent anti-inflammatory agents, block the
induction of COX-2 but have no effect on COX-1
[102, 103]. Most of the available nonsteroidal
anti-inflammatory agents are nonselective with
respect to their inhibition of cyclooxygenases.
Ibuprofen (Motrin), naproxen (Naprosyn), and
piroxicam (Feldene) are competitive inhibitors of
cyclooxygenases, and indomethacin (Indocin)
and diclofenac (Voltaren) are time-dependent,
these nonselective NSAIDs inhibit the physio-
logical functions regulated by COX-1, and this
action leads to an increase in gastrointestinal
intolerance including peptic ulcer disease and
bleeding as well as the possibility of renal
insufficiency [104, 105].
Studies have compared the inhibitory effect of
nonselective NSAIDs on COX-1 and COX-2
activities [237, 238]. Ideally, one would expect
the most effective and least toxic anti-
inflammatory agents to be the most potent inhibi-
tors of COX-2 with the least activity against
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
COX-1. In contrast, the most potent inhibitors of
COX-1 activity would be the most likely to cause
ulcerations and bleeding from the gastrointestinal
tract. When S-ibuprofen, meclofenamate, and
flurbiprofen were investigated in vitro for their
preference as an inhibitor of COX-2 as compared
to COX-1, it was found that S-ibuprofen has a
twofold preference for COX-2, Meclofen a sev-
enfold preference, and flurbiprofen was in
between these levels of preference. When sulin-
dac sulfide, indomethacin, and piroxicam were
compared for their inhibitory capacity against
these same enzymes, it was found that these drugs
were 10–30 times more inhibitory of COX-1 than
COX-2. The only drug investigated in this study
that was a more potent inhibitor of COX-2 activ-
ity as compared to COX-1 was nabumetone
(Relafen) that was shown to be a sevenfold more
potent inhibitor of COX-2 as compared to COX-1
[237]. However, the selectivity of different
NSAIDs for COX-1 and COX-2 may vary some-
what depending on the assay system. For exam-
ple, in whole blood studies, indomethacin,
ibuprofen, and naproxen had similar activities
against COX-1 and COX-2 [106–108, 111].
Prior to the development of the highly selec-
tive COX-2 inhibitors, some investigators postu-
lated that these drugs might promote
cardiovascular toxicity. It was suggested that
intravascular clotting was in part prevented by
the production of prostacyclin (PGI2) by endothe-
lial cells. PGI2 causes vasodilatation and inhibits
platelet aggregation, thereby helping to maintain
vascular flow, and that this counteracted the
effects of thromboxane B2 by platelets, which
both promotes platelet aggregation and vasocon-
striction. It had been suggested that selective
inhibition of COX-2 from the endothelium would
leave the vasoconstrictive effects of thrombox-
ane produced by COX-1 in platelets unopposed
and predispose to vascular occlusion that could
cause coronary occlusion and strokes. Subsequent
studies have shown that this hypothesis was at
least to some extent correct. Numerous studies
have shown that COX-2-specific inhibitors are
associated with untoward cardiovascular events,
and one of these, rofecoxib, has been removed
from the market because of this toxicity. Other
303
COX-2 inhibitors remain but do have a tendency
to cause cardiovascular toxicity. Studies have
also shown that most of the nonselective COX
inhibitors also have risks of cardiovascular toxic-
ity, although the mechanisms are not known. The
inhibition on both classes of cyclooxygenases or
other secondary effects such as renal function
and blood pressure could be contributing factors.
Regardless of mechanisms, there are differences
in the relative risks of cardiovascular diseases
produced by individual NSAIDs. For example,
diclofenac has one of the higher risks compared
to other NSAIDs. Naproxen has been found to
have the least association with cardiovascular
risk. The reason for the apparent variation in car-
diovascular risk with different NSAIDs is
unknown, but it may make agents such as
naproxen a good choice of NSAIDs from this
point of view [109, 110].
NSAIDs like sulindac (Clinoril), naproxen
(Naprosyn), fenoprofen (Nalfon), ibuprofen
(Motrin), ketoprofen, and fenamates (flufenamic,
mefenamic, and meclofenamic acids) have also
been used in the treatment of gout, but none
appeared to be more effective than indomethacin
[112–118]. Phenylbutazone is no longer avail-
able for use due to its bone marrow toxicity, but
it was a very effective drug for acute gout, and its
structure may provide a means of designing less
toxic compounds for the treatment of gout.
Sulindac is similar to indomethacin in structure,
whereas naproxen is related to arylpropionic
acid NSAIDs, and fenamates are
N-phenylanthranilic acid-substituted NSAIDs.
The pharmacokinetics and metabolism of some
nonsteroidal anti-inflammatory agents are shown
in Table 9.8. For the most part, these drugs have
side effects in the human similar to those
described for indomethacin, but a few distinctive
toxicities are emphasized subsequently for each
of these drugs. Their pharmacokinetic properties
are also similar with the exception of sulindac
and naproxen which have longer half-lives (8–17
h) than the other agents which have much shorter
half-lives (1–3 h) [118–120]. In addition to its
NSAID-like toxicities, sulindac should not be
used in patients who cannot tolerate prolonged
bleeding times.
304 9 Management of Hyperuricemia and Gout

Table 9.8 Nonsteroidal anti-inflammatory agents: pharmacokinetics and metabolism

Colchicine Sulindac Indocin Naproxen Motrin
GI absorption (%) Small bowel 88 Rapid Complete/rapid Rapid
Plasma protein binding (%) Not detected 93 98–99 99 99
Peak plasma levels (h) 0.5–2a 1–2 0.75b 2–4 1–2
1–2c
Half-life (h) 0.33d Biphasice 8 and 18 Biphasicf 1 and 9 17 2.5
Metabolism Renal (hepatic) Hepatic (renal) Hepatic (renal) Hepatic Hepatic
Volume of distribution (L/kg) 2.2 – 0.3–1.6 0.09 0.15
Excretory routes Urine/lung Urine > stool Urine > stool Urine Urine
Data for fenoprofen and ketoprofen are comparable to ibuprofen (Motrin)
a
After 1 mg of colchicine
b
Peak plasma levels depend on food intake but are rapid in the fasting state
c
Peak plasma levels are delayed in the fed state
d
After 2 mg of IV colchicine
e
Sulindac undergoes extensive enterohepatic recirculation
f
Indomethacin undergoes partial enterohepatic recirculation

Toxicity of NSAIDs lndomethcin

CH3O CH2CO2H
The potential toxicities of the NSAIDs are impor-
tant to recognize since these are such a widely N CH3
used group of drugs, especially since they are
readily available as nonprescription drugs in C O
many cases. The most frequent toxicity of these
drugs is from their effects on the upper GI tract.
The nonselective NSAIDs inhibit the enzyme
cyclooxygenase 1 in the gastric mucosa that pro- CI
duces PGE2. PGE2 helps to maintain the protec- Sulindac
tive gastric mucosal barrier and inhibits gastric
acid secretion, thus reducing the tendency for CH2CO2H
F
gastric mucosal erosions and their complications
of bleeding, perforation, and obstruction. One of
the major benefits of the selective COX-2 inhibi- CH3
tors is their sparing of COX-1, which reduces the CH3
development of upper GI toxicity. A second
major toxic effect of the NSAIDs is their renal O
effects which can lead to renal failure and hyper-
CH3S
tension, and this toxicity is shared by both classes
of COX inhibitors. Fig. 9.3 The structures of indomethacin and sulindac.
Physicians should become familiar with the Indomethacin is an indole acetic acid with a pKa of 4.5. It
use of one or two NSAIDs useful for the manage- is stable in neutral or acidic environments. Sulindac is
ment of acute gout and use them routinely for prodrug; the sulfide metabolite is the active moiety. As
can be seen, sulindac is an indene acetic acid derivative
acute gouty arthritis. The structure and properties that is chemically related to indomethacin
of naproxen and other commonly used anti-
inflammatory drugs are shown in Tables 9.13,
9.14, and 9.15 and Fig. 9.3. ment of acute gout, the fact that monosodium urate
Even though there are few published reports of crystals induce COX-2 expression in monocytes
the use of COX-2-specific inhibitors in the treat- with the resultant production of proinflammatory
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
prostaglandins provides a rationale for their use in
gout [121]. The two most commonly used COX-2
inhibitors, celecoxib (Celebrex) and, before its
removal from the market, rofecoxib (Vioxx), have
proven to be effective anti-inflammatory agents
for the treatment of rheumatoid arthritis and
osteoarthritis, and these data suggest that they
might be very effective in other joint diseases as
well. Another premise for the use of COX-2 inhib-
itors is that these specific inhibitors reduce
inflammation but do not alter the protective prosta-
glandins in the stomach and kidney produced by
COX-1 activity [122]. However, investigations
have shown that COX-2-specific inhibitors spare
the COX-1 prostaglandin-dependent mucosal pro-
tective mechanisms active in the gastrointestinal
tract but do not preserve all the renal functions
controlled by prostaglandins [123]. Many investi-
gations have now confirmed that COX-2 inhibitors
significantly reduce the morbidity and mortality
from the gastrointestinal effects caused by the use
of conventional NSAIDs [124–130].
The relative lack of upper GI toxicity seen
with the selective COX-2 inhibitors has led to
their use in some patients receiving anticoagu-
lants, such as warfarin and heparin. Nonselective
COX inhibitors are hazardous in patients receiv-
ing anticoagulants because of a high risk of upper
GI bleeding. Nonetheless, patients receiving anti-
coagulants and selective COX-2 inhibitors should
be monitored carefully. While most experience is
related to warfarin anticoagulation, it is logical to
assume that the same precautions will hold for
the newer anticoagulants, antithrombin, and anti-
factor X agents that are coming into wide use.
With respect to the effects of COX-2-specific
inhibitors on the kidney, the results of many stud-
ies have determined that COX-2 inhibitors induce
a decrease in glomerular filtration rates as well as
sodium and potassium retention. Thus, COX-2-
specific inhibitors induce renal complications
comparable to those observed with the use of non-
selective NSAIDs [121–145]. Cyclooxygenase-2
has been localized to the macula densa of the kid-
ney and the adjacent cortical thick ascending limb
in the renal cortex, and it functions in regulating
renin content and maintaining normal renal func-
tion in volume-depleted states, or in patients with
305
decreased effective intravascular volume, such as
in congestive heart failure [146–150]. In animal
studies, there is evidence that angiotensin II inhib-
itors upregulate renal cortical COX-2 in volume-
depleted states [151]. These early investigations
of COX-2-specific inhibitors indicate that caution
should be exercised with the use of these drugs in
those patients with underlying renal disease,
patients who are elderly, those with volume-
depleted states, and those on low-sodium diets. A
few studies have also emphasized additional
advantages of the COX-2 inhibitors including the
absence of effects on platelet aggregation, throm-
boxane B2 production, and methotrexate renal
clearance and pharmacokinetics [152, 153].
Further, studies in rats have shown that blocking
mineralocorticoid receptors with spironolactone
causes an upregulation of renal cortex COX-2
[154]. Recent data have shown that COX-2 inhib-
itors may cause adverse cardiovascular events,
and these toxic parameters are reviewed at the end
of this section.
Other Toxicities of NSAIDs
Magnesium aluminum hydroxide does not affect
ketoprofen absorption [155, 156]. Thus, these
antacids are favored if one is seeking maximal
absorption of this class of NSAID along with
reduction in gastrointestinal disturbances. At the
doses of ibuprofen and ketoprofen used in gout,
warfarin is displaced from its binding site on
plasma proteins resulting in increased anticoagu-
lant effects [119, 157]. Similar effects are observed
with naproxen [158–160, 163–165]. In addition,
patients taking anticoagulants are at increased
risk of bleeding generally, and anticoagulants
increased the risks of NSAID-induced bleeding
from the upper GI tract in particular. In general,
NSAIDs should be avoided in patients on all anti-
coagulants. The COX-2-specific inhibitors may
be used in patients on anticoagulants cautiously
since these drugs have minimal effects on the gas-
tric mucosa and on platelets. Aspirin in combina-
tion with ibuprofen, fenoprofen, naproxen, or
ketoprofen decreases plasma concentrations of
the NSAID, does not enhance clinical efficacy,
306
and is likely to cause greater toxicity [131, 161–
165]. Fenemates cause significant gastrointestinal
toxicities, but unlike other NSAIDs, diarrhea is
the most prominent side effect [132–135].
Naproxen like indomethacin has the capacity to
increase significantly the level of prednisolone
even though total concentrations of this corticos-
teroid are unaffected [136]. Ibuprofen, like indo-
methacin, can also cause hyperkalemia and acute
renal insufficiency [137]. Piroxicam (Feldene)
has the same propensity [138–140].
The antithrombotic effect of aspirin may be
inhibited by NSAIDs.
Some NSAIDs may interfere with the antico-
agulant effect of low doses of aspirin. Aspirin at
once daily doses of 81 or 325 mg is commonly
given to patients with cardiovascular disease to
prevent further myocardial infarction and strokes.
Studies have shown conclusively that aspirin
lowers the incidence of these vascular disorders.
It is not generally recognized that NSAIDs may
prevent this important effect of aspirin. In partic-
ular, ibuprofen given before aspirin enters the
active site of platelet cyclooxygenase (COX-1)
and blocks the access of aspirin. Thus, it is impor-
tant that aspirin be given at least one-half hour
prior to the use of ibuprofen and probably other
low molecular weight NSAIDs in order to achieve
the prophylactic effect of aspirin on cardiovascu-
lar disease. In addition, it should be noted that if
ibuprofen is used several times daily, there may
be sufficient quantities of the drug in the blood to
prevent the effect of aspirin on platelets, even if
aspirin is given before the first dose of ibuprofen
in the morning [166]. However, this does not
apply to COX-2 inhibitors. The larger size of the
COX-2 inhibitors prevents their access to the
active site of COX-1 enzymes, and thus these
drugs do not inhibit the prophylactic effect of
aspirin on platelets.
Several additional drug interactions may occur
with the use of indomethacin as well as other
NSAIDs. These drugs (NSAIDs) displace other
pharmacologic agents from plasma protein-bind-
ing sites resulting in an increase in the fraction of
circulating free drug [167, 168]. By this mecha-
nism, indomethacin and other NSAIDs may
increase the toxicity of methotrexate, sulfonylurea,
9 Management of Hyperuricemia and Gout
hypoglycemic drugs, and phenytoin [167–178].
On the other hand, indomethacin protein binding
is decreased by ibuprofen (Motrin) [179].
Indomethacin also appears to increase the free
drug levels of prednisone even though the total
levels of this agent are unchanged [180].
Indomethacin may also interfere with the clear-
ance of other drugs such as lithium, blood levels
of which are increased when it is administered
concomitantly with an NSAID [181]. Conversely,
as noted previously, probenecid interferes with
the clearance of indomethacin [169, 170, 182].
NSAIDs are also said to interfere with the antihy-
pertensive effects of some b-adrenergic blocking
agents [183, 184]. It has been postulated that such
an effect is due to the inhibition of endogenous
prostaglandin production and the ultimate vasodi-
latory effects of certain prostanoids [184]. The
initial studies suggesting this effect were per-
formed in rabbits, but some documentation of this
problem in humans has been published [183].
Interactions between aspirin and indometha-
cin have been the subject of a continuing contro-
versy, which remains incompletely resolved.
Indomethacin levels after both a single dose of
the drug and chronic treatment with this drug are
increased when aspirin is given concurrently
[185, 186]. Such increments are roughly 10–20
% greater than in the absence of salicylate treat-
ment. Chronic aspirin therapy also reduces the
bioavailability of indomethacin to a level of 80 %
suggesting a decrease in indomethacin absorp-
tion. Renal clearance of indomethacin is also
decreased in the presence of chronic aspirin ther-
apy [185]. Despite the fact that aspirin decreases
the absorption and clearance of indomethacin,
there is little evidence to indicate that any thera-
peutic differences occur when these pharmaco-
logic agents are used together. In fact, the only
documented study in the literature found no dif-
ference in the therapeutic effect when these drugs
were used together, but a significant increase in
adverse effects provides the rationale for not
using these drugs together [187]. The pharmaco-
logic activity of hydrochlorothiazide is not altered
by indomethacin, so this diuretic represents a
useful alternative to furosemide whose effect is
dampened by indomethacin [188]. Finally, the
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 307

Table 9.9 Classification of cyclooxygenase inhibitors The dynamic interaction between the vasodilatory
COX inhibitor Inhibitor type IC50 (COX-1/ forces of the prostaglandins and the vasoconstric-
COX-2) ratio tive responses mediated by angiotensin II and nor-
Aspirin Selective COX-1 0.01 epinephrine maintains normal renal hemodynamics,
Ibuprofen Nonselective COX 0.50 but in the absence of the vasodilatory prostaglan-
Naproxen Nonselective COX 0.56 dins, blood flow to the kidney is decreased and
S-ketoprofen Nonselective COX 0.61 renal function is impaired [189]. Thus, prosta-
Flurbiprofen Nonselective COX 1.00 glandins I2 and E2 have a significant role in renal
Sodium Nonselective COX 1.03
vasodilatory responses, renin secretion, and
salicylate
Indomethacin Nonselective COX 1.90
sodium and water excretion, but in the presence of
Piroxicam Nonselective COX 3.12 prostaglandin inhibitors, there is an increase in
Meloxicam Relatively selective 11.16 vascular tone, an antinatriuretic response, an anti-
COX-2 renin effect, and an antidiuretic response. The
Nimesulide Relatively selective 17.69 most effective way to prevent NSAID-induced
COX-2 changes in renal hemodynamics leading to renal
Diclofenac Relatively selective 18.90 insufficiency is to recognize the predisposing fac-
COX-2
tors that are likely to cause these deleterious renal
Celecoxib Selective COX-2 >30
responses. Those predisposing conditions include
Rofecoxib Selective COX-2 >400
(Vioxx) patients with congestive heart failure, cirrhosis,
These results are modified from published data contained
cirrhosis and ascites, underlying renal disease,
in the following citations: [286, 301] diuretic therapy, septicemia, hypertension, and
Aspirin inhibits COX-1 irreversibly and may cause GI shock. Patients over 65 years of age and postop-
bleeding. Sodium salicylate does not cause gastric dam- erative patients with fluid accumulation in a third
age. The phenylpropionic acids inhibit both COX-1 and
COX-2 and may cause GI and renal side effects.
space are also at increased risk for NSAID-
Nimesulide and meloxicam at high doses inhibit COX-1 induced renal insufficiency. Renal failure induced
more than COX-2. Vioxx has been removed from the mar- by indomethacin is usually rapid in its onset (24–
ket due to its adverse cardiovascular effects. Selective 48 h after indomethacin administration) and is
COX-2 inhibitors have the same effects on renal prosta-
glandins as nonselective NSAIDs
associated with oliguria. Serum creatinine levels
rise, fractional sodium excretion decreases (usu-
ally <1 %), and serum potassium levels increase.
effect of indomethacin on the gastrointestinal Of all the NSAIDs that may cause renal failure,
tract is enhanced by ethanol. This potential for indomethacin is the most common cause of this
the augmentation of the ulcerogenic properties of condition [190–192]. The combination of indo-
indomethacin also occurs with other NSAIDs as methacin and triamterene should be avoided since
well. These drug-drug interactions are summa- acute renal failure has been reported in subjects
rized in Table 9.9. with normal renal function taking this combina-
The single most significant side effect other tion of drugs [193]. Rather high doses of triam-
than gastrointestinal bleeding is the different terene were administered in these studies and may
nephrotoxic responses that may be observed with have been responsible for the marked renal distur-
indomethacin and other NSAIDs. These renal bances observed. However, on the basis of this
dysfunctions are important to recognize early report, the use of this diuretic in association with
since they are often reversible. Nephrotoxic disor- indomethacin should be avoided. Early recogni-
ders secondary to NSAID usage include acute tion of renal insufficiency and discontinuation of
renal failure, interstitial nephritis, hyperkalemia, the NSAID usually lead to improvement in renal
salt and water retention, and hypertension. The function, but short-term dialysis may be necessary
clinical syndromes associated with these nephro- [194]. Rarely, some patients may require chronic
toxic responses primarily result from the inhibi- dialysis [195]. As might be expected, hyper-
tion of renal prostaglandin synthesis by NSAIDs. kalemia is a common problem accompanying
308
NSAID-induced renal failure, and the fractional
excretion of sodium may be low as well in a small
percentage of patients with NSAID-related acute
renal failure [196].
Special consideration must be given to those
patients with underlying renal disease since
NSAIDs often cause increased impairment of
their already somewhat compromised renal func-
tion [197–199]. In the presence of underlying
renal disease, the kidney may manifest an
increased production of prostaglandins to main-
tain a normal hemodynamic state, and the inhibi-
tion of prostaglandin synthesis may significantly
diminish renal blood flow and glomerular
filtration rate in the prostaglandin-dependent
state. A number of mechanisms may contribute
to the increased risk of NSAID-induced renal
failure in the elderly, an important patient popu-
lation that often receives NSAIDs. They may
have low serum albumin levels with a resultant
decrease in NSAID protein binding and an
increase in the free drug level. Similarly, dimin-
ished total body water, a state often observed in
the elderly, causes an increase in NSAID concen-
tration, and decreased hepatic metabolism of
NSAIDs in the elderly may also lead to increased
NSAID concentrations. Finally, any state which
reduces the effective intravascular volume, such
as congestive heart failure, may predispose
patients to increased cardiac failure and fluid
retention, and these drugs should be avoided
under these circumstances.
To avoid these nephrotoxic effects, some have
proposed the use of NSAIDs that are less depen-
dent on the kidney for their metabolism [200].
The rationale for the use of sulindac is that its
inactive prodrug, sulindac sulfoxide, requires the
liver for conversion to its active metabolite, sulin-
dac sulfide. However, the kidney is also capable
of activating this prodrug as well [201, 202].
Although sulindac spares the kidney to some
extent, clearly, renal failure and hyperkalemia
can occur when this drug is used [197, 203–211].
Another problem with sulindac leading to renal
problems is its long half-life that results in the
accumulation of its active agent, sulindac sulfide,
in the plasma over time [212]. In fact, plasma lev-
els of the drug may be increased twofold or
9 Management of Hyperuricemia and Gout
greater than the level observed in normal indi-
viduals. Recently, parenteral ketorolac has also
been associated with renal insufficiency [213,
214]. A retrospective analysis of ketorolac has
concluded that short-term usage (<5 days) does
not cause renal insufficiency [215]. Even though
NSAID-induced renal failure is a common occur-
rence, it is often a reversible state so that its early
recognition is important. For this reason, avoid-
ing the use of NSAIDs in high-risk patients and
carefully monitoring those patients in whom
these drugs must be used are essential.
Acute renal papillary necrosis is another
NSAID-induced syndrome rarely observed in
association with these drugs [216–220]. This dis-
order may occur as a solitary finding related to
NSAID use or as a result of combined therapy
with aspirin. Other studies have investigated the
frequency of renal papillary necrosis in associa-
tion with chronic use of NSAIDs [221, 222]. As
a general rule, combinations of analgesics includ-
ing NSAIDs should be avoided, and patients
using NSAIDs on a chronic basis should be care-
fully monitored for symptoms and signs of renal
disease [223].
Although NSAID-induced interstitial nephri-
tis with or without an accompanying nephrotic
syndrome is not a disorder that intermittent
NSAID users are prone to develop, it may be seen
in patients who use NSAIDs for long periods of
time (>6 months). It rarely occurs after short-
term NSAID use. The primary features of this
renal disease are proteinuria (usually >3 g/day),
nonoliguric renal failure, and focal interstitial
cellular infiltrates with patchy fibrosis on renal
biopsy [224–227]. In addition to these constant
features, some kidney biopsies have shown vari-
able immunofluorescent staining of the intersti-
tial membranes with IgG, IgM, IgA, and C3, and
electron-dense deposits in the mesangium may
also be present in a few patients. Elderly females
appear to be particularly susceptible to this con-
dition, and peripheral edema, oliguria, anuria,
skin rashes, proteinuria, microscopic hematuria
and granular casts, and eosinophilia are the most
common clinical and laboratory features of this
drug-induced syndrome of renal failure [228].
Not all these findings appear in every patient, but
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
renal insufficiency with significant proteinuria
and changes in the urine sediment are the most
common findings in such patients. The etiology
of interstitial nephritis remains unclear, but a
delayed hypersensitivity response to NSAIDs,
altered arachidonic acid metabolism, and preex-
isting renal insufficiency has all been proposed as
possible contributors to this form of renal disease
[229–234].
Other common complications of NSAID ther-
apy are sodium retention and hypertension [235–
241]. Edema due to salt retention occurs in
roughly 25 % of patients receiving NSAIDs, and
careful monitoring of patients at risk for pulmo-
nary edema is essential if NSAIDs are required as
therapy in these high-risk patients. Further, in
clinical settings where parental diuretics are to be
used, the potential for NSAIDs to block diuresis
with the resultant retention of sodium needs to be
carefully monitored as well. NSAIDs have also
been documented to increase blood pressure both
in normotensive patients and in those with preex-
isting hypertension. In hypertensive patients
receiving b-blockers and diuretics, this NSAID-
induced hypertensive effect is very prevalent.
Patients at highest risk for such events are those
with low-renin hypertension such as patients in
the older age groups and blacks [242]. Although
the effects of NSAIDs on hypertension are often
modest (6–10 mmHg), such small changes may
be of significance in patients with labile blood
pressure or hypertension, and mechanism for this
NSAID-induced hypertensive effect remains
incompletely understood, but the inhibition of
vasodilatory prostaglandins is certainly a promi-
nent factor [242–249].
Two additional less common electrolyte dis-
turbances, hyperkalemia and hyponatremia, may
be observed in association with NSAID usage
[250–254]. Hyperkalemia following indometha-
cin therapy has occurred in both patients with
normal renal function and in those with preexist-
ing renal disease [228, 255]. The clinical picture
is identical to that observed with hyporeninemic
hypoaldosteronism [174, 255]. Patients at risk
for hyperkalemia associated with indomethacin
therapy include those with renal dysfunction
and those taking potassium-sparing diuretics
309
(spironolactone, triamterene, and amiloride),
beta-adrenergic blockers, potassium-containing
salt substitutes, and inhibitors of angiotensin
1-converting enzymes. Extremely careful moni-
toring of serum potassium levels is imperative if
indomethacin is used in these settings. Alternative
diuretics may be used to decrease the risk associ-
ated with the potassium-sparing agents [193,
256]. It is prudent to follow patients closely who
need NSAID treatment and have serum potas-
sium levels at the upper limits of normal
(>5 meq/l) and monitor them for the possible
occurrence of superimposed hyperkalemia. Since
NSAIDs may antagonize the effects of vasopres-
sin, urinary dilution may be impaired and hypona-
tremia may ensue [257, 258].
In summary, even though the prevalence of
NSAID-induced nephrotoxicity is relatively low,
the extensive use of these agents for gout and
many other inflammatory conditions places many
patients at risk for the renal diseases and electro-
lyte imbalances associated with NSAID therapy.
The sale of over-the-counter NSAIDs further
complicates the problem. To identify and monitor
those patients at risk for the renal complications
of NSAID therapy, those patients with hyperten-
sion, diabetes mellitus, cirrhosis, and heart dis-
ease should be identified as well as those using
diuretics and antihypertensive drugs since those
patients deserve careful attention when they have
been prescribed NSAIDs. It is also reasonable to
measure renal function (serum creatinine), serum
sodium, and serum potassium levels prior to the
institution of NSAID therapy. A review of the
nephrotoxicity of NSAIDs, their diagnosis, and
management is available for additional consider-
ations regarding these disorders [259].
Other toxic effects of NSAIDs are seen in
pregnancy. Several studies have shown that the
use of NSAIDs in pregnancy leads to a significant
increase in the incidence of abortion [260]. A
large nested case-controlled study found that sev-
eral nonaspirin NSAIDs led to an increased inci-
dence of spontaneous abortions in the first
20 weeks of pregnancy with an overall odds ratio
of 2.43. Other studies have reported an increased
risk of congenital anomalies associated with the
use of NSAIDs in pregnancy.
310
The toxicity of NSAIDs with respect to their
mechanisms of action and possible alternative
inhibitors of prostaglandin production deserves
further discussion since the advent of data show-
ing adverse cardiovascular events associated
with COX-2 inhibitors. First, the recent demon-
stration of two isoforms of the cyclooxygenase
enzyme designated as COX-1 and COX-2 that
lead to the conversion of arachidonic acid to the
prostaglandin endoperoxides (PGG2 and PGH2)
and subsequently to PGE2 and other prostanoids
has significantly modified the views of the roles
of prostaglandins in both inflammatory and toxic
responses [261]. COX-1 is constitutively
expressed and mediates physiological responses.
It catalyzes the synthesis of cytoprotective pros-
taglandins in thrombocytes, vascular endothe-
lium, stomach mucosa, kidneys, pancreas,
seminal vesicles, and brain tissue [262, 263].
The COX-1 products (PGE2 and PGI2) reduce
gastric acid secretion, increase the thickness of
the mucus layer of the stomach, stimulate bicar-
bonate secretion, and enhance mucosal blood
flow [263–266]. PGE2 also increases mucus
secretion via the activation of cyclic AMP in
gastric epithelial cells [267]. These functions of
the COX-1 product, PGE2, clearly demonstrate
why inhibition of COX-1 activity may impair
gastroprotective functions. Such COX-1 func-
tions demonstrate why the pursuit of COX-2
inhibitors appeared to be a means of preventing
inflammatory responses and avoiding gastroin-
testinal side effects.
Although COX-1 and COX-2 isoforms have
similar amino acid sequences, they have quite
different functions [263, 268]. COX-2 is respon-
sible for the production of prostanoids involved
in pathological processes like inflammation, and
this enzyme is induced by various proinflammatory
agents and endotoxins [269–273]. The other
important organ system related to NSAIDs and
their effects on organ function is the kidney.
COX-1 is constitutively expressed in the kidney
and has been localized to mesangial cells, arte-
riolar smooth muscle cells, endothelial cells,
parietal epithelial cells of Bowman’s capsule,
and the cortical and medullary collecting ducts
[274, 275]. COX-2 has been detected in the mac-
9 Management of Hyperuricemia and Gout
ula densa of the renal cortex and cells adjacent to
them [276–281]. This enzyme has also been
detected in interstitial cells in the inner medulla
and renal papilla, in the inner medullary collect-
ing duct cells, in the renal cortex, and in the
medullary vasa recta as well as in human podo-
cytes and arteriolar smooth muscle cells [275,
277, 279, 281–284]. Although there are addi-
tional organs that may fall prey to the use of
NSAID inhibitors of prostaglandins and other
biochemical mediators, the gastrointestinal tract,
the cardiovascular system, and the kidney are the
major organ systems to be evaluated before using
either COX-1 or COX-2 inhibitors for the man-
agement of inflammatory arthritides. Since
COX-2 is an inducible enzyme in inflamed sites,
selective COX-2 inhibitors were developed to
act as therapeutic agents in inflammatory disor-
ders like gout. The use of such selective COX-2
inhibitors was also hypothesized as a means of
avoiding the gastrointestinal toxicity of the
COX-1 inhibitors like the traditional NSAIDs.
COX-1 is the predominant cyclooxygenase iso-
form detected in the kidney and may be a key
producer of mediators regulating renal function
such as intrarenal plasma flow and electrolyte
balance [285, 286]. Since the selectivity of
cyclooxygenase inhibitor varies between selec-
tive COX-1 inhibitors and selective COX-2
inhibitors, a method has been devised to classify
NSAIDs into four categories: selective COX-1
inhibitors, nonselective COX inhibitors, rela-
tively selective COX-2 inhibitors, and highly
selective COX-2 inhibitors. This classification
has been derived from published data, and the
separation into these categories is based on
in vitro whole blood assays using NSAIDs to
determine IC50 values for COX-1 and COX-2
inhibition [283–288]. Using this IC50 COX-1/
COX-2 ratio, the following drugs can be classified
into those four categories (Table 9.9). As can be
determined from the data, the selective COX-1
and nonselective COX inhibitors have COX-1/
COX-2 ratios between 0.5 and 3.5, whereas the
selective (relatively) and highly selective COX-2
inhibitors have IC50 values between 10 and 400.
Gastrointestinal and cardiovascular toxicities of
the NSAIDs are delineated.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Although there are a variety of toxic responses
to NSAIDs, the three most significant organ sys-
tems affected by these agents are the gastrointes-
tinal tract, the kidney, and the cardiovascular
system. Nonsteroidal anti-inflammatory drugs,
especially those NSAIDs that are nonselective
inhibitors of cyclooxygenase, are known to place
patients at increased risk for gastrointestinal
mucosal damage [289–302]. Thus, a variety of
esophageal, gastric, and small bowel lesions can
occur such as esophagitis, esophageal stricture,
gastritis, gastric mucosal erosions, gastric bleeds,
peptic ulceration, small bowel erosions, and large
bowel erosions [303–305]. Increased risks of
gastrointestinal disease are well documented in
patients using NSAIDs as well as in patients older
than 65 years of age; in those with a history of
peptic ulcer disease, GI bleeding, or the use of
antacids; the concomitant use of steroids and
NSAIDs; the presence of comorbid conditions
like cardiovascular disease; high doses of
NSAIDs; and combinations of NSAIDs.
It has also been well recognized that nonselec-
tive NSAIDs have adverse effects on the kidneys
since they may cause salt retention and increase
in blood pressure and a reduction in glomerular
filtration rates in some patients. Such findings
were a part of the impetus for evaluating COX-2
inhibitors that might avoid these side effects
[306]. Despite the concept that COX-1-derived
PGE2 regulates salt and water balance and COX-2
inhibitors do not influence sodium excretion,
there is now evidence that renal medullary inter-
stitial cells express COX-2, and inhibitors of the
production of prostanoids by COX-2 reduce salt
excretion and lead to salt-dependent hyperten-
sion [144, 307–312]. In addition to these changes
in salt and water regulation by prostaglandins,
COX-1 inhibitors may also impair the diuretic
effects of furosemide and the antihypertensive
effects of other antihypertensive medications
including angiotensin-converting enzyme inhibi-
tors, b-blockers, and diuretics [313–317]. On the
basis of the foregoing data as well as other stud-
ies, both COX-1 and COX-2 inhibitors need to be
carefully monitored for changes in blood pres-
sure and sodium balance in patients treated with
these agents. These risk factors are especially
311
pertinent to those patients who are elderly, have
preexisting renal dysfunction, or who have hyper-
tension [306, 318–320].
Many human and animal studies have investi-
gated the role of prostaglandins in renal hemody-
namics [150, 277, 321–333]. In animals, COX-2
inhibitors have been shown to decrease plasma
renin levels, renal renin release, and COX-2
mRNA expression in certain high-renin settings
[150, 325–332]. Humans utilizing a low-sodium
diet and/or receiving furosemide demonstrated
an inhibition of renin release when treated with
COX-2 inhibitors [324, 333]. Some COX-2
inhibitors have also been shown to block the
hyperreninemia associated with antenatal
Bartter’s syndrome/hyperprostaglandin E syn-
drome [334, 335]. There is also evidence to sug-
gest that COX-2 inhibition impairs the
vasodilatory responses mediated by COX-2 prod-
ucts that regulate renal blood flow and glomeru-
lar filtration rates, especially in volume-depleted
states [336, 337]. In addition to these findings
and others, COX-2 inhibitors have been reported
to cause type IV renal tubular acidosis/acute isch-
emic renal insufficiency and hyperkalemia [337–
341]. It is clear, then, from reviews of the renal
effects of COX-1 and COX-2 inhibitors that treat-
ment with these inhibitors may be associated
with edema, hypertension, and acute renal failure
in some patients [342–353].
Despite all the data concerning COX-1 and
COX-2 prostanoid production and their role in
the functions of the kidney in health and disease,
it remains to be completely resolved whether
COX-1 or COX-2 is the predominant regulator of
renal functions. However, there is no question
that there are risks to the kidney when either
COX-1 or COX-2 inhibitors are used. In the kid-
ney, COX-1 provides the kidney with PGE2, PGI2,
and TXA2, whereas COX-2 generates PGE2, PGI2,
TXA2, and PGD2. The receptors for these metab-
olites have been localized to a variety of renal cell
types [344]. The PGE2 receptor subtypes have
been found in the following cells: EP1 in the pod-
ocytes and collecting duct; EP2 in the vasculature,
interstitial cells, and macula densa; EP3 in the dis-
tal tubule, collecting duct, and vasculature; and
EP4 in the vasculature, podocytes, glomerulus,
312
mesangial cells, macula densa, interstitial cells,
and proximal tubule. The IP receptor for PGI2 is
found in the vasculature, mesangial cells, macula
densa, distal tubule, collecting duct, and proximal
tubule. TP, the receptor for TXA2, is found in
most renal cells, and FP, the receptor for PGF2a,
has been localized to the podocytes, distal tubule,
collecting duct, and fibroblasts. The EP receptors
mediate the effects of PGE2, IP receptor mediates
the PGI2 effects, the TP receptor mediates the
effects of thromboxane A2, and the FP receptor
mediates the effects of PGF2a. Little is known
about the DP receptor for PGD2 in the kidney, but
evidence does show the presence of its product
and its effects in animal kidney cells [354–358].
These prostaglandin receptors are associated with
a variety of functions. The EP1 receptor is involved
with hemodynamics and transport, and the EP2
receptor is a mediator of renin release. The EP3
receptor is involved in vasoconstrictive responses
and transport functions, whereas the EP4 receptor
is associated with transport functions, vasodila-
tion, hemodynamics, renin release, antiapoptosis,
cytoskeletal functions, and growth. The IP recep-
tor mediates a variety of functions including
vasodilation, hemodynamics, transport, matrix
synthesis, renin release, antiapoptosis, fibrosis,
and growth. The TP receptor is involved with
vasoconstriction, hemodynamics, transport,
matrix synthesis, apoptosis, fibrosis, and growth.
Finally, the FP receptor is associated with trans-
port and cell transformation. As can be deter-
mined from the functions subtended by their
prostaglandin receptors, many different functions
are mediated by these receptors and the balance
between such functional parameters is incom-
pletely characterized at this point in time. This
picture of renal functions is also complicated by
species differences in the localization of such
receptors and their functions [359–363]. These
studies demonstrate the differences in the pros-
tanoids and their functions between species and
indicate the difficulties in drawing simple conclu-
sions across species. In conclusion, the use of
prostaglandin inhibitors in humans with preexist-
ing renal disease, hypertension, or electrolyte
imbalance needs to be carefully monitored. These
COX-1 and COX-2 inhibitors when used in the
9 Management of Hyperuricemia and Gout
healthy host should also be monitored for changes
in blood pressure, electrolytes, or other nephro-
toxic responses.
The last and perhaps the most significant toxic
manifestation related most specifically to the use
of COX-2 inhibitors is the increased risk of car-
diovascular events such as myocardial infarction,
cerebrovascular disease, and peripheral vascular
disease as well as hyperlipidemia. COX-2 inhibi-
tors also increase the risk of atherothrombotic
events in diabetic patients. The initial studies of
COX-2 inhibitors showed that these agents were
as effective as COX-1 inhibitors in the manage-
ment of inflammation and pain [364–367]. The
second conclusion concerning COX-2 inhibitors
is that these drugs have fewer gastrointestinal
side effects than standard or traditional NSAIDs
in many but not all studies [130, 368–376]. The
most critical element with respect to cardiovascu-
lar and vascular diseases has been related princi-
pally but not completely to the functions of the
two prostanoids, PGI2 and TXA2 [377]. One
method that confirms the importance of PGI2 and
TXA2 to vascular functions is the measurement
of the TXA2 and PGI2 metabolites in the blood
and urine. The serum levels of 6-keto-PGF1a and
the urinary levels of 2,3-dinor 6-keto-PGF1a rep-
resent indices of PGI2 production, whereas serum
TXB2 levels and urinary levels of 11-dehydro
TXB2 represent indices of TXA2 production.
Many studies have now shown that both COX-1
and COX-2 inhibitors significantly reduce the
levels of PGI2 metabolites [378–383]. Thus, the
reduction of PGI2 and the increase in unopposed
TXA2 have been proposed as the means by which
cardiovascular events associated with NSAIDs
occur. There is now a significant body of evi-
dence that implicates an increased frequency of
thrombotic events including myocardial infarc-
tion and strokes in association with the use of
both traditional NSAIDs and the newer COX-2
inhibitors [368, 384–404].
The most recent publications and reviews sort
out the role of COX-1 and COX-2 inhibitors on
the risk of cardiovascular events but do not
resolve the issue and do not conclude with a
strong recommendation for a single agent to
circumvent these toxic events [302, 388, 394,
Indomethacin (Indocin)
404, 405]. The removal of some of the COX-2
inhibitors from the market has helped to simplify
the decisions to use these drugs or not. A wide
variety of studies have evaluated cardiovascular
and gastrointestinal risks including long-term
placebo-controlled trials, comparative trials
between COX-2-specific inhibitors and tradi-
tional NSAIDs, and epidemiological studies
comparing users of COX-2-specific inhibitors
and NSAIDs and nonusers of anti-inflammatory
drugs [392]. The initial observations of the link
between myocardial infarction and NSAID use
were determined in the year 2000 and appeared
to be associated with the commencement of
NSAID therapy [406]. A review of this subject in
subsequent studies confirmed that the COX-2
inhibitor rofecoxib caused an increase in myocar-
dial infarction in 12–14 studies evaluating the use
of this drug. Furthermore, the increased risk of
myocardial infarction in other studies varies
depending on the COX inhibitor. When celecoxib
was evaluated, only 4 of 15 studies demonstrated
a significant risk for myocardial infarction [407–
410]. The general conclusion from all these dif-
ferent studies permits the following conclusions.
Rofecoxib, now off the market, yields a high risk
for myocardial infarction. Celecoxib studies
reveal some risks for myocardial infarction. It has
also been determined that indomethacin,
diclofenac, and meloxicam may have cardiovas-
cular risk factors similar to rofecoxib. There are
some shortcomings in these population studies
where smoking, alcohol use, and obesity were
not considered, and these variables may influence
the occurrence of cardiovascular and gastrointes-
tinal toxicities [411]. Thus, further studies includ-
ing analyses of the foregoing factors may define
a more complex set of risk factors for cardiovas-
cular events.
In summary, nonspecific inhibitory NSAIDs
together with a proton pump inhibitor or other
gastroprotective agents may circumvent the use of
COX-2 inhibitors and avoid gastrointestinal com-
plications from these drugs. This strategy is espe-
cially useful in elderly patients with cardiovascular
risk factors or those who have had previous myo-
cardial infarctions or other atherothrombotic epi-
sodes. Celecoxib appears to be the safest COX-2
313
inhibitor on the market presently since it shows
no increased risk for hypertension or edema over
a dose range of 200–300 mg/day. Celecoxib also
carries the lowest risk for gastrointestinal side
effects. There is some evidence that acetamino-
phen, nonselective NSAIDs, or selective COX-2
inhibitors used for more than 2 weeks in females
may increase the risk of hypertension or cardio-
vascular events [411]. Finally, three additional
facets with respect to NSAIDs are worth empha-
sizing. First, all the available NSAIDs have the
propensity to increase the risk of cardiovascular
events. Second, the lowest efficacious dose of any
NSAID should be used to avoid any potential side
effects. Third, if hypertension or edema occurs
during the use of an NSAID, this complication
should be treated aggressively.
We will review two NSAIDs in detail, indo-
methacin and naproxen, since these two agents
are among the most frequently used and both
have been validated for the treatment of acute
gouty arthritis in randomized controlled clinical
trials. Controlled trials have been performed with
other NSAIDs but only as comparators with indo-
methacin or naproxen.
Indomethacin (Indocin)
The structure of this NSAID is shown in Fig. 9.3.
Indomethacin is as effective as phenylbutazone in
the treatment of acute gout and is much less likely
to cause aplastic anemia. For these reasons, it is
often the drug of choice for the management of
acute gout. Indomethacin is an indole acetic acid
whose chemical structure is similar to the sulfox-
ide sulindac but not to other nonsteroidal anti-
inflammatory drugs. Its pharmacologic properties
are listed in Table 9.10. In addition to these prop-
erties, it should be recognized that this drug
crosses the placental membrane, and significant
concentrations of the drug have been measured in
fetal cord blood. The half-life of indomethacin is
prolonged in newborns and infants (>15 h) as
compared to adults. Indomethacin is recirculated
via the biliary tract making its serum half-life
difficult to measure accurately. This drug is
significantly bound to plasma albumin where a
314
Table 9.10 Indomethacin: pharmacologic properties
Peak fasting concentrations occur in 45 min after an
oral dose
Protein binding is 98–99 %
Bioavailability is 90–98 %
Biological half-life is 5–10 h
Indomethacin has one high-affinity protein-binding site
as well as secondary binding sites
Ibuprofen decreases indomethacin protein binding
Indomethacin increases plasma lithium levels
Indomethacin interferes with antihypertensive effects
of b-adrenergic agents
Probenecid decreases biliary clearance of indomethacin
Probenecid increases clinical effectiveness of
indomethacin
Synovial fluid indomethacin levels are equal to or
above serum levels for 9 h after one dose
Aspirin decreases indomethacin absorption and renal
clearance
Aspirin increases biliary clearance of indomethacin
Table 9.11 Indomethacin metabolism
Indomethacin undergoes enterohepatic recirculation
Indomethacin is metabolized by O-demethylation,
N-deacylation, and glucuronidation to inactive
metabolites
After an oral dose about, 16 % of indomethacin is
found in the urine as a free drug, and 82.5 % is
metabolized or conjugated, and 1.5 % appears as a free
drug in the feces
single high-affinity site has been characterized
with seven secondary sites to which indometha-
cin also binds [179]. Extensive metabolism of the
drug occurs in vivo including O-demethylation,
N-deacylation, and glucuronidation (Table 9.11).
In the range of 20 % of the free drug is excreted
by the kidney, so renal disease has the propensity
to alter its excretion and increase its toxicity.
Treatment Schedules
Recommended regimens for the treatment of
acute gouty arthritis include the following: 50 mg
orally three times daily for 2 days and followed
by 25 mg three times daily for 3 days or, alterna-
tively, 50 mg three times daily for 3 days and fol-
lowed by 25 mg three times daily for 4–7 days or
9 Management of Hyperuricemia and Gout
Table 9.12 Relative contraindications to indomethacin
therapy
Peptic ulcer disease
Inflammatory bowel disease
Renal or cardiac failure
Cirrhosis with ascites
Psychiatric disorders
Epilepsy
Parkinson’s disease
Platelet dysfunctions
Salt-dependent hypertension
Potassium-retaining diuretics
Furosemide therapy (antagonist to natriuresis)
Thiazide diuretics
Beta-adrenergic agents
Aspirin sensitivity
Probenecid therapy (indomethacin excretion is
blocked)
until the attack has resolved. In each case, the
treatment schedule may have to be prolonged
with severe flares of gout [412].
There are relative contraindications to indo-
methacin, and these are summarized in
Table 9.12.
The uricosuric drug probenecid inhibits the
tubular excretion of indomethacin by the kidney
and may interfere with the biliary clearance of
indomethacin which may enhance the clinical
efficacy of the drug and increase its toxicity
[169–171, 182]. Thus, a lower dose of indo-
methacin may be used in patients taking the uri-
cosuric drug probenecid (Benemid).
Toxicity
The toxicity of indomethacin is similar to the tox-
icity of all nonselective cyclooxygenase inhibi-
tors. Gastrointestinal and renal toxicity are
probably the most common. In addition, central
nervous system symptoms such as confusion,
inability to concentrate, headache, drowsiness,
tremor, and even psychosis occur in a frequency
comparable to the gastrointestinal side effects of
the drug. Skin rashes, hepatocellular damage,
coagulation disturbances, and bone marrow apla-
sia rarely occur (Table 9.13).
Naproxen
Table 9.13 Indomethacin toxicity
Gastrointestinal – dyspepsia, nausea, diarrhea,
abdominal pain, and peptic ulcer
CNS – headache and dizziness
Skin – rashes
Cardiovascular – tachycardia
Hematological – anemia, rarely aplastic anemia
Table 9.14 Pharmacology of naproxen
Naproxen is 99 % bound to plasma proteins (albumin)
Its mean plasma half-life is 14 h
Its volume of distribution is 0.09 l/kg
Its total clearance is 0.004 l/kg/h
It is metabolized to glucuronide conjugates
Ten percent is eliminated as the unchanged drug
Sixty percent is eliminated as conjugated naproxen
Twenty-eight percent is converted to
6-desmethylnaproxen
Urinary excretion is primarily as the conjugated drug or
its metabolite 6-desmethylnaproxen
Table 9.15 Naproxen: drug-drug interactions
Naproxen may alter prothrombin time
Naproxen may increase the effects of warfarin
compounds
Aspirin increases the clearance of naproxen
Benemid increases naproxen half-life and retards its
clearance
Naproxen
Another NSAID frequently used for the treat-
ment of acute gouty arthritis is naproxen. Two
treatment regimens include either 500 mg twice
daily for 5 days or 375–500 mg twice daily for
3 days, followed by 250–375 mg orally twice
daily for 4–7 days or until the attack resolves
[412].
Side effects of naproxen are similar to those of
other NSAIDs described above. However, the
cardiovascular toxicity of myocardial infarction
and strokes that are seen with both COX-1 and
COX-2 inhibitors have been found to be lower
with naproxen than any other NSAID in epide-
miologic studies (Tables 9.14, 9.15, and 9.16).
Since the major effect of NSAIDs appears to
be the inhibition of cyclooxygenase products, it
315
Table 9.16 Naproxen toxicity
Gastrointestinal – heartburn, GI bleeding, and
abdominal discomfort
CNS – headache, drowsiness, and lightheadedness
Skin – rarely urticaria, ecchymoses, and vasculitis
Renal – rarely causes acute interstitial nephritis or renal
papillary necrosis
Hepatic – rarely jaundice
Pulmonary – naproxen-induced asthma
might have been predicted that these agents
would only have minor effects of acute gout since
several mediators are thought to be involved in
this inflammatory reaction. Nonetheless, NSAIDs
are very effective therapeutic agents for acute
gout, suggesting that prostaglandins are major
mediators here. The NSAIDs are thought to be
most effective when given early in the acute
attack, indicating that other mediators than
cyclooxygenase products may become important
later in the attack.
There are additional prospects for the treat-
ment of the acute inflammation associated with
gouty arthritis that may become a reality in the
future. It is possible that leukotriene B4 receptor
antagonists might be of use in acute gout; how-
ever, the redundancy of the neutrophil chemot-
axins makes it unlikely that these inhibitors
would be useful. More likely candidates are the
phospholipase inhibitors that block the genera-
tion of the substrate for the proinflammatory
prostaglandins, arachidonic acid. However, these
inhibitors must be designed to inhibit specific
phospholipases and not impair those prostaglan-
din-generating molecules critical for physiologi-
cal purposes. Since monosodium urate crystals
have been shown to stimulate phospholipase A2
activities and the synthesis of a phospholipase
A2-activating protein, inhibitors of phospholi-
pases might be useful for the suppression of the
proinflammatory cytokines synthesized by this
route. In addition, it appears that there are differ-
ent arachidonic acid sources arising from differ-
ent phospholipases. On a speculative basis, the
development of specific phospholipase inhibi-
tors in the future may have some relevance to the
treatment of gout [413–415]. Many different
studies have now been published on the role of
316
phospholipases in the release of arachidonic acid
and the regulation of these enzymes [416–419].
Thus, the contributions of phospholipases to the
synthesis of inflammatory mediators represent a
complex process since it necessitates interac-
tions between cytoplasmic phospholipase A2s,
secretory phospholipase A2s, and the cyclooxy-
genases. Different stimuli coupled to a variety of
prostaglandin biosynthetic enzymes act on dif-
ferent cellular arachidonic acid pools at different
locations to give rise to immediate and delayed
arachidonic acid-derived mediators. These com-
plex reactions are in the early stages of investi-
gation with respect to the synovial compartment
and its cellular components in healthy and dis-
eased tissues [420–423]. The significance of the
phospholipases to the generation of inflammatory
mediators is clear, and in the future, the path-
ways responsible for the hydrolysis of mem-
brane phospholipids and the production of
arachidonic acid for mediator synthesis may
become therapeutic targets [424]. In fact, anti-
bodies specific for secretory phospholipase A2
isoforms have been constructed and utilized to
determine the tissue location and cell-specific
functions of these phospholipases [425]. If such
antibodies against phospholipases are deter-
mined to have specificity for specific tissues,
they could also be used as therapeutic agents to
block mediator production in specific tissues.
Thus, as the phospholipase pathways leading to
the generation of prostaglandins, leukotrienes,
and other lipid mediators are better character-
ized, the inhibition of such reactions may pro-
vide additional potent therapeutic tools for the
management of acute inflammatory responses
like those observed in gout. It is important to
recognize that there are a number of physiologi-
cal compounds that have recently been discov-
ered from investigations of the resolution of
acute inflammatory processes, and these com-
pounds may well have properties useful for the
resolution of an acute attack of gout. These com-
pounds are reviewed in Chap. 8. There are other
new initiatives related to the discovery of more
effective drugs against inflammatory responses,
and they are discussed at the end of this
chapter.
9 Management of Hyperuricemia and Gout
Glucocorticoids
Glucocorticoids are used in the treatment of a
wide variety of inflammatory and immune disor-
ders since they suppress the generation and
release of mediators of inflammation. They also
modify the functions of cells recruited to
inflammatory sites. In the human, endogenous
levels of cortisol in the plasma vary between 5
and 25 ug of cortisol/100 ml of plasma, and
almost all the hormone (90 %) circulates bound
to plasma proteins. About 80 % is bound to a-
globulin transcortin (transcortin-corticosteroid-
binding globulin) through a high-affinity binding
site, whereas a low-affinity site exists on albumin
[426, 427]. Since this discussion is concerned
with exogenously administered corticosteroids,
emphasis is placed on the absorption, metabo-
lism, and excretion of those agents commonly
used as anti-inflammatory corticosteroids such as
hydrocortisone, prednisone, prednisolone, and
dexamethasone. These drugs are absorbed pri-
marily in the upper jejunum, and peak plasma
levels are attained within 1 h or 2 after their inges-
tion. Low serum albumin and transcortin levels
as a result of hepatic disease cause an increase in
free drug levels [428]. The plasma half-life of
synthetic glucocorticoids such as prednisone is
about 1 h, whereas the biological half-life of the
drug lasts much longer than the plasma half-life.
Glucocorticoids are metabolized primarily by the
liver where they are reduced and conjugated with
glucuronic acid and subsequently excreted in the
urine. As noted previously, liver disease may
increase free drug levels and prolong the half-life
of the drug. In terms of relative potency with
hydrocortisone designated as one, prednisone
and prednisolone have four times the potency of
hydrocortisone [427]. The pharmacokinetic and
metabolic parameters of some steroids are shown
in Tables 9.17, 9.18, and 9.19, and the structure
of some common steroids is shown in Figs. 9.4
and 9.5.
The mechanism of action of corticosteroids is
a complex process incompletely characterized at
this time. Glucocorticoids enter cells via simple
or facilitated diffusion. They induce changes in
cyclic nucleotides, membrane fluidity, and ion
Glucocorticoids 317

Table 9.17 Steroidal anti-inflammatory agents: pharma- Table 9.19 Pharmacokinetics of intravenous prednisone
cokinetics and metabolism and prednisolone at different doses
Pharmacokinetics Prednisone/prednisolone Parameters Plasma Plasma
GI absorption (%) Rapid/variable prednisone prednisolone
Plasma protein binding (%) 65–70 5-mg dose
Peak plasma levels (h) Dose dependent T ½ (h) 2.7 ± 0.4 3.0 ± 2.1
Half-life (hrs) 2.5–3 MRT (h) 3.8 ± 0.5 5.1 ± 3.2
Metabolism Hepatic Dose PDL/AUC (PDL) 111 ± 5.0 712 ± 256
Volume of distribution (l/kg) 0.4–1.0 ml/min/1.73 m2 (calculated)
Excretory route Urine AUC (PDL)/AUC (PD) 4.99 –
20-mg dose
T ½ (h) 2.6 ± 0.5 3.2 ± 1.0
Table 9.18 Pharmacokinetics of oral prednisone/predni- MRT (h) 3.9 ± 0.6 5.8 ± 1.3
solone at different doses
Dose PDL/AUC (PDL) 157 ± 25 1,436.8 ± 520.1
Parameters Plasma Plasma ml/min/1.73 m2
prednisone prednisolone (calculated)
5-mg dose AUC (PDL)/AUC (PD) 7.2 –
T ½ (h) 3.5 ± 2.5 2.3 ± 0.3 40-mg dose
MRT (h) 4.9 ± 0.9 3.9 ± 0.4 T ½ (h) 3.5 ± 0.51 4.2 ± 1.0
Dose PD/AUC (PDL) 572 ± 155 116 ± 25 MRT (h) 4.6 ± 0.5 6.6 ± 1.2
ml/min/1.73 m2 Dose PDL/AUC (PDL) 194 ± 29 2,028.8 ± 363.2
AUC (PDL)/AUC (PD) 4.7 ± 1.1 – ml/min/1.73 m2
20-mg dose AUC (PDL)/AUC (PD) 10.4 –
T ½ (h) 3.3 ± 1.1 2.9 ± 0.6 These data are all modified from data published by Rose
MRT (h) 6.5 ± 0.8 5.5 ± 0.9 [1048]
Dose PD/AUC (PDL) 1,034 ± 139 185 ± 23 Examining the AUC ratios demonstrates a nonlinear dose
ml/min/1.73 m2 response. The rapid conversion of PD to PDL is consistent
with first-pass extraction or presystemic biotransforma-
AUC (PDL)/AUC (PD) 6.1 ± 0.8 –
tion. The nonlinear pharmacokinetics is most likely due to
50-mg dose concentration-dependent binding of PD to transcortin and
T ½ (h) 3.4 ± 1.1 3.4 ± 1.0 albumin, the interconversion of PD and PDL, and the
MRT (h) 7.1 ± 2.2 5.9 ± 1.8 concentration-dependent clearance
Dose PD/AUC (PDL) 2,271 ± 791 233 ± 28 The abbreviations used in this table and Table 9.18 are
ml/min/1.73 m2 MRT (mean residence time of drug in the body), PD pred-
AUC (PDL)/AUC (PD) 10 ± 4.0 – nisone, PDL prednisolone, and AUC area under the curve

channels, but their principal effect of significance
to their anti-inflammatory properties is to bind to
intracellular glucocorticoid receptors with the
subsequent induction of cellular responses lead-
ing to new protein synthesis [429–437]. The
emphasis in this discussion is on the glucocorti-
coid receptor-mediated effects since they are the
most relevant to the acute inflammation observed
in gout.
Intracytoplasmic glucocorticoid receptors are
present in many different cell types including
neutrophils and monocytes [433, 438, 439]. Once
glucocorticoids interact with these intracytoplas-
mic receptors, the glucocorticoid-receptor com-
plex is then translocated to the nucleus of the cell
where it binds to glucocorticoid response ele-
ments (GRE) in the chromatin. Binding of the
steroid receptor complex to GRE in the promoter
region of genes and interactions with other tran-
scription factors result in the transcription of
DNA and the formation of specific mRNAs
[440–443].
Since the identification of an inducible form of
cyclooxygenase-2 and its linkage to inflammatory
responses, the inhibition of eicosanoid biosynthe-
sis by glucocorticoids has been clearly demon-
strated in many studies and its significance to the
inflammatory process vigorously pursued [94,
444–446]. Glucocorticoids inhibit both in vivo
and in vitro prostaglandin production in cells and
318 9 Management of Hyperuricemia and Gout

Naproxen CH3 concentration-dependent manner [453]. These

CHCOOH
CH3O
Fig. 9.4 The structure of naproxen (Naprosyn). The
chemical name for naproxen is (S)-6-methoxy-a-methyl-
2-naphthyleneacetic acid. It is a propionic acid derivative
related to the arylacetic acid group of nonsteroidal anti-
inflammatory drugs and is soluble in lipids and water at a
high pH. It is insoluble in water at a low pH. This drug has
anti-inflammatory, analgesic, and antipyretic properties
Steroid Nucleus
12 17
11 16
1
2 9 14 15
10 8 seen at high concentrations of these agents. It
3 7
5
4 6
CH2OH
Cortisol (hydrocortisone)
C O
HO OH
O glucocorticoid-inducible proteins that bind
Fig. 9.5 The structure of the steroid nucleus and the cor-
tisol molecule. The attachment of the two-carbon chain at
position 17 of the steroid nucleus gives rise to the C-21
steroids. Glucocorticoid activity is completely dependent
on the presence of a hydroxyl group at position 11 of the
steroid nucleus. The addition of a double bond between
atoms 4 and 5 of the steroid nucleus increases the anti-
inflammatory action of the molecule
tissues exposed to these drugs [93, 94, 99, 102,
447–452]. Prednisone administered orally to
human volunteers at a dose of 60 mg for 7 days
has been shown to inhibit zymosan-induced
eicosanoid release from alveolar macrophages
[453]. Treatment of cultured macrophages with
hydrocortisone has also been shown to inhibit
the release of eicosanoids in a time- and
studies have now been supplemented by data
showing glucocorticoid-induced inhibition of
cyclooxygenase synthesis in human dermal
fibroblasts, differentiated human macrophage cell
lines (U937), blood monocytes, cultured vascular
cells, and mouse peritoneal macrophages [449,
450, 454–456]. It has now been documented that
glucocorticoids are only effective as inhibitors of
COX synthesis in cells in which COX can be
induced by IL-1, LPS, or other inducing agents.
Although many of the effects of glucocorti-
coids are related to their binding to the intracel-
lular glucocorticoid receptor, binding which is
saturated at relatively low concentrations, other
studies have indicated that there are effects of
glucocorticoids which are apparently not
accounted for by this receptor binding [457]. This
may be for some of the actions of glucocorticoids
may provide a rationale for the use of pulses of
intravenous glucocorticoids at high concentra-
tions that are employed under various circum-
stances [457].
The key to understanding the role of the glu-
cocorticoid-induced anti-inflammatory proteins
and the possible means by which therapeutic
agents mimicking their effects lies with the char-
acterization of the glucocorticoid-induced pro-
teins. The discovery of the annexin family of
anionic phospholipids in a calcium-dependent
manner represented a major breakthrough [458].
The fact that annexins including annexin-1 have
been found in synovial fluid provides further evi-
dence for their role in arthritic processes [459,
460]. The finding that sealed the association
between arthritis and annexins was the anti-
inflammatory effect of annexin (lipocortin-1) in
the experiment of arthritides [461–463]. From
these studies, it was clear that annexin-1 is one of
the key endogenous regulators involved in
inflammatory arthritides.
The mechanism of action of the 37-kD gluco-
corticoid-inducible protein annexin is through
its export to the cell surface and its interaction
with specific binding sites that alter phospho-
lipid release [464]. Subsequently, a number of
Glucocorticoids
Prednisone CH2OH
C O
O teins (C3 and factor B); reduce the biosynthesis
OH
O
Prednisolone CH2OH
C O
HO OH
O
Fig. 9.6 The structure of prednisone and prednisolone.
These are two commonly used glucocorticoids with anti-
inflammatory properties
investigations have demonstrated that annexins
and their analogs reduce phospholipase activity,
the source of arachidonic acid used for the syn-
thesis of proinflammatory mediators [460, 465–
474] (Fig. 9.6).
Recent studies have examined more critically
glucocorticoid-induced annexin in leukocyte
subsets and measured their intracellular content
as well as their capacity to secrete annexins
[475–477]. Dexamethasone at a concentration of
10−6 M induced the secretion of annexin-1 from
human-cultured monocytes [477]. This secretory
process is rapid, occurring within 15 min after
exposure to this corticosteroid. Constitutive lipo-
cortin-1 concentrations were found to be highest
in neutrophils and monocytes and lowest in B
lymphocytes [475]. Annexin binding sites are
increased in neutrophils following adhesion to
endothelial cells [476]. Such investigations set
the stage for understanding the role that annexin
(lipocortin) plays in inflammatory cells and their
functional responses. Since glucocorticoids mod-
ulate both noncyclooxygenase functions, cellular
components of the inflammatory and immune
responses, and cyclooxygenase-dependent func-
tions, a wide variety of cellular activities could be
regulated by annexins. For example, glucocorti-
319
coids suppress total immunoglobulin production
(especially IgA and IgG subtypes and IgE);
decrease the alternate complement pathway pro-
of leukotriene B4, prostaglandin E2, and prosta-
glandin F2a; suppress the induction of cytokine
mRNAs by IL-1 for IL-1b, IL-6, granulocyte/
macrophage-colony-stimulating factor; suppress
the induction of cytokine mRNAs by lipopoly-
saccharide for human monocyte-derived neutro-
phil and T cell chemotactic factors (IL-8);
suppress histamine release; and enhance the pro-
duction of IL-1 and IL-6 receptors as well as the
acute phase reactants induced by IL-1 and IL-6
[477–495]. Glucocorticoids also cause a periph-
eral blood neutrophilia with a neutropenia at the
site of inflammation, a depletion of peripheral
blood monocytes, and a depletion of eosinophils
and basophils as well [494, 496–502]. These ste-
roids also inhibit the chemotaxis of professional
phagocytes, inhibit phagocytosis and pinocyto-
sis, suppress oxidative antimicrobial functions,
and decrease specific granule release from baso-
phils. These hormonal agents also inhibit anti-
gen-induced cell proliferation and suppress the
production of lymphokines [496]. The multiplic-
ity of glucocorticoid effects including their direct
effect on inflammatory cells clearly establishes
the mechanisms of action for these potent anti-
inflammatory agents that would alter the acute
inflammatory response to monosodium urate
crystals.
The questions concerning the relationships
between glucocorticoid-induced functions,
annexin, and inflammatory responses have now
begun to be characterized in greater detail. In a
rodent model of inflammation, lipopolysaccha-
ride has recently been shown to induce the adhe-
sion and subsequent emigration of neutrophils
from the postcapillary venules [503]. Annexin-1
or dexamethasone reduced the adhesion and
transmigration of neutrophils induced by lipopoly-
saccharides in this animal model. Other animal
studies have characterized the action of annexins
in more detail as to their capacity to alter an
inflammatory reaction [504–512]. Dexamethasone
has been shown to inhibit leukocyte transmigra-
tion in the hamster cheek pouch model, but it does
320
not alter leukocyte rolling or adhesion [507].
Thus, lipocortin inhibits leukocyte diapedesis
directly. The mechanism by which transendothe-
lial passage of neutrophils is blocked results from
the mobilization of lipocortin and its externaliza-
tion after neutrophils adhere to venular endothe-
lium [509]. Subsequently, studies of mouse
mesenteric postcapillary venules using phago-
cytic stimulus, zymosan, definitively demon-
strated that recombinant human lipocortin
provoked the detachment of adherent neutrophils
from activated postcapillary endothelium [508].
In addition, glucocorticoids via the lipocortin
mechanism have been shown to reduce IL-1 beta-
induced neutrophil adhesion and the expression
of intercellular adhesion molecule-1 (ICAM-1) in
postcapillary venules [506]. Glucocorticoids also
significantly reduce IL-1- and IL-8-induced neu-
trophil migration and tissue infiltration [504].
Corticosteroids also suppress the rate of particle
phagocytosis and monocyte recruitment via lipo-
cortin induction [510]. Very recent studies have
also identified the site of lipocortin action as the
formyl peptide receptor on human neutrophils
and determined that neutrophils are desensitized
to chemoattractants by annexins [512]. Work is
now beginning to identify the pathways by which
intercellular processing of lipocortin occurs [505].
Clearly, all these studies have pertinence to the
monosodium urate crystal-induced inflammatory
response since it involves phagocytosis, IL-1- and
IL-8-mediated inflammatory reactions, and
transendothelial migration of inflammatory cells.
In addition to these lipocortin-dependent pro-
cesses, glucocorticoids also inhibit vasodilation
of the microcirculation and prevent increases in
vascular permeability [513]. Hydrocortisone also
inhibits the generation of reactive oxygen species
(ROS) from mononuclear cells [514]. Finally,
annexin-1 inhibits bradykinin-induced plasma
extravasation in the rat knee joint [513]. Since
bradykinin is known to interact with synovial
cells, this may be another inflammatory response
impeded by annexins [515, 516].
It is likely that annexins play a significant role
in the acute inflammatory responses generated by
monosodium urate crystals, and clearly, gluco-
corticoids can suppress such responses in the
9 Management of Hyperuricemia and Gout
human. The focus on identifying the sites of
action of glucocorticoids and their functional
responses as well as their mechanism of action
may lead to the development of glucocorticoid-
like molecules with fewer or no side effects.
Further, the use of glucocorticoid-induced pro-
teins, like the annexins, with anti-inflammatory
properties may lead to the development of a
totally new class of therapeutic modalities.
Therapeutic Regimens
Oral corticosteroids are frequently useful for the
treatment of acute gout when there is a contrain-
dication to the use of other medications.
Glucocorticoids are particularly useful for the
treatment of acute gout under circumstances
where NSAIDs and colchicine are contraindi-
cated, such as patients with renal failure or car-
diovascular disease. One recommended schedule
is 30–35 mg of prednisone of prednisolone orally
daily for 5 days. However, although there may
be an initial response, subsequent flares may be
seen. Alternatively, the acute attack may be
treated with 30–60 mg prednisone or predniso-
lone for 2 days (depending on the severity of the
attack), followed by tapering the dose by 5–10 mg
every 2 days over a 10-day period [412]. Two
randomized placebo-controlled studies have been
reported using oral prednisone for a 5-day period,
30 mg/day in one study and 35 mg/day in the
other. Prednisolone was equivalent to standard
courses of indomethacin compared to predniso-
lone 30 mg/day [517] and to naproxen compared
to the 35 mg/day dose [518].
The intra-articular injection of steroids (20–
40 mg of prednisolone, methylprednisolone, tri-
amcinolone, or other long-acting glucocorticoids)
is especially effective in patients when oral medi-
cations are contraindicated or cannot be effectively
administered to a patient. Thus, patients with acute
gout involving one or two joints after major sur-
gery can be effectively treated with intra-articular
steroids. Polyarticular gout, a clinical syndrome
most frequently seen in older age groups, is effec-
tively treated by oral glucocorticoid therapy.
Under such circumstances, prednisone at doses
Glucocorticoids
beginning at 40–60 mg orally per day and tapering
over 10 days to 2 weeks is a reasonable treatment
regimen. Low-dose intra-articular triamcinolone
(10 mg) has also been used successfully to treat
acute gout in small- and medium-sized joints
including knees, ankles, metatarsophalangeal
joints, and wrists [519]. Clearly, such therapy is a
short-term solution to what may be a recurrent
problem, and other treatment regimens need to be
considered over the long term.
Glucocorticoids are absorbed rapidly and
attain therapeutic levels in a short period of time
(Table 9.17). Here again, the major risk attendant
to such a treatment regimen is the possible dis-
semination of a microbial agent from an undiag-
nosed septic arthritis presenting as a mimicker of
acute gout. Delayed wound healing may also
pose a problem in steroid-treated patients.
Recently, mini-pulse methylprednisolone
therapy has been used in the management of
patients either with chronic disabling polyarticu-
lar gout or postoperative gout in which oral treat-
ment may be contraindicated. In these settings,
intravenously administered methylprednisolone
(100 mg in 5 % dextrose) over a 2- or 3-h time
period for three consecutive days is very effec-
tive. In the small number of patients in which this
regimen has been used, the frequency of rebound
gouty attacks has been low and prevented by the
use of maintenance colchicine in those with pol-
yarticular gout. The induction of microsomal
enzymes by other drugs (barbiturates, phenytoin,
or rifampin) enhances the metabolism of corti-
costeroids to inactive metabolites and decreases
the effectiveness of the total dose of steroid [520].
In contrast, estrogens potentiate the biological
effects of prednisolone by inhibiting its
microsomal oxidation to 6b-hydroxylated pred-
nisolone derivatives [516]. Women taking estrogen-
containing oral contraceptives and elderly
subjects (>65 years of age) have a decreased rate
of 6b-hydroxyprednisolone formation, and such
individuals are likely to require lower doses of
methylprednisolone or prednisolone on the basis
of these changes in pharmacokinetics and drug
clearance rates [520]. Estrogens block the activ-
ity of microsomal liver oxidase preventing the
conversion of prednisolone to its catabolites, and
321
in the elderly, the activity of these oxidases is
diminished by age alone. If one assumes that tar-
get organ responses are not altered in such
patients, reduced doses of prednisolone are indi-
cated in these clinical settings. In hyperthyroid-
ism, glucocorticoids are catabolized at an
increased rate resulting in the decreased systemic
availability of the active drug. Thus, hyperthyroid
patients may require increased doses of glucocor-
ticoids. The other pharmacokinetic properties of
prednisone and prednisolone are shown in
Tables 9.17 and 9.18 and document the short
half-life of these agents. The pharmacokinetics of
intravenous methylprednisolone is shown in
Table 9.19. Both prednisone and prednisolone
increase tissue catabolism and may aggravate
azotemia. The toxicities observed with short-term
usage of these drugs include sodium retention,
hypertension, and glucose intolerance. In severe
liver diseases, conversion of prednisone to pred-
nisolone, the active glucocorticoid, is slightly
impaired, but this altered rate of conversion is
counterbalanced by a reduced catabolism of
prednisone to its 6b-hydroxyprednisolone metab-
olite [520, 521]. The fraction of prednisone
excreted in the urine as the 6b-hydroxypredniso-
lone metabolite decreases as a function of increas-
ing hepatic dysfunction [521]. Thus, hepatic
6b-hydroxylase activity is decreased in the pres-
ence of impaired hepatic function, whereas the
11b-hydroxysteroid dehydrogenase enzymes that
convert prednisone to prednisolone and vice versa
appear to be relatively well maintained in the face
of liver disease [520–522].
Adrenocorticotrophic hormone (ACTH) may
be a useful means of treating gout when other
drugs are contraindicated or cannot be tolerated
[523]. It is especially useful when oral medica-
tions are contraindicated or when active gastroin-
testinal bleeding, not associated with steroid
treatment, is the primary problem associated with
the acute gouty episode. ACTH (40 units) can be
given every 6 h for 3 days, then every 8 h for 1
day, and then every 12 h for 1 day. Rebound
arthritis may necessitate additional treatment, but
recent studies have not found this complication
to be a significant problem since the relapse rate
for acute gout was similar to that observed with
322 9 Management of Hyperuricemia and Gout

Table 9.20 Pharmacokinetics of intravenous acid or urinary uric acid levels. On the other
methylprednisolone hand, ACTH has been shown to be a uricosuric
Parameters Methylprednisolone agent with a modest capacity to increase urate
5-mg dose excretion by the kidney (Table 9.21).
T ½ (h) 2.8 (13.9)
MRT (h) 4.3 (12.7)
Dose/AUC ml/h/kg 336.5 (30.2) Interleukin 1 Inhibitors
20-mg dose
T ½ (h) 2.7 (13.9)
Finally, a new class of anti-inflammatory drugs is
MRT (h) 4.3 (11.7)
being investigated for the treatment of acute
Dose/AUC ml/h/kg 330 (22.2)
gouty arthritis. The recognition of gout as an
40-mg dose
T ½ (h) 2.6 (7.6)
autoinflammatory disease that is mediated by the
MRT (h) 4.0 (7.4) interactions of sodium urate crystals with the
Dose/AUC ml/h/kg 345 (17.1) inflammasome NLRP3 in inflammatory cells has
The figures in parentheses are the coefficients of variation
indicated that urate-mediated inflammation is
in percent. These data are modified from those published dependent on IL-1 activation, as discussed in
by Szefler et al. [1049] detail elsewhere in this book. Thus, IL-1 block-
The pharmacokinetic data for prednisone, prednisolone, ing agents would be expected to be effective
and methylprednisolone show dose-dependent pharma-
cokinetics as a result of gut metabolism, first-pass metab-
agents for the treatment of acute gouty arthritis,
olism, reversible metabolism, and concentration-dependent and in fact several trials have been carried out
elimination. Methylprednisolone has a low affinity for that demonstrate the proof of this principle.
binding to transcortin and demonstrates linear nonspecific However, the role of these agents in the manage-
protein binding. For these reasons, methylprednisolone
shows more linear pharmacokinetics than either predni-
ment of gout is uncertain for several reasons.
sone or prednisolone First, there are already several effective drugs
available for the treatment of acute gout. Second,
Table 9.21 Relative contraindications to treatment with the studies of IL-1 inhibitors are preliminary and
ACTH leave questions about their effectiveness. Third,
Tuberculosis (including latent disease) many inflammatory mediators aside from IL-1
Psychiatric disorders are involved in the pathogenesis of acute gout.
Cirrhosis (sodium retention) Fourth, the IL-1 inhibitors are expensive. Finally,
Salt-dependent disorders (e.g., hypertension) their long-term toxicity has been incompletely
Hypokalemia studied [524, 525].
Infection The three IL-1 inhibitors currently available
Peptic ulcer disease (?) are anakinra, canakinumab, and rilonacept.
Studies of each of these agents in the treatment of
gouty arthritis have been published. Each of these
indomethacin treatment [523]. There are rela- agents has been approved by the US FDA for
tively few contraindications to ACTH treatment, treatment of patients with CAPS, the cryopyrin-
but the issue of aggravation of gastrointestinal associated periodic syndromes discussed else-
bleeding has not been completely resolved where in this book. Anakinra has been approved
(Table 9.20). ACTH dosage is more difficult to by the FDA for rheumatoid arthritis. Each of
regulate than orally or intravenously adminis- these agents has been demonstrated to be effec-
tered steroids. The time for complete pain relief tive in treatment of CAPS.
after a single dose of ACTH (40 units) was 3 ± 1 h, Anakinra is a recombinant form of the human
whereas after 50 mg of indomethacin four times IL-1 receptor antagonist. It differs from the native
a day, the time interval was 24 ± 10 h [523]. It is human IL-1 receptor antagonist by having a sin-
important to recognize that neither NSAIDs nor gle methionine at its amino terminus. It blocks
colchicine has any effect on either serum uric the action of IL-1b and IL-1a by competitively
Urate-Lowering Therapy: Uricosuric and Other Hypouricemic Drugs
inhibiting the interaction of IL-1 with the type 1
interleukin-1 receptor. Anakinra was shown to
have some anti-inflammatory effects in acute and
chronic gout in a small pilot study, but clearly
further studies are needed [526].
Canakinumab is a recombinant human mono-
clonal antibody with specificity for human IL-1b.
It belongs to the IgG1/k subclass. A single-blind
dose-finding phase II study of canakinumab for
the treatment of acute gouty arthritis in patients
with intolerance to NSAIDs and colchicine was
reported [527]. Five different doses of canaki-
numab were compared to treatment with a single
40-mg IM dose of triamcinolone, in all patients
within 5 days of the onset of an attack of acute
gout. Patients receiving all doses of canakinumab
were reported to have had less pain than controls
receiving triamcinolone, but the difference was
only statistically significant with the highest dose
of 150 mg of canakinumab. In addition, at
8 weeks, patients receiving 150 mg of canaki-
numab had a 94 % reduction of recurrent gout
flare, compared to the patients receiving triamci-
nolone. As pointed out by Neogi [528] in an edi-
torial accompanying this report, the findings are
promising, but the study has several shortcom-
ings which must be considered before this drug
can be recommended as a standard practice
option. The choice of comparator drug, 40 mg
triamcinolone, has not been shown to be optimal
therapy. Furthermore, the timing of entry of
patients into the study may not have been ideal,
risks of infection from IL-1 suppression remain a
consideration, and the expense of the drug are all
factors requiring further study.
Rilonacept is an IL-1 trap. It is a dimeric
fusion protein consisting of the extracellular
domains of the human IL-1 type 1 receptor with
its IL-1 binding domain and the IL-1 receptor
accessory protein both linked to the Fc portion of
human IgG1. Rilonacept acts as a soluble decoy
receptor, binding both IL-1a and IL-1b. It also
binds the IL-1 receptor antagonist although with
a lower affinity than IL-1a and b. In a pilot study
of acute gout, rilonacept was less effective than a
standard regimen of indomethacin [529]. In
another small study of chronic active gout,
rilonacept reduced pain more than placebo [530].
323
Finally, in a study of the prophylactic effects of
rilonacept, patients initiating allopurinol received
either rilonacept or placebo for 16 weeks. In this
study, the frequency of acute gout flares was
reduced by as much as 80 % compared to pla-
cebo. However, efficacy of rilonacept was not
compared to standard regimens [528].
In summary, the role of the IL-1 blockers in
the treatment of acute gout and for the prophy-
laxis of acute gout during urate-lowering therapy
has not been established at this time. These agents
may expose patients to risks of serious infections,
and expense remains an issue. Furthermore, it is
logical to assume that they must be used early in
the course of an acute attack of gout since IL-1
appears to be an early mediator of gouty
inflammation. Later in the course of acute gout,
other mediators become important, and these
would not be influenced by IL-1 blockers. In
addition, IL-1 independent mediators such as
endothelial adherence factors and complement
components may play a role in acute gout.
Urate-Lowering Therapy: Uricosuric
and Other Hypouricemic Drugs
Ultimately, the effective treatment of gout
requires that the concentrations of urate in the
extracellular fluid must be reduced below the
solubility limit of monosodium urate. Since
the solubility of monosodium urate in extracel-
lular fluid under physiological conditions is
6.8 mg/dl, the concentrations of urate in the
serum must be reduced below this level to pre-
vent precipitation of sodium urate crystals in tis-
sues and to promote the dissolution of sodium
urate crystals from body tissues. Since the patho-
logical consequences of gout arise from the pres-
ence of urate crystals in tissues, primarily in and
around joints, these crystals must be dissolved
from the tissues and prevented from forming.
From a practical viewpoint, the therapeutic goal
should be to reduce the serum urate concentra-
tion to less than 6.0 mg/dl. The other major path-
ological consequence of urate in the body is the
formation of uric acid stones in the urinary tract.
Since uric acid stones are formed in the usually
324
Table 9.22 Criteria for treatment with uricosuric drugs
Chronic tophaceous gout
Diuretic-induced hyperuricemia (serum uric acid in the
range of 8–10 mg/dl)
Absence of renal disease or factors known to damage
the kidney
Absence of uric acid/calcium oxalate lithiasis
Absence of enzyme abnormalities associated with
gout
Urinary uric acid excretion of greater than1 g/24 h
Recurrent gouty episodes despite colchicine
prophylaxis
Intolerance to allopurinol
acid environment of the urine, urate deposits as
unionized uric acid rather than ionized urate.
Risk factors for uric acid stone formation are uri-
nary acidity and the quantities of urate excreted
in the urine. Therefore, prevention of uric acid
stones is promoted by increased urine output and
alkalinization of the urine. These considerations
should be borne in mind when choosing between
urate-lowering agents which either inhibit urate
formation or promote urate excretion by the
kidney.
Criteria for the use of allopurinol are reasonably
straightforward, and by exclusion, indications for
uricosuric drugs can be derived (Tables 9.21 and
9.22). The structures of probenecid, sulfinpyrazone,
allopurinol, and febuxostat are shown in Figs. 9.7
and 9.8. The pharmacokinetics and metabolism of
the uricosuric and hypouricemic drugs are shown
in Table 9.23. As can be determined by the criteria
for uricosuric and hypouricemic treatment criteria,
no mention has been made of the use of these drugs
in the management of asymptomatic hyperurice-
mia. The latter condition is a frequently encoun-
tered laboratory abnormality, and its clinical
significance must be carefully evaluated. As noted
previously, there is a multiplicity of causes for
hyperuricemia, and asymptomatic hyperuricemic
patients should be educated as to the associations
between hyperuricemia and fasting, obesity, and
excessive alcohol use. The indications for the treat-
ment of asymptomatic hyperuricemia have been
summarized in Table 9.1 and have been discussed
in the chapter on clinical gout and hyperuricemia.
There remains the enigma as to whether patients
with significant renal impairment and asymptomatic
9 Management of Hyperuricemia and Gout
Probenecid
CH3CH2CH2
NSO2 COOH
CH3CH2CH2
Allopurinol
OH
N
N
N
N N
H
Fig. 9.7 Structures of probenecid and allopurinol and
febuxostat. Probenecid (p-(di-n-propylsulfamyl) benzoic
acid) was originally developed to sustain high blood levels
of penicillin by inhibiting its renal tubular excretion.
Probenecid (Benemid) increases uric acid clearance by
inhibiting its reabsorption by the kidney, and low doses of
salicylate abrogate this activity. Allopurinol (4-hydroxy-
pyrazolo (3, 4-d) pyrimidine) was first synthesized for use
as a chemotherapeutic agent but was determined to block
the synthesis of uric acid by xanthine oxidase. Its major
metabolic product oxypurinol (4, 6-dihydroxypyrozolo
(3, 4-d) pyrimidine has a long half-life (28 h) and is the
primary inhibitor of xanthine oxidase activity. Allopurinol
and oxypurinol are analogs of hypoxanthine and xanthine,
respectively
N O
N
S
O
O
Fig. 9.8 The structure of febuxostat, a xanthine oxidase
inhibitor that is not a purine analogue
Table 9.23 Indications for allopurinol therapy
Uric acid nephrolithiasis
Heritable enzyme defects (HGPRTase and PRPP
synthetase)
Calcium oxalate nephrolithiasis with hyperuricosuria
Adenosine phosphoribosyltransferase deficiency
(complete)
Chemotherapy with cytolytic agents or radiotherapy
Gouty nephropathy (serum uric acid usually above 8
or 9 mg/dl)
Allergic reactions to uricosuric drugs
Acute uric acid nephropathy
Ineffective control of hyperuricemia by uricosuric
drugs
Uricosuric Drugs: Sulfinpyrazone, Probenecid, and Benzbromarone
Table 9.24 Uricosuric and hypouricemic drugs: pharmacokinetics and metabolism
Probenecid
GI absorption (%) 100 rapid
Plasma half-life (h) 4–8a
Peak blood levels (h) 4 1
Plasma protein binding (%) 85–95
Volume of distribution (%) 0.15 ± 0.02
Excretory route Kidney
a
The half-life of probenecid is dose dependent
b
The sulfide metabolite of sulfinpyrazone has a half-life of 14.5 h
c
Seventy percent of allopurinol is converted to oxypurinol that has a half-life of 25 h
hyperuricemia should be treated with allopurinol
to prevent urate-induced renal parenchymal dam-
age. No carefully controlled studies have been per-
formed to permit an objective analysis of this
problem. Since most chronic renal diseases prog-
ress slowly and serum uric acid levels often do not
exceed 10–12 mg/dl, allopurinol therapy is not
indicated. However, renal function should be mea-
sured periodically to ensure that renal function is
not deteriorating at an unacceptable rate. The labo-
ratory parameters that have been used to define
those patients with chronic renal disease who are at
risk for urate-induced renal disease are probably
patients with serum uric acid levels in the range of
10–13 mg/dl, urinary uric acid to creatinine ratios
of greater than one, urinary uric acid concentra-
tions of greater than 1,000 mg/24 h, and serum uric
acid increments of 2.5 mg/dl/day or greater.
Whether patients with polycystic kidney disease
and hyperuricemia deserve early treatment for their
hyperuricemic state remains an unresolved ques-
tion, but there appears to be a higher frequency of
gout in this disorder as compared with other causes
of renal failure. Such data may provide a cogent
rationale for using drugs to diminish serum uric
acid concentrations in individuals with this disor-
der (Table 9.24).
Uricosuric Drugs: Sulfinpyrazone,
Probenecid, and Benzbromarone
Sulfinpyrazone
The two uricosuric drugs generally used in
the United States are probenecid (Benemid)
and sulfinpyrazone (Anturane). In some other
325
Sulfinpyrazone Allopurinol
100 rapid 80
2.5–3.5b 2–3c
0.5–1.0
98 –
0.6 0.5
Kidney Kidney
countries abroad, benzbromarone has been used
extensively as a uricosuric agent and in combina-
tion with allopurinol, the xanthine oxidase inhibi-
tor. As will be discussed subsequently,
benzbromarone has now been withdrawn from
the market because of its toxicity. Sulfinpyrazone
impairs platelet aggregation and prolongs platelet
survival; these properties make the use of this
drug particularly attractive in patients with gout
who are at high risk for serious cardiovascular
disorders and their platelet-mediated complica-
tions [531–537]. Both sulfinpyrazone and its
sulfide metabolite inhibit platelet cyclooxygenase
activity; the sulfide metabolite has a more potent
and prolonged effect on prostaglandin generation
than the parent drug [533]. The plasma half-life
of sulfinpyrazone is approximately 3 h, whereas
its sulfide metabolite has a half-life of greater
than 14 h. Controversy exists as to whether such
alterations in platelet functions have any role in
the prevention of thromboembolism of the myo-
cardium or brain. Studies indicating their thera-
peutic value in such conditions have shown that
the drug must be given in dosages of 800 mg/day
for 7 days to have clinically relevant effects on
platelet function [538, 539].
Sulfinpyrazone is also a more potent uricosu-
ric drug than probenecid on a mole for mole basis,
and studies reported three decades ago deter-
mined that the former agent is better tolerated by
patients than the latter drug [540–542]. The fail-
ure of Anturane to control hyperuricemia is usu-
ally related to the concomitant use of salicylates
or renal insufficiency. Salicylates antagonize the
uricosuric effects of probenecid and sulfinpyrazone
by abolishing the renal tubular elimination of
urate [543, 544]. The antituberculous drug
326
pyrazinamide also antagonizes the uricosuric
effects of Anturane and Benemid [543].
Sulfinpyrazone competes with para-aminohippu-
ric acid (PAH), phenolsulfonphthalein (PSP),
salicylates, and probenecid for their renal tubular
transport systems [545–548]. Thus, laboratory
tests using PAH or PSP as agents for the measure-
ments of specific membrane transport functions
are not accurate in the presence of these uricosu-
ric agents, and the competition of probenecid and
sulfinpyrazone for same of transport system
delays the excretion of the latter drug prolonging
its uricosuric effect. Sulfinpyrazone may also
potentiate the effects of sulfa drugs and oral
hypoglycemic agents [549]. The renal transport
systems for uric acid are discussed in detail in
chapter 2.
Sulfinpyrazone is largely excreted in the urine
unchanged, and the remainder is excreted as the
glucuronide conjugate of its sulfone metabolite
(>30 %) as p-hydroxysulfinpyrazone (10 %)
and as other metabolites [550, 551]. Since
sulfinpyrazone is extensively bound to plasma
proteins, it is not filtered at the glomerulus but
eliminated via the renal tubules. Its uricosuric
properties result from interference with the post-
secretory reabsorption of uric acid via the renal
tubules. Both sulfinpyrazone and its metabolite,
p-hydroxysulfinpyrazone, are potent uricosurics
[552]. These drugs are highly selective since they
only interfere with the trihydroxypurine, uric
acid, and do not alter the excretion of the dihy-
droxypurine and monohydroxypurine, xanthine,
and hypoxanthine. Probenecid interferes with
the secretion of sulfinpyrazone, whereas
sulfinpyrazone does not block the secretion of
probenecid by the kidney [546]. Thus, the urico-
suric effect of sulfinpyrazone enhances the effect
of probenecid.
Sulfinpyrazone causes gastrointestinal toxicity
in approximately 10–15 % of patients, and skin
rashes occur rarely (about 3 % of patients) with
the use of this drug. Sulfinpyrazone is a phenylb-
utazone analog, and like the latter drug, it may
suppress bone marrow activity. Although uncom-
mon, the toxic response may account for its
decreased clinical usage despite its advantageous
properties and its few clinical contraindications.
9 Management of Hyperuricemia and Gout
Table 9.25 Pharmacologic properties of probenecid
Probenecid is rapidly and completely absorbed
Peak blood levels are obtained at approximately 4 h
Uricosuric effects occur in about 40 min after
administration of the drug
Serum half-life (mean) is 4–12 h
Probenecid is 90–95 % bound to serum albumin
Probenecid is metabolized in the liver to an
acylglucuronide
Hydroxylated and carboxylated derivatives of
probenecid are also formed
The only relative contraindications to the use of
this drug are the presence of peptic ulcer disease,
skin rashes, and, of course, known allergies to the
drug. The recent use of benzbromarone in Europe
before its removal from the market may have
caused sulfinpyrazone to be used less frequently.
In addition, this drug is infrequently used for the
management of gout since allopurinol is the most
frequently prescribed drug for lowering the serum
uric acid levels.
Probenecid
The uricosuric drug probenecid has been used for
decades and is usually not associated with serious
toxicity. It decreases the renal excretion of many
drugs by competing for a common organic acid
secretory mechanism [552]. Its structure is shown
in Fig. 9.7. By this competition with other drugs,
it raises the serum levels of antibiotics (penicillin,
synthetic penicillins, rifampin, and dapsone), anti-
viral agents (acyclovir), anti-inflammatory agents
(indomethacin, naproxen, salicylic acid), and
diuretics (acetazolamide, furosemide, thiazides)
[552–561]. Probenecid is rapidly and completely
absorbed and reaches peak plasma concentrations
within 4 h (Table 9.25). Its uricosuric effects begin
early (40 min after its administration), and its
half-life in plasma increases in a dose-dependent
fashion. Even though approximately 70 % of the
drug disappears from the plasma in 24 h, less than
5 % of the native molecule appears in the urine
[562]. The majority of the ingested probenecid is
metabolized by the liver to an acylglucuronide
and to various hydroxylated and carboxylated
Uricosuric Drugs: Sulfinpyrazone, Probenecid, and Benzbromarone
derivatives [562–565]. The latter derivatives are
also uricosuric. The mechanism of action of
probenecid is similar, if not identical, to
sulfinpyrazone. Like sulfinpyrazone, it does not
alter xanthine or hypoxanthine excretion by the
kidney. It does block the reabsorption of oxy-
purinol, the active metabolite of allopurinol,
which prolongs its half-life [566]. Nonetheless,
probenecid and allopurinol when used together
have an additive effect on the elimination of uric
acid and lowering serum uric acid levels [566]. It
is important to recognize that probenecid is inef-
fective as a uricosuric when the glomerular
filtration rate is less than 50 ml/min [567]. Acute
gouty arthritis and uric acid nephrolithiasis are the
most common complications of probenecid ther-
apy. The frequency of acute gout in association
with probenecid therapy can be significantly
reduced by the concomitant administration of
colchicine or indomethacin. Nephrolithiasis sec-
ondary to probenecid can be prevented by initiat-
ing treatment with probenecid at a low dose,
encouraging a high fluid intake (about 2–3 l/day),
and using sodium bicarbonate (2–6 g/day) to
increase the urine pH and the solubility of uric
acid in the urine. Similar complications can occur
with sulfinpyrazone therapy and can be controlled
in an identical manner.
Drug toxicity from probenecid includes gas-
trointestinal side effects, hypersensitivity reac-
tions to the drug, skin rashes, and drug-induced
fever (Table 9.26), and its pharmacologic proper-
ties are shown in Table 9.25. Such toxic reactions
are not common, only occurring in about 10 % of
patients, and there are relatively few contraindi-
cations to the use of probenecid such as peptic
ulcer disease, skin rashes (penicillin-like), neph-
rotic syndrome, and epilepsy. More serious reac-
tions to this drug such as the nephrotic syndrome
and hepatocellular damage are rare.
One serious complication of probenecid ther-
apy is its interaction with methotrexate [568].
Probenecid potentiates methotrexate toxicity by
inhibiting the renal tubular excretion of metho-
trexate and its metabolites, by displacing metho-
trexate bound to plasma proteins and by inhibiting
methotrexate secretion into the bile [569–571]. A
single patient with rheumatoid arthritis who was
327
Table 9.26 Probenecid toxicity
GI intolerance
Skin rashes
Fever
Hypersensitivity reactions
Flank pain and stone passage
Acute gout
Rarely nephrotic syndrome
treated with probenecid for hyperuricemia (serum
uric acid of 15.6 mg/dl) developed pancytopenia
(total white blood cell count of 1,700 cells/mm3,
hemoglobin of 7.1 g/dl, and a platelet count of
13,000 cells/mm3) [464]. A bone marrow aspirate
from this patient showed marked hypocellularity,
most apparent in the myeloid elements (M:E ratio
of 1:5). The bone marrow also showed megalo-
blastic changes with an MCV of 90. Cessation of
all medications including probenecid and the use
of platelet and packed cell transfusions as well as
the administration of folic acid (1 mg/day) led to
the recovery of the bone marrow. Such a catastro-
phe emphasizes the need for documenting drug-
drug interactions prior to the use of any drug in
patients and the adherence to appropriate criteria
for the clinical indications for such drugs like
allopurinol and probenecid. It is worth pointing
out that gout is extremely rare in association with
established rheumatoid arthritis.
Standard treatment regimens for Benemid
begin with a dose of 250 mg twice a day for 1
week increasing the dose to 500 mg twice a day
to attain the appropriate reduction in serum uric
acid levels. As much as 2 g of Benemid may be
administered as 100- or 200-mg doses twice a
day for 1 week increasing the dose to 200 mg
four times a day if necessary to control hyperuri-
cemia (Table 9.26).
Salicylates
Salicylates are potent uricosuric drugs at high
doses (4–5 g/day), but few patients are able to
tolerate these doses. The low serum urate levels
seen in the past when patients with rheumatoid
arthritis were treated with high-dose salicylates
were the result of the uricosuric properties of
328
acetylsalicylic acid and its derivatives. Aspirin
should only be prescribed when toxicity prevents
the use of all other antihyperuricemic drugs, and
such situations probably almost never occur.
Since many individuals use aspirin as a preventa-
tive measure for cardiac insults and for many
other medical conditions including over-the-
counter preparations, any effect of very low-dose
aspirin may have a negative impact on renal func-
tion and alter the 24-h urinary uric acid excretion.
A recent study has demonstrated that aspirin at
doses of less than 500 mg/day results in a
significant decrease in the rate of uric acid excre-
tion (~ 15 % decrease in the rate of uric acid
excretion) with a concomitant elevation in serum
uric acid levels in an elderly population (ages
61–94) [572]. These effects were more pro-
nounced in hospitalized patients that had low
serum albumin concentrations (<3 g/dl) and those
receiving long-term diuretic therapy (furosemide
20–40 mg/day). Even though very low-dose aspi-
rin does not cause dramatic changes in renal
function or serum uric acid levels, such data are
worth considering when assessing renal function,
urinary uric acid concentrations, and serum urate
levels.
In addition to probenecid and sulfinpyrazone,
other uricosuric drugs are being developed. For
example, during the treatment of patients with
HIV infection with the nonnucleoside reverse
transcriptase inhibitor RDEA806, this agent was
noted to have uricosuric effects due to inhibition
of the renal tubular uric acid transporter URAT 1
[573].
Benzbromarone
Benzbromarone is a halogenated benzofuran
derivative with potent uricosuric properties avail-
able in Europe until very recently. Micronized
benzbromarone is rapidly absorbed attaining
peak blood levels in 2–3 h [574]. The drug is
dehalogenated in the liver to bromobenzarone
after the removal of a single bromine atom and
subsequently to benzarone with both bromine
atoms removed. About 60 % of the native mole-
cule is absorbed, and derivatives of bromoben-
9 Management of Hyperuricemia and Gout
zarone and benzarone are conjugated to glucuronic
acid and excreted in the bile (80 %) and urine
(20 %). Although the serum half-life of benzbro-
marone is roughly 12 h, enterohepatic recircula-
tion of its dehalogenated metabolite, benzarone,
permits the detection of this metabolite for over
48 h [575]. The drug is strongly bound to plasma
proteins. A variety of benzbromarone metabo-
lites have been isolated from the urine and their
structure characterized [576–579].
The hypouricemic and uricosuric properties of
benzbromarone were first reported in the 1980s,
and subsequently a large number of publications
have confirmed this drug’s role in the manage-
ment of gout [580–587]. The mechanism of
action of benzbromarone is via the selective inhi-
bition of tubular reabsorption of uric acid by the
renal tubules. Recent evidence has demonstrated
the binding of benzbromarone to the urate/anion
exchanger at the brush-border membrane vesicles
of the proximal renal tubules in humans [588]. It
has been used extensively in Europe until recently
in the treatment of gout and hyperuricemia and
has been most effective in certain special clinical
settings. Benzbromarone is an effective alterna-
tive drug for the reduction of serum urate levels
in patients who are allergic to allopurinol [589,
590]. The drug is especially useful in patients
who develop cyclosporine-induced hyperurice-
mia after undergoing organ transplantation [591].
Two published benzbromarone/benziodarone-
treated patients have documented the success of
this agent in organ-transplant patients [591, 592].
In one series of 25 patients, 100 mg of benzbro-
marone decreased the serum uric acid levels from
mean values of 9.72 ± 0.3–5.26 ± 0.4 mg/dl with
no side effects, and in another series of 20
patients, 50–100 mg of benziodarone reduced the
mean serum uric acid levels from 10.1 ± 1.8 to
5.1 ± 1.4 mg/dl without significant adverse reac-
tions [591]. In these cases, allopurinol was con-
traindicated because of its interaction with
azathioprine, whereas benzbromarone at a dose
of 100 mg/day normalized the serum uric acid
level and increased the urinary uric acid excre-
tion without any effect on azathioprine. It is valu-
able to reemphasize the rapidity with which
tophaceous gout can develop in organ-transplant
Xanthine Oxidase Inhibitors: Allopurinol and Febuxostat
patients taking cyclosporine and the unusual
clinical presentations such patients may have
[593–596]. The drug has also been used success-
fully in the treatment of familial juvenile gouty
nephropathy and in a small number of patients
with renal insufficiency [585, 597]. The drug is
only effective as a uricosuric agent when the cre-
atinine clearance is greater than 20 ml/min [598].
Combination drugs containing allopurinol and
benzbromarone have also been available in
Europe, but they do not appear to confer any dis-
tinct advantages over the use of single agents
[599]. As might be expected, the combination of
drugs is more effective in lowering the serum uric
acid levels than allopurinol alone [600, 601]. One
report in the literature documented a concomitant
reduction of serum lipids (triglycerides and cho-
lesterol) and serum uric acid during benzbroma-
rone use [602].
Benzbromarone is a potent competitive inhibi-
tor of the 7-hydroxylation of the anticoagulant
S-warfarin [603]. Thus, benzbromarone prolongs
the anticoagulant action of S-warfarin.
Pyrazinamide and low-dose aspirin abrogate the
uricosuric effect of benzbromarone, and the latter
drug appears to have no effect on the elimination
of penicillin [604–606]. It is also has little or no
effect on the diuresis induced by thiazide drugs
[604–606]. Like other uricosuric drugs, benzbro-
marone is ineffective at low glomerular filtration
rates (<25 ml/min) [607]. Like other uricosuric
drugs, the most common side effects are the pre-
cipitation of an acute episode of gouty arthritis or
the formation of uric acid calculi [606, 608].
Utilizing colchicine prophylaxis, using low doses
of benzbromarone at the outset of therapy,
encouraging high fluid intake, and alkalinizing
the urine can easily avoid these complications.
Gastrointestinal intolerance occurs in about 10 %
of patients taking the drug, and skin rashes are
rarely observed [583].
Benzbromarone at a dose of 40 mg is equiva-
lent to 1 or 1.5 g of Benemid or 400–800 mg of
Anturane [606]. A single dose of 80 mg of benz-
bromarone causes a reduction of serum uric acid
levels by one-third to two-thirds [582, 606].
Benzbromarone at 40 mg/day for 1 week reduced
serum uric acid levels by one-third [606]. Finally,
329
a dose of 100 mg of benzbromarone has been
shown to reduce serum uric acid levels more than
1 g of Benemid or 300 mg of allopurinol [609].
Thus, this drug appears to be an efficacious agent
for patients with hyperuricemia and gout in which
uricosuric agents are indicated and is especially
useful in those patients who have undergone organ
transplantation and are receiving cyclosporine.
As noted previously, all this data concerning
benzbromarone are moot since its toxicity has
resulted in its removal from the European and US
markets; however, the drug is still available in
some countries, and its properties make it a desir-
able agent for the treatment of some types of
gout. Therefore, its structure may provide a
model for other modified drugs that might be
synthesized in the future. Benzbromarone is a
benzofuran derivative that reduces the proximal
tubular reabsorption of uric acid [610].
Benzbromarone and its metabolite benzarone
have a similar structure to amiodarone, and the
latter drug causes toxicity to liver mitochondria
[610–612]. Recent studies have also shown that
benzarone and benzbromarone inhibit the mito-
chondrial respiratory chain and b-oxidation. They
also uncouple phosphorylation [613]. These
agents also trigger reactive oxygen species pro-
duction and mitochondrial swelling that leads to
apoptosis and cellular necrosis. The use of benz-
bromarone can lead to severe hepatotoxicity and
death [614–616]. In view of these life-threatening
toxicities, benzbromarone was withdrawn from
the European market in 2003.
Xanthine Oxidase Inhibitors:
Allopurinol and Febuxostat
Allopurinol
The hypoxanthine analog allopurinol inhibits the
conversion of the oxypurines hypoxanthine and
xanthine to uric acid [617–619]. Both allopurinol
and its oxidative product alloxanthine (oxy-
purinol) inhibit xanthine oxidase activity. Both
these drugs have structures similar to their natu-
ral purine analogs, hypoxanthine and xanthine,
except for the reversal of the carbon and nitrogen
330
atoms at position 7 and 8 of the purine ring
(Fig. 9.6). Allopurinol is a competitive inhibitor
of xanthine oxidase since its structure is almost
identical to the natural substrate of this enzyme,
hypoxanthine [620]. Allopurinol is a much more
potent inhibitor of xanthine oxidase activity (five-
to ten-fold) than oxypurinol in vitro, but this
mechanism may not be operative in vivo since
oxypurinol appears to be the major xanthine oxi-
dase inhibitor on the basis of its prolonged half-
life (>25 h) [621]. In addition to the decrease in
uric acid synthesis via the xanthine oxidase path-
way, these hypouricemic agents also inhibit
de novo purine biosynthesis presumably as a
result of a combination of feedback inhibition by
adenine and guanine nucleotides on the first irre-
versible step in de novo purine biosynthesis
(phosphoribosylpyrophosphate amidotransferase)
and the depletion of its substrate phosphoribo-
sylpyrophosphate (PRPP) [622–624]. There is an
absolute requirement for the enzyme hypoxan-
thine-guanine phosphoribosyltransferase since it
converts free purine bases and allopurinol into
their respective nucleotides that are known to be
feedback and pseudofeedback inhibitors, respec-
tively, of de novo purine biosynthesis [625, 626].
Both allopurinol and oxypurinol also alter
pyrimidine synthesis by inhibiting orotidine-5-
monophosphate decarboxylase causing an
increase in the urinary excretion of orotidine and
orotic acid [623, 626–628]. These effects on
pyrimidine metabolism have not been associated
with any adverse effects, but their interference
with pyrimidine metabolism may play a role in
the increased bone marrow toxicity of cyclophos-
phamide observed in patients taking allopurinol
[629, 630]. Both allopurinol and oxypurinol have
also been used as therapeutic agents, and they
reach peak serum concentrations rapidly
(Table 9.27). Oxypurinol is not absorbed as well
as allopurinol (80 versus 40 %), and higher doses
(twofold) of the former drug must be used to
achieve changes in the serum and urinary uric
acid levels comparable to those observed when
allopurinol is used [23, 631]. The conversion
of allopurinol to oxypurinol in vivo is rapid (1–2
h), and the rate of allopurinol excretion by the
kidney approaches the glomerular filtration rate
9 Management of Hyperuricemia and Gout
Table 9.27 Pharmacologic properties of allopurinol and
oxypurinol
Peak serum concentrations occur in 2–3 h for
allopurinol or oxypurinol
Neither drug is protein bound
Oral allopurinol is easily absorbed (~ 80 %)
Oral oxypurinol is absorbed less easily (~ 40 %)
Allopurinol has a half-life of 2–3 h
Oxypurinol has a longer half-life of 18–33 h
Allopurinol is filtered and excreted by the kidney
Oxypurinol is filtered and reabsorbed by the kidney
Minor metabolic products include allopurinol and
oxypurinol ribonucleosides and their corresponding
nucleotides
[23]. In contrast, oxypurinol has a much longer
half-life than allopurinol and is filtered at the
glomerulus and reabsorbed by the tubules such
that it is cleared at a rate that is only 10–20 % of
the glomerular filtration rate [23]. Diminished
renal function decreases oxypurinol clearance,
whereas uricosuric agents enhance its clearance
[23]. Since 6-mercaptopurine and azathioprine
are inactivated by oxidation via the xanthine oxi-
dase pathway, allopurinol therapy significantly
increases the activity of these antimetabolites by
delaying their breakdown to inactive metabolites
[618]. The activity of cyclophosphamide is also
enhanced by allopurinol: The mechanism for this
latter effect is poorly understood, but it may be
related to an effect on pyrimidine metabolism
[627, 628]. Allopurinol also blocks hepatic drug-
metabolizing enzymes and slows the degradation
of drugs such as antipyrine and bishydroxycou-
marin (dicoumarol) that are metabolized via the
microsomal enzyme system [632]. Drugs metab-
olized by this pathway should not be used in con-
junction with allopurinol. Reduced drug dosage
and careful monitoring of in vivo drug levels
should be undertaken if allopurinol and other
drugs metabolized by these microsomal hepatic
enzymes are being used in combination.
Standard treatment regimens for allopurinol
use 100 mg of the drug daily for 1 week and then
increasing the dose to 300 mg daily that may be
given in a single dose. In severe tophaceous gout,
400–600 mg of the drug may be necessary to
control the metabolic derangement in uric acid
Xanthine Oxidase Inhibitors: Allopurinol and Febuxostat
metabolism. Prophylactic colchicine at a dose of
0.5–0.6 mg twice a day is recommended when
allopurinol therapy is being initiated.
In general, the activity of allopurinol as a xan-
thine oxidoreductase inhibitor is mediated in part
by its active metabolite oxypurinol. Nonetheless,
allopurinol dosage should be individualized to
attain a sufficient decrease in plasma urate con-
centrations, and such adjustments may require a
dose higher than the recommended daily dose of
300 mg/day. When this strategy is selected, care-
ful monitoring of patients must be done to reduce
the chance of adverse reactions, especially to pre-
vent xanthine/oxypurinol stone formation or
allopurinol hypersensitivity responses [633, 634].
Perhaps, a less hazardous regimen would be the
use of allopurinol in combination with probenecid.
Such a regimen has been evaluated in both healthy
humans and those with gout [635, 636]. In healthy
humans, allopurinol (300 mg/day) and probenecid
(1,000 mg/day) had a greater hypouricemic effect
than either drug alone. This occurred even though
the combination of these drugs reduced the steady-
state oxypurinol concentration (5.1 ± 1 mg/l) more
than allopurinol alone (9.7 ± 2.1 mg/l). In the
gouty patients under treatment, the goal was to
attain a serum uric acid level of less than
0.36 mmol/l since recurrent gouty episodes are
better prevented at this level of serum uric acid,
and tophaceous deposits are dissolved more read-
ily [637–643]. Of the 32 patients treated with
allopurinol alone at a mean dose of 256 mg/day,
only 25 % attained a serum uric acid level of less
than 0.30 mmol/l, and only 53 % reached a level
of less than 0.36 mmol/l. In the 14 patients receiv-
ing both drugs with the mean dose of allopurinol
of 243 mg/day and probenecid at 1,000 mg/day,
86 % attained a serum uric acid of less than
0.30 mmol/l and 100 % achieved a level of less
than 0.36 mmol/l. Thus, these data suggest that
the combination of allopurinol and probenecid
might be an effective way to reduce serum uric
acid levels and prevent recurrent acute gouty epi-
sodes in patients with no contraindications to uri-
cosuric drugs. Since simple methods are available
to monitor allopurinol and oxypurinol in human
serum, this methodology might be very useful for
the detection of the toxic levels of these drugs and
331
for the determination of the range of concentra-
tions causing adverse reactions [644, 645]. The
long-term use of this combined therapy has not
been evaluated, and the possible adverse reactions
from such a treatment regimen remain to be
assessed.
Several potential clinical complications may
occur as a result of allopurinol therapy. These
include the precipitation of acute gouty arthritis
as a result of the rapid changes in the mobilization
of tissue secondary to the reduction in serum uric
acid levels. Both prophylactic colchicine and low
initial doses of allopurinol reduce the frequency
of such gouty episodes. Urinary oxypurine excre-
tion increases significantly in the presence of
allopurinol, and the relative insolubility of the
increments in serum xanthine levels may cause
xanthine renal calculi or crystalluria. Oxypurinol
has also been identified with renal stones and uri-
nary tract sludge in rare patients [646, 647]. The
dioxygen oxidative product of allopurinol, oxy-
purinol, is also insoluble and has been demon-
strated along with hypoxanthine and xanthine in
muscle biopsy specimens from patients treated
with allopurinol after its initial release as a thera-
peutic agent [648]. No specific clinical problems
were related to the changes observed in these
biopsies, and subsequent use of this drug has not
been associated with such muscle pathology. In
elderly patients, the elimination of the allopurinol
metabolite oxypurinol is reduced probably as a
result of diminished renal function in the aged
population [649]. This metabolite also appears to
have less inhibitory action against xanthine oxi-
dase in the elderly. The resultant increase in oxy-
purinol levels in the elderly has been proposed as
a mechanism for the increased allopurinol toxic-
ity in older patients and perhaps those patients
with renal insufficiency.
Even though allopurinol is well tolerated and
useful as a therapeutic agent in certain clinical
settings, it is important to emphasize that in a
series of patients who manifested serious toxic
reactions, more than 20 % died [650]. For this
reason, therapy with this drug should not be
undertaken without appropriate indications.
Toxic reactions such as gastrointestinal symp-
toms, skin rashes, hypersensitivity of the
332
Table 9.28 Relative contraindications to allopurinol
therapy
Anticoagulant therapy
Skin rashes
Asthma (theophylline)
Antineoplastic agents (6-mercaptopurine/azathioprine)
Renal failure
Leukopenia
Hepatocellular diseases
Stevens-Johnson type, alopecia, bone marrow
suppression, hepatocellular dysfunction, and vas-
culitis occur in about 10 % of patients taking
allopurinol. Such reactions are most frequently
observed in patients with renal insufficiency and
in association with thiazide drug use [650]. Skin
rashes seem to be more common in patients receiv-
ing allopurinol together with ampicillin [651].
Allopurinol dose reduction and symptomatic
treatment may cause an abatement of skin rashes.
There are certain relative contraindications to
the use of the drug (Table 9.28). Discontinuance
of allopurinol is a necessity when skin manifesta-
tions such as toxic epidermal necrolysis and/or
vasculitis occur. In view of the increased morbid-
ity and mortality associated with allopurinol
hypersensitivity reactions, there is a need to iden-
tify patients at risk for this syndrome. Recent data
suggest that intradermal skin challenge and lym-
phocyte transformation with allopurinol or oxy-
purinol may detect those patients at risk for
hypersensitivity reactions to these drugs [652].
Further, six of these nine patients had significant
blastogenic responses when their mononuclear
cells were exposed in vitro to oxypurinol but not
allopurinol. Despite the positive results from
these in vitro tests, further studies of this method-
ology showed that this testing did not identify all
those patients with hypersensitivity to allopurinol
or its metabolite. A modest increase in the risk
for cataracts has been determined in patients who
have used allopurinol for more than 3 years or at
a dose of more than 400 mg/day [653].
To emphasize the importance of using defined
criteria when allopurinol treatment is contem-
plated, a hospital-based Veterans Administration
study determined the frequency of the inappro-
priate use of allopurinol [654]. In that study, less
9 Management of Hyperuricemia and Gout
than 20 % of the patients for whom allopurinol
was prescribed had a definite indication for the
use of the drug. By definition in this study, neph-
rolithiasis, chronic renal insufficiency, idiopathic
uric acid overproduction, tophaceous gout, pso-
riasis, or hematologic cancers represented the
disorders for which allopurinol should have been
prescribed. However, over 80 % of the 254
patients were treated with the drug without
fulfilling these defined criteria. Of even greater
significance, joint aspiration was performed in
approximately 4 % of the patients, only 20 % of
the patients had radiographic studies to charac-
terize tophaceous deposits, and just 3 patients of
the 209 patients that did not have a definite indi-
cation for allopurinol had their 24-h urinary uric
acid levels measured. More than 50 % of the
patients treated with allopurinol have serum crea-
tinine levels documented prior to their treatment.
As one might suspect, many of the patients treated
had diuretic-induced hyperuricemia which in
some cases was associated with obesity. Such
data, if they are representative of the prescribing
habits of physicians in general, demonstrate a
deficiency in physician education as to the proper
use of allopurinol and place the recipient patient
at increased risk for unnecessary adverse drug
reactions. Further, the increased cost of prescrib-
ing a drug for which there is no clear indication
or therapeutic rationale seems inappropriate to
say the least.
On rare occasions, patients with severe topha-
ceous gout and normal renal function may be
candidates for a combined therapeutic program
using allopurinol and Benemid. Allopurinol
extends the half-life of Benemid and potentiates
its uricosuric effect, whereas Benemid increases
the clearance of oxypurinol diminishing the inhi-
bition of xanthine oxidase [608, 655]. These
mechanisms would suggest that the usual doses
of allopurinol should be increased, whereas stan-
dard doses of Benemid should be decreased.
Nonetheless, such combined drug therapy is more
effective than either drug alone in reducing serum
uric acid levels.
Hypersensitivity reactions deserve some fur-
ther discussion because recent findings may assist
the physician more directly in the detection of at
Xanthine Oxidase Inhibitors: Allopurinol and Febuxostat 333

risk patients [656]. Since the first description of Table 9.29 Allopurinol hypersensitivity: diagnostic
allopurinol hypersensitivity was reported in 1970, criteria
more than 100 cases of this syndrome have been Major criteria
recorded in the literature [657]. This condition is Diffuse maculopapular rash, exfoliative dermatitis,
said to be relatively infrequent since there are an erythema multiforme, toxic epidermal necrolysis
Decreasing renal function/acute hepatic toxicity
estimated 250 million doses of allopurinol pre-
Minor Criteria
scribed annually as calculated for the year 1985
Fever
[658]. Recent calculations indicate that between
Eosinophilia/leukocytosis
2 and 5 % of the patients prescribed allopurinol Lack of exposure to drug that causes a hypersensitiv-
develop an adverse cutaneous reaction [659, 660]. ity reaction
More recent publications have reported the fre-
quency of the Stevens-Johnson syndrome (STS)
Table 9.30 Symptoms and signs of possible severe cuta-
and toxic epidermal necrolysis (TEN) have neous reactions
increased with respect to the use of allopurinol
Confluent erythema
[661]. Severe adverse cutaneous reactions such as
Facial edema
the allopurinol hypersensitivity syndrome occur
Painful skin
in about 0.4 % of patients receiving allopurinol Palpable purpura
[662]. However, the major issue with respect to Necrotic skin
allopurinol and hypersensitivity reactions is the Blisters
mortality rate that can reach a level of 26 % of Skin detachment
patients being treated with allopurinol [657, 658]. Mucous membrane erosions
In addition to STS and TEN, there is another drug Urticaria
hypersensitivity syndrome associated with Swollen tongue
allopurinol called drug rash with eosinophilia and Lymphadenopathy
systemic syndrome (DRESS) [663–666]. This Fever (>40 °C)
rare idiosyncratic reaction is also associated with Arthralgias/arthritis
a high mortality rate (10 %) [667–669]. Wheezing
Cutaneous drug eruptions or allergic reactions Dyspnea
to drugs are common in both hospitalized patients Hypotension
Eosinophilia (>1,000/mm3)
and outpatients [670–673]. The major diagnostic
Lymphocytosis with atypical lymphocytes
effort with respect to these skin reactions should
Abnormal liver function tests
be on the early recognition of severe drug reac-
Abnormal renal function
tions and the withdrawal of the causative drug.
Most drug reactions present as morbilliform or
exanthematous rashes and may be confined to the Table 9.31 General manifestations of a drug hypersensi-
tivity syndrome
trunk or pressure areas. A number of factors
should alert the clinician to the possibility of a Fever and rash
severe cutaneous reaction (Table 9.29). The two Hepatitis
most common severe cutaneous reactions are the Mucous membrane lesions
Stevens-Johnson syndrome and toxic epidermal Lymphadenopathy
Facial edema
necrolysis [674–676]. These two conditions have
Renal involvement
now been determined to be components of a sin-
Pulmonary symptoms or signs
gle disease with common causes and mechanisms
[667, 677–680]. The principal difference between
these two disorders is the extent of the skin frequent clinical findings of these disorders are
detachment since it is limited in the Stevens- shown in their decreasing order of their frequency
Johnson syndrome but much more extensive in in Table 9.30. Common signs of a drug hypersen-
toxic epidermal necrolysis [667, 679]. The most sitivity syndrome are recorded in Table 9.31.
334
The original report of Stevens-Johnson syn-
drome was described in patients with febrile ero-
sive stomatitis, severe ocular involvement, and
disseminated, discrete dark red macules with an
occasional necrotic center [681]. Much later toxic
epidermal necrolysis was described with exten-
sive loss of the epidermis that gave the underly-
ing skin a scalded appearance [682]. Mucosal
lesions are common in both disorders and may
lead to painful micturition, photophobia, and
difficulty swallowing [673–685]. As can be imag-
ined, with extensive skin loss, there is massive
fluid loss (3–4 l/day), electrolyte imbalance, and
prerenal azotemia [676]. Skin biopsies can dif-
ferentiate these two conditions from bullous dis-
orders unrelated to drugs, and infection is a
common complication of Stevens-Johnson syn-
drome and toxic epidermal necrolysis.
Although most drug reactions appear to occur
as manifestations of T cell-mediated delayed
hypersensitivity with the production of cytokines,
however, the complete pathogenesis of such reac-
tions remains incomplete [686–688]. It is also
now apparent that genetic factors play a role in
such adverse drug reactions [689–695]. It has
been established in some patients with allopurinol
hypersensitivity that lymphocytes from hyper-
sensitive patients are moderately stimulated by
allopurinol (increased 3H-thymidine uptake), and
oxypurinol markedly stimulated lymphocytes
from hypersensitive patients when compared to
allopurinol-treated patients without hypersensi-
tivity and normal subjects [688]. Such testing has
also been found in patients who are hypersensi-
tive to drugs other than allopurinol [687]. Despite
these lymphocyte tests, this methodology is not
diagnostic of drug hypersensitivity and should
not be used to detect hypersensitive patients.
There are some distinct clinical features of
allopurinol hypersensitivity. Renal dysfunction is
a prominent abnormality observed with
allopurinol hypersensitivity as compared to other
causes of drug hypersensitivity (84 % of patients
with allopurinol hypersensitivity versus 40 % of
patients with other drug hypersensitivities in one
study) [696]. Elevated levels of oxypurinol have
also been correlated with the risk of the develop-
ment of allopurinol hypersensitivity [697]. This
9 Management of Hyperuricemia and Gout
raises the issue of age and the clearance of oxy-
purinol since decreased renal function decreases
oxypurinol clearance by the kidney, and renal
function is often diminished in elderly popula-
tions [698]. Since diminished renal function may
prolong the half-life of oxypurinol and increase
the risk of hypersensitivity, creatinine clearance
should probably be measured in patients who are
candidates for allopurinol treatment [699].
Determination of Renal Function
Estimating creatinine clearance can be accom-
plished by the Cockcroft and Gault formula as
defined here. Creatinine clearance (ml/min) is
equal to 1.2 × (140 – age in years) × weight (kg)/
serum creatinine (umol/l). This formula calcu-
lates creatinine clearance for males, and when
females are to be assessed, the result should be
multiplied by 0.85 [700]. Some investigators
have also indicated that the use of thiazide and
allopurinol together may prolong the half-life of
oxypurinol, the metabolite of allopurinol [697,
701, 702]. Other literature emphasizes that thiaz-
ides have no effect on allopurinol in the presence
of normal renal function [703–705]. Renal
insufficiency may occur in the face of allopurinol
therapy. Acute interstitial nephritis, focal seg-
mental glomerulonephritis, and vasculitis have
all been described in patients treated with
allopurinol [706–709].
The primary challenge for these severe cuta-
neous reactions is to determine a method for
detecting which patients might be at risk for
allopurinol hypersensitivity. Early studies recog-
nized that T cells were a primary route for drug
recognition, and subsequently, they may trigger
hypersensitivity [710]. These studies also showed
major histocompatibility complex relationships
in drug-induced hypersensitivity.
The presence of two major criteria or one
major and one minor criterion makes the diagno-
sis of allopurinol hypersensitivity
Recently, studies have reported strong associ-
ations between histocompatibility locus antigen
(HLA) molecules and drug-induced hypersensi-
tivity reactions [711–717]. HLA-A29, HLA-B12,
Xanthine Oxidase Inhibitors: Allopurinol and Febuxostat
and HLA-DR7 are observed more frequently in
patients with sulfonamide-induced Stevens-
Johnson syndrome, and HLA-A2 and HLA-B12
are found more frequently in NSAID-induced
Stevens-Johnson syndrome [711, 712]. When eye
involvement occurs in Stevens-Johnson syn-
drome, the HLA-B59 allele is frequently observed
[713]. Carbamazepine-induced Stevens-Johnson
syndrome is often associated with HLA-B*1502
[715]. Abacavir hypersensitivity is associated
with HLA-B*5701 as well as a haplotype Hsp
70-Hom variant [716–718]. HLA-AW33 and
HLA-B17/BW58 have been found frequently in
association with allopurinol drug eruptions [714].
However, the most striking HLA association with
a severe cutaneous adverse reaction and
allopurinol treatment is the strong association of
HLA-B*5801 in the Han Chinese of Taiwan
[656]. This allele was found in 100 % of Chinese
affected with allopurinol-induced hypersensitiv-
ity syndrome, Stevens-Johnson syndrome, and
toxic epidermal necrolysis. The calculated odds
ratio in this population exceeds that for the pres-
ence of HLA-B27 and ankylosing spondylitis
[719, 720]. The HLA-B*5801 allele also exists at
a frequency of less than 10 % in African,
Caucasian, and Asian Indian populations [721].
Although HLA-B*5801 represents a striking
association with severe adverse cutaneous reac-
tion in a Taiwanese Chinese population, it is not
as high in association with skin reactions in other
populations sensitive to allopurinol [656, 722].
HLA-B*5801 was present in 15 % of the
allopurinol-tolerant subjects, and it was also
observed in 20 % of the general population. Thus,
in this Chinese population, HLA-B*5801 is
sufficient to be closely associated with severe
cutaneous responses to allopurinol, but it is not
the only factor involved since some HLA-
B*5801-positive subjects are allopurinol tolerant.
In Europeans, the HLA-B*5901 allele was asso-
ciated with Stevens-Johnson syndrome or toxic
epidermal necrolysis and allopurinol treatment
only at a level of 55 %. Therefore, the HLA-
B*5801 allele is not as strong a risk factor in this
population as in the Taiwanese population. Thus,
it would appear that in the Taiwanese Chinese,
the HLA-B*5801 allele might be used as a marker
335
for a high-risk patient for the development of a
severe cutaneous reaction to allopurinol, but its
presence should not obviate the use of allopurinol
since many allopurinol-tolerant patients express
this allele as well.
Clearly, patients who manifest a toxic response
to allopurinol should have the drug withdrawn,
delivered supportive therapy for their condition,
and monitored carefully for possible organ fail-
ures. Recent retrospective studies in Europe
(France and Germany) provided data to show that
neither intravenous immunoglobulins nor corti-
costeroids had beneficial effects on Stevens-
Johnson syndrome or toxic epidermal necrolysis
when compared to patients receiving supportive
care [723]. Even though corticosteroids are
administered to patients with drug-induced severe
cutaneous reactions, the beneficial effects of such
agents remain a question.
Patients who are either allergic to uricosuric
agents or have reduced renal function may be
candidates for allopurinol therapy. When the
glomerular filtration rate is less than 30 ml/min,
uricosuric agents are ineffective, and allopurinol
is the alternative. Similarly, when uricosuric
drugs fail to reduce the serum urate concentra-
tions to less than 7 mg/dl in patients with normal
renal function, allopurinol may be added to the
treatment regimen.
Newer Urate-Lowering Drugs
Febuxostat
The most well-evaluated xanthine oxidase inhibi-
tor is allopurinol, but recently, several nonpurine
inhibitors of xanthine oxidase have been
described. In a rat model, a group of 1-phenylpyra-
zoles have shown xanthine oxidase inhibitory
activity [725–729]. The compound showing the
most potent activity in this capacity in rats was
chosen for further evaluation in the human. The
molecule fitting this criterion was 1-(3-cyano-4-
neopentyloxyphenyl) pyrazole-4-carboxylic acid
(Y-700), and it causes long-lasting hypouricemic
effects and is excreted primarily via the liver
[701–703]. In studies of healthy Japanese volun-
teers, this compound was rapidly absorbed after
336
oral administration and had a half-life of 20–40
h. Excretion in the urine was less than 1–1.5 % of
the ingested dose. Adverse effects included
abdominal cramps, abdominal pain, and
flatulence. Serum uric acid levels were reduced in
a time- and dose-dependent manner. Its principal
route of metabolism is by the liver with relatively
little excreted by the kidney. This makes it an
ideal agent for patients with renal disease.
Febuxostat (2-[3-cyano-4-isobutoxphenyl]-4-
methylthiazole-5-carboxylic acid) is a nonpurine
selective inhibitor of xanthine oxidase and is a
potent inhibitor of both the oxidized and reduced
forms of xanthine oxidase [730]. Its structure is
shown in Fig. 9.8. This agent is more potent, and
its effects are of longer duration than allopurinol
[730–736]. Studies of the crystal structure of the
xanthine oxidase-febuxostat (enzyme-inhibitor)
complex and the mechanism of inhibition showed
a mixed type of inhibition with Ki and Ki ‘values
of 1.2 ± 0.05 × 10−10 and 9.0 ± 0.05 × 10−10, respec-
tively [730]. Febuxostat inhibits the enzyme for
long time periods, whereas oxypurinol, the
allopurinol metabolite that inhibits xanthine oxi-
dase activity, is relatively rapidly reactivated with
a t1/2 time of 300 min at 25 °C. Furthermore,
febuxostat and its metabolites have been studied
in humans with mild (CCR of 50–80 ml/min),
moderate (CCR of 30–49 ml/min), and severe (CCR
of 10–29 ml/min) renal impairment. Febuxostat
therapy showed no change in the effectiveness of
this drug to lower the serum uric acid levels in the
face of renal failure [737–739]. This is in contrast
to allopurinol where a dose reduction of
allopurinol is advised when renal failure is pres-
ent. Using three different doses of febuxostat (40,
80, and 120 mg), the levels of serum uric acid
were reduced significantly when compared with
patients receiving placebo [740].
A febuxostat dose of 40 mg was less effective
in reducing serum uric acid levels than the higher
doses, and on this basis, it was concluded that
a dose of 80–120 mg was probably the appropri-
ate dose range for clinical use. Furthermore, the
presence of elevated serum levels of hypoxan-
thine and xanthine during febuxostat treatment
documents xanthine oxidase inhibition as the pri-
mary mechanism of action of this drug [740].
9 Management of Hyperuricemia and Gout
Gouty arthritis flares occurred during treatment
with this drug, and such episodes were reduced
by the administration of colchicine. Adverse
effects occurring with this agent have a low fre-
quency, but abnormalities in liver function tests
(primarily transaminases), diarrhea, gastrointes-
tinal complaints, and headaches do occur [736,
740]. Since allopurinol alters the activities of
other enzymes involved in purine and pyrimidine
metabolism, it was important to assess febuxostat
for its activities against these enzymes as well
[696, 730, 736, 741]. Examining the effect of
febuxostat on guanine deaminase, hypoxanthine-
guanine phosphoribosyltransferase, orotate phos-
phoribosyltransferase, orotidylic acid
decarboxylase, and purine nucleoside phospho-
rylase activities demonstrated no change in
enzyme activity in the presence of febuxostat
concentrations of 1, 10, and 100 mm.
In summary, febuxostat is a more selective
inhibitor of xanthine oxidase than allopurinol and
its metabolites. It diminishes serum and urinary
uric acid levels in the dose range of 40–80 mg/
day. It has few side effects in the human and is
useful in patients with decreased renal function
since the kidney plays only a very minor role in
febuxostat metabolism [738, 739]. In a study
comparing allopurinol with febuxostat, four
deaths occurred in subjects receiving the latter
drug at doses of 80 and 120 mg. These deaths did
not appear to be related to the drug (congestive
heart failure and respiratory failure in one patient,
retroperitoneal bleeding in a patient receiving
anticoagulants, metastatic colon cancer in another
patient, and cardiac arrest in another) [736, 740].
No serious life-threatening rashes have been
reported in contrast to the deaths reported with
allopurinol hypersensitivity reactions [637, 657,
742]. Febuxostat undergoes glucuronidation and
oxidation in the liver and is excreted either as an
unchanged molecule or as its metabolites. It can
be used in patients with mild or moderate liver
disease without complications but cannot be used
in the presence of severe liver disease.
The significance of this agent for the treatment
of gout relates to its differences from allopurinol.
Febuxostat resides in a channel leading to the
active site of the enzyme xanthine oxidase and
Xanthine Oxidase Inhibitors: Allopurinol and Febuxostat
impedes the access of the substrate for the enzyme
to interact with the active site of the enzyme,
whereas allopurinol and oxypurinol bind directly
to the active site of xanthine oxidase [724, 730,
743–746]. Allopurinol is rapidly oxidized to its
active metabolite oxypurinol by xanthine oxi-
dase. Oxypurinol has a longer tissue half-life
(14–30 h) than allopurinol (2–3 h) and accounts
for the principal pharmacological effects of these
two compounds. The longer half-life of oxy-
purinol is the result of its renal reabsorption
[747]. Allopurinol binds to the oxidized form of
xanthine oxidase at the Mo6+-pterin coenzyme,
whereas febuxostat blocks the access of xanthine
oxidase substrates to the molybdenum-pterin
moiety. At low concentrations, both allopurinol
and its active metabolite oxypurinol are competi-
tive inhibitors of xanthine oxidase. At higher
concentrations, both compounds are noncompeti-
tive inhibitors of xanthine oxidase. Oxypurinol
binds to the reduced form of the enzyme xanthine
oxidase with high affinity, but it is released when
the enzyme is reoxidized via its sulfhydryl resi-
dues or by proteolysis. The potent nonpurine
xanthine oxidoreductase inhibitor febuxostat
exhibits a mixed type inhibition with Ki and K¢i of
1.2 ± 0.05 × 10−10 and 9.0 ± 0.05 × 10−10 M, respec-
tively. In contrast to allopurinol, febuxostat inhib-
its both the oxidized and reduced forms of
xanthine oxidase [724, 730]. The latter drug also
has only minor effects on purine and pyrimidine
enzymes except for xanthine oxidase in contrast
to allopurinol that inhibits not only xanthine oxi-
dase activity but also blocks orotidine-5’-mono-
phosphate decarboxylase and purine nucleoside
phosphorylase activities [741, 748]. Febuxostat
has no effect on guanine deaminase, hypoxan-
thine-guanine phosphoribosyltransferase, and
orotate phosphoribosyltransferase activities and
does not increase PRPP levels. The other key dif-
ference between allopurinol and febuxostat is
that the latter compound is principally metabo-
lized by the liver and not the kidney [749, 750].
Hepatic metabolism converts febuxostat to an
acyl-glucuronide metabolite and to an oxidative
metabolite. These metabolites have been desig-
nated as 67 M-1, 67 M-2, and 67 M-3. Both
allopurinol and febuxostat are rapidly absorbed,
337
and both drugs reach peak concentrations within
1 h [747, 749, 750]. The metabolites of febuxo-
stat are excreted equally in the stool and urine. As
noted previously, allopurinol causes a rash in
about 2 % of patients; about 10 % of patients
manifest intolerance to the drug due to abnormal
hepatic enzymes, gastrointestinal side effects, or
central nervous system effects; and it is contrain-
dicated in patients receiving 6-mercaptopurine or
azathioprine due to the allopurinol-induced delay
in the metabolism of these antimetabolites that
increases their toxicity. Alterations in the renal
elimination of oxypurinol may lead to oxypurinol
calculus formation. Finally, the most significant
side effect is the allopurinol-induced hypersensi-
tivity syndrome that occurs in roughly 1 in a
1,000 patients taking allopurinol. This syndrome
is associated with a high mortality rate [748].
Recent studies have also determined that some
severe cutaneous adverse reactions caused by
allopurinol are linked to the genetic marker HLA-
B*5801 haplotype [656]. These studies have only
been reported in Chinese subjects and need to be
evaluated in other population groups.
The most common adverse reactions associ-
ated with febuxostat treatment are abnormal liver
function tests, diarrhea, headache, arthralgias,
musculoskeletal pain and stiffness, vomiting, diz-
ziness and dysgeusia, asthenia and fatigue, and
peripheral edema [736, 751]. Of all the adverse
reactions associated with febuxostat therapy,
abnormal liver function tests and gouty flares are
the most frequent when doses of 80–120 mg/day
are used. On the basis of the foregoing findings,
febuxostat appears to have some distinct advan-
tages when compared with allopurinol in specific
clinical settings, but a better evaluation of febuxo-
stat will become available when the drug is
released for general usage. Since febuxostat is
metabolized by the liver and not dependent on the
kidney for its metabolism, it may be a useful
agent for the treatment of patients with impaired
renal function, but sufficient data are not avail-
able at this time to assess the drug in patients with
impaired renal function [752]. If febuxostat ther-
apy proves efficacious in the presence of renal
failure, this would be a major advance for the
management of hyperuricemia and gout as well
338
as other clinical settings associated with impaired
renal function. Febuxostat at a dose of 80 mg/day
appears to be more efficient drug than allopurinol
300 mg/day for lowering the serum urate levels
[736]. Both allopurinol and febuxostat at doses of
300 and 80 mg/day, respectively, reduce the num-
ber of gout flares and the size of tophaceous
deposits, but the number of patients achieving
serum urate levels of less than 6 mg % was greater
in the febuxostat 80–120 mg/day groups than in
the allopurinol 300 mg/day group. Pharmacoki-
netic data show that febuxostat may be used
either with indomethacin or naproxen without
any dose adjustment of febuxostat [753]. Antacids
have been shown to have no effect on the absorp-
tion of febuxostat, and even though food decreased
febuxostat absorption, it has no effect on febuxo-
stat pharmacodynamics.
In addition to these studies in humans, two
different animal studies are relevant to the use of
febuxostat, if these results are confirmed in
human subjects. A high-fructose diet in rats leads
to hyperuricemia, hypertension, triglyceridemia,
and hyperinsulinemia [754, 755]. These studies
compared rats on a high-fructose diet with pla-
cebo in their drinking water with rats on the same
diet but with febuxostat in their drinking water.
Febuxostat-treated rats manifested a significantly
lower blood pressure, serum uric acid, triglycer-
ide, and insulin levels. In addition, the febuxo-
stat-treated rats also had significantly reduced
glomerular pressure, renal vasoconstriction, and
afferent arteriolar area when compared to place-
bo-treated rats. Thus, febuxostat not only normal-
izes the serum uric acid levels but also decreases
the metabolic, morphologic, and glomerular
hemodynamic changes associated with the fruc-
tose-induced metabolic syndrome. These studies
suggest a potential role for febuxostat in the man-
agement of the human metabolic syndrome, but
investigations of humans with this syndrome
have yet to be conducted. The second study used
oxonic acid-induced hyperuricemia in rats to
evaluate the associated hypertension and renal
alterations that can be prevented by allopurinol
therapy [756]. Rats treated with oxonic acid and
febuxostat showed a reduction in their serum uric
acid levels and improvement in systemic arterio-
9 Management of Hyperuricemia and Gout
lar disease as compared to rats exposed to oxonic
acid and placebo. These febuxostat-treated rats
also showed a decrease in mesangial matrix
expansion and in the development of preglomer-
ular arteriolar disease. Thus, these animal studies
suggest that the hypertension commonly observed
in some gouty patients may respond to febuxostat
therapy, but proof of such a therapeutic effect
must await the use of febuxostat in hypertensive
gouty patients.
Finally, since febuxostat as well as other med-
ical disorders can lead to abnormalities in hepatic
functions, evaluations of the use of febuxostat in
humans need to be preceded by an examination
of the patient for preexisting liver abnormalities.
Recent studies have reported the effect of febuxo-
stat on patients with normal liver function and
those with mild and moderately impaired hepatic
functions [757]. At a dose of 80 mg/day of
febuxostat, no statistically significant difference
in plasma pharmacokinetics has been determined
for febuxostat or its metabolites in patients with
normal hepatic functions or those patients with
mild or moderately impaired liver functions.
There was, however, a statistically significant
difference in the mean percentage decrease in
serum uric acid when those with hepatic impair-
ment were compared to those with normal
hepatic functions. These differences turned out
to be relatively small (13–14 % less in patients
with hepatic impairment), and those changes
were considered to be insignificant by the authors
of the study. Furthermore, there was an increase
in mean serum and urinary xanthine values in
those with impaired hepatic functions. Although
this small group of individuals manifested no
apparent adverse reactions from this increment
in serum xanthine levels, a larger number of
patients might detect the occurrence of xanthine
stones in such febuxostat-treated patients with
hepatic dysfunction. As documented by the fore-
going discussion, febuxostat appears to have
properties that would be useful to patients with
gout and renal disease. It may also have a role in
the treatment of gout associated with hyperten-
sion and the metabolic syndrome. More persua-
sive documentation of the clinical use of
febuxostat must await more extensive clinical
Special Treatment Regimens
trials with careful documentation of adverse
reactions to this agent.
A number of studies clearly document the
association of increased serum uric acid levels
with cardiovascular disorders, and there has been
a concerted interest in improving the risk of car-
diovascular disease by lowering uric acid levels,
although it has not been proven that hyperurice-
mia itself is a causative factor in cardiovascular
diseases or whether hyperuricemia is simply
associated with other risk factors for cardiovas-
cular disease, such as obesity [758–771].
However, several drugs designed for the treat-
ment of cardiovascular diseases, such as
fenofibrate and losartan, may also be useful in the
management of refractory gout since they reduce
serum uric acid levels.
Low-Purine Diet
There are relatively few clinical circumstances in
which strict dietary purine restriction is necessary
since effective urate-lowering drugs are available.
Nonetheless, where it is important to know the
absolute metabolism and excretion of urate, such
dietary restrictions are used (Table 9.32). Further,
one may wish to inform patients who are at
increased risk for gouty episodes and who are
prone to overeat foods containing large quantities
of purines to avoid such foods. In addition, some
patients with gout can identify specific foods or
beverages that trigger an acute attack of gout, and
if these are identified, patients may wish to avoid
these foods or beverages.
The absolute restrictions for purine-free diets
include no meats or poultry; no fish or seafood; no
herring, sardines, or anchovies; no organ foods
(liver, kidney, or heart); no meat extracts or gra-
vies; no yeast or yeast products; no beer, ale, or
alcohol; and no asparagus, beans, cauliflower, len-
tils, mushrooms, oatmeal, or spinach. As one can
imagine from this list, such a diet is almost unpal-
atable. Refined cereals and cereal products, white
bread, flour, sago, arrowroot, tapioca, milk, milk
products, cheese, eggs, sugar and sweets, gelatin,
butter, polyunsaturated margarine, fats of any
type, fruits, nuts, peanut butter, lettuce, tomatoes,
339
Table 9.32 Dietary restrictions for a low-purine diet
Absolute restrictions
No meats or poultry
No fish or seafood
No herring, sardines, or anchovies
No organ foods (liver, kidney, or heart)
No meat extracts or gravies
No yeast or yeast products
No beer, ale, or alcohol
No asparagus, beans, cauliflower, lentils, mush-
rooms, oatmeal, or spinach
Unrestricted foods
Refined cereals and cereal products
White bread, flour, sago, arrowroot, and tapioca
Milk, milk products, cheese, and eggs
Sugar and sweets
Gelatin
Butter, polyunsaturated margarine, and fats of any type
Fruit, nuts, and peanut butter
Lettuce, tomatoes, and green vegetables except for
those cited under restricted foods
Beverages
Water, fruit juices, and carbonated drinks
Tea, coffee, and cocoa should be excluded if uricase
or HPLC methods are not used to measure uric acid
since methylxanthines interfere with the accurate
measurement of uric acid by colorimetric methods
and green vegetables except those noted under
restricted foods are all permitted. Vegetables and
cream soups without meat or meat stock are also
permitted, but such a purine-free diet is still not a
very healthy or palatable diet.
Water, fruit juices, carbonated drinks, tea, cof-
fee, and cocoa are permitted ad libitum. If uricase
or high-performance liquid chromatography is
used to measure uric acid in the urine, methylx-
anthines do not interfere with uric acid assays.
Special Treatment Regimens
Management of Acute Uric Acid
Nephropathy
Uric acid nephropathy is only one of a myriad of
intraluminal, intramural, and extrinsic causes that
can lead to urinary tract obstructions. Uric acid
nephropathy is usually a complication of the use
340
of alkylating agents in the treatment of malignant
neoplasms of the hematopoietic system [772].
Rarely, this complication has also been reported
in association with disseminated adenomatous
carcinoma of the gastrointestinal tract [773].
Usually, acute uric acid nephropathy is evident
because of the use of alkylating agents, but in the
case of disseminated carcinoma, it may present as
an unexpected event. The hallmarks of managing
this disorder rest with a careful physical examina-
tion accompanied by a laboratory and radiologic
evaluation. Assessment of extracellular volume
depletion or volume overload as well as a search
for features of urinary tract malfunction is essen-
tial before appropriate treatment is undertaken.
Urinalysis should include a careful examination
of the urinary sediment for the presence of micro-
scopic hematuria or crystals (uric acid or others).
A white blood cell count may indicate or confirm
an underlying hematopoietic malignancy. Serum
electrolytes, blood urea nitrogen and creatinine
concentrations, serum calcium, magnesium, uric
acid, phosphorus, and albumin are measured to
assess the presence of prerenal azotemia or intrin-
sic renal failure. Since ultrasonography has a high
sensitivity and specificity for the detection of
hydronephrosis, this is the procedure of choice as
the initial radiologic evaluation [774–776]. If a
stone is suspected, then a flat plate of the abdo-
men will reveal a radiopaque stone. In cases
where ultrasonography and a flat plate are unre-
warding, then spiral computed tomography is the
procedure of choice [777, 778].
Acute uric acid nephropathy causes a tubular
interstitial nephritis, which must be treated
promptly if this form of acute renal failure is to
be reversed. Prevention is the best approach to
this clinical problem, but in the clinical setting in
which this disorder is suspected, three principles
govern its management: early recognition, induc-
tion of a high urine flow rate, and reduction of the
urate load to the kidney. The criteria for early rec-
ognition have been discussed in the chapter on
clinical gout and will not be reiterated here.
Both the induction of a high urine flow and the
reduction of urate loads to the kidney should be
undertaken concurrently. Neither procedure alone
can reverse this form of acute renal failure.
9 Management of Hyperuricemia and Gout
Hydration with intravenous fluids, if no signs of
volume overload exist, should be undertaken
immediately after the diagnosis has been
confirmed and urine alkalinization accomplished
by the infusion of base. Treatment regimens for
urinary alkalinization have been described in
detail in the previous section dealing with the
management or urinary uric acid calculi. Urinary
pH should be monitored at regular intervals to
ensure the alkalinity of the urine. Further, careful
monitoring of urine output, electrolyte imbal-
ance, and other metabolic parameters should be
instituted to prevent fluid overload and other clin-
ical problems (metabolic alkalosis) associated
with overhydration and alkalinization. Allopurinol
is the conventional drug utilized to decrease the
urate load. Since both allopurinol and xanthine, a
product of xanthine oxidase inhibition by
allopurinol, are relatively insoluble, care must be
taken to maintain a high urine flow rate during
the administration of this hypouricemic drug.
In patients who cannot be diuresed, hemodi-
alysis or peritoneal dialysis can be utilized to
remove significant quantities of urates [779,
780]. Peritoneal uric acid clearance is about
11 ml/min and may be sufficient to reduce ele-
vated serum urate levels. When the serum uric
acid level is 15 mg/dl or greater, hemodialysis
should be used. Hemodialysis should not only be
directed at removing excess urate but also at cor-
recting the azotemic state. If uric acid sludge
obstructs the urine flow, then surgical irrigation,
which has been discussed in the section on the
management of uric acid nephrolithiasis, should
be undertaken.
Management of Tophaceous Deposits
Surgery to remove tophaceous deposits is per-
fectly reasonable when such tophi are large, and
their removal will decrease the uric acid load
excreted by the kidney, increase the rate of nor-
malization of the serum uric acid levels, and
improve the cosmetic appearance and function of
a joint. Carpal and tarsal tunnel syndromes caused
by tophaceous deposits do occur, and surgical
repair is certainly indicated to prevent functional
Special Treatment Regimens
disturbances that are likely to occur from persis-
tent nerve/muscle damage.
Lesch-Nyhan Syndrome
The treatment of Lesch-Nyhan disease entails a
complex set of therapeutic measures that include
the treatment of the purine metabolic alterations,
the management of the neurological dysfunctions,
and the control of the behavioral manifestations.
The treatment of the purine abnormalities is
accomplished with allopurinol and monitoring of
the serum uric acid levels. The objective is to
reduce the level of serum uric acid to as near to
normal as possible without inducing the compli-
cations associated with allopurinol therapy and to
prevent the formation of renal calculi and their
complications. The dose of allopurinol to accom-
plish these tasks varies depending on the age and
weight of the affected individual, but it is usually
in the range of 100–600 mg/day in divided doses.
Uric acid stones are treated with a high fluid intake
and urine alkalinization. If this regimen fails, then
lithotripsy or surgery is necessary [781].
There are risks to the use of allopurinol includ-
ing hypersensitivity reactions, xanthine stones,
and oxypurinol stones [657, 782, 783]. In patients
with hypersensitivity syndromes to allopurinol,
desensitization may be a useful approach to this
problem; otherwise, uricosuric agents may be
helpful, but they result in an increased risk for
uric acid calculi. Some of the newer pharmaco-
logic agents, such as febuxostat and urate oxi-
dase, may be useful in this. Increased hydration is
an absolutely critical component of all treatment
regimens as a means of reducing the formation of
renal calculi. In addition, to prevent the deteriora-
tion of kidney function from nephrocalcinosis or
recurrent stones, regularly scheduled renal ultra-
sound evaluations should be done [781, 784].
Xanthine stones are difficult to treat since
they are not very soluble, even with urine alka-
linization [785]. Although it has been suggested
that increasing the dose of allopurinol may favor
the production of the more soluble purine prod-
uct hypoxanthine, such increments in allopurinol
doses may lead to the formation of oxypurinol-
341
containing stones. The key to the therapy of
these nonurate stones is adequate hydration, and
when renal colic or renal failure occurs in asso-
ciation with xanthine stones, then shock wave
lithotripsy is favored over lithotomy. Of course,
renal failure must be treated appropriately before
more extensive procedures like lithotripsy are
undertaken.
Glycogen Storage Disease
Type I glycogen storage disease is often compli-
cated by gouty arthritis in its late stages [786].
Such patients may also have proteinuria and a
reduced capacity to concentrate their urine that
may lead one to conclude that these renal abnor-
malities are related to the presence of gouty neph-
ropathy. However, some patients with glycogen
storage disease have been reported to have proxi-
mal renal tubular defects with b2-microglobuli-
nuria; generalized aminoaciduria with markedly
elevated levels of alanine, citrulline, cystine, and
lysine; reduced renal tubular phosphate reabsorp-
tion; and proteinuria [787]. Institution of a regi-
men that includes frequent feedings, nocturnal
glucose infusion, and uncooked cornstarch
significantly reduces serum uric acid levels and
improves proximal tubular abnormalities observed
initially in patients with untreated or poorly man-
aged glycogen storage disease [787–789]. When
severe hepatic disease is observed in association
with glycogen storage disease, fresh frozen
plasma or exchange transfusions may be used to
correct the defective clotting and complement
deficiencies incurred by liver disease [790].
Hereditary Fructose Intolerance (HFI)
Since gout has been observed in patients with
hereditary fructose intolerance, diagnosis and
treatment of the underlying carbohydrate abnor-
mality will improve the alterations in uric acid
metabolism as a result of the defective fructose
metabolism observed in such patients [791, 792].
Such treatment has the potential to significantly
decrease the episodes of gout or completely cure
342
the gouty arthritis that accompanies hereditary
fructose intolerance.
Appropriate treatment of HFI requires the
complete elimination of all sources of sucrose
and fructose form the diet [791–794]. Even slight
relapses in such dietary restrictions to permit the
ingestion of 250 mg/kg of fructose per day have
been shown to cause a sustained increase in serum
and urinary uric acid levels [795]. The fructose
and sucrose content of various fruits and vegeta-
bles has been documented, and these published
tables of food composition illustrate the broad
distribution of these sugars in fruits, nuts, fruit
juices, and vegetables [793, 794]. In the absence
of dietary sources of fructose and sucrose, HFI
patients thrive and live a long life [795, 796].
Since solutions containing sorbitol, fructose, and
other invert sugars are still used in some hospi-
tals, patients with HFI should be warned as to the
use of such feeding solutions and the need to alert
physicians to their carbohydrate intolerance.
These admonitions to patients should not be taken
lightly since fatalities have occurred when such
parental therapy has been administered to patients
with HFI in hospital settings [797].
Refractory Gout
A small group of patients suffers from recurrent
flares of gouty arthritis and progressive topha-
ceous deposits with an associated chronic arthri-
tis despite a variety of available medications for
lowering serum uric acid levels and for prevent-
ing the progression of gout. Affected patients
have been described by the term “refractory
gout,” and they represent therapeutic challenges.
A number of underlying causes for this disorder
have been documented as responsible for this
refractory condition including the delayed insti-
tution of urate-lowering drugs, no use of such
urate-lowering drugs, medication intolerances
(allopurinol), incomplete patient responses
despite appropriate treatment regimens, and
patient noncompliance. To assess the regulation
of the number of gouty episodes and the abroga-
tion of the progression of chronic tophaceous
gout, two key markers are utilized. First, the
9 Management of Hyperuricemia and Gout
attainment and maintenance of serum uric acid
levels below 6.0 mg/dl have been documented in
many publications as a means of preventing
recurrent episodes of acute gout [638, 798, 799].
Thus, the documentation of repetitive episodes of
gout suggests an absence of the reduction of
serum uric acid to appropriate levels. Second, the
disappearance of tophi observed by physical
examination or radiographically is an indicator of
the improvement of chronic tophaceous gout.
Studies have also shown that a failure to regulate
recurrent gouty episodes not only causes a pro-
gression of the disease but also impairs the life-
style of affected patients [800–803]. Another
parameter worth considering with respect to
refractory gout is that approximately 20 % of
patients prescribed 300 mg of allopurinol/day
attain and maintain serum uric acid levels of
6 mg/dl [736, 801, 804]. However, if most patients
(80 %) treated with 300 mg of allopurinol fail to
obtain therapeutic serum uric acid levels sufficient
to reduce the number of recurrent gouty episodes,
other therapeutic initiatives need to be consid-
ered. It is also important to recognize that 90 %
of the patients with gout are prescribed allopurinol
at a dose of 300 mg/day. Another significant fac-
tor that clearly influences the control of acute
gouty episodes is the number of patients who are
noncompliant with respect to their prescribed
urate-lowering drug regimens. Such noncompli-
ance appears also to increase over time [805,
806]. The presence of chronic kidney disease also
influences the management of gout. A general
principle regarding the treatment of gout in
patients with diminished kidney function has
been to reduce the allopurinol dose to avoid pre-
cipitating an allopurinol hypersensitivity syn-
drome and/or triggering the formation of
oxypurinol stones. An allopurinol dosing regi-
men has been published based on the half-life of
oxypurinol that has been designed to prevent
allopurinol-induced complications in patients
with chronic renal disease [650]. However, recent
data show that such modified dosing regimens do
not appear to control allopurinol-induced hyper-
sensitivity reactions [807, 808]. Furthermore, the
reduction in allopurinol dosage based on the
Hande algorithm not only fails to protect patients
Special Treatment Regimens
from the allopurinol hypersensitivity syndrome
but also fails to reduce the serum uric acid levels
sufficiently for the control of acute episodes of
gout in the face of chronic renal disease.
The issues raised by the foregoing data are
what are the most effective means for managing
refractory gout and, more specifically, what ther-
apeutic regimens can be used to reduce serum
uric acid levels to prevent recurrent gouty epi-
sodes. As the subsequent discussion will describe,
a number of different drugs have been utilized to
manage refractory gout. Such treatment regimens
not only have shown that modified allopurinol
doses can effectively lower serum uric acid levels
in refractory gout but a variety of other drugs
including uricase, losartan, fenofibrate, febuxo-
stat, and anakinra have been proposed or actually
used for the management of such patients.
Purified uricase has been approved in the
United States for the treatment of tumor lysis
syndrome. It has also been used successfully in
some patients with refractory gout [809–811].
However, the availability of pegylated recombi-
nant mammalian uricase pegloticase is the pre-
ferred form of uricase for the treatment of
refractory gout. The other therapeutic approaches
to refractory gout include the use of losartan and
fenofibrate, two uricosuric agents that have a
modest uricosuric effect [812–815]. Finally,
febuxostat, a nonpurine xanthine oxidase inhibi-
tor that is metabolized in the liver and appears to
be safe in patients with chronic renal insufficiency,
is a safe, effective urate-lowering agent and is
particularly useful in patients who are allergic to
or do not tolerate allopurinol.
The original studies reporting on the use of
uricase as a therapeutic agent in humans were
conducted in France in 1975 and in Italy in 1984
[816]. Initially, the uricase used was a nonrecom-
binant agent purified from Aspergillus flavus.
This agent led to a variety of hypersensitivity
reactions with skin rashes, urticaria, and angioe-
dema occurring about 5 % of the treated patients.
More recently, this enzyme molecule has been
obtained using recombinant DNA technology
from a strain of Aspergillus flavus and marketed
under the name of Elitek in the United States
[817]. This recombinant-based urate oxidase
343
(rasburicase) has now been approved for short-
term use in patients treated for malignancies that
are expected to induce the tumor lysis syndrome
[818].
Uricase preparations have been utilized as
treatment for uric acid accumulations in disease
states for a number of additional reasons. Urate
oxidase (uricase) catalyzes the degradation of
uric acid to a metastable intermediate, 5-hydroxy-
isourate, and then this intermediate is spontane-
ously converted to allantoin [819]. The latter
compound is roughly five to ten times more solu-
ble than uric acid [820]. Uricase preparations
resolve not only the deposition of newly synthe-
sized urate but also long-standing tissue deposits,
whereas allopurinol only impairs the synthesis of
uric acid and has no effect on tissue deposits of
urate. Rasburicase, the recombinant form of the
urate oxidase enzyme, has a half-life of 16–22 h
in the human [821, 822].
The advantages of rasburicase are its potency,
its more rapid action compared with allopurinol,
its activity against uric acid directly rather than
the inhibition of only newly synthesized uric acid,
and the very low rate of dialysis needed to reverse
the nephrotoxicity of uric acid in rasburicase-
treated patients. The absence of the need for dial-
ysis usually only applies to the use of rasburicase
in the tumor lysis syndrome. Comparisons have
been made between the use of intravenous rasbu-
ricase (0.20 mg/kg) and oral allopurinol [823].
With rasburicase, an 86 % reduction in plasma
uric acid levels occurs in 4 h after the first dose,
whereas the reduction in uric acid levels after oral
allopurinol showed only a 12 % reduction. Thus,
rasburicase is a more rapid acting agent in terms
of uric acid level reduction than allopurinol.
Finally, allopurinol inhibits the enzyme xanthine
oxidase, so it blocks the conversion of hypoxan-
thine and xanthine to uric acid and has no effect
on the uric acid molecule itself. This mode of
action is quite different from that of uricase which
acts directly on the uric acid molecule. The disad-
vantages to the use of rasburicase relate princi-
pally to allergic reactions, and such hypersensitivity
responses vary depending on the publication
under review. The most recently published data
concerned with severe adverse reactions shows
344
such responses to occur in less than 1 % of the
population evaluated [824]. The most severe
reactions to this drug are anaphylaxis, skin rashes,
hemolysis, and methemoglobinemia [825, 826].
Published data show skin rashes occur in about
1.4 % of patients undergoing treatment, broncho-
spasm occurs in less than 1 % of patients, and
anaphylactic shock also occurs in less than 1 % of
patients. Other reactions such as urticaria, dysp-
nea, and hypoxemia also occur rarely [825]. Other
documented adverse reactions include fever
(~ 7 %), neutropenia with fever (4 %), respiratory
distress (3 %), sepsis (3 %), neutropenia (2 %),
mucositis (2 %), nausea (1.7 %), vomiting
(1.4 %), headache (0.9 %), diarrhea (0.9 %), and
abdominal pain [827].
Pegloticase
A more effective form of uricase for the treat-
ment of refractory gout is pegloticase, a mamma-
lian recombinant uricase conjugated to
monomethoxypoly(ethylene glycol). This drug
was approved by the FDA for the management of
refractory gout in September 2010. A compre-
hensive study of this agent has been published. In
this study, two replicate, randomized, double-
blind placebo-controlled trials were carried out in
multiple centers in the USA, Canada, and Mexico.
A total of 225 patients were studied, approxi-
mately half of that number in each of the two tri-
als, over a period of 6 months. All patients had
severe refractory gout. The primary end point of
the trial was plasma urate levels of less than
6.0 mg/dl, for at least 80 % of the time, at both
3 months and 6 months into the trial. Patients
were divided into three groups: one group receiv-
ing pegloticase every 2 weeks, one group every
month, and the third group received placebo.
When the results of the two trials were pooled,
the primary end point was achieved in 42 % of
patients in the biweekly treated group and 35 %
in the monthly treated group. None of the patients
in the placebo-treated group achieved the primary
end point.
Secondary end points in this study included
tophus resolution, reductions in gouty flares,
9 Management of Hyperuricemia and Gout
reductions in tender and swollen joint counts, and
changes in reported pain. All of the secondary
end points were achieved in more patients in the
pegloticase-treated groups than in the placebo-
treated groups, and all but the swollen joint count
reached statistical significance.
Serious adverse events were common and
occurred more often in the pegloticase-treated
patients. Gout flares occurred in approximately
80 % of all patients and occurred more frequently
in the pegloticase-treated patients. Infusion reac-
tions occurred in 26 % of biweekly and 42 % of
monthly treated patients and 5 % in placebo
treated. Anaphylaxis occurred in five patients
treated with pegloticase, but there were no related
fatalities. Seven deaths occurred during the trial,
four among pegloticase-treated and three in the
placebo group, but none of these were attributed
to the treatments. Antibodies to pegloticase were
detected in 89 % of pegloticase-treated patients,
and these tended to correlate with infusion reac-
tion, especially if high titers of antibody were
found. It was noteworthy that most of the treated
patients experiencing infusion reactions had an
associated loss of urate-lowering effect. Infusions
were given with infusion-reaction prophylaxis
which may have reduced the frequency and sever-
ity of the reactions.
Pegloticase (Krystexxa) is recommended for
the treatment of refractory gout, which is esti-
mated to be approximately 3 % of patients with
gout. The recommended procedure is to adminis-
ter 8 mg every 2 weeks intravenously over a
period of at least 2 h, carefully monitoring during
and after the infusion for signs of infusion reac-
tions. Patients should be premedicated with a
glucocorticoid and an antihistamine for each
infusion. Serum uric acid levels should be mea-
sured prior to each infusion both to document the
efficacy of the treatment, and because the loss of
the urate-lowering effect of the drug is associated
with antibodies to pegloticase, and an increased
frequency of infusion reactions. Treatment should
be discontinued if the serum uric acid level is
>6 mg/dl on two occasions. Extra caution should
be used in administering pegloticase to patients
with active cardiovascular comorbidities, espe-
cially with congestive heart failure.
Other Agents with Urate-Lowering Effects
Pegloticase is contraindicated in patients with
glucose-6-phosphate deficiency because of hemo-
lysis and methemoglobinemia. Patients of African
or Mediterranean descent should be screened for
G6PD deficiency.
Finally, because gout flares are associated
with any urate-lowering therapy and have been
seen frequently with pegloticase treatment, all
patients should have prophylaxis with either
colchicine 0.6 mg once or twice daily or with an
NSAID.
Other Agents with Urate-Lowering
Effects
Fenofibrate
Fenofibrate is a fibric acid derivative that has a
major effect on lipids but also reduces serum uric
acid levels [815, 828–830]. Reports have docu-
mented that fenofibrate reduces serum uric acid
levels in healthy subjects, hypertensives, and dia-
betic patients by 20–46 % [829, 831]. The other
pharmacologic property of fenofibrate of
significance to gout is its capacity to reduce blood
lipid concentrations. It lowers total and LDL cho-
lesterol by roughly 15 % and increases HDL cho-
lesterol by about the same amount, but its
principal antilipid activity is against triglycerides
[828]. Since there are associations between hype-
ruricemia and hyperlipidemia, hypertriglyceri-
demia, and gout, fenofibrate may be useful as a
therapeutic agent in patients with hyperuricemia
and gout associated with hyperlipidemia
[832–835]. Of more pertinence to the present dis-
cussion on the management of refractory gout,
fenofibrate (200 mg/day) causes a significant
reduction in serum uric acid levels (~ 20 %) in
patients utilizing allopurinol [836]. Of additional
significance is the fact that patients in that study
had no flares of their gout while being treated
with allopurinol and fenofibrate. In general,
fenofibrate has been shown to reduce serum uric
acid to levels as low as 46 % in healthy volun-
teers, hypertensive, and diabetic patients as well
as in gouty patients on specific urate-lowering
drugs. Fenofibrate also causes an increase in the
345
renal clearance of urate in humans [766, 813,
815, 829, 837, 838]. Fenofibrate at a dose of
150 mg three times a day increases the fractional
clearance of xanthine, uric acid, and oxypurinol
[839]. Thus, fenofibrate therapy should be con-
sidered in gouty subjects with triglyceridemia. It
may also be useful in patients who need an addi-
tional drug to reduce their serum uric acid level to
a range where recurrent gouty episodes do not
occur.
Losartan
A number of published investigations have evalu-
ated the antihypertensive effects and urate-lower-
ing effects of losartan potassium, a subtype 1
(AT1)-selective angiotensin II (AII) receptor
antagonist (ARB). Losartan has a relatively mod-
est uricosuric effect [588, 813]. In large popula-
tion studies (29,850 subjects), there are relatively
few adverse effects associated with losartan ther-
apy [840]. Only 46 patients in this study experi-
enced major adverse effects including dizziness,
electrolyte disturbances, hepatic function abnor-
malities, headache, anemia, cough, blood creati-
nine phosphokinase increases, and blood pressure
decreases (hypotension). Among the foregoing,
cough and hyperkalemia are probably the most
frequent side effects of ARBs. One additional
adverse effect has been reported in a patient with
idiopathic renal hypouricemia who suffered from
exercise-induced acute renal failure while being
treated with losartan and trichloromethiazide
[841]. The patient’s acute renal failure improved
after the cessation of both losartan and the thiaz-
ide diuretic. The authors suggested that the epi-
sode of exercise-induced acute renal failure may
have been related to the use of losartan and thiaz-
ide-induced diuresis. The rationale for suggest-
ing losartan as the possible vector of the acute
renal failure is the fact that uric acid is an antioxi-
dant and prevents oxygen free radical-induced
kidney damage, and the lowering of uric acid lev-
els may have reduced the antioxidant effects of
uric acid [842]. Another less likely explanation
for acute renal failure in patients with renal
hypouricemia is the increase in urinary uric acid
346
concentrations related to the uricosuric effects of
losartan and the occurrence of acute uric acid
nephropathy [843].
The uricosuric effect of losartan has been doc-
umented in a number of publications [588, 844–
849]. In one publication, the reduction of serum
uric acid levels was demonstrated to be in the
range of 0.05 mmol/l [892]. The use of losartan
also counterbalances the rise in serum uric acid
levels induced by thiazide diuretics [850, 851].
Losartan is also useful in the management of
hypertensive cyclosporine-treated renal trans-
plant patients [852]. In these patients, 50 mg of
losartan caused an increase in the fractional
excretion of uric acid (17 %) and a modest reduc-
tion in serum uric acid levels (8 %). Of even
greater significance to the management of serum
uric acid reductions, a combination of fenofibrate
and losartan caused a greater decrease in serum
uric acid levels than either agent alone [813, 830,
853]. The combination of losartan and fenofibrate
results in an additive urate-lowering effect in
comparison to either agent alone, and losartan
may protect against uric acid lithiasis by its urine
alkalinization effect [854]. The literature recom-
mends that allopurinol therapy be initiated before
adding fenofibrate and losartan to treatment regi-
mens to avoid urolithiasis due to the induced
changes in uric acid metabolism by allopurinol
[813]. Losartan also increases the urinary excre-
tion of xanthine and oxypurinol [839]. The use of
losartan in combination with fenofibrate certainly
reduces serum uric acid levels, has a positive
effect on lowering serum triglycerides, and would
likely reduce the risk factors caused by uric acid
in cardiovascular events, renal disease, hyperten-
sion, and diabetes [855]. The foregoing effects of
losartan and fenofibrate therapy document the
potential usefulness of these drugs in refractory
gout.
Management of Nephrolithiasis
The management of nephrolithiasis is reasonably
straightforward when the chemical composition
of the stone is known, but more often than not,
only a history of renal colic is obtained, and the
9 Management of Hyperuricemia and Gout
Table 9.33 The frequency of specific types of renal
calculi
Calcium oxalate 60 %
Calcium phosphate or calcium oxalate 20 %
and calcium phosphate
Uric acid 8%
Magnesium ammonium phosphate 8%
Other types 4%
chemical composition of the stone is unknown.
Renal calculi are relatively common in the United
States since about 12 % of males and 5 % of
females have an attack of renal colic by the age of
70 [856]. One cannot assume that all renal calculi
associated with the clinical and laboratory fea-
tures of derangements in uric acid metabolism
are due to uric acid. In fact, although uric acid
stones are not uncommon, other stones are much
more common and may be associated with abnor-
malities in uric acid metabolism (Table 9.33).
This discussion emphasizes the general principles
related to the management of uric acid nephro-
lithiasis, whereas a more extensive discussion of
the treatment of uric acid stones is provided in
Chap. 5.
The most common risk factors associated with
renal stone formation are a low urine volume,
hypercalciuria, hyperuricosuria, hyperoxaluria,
hypocitric aciduria, altered urinary pH, and cysti-
nuria. These risk factors must be identified if
recurrent stones are to be prevented [857]. Which
patients deserve a comprehensive evaluation after
their first renal calculus remains a debatable sub-
ject. Some have suggested that a simple regimen
of a high fluid intake and the avoidance of dietary
excesses are sufficient to decrease the recurrence
of stones [858]. Others have provided data to
suggest that in men, more than 50 % have a recur-
rence of stone formation within 7 years of their
first stone and need diagnostic evaluations and
treatment to prevent such recurrences [859].
There is general agreement that individuals
with metabolically active stones (calculi that
increase in size over time) and significant risk
factors (family history of stones, age of onset of
less than 30, the presence of small or large bowel
disease, urinary tract infections, osteoporosis,
gout, and pathological or minimal trauma
Management of Nephrolithiasis 347

Table 9.34 Medical evaluation of high-risk stone Table 9.35 Renal calculus without risk factors: labora-
formers tory and radiological evaluations
Historical data Blood and urine tests
Dietary history (oxalate and vitamin C) Fasting serum calcium (ionized)
Immobilization Fasting serum bicarbonate
Medications Fasting serum phosphorus
Furosemide Serum electrolytes
Thiazide Urinalysis and urine culture
Uricosurics 24-h urine
Alkali Total volume
Vitamin A Uric acid
Vitamin D Calcium
Methoxyflurane Creatinine
Acetazolamide Serum uric acid and creatinine
Radiological examination Radiological analyses
Nephrocalcinosis Plain film of the abdomen for nephrocalcinosis to
Stones (radiodense/radiolucent) assess the possible presence of RTA, primary
Fasting serum concentrations hyperparathyroidism, medullary sponge kidney, or
polycystic kidneys
Calcium (ionized and total)
Renal ultrasonography to assess the presence of
Phosphorus
hydronephrosis or stone
Bicarbonate
CT scan
Chloride
Other radiological procedures if necessary (IVP)
Creatinine
Uric acid
Albumin suspected of having stones composed of cystine,
Urinalysis
uric acid, or magnesium ammonium phosphate
pH by nitrazine paper
(struvite); have recurrent stones; or have risk fac-
Urine culture for urea-splitting organisms
tors noted previously. It should be recognized
24-h urine specimen on a defined diet of 1 g of
calcium, 1 g of protein/kg, and 100 mg of sodium for that risk factors such as hypercalciuria, hyperuri-
24 h for the following measurements cosuria, hyperoxaluria, and hypocitraturia do not
Calcium just occur as solitary findings. For example, of
Sodium the patients with hyperuricosuria (4,800 umol/
Uric acid day in men and 4,400 umol/day in women),
Creatinine approximately 56 % will have hypercalciuria
Phosphorus (>7 mmol/24 h), 22 % will have hypocitraturia
Oxalate (<1.2 mmol/24 h), and 19 % will have hyperox-
Cystine aluria (>0.625 mmol/24 h) [857]. Hyperuricosuria
Optional tests
is also frequently observed in association with
Ammonium chloride load (0.1 g/kg)
hypercalciuria and hyperoxaluria. For example,
Parathormone assay
47 % of patients with hypercalciuria have been
24-h urinary citrate
shown to have hyperuricosuria [857]. Such data
emphasize the need for a careful evaluation of
fractures) require a complete medical evaluation. patients who present with renal calculi of
Further, all children with stones deserve a careful unknown composition. It is also clear that abnor-
and complete evaluation. malities in serum and urinary uric acid are not
Simple outpatient medical evaluations can be absolute indicators of underlying gout since they
performed in those patients without significant may also be observed in patients with hypercal-
risk factors (Tables 9.34 and 9.35). More exten- ciuria and hyperoxaluria due to causes quite apart
sive evaluations are required when patients are from a defect in purine metabolism [857, 860, 861].
348
Such patients often need treatment with
allopurinol but for reasons somewhat different
from the rationale for the use of this drug in
gout.
When the composition of a stone is known to
be pure uric acid or primarily uric acid, then the
diagnostic studies and management of such
patients are relatively simple. As noted, uric acid
nephrolithiasis is most often observed in patients
with secondary gout (especially hematologic dis-
orders), primary idiopathic gout, inherited defects
in uric acid metabolism (hypoxanthine-guanine
phosphoribosyltransferase deficiency and phos-
phoribosylpyrophosphate synthetase overactivity
and glucose-6-phosphatase deficiency), the use
of uricosuric agents (probenecid, high-dose sali-
cylates, and X-ray contrast materials), persis-
tently acid urine with or without gout, idiopathic
uric acid stones, chronic inflammatory bowel dis-
ease, patients with ileostomies, or dehydration
associated with these clinical problems.
Uric acid calculi associated with gout require
specific treatment regimens quite different from
their use to manage acute and chronic gouty
arthritis. Uric acid nephrolithiasis observed in
association either with enzyme mutations in
purine biosynthesis, acquired uric acid overpro-
duction, or abnormal urate excretion are managed
by increasing the urine volume, decreasing uri-
nary uric acid excretion, and alkalinization of the
urine.
There is no rationale for a rigid restriction of
dietary purines and proteins in the management
of gout or nephrolithiasis associated with gout.
However, alcohol, especially beer, can increase
uric acid excretion [862]. High alcohol intake has
also been associated with uric acid stones [863].
Such data indicate that curbing alcohol intake
may be a useful therapeutic maneuver in the man-
agement of uric acid nephrolithiasis.
Allopurinol Treatment of Stones
Allopurinol at a dose of 300 mg/day is used to
reduce the urinary excretion of uric acid, and two
strategies exist for preventing the onset of acute
gout when this drug is used. First, low doses of
9 Management of Hyperuricemia and Gout
colchicine (0.5–1 mg/day) are recommended for
patients beginning allopurinol therapy. The 1-mg
dose is given in divided dose. Second, initiating
allopurinol at a low dose and gradually increas-
ing the dose over several weeks to 300 mg/day
also reduce the likelihood of sudden large changes
in the uric acid pool giving rise to acute gouty
arthritis. Occasionally, patients overindulge in
high-purine foods and require modification of
their diets to reduce their uric acid intake
(Table 9.32).
The Role of Diet and Comorbidities
and Their Management in Gout
In terms of the management of gout, one must
also consider dietary factors and lifestyles that
can modify the gouty diathesis. Several facets of
the diet are important to the reduction of the risks
of a gouty episode: meat and seafood intake,
alcohol use, and obesity. Although many physi-
cians still advise patients to reduce their dietary
intake of purines, purine-restricted diets only
reduce mean serum urate levels by 0.6 mM/l, and
such diets are relatively unpalatable [864–866].
Other studies have also documented decreases in
the urinary uric acid excretion by approximately
200–400 mg/day and mean serum uric acid levels
by roughly 1–2 mg/dl when the patients were
restricting their purine intake [864–866]. For the
moment, the best data related to diet comes from
a recent study of 47,150 men over a 12-year
period that shows meat and seafood increase the
risk of gout [867]. In contrast, dairy products,
especially low-fat dairy products, are able to
decrease the risk of gout in men. In addition to
food, alcohol is another significant risk factor for
gout. The relationship between gout and alcohol
is more complex. Acute alcohol intoxication in
individuals documents a higher plasma urate
concentration when urate levels are measured
after individuals have become sober [868]. Such
urate alterations may also occur as a result of not
eating and the presence of ketosis. The latter state
and its circulating ketones and lactate block urate
excretion causing hyperuricemia. In normal
individuals, elevated plasma levels of ethanol
The Role of Diet and Comorbidities and Their Management in Gout
(> 200 mg/dl) cause a reduction in urinary urate
levels [869, 870]. When moonshine whiskey was
produced from lead-soldered stills, saturnine gout
or lead-induced gout was a common occurrence
in the southern part of the United States [871].
Finally, beer contains a purine (guanosine) that
can be metabolized to uric acid [872–880]. Recent
studies of 14,809 individuals in the Third National
Health and Nutrition Examination Survey
(NHANES) examined the role of beer, wine, and
hard liquor in relation to uric acid [881, 882]. In
this study, beer and hard liquor intake were posi-
tively correlated with hyperuricemia. It has been
proposed that a glass of wine as a replacement for
beer or hard liquor might reduce the incidence of
gout [874, 883]. Both alcohol intake and obesity
can cause an increase in urate production and a
decrease in its elimination by the kidney [884–
902]. When the body mass index (BMI) is evalu-
ated with respect to the relative risk of gout on an
age-adjusted basis, the following data have been
obtained. For a BMI of 23–24.9 kg/m2, there was
a relative risk for gout of 1.4, and for a BMI of
25–29.9 kg/m2, the relative risk increased to 2.35.
When the BMI was 30–34.9 kg/m2, the relative
risk for gout was 3.26, and for a BMI of greater
than 35 kg/m2, the relative risk for gout was 4.41
when compared to individuals with a BMI of
21–22.9 kg/m2 [891, 903–905]. As noted, obesity
increases the urate production and decreases
renal urate excretion. As further proof of the
association between obesity and uric acid levels,
weight reduction results in a decrease in serum
urate levels. It is also important to remember that
hyperuricemia and gout are also associated with
the metabolic syndrome. The incidence of this
cluster of clinical findings (central obesity, dys-
lipidemia, hypertension, insulin resistance, glu-
cose intolerance/type 2 diabetes mellitus,
hyperuricemia, and a proinflammatory and pro-
thrombotic state) associated with the metabolic
syndrome has a prevalence of 20–30 % in some
populations [904–919]. Recently, an additional
dietary factor has been discovered that may have
an impact on the risk of gout [920, 921]. Sugar-
sweetened soft drinks containing fructose are
strongly associated with an increased risk of gout
and hyperuricemia in men, but diet soft drink
349
consumption does not increase the risk of gout
[920, 921].
Hypertension
Initial studies attributed the association between
the hyperuricemic state and hypertension either
to reduced renal function, the use of diuretics, the
presence of hyperinsulinemia and oxidative
stress, or elevated renal vascular resistance [922].
These relationships between hypertension and
hyperuricemia led to the conclusion that hyperu-
ricemia was not a true risk factor for hyperten-
sion [923, 924]. However, more recent evidence
has reported that hyperuricemia is an indepen-
dent risk factor for the development of hyperten-
sion [925–929]. A greater percentage of
adolescents have been determined to manifest
hyperuricemia in association with essential
hypertension (89 %) in contrast to a few (30 %)
with secondary hypertension, none with essen-
tially normal blood pressure, and none with
white-collar hypertension [930]. These human
studies have been supplemented by animal stud-
ies using oxonic acid to inhibit uricase activity
and to increase uric acid levels in the serum of
rats [931, 932]. In these animal models, the
hypertensive response has been attributed to a
reduction in endothelial nitric oxide levels medi-
ated by uric acid and a stimulation of renin
expression [933, 934]. Studies demonstrating
uric acid-mediated alterations in endothelial
function and renin levels have now been shown to
be present in humans as well [935–938]. Finally,
xanthine oxidase inhibition and the lowering of
serum uric acid levels have been shown to
improve endothelial cell function in chronic heart
failure and other cardiovascular conditions
[939–941].
The foregoing data provided the impetus to
evaluate the possible role of antihyperuricemic
drugs like allopurinol on hypertension. A small
group of children have now been evaluated in
double-blind, placebo-controlled crossover study
to determine whether allopurinol therapy admin-
istered to lower the uric acid levels has any effect
on the essential hypertension manifested by these
350
adolescents [942]. The results of this therapeutic
trial demonstrated a mean change in 24-h ambu-
latory blood pressure of 6.3 mmHg with
allopurinol treatment versus 0.8 mmHg with pla-
cebo treatment. Similarly, the mean 24-h ambula-
tory diastolic blood pressure was 4.6 mmHg with
allopurinol therapy and only 0.3 mmHg with pla-
cebo treatment. These decreases in blood pres-
sure with allopurinol treatment matched the
decrement in blood pressure induced by standard
antihypertensive medications. Of the 30 patients
enrolled in this study and treated with 200 mg of
allopurinol twice a day, 20 attained normal blood
pressure levels while being treated with
allopurinol, and only 1 patient achieved a normal
blood pressure on placebo.
Several aspects of this small, preliminary
study are important to recognize since they may
bear on the putative suggestion that this therapeu-
tic initiative might be applied to the general pop-
ulation with essential hypertension and elevated
serum uric acid levels. First, 70 % of the adoles-
cents studied were obese. Thus, even though
blood pressure cuff size was carefully selected to
monitor the blood pressure, obesity is not a uni-
versal factor representative of the general hyper-
tensive population. On the other hand, many
gouty subjects are obese and manifest hyperten-
sion. Such gouty patients with hypertension may
warrant treatment with allopurinol even though
they often do not meet the criteria for the use of
allopurinol. Since severe and long-standing
hypertension in patients has been documented to
produce renal vascular changes, such vascular
alterations cause renal- and salt-dependent mech-
anisms to drive the hypertensive response [925].
These data suggest that allopurinol therapy is not
likely to modify well-established hypertension.
In contrast, allopurinol may be useful in the man-
agement of new-onset essential hypertension and
may also suggest its use early after the onset of
hypertension in gouty subjects.
Of course, the most serious consequence of
allopurinol therapy is the capacity of this drug to
cause life-threatening adverse reactions.
Nonetheless, the results of this preliminary study
of allopurinol therapy as an antihypertensive drug
focus attention on the newer agents that act as
9 Management of Hyperuricemia and Gout
xanthine oxidase inhibitors and reduce serum
uric acid levels [943, 944]. Studies aimed at
improving endothelial function in heart failure
patients showed that in contrast to allopurinol,
the uricosuric agent probenecid did not improve
endothelial function but that reactive oxygen spe-
cies mediate the effects of endothelial function
[945–948]. Despite all the possible shortcomings
of this small, preliminary study in a group of ado-
lescents whose elevated blood pressure responded
well to the short-term treatment with allopurinol
(4 weeks), the notion that uric acid may play a
role in the mediation of hypertension without
question defines the need for additional investi-
gations of hypertension and its association with
hyperuricemia. It also clearly documents the role
that xanthine oxidase inhibitors might have in the
management of essential hypertension in its early
stages. Finally, these data emphasize the impor-
tance of newer xanthine oxidase inhibitors and
the significant role they might play in the man-
agement of hypertension. Such data also empha-
size the need for the early detection and
management of hypertension in gouty subjects.
These reductions in both casual and ambulatory
blood pressure in the allopurinol-treated patients
were similar to those found when conventional
therapy with b-blockers, a-blockers, and angio-
tensin-converting enzyme inhibitors were evalu-
ated in adults with mild hypertension [949].
Scientific research has now changed the way
uric acid is characterized as to its role in the
human, and this new evidence has altered the
clinical assessment and follow-up evaluations in
patients with gout. Originally, uric acid was
considered a nitrogenous waste product of
human metabolism that was excreted by the kid-
ney and bowel. Despite a host of hypotheses
generated to the contrary, this nonfunctional
concept of uric acid has remained in vogue until
recent studies have begun to provide the scientific
evidence with respect to the potential and true
biological functions of uric acid [950–953]. A
variety of investigations have now linked the
causes of hypertension, salt retention, hypertrig-
lyceridemia, cardiovascular adverse events, and
obesity to increased serum uric acid levels [871,
925–927, 929, 931, 936–941, 954–973]. In addi-
The Role of Diet and Comorbidities and Their Management in Gout
tion to clinical data implicating uric acid levels
with cardiovascular events like hypertension,
the pathological mechanisms for such associa-
tions including the development of renal dis-
ease, renin-angiotensin system activation, and
endothelial dysfunction have been characterized
[930, 931, 936–940, 943, 960, 974–979].
Although the data relating to the generation of
ROS and nitric oxide and the production of
endothelial dysfunction remains controversial,
there is an increasing body of evidence that links
hyperuricemia with hypertension and renal dam-
age [929–931, 933, 960, 980–982]. Despite the
fact that absolute correlations do not exist
between uric acid and hypertension and its
pathologic mechanisms, sufficient data do exist
to encourage the careful monitoring for the onset
of hypertension in gouty patients. Furthermore,
evidence also suggests that the hyperuricemic
state accompanying gout should be treated with
hypouricemic agents along with the aggressive
management of hypertension [983].
Gout has also been documented to be associ-
ated with obesity, dyslipidemia, and hyperglyce-
mia along with hypertension [832, 865, 891, 984,
985]. With respect to obesity and the insulin
resistance syndrome, elevated serum uric acid
levels have been observed with these clinical
findings as well [986–988]. Further evidence of
the association between gout and obesity comes
from studies showing that the risk of gout dimin-
ishes with weight reduction [897, 989]. Recently,
obesity, hypertension, lipidemia, and hyperglyce-
mia have been considered as a cluster of findings
characteristic of a syndrome of multiple interre-
lated conditions called the metabolic syndrome
[990]. This so-called metabolic syndrome is diag-
nosed on the basis of the following revised crite-
ria: abdominal obesity (waist circumference of
>102 cm in men and >88 cm in women), hyper-
triglyceridemia (>150 mg/dl or 1.69 mmol/l), low
high-density lipoprotein (HDL) cholesterol
(<40 mg/dl or 1.04 mmol/l in men and <50 mg/dl
or 1.29 mmol/l in women), a blood pressure read-
ing of less than 130/80 mmHg, and a fasting glu-
cose level of more than 100 mg/dl or more than
5.6 mmol/l [991]. Two facts stress the importance
of identifying the metabolic syndrome in gouty
351
patients. First, the metabolic syndrome increases
the risk of cardiovascular disease up to three
times and the risk for type 2 diabetes mellitus up
to five times [992, 993]. It also causes an increase
in mortality from cardiovascular diseases as well
as all-cause mortality [994, 995]. Second, the
prevalence of the metabolic syndrome in gouty
patients is strikingly high (62.8 % in US adults
and 43.6 % in Korean adults) as compared with a
general population without gout (25.4 % in the
USA and 5.2 % in Korea) [911, 915]. This asso-
ciation between gout and the metabolic syndrome
has been confirmed in other studies as well [908,
912]. Cardiovascular disease in gouty patients at
high risk, those with type 2 diabetes mellitus,
stroke, congestive heart failure, or coronary heart
disease, showed an independent association of
gout with cardiovascular disease and mortality
[996, 997]. Low-risk gouty patients without these
accompanying findings have determined that
serum uric acid levels are poor predictors of car-
diovascular morbidity and mortality [969, 998].
There are a number of publications that
address components and complications of the
metabolic syndrome in connection with the risk
of vascular disease, the occurrence of insulin
resistance, the presence of ischemic heart dis-
ease, cardiovascular mortality, and the presence
of accompanying disorders at the time of the ini-
tial diagnosis of gout [910, 913, 999–1011].
Hyperuricemia is associated with an increased
risk for vascular disease in some studies, but
other investigations only demonstrate a link
between gout and death from cardiovascular dis-
eases but not with hyperuricemia [999, 1002].
The prevalence of gout as well as insulin resis-
tance is higher in patients with gout than in nor-
mal healthy control groups [1000]. Patients with
gout in one study were all shown to manifest the
metabolic syndrome, and 16 % had ischemic
heart disease [913]. A recent review of the clini-
cal status of patients with respect to their first epi-
sode of gout and the diagnosis of the metabolic
syndrome and its components and complications
showed that 90 % of the first attacks of gout pre-
ceded the diagnosis of the metabolic syndrome,
its components, and its complications [1001]. At
the time of the inclusion of gouty patients into
352
this study (a mean of 13.7 years after the first
attack of gout), 93 % of these patients had at least
one associated disorder. The most common asso-
ciated disorders included hypertriglyceridemia,
63 %; obesity, 54 %; hypertension, 45.6 %; meta-
bolic syndrome, 40 %; hyperglycemia, 37 %; low
HDL, 17 %; diabetes mellitus, 15 %; chronic
renal failure, 17 %; and ischemic heart disease,
6.6 %. These data emphasize the need for careful
follow-up evaluations of patients with gout.
Another study showed a 2:1 ratio of the preva-
lence of essential hypertension, hyperlipidemia,
diabetes mellitus without complications, and cor-
onary atherosclerosis in patients with gout as
compared with subjects without gout [910]. A
strong correlation has also been shown to exist
between diminished urinary uric acid levels and
the presence of the metabolic syndrome [1010].
The proposed mechanism for this abnormality of
uric acid excretion is an impairment of renal uric
acid excretion mediated by hyperinsulinemia-
enhanced proximal tubule sodium reabsorption
and the diminished uric acid excretion [1009,
1011].
Although medications are usually the means
by which recurrent gouty episodes are controlled,
there are certain dietary restrictions that may be
useful as well. It has been shown that meat and
seafood intake are associated with an increased
risk of gout. Meat including beef, lamb, and pork
as well as bologna, sausage, salami, bacon, hot
dogs, chicken, turkey, hamburger, chicken liver,
and beef liver are the most well-characterized
offenders as inducers of gouty episodes. Seafood
associated with an increase risk of gout include
tuna, dark fish, shrimp, lobster, clams, and scal-
lops. There are also some purine-rich vegetables
like peas, lentils, spinach, mushrooms, oatmeal,
and cauliflower, but they do not appear to increase
the risk of gout [865, 866, 882, 1012, 1013]. In
contrast to these high-purine-containing foods,
there are some foods with low-purine content
such as milk, cheese, yogurt, ice cream, breads,
pasta, vegetables other than those with a high-
purine content, fruits, nuts, sugars, and sweets.
Of course, it is important to recognize that beef,
cheese, ice cream, and some other foods are not
appropriate for those with lipid abnormalities.
9 Management of Hyperuricemia and Gout
Usually, gout is associated with type IV hyper-
lipidemia or hypertriglyceridemia. These dyslipi-
demias occur in about 25–60 % of gouty patients
[832, 865]. It is also worth remembering that
roughly two-thirds of the purines in the human
are produced by cell and tissue turnover, whereas
only one-third of purines are contributed by
dietary intake.
Alcohol ingestion in excess and its association
with gout has been known since antiquity [865,
868, 1014–1016]. Beer has a special capacity to
raise the serum uric acid levels and put patients at
risk for gouty episodes since it contains guanos-
ine, a purine that is easily converted enzymati-
cally to uric acid. Finally, many patients will tell
their physician that particular foods or alcoholic
beverages will trigger an attack of gout. In these
cases, physicians should heed the patient’s infor-
mation and ask the patient to restrict their intake
of the offending agent.
There are some general rules that are useful
when considering dietary modifications for
patients with gout. Overweight patients should
make a concerted effort to lose weight by diet and
exercise. Measurement of fasting blood lipids is
essential to exclude hyperlipidemia as a contrib-
uting factor to underlying health problems.
Appropriate diets and medications should be
instituted to decrease the low-density lipoprotein
(LDL) levels (bad cholesterol) and increase the
high-density lipoprotein (HDL) levels (good cho-
lesterol) if hyperlipidemia exists. Gouty patients
should also be encouraged to eat a balanced diet
with less red meat and less seafood than usual. In
general, the three foods/beverages that place
patients at risk for gout are red meat, beer, and
fructose, a sugar commonly found in sugar-
sweetened soft drinks. Finally, patients with gout
should decrease their use of hard liquor and beer
with a substitution of wine if necessary.
Hyperuricemia is the precursor of gout and
kidney stones, and therefore, the mechanisms
that increase serum uric acid levels become
important to understand and modify, if necessary.
Serum uric acid levels represent a balance
between cell and tissue breakdown, the synthesis
of uric acid and its precursors by the de novo
purine and salvage pathways, the renal elimination
Summary
of urate, and the dietary intake of purines and
other chemicals known to influence urinary uric
acid excretion. Genetic parameters have been
described in monogenic disorders including
hypoxanthine-guanine phosphoribosyltransferase
deficiency, phosphoribosylpyrophosphate syn-
thetase overactivity, familial juvenile hyperurice-
mic nephropathy, and glycogen storage disease,
but these disorders only represent about 10 % of
the patients with gout. The majority of patients
with gout have a drug-induced or undefined alter-
ation in their renal elimination of uric acid.
Summary
Despite the foregoing knowledge base, many
patients with hyperuricemia and gout remain
improperly diagnosed, inappropriately treated for
a disease they often do not have, insufficiently
managed by the inadequate use of available med-
ications, and poorly followed to ensure the pri-
mary objective of eliminating urate crystal
deposits from their joints and other tissues and to
prevent the occurrence of gouty episodes [1017–
1026]. Gout represents the end expression of
many different causes, and such etiologic factors
are often not evaluated. This is especially true for
comorbid conditions like the metabolic syndrome
and its components (hypertension, insulin resis-
tance, dyslipidemia, and abdominal obesity)
[911, 1027, 1028]. Furthermore, many physicians
only treat acute gouty episodes and fail to recog-
nize and manage the deformities and functional
impairments caused by tophaceous deposits and
their potential to suppress kidney function.
A careful and complete history should provide
information concerning other family members
with gout, the potential for or the presence of
renal disease including nephrolithiasis, and the
presence of any neurological deficits in patients
or his/her family. In addition, age and sex of the
patient and affected family members are likely to
provide clues to any underlying genetic disorder
associated with gout. The latter is especially true
if young males or females are documented to
have hyperuricemia or gout. A careful history of
medications may often reveal a likely causative
353
agent such as diuretics that may account for the
presence of hyperuricemia and/or gout. Finally, a
vague history of joint complaints with an elevated
serum uric acid does not constitute a diagnosis of
gout, but intermittent episodes of an acute
inflammatory joint process with redness and
severe pain are suspicious of an attack of acute
gouty arthritis. Further evidence in support of the
shortcomings associated with the diagnosis of the
causes of hyperuricemia and gout are apparent
when the combination of clinical analysis and
imaging data as proposed by the American
College of Rheumatology (ACR) criteria is used
as an alternative to the absolute diagnosis pro-
vided by the detection of MSU crystals. The fact
is that the validity of the ACR criteria as well as
the Rome and New York criteria leads to less than
optimal performance results [1029, 1030]. To
emphasize further this defect in the use of clinical
criteria alone for the diagnosis of gout, the ACR
criteria only have a sensitivity of 68 % and a
specificity of 78 %. As a supplement to the his-
torical data, a thorough physical examination is
required including a search for tophi and an
abdominal examination to elicit enlargements of
the liver, spleen, or kidney; an estimation of renal
function (serum creatinine); a careful neurologi-
cal examination to exclude Lesch-Nyhan vari-
ants; and a synovial fluid or tophus aspiration to
document the presence or absence of MSU
crystals.
With respect to the physical examination, it is
important to recognize that the involvement of the
first metatarsal phalangeal (MTP) joint may not
represent podagra but infection, other crystal-
induced arthropathies, or psoriatic arthritis
[1031–1034]. Although most patients with gout
manifest classical podagra at some time during
the lifetime of their disease, it is essential to rec-
ognize that many unusual sites such as the tem-
poromandibular joint, manubriosternal joint,
sternoclavicular joint, acromioclavicular joint,
sacroiliac joint, lumbar spine, hip joints, symphy-
sis pubis joint, and flexor tenosynovitis with car-
pal tunnel syndrome may be involved in acute and
chronic gout [1035–1043]. Finally, tophaceous
gout may mimic other disorders as a result of its
unusual location and its tumor-like appearance
354
[1044–1046]. A most significant reason for per-
forming a synovial fluid aspiration is the possible
concomitant occurrence of a septic arthritis along
with gout [1047].
Summary of Principles
of Management
Lifestyle
Attention should be directed to obesity, hyperten-
sion and renal insufficiency, diabetes, alcohol
intake, and drugs which might elevate serum uric
acid levels. Diuretics should be avoided for treat-
ment of hypertension if possible. Losartan may
be a good choice since it has a modest uricosuric
effect. Fenofibrate also has some urate-lowering
effect, making it a good choice for treating hyper-
lipidemia in patients with gout.
Treatment decisions also depend on the num-
ber of previous acute attacks of gout, age of the
patient, presence of tophi, and radiographic
signs.
Acute Attacks
Oral colchicine and NSAIDs are the first-line
agents for the treatment of acute attacks of gout.
Colchicine has been shown to be effective in
lower doses than commonly used in the past, with
less toxicity. A study of 1.0 mg followed by
0.5 mg 1 h later compared to 1.0 mg followed by
0.5 mg every 2 h until GI toxicity has been pub-
lished. There was equal anti-inflammatory effec-
tiveness of the two regimens at 48 h with reduced
toxicity in the low-dose group.
The NSAIDs are also effective agents for
acute gout. Studies have shown that several
NSAIDs have comparable effectiveness. Upper
GI toxicity with bleeding is a major concern with
these agents. This risk may be reduced with con-
comitant use of proton pump inhibitors or with
Cox-2 selective inhibitors. Cardiovascular risks
occur with NSAIDs, but naproxen appears to
have less cardiovascular risk than other
NSAIDs.
9 Management of Hyperuricemia and Gout
Glucocorticoids are effective in acute gout and
are the drugs of choice in patients with significant
renal disease and other comorbidities. They may
be given orally in doses beginning with 40–60 mg/
day of prednisone or its equivalent tapering off
over a period of about 10 days. Intra-articular glu-
cocorticoids are effective and safe for the treat-
ment of acute gout, especially when monoarticular.
At the same time, samples of synovial fluid may
be obtained for crystal analysis and culture.
Chronic Gout
Urate-lowering treatment is indicated in patients
with recurrent acute attacks of gout, tophi on
physical examination, or radiographic changes of
gout. The therapeutic goal of urate-lowering ther-
apy is to reduce the serum uric acid to levels
below the saturation level of monosodium urate
in order to dissolve monosodium urate that is
present in tissues and prevent further precipita-
tion. Practically, the therapeutic goal is a serum
uric acid level of <6.0 mg/dl or <360 mmol/l. It is
very important to achieve this goal with adequate
doses of the urate-lowering drug, or treatment
will be ineffective. It is generally recommended
that urate-lowering therapy not be started during
an acute attack. However, if a patient is already
taking urate-lowering therapy when an attack
occurs, the drug may be continued during the
attack.
The most commonly used urate-lowering drug
is the xanthine oxidase inhibitor allopurinol. It
should be started at a dose of 100 mg/day in
patients with normal renal function and increased
every 2–4 weeks until the target level of serum
uric acid is reached. The dose needed is variable
from patient to patient. Doses as high as 800 mg/
day have been approved by the US Food and
Drug Administration. It is also important to warn
patients of possible side effects since up to 5 % of
patients may develop allergy to allopurinol, and a
much lower number can develop the potentially
life-threatening allopurinol hypersensitivity
syndrome.
Another useful urate-lowering drug is febuxo-
stat. This is a particularly useful drug for patients
References
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used in patients with moderate renal insufficiency
since it is metabolized by the liver. It should be
started at a dose of 40 mg/day and increased to
120 mg/day if needed.
Alternative urate-lowering drugs are the uri-
cosuric agents. The most commonly used is
probenecid, and sulfinpyrazone is used less com-
monly. However, normal or only slightly impaired,
renal function is required, and these drugs should
not be used if the patient has had uric acid renal
stones. As with other urate-lowering drugs, the
doses of uricosuric drugs must be adequate to
reduce the serum uric acid to the target levels.
Prophylaxis against acute attacks is required
for at least the first few months of urate-lowering
therapy, regardless of which drug is used. The
most common agent is colchicine, 0.5 or 0.6 mg
once or twice daily as tolerated. If colchicine is
not tolerated, an NSAID may be used, although
the evidence for efficacy of NSAID prophylaxis
is limited. While a period of 6 months of prophy-
laxis is sometimes recommended, it may be
required for much longer periods since it may
take longer periods to dissolve all of the tissue
urate, especially in patients with tophaceous
gout.
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 Index

A Acute gouty arthritis, 92, 95, 96, 99, 101, 116, 124, 136,
ABCG2. See ATP-binding cassette subfamily G member 137, 140, 141, 191, 199, 200, 207–209, 211,
2 (ABCG2) 212, 218, 219, 228, 229, 237, 238, 240, 243,
Accelerated ATP degradation 252, 253, 255, 259, 262, 294–297, 301, 304,
acetaldehyde, 78 313–315, 322, 323, 327, 331, 348, 353
acetyl-AMP, 78 Acute inflammatory response, 187, 207, 208, 218, 231,
acetyl-CoA synthetase, 78 232, 234, 253, 259, 261–263, 270, 276, 278,
alcohol dehydrogenase, 78 316, 319, 320
b-hydroxybutyrate, 78 Acute uric acid nephropathy
carnitine palmityltransferase deficiency, 78 medullary cystic disease, 117
ethyl alcohol, 78 polycystic kidney disease, 117
glucose-6-phosphatase deficiency, 75 Acute uric acid nephropathy management
glycogen storage diseases, 78 alkylating agents, 340
hypoxemia, 80 allopurinol, 340
inosine, 79 hematopoietic system, 340
lactate, 78 hemodialysis/peritoneal dialysis, 340
muscle metabolism, 78 malignant neoplasms, 340
NADH, 78 tubular interstitial nephritis, 340
nicotinamide adenine dinucleotide ultrasonography, 340
(NAD), 78 urine alkalinization, 340
phosphofructokinase deficiency, 78 Adenine, 4, 25, 77, 107, 249, 330
phosphoglycerate mutase Adenine phosphoribosyltransferase (APRTase), 35, 42,
deficiency, 78 47–54, 131–133
secondary gout, 75 ACG, 51
Von Gierke’s disease, 75 adenosine monophosphate (AMP), 47
xanthine oxidase, 79 APRT enzyme forms, 51
Accelerated nucleotide degradation ATG, 51
AMP deaminase, 84 deficiency, 47
myoadenylate deaminase, 83 de novo, 54
Acute attack, 93, 97, 207–278, 295, 296, 315, 316, 320, 2,8-dihydroxyadenine stones, 51
323, 339, 354, 355 2,8-dihydroxyadenine urolithiasis, 52
Acute attack gout mechanisms familial juvenile hyperuricemic nephropathy
acute gouty arthritis, 207–208, 211, 212, 218, 219, (FJHN), 53
228, 229, 237, 238, 240, 243, 252, 253, 255, gene, 49
259, 262 hereditary orotic aciduria, 54
acute inflammatory response, 207, 208, 218, 231, inhibition of APRTase activity, 47
232, 234, 235, 259, 261–263, 270, 276, 278 Morquio syndrome, 52
apoptosis, 208, 216, 230, 233, 234, 256, 257, 260, mutant forms of APRTase, 49
262, 269–272 TGA, 51
cell migratron, 208, 243, 247 TGG, 51
phagocytosis, 207–209, 230, 233, 234, 242, 247–252, type I APRTase deficiency, 49
256, 258–260, 263, 265, 269, 270, 273 Adenosine deaminase, 34, 79, 108, 140
Acute attacks Adenosine kinase, 34, 35
prophylaxis against, 355 Adenosine monophosphate (AMP), 11, 28, 30, 31,
treatment, 354 33–36, 38, 40–43, 47, 54, 76, 79–84, 101, 107,
urate-lowering treatment, 354 108, 140, 235, 263, 269, 276, 310

D.S. Newcombe, Gout, 387

DOI 10.1007/978-1-4471-4264-5, © Springer-Verlag London 2013
388 Index

Adenylic, 27, 55 Antituberculous drugs, 137, 326

Adenylosuccinase, 33, 34, 40 Anton de Storck, 4
Adenylosuccinate, 33, 34, 40 Anton van Leeuwenhoek, 2
Adhesion molecules, 210, 211, 216, 217, 219, 221, 228, Apoptosis, 208, 216, 230, 233, 234, 256, 257, 260, 262,
237–245, 255, 261, 272, 277 269–272, 312, 329
E-selectin, 242–243 APRTase. See Adenine phosphoribosyltransferase
integrins, 238, 243 (APRTase)
integrins ligand, 245–247 Archibald E.Garrod, 5
integrin structure, 243–245 Arthrocentesis techniques, 188–189
L-selectin, 239–240 Associated disorders
P-selectin glycoprotein ligand-1, 239 DNA Polymorphisms, 151–152
selectins (structures), 238–239 familial apolipoprotein c-II deficiency, 149
unique L-selectin properties, 240–242 familial combined hyperlipidemia, 149
ADPKD. See Autosomal dominant polycystic kidney familial lipoprotein lipase deficiency, 149
disease (ADPKD) familial lipoprotein lipase inhibitor, 149
AIC. See 5-amino-4-imidazolecarboxamide (AIC) fish-eye disease, 151
Albrecht Wallenstein, 6 high density lipoprotein (HDL), 148
Alcohol, 11, 12, 78, 80, 93, 100, 101, 105, 116, 135, 136, lecithin/cholesterol acyltransferase (LCAT)
141, 142, 148–150, 188, 191, 194, 199, 202, deficiency, 151
222, 266, 291, 293, 313, 324, 339, 348, 349, low density lipoproteins (LDL), 148
352, 354 monogenic hypertriglyceridemia, 149–150
Alexander Gutman, 5 nonsteroidal anti-inflammatory drugs
Alexander Hamilton, 6 (NSAIDS), 148
Alexander of tralles, 2 type III hyperlipoproteinemia, 150–151
Alexander the great, 6 very low density lipoproteins (VLDL), 148
Alfred Garrod, 5 Asymptomatic hyperuricemia
Allopurinol chlorthalodine, 293
acute gouty arthritis, 331 chronic renal disease, 292
alloxanthine (oxypurinol), 329 diuretics, 293
azathioprine, 330 drug-induced hyperuricemia, 293
cyclophosphamide, 330 ethambutol, 294
de novo, 330 hypertension, 293
feedback inhibition, 330 nicotinic acid, 294
histocompatibility locus antigen (HLA), 334 pyrazinamide-induced hyperuricemia, 294
hypersensitivity reactions, 332 renal calculi, 292
induced gout, 136–137 salicylates, 293
6-mercaptopurine, 330 Atherosclerosis, 11, 147, 148, 150, 151, 153, 154, 352
orotidine-5-monophosphate decarboxylase, 330 ATP-binding cassette subfamily G member 2 (ABCG2),
oxypurinol, 331 16, 17
prophylactic colchicine, 331 ATP degradation, 75–81, 83, 107, 108, 113, 125
standard treatment regimens, 330 Aulus Cornelius Celsus, 1
Stevens-Johnson syndrome (STS), 333 Autosomal dominant polycystic kidney disease
T cell-mediated delayed hypersensitivity, 334 (ADPKD)
toxic epidermal necrolysis (TEN), 332, 333 cerebral aneurysms, 119
toxic reactions, 331 hypertension, 119
treatment stones, 348 renal failure, 119
vasculitis, 332 urinary tract infections, 118
in vitro, 330, 332 Avascular necrosis, 95, 199, 202 See also Osteonecrosis
in vivo, 330
xanthine oxidase, 330
Amino acid structure of CSa, 235 B
5-amino-4-imidazolecarboxamide (AIC), 48 Bacterial arthritis, 96, 97, 194
AMP. See Adenosine monophosphate (AMP) Beer, 11, 12, 136, 339, 348, 349, 352
Ancient greek and roman civilization, 1 Benjamin Franklin, 4, 6
Annexins, 278 Ben Johnson, 6
Anti-inflammation, 265, 270–271 Benzbromarone, 14–16, 96, 133, 138, 139, 325–326,
Anti-inflammatory eicosanoid, 232, 262–263 328–329
Anti-inflammatory lipoxins effects severe hepatotoxicity, 329
in vivo, 265 Biological functions of PAF, 227–228
Antimetabolites, 35, 48, 106, 291, 295, 330, 337 Blunt ends, 192
Index 389

Body mass index, 11, 349 Colchicum autumnale, 6

Bony erosions, 199–201 Co-morbidities
tophi, 200 alcohol, 348
Bursa, 92, 94, 95, 199, 200, 203, 208 beer, 349
Byzantine empire, 2 dietary factors, 348
wine, 349
Compensated polarized microscopy, 191, 192, 194
C Complement fragments, 220–221
C5a, 210, 218–222, 227, 229, 235, 240, Cotton Mather, 6
241, 243, 244 Count Nikolaus Ludwig von Zinzendorff (German
C5a des Arg, 220–221 theologian), 6
Calcium pyrophosphate dihydrate (CPPD) crystals, 98, Crystal identification, 99, 191, 192, 296
188, 191–193, 202, 209, 215, Cyclooxygenase inhibitors classification
257, 297, 298 cardiovascular events, 312
Cardinal Wolsey (the last medieval prince of the renal hemodynamics, 311
church), 6 Cyclosporine, 91, 93, 95, 96, 118, 128, 135, 137–139,
Cardiovascular disease, 10, 15, 147, 153, 232, 303, 306, 145, 294, 300, 301, 328, 329, 346
311, 320, 339, 351 Arthrobacter protoformiae, 138
C5a receptor, 220–222, 227 Aspergillus flavus, 138
Carl Linnaeus, 6 Candida utilis, 138
Carl Scheele, 3 Cytokines, 15, 194, 210, 211, 214–218, 220, 236–238,
Carpal tunnel syndrome, 94, 105, 353 240–242, 244, 245, 253, 255–262, 264, 269,
Cell membrane, 14, 43, 209, 241, 249, 250, 257, 271, 273, 275, 277, 315, 319, 334
259–260, 275, 297, 301, 302 Cytotoxic agents, 135, 136, 294
Cell migration, 208, 243, 247
Charles Darwin, 6
Chemoattractants, 207, 209, 210, 218–220, 222, D
227–229, 235–237, 240, 241, 244–246, 253, DAMPs. See Inflammasome
263, 320 DAP. See 2,6-diaminopurine (DAP)
Chemotactic peptide generation, 297 Decreased hypoxanthine reutilization, de novo, 74, 75
Cholesterol, 10, 12, 109, 110, 139, 148–153, 329, 345, DECT. See Dual energy computed tomography (DECT)
351, 352 Denis, W., 4
Chondrocalcinosis, 98, 199, 202–203 De novo, 5, 13, 25, 30–34, 37, 39–44, 46, 47, 53–55,
pseudogout, 202 69–76, 81, 82, 103, 104, 106–108, 111, 127,
Chondrocytes, 15, 266 140, 141, 223, 226, 227, 330, 352
Chronic gouty arthritis, 2, 94–96, 348 De novo purine nucleotide synthesis
Chronic renal failure, 10, 53, 87, 105, 118, adenosine monophosphate, 30
127, 142, 352 adenosine triphosphate (ATP), 30
Chronic tophaceous gout, 2, 5, 92–96, 98, 99, 109, 137, adenylosuccinase, 30
200, 324, 342 aspartic acid, 30
Clinical aspects of gout and associated carbon dioxide, 30
disease states de novo, 30
decreased renal clearance of urate, 91 energy phosphate compounds, 30
increased purine biosynthesis, 91 formate, 30
microcrystals, 91 10-formyl-tetrahydrofolate, 30
primary gout, 91 fumarate, 30
pseudogout, 91 glutamine, 30
Secondary gout, 91 glycine, 30
synovium, 91 guanosine monophosphate, 30
uric acid overproduction and underexcretion, 91 inosine-5’-phosphate (IMP), 30
Colchicine 5, 10-methenyltetrahydrofolate, 30
acute gout, 296 5-phospho-a-D-ribosyl pyrophosphate (PRPP), 30
gastrointestinal toxicity, 296 (COMP: Please insert correct symbol.)
mechanism action, 297 phosphoribosylamine, 30
myopathy, 96, 300 5’-phosphoribosyl-5-aminoimidazole
pharmacokinetics, 298–299 (AIR), 30
toxicity 5’-phosphoribosyl-5-aminoimidazole-4-carboxamide
colchicine-induced myopathy, 299 (AICAR), 30
colchicine myoneuropathy, 299 phosphoribosylaminoimidazolecarboxamide formyl
intravenous colchicine, 300 transferase, 30
390 Index

De novo purine nucleotide synthesis (cont.) hypomagnesemia, 98

phosphoribosylaminoimidazole hypophosphatasia, 98
carboxylas, 30 immunocompromised host, 96
5’-phosphoribosyl-5-aminoimidazole-4-carboxylate infected prosthetic joints, 97
(CAIR), 30 joint infections, 97
5’-phosphoribosyl-5-aminoimidazole-4-(N-succino) N. gonorrhoeae, 97
carboxamide (Succino-AICAR), 30 positive birefringence, 98
phosphoribosylaminoimidazole-succinocarboxamide pseudogout, 96, 97
synthetase, 30 Pseudomonas aeruginosa, 97
phosphoribosylaminoimidazole synthetase, 30 psoriatic arthritis, 98
5’-phosphoribosyl-5-formamidoimidazole-4- Reiter’s syndrome, 98
carboxamide (formyl-AICAR), 30 S. aureus, 97
phosphoribosyl-formylglycineamidine synthetase, 30 septic arthritis, 96
5’-phosphoribosyl-glycineamide (GAR), 30 Serratia marcescens, 97
phosphoribosylglycineamide formyl transferase, 30 severe degenerative arthritis, 96
phosphoribosylglycineamide synthetase, 30 synovial fluid
5’-phosphoribosyl-N-formylglycinamidine culture, 97
(FGAM), 30 glucose, 97
5’-phospho-ribosyl-N-formylglycine (FGAR), 30 white blood cell count, 97
phosphoribosylpyrophosphate amidotransferase, 30 syphilis, 97
purine salvage pathways, 30 traumatic arthritis, 96, 98
ribosylamine, 30 2,8-dihydroxyadenine lithiasis
Deoxyribo nucleic acid (DNA), 25, 26, 28, 39, 44, 46, adenine phosphoribosyltransferase, 132
47, 49, 53, 119, 148, 245, 251, 260, 261, 271, adenine phosphoribosyltransferase
273, 275–278, 317, 343 deficiency, 133
Deoxyribose phosphate, 26 2,8-dihydroxyadenine stones, 36, 124, 127, 129, 132
Desquamation, 93 Diuretic(s), 11, 86, 87, 91, 93, 95, 100, 105, 115, 117,
Destructive arthropathy, 94 127, 135–137, 145–147, 148, 150, 152, 194,
DeWitt Stetten, 5 293, 306, 307, 309, 311, 314, 324, 326, 328,
Diabetes mellitus, 10, 11, 96, 98, 100, 139, 147, 149, 332, 345, 346, 349, 353, 354
150, 152, 189, 294, 295, 309, 349, 351, 352 amiloride, 135
2,6-diaminopurine (DAP), 33, 38, 48, 50, 51 benzothiadiazines, 135
Dicarboxylates, 16, 17 diuretic-induced gout, 135
Diet ethacrynic acid, 135
alcohol, 348 furosemide, 135
beer, 349 induced hyperuricemia, 115
dietary factors, 348 spironolactone, 135
wine, 349 triamterene, 135
Dietary restrictions, 11, 12, 339, 342, 352 Drug-induced hyperuricemia and gout, 135
Differential diagnosis Dual energy computed tomography
acute neuropathic joints, 98 (DECT), 203–204
aspiration, 97 Dyslipidemia, 10, 11, 152, 154, 349, 351–353
bacterial arthritis (septic arthritis), 96
calcification, 98
calcium pyrophosphate E
crystal deposition disease, 96 Egyptian archeology, 1–2
dihydrate, 97 Elimination of uric acid
charcot joints, 98 acetoacetate, 85
chondrocalcinosis, 98 b-hydroxybutyrate, 85
chronic neuropathic joints, 98 lactate, 85
chronic tophaceous gout, 98 urate reabsorption mechanisms, 85
E. coli, 97 uric acid renal elimination, 84
gram-negative infections, 97 urinary uric acid excretion, 85
gram-positive organisms, 97 Emil Fischer, 4, 25
gram stain, 97 Empress Maria Theresa of Austria, 4
hemochromatosis, 98 Endonucleases, 26
hemodialysis, 97 E-selectin, 210, 237–239, 241–243, 261
HIV disease, 97 Ethanol, 77, 78, 80, 100, 101, 103, 105, 107, 135–137,
hyperparathyroidism, 98 307, 348
Index 391

Excessive purine intake, 84, 105, 128 intercellularadhesionmolecule-1(ICAM-1), 320

Exonucleases, 26 lipocortin-1, 318
Extra-articular tophi, 94, 199, 201 mechanism, 316
methylprednisolone, 322
neutrophilia, 319
F neutrophil migration, 320
Familial juvenile gouty nephropathy (FJGN), 120–121, phospholipase, 319
144, 145 prednisone, 316
Familial juvenile hyperuricemic nephropathy (FJHN), transcortin, 316
13, 53–55, 120, 145, 353 in vitro, 317
Famous sufferers, 6 in vivo, 317
Fatty acid oxidation deficiencies Glucose/fructose transporter, 13
carnitine palmitoyltransferase II, 113 GLUT9, 14–16
heritable palmitoyltransferase deficiency, 113 Glutamine hypothesis, 72
myoglobinuria, 113 GLUT9DN, 14
Febuxostat GLUT9L, 14
adverse reactions, 337 GLUT9S, 14
hepatic metabolism, 337 Glycogen storage diseases (GSD)
xanthine oxidase, 337 b2-microglobulinuria, 341
Females gout calcium oxalate, 109
hyperuricemia and gout in pregnancy, 146 creatine phosphokinase, 110
juvenile hyperuricemia and gout, 144–145 debranching enzyme
postmenopausal hyperuricemia and gout, 146–147 deficiency, 109
premenopausal hyperuricemia and gout, 145–146 de novo, 111
Fenofibrate generalized aminoaciduria, 341
Fenofibrate, hyperlipidemia, 345 glucose-6-phosphatase deficiency, 108
Fever and chills, 92 glycogen storage disease type XI, 113
FJGN. See Familial juvenile gouty nephropathy (FJGN) hemolytic anemia, 112
FJHN. See Familial juvenile hyperuricemic nephropathy inosine monophosphate, 111
(FJHN) lactate dehydrogenase-A deficiency, 113
Folin, O., 4 metabolic myopathies, 111
Fructose, 11–16, 76–78, 107, 111, 127, 133, 135, muscle phosphoglycerate mutase
139–140, 338, 341–342, 349, 352 deficiency, 112
Fructose-1,6-bisphosphatase deficiency, 78, 107 myoadenylate deaminase deficiency, 111
Fructose-induced hyperuricemia, 11, 12, 107, 139–140 myoglobinuria, 110
de novo, 140 myopathy, 110
Fructose-1-phosphate, 11, 140 nephrocalcinosis, 109
phosphofructokinase activity deficiency, 111
phosphofructokinase deficiency, 110
G phosphoglycerate kinase deficiency, 112
Galen, 1 phosphoglycerate mutase deficiency, 111
Gemfibrozil, 12 phosphorylase kinase deficiency, 112
Generation of reactive oxygen radicals, 247 Tarui’s disease, 110
Genetic abnormalities, 13–17 type III, 110
Genetic polymorphisms of SLC2A9/GLUT9, 14 type V, 110
Genome-wide association studies (GWAS), 13, 14, 16 type VII, 110
George Hitchings, 5 GMP. See Guanosine-5’-monophosphate
George Mason (American statesman and drafter of the (GMP)
constitution), 6 GRE. See Glucocorticoids
Gertrude Elion, 5 GTP, 33, 34, 36, 82, 83, 140, 216, 221
Glucocorticoids, 278 Guanine, 4, 25, 27, 28, 30, 34, 42–44, 46, 72, 81, 130,
annexin, 318 249, 330, 336, 337
chemotaxis, 319 Guanosine-5’-monophosphate (GMP), 31, 33–35, 40–43,
cyclooxygenase synthesis, 318 46, 55, 82, 272
dexamethasone, 316 Guanosinic acid, 72
glucocorticoid-induced inhibition, 318 Guanylic, 26
glucocorticoid-inducible protein, 318 Guanylic acid, 27, 28, 55
glucocorticoid response elements (GRE), 317 GWAS. See Genome-wide association
hydrocortisone, 316 studies (GWAS)
392 Index

H solubility uric acid, 99

HapMap, 14 toxemia pregnancy, 100
Hematological malignancies, 108, 128 urate nephropathy, 100
Henry Fielding, 6 urolithiasis, 100
Hereditary fructose intolerance (HFI), 77, 78, 107, 127, management
133, 139, 140, 341–342 colchicine, 291
Hereditary xanthinuria, migratory polyarthritis, 131 corticosteroids, 291
Heterozygote carriers of HGPRTase deficiencies, 72 NSAIDs, 291
HFI. See Hereditary fructose intolerance (HFI) overview, 291–292
HGPRTase. See Hypoxanthine-guanine proper, 291
phosphoribosyltransferase (HGPRTase) uric acid lowering therapy, 291
High-energy phosphates, 30, 31, 34, 101, 140 uricosuric agents, 291
Hippocrates, 1 Hyperuricemia mechanisms
Histone acetylation and glucocorticoids, 277–278 1-14C-glycine, 72
HLA. See Allopurinol de novo, 72
HPRTase. See Hypoxanthine-guanine Hyperuricemia renal mechanisms
phosphoribosyltransferase (HGPRTase) decreased tubular secretion, 85
Hydrogen peroxide, 11, 248, 250–252, 260 postsecretory reabsorption, 85
Hyperglycemia, 10, 152, 217, 351, 352 pyrazinamide suppression test, 85
Hyperlipidemia, 11, 12, 108, 109, 147–154, 291, 294, urate excretion, 85
312, 345, 352, 354 urate underexcretion, 86
Hypertension Hyperuricosuric calcium oxalate nephrolithiasis, calcium
alcohol, 352 oxalate, 134
de novo, 352 Hypoxanthine, 5, 13, 25, 71, 101, 291
dyslipidemia, 351 Hypoxanthine-guanine phosphoribosyltransferase
meat, 351 (HGPRTase)
metabolic syndrome, 351 adenine phosphoribosyltransferase (APRTase), 42
obesity, 351 deficiency, 41, 72, 73, 106, 121, 123, 124, 144, 145
seafood, 351 de novo, 42–44, 46
vascular disease, 351 dimagnesium PRPP, 43
Hypertriglyceridemia, 9–12, 33, 148–152, 345, 350–352 DNA methylation, 46
Hyperuricemia hypoxanthine-guanine phosphoribosyltransferase
chemical properties of the uric acid, 187 deficiency, 44
uric acid has a solubility, 187 enzyme, 44
Hyperuricemia and gout gene, 44
diagnostic criteria for pseudogenes, 43
acetate, 101 inosine monophosphate (IMP) dehydrogenase, 45
acetoacetate, 101 Kelley-Seegmiller syndrome, 45
acetylcoenzyme A, 101 Lesch-Nyhan syndrome, 45
acute renal failure, 101 NAD synthetase, 45
adenosine monophosphate, 101 nicotinamide adenine dinucleotide (NAD), 45
adenosine triphosphate, 101 nicotinic acid phosphoribosyltransferase, 45
asymptomatic hyperuricemia, 100 X-chromosome activation, 46
b−hydroxybutyrate, 101 X-chromosome inactivation, 46
chemotherapy, 102
compensated polarized light microscopy, 99
ethanol, 101 I
hypercatabolic states, 101 ICAM-1. See Glucocorticoids
hyperlacticacidemia, 101 ICAMs. See Intercellular adhesion molecules (ICAMs)
hyperuricemia, 100 IkB, 261, 262, 273, 274
inosine, 101 IL-8 gene, in vitro, 237
lactate, 101 Immunoglobulin, 192, 213, 230, 233, 245, 319, 335
needle-like uric acid crystals, 99 IMP. See Inosine monophosphate (IMP)
nitroglycerin, 101 Increased cells deficient, 33
normal serum uric acid levels, 99 Increased nucleic acid turnover
nucleoproteins, 101 adenine phosphoribosyltransferase, 81
5’-nucleotidase, 101 ATP degradation, 83
radiation, 102 de novo, 81
rhabdomyolysis, 101 epidermal turnover, 81
seizures, 102 hemoglobinopathies, 81
Index 393

hemolytic anemias, 81 polycystic kidney disease, 94

hyperlacticacidemia, 83 sarcoidosis, 94
hyperuricosuria, 83 Interleukin-8 (IL-8), 209, 210, 218–221, 227–229,
ineffective erythropoiesis, 81 235–238, 240, 241, 244–246, 253, 255, 256,
multiple myeloma, 81 258, 259, 261, 267, 274, 319, 320
muscle contractions, 83 amino acid structure, 235–236
muscular exercise, 83 Amino Acid Structure of CSa, 235
myeloproliferative disorders, 81 Amino Acid Structure
neoplams, 81 of IL-8, 235
nucleotide degradation, 81 Interleukin-18, 216–217
pentose phosphate pathway, 81 Interleukin-1b, 216–217
pernicious anemia, 81 Interleukin-1band interleukin-18, 216–217
phosphoribosylpyrophosphate (PRPP), 81 Interleukin 1 inhibitors
polycythemia, 81 anakinra, 322
psoriasis, 81 canakinumab, 323
Indomethacin decoy receptor, 323
toxicity, 314 rilonacept, 323
in vivo, 314 In vitro, 35, 54, 131, 210, 212, 213, 237, 249, 255, 264,
Inflammasome 297, 303, 310, 317, 330, 332
autoinflammatory, 213, 322 In vivo, 54, 234, 235, 237, 241, 249, 264, 265, 273, 297,
caspase-1, 214, 216–218 314, 317, 330
cryopyrin, 213, 216 Isaac Newton, 6
danger-associated molecular patterns (DAMPs), Ischemic heart disesae, 10, 115, 152, 351, 352
214–215 Isotopes
IL-1b, 15, 213–215, 218 accelerated production of uric
IL-1b, 216 acid, 54
innate immune system, 213–216 de novo, 54, 55
NLRP3, 213–217 estimation, 54
Nod (nucleotide oligomerization domain)-like glycine alpha-N15, 54
receptors (NLRs), 215, 216 glycine-1-C14, 54
pathogen-associated molecular patterns (PAMPs), rate of purine synthesis, 54
214–215 in vitro, 54
periodic fever syndrome, 213, 214 in vivo, 54
periodic fever syndromes, 213, 214
pro-IL-1b, 216, 217
RIG-I-like receptors (RLRs), 215 J
Inflammatory cell chemotaxis, 297 James Wyngaarden, 5
Inflammatory response, 53, 92, 127, 187, 188, 194, 207, Jay Seegmiller, 5
208, 210, 212, 215, 216, 218, 221, 223, 227, Johann Wolfgang von Goethe, 6
230–232, 234, 237, 238, 243, 246, 247, John Buchanan, 5
252–256, 258–267, 270–274, 276–278, 294, John Calvin, 6
297, 298, 301, 302, 310, 316, 317, 319, 320 John Dryden, 6
Inhibitory concentration, 297 John Hunter, 6
Inosine monophosphate (IMP), 30, 31, 33–35, 40, 43, 45, John Milton, 6
46, 55, 74, 79, 80, 82, 83 John Wesley (English evangelist and
Inosine 5’-phosphate dehydrogenase, 34 theologian), 6
Inosinic acid, 27, 28, 33, 34, 40, 72–74, 79, 80, 82, 83, Joint effusions, magnetic resonance
108 image, 200
Insulin resistance, 10, 12, 139, 149, 152, 349, 351, 353 Joint involvement, 92, 94, 147
Insulin resistance syndrome, 10, 152, 351
Integrins, 210, 211, 237, 238
Integrins, 210, 211, 227–229, 237, 238, 240, 241, K
243–247, 258 Kelley-Seegmiller syndrome
Integrin structure, 243–245 hypoxanthine-guanine phosphoribosyltransferase,
Intercellular adhesion molecules (ICAMs), partial deficiency, 104
210, 245 nephrolithiasis, 105
Intercritical gout, 92–94, 193 neurological dysfunction, 105
asymptomatic gout, 94 Kidney stones, 11, 12, 15, 47, 48, 104–106, 122–125,
familial juvenile gouty nephropathy, 94 128, 132, 134, 187, 201, 352
glomerulonephritis, 94 Kossel, 25
394 Index

L Monoarticular or oligoarticular arthritis,

Leonardo da Vinci, 6 92, 95, 96, 99, 354
Lesch-Nyhan, 5, 35, 44, 45, 103–105, 115, 120, 123, Monocarboxylates, 16, 17
124, 127–129, 131, 141, 145, 341, 353 Monogenic mutations, 15
Lesch-Nyhan syndrome Monosodium urate (MSU)
central nervous system dysfunction, 103 crystal-induced neutrophil activation, 256
choreoathetosis, 104 crystallization
de novo, 104 acute gout, 211
hypoxanthine-guanine diagnosis of acute gout, 211
phosphoribosyltransferase, 103 hyperuricemia, 211
nephrolithiasis, 103 immunoglobulins, 213
neurological disorder, 103 intra-articular temperatures, 212
Leukotriene B4 (LTB4), 218, 219, 229–231, 233, 235, serum, 211, 212
253, 315, 319 in vitro, 212, 213
biosynthesis crystals, 93, 94, 191–193, 199, 204, 207, 213, 215,
lipoxygenase, 230–231 217, 218, 237, 253–260, 273, 298, 353
phospholipase A2, 230–231 monohydrate crystals, 91, 116
Lifestyle, 354 Monosodium urate crystal
Ligands for integrins, VEGF, 246 in vitro, 210, 255
Lipoxin biosynthesis Musculoskeletal ultrasound
in vitro, 264 hyperechoic enhancement, 203
in vivo, 264 radiological examinations, 199
Lord Beaverbrook, 6 urate deposits, 203
Lord Howe, 6 Myeloperoxidase (MOP), 230, 250–252, 260
Losartan Myelosuppression, 96
angiotensin II (AII) receptor antagonist Myoadenylate deaminase deficiency,
(ARB), 345 83, 108, 111, 112
uricosuric effect, 346
Low-purine diet, 49, 339
purine-free diets, 339 N
L-selectin, 210, 238–243 NAD+, 34
LTA4 Hydrolase, 230–232 NADPH oxidase assembly
in vitro, 249
in vivo, 249
M Naproxen
MAP kinase, 230, 249, 256, 259, 278 cardiovascular toxicity, 315
Marshal Saxe, 6 treatment regimens, 315
Martin Luther, 6 Neoplastic disease
Mechanisms of NLRP3 activation acute uric acid nephropathy, 295
asbestos, 217 antineoplastic treatment, 295
MSU crystals, 217 Nephrogenic diabetes insipidus (NDI), 121–122
reactive oxygen species (ROS), 217 Nephrolithiasis, uric acid calculi, 348
silica, 217 Neurological deficits, 44, 95, 104–106, 353
Medullary cystic disease (MCD), 119–120 Neutrophil and macrophage apoptosis, 260
Megaloblastic anemia, 104, 106, 117, 140–141 Neutrophil chemoattractants
de novo, 141 chemoattractants, 207, 218–219, 227, 229, 235, 237,
Mercaptopurine, 5, 25, 27, 31, 35, 37, 42, 96, 137, 138, 253, 263
295, 330, 332, 337 chemotactic cytokines, 218, 219
6-mercaptopurine, 5, 25, 27, 31, 35, 37, 42, 96, 137, 138, neutrophil chemotaxis, 218–220, 227
295, 330, 332, 337 Neutrophil migration, 207, 219–220, 235, 237, 240, 241,
Metabolic myopathies, 77–79, 107, 111, 113 247, 320
Metabolic syndrome, 10–12, 15, 16, 152, 338, 349, NF-kB, 215, 256, 261, 262, 271–275, 277
351–353 NHANES III, 9
Michael Lesch, 5 Nicotinic acid, 45, 87, 135, 139, 294
Miscible pool of urate Nitric oxide, 9, 216, 217, 242, 248, 251–252, 264, 265,
de novo, 70 270–274, 349, 351
15
N-labeled uric acid, 71 Nitric oxide and bacterial killing, 251–252
Mode of action NLRP3 activation mechanisms
glucocorticoid receptors, 275 asbestos, 217
glucocorticoids, 277–278 MSU crystals, 217
Index 395

reactive oxygen species (ROS), 217 P

silica, 217 PAF. See Platelet-activating factor (PAF)
NLRs. See Inflammasome PAMPs. See Inflammasome
Nonsteroidal anti-inflammatory drugs Pegloticase
(NSAIDs) adverse events, 344
arachidonic acid, 301 antibodies, 344
cyclooxygenase-1 [COX-1], 301 glucose-6-phosphate deficiency, 345
cyclooxygenase-2 [COX-2]), 301 infusion reactions, 344
eicosanoids, 301 Krystexxa, 344
inhibition of cyclooxygenase, 301 mammalian recombinant uricase, 344
nonselective NSAIDs, 302 Phagocytosis, 207–209, 230, 233, 234, 242, 247–252,
prostaglandin endoperoxides, 301 256, 258–260, 263, 265, 269, 270, 273, 297,
selective COX-2 inhibitors, 303 319, 320
toxicity Phosphatases, 33, 34, 75, 249, 265, 298, 299
acute renal papillary Phosphoenol pyruvate carboxykinase deficiency, 107
necrosis, 308 Phospholipase classification, in vivo, 234
gastrointestinal bleeding, 307 Phospholipase D, 257–258, 298
hyperkalemia, 309 Phospholipids metabolizing enzymes, 258
hypertension, 309 Phosphoribosylamine (PRA), 33, 72, 81
hyponatremia, 309 5-phosphoribosyl-1-pyrophosphate, 33, 37
hyporeninemic hypoaldosteronism, 309 Phosphoribosyl pyrophosphate (PRPP), 5, 13, 30–47, 50,
nephrotoxic disorders, 307 51, 54, 55, 71–76, 81, 82, 103, 105–107, 111,
NSAID-induced interstitial nephritis, 308 117, 120, 123, 124, 127, 128, 132, 133,
NSAID-induced nephrotoxicity, 309 139–141, 145, 291, 292, 330, 337, 348, 353
sodium retention, 309 amidotransferase
upper GI toxicity, 305 adenosine monophosphate (AMP), 40–42
in vitro, 303 de novo, 40–42
NPT1, 16, 17 feedback inhibitors, 40
Nucleases, 26, 261 feedback regulation, 40
Nucleic acids, 4, 26, 28, 30, 31, 33, 55, 69, 70, gene, 41
75, 78, 81–83, 91, 100, 103, 105, 107, glutamine phosphoribosylpyrophosphate
108, 111, 115–117, 124, 128, 129, amidotransferase, 40
136, 145, 261, 262 guanosine monophosphate (GMP), 40–42
Nucleoside, 27, 28, 34, 54, 70, 75, 79, 80, 140, inosine monophosphate (IMP), 40
218, 328, 330, 336, 337 5-phosphoribosylamine, 40
Nucleoside phosphorylase(s), 27, 28, 34, 54, 79, phosphoribosylpyrophosphate (PRPP), 40–42
80, 140, 336, 337 ribonucleotides, 40
5’-nucleotidases, 28, 34, 35, 79, 80, 101, 140 Phosphoribosyl pyrophosphate synthetase (PRPP
Nucleotide, 11, 14, 15, 17, 25, 30–43, 47, 52, 54, 70, 71, synthetase), 5, 13, 32, 33, 36–40, 71, 73, 82,
73–77, 81–84, 100, 106, 108, 110, 127, 214, 103, 106, 117, 120, 123, 124, 128, 132, 133,
215, 227, 232, 249, 251, 258 348, 353
allosteric regulation, 36
amidotransferase, 36
O de novo, 37, 39
Obesity, 9, 10, 12, 33, 100, 147–150, 152–154, 291, 293, hypoxanthine-guanine phosphoribosyltransferase, 36
294, 313, 324, 332, 339, 348–354 overactivity
Oded Sperling, 5 de novo, 106
Olecranon bursa, 92, 94, 95, 200, 203 neurological deficits, 106
Oligoarticular, 92 phosphoribosylpyrophosphate
Organ transplantation, 95, 137, 145, 202, 328, 329 amidotransferase, 106
Orotic acid, 33, 38, 54, 330 pretranslational regulation, 39
Osteonecrosis, 202 Platelet-activating factor (PAF), 210, 218–230, 232, 235,
Oxidants and oxidant-mediated destructive 238, 241, 244, 255, 259, 263, 264, 270, 271
responses acetylhydrolase, 228–229, 270–271
fenton reaction, 250 biological functions, 227–228
haber-weiss reaction, 250 de novo, 223, 230
Oxidants and uric acid destruction, 252 receptor, 222, 223, 227, 241
Oxipurinol calculi, 133 Podagra, 1, 92, 99, 212, 353
Oxygen free radicals, 11, 255, 259 Polyarticular, 92, 95–98, 320, 321
Oxygen radical generation, 227, 247–249 Polyarticular gout, 92, 98, 320, 321
396 Index

Polymerase chain reactions, 194 Renal tubular transport, 13–17

Prepatellar bursae, 94, 200 Resolvin biosynthesis, resolution, 266
Prevalence, 9–17, 100, 122, 123, 148, 309, 349, 351, 352 Resolvin receptors, 266–270
Primary underexcretor gout, 114 Rheumatoid nodules, 95
Probenecid Rhomboid, 192, 193
acute gouty arthritis, 327 Ribo nucleic acid (RNA), 404, 442, 449, 450, 579, 583,
benemid treatment regimens, 327 585, 587
methotrexate toxicity, 327 Ribonucleotides, 31, 33, 35, 40
uric acid nephrolithiasis, 327 Ribose phosphate, 26, 33
Proinflammatory mediators Ribose-5-phosphate, 32, 33, 36–39, 73, 75, 111, 140
bradykinin, 254 Ribose phosphate pyrophosphokinase, 31, 33, 34, 37,
non-chemotactic, proinflammatory cell 39–42, 46, 55, 72, 105, 123, 124, 140, 141,
mediators, 253 145, 291, 292, 324. See also Phosphoribosyl
tumor necrosis factor, 254–255 pyrophosphate synthetase (PRPP synthetase)
vasoactive arachidonic acid metabolites, 253 RLRs. See Inflammasome
Prophylactic colchicine, 93, 331 Roentgenographic findings, 199–204
Proteinases, 219–220, radiological examinations, 199
237, 252
P-selectin glycoprotein ligand-1, 220, 239, 242, 243
Purine(s), 4, 11, 25–55, 69, 91, 187, 201, 260, 291 S
kinase, 34 Salicylates, 102, 115, 126, 133, 135, 136, 138, 294,
nucleotides, 25, 28, 30–34, 37–43, 52, 54, 70, 71, 325–328, 348
73–76, 78–82, 100, 106–108, 127, 136, 141, Salvage pathways, 13, 30, 33–38, 40, 43, 54, 352
336, 337 Samuel Johnson, 6
Purine biosynthesis Secondary gout renal mechanisms
decreased renal function, 70 acetoacetate, 87
de novo, 69, 70 b-adrenergic blockers, 87
glycine, 70 b-hydroxybutyrate, 87
hereditary renal hypouricemia, 70 branched chain keto acids, 87
overproducers of uric acid, 70 catecholamines, 87
secondary gout, 70 chronic renal disease, 86
urate excretion, 70 cyclosporin A, 87
urate overexcretors, 70 decreased glomerular filtration rate, 86
uric acid excretion, 69 dehydration, 87
uric acid overexcretion, 70 diabetes insipidus, 87
urinary uric acid excretion, 70 diuretic-induced hyperuricemia, 87
Pyruvate carboxylase deficiency, 107 furosemide, 87
Pyruvate dehydrogenase deficiency, 107 hyperuricemia of renal failure, 87
lactate, 87
lacticacidemia, 87
Q lead, 87
Queen Anne (queen of England, Scotland), 6 lead intoxication, 86
levodopa, 87
nicotinic acid, 87
R nonsteroidal anti-inflammatory drugs, 87
Reactive oxygen species (ROS), 9, 214, 217, 229, 241, pyrazinamide, 87
242, 248, 250, 274, 320, 329, 350, 351 salicylate, 87
Refractory gout saturnine gout, 87
allantoin, 343 secondary hyperuricemia, 86
allergic reactions, 343 tubular reabsorption of urate, 86
Aspergillus flavus, 343 tubular secretion of urate, 86
hydroxyisourate, 343 Secondary hyperuricemia, 81, 86, 87, 103, 105, 107–108
pegloticase, 343 Selectins (structures), 210, 211, 237–241,
rasburicase, 343 243–245, 247, 258
tumor lysis syndrome, 343 Septic joints, 92, 97, 98, 191
uricase, 343 Single nucleotide polymorphisms (SNPs), 14–17
Renal function determination Sir Alfred B. Garrod, 4
cockcroft formula, 334 Sir Thomas Sydenham, 2
gault formula, 334 SLC2A9, 13–17
Index 397

SLC5A8, 16, 17 Tophi, 1, 3, 70–72, 78, 91, 94–96, 99, 100, 105, 112,
SLC 5A12, 16, 17 137, 147, 199–204, 211, 213, 218, 294, 340,
SLC17A1, 16 342, 353, 354
SNPs. See Single nucleotide polymorphisms (SNPs) Transplant gout, 95, 96
Soft tissue swelling, 98, 199–200 Tsai F.Yu, 5
magnetic resonance image, 200 Type A synovial membrane lining cells (macrophage-like
STS. See Allopurinol synoviocytes), 209, 218
Sugar-sweetened soft drink, 11, 12, 15, 349, 352 Type B synovial membrane cell (fibroblast-like
Superoxide, 11, 221, 227, 230, 232, 248, 250–252, 257, synoviocyte), 209
258, 265, 272
Symptomatic drug-induced hyperuricemia
drug-induced, 294 U
symptomatic hyperuricemia, 294 URAT1, 14–17
Synovial fibroblast-like cells, 237, 255, 256 Urate-lowering therapy, uricosuric drugs, 324
Synovial fluid Urate nephropathy
analysis, 93, 97, 188, 189, 193 microbial uricase, 115
culture, 97, 99, 188–190 microtophi, 115
differential cell, 191 urate nephropathy, 115, 116
gram stain, 190, 191 Urate reabsorption, 14–16, 85, 86, 114, 115,
white blood cell counts, 97, 189–191, 194 125–127, 135
Synovial membrane, 207–211, 218, 219, 223, 231, 239, Urate transport, 13–16, 121, 126, 133
241, 255, 259, 264 Urate turnover, 72
chemoattractants, 207, 209, 210, 218–223, 227–229, Uric acid
235–237, 240, 241, 244–246, 253, 263 calculus
cytokines, 210, 211, 214–218, 220, 236, 238, 241, ultrasonography, 201
242, 244, 253, 255, 256, 259–262, 264, 269, uric acid nephrolithiasis, 201
271, 273, 275, 277, 315 excretion, decrease, 114–121
integrins, 210, 211, 241 metabolism
inter cellular adhesion molecules (ICAMs), 209, 210, de novo, 69
237, 240, 242, 244, 245, 256, 261 gout, 69
selectins, 210, 211, 239, 241, 243 hyperuricemia, 69
type A synovial membrane lining cells, 209, 218 mechanisms, 69
type B synovial membrane cell, 209 nucleic acids, 69
in vitro, 210, 212, 213, 237, 249, 255, 264 uric acid, 69
nephrolithiasis, 122–135
cystine stones, 125
T cystinuria, 125
TEN. See Allopurinol de novo, 127
Therapeutic regimens hemoglobinopathies, 125
ACTH dosage, 322 hereditary renal hypouricemia, 125
adrenocorticotrophic hormone (ACTH), 321 hypercalciuria, 126
estrogens, 321 hypouricemia, 125
hyperthyroidism, 321 Kelley-Seegmiller syndrome, 124
intra-articular injection steroids, 320 Lesch-Nyhan syndrome, 124
intravenous methylprednisolone, 321 malignancies, 127
mini-pulse methylprednisolone, 321 Prader-Willi syndrome, 129
polyarticular gout, 320 xanthinuria, 127
toxicities, 321 overproduction
6-thioguanine, 35, 37 de novo, 103
Thomas Gray, 6 hyperuricemia and gout, secondary
Tissue hypoxia, 77, 80, 81, 103, 105, 107, 154 forms, 103
Tophaceous deposts management Kelley-Seegmiller syndrome, 103
Lesch-Nyhan disease, 341 Lesch-Nyhan syndrome, 103
lithotripsy, 341 phosphoribosylpyrophosphate
oxypurinol stones, 341 (PRPP), 103
surgery, 340 phosphoribosylpyrophosphate synthetase
xanthine stones, 341 superactivity, 103
Tophaceous gout, 2, 5, 92–96, 98, 99, 106, 109, 137, 142, secondary hyperuricemia
152, 200, 292, 324, 328, 330, 332, 342, 353, 355 and gout, 103
398 Index

Urinary uric acid measurements William Heberden, 3

24-h urinary uric acid, 102 William Kelley, 5
24-h urine collection, 102 William Nyhan, 5
overproducer, 102 William Pitt the Elder and the Younger, 6
radiocontrast materials, 102
underexcretor, 102
uricase method, 102 X
Xanthine
dehydrogenase, 11, 124, 127, 130, 131
V lithiasis, 123, 129–130
Vascular disease, 10, 150, 151, 153, 312, 351 oxidase, 5, 11, 25, 27, 28, 48, 49, 52, 53, 73, 79,
Visceral tissues, 95 80, 130, 131, 133, 137, 140, 154, 217, 291,
294, 295, 324, 325, 329–337, 340, 343,
349, 350, 354
W Xanthinuria, 123, 127, 129–133
Wayne Rundles, 5 Xanthosine monophosphate (XMP), 31, 34, 45
William Congreve, 6 XMP. See Xanthosine monophosphate (XMP)