• DOI:10.7326/0003-4819-143-7-200510040-00009
• Corpus ID: 194570

Pathogenesis of Gout

@article{Choi2005PathogenesisOG,
  title={Pathogenesis of Gout},
  author={Hyon K. Choi and David B. Mount and Anthony M. Reginato},
  journal={Annals of Internal Medicine},
  year={2005},
  volume={143},
  pages={499-516}
}

• Hyon K. Choi, D. Mount, A. Reginato
• Published 4 October 2005
• Medicine, Biology
• Annals of Internal Medicine

Clinical Principles The overall disease burden of gout is substantial and may be increasing. As more scientific data on the modifiable risk factors and comorbidities of gout become available, integration of these data into gout care strategies may become essential. Hyperuricemia and gout are associated with the insulin resistance syndrome and related comorbid conditions. Lifestyle modifications that are recommended for gout generally align with those for major chronic disorders (such as the insulin resistance syndrome, hypertension, and cardiovascular disorders); thus, these measures may be doubly beneficial for many patients with gout and particularly for individuals with these comorbid conditions. Effective management of risk factors for gout and careful selection of certain therapies for comorbid conditions (such as hypertension or the insulin resistance syndrome) may also aid gout care. The urateanion exchanger URAT1 (urate transporter-1) is a specific target of action for both antiuricosuric and uricosuric agents. The long-term health effect of hyperuricemia (beyond the increased risk for gout) needs to be clarified, including any potential consequences associated with the chronic hyperuricemia that anti-inflammatory treatment does not correct. Pathophysiologic Principles A direct causal relationship exists between serum urate levels and the risk for gout. Lifestyle factors, including adiposity and dietary habits, appear to contribute to serum uric acid levels and the risk for gout. Urate is extensively reabsorbed from the glomerular ultrafiltrate in the proximal tubule via the brush-border urateanion exchanger URAT1. Sodium-dependent reabsorption of anions increases their concentration in proximal tubule cells, resulting in increased urate exchange via URAT1, increased urate reabsorption by the kidney, and hyperuricemia. Genetic variation in renal urate transporters or upstream regulatory factors may explain the hereditary susceptibility to conditions associated with high urate levels and a patient's particular response to medications; these transporters may also serve as targets for future drug development. Urate crystals are able to directly initiate, to amplify, and to sustain an intense inflammatory attack because of their ability to stimulate the synthesis and release of humoral and cellular inflammatory mediators. Cytokines, chemokines, proteases, and oxidants involved in acute urate crystalinduced inflammation also contribute to the chronic inflammation that leads to chronic gouty synovitis, cartilage loss, and bone erosion. For definition of terms used, see Glossary. Gout is a type of inflammatory arthritis that is triggered by the crystallization of uric acid within the joints and is often associated with hyperuricemia (Figure 1). Acute gout is typically intermittent, constituting one of the most painful conditions experienced by humans. Chronic tophaceous gout usually develops after years of acute intermittent gout, although tophi occasionally can be part of the initial presentation. In addition to the morbidity that is attributable to gout itself, the disease is associated with such conditions as the insulin resistance syndrome, hypertension, nephropathy, and disorders associated with increased cell turnover (1, 2). Figure 1. Overview of the pathogenesis of gout. The overall disease burden of gout remains substantial and may be increasing. The prevalence of self-reported, physician-diagnosed gout in the Third National Health and Nutrition Examination Survey was found to be greater than 2% in men older than 30 years of age and in women older than 50 years of age (3). The prevalence increased with increasing age and reached 9% in men and 6% in women older than 80 years of age (4). Furthermore, the incidence of primary gout (that is, patients without diuretic exposure) doubled over the past 20 years, according to the Rochester Epidemiology Project (4). Dietary and lifestyle trends and the increasing prevalence of obesity and the metabolic syndrome may explain the increasing incidence of gout. Researchers have recently made great advances in defining the pathogenesis of gout, including elucidating its risk factors and tracing the molecular mechanisms of renal urate transport and crystal-induced inflammation. This article reviews key aspects of the pathogenesis of gout with a focus on the recent advances. Absence of Uricase in Humans 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 mol/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 M) are approximately 6 times those of vitamin C in humans (8, 9). Other potential advantages of the relative hyperuricemia in primate species have been speculated (8, 10, 11). 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). The Role of Urate Levels Uric acid is a weak acid (pKa, 5.8) that exists largely as urate, the ionized form, at physiologic pH. As urate concentration increases in physiologic fluids, the risk for supersaturation and crystal formation generally increases. Population studies indicate a direct positive association between serum urate levels and a future risk for gout (13, 14), as shown in Figure 2. Conversely, the use of antihyperuricemic medication is associated with an 80% reduced risk for recurrent gout, confirming the direct causal relationship between serum uric acid levels and risk for gouty arthritis (15). The solubility of urate in joint fluids, however, is influenced by other factors in the joint, as shown in Figure 3. Such factors include temperature, pH, concentration of cations, level of articular dehydration, and the presence of such nucleating agents as nonaggregated proteoglycans, insoluble collagens, and chondroitin sulfate (see Glossary) (16-18). Variation in these factors may account for some of the difference in the risk for gout associated with a given elevation in serum urate level (13, 14). Furthermore, these factors may explain the predilection of gout in the first metatarsal phalangeal joint (a peripheral joint with a lower temperature) and osteoarthritic joints (18) (degenerative joints with nucleating debris) and the nocturnal onset of pain (because of intra-articular dehydration) (19). Figure 2. The relationship between serum uric acid levels and the incidence of gout. Figure 3. Mechanisms of monosodium urate crystal formation and induction of crystal-induced inflammation. MSU Urate Balance 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 The dietary intake of purines contributes substantially to the blood uric acid. For example, the institution of an entirely purine-free diet over a period of days can reduce blood uric acid levels of healthy men from an average of 297 mol/L to 178 mol/L (21, 22). The bioavailable purine content of particular foods would depend on their relative cellularity and the transcriptional (see Glossary) and metabolic activity of the cellular content (20). Little is known, however, about the precise identity and quantity of individual purines in most foods, especially when cooked or processed (23). When a purine precursor is ingested, pancreatic nucleases break its nucleic acids into nucleotides (see Glossary), phosphodiesterases break oligonucleotides into simple nucleotides, and pancreatic and mucosal enzymes remove phosphates and sugars from nucleotides (20). The addition of dietary purines to purine-free dietary protocols has revealed a variable increase in blood uric acid levels, depending on the formulation and dose of purines administered (21). For example, RNA has a greater effect than an equivalent amount of DNA (24), ribomononucleotides have a greater effect than nucleic acid (21), and adenine has a greater effect than guanine (25, 26). A recent large prospective study showed that men in the highest quintile of meat intake had a 41% higher risk for gout compared with the lowest quintile, and men in the highest quintile of seafood intake had a 51% higher risk compared with the lowest quintile (27). Correspondingly, in a nationally representative sample of men and women in the United States, higher levels of meat and seafood consumption were associated with higher serum uric acid levels (28). However, consumption of oatmeal and purine-rich vegetables (for example, peas, beans, lentils, spinach, mushrooms, and cauliflower) was not associated with an 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 p