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Pathogenesis of Gout

Hyon K. Choi, MD, DrPH; David B. Mount, MD; and Anthony M. Reginato, MD, PhD
[+] Article and Author Information

From Arthritis Research Centre of Canada, University of British Columbia, Vancouver, British Columbia, Canada; Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, and VA Boston Healthcare System, Boston, Massachusetts.

Acknowledgments: The authors thank Dr. John Seeger for his critical review of the manuscript.

Potential Financial Conflicts of Interest: Consultancies: H.K. Choi (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.

Current Author Addresses: Dr. Choi: Division of Rheumatology, Department of Medicine, University of British Columbia, Arthritis Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z 1L7.

Dr. Mount: Brigham and Women's Hospital, Renal Division, Room 540, 4 Blackfan Circle, Boston, MA 02115.

Dr. Reginato: Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114.

Ann Intern Med. 2005;143(7):499-516. doi:10.7326/0003-4819-143-7-200510040-00009
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Humans are the only mammals in whom gout is known to develop spontaneously, probably because hyperuricemia only commonly develops in humans (5). In most fish, amphibians, and nonprimate mammals, uric acid that has been generated from purine (see Glossary) metabolism undergoes oxidative degradation through the uricase enzyme, producing the more soluble compound allantoin. In humans, the uricase gene is crippled by 2 mutations that introduce premature stop codons (see Glossary) (6). The absence of uricase, combined with extensive reabsorption of filtered urate, results in urate levels in human plasma that are approximately 10 times those of most other mammals (30 to 59 µmol/L) (7). The evolutionary advantage of these findings is unclear, but urate may serve as a primary antioxidant in human blood because it can remove singlet oxygen and radicals as effectively as vitamin C (8). Of note, levels of plasma uric acid (about 300 µM) are approximately 6 times those of vitamin C in humans (89). Other potential advantages of the relative hyperuricemia in primate species have been speculated (8, 1011). However, hyperuricemia can be detrimental in humans, as demonstrated by its proven pathogenetic roles in gout and nephrolithiasis and by its putative roles in hypertension and other cardiovascular disorders (12).


gout ; urate level

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Figure 1.
Overview of the pathogenesis of gout.

Gout is mediated by the supersaturation and crystallization of uric acid within the joints. The amount of urate in the body depends on the balance between dietary intake, synthesis, and excretion. Hyperuricemia results from the overproduction of urate (10%), from underexcretion of urate (90%), or often a combination of the two. Approximately one third of urate elimination in humans occurs in the gastrointestinal tract, with the remainder excreted in the urine.

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Figure 2.
The relationship between serum uric acid levels and the incidence of gout.

Annual incidence of gout was less than 0.1% for men with serum uric acid levels less than 416 µmol/L, 0.4% for men with levels of 416 to 475 µmol/L, 0.8% for men with levels of 476 to 534 µmol/L, 4.3% for men with levels of 535 to 594 µmol/L, and 7.0% for men with levels greater than 595 µmol/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.

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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.

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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 ω-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 ω-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.

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Figure 5.
Urate production pathways implicated in the pathogenesis of gout.

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.

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Figure 6.
Urate transport mechanisms in human proximal tubule.

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, β-hydroxybutyrate, and acetoacetate), presumptively through the sodium–anion 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 α-ketoglutarate, leading to urate-α-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.

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Figure 7.
Dual effects of pyrazinoate on urate transport.

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.)

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Figure 8.
Putative mechanisms for initiation, perpetuation, and termination of an acute monosodium urate crystal-induced 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-α = peroxisome proliferator-activated receptor-α ligand; PPARγ = peroxisome proliferator-activated receptor-γ ligand; TGF-β = transcription growth factor-β; TNF-α = tumor necrosis factor-α; S100A8/A9 = myeloid-related protein; sTNFr = soluble tumor necrosis factor receptor.

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Figure 9.
Putative mechanisms for chronic monosodium urate-induced 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.

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