193 Etiology and pathogenesis of gout
Tanya J. Major • Nicola Dalbeth
Key Points
■ Gout is a chronic disease of monosodium urate crystal deposition, which typically
presents as recurrent episodes of severe, painful inflammatory arthritis. Monosodium
urate crystals form from extracellular fluids saturated with urate, the endproduct of
human purine metabolism.
■ The gout flare is a severe but self-limited arthritis caused by an inflammatory response
to monosodium urate crystals. Repeated gout flares and persistent crystal deposition
can lead to chronic gouty arthritis, tophi, and erosive gout.
■ Hyperuricemia (elevated serum urate concentration) is the central biochemical
precursor for gout. It is generally classified as a serum urate concentration exceeding
about 6.8 mg/dL (≈400 μM).
■ Hyperuricemia results from an imbalance between urate production and excretion.
In most patients with gout, hyperuricemia results from impairment of renal and gut
excretion.
■ Phagocytes from the synovial fluid of people with asymptomatic hyperuricemia and
gout often contain monosodium urate crystals, without any overt inflammation,
indicating crystals in the synovial compartment do not always elicit an inflammatory
response.
■ The gout flare is initiated by resident synovial cells, including phagocytes, which
secrete chemokines and cytokines to attract and activate the neutrophils that
predominate in the synovial cavity of acutely inflamed joints.
■ Activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)
inflammasome by monosodium urate crystals, leading to release of mature interleukin-
1β, is central to initiation of the gout flare.
■ Termination of the gout flare is regulated by macrophage differentiation, release
of antiinflammatory soluble mediators, and formation of aggregated neutrophil
extracellular traps (NETs) that degrade proinflammatory cytokines. Aggregated NETs
may also play a role in tophus formation.
■ Joint damage in advanced gout is strongly linked to intraarticular tophi, with
activation of catabolic pathways leading to focal cartilage and bone degradation.
■ Defects in purine metabolic enzymes (e.g., hypoxanthine-guanine
phosphoribosyltransferase and 5-phosphoribosyl 1-pyrophosphate synthetase 1) that
result in urate overproduction are well-characterized causes of gout but account for
fewer than 1% of cases.
■ Large genetic studies have revealed many candidate genes associated with
hyperuricemia and gout. These include genes involved in urate transport, metabolic
pathways, regulation of inflammation, and regulation of gene expression. Genetic
variations in the urate transporters SLC2A9 and ABCG2 are consistently and strongly
associated with hyperuricemia and gout.
Gout is a chronic disease of monosodium urate (MSU) crystal deposition
presenting as a painful and potentially destructive arthritis arising in the set-
ting of hyperuricemia. Urate is the obligatory endproduct of human purine
metabolism. The clinical manifestations of gout arise as a consequence of
monosodium urate crystal deposition and include the gout flare, chronic
gouty arthritis, and tophi. This chapter focuses on the pathophysiology of
articular manifestations of gout, detailing the various “checkpoints” neces-
sary in developing clinically evident gout (Fig. 193.1).
URATE PHYSIOLOGY
The clinical features of gout occur as the result of inflammatory responses to
monosodium urate crystals deposited because of one or more derangements
in the physiology of urate. In contrast to the case in most mammals, urate
is the final product of purine metabolism in humans and higher primate
species, in which the gene encoding the enzyme uricase (urate oxidase) has
been silenced by loss-of-function genetic variants.1
Urate is the most abundant natural antioxidant in the human body
(Box 193.1). The traditional view has been that a major physiologic role of
urate is to remove reactive oxygen species (ROS), possibly providing pro-
tection against oxidant-induced neurologic and cardiovascular degenerative
1700
F 2 A 2 2, A 2 2 2 A D
, 3AD2A , A A 2 D 0 C AD
processes. However, pegloticase, which leads to dramatic reductions in serum
urate concentrations, did not show increased lipid or protein oxidation, sug-
gesting that urate is not a major factor controlling oxidative stress in vivo.2
Urate may also have an important role in immune surveillance. Distressed
and dying cells produce locally high urate concentrations as a “danger” sig-
nal, which acts as an endogenous adjuvant to help trigger inflammatory and
both innate and specific immune responses (discussed in more detail later).3
Urate may also have had an evolutionary role in maintenance of blood pres-
sure and intravascular volume.4
FORMS OF URATE
Urate exists in biologic systems in two forms with limited solubility, the ion-
ized form (uric acid) and the unionized form (urate; Fig. 193.2). Uric acid
(C5H4N4O3; 2, 6, 8-trioxypurine) is a weak organic acid ionized at position 9
with a functional pKa1 in serum of 5.75. At the physiologic pH of most body
fluids (pH of 7.4), urate ion levels exceed those of unionized uric acid in a
ratio of about 50 to 1. In acidic body fluids (such as urine, pH of 5.0), union-
ized uric acid predominates. Because of the high concentration of sodium in
extracellular fluid, urate mainly functions as monosodium urate (MSU). As
a consequence, the high solubility of the urate ion (≈120 mg/dL or 7.1 mM)
is replaced by the much lower solubility of monosodium urate (≈6.8 mg/dL
or 400 μM). Similarly, the solubility of uric acid is only about 10 to 15 mg/
dL (≈600–900 μM).
Serum urate concentrations exceeding 6.8 mg/dL are saturating, a con-
dition referred to as hyperuricemia. Persistent hyperuricemia reflects
extracellular fluid urate saturation. At these saturated levels, monosodium
urate monohydrate crystals are able to form and deposit in the joints and
other tissues. In the acidic environment of the urine, uric acid crystals and
stones (distinct from monosodium urate crystals) form in the urinary tract.
Increasing levels of hyperuricemia impart increasing risk for monosodium
urate crystal deposition and the associated clinical consequences.5
Hyperuricemia is very common, affecting more than 20% of adult White
men in the United States,6 and is even more common among certain ethnic-
ities. Although hyperuricemia most often does not evolve into clinical gout,
it is associated with several highly prevalent chronic disorders, as discussed
in Chapter 192.
URATE PRODUCTION AND EXCRETION
URATE BALANCE
Urate levels are maintained through a delicate balance between production
and excretion. This balance can be altered by many factors, including genet-
ics, environment, other clinical conditions, and medications (see Fig. 193.3
and Box 193.2). These factors alter both production and excretion, with
some having much larger influence than others.
The bulk of urate usually derives from endogenous synthesis of purines
from small-molecule nonpurine precursors, breakdown of dietary purines,
and reutilization of preformed body purine compounds, as diet contains little
urate, and dietary urate is poorly absorbed.7 Urate production occurs largely
in the liver and to a minimal degree the small intestine. Urate released from
cells circulates relatively free (<4%) of serum protein binding7 so that all or
nearly all circulating urate is filtered at the glomerulus. Under steady-state
conditions, urate production is balanced by excretion, largely through renal
excretion of uric acid (equivalent to about two thirds of daily production).
Urate secretion into the small intestine, with breakdown of urate by gut bac-
teria (intestinal uricolysis), accounts for nearly all the rest of urate excretion.
The body pool of urate is expanded in hyperuricemic states resulting from
impaired urate excretion or urate overproduction.
Urate pools in normal men range from about 800 to 1500 mg and in
women from 500 to 1000 mg. Daily turnover of the body’s urate pool (bal-
anced production and excretion) is considerable, averaging 0.6 to 0.7 pools
(≈0.5 to 1 g) every day.
D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A
F C DC A ) A C E A ( A C A AE
 CHAPTER 193 Etiology and pathogenesis of gout 1701

GOUT CHECKPOINTS, DISEASE STAGES, AND INFLUENCING FACTORS

“Check points” Disease Stages Influencing Factors

Normouricemia
Genetics, environment,
Increased serum urate medications, clinical features
(overproduction and/or (see Box 193.2)
underexcretion)

Hyperuricemia

Seed nucleus, temperature,

Crystal formation
pH (see Box 193.3)

Monoscdium urate
crystal deposition

Acute inflammatory
Genetics, crystal coating/size,
response initiated by NLRP3
trigger events (see Box 193.3)
inflammasome activation

Recurrent gout flares

Chronic inflammatory Genetics, kidney function,

response/tophus formation sustained hyperuricemia

Chronic gouty arthritis,

tophaceous gout, gouty
bone erosion

FIG. 193.1 There are a number of “checkpoints” involved in the development and progression of gout: (1) development of hyperuricemia; (2) formation and deposition of
monosodium urate crystals; and (3) clinical manifestations of gout (gout flares, chronic gouty arthritis, and tophaceous gout).

BOX 193.1 PHYSIOLOGIC FUNCTIONS OF PURINES

FACTORS AFFECTING URATE BALANCE
Antioxidation (urate)
Nucleotide building blocks for nucleic acids (DNA and RNA)
Nucleotide components of coenzymes (e.g., coenzyme A, FAD, NAD) Renal tubular reabsorption (e.g., URAT1, GLUT9)
High-energy phosphate donors in enzyme reactions (e.g., ATP) Dietary purines, alcohol
Metabolic regulators (e.g., cyclic AMP, cyclic GMP) Metabolic disorders, insulin resistance
Neurotransmitters Purine salvage pathways
Extracellular messengers (e.g., adenosine, ATP) ATP turnover (e.g., ethanol, fructose, illness)
Intestinal excretion
Intracellular second messengers (e.g., G protein–coupled receptors) (mediated by ABCG2)
Raise
Immunologic adjuvants, endogenous “danger” signal for innate immunity Glomerular filtration
urate pool
Maintenance of extracellular volume, vascular tone (urate) (hypothesized) Urate-lowering drugs, diet
Weight reduction
AMP, Adenosine monophosphate; ATP, adenosine triphosphate; FAD, flavin adenine dinucleotide; GMP, Renal tubular secretion
guanosine monophosphate; NAD, nicotinamide adenine dinucleotide. (e.g., ABCG2, NPT1, MRP4)

Lower
urate pool
URIC ACID AND THE URATE ANION

O O
H H
C6 N C6 N
HN1 5 C
7
pKa1 = 5.75 HN1 5 C
7
FIG. 193.3 The systemic urate pool and the likelihood of gout are determined by
+
2 8 C O 2 8 C O+H the dynamic balance between endogenous synthesis and recycling of purines and
O C 3
4
C 9 O C 3
4
C 9
N N N N– excretion by the kidney and gut. ABCG2, ATP-binding cassette subfamily G member
H H H 2; ATP, adenosine triphosphate; GLUT9, glucose transporter 9; MRP4, multidrug
resistance protein 4; NPT1, sodium phosphate transport protein 1; URAT1, urate
Uric acid Urate anion
transporter 1.

FIG. 193.2 At physiologic pH (7.4), urate predominates at about 50 : 1 over union-

ized uric acid. Urate ion solubility is functionally reduced at the high sodium concen-
tration of extracellular fluids, so monosodium urate and uric acid have relatively low
solubilities in biologic fluids.
Serum urate concentrations in children are lower than those in adults.
During male puberty, values increase into the adult male range. Serum urate
levels remain lower in women of reproductive age than in their male coun-
terparts.8 This gender difference results mostly from the action of estrogens,9
which alter the activity of key urate transporter proteins in the kidney. This
results in less renal tubular uric acid reabsorption and thus increased uric
acid clearance in women. With the onset of menopause, serum urate values
in women increase and approach or equal those of men.
Urate saturation of extracellular fluids (for which hyperuricemia is a
surrogate marker) predisposes to monosodium urate crystal formation and
deposition, events required for clinical expression of gout. The natural dif-
ferences in serum urate levels between men and women explain the greater
prevalence of gout in men. Additionally, the increase in serum urate levels
in postmenopausal women is accompanied by increases in the incidence of
hyperuricemia and, over the succeeding 2 to 3 decades, gout.

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE
1702 SECTION 17 Crystal-Related Arthropathies

BOX 193.2 FACTORS ASSOCIATED WITH URATE VARIATION

Genetic Factors Environmental Influences Clinical Associations
Male sex Associated with increased urate Older age
Common variants associated with hyperuricemia ■ Fasting/starvation Postmenopause in women
(replicated) ■ High purine foods (e.g., red meat, liver, offal, Medical comorbidities
■ SLC2A9 shellfish) ■ Hemolytic disorders
■ ABCG2 ■ Dehydration ■ Hemopoietic malignancies; tumor lysis
■ PDZK1 ■ Lead exposure ■ Lactic or ketoacidosis; hypoxemic states
■ GCKR ■ Fructose- and sugar-sweetened drinks ■ Lead nephropathy, chronic low-level exposure
■ RREB1 ■ Alcohol (beer and spirits) ■ Preeclampsia
■ SLC17A3 Associated with lower urate ■ Renal impairment
■ SLC16A9 ■ Low-fat dairy products ■ Psoriasis
■ SLC22A11 ■ DASH diet ■ Vasopressin-resistant diabetes insipidus
■ SLC22A12 ■ Mediterranean diet ■ Bartter and Gitelman syndromes
■ INHBC ■ Cherries ■ Down syndrome
Rare monogenic causes ■ Vitamin C ■ Hypertriglyceridemia
■ HPRT deficiencies: complete (Lesch-Nyhan ■ Coffee ■ Hypertension
syndrome), partial (Kelley-Seegmiller syndrome) ■ Obesity
■ PRPP synthetase overactivity ■ Cardiovascular disease
■ Glucose-6-phosphatase deficiency Medications associated with hyperuricemia
■ Fructose-1-P aldolase deficiency ■ Aspirin (low dose)
■ Myogenic glycogenoses (types III, V, VII) ■ Chemotherapeutic cytotoxics
■ Uromodulin-associated kidney disease: FJHN, ■ Diuretics
MCKD types 1 and 2 ■ Pyrazinamide
■ Ethanol
■ Levodopa
■ Nicotinic acid
■ Cyclosporine and tacrolimus
Medications associated with reduced serum urate
■ Losartan
■ Fenofibrate
■ Leflunomide
■ Calcium channel blockers
■ Atorvastatin
■ Sevelamer

FJHN, Familial juvenile hyperuricemic nephropathy; HPRT, hypoxanthine-guanine phosphoribosyltransferase; MCKD, medullary cystic kidney disease; PRPP, 5-phosphoribosyl 1-pyrophosphate.

PURINE METABOLISM AND URATE PRODUCTION
Urate is the endproduct of purine metabolism in humans and other great
apes, as well as birds and reptiles. Purines are compounds possessing the
nine-member purine nucleus composed of fused pyrimidine and imidazole
rings. Purines fulfill essential functions in all living cells (see Box 193.1).
Most functions of purines are carried out by nucleotide and nucleo-
side derivatives of the purine bases adenine, hypoxanthine, and guanine.
Representative structures of purine bases, nucleosides, and nucleotides are
shown in Fig. 193.4.
The biochemical pathways of purine metabolism and their regulation are
discussed in more detail elsewhere.10 The only endogenous pathway of net
purine production is called purine synthesis de novo and involves 10 steps
(Fig. 193.5). The purine ring is synthesized on a backbone of ribose-5-phos-
phate donated by the key regulatory substrate, 5-phosphoribosyl 1-pyrophos-
phate (PRPP) from the pentose phosphate sugar pathway. The endproduct
of this pathway is the nucleotide inosine monophosphate (IMP). IMP serves
as a branch point in the conversion of new purines into the adenylate and
guanylate classes of purine nucleotides or, alternatively, into the purine deg-
radation pathway, culminating in urate formation.
Purine synthesis de novo is an energy costly process. Considerable sav-
ing in cellular energy expenditure is achieved by an extensive network of
reactions that interconvert and salvage purine nucleotides, nucleosides, and
bases. This saves energy and provides flexibility in the provision of specific
purines to a wide array of cellular functions.
Degradation of purine nucleotides and nucleosides to purine bases cul-
minates in the key urate precursors, hypoxanthine and guanine. These
are mostly reused in salvage reactions with PRPP, catalyzed by the enzyme
hypoxanthine-guanine phosphoribosyltransferase (HPRT). The remainder
of guanine is deaminated to xanthine. Unsalvaged hypoxanthine is oxidized
to xanthine, which undergoes further oxidation to urate. The enzyme xan-
thine oxidoreductase (XOR) catalyzes both the conversions of hypoxanthine
to xanthine and xanthine to urate.
Xanthine oxidoreductase is a molybdopterin cofactor and iron sulfide
cluster-containing flavoprotein that exists in interconvertible forms: an
oxidase form (xanthine oxidase [XO]) that uses oxygen (O2) to convert
hypoxanthine and xanthine to urate and a dehydrogenase form (XDH) that
uses the nucleotide NAD+. Inhibition of XOR activity is the major action of
the most common class of agents used for urate lowering in patients with
gout.11 Other roles for xanthine oxidoreductase have been proposed, includ-
ing protection from infection and tissue injury (caused by the generation of
unstable oxygen radicals) during and after ischemia.
Purine nucleotide synthesis and degradation are both carefully regulated
processes (Fig. 193.6).10 Malfunctions in this regulatory process lead to
increased cellular levels of PRPP, resulting in accelerated purine nucleotide
and urate production. This occurs in two rare X chromosome–linked disor-
ders (discussed later).10 Similarly, excessive cellular adenosine triphosphate
(ATP) depletion (e.g., in tissue hypoxia or acute alcohol intoxication) can
lead to reduced inhibitory nucleotide concentrations and consequent urate
overproduction. Other states of excessive urate production among patients
with gout are not as well characterized at the pathway level.
URATE EXCRETION
Urate excretion is mediated by multiple transporter proteins in the renal
proximal tubule and the intestinal mucosa. The majority of urate is disposed
of through the renal pathway (~60%), with the remaining ~30% being dis-
posed of via the intestinal pathway. The sum of urate excretion via these
two pathways almost makes up the total urate clearance, and each pathway
can compensate, to a small extent, for underexcretion by the other pathway.
Extrarenal urate excretion
Urate excretion in the intestines is primarily mediated by ABCG2, an ATP-
binding cassette (ABC) transporter, encoded by the gene ABCG2. ABCG2
functions in both the kidney and intestine, and dysfunction is associated
with hyperuricemia and gout.12 Analysis of the role of ABCG2 in intestinal
handling of urate has challenged the conventional concept of hyperurice-
mia caused by urate overproduction.13 Abcg2 knockout mice have reduced
intestinal urate excretion, leading to higher serum urate levels. Despite also
lacking Abcg2 in the kidneys, renal uric acid excretion in this situation is

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE
 CHAPTER 193 Etiology and pathogenesis of gout 1703

PURINE STRUCTURES

Purine base (e.g., adenine) Urate anion Pyrimidine base (e.g., thymine)

NH2 OH H

C6 N7 C N C4
N1 C5 N C H N3 C5 CH3
–
C8 H C O
H C2 C4 HO C C O C2 C6 H
–
N3 N9 N N N1

H H

Nucleoside (e.g., adenosine) Nucleotide (e.g., dATP)

NH2 NH2

2–
HOCH2 PO4 PO3– PO3– OCH2
5’ 4’ 1’
3’ 2’
HO OH HO H

FIG. 193.4 Purine ring atoms are numbered 1 to 9 as shown in the upper left panel. Pentose sugar carbon atoms are numbered 1′ to 5′, as shown in the lower left panel. In
purine nucleosides, a purine base is joined to a pentose ring through an N-glycoside bond between the purine 9 and pentose 1′ atoms. Nucleotides are phosphate esters of
the nucleoside, containing one, two, or three phosphate groups (nucleoside mono-, di-, or triphosphates, respectively) attached at the 5′ carbon of the sugar. Nucleotidases
remove phosphate groups. Phosphorylases remove both the phosphate group(s) and the sugar. Kinases transfer a high-energy phosphate group (usually donated by ade-
nosine triphosphate). The nucleoside of hypoxanthine is known as inosine, and the respective nucleotide is inosine monophosphate. dATP, Deoxyadenosine triphosphate.

PURINE SYNTHESIS, INTERCONVERSION, AND DEGRADATION IN HUMANS

Ribose-5-P, Mg-ATP

PRS
DNA, RNA DNA, RNA
PRPP

ATP GTP
10 steps

AMP AMPD IMP GMP

ND ND ND

APRT Adenosine ADA Inosine HPRT Guanosine HPRT

PNP PNP

Adenine Hypoxanthine Guanine

XO

Xanthine

XO

Urate

FIG. 193.5 The gene for uricase (urate oxidase) has been inactivated in humans and other primate species, so that urate is the end-product of purine metabolism. Intermediates
and enzymes not pertinent to hyperuricemia and gout have been omitted from this figure for simplicity. ADA, Adenosine deaminase; AMPD, AMP deaminase; APRT, adenine
phosphoribosyltransferase; GMP, guanosine monophosphate; ND, 5′-nucleotidase; PNP, purine nucleoside phosphorylase; XMP, xanthosine monophosphate; XO, xanthine
oxidase (oxidoreductase). For other abbreviations, see text.

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE
1704 SECTION 17 Crystal-Related Arthropathies
still higher than normal, indicating that other transporters in the kidney can
REGULATION OF PURINE NUCLEOTIDE SYNTHESIS partially compensate.
Reduced extrarenal urate excretion leads to an increase in the renal excre-
ATP + Rib-5-P tion load, which gives the appearance of urate overproduction. Thus it has
been suggested that urate overproduction may be better described as “renal
– PRPP overload,” consisting in turn of “extrarenal underexcretion” and “genuine
synthetase urate overproduction” subtypes.13
PRPP
Renal urate excretion
+ Despite nearly complete filtration of urate at the glomerulus, renal uric acid
– clearance in adults averages only 5% to 10% that of creatinine clearance,
Amido-PRT reflecting net renal tubular reabsorption of about 90% of filtered uric acid.
Adenine Hypoxanthine Within the renal tubule, uric acid reabsorption and secretion are regulated
APRT HPRT Guanine by a series of transporter proteins that ultimately regulate serum urate
concentrations.
Most people with hyperuricemia resulting from impaired renal uric acid
excretion show normal amounts of uric acid in the urine but have selectively
reduced uric acid clearance.14,15 Excretion of “normal” amounts of uric acid
Purine is accomplished by patients with gout only when serum urate levels are 2 to
nucleotides 3 mg/dL (120 to 180 μM) higher than in healthy people excreting the same
amounts of uric acid. The hyperuricemia that results from this is the prime
risk factor for developing gout.
FIG. 193.6 The major purine synthetic steps targeted by regulation are (1) the syn- Many mechanisms contribute to net uric acid excretion. Molecular and
thesis of PRPP in the PRPP synthetase (PRS) reaction and (2) the utilization of genomic approaches have identified several transporters involved in renal
PRPP in the first step of purine synthesis de novo. Rates of the 10-step de novo uric acid excretion, including some with substantial specificity for uric
pathway of purine nucleotide synthesis (vertical arrows) are regulated by the activ- acid.16 Alterations in uric acid movement may be caused by changes in these
ity of the enzyme AmidoPRT, which catalyzes the first step. AmidoPRT activity is urate transporters, changes in associated proteins or ion cotransporters, or
allosterically controlled by the antagonistic interaction of pathway purine nucleotide regulation of transport function. Two of these urate transporters, glucose
products that inhibit (−) the enzyme and the regulatory substrate 5-phosphoribosyl transporter 9 (GLUT9) and urate transporter 1 (URAT1), have strong effects
1-pyrophosphate (PRPP) that activates (+) AmidoPRT. Purine nucleotides also on serum urate levels (Fig. 193.7).
inhibit (−) PRPP synthetase, the enzyme-catalyzing synthesis of PRPP. Regulation
directed at these sequential reactions provides a flexible means to control purine Urate transporters
nucleotide production in an economical manner, a process potentiated by preferen- Glucose transporter 9
tial single-step salvage of preformed purine bases in reactions with PRPP catalyzed Glucose transporter 9 (GLUT9) is the product of the SLC2A9 gene. It is a
by the phosphoribosyltransferase enzymes hypoxanthine-guanine phosphoribosyl- voltage-driven urate transporter that mediates uric acid reabsorption from
transferase (HPRT) and APRT (depicted by the curved arrows). APT, Adenosine the tubular cell to the circulation. Glucose transporter 9 also transports the
triphosphate; Rib-5-P, ribose-5-phosphate. sugars glucose and fructose. In humans, GLUT9 exists in two isoforms:

RENAL HANDLING OF URATE

Proximal tubule lumen

Apical brush border

NPT1 MRP4 ABCG2 URAT1 GLUT9 Others Proximal

tubular
cell

Basolateral membrane

OATs and others GLUT9

Peritubular capillary

FIG. 193.7 The key players in reabsorption and secretion of uric acid across the proximal tubule epithelial cell. Exchange of uric acid for other anions is mediated by specialized
channels and transport proteins embedded in the tubular cell membrane. Whereas urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are significant contributors
to uric acid absorption (such that defective function is associated with hypouricemia), ATP-binding cassette subfamily G member 2 (ABCG2), sodium-dependent phosphate
transporter protein 1 (NPT1), and multidrug resistance protein 4 (MRP4) are associated with net uric acid excretion. Uric acid transport is driven in part by a pH gradient pro-
duced by active sodium–hydrogen ion exchange. Several other organic anion transporters (OATs) have been implicated in uric acid transport. Transporters may be linked with
each other and with regulatory and signaling elements by PDZK1 scaffolding proteins, comprising the urate transportasome. Many of the drugs and endogenous mediators that
affect renal uric acid disposition interact with these proteins (e.g., the uricosuric drugs probenecid, benzbromarone, and lesinurad inhibit uric acid reabsorption by URAT1).

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE

GLUT9L, identified on the basolateral aspects (“blood” side) of the prox-
imal renal tubular epithelial cell, and GLUT9S on the apical (“urine”)
side.17–19
Glucose transporter 9 is also expressed in the basolateral membrane of
hepatocytes and regulates serum urate concentrations through dual roles in
uric acid handling in the kidney and uptake in the liver.20 Mice with systemic
knockout of Slc2a9 (Glut9) have moderate hyperuricemia, massive hyper-
uricosuria, and an early-onset nephropathy. In contrast, specific inactivation
of the Slc2a9 gene in the livers of adult mice leads to severe hyperuricemia
and hyperuricosuria, without renal disease.20
Urate transporter 1
Urate transporter 1 (URAT1) is encoded by the SLC22A12 gene and has a
typical organic anion transporter structure.21 URAT1 is highly specific for
uric acid. URAT1 mediates the exchange of uric acid for a variety of endog-
enous and drug anions known to affect renal uric acid transport. Similar to
GLUT9S, URAT1 localizes to the apical brush border membrane of proximal
tubular epithelial cells and is involved in the reabsorption of uric acid from
the lumen. The uricosuric drugs probenecid, benzbromarone, and lesinurad
increase uric acid excretion by inhibiting URAT1 and other OATs.21,22
URAT1 interacts with the scaffolding protein PDZK1. PDZ motifs are
typically involved in protein–protein interactions that support intracellular
signaling and are also present in other urate transporters, including OAT4
and sodium phosphate transport protein 1 (NPT1, discussed below). This
suggests that a more extensive multiprotein complex, the “urate transpor-
tasome” (containing transporters, transport regulatory molecules, hormone
receptors, and intracellular signaling elements), may be involved in regu-
lating bidirectional uric acid transport across the renal tubular epithelial
cell. The fractional renal excretion of Uric acid (FEua = uric acid clearance/
creatinine clearance × 100%) in Slc22a12 (Urat1) knockout mice23 remains
substantially less than 100%. This confirms that there are multiple mecha-
nisms of uric acid reabsorption.
Other urate transporters
Many other urate transporters are known. The sodium-dependent phosphate
cotransporters type 1 and type 4 (NPT1 and NPT4; encoded by SLC17A1 and
SLC17A3, respectively) are located at the apical membrane of the proximal
tubule and mediate net tubular uric acid secretion.24 Multidrug resistance
protein 4 (MRP4; encoded by ABCC4) is another renal apical organic anion
efflux transporter that may contribute to tubular secretion of uric acid.25 In
addition, ABCG2 is also expressed on the apical surface of the renal tubule
and might play a role in secretion of uric acid into the tubular lumen, as well
as its role within the gut.26
The relative importance of the many other OATs and exchangers in
human renal uric acid handling is also uncertain. For example, OAT4,
encoded by SLC22A11 and localized at the apical membrane of the proximal
tubules, is also associated with serum urate level,27 and OAT10 is a second-
ary target for some uricosuric drugs.
HYPERURICEMIA
CONDITIONING FACTORS
Several genetic and physiologic circumstances predispose all humans to
the development of hyperuricemia and gout, namely: the species-wide defi-
ciency of uricase, the enzyme catalyzing conversion of urate to the much
more soluble excretory product allantoin; net reabsorption of 90% of urate
filtered at the glomerulus; and the limited solubility of both urate and mono-
sodium urate in body fluids.
Despite these conditioning factors, most people do not display the sus-
tained hyperuricemia that reflects extracellular fluid saturation, and even
fewer develop monosodium urate crystal deposition or gout. Studies into
the influences of serum urate levels have identified a number of factors asso-
ciated with increased or decreased urate, including genes, environmental
or clinical factors, and medications (Fig. 193.3; see also Box 193.2). For
some of these associations, the causal relationship and underlying mecha-
nisms have been determined (e.g., lead poisoning–induced kidney failure),
whilst others have less certain mechanisms (e.g., reduction in urate levels
associated with low-fat dairy consumption). The many processes influenc-
ing development of hyperuricemia operate through impaired renal uric acid
excretion (most commonly), excessive urate production, reduced extrarenal
excretion, or a combination of these mechanisms.14
With increased urate production or decreased renal uric acid excretion,
intestinal uricolysis increases. On the other hand, when intestinal urate
excretion is impaired, the kidneys are confronted with a higher urate load.7
In individuals with hyperuricemia these two excretory mechanisms are
F 2 A 2 2, A 2 2 2 A D
, 3AD2A , A A 2 D 0 C AD
CHAPTER 193 Etiology and pathogenesis of gout 1705
unable to fully compensate for each other, resulting in lower total uric acid
excretion and higher serum urate levels overall.
CLASSIFICATION OF HYPERURICEMIA
Hyperuricemia and gout may arise in the presence or absence of an under-
lying clinical disorder or toxin or drug exposure. When a specific process
resulting in hyperuricemia is identifiable, it is said to be secondary. When
no such process is evident, hyperuricemia is termed primary or idiopathic.
Several diseases, toxic states, and medications lead to hyperuricemia as a
result of urate overproduction (see Box 193.2). Foremost among these are
diseases associated with cellular proliferation and destruction, such as acute
leukemias and lymphomas, tumor lysis syndromes, hemolytic states, and
psoriasis.
The causes of hyperuricemia have traditionally also been divided into
overproduction causes (mainly comprising metabolic factors) and underex-
cretion causes (mostly renal). Many patients with gout have a combination
of underexcretion and overproduction causes, with relative uric acid under-
excretion by the kidneys contributing the most to hyperuricemia.
MONOSODIUM URATE CRYSTAL FORMATION
The formation of monosodium urate crystals requires sustained high (super-
saturated) concentrations of urate. Crystal formation is influenced by many
other factors, including the presence of particulate seed nuclei such as carti-
lage debris, collagen, chondroitin, and hyaluronate released by joint trauma
or osteoarthritis (OA); local cation concentrations; pH, temperature, and
dehydration; and the balance between macromolecular inhibitors and pro-
moters of crystal formation (Box 193.3).28 Immunoglobulin G (IgG) and
immunoglobulin M (IgM) may also promote crystal formation in patients
with gout by providing a stable molecular platform for crystal nucleation
and growth.29,30 Monosodium urate crystals preferentially form at certain
sites, particularly the first metatarsophalangeal joint, midfoot, and Achilles
tendon.31
There is growing evidence to suggest a link between the presence of osteo-
arthritis and sites of monosodium urate crystal deposition.32 A cadaveric
study reported that monosodium urate crystals were nearly always located
within or adjacent to an osteoarthritic cartilage lesion.33 The osteoarthritic
BOX 193.3 GOUT PROMOTERS AND INHIBITORS
Crystal formation
Seed nucleus (particulate)
Immunoglobulin
Phagocytes
Low temperature
Low pH
Cation concentration
Intraarticular dehydration
Other (unknown) macromolecules
Triggering the gout flare (local factors)
Rapid change in urate level
Crystal release
IgG coat (apolipoproteins B, E inhibitory)
Complement activation (classical, alternate, MAC)
NLRP3 inflammasome activation
Cytokine and chemokine release
Endothelial activation (e-selectin, ICAM-1, VCAM-1)
Local trauma (?)
Presence of susceptible phagocytes, mast cells (systemic events)
Surgery, trauma
Infections, other intercurrent systemic illness
Alcohol, dietary intake
Drugs that raise or lower circulating urate level
A diverse array of proteins and other mediators have been identified on the surfaces of monosodium
urate crystals. In addition to their proinflammatory effect through opsonizing existing crystals,
immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies may promote crystal formation by
providing a stable molecular platform for crystal nucleation and growth. Apolipoproteins are the best
characterized of the antiinflammatory molecules that coat crystals. The characteristics of the phagocytes
encountering the crystals may be crucial; macrophages that are more differentiated are less likely to
elicit proinflammatory cytokines.
ICAM-1, Intercellular adhesion molecule 1; MAC, membrane attack complex; VCAM-1, vascular cell
adhesion molecule 1.
D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A
F C DC A ) A C E A ( A C A AE
1706 SECTION 17 Crystal-Related Arthropathies
joint has increased levels of cartilage degradation products present, such as
chondroitin sulphate, which lowers urate solubility and promotes nucle-
ation and growth of monosodium urate crystals.34–36 In addition, the pres-
ence of type 2 cartilage from osteoarthritic joints encourages the formation
of smaller monosodium urate crystals. These smaller crystals have a higher
inflammatory potential than larger crystals.37
One reason why most people with persistent hyperuricemia do not get
gout may lie in individual variation in the propensity for forming crystals.
However, microscopic and imaging studies have shown that many people
with asymptomatic hyperuricemia have evidence of monosodium urate crys-
tals within joints,38 suggesting that crystals may be present within the joint
for long periods of time without eliciting an overt inflammatory response
leading to the presentation of gout.
PROTEINS BINDING TO MONOSODIUM URATE CRYSTALS
Monosodium urate crystals are composed of a highly ordered, regular array
of urate and sodium ions and water molecules. Although the monosodium
urate crystal surface has a net negative charge, some positive charges are
also exposed. Monosodium urate crystal surfaces can bind a variety of lipids,
lipoproteins, and proteins. These proteins and lipids binding the surface of
monosodium urate crystals may change the inflammatory potential of crys-
tals. For example, monosodium urate crystal binding of immunoglobulin G
(IgG), which attaches through both charge interactions and hydrogen bond-
ing, results in a conformational change in IgG, encouraging inflammation
via phagocytosis by cells with Fcγ receptors (e.g., FcγRIII, CD16).
Apolipoprotein coating of monosodium urate crystals can counter the
effects of IgG by decreasing the attractiveness of monosodium urate crystals
to phagocytes.39 ApoB is a major component of the serum low-density lipo-
protein fraction and can coat crystals to inhibit stimulation of neutrophils.
ApoE has similar effects and can be made locally by synovial macrophages.
Other proteins detected on monosodium urate crystal surfaces include
further complement activation products, lysosomal enzymes, and the anti-
inflammatory cytokine transforming growth factor-β (TGF-β). The inflam-
matory potential of monosodium urate crystals reflects the balance between
pro- and antiinflammatory elements of this coating.
THE GOUT FLARE
A gout flare occurs when monosodium urate crystals interact with host cells
to initiate an acute inflammatory response.40 Despite potent proinflamma-
tory potential, monosodium urate crystals do not necessarily trigger acute
inflammation. Patients with gout and healthy hyperuricemic individuals
may have monosodium urate crystals in clinically uninvolved joints. Heavily
crystal-laden fluids (“urate milk”) are sometimes found in relatively unin-
flamed bursae and joints. The dense masses of monosodium urate crystals
in tophi (described in detail later) can reach massive dimensions often with
little apparent inflammatory response. In confined spaces, such as in axial
or visceral sites, tophi can enlarge progressively without eliciting symptoms
until there is critical compression of neighboring tissues.
Similarly, patients with intercritical and advanced gout may have pro-
longed periods with absent or relatively low-grade synovitis despite the
ongoing presence of monosodium urate crystals in the synovial environ-
ment. Furthermore, synovial fluid phagocytes from noninflamed joints of
patients with gout often contain monosodium urate crystals.41 This indicates
that crystals in the synovial compartment do not necessarily elicit overt
inflammation despite active engagement with phagocytes. Thus whether
monosodium urate crystals initiate clinically significant inflammation
depends on multiple factors, including crystal size, the proteins and other
molecules coating them, the local cytokine milieu, and which cells they first
encounter.
In the gout flare, the predominant inflammatory cell in the synovial
fluid and synovial membrane is the neutrophil, and activation/recruit-
ment of neutrophils seems to contribute the bulk of the proinflammatory
stimulus. However, healthy joints do not contain a significant resident
population of neutrophils. Monosodium urate crystals have their initial
interaction with cells normally resident in the tissue.42,43 Resident mono-
cytes and macrophages within the synovial membrane play a central role in
initiation and driving of the initial inflammatory response to monosodium
urate crystals within the joint.43 Activation of cells by monosodium urate
crystals leads to the production of a diverse array of inflammatory medi-
ators, which contribute to massive migration of neutrophils toward the
monosodium urate crystals that have triggered the inflammatory episode.
Other cells such as synovial fibroblasts, antigen-presenting dendritic cells
(DCs), eosinophils, and mast cells may also play a role in the initiation
phase of the gout flare.
F 2 A 2 2, A 2 2 2 A D
, 3AD2A , A A 2 D 0 C AD
Although the inflammation that monosodium urate crystals trigger via
the inflammasome is clearly detrimental in the context of the gout flare,
it may play a physiologic role in activating the innate immune response
by providing a “danger” signal.3 Danger signals from monosodium urate
crystals and from other purines (e.g., ATP) may also help trigger the
adaptive immune response by activating antigen-presenting dendritic
cells.3 The dendritic cells provide stimulatory signals that help drive
the activation of T lymphocytes, including type 17 helper T cell (Th17)
differentiation.
NLRP3 INFLAMMASOME ACTIVATION
The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflam-
masome is a multiprotein cytoplasmic complex that senses cell damage and
the presence of microbial products.44 It consists of a sensor protein: NACHT,
LRR, and PYD domains containing protein 3 (NALP3, also known as cryopy-
rin, encoded by the NLRP3 gene), an adaptor protein: apoptosis-associated
speck-like protein containing a CARD (ASC, also known as PYCARD), and
an effector enzyme: caspase 1.44 Assembly of the NLRP3 inflammasome leads
to the release of two proinflammatory cytokines, IL-1β and IL-18, resulting
in an acute inflammatory cascade. Activation of the NLRP3 inflammasome
is central to the gout flare, and clinical trials have reported efficacy of IL-1
antagonists such as anakinra and canakinumab in both treating and prevent-
ing gout flares.
The activation of the NLRP3 inflammasome involves two signaling path-
ways, a priming signal via toll-like receptors and an assembly signal from
monosodium urate crystals. This two-signal system may explain the spo-
radic nature of gout flares.
Priming signal
The NLRP3 inflammasome priming signal controls the production of the
sensor, adaptor, and effector proteins that make up the inflammasome com-
plex. This signal is mediated by toll-like receptor (TLR) proteins, in partic-
ular TLR-2 and TLR-4. These TLR proteins do not seem to directly interact
with monosodium urate crystals, but with other inflammatory mediators or
external factors.45
During phagocyte cell activation the S100 protein heterodimer S100A8/9,
formed by the calgranulin proteins S100A8 and S100A9 (formerly myeloid
release proteins MRP8 and MRP14), is secreted. The S100A8 and S100A9
proteins are endogenous ligands of TLR-4 and are among the earliest inflam-
matory mediators produced in the response to monosodium urate crystals.
The S100A8/9 heterodimer is also elevated in synovial fluid and serum
during the gout flare, indicating it may be an important initial stimulus to
attract and activate other inflammatory cells.46
The toll-like receptor TLR-2 may mediate the priming signal in gouty
inflammation through its interaction with long-chain free fatty acids.47
Research into NLRP3 inflammasome activation by monosodium urate crys-
tals found crystals alone were unable to stimulate an inflammatory response,
but when combined with long-chain free fatty acids an inflammatory
response was observed.48 This response was mediated by TLR-2.
Once the toll-like receptor proteins have interacted with an inflam-
matory mediator or other factor the priming signal pathway proceeds via
myeloid differentiation factor 88 (Myd88) and a chain of intracellular
mediators (see Box 193.4)48 that converge on nuclear factor-κB (NF-κB),
allowing the production of the NLRP3 inflammasome components. Other
adaptor molecules in the TLR-2 and TLR-4 signaling pathways (e.g., CD14)
may also play a role.
Assembly signal
Monosodium urate crystals have a strong surface reactivity, enabling the
crystals to cross-link membrane glycoproteins and directly activate proin-
flammatory signaling pathways at several levels within the phagocyte.49 The
crystals interact directly with signaling proteins in the cell membrane (see
Box 193.4 and Fig. 193.8),45 bypassing the mechanisms that should nor-
mally regulate these pathways.
Monosodium urate crystals act as damage-associated molecular patterns
(DAMPs) in macrophages.50 This DAMP activity signals macrophage cells to
assemble the NLRP3 inflammasome components, produced in the priming
signal pathway, creating an active NLRP3 inflammasome complex.44
After NLRP3 inflammasome assembly, caspase 1 is able to cleave the
immature proinflammatory interleukins, pro–IL-1β and pro–IL-18, into their
active, inflammation-promoting forms. Interleukin-1β (IL-1β) is among the
first inflammatory mediators released after cell exposure to monosodium
urate crystals. Release of active IL-1β and IL-18 leads to the rapid recruit-
ment of neutrophils to the site of monosodium urate crystal deposition and
full initiation of the acute inflammatory episode.50
D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A
F C DC A ) A C E A ( A C A AE
 CHAPTER 193 Etiology and pathogenesis of gout 1707

BOX 193.4 INFLAMMATORY EVENTS IN THE GOUT FLARE

Sequence of cellular events
1. Deposition and release of monosodium urate microcrystals
2. Proinflammatory coating (e.g., IgG, complement)
3. Initial interaction with resident cells: tissue macrophages ± fibroblasts, mast cells, others
4. Activation of membrane signaling molecules (TLR, CD14, TREM)
5. NLRP3 inflammasome activation: mature IL-1β release
6. Release of other cytokines and chemokines
7. Activation of endothelial cell adhesion molecules
8. Emigration, attraction, and activation of neutrophils
9. Phagocytosis of crystals by neutrophils
10. Cross-linking of inflammatory signaling proteins
11. Removal of crystal coating, membrane damage, phagolysosome rupture
12. Enzyme and mediator release
13. Resolution: aggregated NET formation, cytokines TGF-β, MC-R and PPAR-γ ligands, AMPK activation, mature macrophages

Membrane mediators
Fcγ receptors (FcγRIII/CD16) Complement receptors
GPCRs (e.g., chemokine receptors) Integrins
TLRs (TLR-2, TLR-4) CD14

Intracellular signaling
NLRP3 inflammasome activation (caspase 1, PYCARD, NALP)
Tyrosine kinases (Syk, Src, Pyk-2) Lipid kinase PI3K
Mitogen-activated protein kinases (p38, JNK, ERK-1, ERK-2)
Downstream TLR pathway (Myd88, IRAK-1, TRAF-6, IK-κB)
Nuclear factors (NF-κB, AP-1)

Soluble mediators released

Mature IL-1β
Chemokines: CXCL (e.g., IL-8), CCL (e.g., MCP-1)
Complement split products Endothelins
TNF-α IL-6
Kinins Leukotrienes
Metalloproteinases ROS
Reactive nitrogen species (NO) Prostaglandins
S100 proteins (S100A8/9; MRP 8/14) Substance P
TGF-β RANKL

Monosodium urate crystals can activate many cell types and trigger the release of a diverse array of proinflammatory mediators. Multiple pathways have been implicated in different experimental systems and based on
the detection of mediators in patients with gout, and it is likely that some of these mechanisms operate in parallel. The clinical efficacy of the inhibition of prostanoids and IL-1 inhibitors has established their role beyond
doubt. Intervention in vivo with selective inhibitors of other mediators to “prove” their significance in humans has not been reported, and it is more difficult to be certain of the size of their contribution. AMPK, Adenosine
monophosphate–activated protein kinase; AP-1, activator protein 1; CCL, chemokine (C-C motif) ligand; CXCL, C-X-C motif chemokine ligand; ERK, extracellular signal-regulated kinase; IgG, immunoglobulin G; IK-κB,
inhibitor of nuclear factor kappa-B kinase subunit beta; IL, interleukin; IRAK-1, nterleukin-1 receptor-associated kinase 1; JNK, c-Jun N-terminal kinase; MCP-1, monocyte chemotactic factor-1; MC-R, melanocortin
receptors; MRP-4, multidrug resistance protein 4; Myd88, myeloid differentiation primary response 88; NALP, NACHT, LRR, and PYD domains-containing protein; NET, neutrophil extracellular trap; NF-κB, nuclear factor
κB; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; PI3K, phosphatidylinositol-4, 5-bisphosphate 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor γ; PYCARD, apoptosis-associated speck-like
protein containing a CARD; RANKL, receptor activator of nuclear factor-κB ligand; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; TRAF-6, TNF
receptor associated factor 6; TREM, triggering receptor expressed on myeloid cells.

ACTIVATION OF PHAGOCYTE BY MEMBRANE-ACTIVE CRYSTALS

Phagocytosis by Fusion of vacuolar and Phagolysosome rupture, Cleavage of pro-IL-1, Release of multiple
leukocyte, interaction lysosomal membranes activation of signaling, transcription, proinflammatory
with membrane receptors, inflammasomes and synthesis mediators
and signaling molecules in cytoplasm of mediators
Monosodium
urate
crystallization
Inflammation
Shedding of
preformed
crystals from
tophi

FIG. 193.8 Crystals interact with cell surface receptors and their associated signaling complexes and are phagocytosed by the cell. Rupture of the phagolysosome releases the
crystals into the cytoplasm, allowing interaction with the inflammasome, leading to activation and release of interluekin-1 (IL-1). Signaling protein kinases and promoters for
cytokines and other proinflammatory genes are activated, with the release of a diverse array of inflammatory mediators (see text). Urate and other crystals also interact with
lipid membranes and bind to cytosolic and membrane-bound proteins, acting directly at important steps controlling proinflammatory signaling.

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE
1708 SECTION 17 Crystal-Related Arthropathies
INFLAMMATORY MEDIATORS INDUCED BY URATE CRYSTALS
Urate crystals
IgG coating Apo-E, B coating
Receptors,
Stimulates signaling Inhibits
molecules
Responding cell
(macrophage, neutrophil)
inflammasome activation
S100A8/9 Substance P
Endothelins
Chemokines Lysosomal PGE2 IL-1 Reactive N
(e.g., CCL2, enzymes LTB4 IL-6 and O metabolites
CXCL8)
TNF-!
FIG. 193.9 Monosodium urate crystals can stimulate a variety of cells to produce a
diverse array of inflammatory mediators, depending on the coating of the crystal and
the receptiveness of the cell. Many mediators have been implicated in experimental
settings, but the dominant mediators appears to be those involved in NLRP3 inflam-
masome activation. The clinical response of the gout flare to nonsteroidal antiinflam-
matory drugs and coxibs and to specific interleukin-1 (IL-1) antagonists supports key
roles for prostanoids and for IL-1, respectively. apo, Apolipoprotein; CCL2, chemok-
ine (C-C motif) ligand 2; CXCL8, C-X-C Motif Chemokine Ligand 8; IgG, immunoglob-
ulin G; LTB4, leukotriene B4; MCP-1, macrophage chemotactic factor 1; N, nitrogen;
O, oxygen; PGE2, prostaglandin E2; TNF-α, tumor necrosis factor-α.
OTHER INFLAMMATORY MEDIATORS
In addition to the release of the proinflammatory cytokines, IL-1β and IL-18,
other inflammatory mediators are released when cells interact with mono-
sodium urate crystals, each of which encourages the recruitment of neutro-
phils to the site of inflammation. The S100A8/9 protein heterodimer, IL-6,
granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor
necrosis factor-α (TNF-α) are among the mediators released within 30 min-
utes of exposure of cells to monosodium urate crystals.
Chemokines are also released in the early stages of inflammation.
Chemokines of the CXC family are important for attracting and activating
neutrophils and are major cytokines in acutely inflamed synovial fluid in
gout (Figs. 193.8 and 193.9; see also Box 193.4). Circulating levels of CXCL8
(IL-8) are increased in patients with gout both during flares and during
the intercritical period.51 In addition, CXCR2, CXCL-1 (Gro-α), CXCL-2
(MIP-2α, Gro-β), and CXCL-3 (MIP-2β, Gro-γ) have been implicated.
The chemokine (C-C motif) ligand 2 (CCL2) (monocyte chemotactic
factor-1 [MCP-1]) aids recruitment of monocytes to sites of inflammation
induced by monosodium urate crystals.52 Assigning relative significance to
individual chemokines is difficult for several reasons: the chemokine family
is large and there is substantial overlap between the various chemokines
binding a given receptor, redundancy in the functions assigned to different
chemokines and receptors, and incomplete translation between mediator
actions in vitro and in animal models and their functions in human disease.
Another early response to cytokine release is increased expression of
E-selectin on nearby vascular endothelial cells. A further mediator involved
in experimental crystal-induced inflammation is endothelin-1, a peptide
modulator of neutrophil migration produced by vascular endothelium.53
Monosodium urate crystals activate de novo synthesis of inducible cyclo-
oxygenase (COX-2) and phospholipase-A2, producing the inflammatory
prostanoids prostaglandin-E2 (PGE2) and thromboxane A2 in phagocytes.54
PGE2 causes vasodilatation, edema, and further leukocyte immigration. The
clinical efficacy of COX inhibition in treating gout flares confirms a signifi-
cant role for prostanoids in monosodium urate crystal inflammation.
Monosodium urate crystals also stimulate neutrophils and fibroblast-like
synoviocytes to undergo the respiratory burst and produce reactive oxy-
gen species and reactive nitrogen species (RNS), including nitric oxide
(NO).55 The release of nitric oxide involves signaling pathways similar
to the proinflammatory cytokines. Depending on its concentration and
F 2 A 2 2, A 2 2 2 A D
, 3AD2A , A A 2 D 0 C AD
microenvironment, nitric oxide can mediate regulatory or direct toxic effects
and can influence neutrophil activation and apoptosis.
NEUTROPHIL ACTIVATION
Resident synovial cells and trafficking monocytes contribute to the initial
burst of proinflammatory mediators important in the initiation of the gout
flare. However, much of the full-blown response observed clinically is medi-
ated by neutrophils. Synovial fluid aspirated during gout flares reveals neu-
trophil counts in a range up to that seen in acute pyogenic septic arthritis.
Neutrophils initially attach to the synovial vascular endothelium through
their selectin ligands. Stronger adhesion occurs when the vascular endo-
thelia express integrin molecules in response to chemokines and cytokines
produced in adjacent tissues. The neutrophils then exit the synovial capillar-
ies and migrate through the synovial matrix to the joint cavity, aided by the
chemotactic gradient. The proinflammatory cytokines prime the neutrophil
for an amplified oxidative and degranulation response to crystals.
Neutrophils have a shorter half-life (i.e., hours) than any other circu-
lating leukocyte. Unless they are activated, normal neutrophils soon die.
Inflammatory mediators involved in gout, particularly colony-stimulating
factors, IL-1, IL-6, chemokines, and prostaglandins, prolong neutrophil sur-
vival by inhibiting spontaneous apoptosis.
Neutrophils and macrophages within the synovial fluid avidly engulf
monosodium urate crystals. Lysosomal enzymes then remove the protein
coating the crystal has acquired in the synovial membrane and cavity. In the
uncoated state, monosodium urate crystals have increased reactivity with
proteins and membranes. Neutrophil activation is marked by activation of
phospholipases and by inositol triphosphate production, leading to a cyto-
plasmic calcium flux. Monosodium urate crystals also induce leukotriene
(LT) production.
Depending on crystal concentration and coating, monosodium urate
crystals can then lyse the phagolysosomal membrane, spilling the phagocy-
tosed crystals and the toxic lysosomal contents (proteases, reactive oxygen
species) into the neutrophil cytoplasm (see Fig. 193.8). Phagosome lysis
allows the monosodium urate crystals to interact with the inflammasome
but can also lead to death of the phagocyte; this releases the lysosomal con-
tents together with newly synthesized acute inflammatory mediators.
According to the intensity of the response and on the size and number
of joints affected, cytokines, including S100A8/9, IL-1, IL-6, IL-8, MCP-1,
and TNF-α, are produced in sufficient quantity to enter the circulation and
stimulate an acute phase response. Patients with gout flares are often sys-
temically unwell, with fever and leukocytosis, and in some patients display
a systemic inflammatory response syndrome easily confused with sepsis (see
Chapter 194).
The clinical response of gout flares to COX-2 inhibitors and IL-1 antag-
onists suggests that prostanoids and IL-1 (see Chapter 195) are prominent
mediators of the intense acute inflammation characteristic of the gout flare.56
Other pain mediators include kinins, neuropeptides such as substance P, and
mast cell products.
TERMINATION OF THE GOUT FLARE
Even without medical intervention, the gout flare is almost always self-limit-
ing. The classic flare resolves spontaneously within a week or two. This is an
intriguing paradox, given the overlap between gout and other arthropathies
at the level of the molecular mediators involved and the persistence of the
crystals that initiated the flare.
After ingestion of monosodium urate crystals, neutrophils undergo
NETosis, with formation of neutrophil extracellular traps (NETs).
Termination of the gout flare is regulated by formation of aggregated NETs
that densely pack monosodium urate crystals and degrade proinflammatory
cytokines, including IL-1β, TNFα, MCP-1, MIP1α, and IL-6. Neutrophil
extracellular trap formation is dependent on reactive oxygen species, which
are important in regulation of termination of the inflammation.57
The increase in vascular permeability after acute synovitis has begun
allows increased entry of antiinflammatory crystal-coating macromolecules
from plasma, such as ApoB. Increasing monosodium urate crystal coating
with ApoB and locally produced ApoE and TGF-β can inhibit neutrophil
activation.
Systemic antiinflammatory mediators include the melanocortins,
products of the hypothalamic–pituitary axis, including adrenocortico-
tropic hormone (ACTH) and melanocyte stimulating hormone (MSH).
Adrenocorticotropic hormone stimulates the release of corticosteroids from
the adrenal cortex. Melanocortins also have a direct antiinflammatory effect
on macrophages in the inflamed joint via macrophage melanocortin recep-
tors (MCRs).58
D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A
F C DC A ) A C E A ( A C A AE

A number of antiinflammatory mediators have been implicated in the
resolution phase of the gout flare. These include ApoE, TGF-β, IL-10, IL-1ra,
soluble TNF receptors, intracellular cytokine inducible SH2-containing pro-
tein (CIS) and suppressor of cytokine signaling 3 (SOCS 3),59 and inducers
of the nuclear hormone receptor peroxisome proliferator-activated receptor
γ.60 Of particular note is the antiinflammatory cytokine IL-37, which is an
inhibitor of the innate immune system. Mature IL-37 is produced alongside
IL-1β via cleavage by caspase-1; however, IL-37 acts to reduce rather than
promote inflammation. Recent evidence has shown IL-37 can inhibit mono-
sodium urate crystal induced inflammation by downregulating proinflam-
matory mediators, reducing the recruitment of neutrophils and monocytes
to the site of inflammation.61
Resolution of the gout flare may also be aided by the presence of progres-
sively more differentiated macrophages, arising in response to the cytokine
milieu,62 and by removal of neutrophils through apoptosis and phagocyto-
sis by mature macrophages. However, mature macrophages seem to be as
capable as monocytes at initiating responses to monosodium urate crys-
tals.43 Induction of TGF-β through neutrophil cannibalism and the release
of microvesicles (ectosomes) by neutrophils may also play a role in the ter-
mination phase.63,64 Adenosine monophosphate–activated protein kinase
(AMPK) is a metabolic biosensor with antiinflammatory activities that plays
an important role in the regulation of MSU crystal-associated inflammation.
AMPK activators increase macrophage antiinflammatory M2 polarization,
inhibit NLRP3 gene expression, and activation of caspase-1 and IL-1β.65
ADVANCED GOUT
In the presence of persistent hyperuricemia, some patients develop advanced
gout, with recurrent flares, clinically evident tophi, chronic gouty arthritis,
and bone erosion.
TOPHUS FORMATION
The tophus (tophi, plural) is a chronic foreign body granuloma-like struc-
ture containing collections of monosodium urate crystals surrounded by
inflammatory cells and connective tissue (Fig. 193.10 and Fig. 193.11).66
Typically, tophi develop in the first metatarsophalangeal joint, the Achilles
tendon, the olecranon bursa, the ear, and the finger pulps, but they can also
develop in other less common sites.
COMPOSITION OF THE GOUTY TOPHUS
Fibrovascular zone
Corona zone
T cell B cell Plasma cell Macrophage
CD68 + MNC Mast cell Neutrophil TRAP + MNC
FIG. 193.10 The central mass of monosodium urate crystals is surrounded by a corona
of cells, including mature macrophages and multinucleated giant cells. Cells of the
adaptive immune response are also present: T and B lymphocytes and plasma cells.
MNC, Multinucleated cells; TRAP, tartrate-resistant acid phosphatase. (Adapted
with permission from Dalbeth N, Pool B, Gamble GD, et al. Cellular characterization
of the gouty tophus: a quantitative analysis. Arthritis Rheum. 2010;62[5]:1549–56.)
F 2 A 2 2, A 2 2 2 A D D 2C ,A2
, 3AD2A , A A 2 D 0 C AD F C DC A
CHAPTER 193 Etiology and pathogenesis of gout 1709
FIG. 193.11 Monosodium urate crystals from tophus. Crystals aspirated from a sub-
cutaneous tophus. Polarized transmission white (halogen) light; 90-degree extinction
filter; 530 nm first-order compensator.
During tophus formation, persistent nests of crystals are enveloped by a
granuloma-like chronic inflammatory response, with a corona zone of dif-
ferentiated macrophages and multinucleate giant cells surrounded in turn
by a fibrovascular layer. Both adaptive and innate immune cells are present
within the tophus, and proinflammatory cytokines, including IL-1 and TNF-
α, are expressed within the corona zone (Fig. 193.10).67 Aggregated neutro-
phil extracellular traps (NETs; discussed above) may also play a role in the
formation of the tophus.57
Tophi usually develop after years of sustained hyperuricemia, although
some individuals who present with tophi will have no prior history of gout
flare. Tophi can be clinically silent for a long time, indicating that the tophus
may represent a physical containment that limits monosodium urate crys-
tal-induced inflammation at the site of crystal deposition.66 Despite this
lack of active inflammatory symptoms, the development of tophi can have
serious consequences, limiting joint function and causing bone destruction,
both of which can lead to substantial disabilities.
JOINT DAMAGE
Bone erosion occurs in proximity to intraarticular or periarticular tophi
and generally has a radiographic appearance that is distinct from that seen
with the erosions of rheumatoid arthritis. Patients with severe erosive and
tophaceous gout have elevated circulating levels of receptor activator of
nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating fac-
tor (M-CSF), factors that aid the maturation of bone-resorbing osteoclasts.68
T cells present within the tophus express RANKL and may contribute to
joint damage.69
Monosodium urate crystals also have profound effects on osteoblasts,
causing reduced cell viability, function, and differentiation.70 These crystals
also reduce the expression of osteoprotegerin, a decoy receptor that inhibits
osteoclastogenesis by preventing the binding of RANKL to its ligand. High
numbers of osteoclasts and infrequent osteoblasts are present at the bone–
tophus interface in patients with advanced gout.68,70 Together, these data
suggest that bone erosion in gout occurs because of uncoupling of osteoclast
and osteoblast function, which in turn promotes bone resorption at sites of
monosodium urate crystal deposition.
Osteocytes are the most abundant cell of bone and play an import-
ant role in regulating bone remodeling. Monosodium urate crystals have
direct effects on osteocyte viability and, through interactions with macro-
phages, indirectly promote a shift in osteocyte function that favors bone
resorption and inflammation. These indirect effects can be inhibited by
COX-2 inhibition. Thus the crystals within the tophus may have direct
effects, and the tissue response to the crystals may have indirect effects
on bone cells.71
Cartilage damage, characterized by radiographic joint space narrowing,
is a relatively late manifestation of advanced gout. Histologic studies have
shown that monosodium urate crystals are deposited radially in the super-
ficial layers of articular cartilage, and cartilage surfaces in advanced gout
are often described as being diffusely “dusted” with white crystal depos-
its.72 Ultrasound studies have highlighted the close relationship between
monosodium urate crystals and articular cartilage. The “double contour”
ultrasound sign can be visualized over the superficial margin of the articular
cartilage in joints of people with asymptomatic hyperuricemia and gout and
is thought to represent monosodium urate crystal deposition.73
Monosodium urate crystals interact with chondrocytes to promote deg-
radation of the cartilage matrix by inducing nitric oxide generation and
expression of matrix metalloprotease (MMP)-3 in articular chondrocytes
2AA @DI 1 E A C A ) 2. 3 E A
) A C E A ( A C A AE
1710 SECTION 17 Crystal-Related Arthropathies
through TLR-2 signaling and upregulation of NF-κB.74 Increased expression
of other MMPs has also been observed in synovial fibroblasts stimulated
with monosodium urate crystals75 and in macrophages obtained from syno-
vial tissue from people with gout and within the tophus.76
THE GENETICS OF GOUT
A familial diathesis to gout was first noted by Seneca two millennia ago. A
positive family history has been reported in as few as 10% or as many as 80%
of patients with gout. This range reflects differences in the populations stud-
ied and the definitions used. Genetic influences on hyperuricemia and gout
are, in most instances, multigenic. Contemporary estimates of the heritabil-
ity of serum urate levels have ranged from 40% to 63%, and comparisons of
contributions to variation in serum urate levels have found a stronger role
for genes over diet or dietary components.77,78
Genes that influence gout could in principle act at any one of the several
“checkpoints” on the path to crystal-induced inflammation (Fig. 193.1). For
example, they could affect urate production, extrarenal or renal handling of
uric acid, crystal nucleation and enlargement, the crystal coating, or the cel-
lular and soluble mediator components of the acute response when inflam-
matory cell meets crystal or the amplification of this response. Supporting
the importance of genes influencing uric acid excretion, monozygotic twins
show a tighter concordance than dizygotic twins for fractional renal uric
acid clearance.79 Genome-wide association studies (GWAS) have identified
common genetic variants within genes involved in urate production, uric
acid excretion, control of inflammation, and control of gene expression.80,81
Recently, large gene sets related to kidney and liver development, morphol-
ogy, and function have been identified as being of particular relevance in
determining serum urate levels.81
TRANSPORTER GENES
Large, well-powered human genome-wide studies have revealed associ-
ations of many genes encoding renal urate transporters with serum urate
concentrations and gout (including SLC2A9, SLC22A12, and ABCG2; along
with SLC2A12, SLC16A9, SLC17A1, SLC17A3, and SLC22A11).80–82 SLC2A9
(GLUT9) has the strongest effect on serum urate levels, and ABCG2 has the
strongest effect on gout risk.80 Variants that reduce protein function for both
these genes have been identified, with loss-of-function variants in SLC2A9
being linked to renal hypouricemia, and the main ABCG2 variant associated
with hyperuricemia (Q141K, glutamine to lysine amino acid change) reduc-
ing protein function by approximately half.83 SLC2A9 has a stronger effect in
women than in men and ABCG2 a stronger effect in men.27,84 The promoter
regions for some of the urate transporter genes contain hormone-responsive
elements that may underlie these effects.
Similarly, SLC22A12 (URAT1) has a strong effect on serum urate levels.
People with loss-of-function variants in the SLC22A12 gene (resulting in
decreased URAT1 activity) show hypouricemia and hyperuricosuria as well
as exercise-induced renal functional impairment.85 Consistent with a signif-
icant role in uric acid excretion, homozygosity for a loss-of-function variant
in this gene is the most common cause of renal hypouricemia in Japanese
patients.85 This polymorphism is more common in healthy Japanese individ-
uals than in those with gout, suggesting that it provides protection against
gout.86
Genetic associations between serum urate level and the PDZK1 gene27
further support the importance of the URAT1-PDZ-NPT complex in con-
trolling net uric acid reabsorption and secretion.
METABOLIC GENES
Several well-defined purine metabolic enzyme defects lead to urate over-
production (see Box 193.2 and below), but these are uncommon. Other
metabolic genes have effects that are less direct and less dramatic. There is
an association between serum urate level and GCKR, which encodes glu-
cokinase regulatory protein, a regulator of glucokinase.87 Glucokinase is an
important enzyme in the glycolytic pathway and acts as a glucose sensor.
GCKR has in turn been linked with metabolic traits associated with gout,
including insulin resistance and hyperlipidemia. Other implicated genes are
involved in lipid or sugar metabolism and in the production of purine pre-
cursors through the pentose phosphate pathway.80–82
GENES INFLUENCING CRYSTAL FORMATION AND CRYSTAL-
TRIGGERED INFLAMMATION
Many people with hyperuricemia do not develop gout. Moreover, the genes
currently known to influence urate level account for a small proportion of
F 2 A 2 2, A 2 2 2 A D
, 3AD2A , A A 2 D 0 C AD
the heritability of gout (<10% when stringent criteria are applied).80 This
suggests that diverse gene variants or a combination of many individually
“weak” genes contribute to the genetic predisposition to gout. Despite pow-
erful contemporary epidemiologic and genetic techniques, the relative con-
tributions of genes and environment remain uncertain.
Numerous variants have been identified in the promoter and structural
regions of genes for inflammatory cytokines, cytokine receptors, and cellu-
lar signaling molecules, including NLRP3 and members of the IL-1 family.
Expression of one or more of these genes might modulate the inflammatory
response to monosodium urate crystals.88,89 GWASs have also implicated
several genes involved in regulation of inflammation.80 Associations between
gout and cytokine gene polymorphisms have not been explored as robustly
as, for example, the URAT1 and SLC2A9 associations.
RARE GENETIC DISORDERS
Gout is not commonly caused by a single-gene disorder. There are, however,
documented cases of rare monogenic disorders resulting in hyperuricemia
and gout. These monogenic disorders provide valuable insight into the bio-
logic processes involved in the development of hyperuricemia and gout.
Purine metabolism syndromes
Two rare X chromosome–linked disorders, deficiency of the salvage enzyme
hypoxanthine-guanine phosphoribosyltransferase (HPRT) and overactivity
of phosphoribosyl pyrophosphate synthetase 1 (PRS-I), provide insight into
the regulatory processes involved in purine nucleotide synthesis and degra-
dation (Fig. 193.6).10
PRPS1 encodes the PRS-I enzyme, which converts ribose-5-phosphate to
phosphoribosyl pyrophosphate (PRPP), the first element in the purine syn-
thesis de novo pathway.90 Rare genetic variants that alter the PRS-I protein
result in super activity of the enzyme, leading to accelerated production of
PRPP and consequently overproduction of urate.90
HPRT is encoded by the HPRT1 gene and catalyzes the conversions of
hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine
monophosphate (GMP) in the PRPP salvage synthesis pathway. Defects
in this enzyme result in the accumulation of hypoxanthine and guanine,
resulting in overproduction of urate. Defects in HPRT also result in an
increase in PRPP, the rate-limiting enzyme in purine synthesis de novo.91
Overproduction of urate occurs in all individuals with a deficiency of
HPRT because of this dysregulation of the purine synthesis de novo path-
way. Individuals with severe HPRT-deficiencies also develop neurologic
conditions.91
Autosomal dominant kidney diseases caused by UMOD
pathogenic variants (ADTKD-UMOD)
Additional insight into uric acid handling has been provided by studies of
patients with autosomal dominant tubulointerstitial kidney disease caused
by UMOD pathogenic variants (ADTKD-UMOD), previously described as
familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic
kidney disease (MCKD). These autosomal dominantly inherited disorders
are characterized by early onset of hyperuricemia (with or without gout),
hypertension, and progressive tubulointerstitial inflammation and fibrosis,
culminating in end-stage renal disease, often by age 40 years.
Most families with ADTKD-UMOD have genetic variants in uromodulin,
long known as the Tamm-Horsfall urinary glycoprotein.92 Uromodulin plays
a role in maintaining the integrity of the ascending loop of Henle by forming
a protective gel-like lattice that coats the luminal (urine) side of the tubule.
Dysfunctional uromodulin accumulates in the endoplasmic reticulum.
Defects in the protective lattice alter solute fluxes, reducing Na+ and Cl−
reabsorption. This results in contracted extracellular volume and compensa-
tory enhancement of sodium-dependent uric acid transport in the proximal
tubule.93
SUMMARY
Gout is a chronic disease of monosodium urate crystal deposition that
typically presents as intermittent episodes of severe joint inflammation.
Dysregulation of the pathways involved in regulating urate production and
excretion, leading to hyperuricemia, is essential in gout. However, there
are a number of other important “checkpoints” that determine whether
an individual will develop clinically evident gout, including monosodium
urate crystal formation, and the onset of an acute inflammatory response
(Fig. 193.1). The development of advanced gout represents chronic inflam-
mation and tophus formation. Genetics, environmental factors, other clin-
ical conditions, and medications are all able to influence the pathways
involved in reaching these “checkpoints.”
D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A
F C DC A ) A C E A ( A C A AE
 CHAPTER 193 Etiology and pathogenesis of gout 1711

ACKNOWLEDGMENT
The authors wish to acknowledge Professor Michael A. Becker and Dr. Lachy
McLean for their contributions to previous versions of this chapter.
REFERENCES
1. Wu XW, Muzny DM, Lee CC, et al. Two independent mutational events in the loss of urate
oxidase during hominoid evolution. J Mol Evol. 1992;34:78–84.
2. Hershfield MS, Roberts LJ, Ganson NJ, et al. Treating gout with pegloticase, a PEGylated
urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo.
Proc Natl Acad Sci USA. 2010;107:14351–14356.
3. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune
system to dying cells. Nature. 2003;425:516–521.
4. Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution, and the pathogenesis of
salt-sensitivity. Hypertension. 2002;40:355–360.
5. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and conse-
quences in the Normative Aging Study. Am J Med. 1987;82:421–426.
6. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general popu-
lation: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum.
2011;63:3136–3141.
7. Wyngaarden JB, Kelley WN. Gout and hyperuricemia. New York: Grune & Stratton; 1976.
1-503 and references therein.
8. Munan L, Kelly A, Petitclerc C. Serum urate levels between ages 10 and 14: changes in sex
trends. J Lab Clin Med. 1977;90:990–996.
9. Antón FM, Puig JG, Ramos T, et al. Sex differences in uric acid metabolism in adults:
evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate.
Metabolism. 1986;35:343–348.
10. Becker MA. Hyperuricemia and gout. In: Scriver CR, ed. The metabolic and molecular bases
of inherited disease. New York: McGraw-Hill; 2001:2513–2535.
11. Sarawate CA, Patel PA, Schumacher HR, et al. Serum urate levels and gout flares: analysis
from managed care data. J Clin Rheumatol. 2006;12:61–65.
12. Woodward OM, Köttgen A, Coresh J, et al. Identification of a urate transporter, ABCG2,
with a common functional polymorphism causing gout. Proc Natl Acad Sci USA.
2009;106:10338–10342.
13. Ichida K, Matsuo H, Takada T, et al. Decreased extra-renal urate excretion is a common
cause of hyperuricemia. Nat Commun. 2012;3:764.
14. Perez Ruiz F, Calabozo M, Erauskin GG, et al. Renal underexcretion of uric acid is present
in patients with apparent high urinary uric acid output. Arthritis Rheum. 2002;47:610–613.
15. Simkin PA. New standards for uric acid excretion and evidence for an inducible transporter.
Arthritis Rheum. 2003;49:735–736.
16. Lipkowitz MS, Leal-Pinto E, Rappoport JZ, et al. Functional reconstitution, membrane
targeting, genomic structure, and chromosomal localization of a human urate transporter.
J Clin Invest. 2001;107:1103–1115.
17. Anzai N, Ichida K, Jutabha P, et al. Plasma urate level is directly regulated by a voltage-driven
urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem. 2008;283:26834–26838.
18. Caulfield MJ, Munroe PB, O’Neill D, et al. SLC2A9 is a high-capacity urate transporter in
humans. PLoS Med. 2008;5:e197.
19. Matsuo H, Chiba T, Nagamori S, et al. Mutations in glucose transporter 9 gene SLC2A9
cause renal hypouricemia. [erratum appears in Am J Hum Genet. 2008;83(6):795]. Am J
Hum Genet. 2008;83:744–751.
20. Preitner F, Bonny O, Laverrière A, et al. Glut9 is a major regulator of urate homeostasis and
its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci
USA. 2009;106:15501–15506.
21. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate
anion exchanger that regulates blood urate levels. Nature. 2002;417:447–452.
22. Sweet DH, Chan LM, Walden R, et al. Organic anion transporter 3 (Slc22a8) is a dicar-
boxylate exchanger indirectly coupled to the Na+ gradient. Am J Physiol Renal Physiol.
2003;284:F763–F769.
23. Eraly SA, Vallon V, Rieg T, et al. Multiple organic anion transporters contribute to net renal
excretion of uric acid. Physiol Genomics. 2008;33:180–192.
24. Urano W, Taniguchi A, Anzai N, et al. Sodium-dependent phosphate cotransporter type 1
sequence polymorphisms in male patients with gout. Ann Rheum Dis. 2010;69:1232–1234.
25. Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion trans-
porter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple
allosteric substrate binding sites. Am J Physiol Renal Physiol. 2005;288:F327–F333.
26. Hosomi A, Nakanishi T, Fujita T, Tamai I. Extra-renal elimination of uric acid via intestinal
efflux transporter BCRP/ABCG2. PloS ONE. 2012;7:e30456.
27. Kolz M, Johnson T, Sanna S, et al. Meta-analysis of 28, 141 individuals identifies com-
mon variants within five new loci that influence uric acid concentrations. PLoS Genet.
2009;5:e1000504.
28. McGill NW, Dieppe PA. The effect of biological crystals and human serum on the rate
of formation of crystals of monosodium urate monohydrate in vitro. Br J Rheumatol.
1991;30:107–111.
29. Kam M, Perl-Treves D, Caspi D, Addadi L. Antibodies against crystals. FASEB J.
1992;6:2608–2613.
30. Kanevets U, Sharma K, Dresser K, Shi Y. A role of IgM antibodies in monosodium urate
crystal formation and associated adjuvanticity. J Immunol. 2009;182:1912–1918.
31. Dalbeth N, Doyle A, Boyer L, et al. Development of a computed tomography method of scor-
ing bone erosion in patients with gout: validation and clinical implications. Rheumatology
(Oxford). 2011;50:410–416.
32. Roddy E, Zhang W, Doherty M. Are joints affected by gout also affected by osteoarthritis?
Ann Rheum Dis. 2007;66:1374–1377.
33. Muehleman C, Li J, Aigner T, et al. Association between crystals and cartilage degeneration
in the ankle. J Rheumatol. 2008;35:1108–1117.
34. Katz WA, Schubert M. The interaction of monosodium urate with connective tissue compo-
nents. J Clin Invest. 1970;49:1783–1789.
35. Laurent TC. Solubility of sodium urate in the presence of chondroitin-4-sulphate. Nature.
1964;202:1334.
36. Burt HM, Dutt YC. Growth of monosodium urate monohydrate crystals: effect of cartilage
and synovial fluid components on in vitro growth rates. Ann Rheum Dis. 1986;45:858–864.
37. Chhana A, Pool B, Wei Y, et al. Human cartilage homogenates influence the crystallization
of monosodium urate and inflammatory response to monosodium urate crystals: a potential
link between osteoarthritis and gout. Arthritis Rheumatol. 2019;71:2090–2099.
38. De Miguel E, Puig JG, Castillo C, et al. Diagnosis of gout in patients with asymptomatic
hyperuricaemia: a pilot ultrasound study. Ann Rheum Dis. 2012;71:157–158.
39. Terkeltaub R, Martin J, Curtiss LK, Ginsberg MH. Apolipoprotein B mediates the capacity
of low density lipoprotein to suppress neutrophil stimulation by particulates. J Biol Chem.
1986;261:15662–15667.
40. Dalbeth N, Haskard DO. Mechanisms of inflammation in gout. Rheumatology.
2005;44:1090–1096.
41. Gordon TP, Bertouch JV, Walsh BR, Brooks PM. Monosodium urate crystals in asymptomatic
knee joints. J Rheumatol. 1982;9:967–969.
42. Chen C-J, Shi Y, Hearn A, et al. MyD88-dependent IL-1 receptor signaling is essential for
gouty inflammation stimulated by monosodium urate crystals. [see comment]. J Clin Invest.
2006;116:2262–2271.
43. Martin WJ, Walton M, Harper J. Resident macrophages initiating and driving inflammation
in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute
gout. Arthritis Rheum. 2009;60:281–289.
44. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regula-
tion to therapeutics. Nature Reviews Immunology. 2019;19:477–489.
45. So AK, Martinon F. Inflammation in gout: mechanisms and therapeutic targets. Nature
Reviews Rheumatology. 2017 Nov;13:639.
46. Joosten LA, Netea MG, Mylona E, et al. Engagement of fatty acids with Toll-like receptor 2
drives interleukin-1beta production via the ASC/caspase 1 pathway in monosodium urate
monohydrate crystal-induced gouty arthritis. Arthritis Rheum. 2010;62:3237–3248.
47. Liu-Bryan R, Scott P, Sydlaske A, et al. Innate immunity conferred by Toll-like receptors
2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate
monohydrate crystal-induced inflammation. Arthritis Rheum. 2005;52:2936–2946.
48. Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3
inflammasome. Nature. 2006;440:237–241.
49. Schlesinger N, Kay JC. Gouty Inflammation. Textbook of Autoinflammation. Cham: Springer;
2019:635–645.
50. Ryckman C, McColl SR, Vandal K, et al. Role of S100A8 and S100A9 in neutrophil recruit-
ment in response to monosodium urate monohydrate crystals in the air-pouch model of
acute gouty arthritis. Arthritis Rheum. 2003;48:2310–2320.
51. Kienhorst LB, van Lochem E, Kievit W, et al. Gout is a chronic inflammatory disease in
which high levels of interleukin-8 (CXCL8), myeloid-related protein 8/myeloid-related pro-
tein 14 complex, and an altered proteome are associated with diabetes mellitus and cardio-
vascular disease. Arthritis Rheumatol. 2015;67:3303–3313.
52. Matsukawa A, Miyazaki S, Maeda T, et al. Production and regulation of monocyte chemo-
attractant protein-1 in lipopolysaccharide- or monosodium urate crystal-induced arthritis
in rabbits: roles of tumor necrosis factor alpha, interleukin-1, and interleukin-8. Lab Invest.
1998;78:973–985.
53. Getting SJ, Di Filippo C, Lam CW, et al. Investigation into the potential anti-inflammatory
effects of endothelin antagonists in a murine model of experimental monosodium urate
peritonitis. J Pharmacol Exp Ther. 2004;310:90–97.
54. Nalbant S, Chen LX, Sieck MS, et al. Prophylactic effect of highly selective COX-2 inhibi-
tion in acute monosodium urate crystal induced inflammation in the rat subcutaneous air
pouch. Journal of Rheumatology. 2005;32:1762–1764.
55. Zamudio-Cuevas Y, Martínez-Flores K, Fernández-Torres J, et al. Monosodium urate crys-
tals induce oxidative stress in human synoviocytes. Arthritis Res Ther. 2016;18:117.
56. Torres R, MacDonald L, Croll SD, et al. Hyperalgesia, synovitis and multiple biomarkers of
inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty
arthritis. Ann Rheum Dis. 2009;68:1602–1608.
57. Schauer C, Janko C, Munoz LE, et al. Aggregated neutrophil extracellular traps limit inflam-
mation by degrading cytokines and chemokines. Nat Med. 2014;20:511–517.
58. Getting SJ, Christian HC, Flower RJ, Perretti M. Activation of melanocortin type 3 recep-
tor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis.
Arthritis Rheum. 2002;46:2765–2775.
59. Chen YH, Hsieh SC, Chen WY, et al. Spontaneous resolution of acute gouty arthritis is
associated with rapid induction of the anti-inflammatory factors TGFbeta1, IL-10 and sol-
uble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3. Ann
Rheum Dis. 2011;70:1655–1663.
60. Akahoshi T, Namai R, Murakami Y, et al. Rapid induction of peroxisome proliferator-activated
receptor gamma expression in human monocytes by monosodium urate monohydrate crys-
tals. Arthritis Rheum. 2003;48:231–239.
61. Liu L, Xue Y, Zhu Y, et al. Interleukin 37 limits monosodium urate crystal-induced innate
immune responses in human and murine models of gout. Arthritis Res Ther. 2016;18:268.
62. Landis RC, Yagnik DR, Florey O, et al. Safe disposal of inflammatory monosodium urate
monohydrate crystals by differentiated macrophages. Arthritis Rheum. 2002;46:3026–3033.
63. Steiger S, Harper JL. Neutrophil cannibalism triggers transforming growth factor beta1
production and self regulation of neutrophil inflammatory function in monosodium urate
monohydrate crystal-induced inflammation in mice. Arthritis Rheum. 2013;65:815–823.
64. Cumpelik A, Ankli B, Zecher D, Schifferli JA. Neutrophil microvesicles resolve gout
by inhibiting C5a-mediated priming of the inflammasome. Ann Rheum Dis. 2016;75:
1236–1245.

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE
1712 SECTION 17 Crystal-Related Arthropathies
65. Wang Y, Viollet B, Terkeltaub R, Liu-Bryan R. AMP-activated protein kinase suppresses urate
crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum
Dis. 2016;75:286–294.
66. Chhana A, Dalbeth N. The gouty tophus: a review. Curr Rheumatol Rep. 2015;17:19.
67. Dalbeth N, Pool B, Gamble GD, et al. Cellular characterization of the gouty tophus: a quan-
titative analysis. Arthritis Rheum. 2010;62:1549–1556.
68. Dalbeth N, Smith T, Nicolson B, et al. Enhanced osteoclastogenesis in patients with topha-
ceous gout: urate crystals promote osteoclast development through interactions with stro-
mal cells. Arthritis Rheum. 2008;58:1854–1865.
69. Lee SJ, Nam KI, Jin HM, et al. Bone destruction by receptor activator of nuclear factor kap-
paB ligand-expressing T cells in chronic gouty arthritis. Arthritis Res Ther. 2011;13:R164.
70. Chhana A, Callon KE, Pool B, et al. Monosodium urate monohydrate crystals inhibit osteo-
blast viability and function: implications for development of bone erosion in gout. Ann
Rheum Dis. 2011;70:1684–1691.
71. Chhana A, Pool B, Callon KE, et al. Monosodium urate crystals reduce osteocyte viability
and indirectly promote a shift in osteocyte function towards a proinflammatory and prore-
sorptive state. Arthritis Res Ther. 2018;20:208.
72. Levin MH, Lichtenstein L, Scott HW. Pathologic changes in gout; survey of eleven necrop-
sied cases. Am J Pathol. 1956;32:871–895.
73. Grassi W, Meenagh G, Pascual E, Filippucci E. “Crystal clear”-sonographic assess-
ment of gout and calcium pyrophosphate deposition disease. Semin Arthritis Rheum.
2006;36:197–202.
74. Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R. TLR2 signaling in chondrocytes drives
calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide gen-
eration. J Immunol. 2005;174:5016–5023.
75. McMillan RM, Vater CA, Hasselbacher P, et al. Induction of collagenase and prostaglan-
din synthesis in synovial fibroblasts treated with monosodium urate crystals. J Pharm
Pharmacol. 1981;33:382–383.
76. Schweyer S, Hemmerlein B, Radzun HJ, Fayyazi A. Continuous recruitment, co-expression
of tumour necrosis factor-alpha and matrix metalloproteinases, and apoptosis of macro-
phages in gout tophi. Virchows Arch. 2000;437:534–539.
77. Kuo CF, Grainge M, See LC, et al. Familial aggregation and heritability of gout in taiwan: a
nationwide population study. Arthritis Rheum. 2012;64:S355.
78. Major TJ, Topless RK, Dalbeth N, Merriman TR. Evaluation of the diet wide contribution to
serum urate levels: meta-analysis of population based cohorts. BMJ. 2018;363:k3951.
79. Emmerson BT, Nagel SL, Duffy DL, Martin NG. Genetic control of the renal clearance of
urate: a study of twins. Ann Rheum Dis. 1992;51:375–377.
80. Kottgen A, Albrecht E, Teumer A, et al. Genome-wide association analyses identify 18 new
loci associated with serum urate concentrations. Nat Genet. 2013;45:145–154.
81. Tin A, Marten J, Kuhns VL, et al. Target genes, variants, tissues and transcriptional pathways
influencing human serum urate levels. Nat Genet. 2019;2:1–6.
82. Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically
defined gout identifies multiple risk loci and its association with clinical subtypes. Ann
Rheum Dis. 2016;75:652–659.
83. Matsuo H, Ichida K, Takada T, et al. Common dysfunctional variants in ABCG2 are a major
cause of early-onset gout. Sci Rep. 2013;3:2014.
84. Döring A, Gieger C, Mehta D, et al. SLC2A9 influences uric acid concentrations with pro-
nounced sex-specific effects. Nat Genet. 2008;40:430–436.
85. Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and molecular analysis of patients with
renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc
Nephrol. 2004;15:164–173.
86. Taniguchi A, Urano W, Yamanaka M, et al. A common mutation in an organic anion trans-
porter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis
Rheum. 2005;52:2576–2577.
87. van der Harst P, Bakker SJ, de Boer RA, et al. Replication of the five novel loci for uric acid
concentrations and potential mediating mechanisms. Hum Mol Genet. 2010;19:387–395.
88. McKinney C, Stamp LK, Dalbeth N, et al. Multiplicative interaction of functional inflam-
masome genetic variants in determining the risk of gout. Arthritis Res Ther. 2015;17:288.
89. Qing YF, Zhou JG, Zhang QB, et al. Association of TLR4 Gene rs2149356 polymorphism
with primary gouty arthritis in a case-control study. PLoS ONE. 2013;8:e64845.
90. de Brouwer AP, van Bokhoven H, Nabuurs SB, et al. PRPS1 mutations: four distinct syn-
dromes and potential treatment. Am J Hum Genet. 2010;86:506–518.
91. Torres RJ, Puig JG. Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency:
Lesch-Nyhan syndrome. Orphanet J Rare Dis. 2007;2:48.
92. Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medul-
lary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet.
2002;39:882–892.
93. Dahan K, Devuyst O, Smaers M, et al. A cluster of mutations in the UMOD gene causes
familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.
J Am Soc Nephrol. 2003;14:2883–2893.

F 2 A 2 2, A 2 2 2 A D D 2C ,A2 2AA @DI 1 E A C A ) 2. 3 E A

, 3AD2A , A A 2 D 0 C AD F C DC A ) A C E A ( A C A AE