Professional Documents
Culture Documents
Pathofisiology Gout PDF
Pathofisiology Gout PDF
Physiology in Medicine: Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD,
Associate Editor; William J. Koopman, MD, Associate Editor
Review
Pathogenesis of Gout
Hyon K. Choi, MD, DrPH; David B. Mount, MD; and Anthony M. Reginato, MD, PhD
Clinical Principles
Pathophysiologic Principles
Review
Pathogenesis of Gout
ABSENCE
OF
URICASE
IN
HUMANS
THE ROLE
OF
URATE LEVELS
Glossary
Adenosine: A condensation product of adenine and D-ribose; a nucleoside
found among the hydrolysis products of all nucleic acids and of the
various adenine nucleotides.
Adenosine triphosphate: A phosphorylated nucleoside C10H16N5O13P3 of
adenine that supplies energy for many biochemical cellular processes by
undergoing enzymatic hydrolysis (especially to adenosine diphosphate).
Anion exchanger: A transport protein that mediates movement of an anion
across the plasma membrane by exchanging it with another anion on the
opposite side of the membrane. Urateanion exchange plays a key role in
the transport of urate across cell membranes.
Antiuricosuric agent: A chemical or drug that results in reduced renal
excretion of urate and hyperuricemia; pyrazinamide, the classic
antiuricosuric drug, exerts its effect by promoting proximal tubular
reabsorption of urate.
Apolipoprotein: The protein component of any lipoprotein complexes that is
a normal constituent of plasma chylomicrons, high-density lipoproteins,
low-density lipoproteins, and very low-density lipoproteins in humans.
Apoptosis: Disintegration of cells into membrane-bound particles that are
then phagocytosed by other cells.
Brush-border membrane vesicles (BBMV): Purified from superficial renal
cortex, BBMV are predominantly derived from the renal proximal tubule;
urate transporter-1 was initially defined as an anion exchanger activity
present in renal BBMV preparations.
Calcium-binding cytoplasmic proteins S100A8, S100A9: Chemotactic factor
that stimulates neutrophil adhesion and migration by activating the
2-integrin CD11b/CD18.
Chemokines: A class of polypeptide cytokines, usually 810 kDa, that are
chemokinetic and chemotactic, stimulating leukocyte movement and
attraction.
Cis-inhibition: Competitive inhibition of urate exchange by a urate
transporter-1 substrate present at the same side of the plasma membrane.
Chondroitin: A mucopolysaccharide occurring in sulfated form; present
among the ground substance materials in the extracellular matrix of
connective tissue (for example, cartilage).
c-Jun N-terminal kinase: Downstream kinase activated by ERK-1/ERRK-2
and p38 cascades, leading to autophosphorylation and regulation of
complex biological responses.
Cyclooxygenase-2 (COX-2): An enzyme that makes the prostaglandins that
cause inflammation, pain, and fever; nonsteroidal anti-inflammatory drugs
relieve symptoms as result of their ability to block COX-2 enzymes.
Cytokines: Intercellular messenger proteins; hormone-like products of many
different cell types that are usually active within a small radius of the cells
producing them.
Docosahexaenoic acid (DHA): All-cis-4,7,10,13,16,19-docosahexaenoic acid,
an -3, polyunsaturated, 22-carbon fatty acid found almost exclusively in
fish and marine animal oils; a substrate for cyclooxygenase.
Eicosapentaenoic acid (EPA): All-cis-5,8,11,14,17-eicosapentaenoic acid, an
-3, polyunsaturated, 20-carbon fatty acid found almost exclusively in
fish and marine animal oils; a substrate for cyclooxygenase.
E-selectin: Endothelial cell adhesion molecules consisting of a lectin-like
domain, an epidermal growth factorlike domain, and a variable number
of domains that encode proteins homologous to complement-binding
proteins; their function is to mediate the binding of leukocytes to the
vascular endothelium.
Familial renal hypouricemia: A recessive genetic disorder caused by
homozygous loss-of-function mutations in the SLC22A12 gene encoding
urate transporter-1. Patients with this disorder have hypouricemia that
does not respond to uricosuric or antiuricosuric agents.
G proteins: A family of similar heterotrimeric proteins found in the
intracellular portion of the plasma membrane; bind activated receptor
complexes and, through conformational changes and cyclic binding and
hydrolysis of guanosine triphosphate, directly or indirectly effect
alterations in channel gating and couple cell surface receptors to
intracellular responses.
Interleukins: A large family of hormone-like messenger proteins produced
by immune cells that act on leukocytes and other cells.
Kinase: An enzyme catalyzing the conversion of a proenzyme to an active
enzyme (for example, enteropeptidase [enterokinase]) or catalyzing the
transfer of phosphate groups.
Kinin: One of a number of widely differing substances having pronounced
and dramatic physiologic effects; kallidin and bradykinin are polypeptides,
formed in blood by proteolysis secondary to some pathologic process
producing vasodilation.
Continued
www.annals.org
Pathogenesis of Gout
Review
GlossaryContinued
GlossaryContinued
Continued
www.annals.org
The amount of urate in the body depends on the balance between dietary intake, synthesis, and the rate of excretion (20), as shown in Figure 1. Hyperuricemia results
from urate overproduction (10%), underexcretion (90%),
or often a combination of the two. The purine precursors
come from exogenous (dietary) sources or endogenous metabolism (synthesis and cell turnover).
The Relationship between Purine Intake and Urate
Levels
Review
Pathogenesis of Gout
increased risk for gout (27). The variation in the risk for
gout associated with different purine-rich foods may be
explained by varying amounts and type of purine content
and their bioavailability for metabolizing purine to uric
acid (28). At the practical level, these data suggest that
dietary purine restriction in patients with gout or hyperuricemia (29, 30) may be applicable to purines of animal
origin but not to purine-rich vegetables, which are excellent sources of protein, fiber, vitamins, and minerals. Similarly, implications of the recent findings (27, 28, 31) in
the management of hyperuricemia or gout were consistent
with the new dietary recommendations for the general
public (32), with the exception of the guidelines for fish
intake (Figure 4). Thus, among patients with gout or hyperuricemia, the use of plant-derived -3 fatty acids or
supplements of eicosapentaenoic acid and docosahexaenoic
acid (see Glossary) instead of fish consumption could be
considered to provide the benefit of these fatty acids without increasing the risk for gout.
PURINE METABOLISM
AND
GOUT
Annual incidence of gout was less than 0.1% for men with serum uric
acid levels less than 416 mol/L, 0.4% for men with levels of 416 to 475
mol/L, 0.8% for men with levels of 476 to 534 mol/L, 4.3% for men
with levels of 535 to 594 mol/L, and 7.0% for men with levels greater
than 595 mol/L, according to the Normative Aging Study (13). The
solid line denotes these data points; the dotted line shows an exponential
projection of the data points.
www.annals.org
Pathogenesis of Gout
Review
Figure 3. Mechanisms of monosodium urate crystal formation and induction of crystal-induced inflammation.
Urate crystallizes as a monosodium salt in oversaturated tissue fluids. Its crystallization depends on the concentrations of both urate and cation levels.
Several other factors contribute to the decreased solubility of sodium urate and crystallization. Alteration in the extracellular matrix leading to an increase
in nonaggregated proteoglycans, chondroitin sulfate, insoluble collagen fibrils, and other molecules in the affected joint may serve as nucleating agents.
Furthermore, monosodium urate (MSU) crystals can undergo spontaneous dissolution depending on their physiochemical environments. Chronic
cumulative urate crystal formation in tissue fluids leads to MSU crystal deposition (tophus) in the synovium and cell surface layer of cartilage. Synovial
tophi are usually walled off, but changes in the size and packing of the crystal from microtrauma or from changes in uric acid levels may loosen them
from the organic matrix. This activity leads to crystal shedding and facilitates crystal interaction with synovial cell lining and residential inflammatory
cells, leading to an acute gouty flare.
tion by net ATP degradation to AMP (41, 44). In addition, decreased urinary excretion as a result of dehydration
and metabolic acidosis may contribute to the hyperuricemia that is associated with ethanol ingestion, as discussed
later in this review (34, 45).
Recently, a large-scale prospective study confirmed
that the effect of ethanol on urate levels can be translated
into the risk for gout (31). Compared with abstinence,
daily alcohol consumption of 10 to 14.9 g increased the
risk for gout by 32%; daily consumption of 15 to 29.9 g,
30 to 49.9 g, and 50 g or greater increased the risk by 49%,
96%, and 153%, respectively. Furthermore, the study also
found that this risk varied according to type of alcoholic
beverage: Beer conferred a larger risk than liquor, whereas
moderate wine drinking did not increase risk (31). Correspondingly, a national U.S. survey demonstrated parallel
4 October 2005 Annals of Internal Medicine Volume 143 Number 7 503
Review
Pathogenesis of Gout
Figure 4. Dietary influences on the risk for gout and their implications within the Harvard Healthy Eating Pyramid.
Data on the relationship between diet and the risk for gout are primarily derived from the recent Health Professionals Follow-Up Study (27, 28, 31).
Implications of these findings in the management of hyperuricemia or gout are generally consistent with the new Healthy Eating Pyramid (32), except
for fish intake. The use of plant-derived -3 fatty acids or supplements of eicosapentaenoic acid and docosahexaenoic acid in place of fish consumption
could be considered to provide patients the benefit of these fatty acids without increasing the risk for gout. Use of -3 fatty acids may have
anti-inflammatory effect against gouty flares. Vitamin C intake exerts a uricosuric effect. (Adapted with permission from reference 32: Willett WC,
Stampfer MJ. Rebuilding the food pyramid. Sci Am. 2003;288:64-71.) Red arrows denote an increased risk for gout, solid green arrows denote a
decreased risk, and yellow arrows denote no influence on risk. Broken green arrows denote potential effect but without prospective evidence for the
outcome of gout.
Pathogenesis of Gout
AND
GOUT
Increased adiposity and the insulin resistance syndrome are both associated with hyperuricemia (5356).
Body mass index, waist-to-hip ratio, and weight gain have
all been associated with the risk for incident gout in men
(28, 57). Conversely, small, open-label interventional studies showed that weight reduction was associated with a
decline in urate levels and risk for gout (58, 59).
Reduced de novo purine synthesis was observed in patients after weight loss, resulting in decreased serum urate
levels (60). Exogenous insulin can reduce the renal excretion of urate in both healthy and hypertensive persons (54,
61, 62). Insulin may enhance renal urate reabsorption
through stimulation of the urateanion exchanger urate
transporter-1 (URAT1) (see Glossary) (63) or through the
sodium-dependent anion cotransporter in brush-border
membranes of the renal proximal tubule (discussed later in
this review). Because serum levels of leptin (see Glossary)
and urate tend to increase together (64, 65), some investigators have also suggested that leptin may affect renal re-
Review
absorption. Finally, in the insulin resistance syndrome, impaired oxidative phosphorylation may increase systemic
adenosine (see Glossary) concentrations by increasing the
intracellular levels of coenzyme A esters of long-chain fatty
acids. Increased adenosine, in turn, can result in renal retention of sodium, urate, and water (66 69). Some researchers have speculated that increased extracellular adenosine concentrations over the long term may also
contribute to hyperuricemia by increasing urate production
(66). The growing epidemic of obesity (70, 71) and the
insulin resistance syndrome (72) present a substantial challenge in the prevention and management of gout.
AND
The de novo synthesis starts with 5-phosphoribosyl 1-pyrophosphate (PRPP), which is produced by addition of a further phosphate group from
adenosine triphosphate (ATP) to the modified sugar ribose-5-phosphate. This step is performed by the family of PRPP synthetase (PRS) enzymes. In
addition, purine bases derived from tissue nucleic acids are reutilized through the salvage pathway. The enzyme hypoxanthine guanine phosphoribosyl
transferase (HPRT) salvages hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP). Only a small proportion
of patients with urate overproduction have the well-characterized inborn errors of metabolism, such as superactivity of PRS and deficiency of HPRT.
Furthermore, conditions associated with net ATP degradation lead to the accumulation of adenosine diphosphate (ADP) and adenosine monophosphate
(AMP), which can be rapidly degraded to uric acid. These conditions are displayed in left upper corner. Plus sign denotes stimulation, and minus sign
denotes inhibition. APRT adenine phosphoribosyl transferase; PNP purine nucleotide phosphorylase.
www.annals.org
Review
Pathogenesis of Gout
Implicated Mechanism
Urate-increasing agents
Pyrazinamide
Nicotinate
Lactate, -hydroxybutyrate, acetoacetate
Salicylate (low dose)
Diuretics
Cyclosporine
Tacrolimus
Ethambutol
-Blockers
Urate-decreasing agents
Uricosurics
Probenecid
Sulfinpyrazone
Benzbromarone
Losartan
Salicylate (high-dose)
Fenofibrate
Amlodipine
Xanthine oxidase inhibitors
Allopurinol
Febuxostat
Uricase
associated risk factors, such as dietary factors, obesity, diuretic use, and renal failure. A recent prospective study,
however, has confirmed that hypertension is associated
with an increased risk for gout independent of these potential confounders (28). Renal urate excretion was found
to be inappropriately low relative to glomerular filtration
rates in patients with essential hypertension (73, 74). Reduced renal blood flow with increased renal and systemic
vascular resistance may also contribute to elevated serum
uric acid levels (75). Hyperuricemia in patients with essential hypertension may reflect early nephrosclerosis, thus implying renal morbidity in these patients. Furthermore,
studies have suggested that hyperuricemia may be associated with incident hypertension or cardiovascular disorders. The proposed role of urate in the pathogenesis of
these disorders has recently been reviewed in the Physiology in Medicine series (12).
RENAL TRANSPORT
OF
URATE
Pathogenesis of Gout
Review
Antiuricosuric agents exert their effect by stimulating renal reabsorption rather than inhibiting tubular secretion (91).
The mechanism appears to involve a priming of renal urate
reabsorption through the sodium-dependent loading of proximal tubular epithelial cells with anions capable of a transstimulation of urate reabsorption (Figure 6). Studies from several laboratories have indicated that a transporter in the
proximal tubule brush border mediates sodium-dependent
reabsorption of pyrazinoate, nicotinate, lactate, pyruvate,
-hydroxybutyrate, and acetoacetate (102104), monovalent
anions that are also substrates for URAT1 (63). Increased
plasma concentrations of these antiuricosuric anions result in
their increased glomerular filtration and greater reabsorption
by the proximal tubule. The augmented intraepithelial concentrations in turn induce the reabsorption of urate by promoting the URAT1-dependent anion exchange of filtered
urate (trans-stimulation) (Figure 6).
Urate reabsorption by the proximal tubule thus exhibits a form of secondary sodium dependency, in that sodiumdependent loading of proximal tubular cells stimulates
Urate transporter-1 (URAT1) is located in the apical membrane of proximal tubular cells in human kidneys and transports urate from lumen to proximal
tubular cells in exchange for anions in order to maintain electrical balance. This exchanger is essential for proximal tubular reabsorption of urate and is
targeted by both uricosuric and antiuricosuric agents. Sodium-dependent entry of monovalent anions (such as pyrazinoate, nicotinate, lactate, pyruvate,
-hydroxybutyrate, and acetoacetate), presumptively through the sodiumanion cotransporter, fuels the absorption of luminal urate via the anion
exchanger URAT1. Basolateral entry of urate during urate secretion by the proximal tubule is stimulated by sodium-dependent uptake of the divalent
anion -ketoglutarate, leading to urate--ketoglutarate exchange via organic anion transporter-1 (OAT1) or organic anion transporter-3 (OAT3). These
proteins or similar transporters may facilitate the basolateral influx or efflux of urate. As discussed in the text, although the quantitative role of human
urate secretion remains unclear, several molecular candidates have been proposed for the electrogenic urate secretion pathway in apical membrane of
proximal tubules, including URAT1, ATP-driven efflux pathway (MRP4), and voltage-driven organic anion transporter-1 (OATV1). FEu renal
clearance of urate/glomerular filtration rate.
www.annals.org
Review
Pathogenesis of Gout
The anti-uricosuric agent pyrazinoate (PZA), a metabolite of pyrazinamide, has dual effects on urate transport by the proximal tubule. Urate
uptake by brush-border membrane vesicles isolated from canine kidney
cortex is shown, in the presence of 100 mM sodium (Na) with 0.1 mM
PZA, 0 PZA, or 5 mM PZA. The concentration results in Na-dependent uptake of PZA and a potentiation of urate uptake via urate transporter-1 (URAT1); in contrast, the higher concentration cis-inhibits
URAT1, thus reducing urate uptake by the membrane vesicles. (Reproduced with permission from reference 93: Guggino SE, Aronson PS.
Paradoxical effects of pyrazinoate and nicotinate on urate transport in
dog renal microvillus membranes. J Clin Invest. 1985;76:543-7.)
Pathogenesis of Gout
Review
Figure 8. Putative mechanisms for initiation, perpetuation, and termination of an acute monosodium urate crystalinduced gouty
inflammation.
Recent advances in the understanding of acute gouty attack are illustrated (left). The attack is primarily neutrophil-dependent and initiated by the
capacity of urate crystals to activate complements and to stimulate synovial lining cells and resident inflammatory cells to induce a variety of inflammatory
mediators. As depicted (right), self-resolution of acute gout is mediated by several mechanisms, including coating of monosodium urate crystals with
proteins and clearance by differentiated macrophages, neutrophil apoptosis, clearance of apoptotic cells, inactivation of inflammatory mediators, and the
release of anti-inflammatory mediators. Dots represent humoral inflammatory mediators, including cytokines and chemokines. Apo B apolipoprotein
B; Apo E apolipoprotein E; C1q, C3a, C3b, C5a, C5b-9 complement membrane attack complex; IL interleukin; LDL low-density
lipoprotein; LTB4 leukotriene B4; MCP-1 monocyte chemoattractant protein-1/CCL2; MIP-1 macrophage inflammatory protein-1/CCL3;
MMP-3 matrix metalloproteinase-3; NO nitrous oxide; PAF platelet-activating factor; PGE2 prostaglandin E2; PLA2 phospholipase A2;
PPAR- peroxisome proliferator-activated receptor- ligand; PPAR peroxisome proliferator-activated receptor- ligand; TGF- transcription
growth factor-; TNF- tumor necrosis factor-; S100A8/A9 myeloid-related protein; sTNFr soluble tumor necrosis factor receptor.
Review
Pathogenesis of Gout
mately 90% of the neutrophil chemotactic activity of human monocytes in response to urate crystals (133). Neutralization of IL-8 or its receptor may substantially reduce
the IL-8 induced neutrophilic inflammatory process (148)
and provide a potential therapeutic target in gout. Several
other neutrophil chemotactic factors, including the calcium-binding proteins (calgranulins) S100A8 and S100A9
(see Glossary) (149, 150), have also been shown to be
involved in neutrophil migration induced by urate crystals
(Figure 8).
SPONTANEOUS RESOLUTION
OF
ACUTE GOUT
Pathogenesis of Gout
Review
Figure 9. Putative mechanisms for chronic monosodium urateinduced inflammation and cartilage and bone destruction.
Low-level inflammation persists during the remissions of acute flares. Cytokines, chemokines, proteases, and oxidants involved in acute inflammation
contribute to chronic inflammation leading to chronic synovitis, cartilage loss, and bone erosion. Monosodium urate (MSU) crystals are able to activate
chondrocytes to release interleukin-1, inducible nitric oxide synthetase, and matrix metalloproteinases, leading to cartilage destruction. Similarly, MSU
crystal activation of osteoblasts, release of cytokines by activated osteoblast, and decreased anabolic function contribute to the juxta-articular bone damage
seen in chronic MSU inflammation. IL interleukin; iNOs inducible nitrous oxide synthase; MMP-9 matrix metalloproteinase-9; PGE2
prostaglandin E2.
SUMMARY
The disease burden of gout remains substantial and
may be increasing. As more scientific data on modifiable
risk factors and comorbidities of gout become available,
integration of these data into gout care strategy may become essential, similar to the current care strategies for
hypertension (163) and type 2 diabetes (164). Recommendations for lifestyle modification to treat or to prevent gout
are generally in line with those for the prevention or treatment of other major chronic disorders (32). Thus, the net
health benefits from these general healthy lifestyle recommendations (32) are expected to be even larger among
many patients with gout, particularly those with coexisting
insulin resistance syndrome, diabetes, obesity, and hypertension.
www.annals.org
Review
Pathogenesis of Gout
have a better risk benefit ratio than diuretics for hypertension in hypertensive patients with gout. Similarly, the uricosuric property of fenofibrate (165) may be associated
with a favorable risk benefit ratio among patients with
gout and the metabolic syndrome.
The recently elucidated molecular mechanism of renal
urate transport has several important implications in conditions that are associated with high urate levels. In particular, the molecular characterization of the URAT1 anion
exchanger has provided a specific target of action for wellknown substances affecting urate levels. Genetic variation
in these renal transporters or upstream regulatory factors
may explain the genetic tendency to develop conditions
associated with high urate levels and a patients particular
response to medications. Furthermore, the transporters
themselves may serve as targets for future drug development.
Finally, advances in our understanding of crystal-induced inflammation indicate that gout shares many pathogenetic features with other chronic inflammatory disorders.
Some newly available potent anti-inflammatory medications (including biological agents that are indicated for
other conditions) may have therapeutic potential in selected subsets of patients with gout, although the high costs
of biological agents would probably prevent their widespread use in gout. Anti-inflammatory agents for gout (including colchicine) are typically used to treat acute gout or
to reduce the risk for rebound gout attacks during the
initiation of urate-lowering therapy but do not lower serum levels of uric acid. The long-term safety profile of
these agents needs to be clarified, including the potential
consequences of chronic hyperuricemia with such anti-inflammatory treatment.
From Arthritis Research Centre of Canada, University of British Columbia, Vancouver, British Columbia, Canada; Massachusetts General Hospital, Brigham and Womens Hospital, Harvard Medical School, and VA
Boston Healthcare System, Boston, Massachusetts.
Acknowledgments: The authors thank Dr. John Seeger for his critical
(TAP Pharmaceutical Products); Honoraria: H.K. Choi (TAP Pharmaceutical Products); Grants received: H.K. Choi (TAP Pharmaceutical
Products).
Requests for Single Reprints: Hyon K. Choi, MD, DrPH, Division of
Rheumatology, Department of Medicine, University of British Columbia, Arthritis Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z 1L7; e-mail, hchoi@partners.org.
References
1. Terkeltaub RA. Clinical practice. Gout. N Engl J Med. 2003;349:1647-55.
[PMID: 14573737].
2. Schlesinger N, Schumacher HR Jr. Gout: can management be improved?
Curr Opin Rheumatol. 2001;13:240-4. [PMID: 11333356]
3. Kramer HM, Curhan G. The association between gout and nephrolithiasis:
the National Health and Nutrition Examination Survey III, 1988-1994. Am J
Kidney Dis. 2002;40:37-42. [PMID: 12087559]
4. Arromdee E, Michet CJ, Crowson CS, OFallon WM, Gabriel SE. Epidemiology of gout: is the incidence rising? J Rheumatol. 2002;29:2403-6. [PMID:
12415600]
5. Johnson RJ, Rideout BA. Uric acid and dietinsights into the epidemic of
cardiovascular disease. N Engl J Med. 2004;350:1071-3. [PMID: 15014177]
6. Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase: primary structure
and evolutionary implications. Proc Natl Acad Sci U S A. 1989;86:9412-6.
[PMID: 2594778]
7. Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational
events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;
34:78-84. [PMID: 1556746]
8. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an
antioxidant defense in humans against oxidant- and radical-caused aging and
cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981;78:6858-62. [PMID:
6947260]
9. Hediger MA. Kidney function: gateway to a long life? Nature. 2002;417:393,
395. [PMID: 12024201]
10. Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in
hominoids and its evolutionary implications. Mol Biol Evol. 2002;19:640-53.
[PMID: 11961098]
11. Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, et al. Uric
acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension.
2002;40:355-60. [PMID: 12215479]
12. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann
Intern Med. 2003;139:761-76. [PMID: 14597461]
13. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks
and consequences in the Normative Aging Study. Am J Med. 1987;82:421-6.
[PMID: 3826098]
14. Lin KC, Lin HY, Chou P. The interaction between uric acid level and other
risk factors on the development of gout among asymptomatic hyperuricemic men
in a prospective study. J Rheumatol. 2000;27:1501-5. [PMID: 10852278]
15. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship
between serum urate level and recurrent attacks of gouty arthritis: evidence for
reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis
Rheum. 2004;51:321-5. [PMID: 15188314]
16. 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;45:858-64. [PMID: 3098195]
17. McGill NW, Dieppe PA. The role of serum and synovial fluid components
in the promotion of urate crystal formation. J Rheumatol. 1991;18:1042-5.
[PMID: 1717687]
18. Fam AG, Stein J, Rubenstein J. Gouty arthritis in nodal osteoarthritis. J
Rheumatol. 1996;23:684-9. [PMID: 8730127]
19. Simkin PA, Pizzorno JE. Transynovial exchange of small molecules in normal human subjects. J Appl Physiol. 1974;36:581-7. [PMID: 4826322]
20. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman M.
Rheumatology. 3rd ed. New York: Mosby; 2003.
21. Griebsch A, Zollner N. Effect of ribomononucleotides given orally on uric
acid production in man. Adv Exp Med Biol. 1974;41:443-9. [PMID: 4832569]
22. Coe FL, Moran E, Kavalich AG. The contribution of dietary purine overconsumption to hyperpuricosuria in calcium oxalate stone formers. J Chronic
Dis. 1976;29:793-800. [PMID: 1010873]
23. Gibson T, Rodgers AV, Simmonds HA, Court-Brown F, Todd E, Meilton
V. A controlled study of diet in patients with gout. Ann Rheum Dis. 1983;42:
123-7. [PMID: 6847259]
24. Zollner N, Griebsch A. Diet and gout. Adv Exp Med Biol. 1974;41:435-42.
[PMID: 4832568]
25. Clifford AJ, Riumallo JA, Young VR, Scrimshaw NS. Effects of oral purines
on serum and urinary uric acid of normal, hyperuricaemic and gouty humans
[Abstract]. J Nutr. 1976;106:428-50.
26. Watson AR, Simmonds HA, Webster DR, Layward L, Evans DI. Purine
nucleoside phosphorylase (PNP) deficiency: a therapeutic challenge. Adv Exp
www.annals.org
Pathogenesis of Gout
Med Biol. 1984;165 Pt A:53-9. [PMID: 6426259]
27. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich
foods, dairy and protein intake, and the risk of gout in men. N Engl J Med.
2004;350:1093-103. [PMID: 15014182]
28. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change,
hypertension, diuretic use, and risk of gout in men: the Health Professionals
Follow-up Study. Arch Intern Med. 2005;165:742-8. [PMID: 15824292]
29. Emmerson BT. The management of gout. N Engl J Med. 1996;334:445-51.
[PMID: 8552148]
30. Fam AG. Gout, diet, and the insulin resistance syndrome [Editorial]. J Rheumatol. 2002;29:1350-5. [PMID: 12136887]
31. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake
and risk of incident gout in men: a prospective study. Lancet. 2004;363:1277-81.
[PMID: 15094272]
32. Willett WC, Stampfer MJ. Rebuilding the food pyramid. Sci Am. 2003;288:
64-71. [PMID: 12506426]
33. Klippel JH. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation; 2001.
34. Koopman WJ. Arthritis & Allied Conditions: A Textbook of Rheumatology.
12th ed. New York: Lippincott Williams & Wilkins; 2001.
35. Woolliscroft JO, Colfer H, Fox IH. Hyperuricemia in acute illness: a poor
prognostic sign. Am J Med. 1982;72:58-62. [PMID: 7058824]
36. Woolliscroft JO, Fox IH. Increased body fluid purine levels during hypotensive events. Evidence for ATP degradation. Am J Med. 1986;81:472-8. [PMID:
3752148]
37. Mineo I, Kono N, Hara N, Shimizu T, Yamada Y, Kawachi M, et al.
Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis
types III, V, and VII. N Engl J Med. 1987;317:75-80. [PMID: 3473284]
38. Fox IH. Adenosine triphosphate degradation in specific disease. J Lab Clin
Med. 1985;106:101-10. [PMID: 3860585]
39. Jinnai K, Kono N, Yamamoto Y, Kanda F, Ohno S, Tsutsumi M, et al.
Glycogenosis type V (McArdles disease) with hyperuricemia. A case report and
clinical investigation. Eur Neurol. 1993;33:204-7. [PMID: 8467838]
40. Yamanaka H, Kawagoe Y, Taniguchi A, Kaneko N, Kimata S, Hosoda S, et
al. Accelerated purine nucleotide degradation by anaerobic but not by aerobic
ergometer muscle exercise. Metabolism. 1992;41:364-9. [PMID: 1556942]
41. Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased
urate production by activation of adenine nucleotide turnover. N Engl J Med.
1982;307:1598-602. [PMID: 7144847]
42. Fox IH, Kelley WN. Studies on the mechanism of fructose-induced hyperuricemia in man. Metabolism. 1972;21:713-21. [PMID: 5047915]
43. Raivio KO, Becker A, Meyer LJ, Greene ML, Nuki G, Seegmiller JE.
Stimulation of human purine synthesis de novo by fructose infusion. Metabolism. 1975;24:861-9. [PMID: 166270]
44. Puig JG, Fox IH. Ethanol-induced activation of adenine nucleotide
turnover. Evidence for a role of acetate. J Clin Invest. 1984;74:936-41.
[PMID: 6470146]
45. Lieber CS, Jones DP, Losowsky MS, Davidson CS. Interrelation of uric acid
and ethanol metabolism in man. J Clin Invest. 1962;41:1863-70. [PMID:
13930523]
46. Choi HK, Curhan G. Beer, liquor, and wine consumption and serum uric
acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2004;51:1023-9. [PMID: 15593346]
47. Gibson T, Rodgers AV, Simmonds HA, Toseland P. Beer drinking and its
effect on uric acid. Br J Rheumatol. 1984;23:203-9. [PMID: 6743968]
48. Fox IH, Palella TD, Kelley WN. Hyperuricemia: a marker for cell energy
crisis [Editorial]. N Engl J Med. 1987;317:111-2. [PMID: 3473283]
49. Emmerson BT. Effect of oral fructose on urate production. Ann Rheum Dis.
1974;33:276-80. [PMID: 4843132]
50. Stirpe F, Della Corte E, Bonetti E, Abbondanza A, Abbati A, De Stefano F.
Fructose-induced hyperuricaemia. Lancet. 1970;2:1310-1. [PMID: 4098798]
51. Gross LS, Li L, Ford ES, Liu S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic
assessment. Am J Clin Nutr. 2004;79:774-9. [PMID: 15113714]
52. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup
in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004;
79:537-43. [PMID: 15051594]
53. Glynn RJ, Campion EW, Silbert JE. Trends in serum uric acid levels 1961
1980. Arthritis Rheum. 1983;26:87-93. [PMID: 6824508]
54. Emmerson B. Hyperlipidaemia in hyperuricaemia and gout. Ann Rheum
www.annals.org
Review
Review
Pathogenesis of Gout
Pathogenesis of Gout
Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107:110315. [PMID: 11342574]
125. Jutabha P, Kanai Y, Hosoyamada M, Chairoungdua A, Kim do K, Iribe
Y, et al. Identification of a novel voltage-driven organic anion transporter present
at apical membrane of renal proximal tubule. J Biol Chem. 2003;278:27930-8.
[PMID: 12740363]
126. Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human
organic anion transporter 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:F327-33. [PMID: 15454390]
127. Terkeltaub RA, Sklar LA, Mueller H. Neutrophil activation by inflammatory microcrystals of monosodium urate monohydrate utilizes pertussis toxininsensitive and -sensitive pathways. J Immunol. 1990;144:2719-24. [PMID:
2108211]
128. Bomalaski JS, Baker DG, Brophy LM, Clark MA. Monosodium urate
crystals stimulate phospholipase A2 enzyme activities and the synthesis of a
phospholipase A2-activating protein. J Immunol. 1990;145:3391-7. [PMID:
2230125]
129. Gaudry M, Gilbert C, Barabe F, Poubelle PE, Naccache PH. Activation of
Lyn is a common element of the stimulation of human neutrophils by soluble
and particulate agonists. Blood. 1995;86:3567-74. [PMID: 7579465]
130. Liu R, OConnell M, Johnson K, Pritzker K, Mackman N, Terkeltaub R.
Extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and
nuclear factor kappaB transcription factors play central roles in interleukin-8
expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells. Arthritis Rheum. 2000;43:1145-55.
[PMID: 10817569]
131. Barabe F, Gilbert C, Liao N, Bourgoin SG, Naccache PH. Crystal-induced
neutrophil activation VI. Involvement of FcgammaRIIIB (CD16) and CD11b in
response to inflammatory microcrystals. FASEB J. 1998;12:209-20. [PMID:
9472986]
132. Liu R, Aupperle K, Terkeltaub R. Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic
THP-1 cells. J Leukoc Biol. 2001;70:961-8. [PMID: 11739559]
133. Terkeltaub R, Zachariae C, Santoro D, Martin J, Peveri P, Matsushima
K. Monocyte-derived neutrophil chemotactic factor/interleukin-8 is a potential
mediator of crystal-induced inflammation. Arthritis Rheum. 1991;34:894-903.
[PMID: 2059236]
134. Schiltz C, Liote F, Prudhommeaux F, Meunier A, Champy R, Callebert J,
et al. Monosodium urate monohydrate crystal-induced inflammation in vivo:
quantitative histomorphometric analysis of cellular events. Arthritis Rheum.
2002;46:1643-50. [PMID: 12115197]
135. Tramontini NL, Kuipers PJ, Huber CM, Murphy K, Naylor KB, Broady
AJ, et al. Modulation of leukocyte recruitment and IL-8 expression by the membrane attack complex of complement (C5b-9) in a rabbit model of antigeninduced arthritis. Inflammation. 2002;26:311-9. [PMID: 12546141]
136. Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P. Synovial fluid
analysis for diagnosis of intercritical gout. Ann Intern Med. 1999;131:756-9.
[PMID: 10577299]
137. Yagnik DR, Hillyer P, Marshall D, Smythe CD, Krausz T, Haskard DO,
et al. Noninflammatory phagocytosis of monosodium urate monohydrate crystals
by mouse macrophages. Implications for the control of joint inflammation in
gout. Arthritis Rheum. 2000;43:1779-89. [PMID: 10943868]
138. Landis RC, Yagnik DR, Florey O, Philippidis P, Emons V, Mason JC,
et al. Safe disposal of inflammatory monosodium urate monohydrate crystals by
differentiated macrophages. Arthritis Rheum. 2002;46:3026-33. [PMID:
12428246]
139. Getting SJ, Flower RJ, Parente L, de Medicis R, Lussier A, Woliztky BA,
et al. Molecular determinants of monosodium urate crystal-induced murine peritonitis: a role for endogenous mast cells and a distinct requirement for endothelial-derived selectins. J Pharmacol Exp Ther. 1997;283:123-30. [PMID:
9336316]
140. Webster ME, Maling HM, Zweig MH, Williams MA, Anderson W Jr.
Urate crystal induced inflammation in the rat: evidence for the combined actions
of kinins, histamine and components of complement. Immunol Commun. 1972;
1:185-98. [PMID: 4663514]
www.annals.org
Review
Review
Pathogenesis of Gout
www.annals.org
partment of Medicine, University of British Columbia, Arthritis Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z
1L7.
www.annals.org