Review - American Physiological Society

PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE 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


Annals of Internal Medicine: Paul Epstein, MD, Series Editor

Pathogenesis of Gout Hyon K. Choi, MD, DrPH; David B. Mount, MD; and Anthony M. Reginato, MD, PhD

Clinical Principles

Pathophysiologic Principles

The overall disease burden of gout is substantial and may be increasing.

A direct causal relationship exists between serum urate levels and the risk for gout.

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.

Lifestyle factors, including adiposity and dietary habits, appear to contribute to serum uric acid levels and the risk for gout.

Hyperuricemia and gout are associated with the insulin resistance syndrome and related comorbid conditions.

Urate is extensively reabsorbed from the glomerular ultrafiltrate in the proximal tubule via the brush-border urate–anion exchanger URAT1.

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 urate–anion 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.


out 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).

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 crystal–induced inflammation also contribute to the chronic inflammation that leads to chronic gouty synovitis, cartilage loss, and bone erosion.

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 See also: Print Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500 Web-Only Conversion of figures and table into slides

Ann Intern Med. 2005;143:499-516. For author affiliations, see end of text. For definition of terms used, see Glossary.

© 2005 American College of Physicians 499


Pathogenesis of Gout

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.






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).




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 ar500 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

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. Urate–anion 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 8–10 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 factor–like 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.


Pathogenesis of Gout




Leptin: A helical protein secreted by adipose tissue; acts on a receptor site in the ventromedial nucleus of the hypothalamus to curb appetite and increase energy expenditure as body fat stores increase. Leukotriene: Substance produced from arachidonic acid by the lipoxygenase pathway; functions as a regulator of allergic and inflammatory reactions; stimulates the movement of leukocytes; identified by the letters A, B, C, D, and E, with subscripts indicating the number of double bonds in the molecule (for example, LTB4). Lipoxins: Any of several conjugated tetraene derivatives of arachidonic acid that oppose the actions of leukotrienes, have potent vasodilating effects, and appear to be toxic to natural killer cells. Matrix metalloproteinases: A family of protein-hydrolyzing endopeptidases that hydrolyze extracellular proteins, especially collagens and elastin. Mitogen-activated protein kinases ERK1/ERK: One of the mitogen-activated protein kinases that signals transduction pathways in eukaryotic cells and integrates diverse extracellular signals; regulates complex biological responses, such as growth, differentiation, and death. Multidrug resistance protein-4 (MRP4): An anion transporter capable of adenosine triphosphate–driven urate efflux, expressed at the apical membrane of the proximal tubule. Nucleotide: A combination of a nucleic acid (purine or pyrimidine), 1 sugar (ribose or deoxyribose), and a phosphoric group. Organic anion transporter-1 (OAT1): A basolateral anion exchanger involved in proximal tubular transport of multiple organic anions, including urate; OAT1 is encoded by the SLC22A6 gene. Organic anion transporter-3 (OAT3): A basolateral anion exchanger involved in proximal tubular transport of multiple organic anions, including urate; OAT3 is encoded by the SLC22A8 gene. ␻-3 fatty acids: Polyunsaturated fatty acids that have the final double bond in the hydrocarbon chain between the third and fourth carbon atoms from 1 end of the molecule; found especially in fish, fish oils, vegetable oils, and green leafy vegetables. Osteocalcin: A vitamin K–dependent, calcium-binding bone protein, the most abundant noncollagen protein in bone; increased serum concentrations are a marker of increased bone turnover in disease states. p38 mitogen–activated protein kinase: One of the mitogen-activated protein kinases that signals transduction pathways in eukaryotic cells and integrates diverse extracellular signals; regulates complex biological responses such as growth, differentiation, and death. Peroxisome proliferator-activated receptor-␥ receptor (PPAR-␥): A nuclear receptor regulating an array of diverse functions in a variety of cell types, including regulation of genes associated with growth and differentiation. Phospholipase: An enzyme that catalyzes the hydrolysis of a phospholipid. Prostaglandin: Any of a class of physiologically active substances present in many tissues; causes vasodilation, vasoconstriction, and antagonism to hormones that influence lipid metabolism. Proteoglycan: Any of a class of glycoproteins of high molecular weight that are found especially in the extracellular matrix of connective tissue. Proximal tubule: The earliest segment of the renal tubule, responsible for the reabsorption of urate and other solutes from the glomerular ultrafiltrate. Purine: A double-ringed, crystalline organic base, C5H4N4, from which the nitrogen bases adenine and guanine are derived; uric acid is a metabolic end product. SLC22 gene family: The “Solute Carrier-22” gene family encompasses more than 20 different genes encoding organic anion and cation transporters, including the urate transporter-1 (URAT1, SLC22A12), organic anion transporter-1 (OAT1, SLC22A6), and organic anion transporter-3 (OAT3, SLC22A8). SLC5A8: A member of the SLC5 gene family of sodium-coupled transporters; a leading candidate for the sodium-dependent lactate/butyrate/pyrazinoate/nicotinate transporter that collaborates with urate transporter-1 in proximal tubular reabsorption of urate. Src tyrosine kinase: One of a group of enzymes of the transferase class that catalyze the phosphorylation of tyrosine residues in specific membrane vesicle–associated proteins. Stop codon: Trinucleotide sequence (UAA, UGA, or UAG) that specifies the end of translation or transcription. Synovitis: Inflammation of a synovial membrane, especially that of a joint; in general, when unqualified, the same as arthritis. Transcription: Transfer of genetic code information from one kind of nucleic acid to another; commonly used to refer to transfer of genetic information from DNA to RNA.

Transforming growth factor-␤ (TGF-␤): A regulatory cytokine that has multifunctional properties and can enhance or inhibit many cellular functions, including interfering with the production of other cytokines and enhancing collagen deposition. Trans-stimulation: Stimulation of urate exchange by a urate transporter-1 substrate when present at the opposite side of the plasma membrane; antiuricosuria apparently results from trans-stimulation of urate reabsorption by anions within the cytoplasm of proximal tubular epithelial cells. Tumor necrosis factor (TNF): A polypeptide cytokine, produced by endotoxin-activated macrophages, that has the ability to modulate adipocyte metabolism, lyse tumor cells in vitro, and induce hemorrhagic necrosis of certain transplantable tumors in vivo. Urate transporter-1 (URAT1): The urate–anion exchanger expressed at the apical brush-border membrane of proximal tubular epithelial cells; URAT1 is encoded by the SLC22A12 gene. Urate transporter/channel (UAT): Also known as galectin-9; may also be involved in proximal tubular urate secretion. Uricosuric agent: A chemical or drug that results in increased renal excretion of urate; urate transporter-1 appears to be the major target for uricosuric drugs. Voltage-driven organic anion transporter-1 (OATV1): A voltage-sensitive organic anion transporter capable of transporting urate and expressed at the apical membrane of the proximal tubule.


thritis (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). 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 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 501


Pathogenesis of Gout

Figure 1. Overview of the 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.


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.



The steps in the urate production pathways implicated in the pathogenesis of gout are displayed in Figure 5. The vast majority of patients with endogenous overproduction of urate have the condition as a result of salvaged purines arising from increased cell turnover in proliferative and inflammatory disorders (for example, hematologic cancer Figure 2. The relationship between serum uric acid levels and the incidence of gout.

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 purinefree 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 purinerich vegetables (for example, peas, beans, lentils, spinach, mushrooms, and cauliflower) was not associated with an 502 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

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.

Pathogenesis of Gout


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.

and psoriasis), from pharmacologic intervention resulting in increased urate production (such as chemotherapy), or from tissue hypoxia. Only a small proportion of those with urate overproduction (10%) have the well-characterized inborn errors of metabolism (for example, superactivity of 5’-phosphoribosyl-1-pyrophosphate synthetase and deficiency of hypoxanthine– guanine phosphoribosyl transferase). These genetic disorders have been extensively reviewed in textbooks (20, 33, 34), and the involved pathways are depicted in Figure 5. Conditions associated with net adenosine triphosphate (ATP) (see Glossary) degradation lead to accumulation of adenosine diphosphate (ADP) and adenosine monophosphate (AMP), which can be rapidly degraded to uric acid (35– 44), as shown in Figure 5. For example, ethanol administration has been shown to increase uric acid

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


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.

associations between these alcoholic beverages and serum urate levels (46). These findings suggest that certain nonalcoholic components that vary among these alcoholic beverages play an important role in urate metabolism. Ingested purines in beer, such as highly absorbable guanosine (23, 47), may produce an effect on blood uric acid levels that is sufficient to augment the hyperuricemic effect of alcohol itself, thereby producing a greater risk for gout than liquor or wine. Whether other nonalcoholic offending factors exist remains unclear, particularly in regard to beer; instead, protective factors in wine may be mitigating the alcohol effect on the risk for gout (28). Fructose is the only carbohydrate that has been shown to exert a direct effect on uric acid metabolism (23). Fructose phosphorylation in the liver uses ATP, and the accom504 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

panying phosphate depletion limits regeneration of ATP from ADP. The subsequent catabolism of AMP serves as a substrate for uric acid formation (48). Thus, within minutes after fructose infusion, plasma (and later urinary) uric acid concentrations are increased (42). In conjunction with purine nucleotide depletion, rates of purine synthesis de novo are accelerated, thus potentiating uric acid production (43). Oral fructose may also increase blood uric acid levels, especially in patients with hyperuricemia (49) or a history of gout (50). Fructose has also been implicated in the risk for the insulin resistance syndrome and obesity, which are closely associated with gout (51, 52). Furthermore, hyperuricemia resulting from ATP degradation can occur in acute, severe illnesses, such as the adult respiratory distress syndrome, myocardial infarction, or status epilepticus (34 –36).

Pathogenesis of Gout




Increased adiposity and the insulin resistance syndrome are both associated with hyperuricemia (53–56). 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 urate–anion 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-


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.



Associations between hypertension and the incidence of gout have been observed (13, 57), but researchers were previously unable to determine whether hypertension was independently associated or if it only served as a marker for

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.

4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 505


Pathogenesis of Gout

Table. Substances Affecting Urate Levels and Their Underlying Mechanisms* Substance

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

Trans-stimulation of URAT1 (63) Trans-stimulation of URAT1 (63) Trans-stimulation of URAT1 (63) Decreased renal urate excretion (78) Increased renal tubular reabsorption associated with volume depletion (79, 80), may stimulate URAT1 (63) Increased renal tubular reabsorption associated with decreased glomerular filtration (81–85), hypertension (86), interstitial nephropathy Similar to cyclosporine (87, 88) Decreased renal urate excretion Unknown (no change in renal urate excretion) (89)

Inhibition of URAT1 (63, 90) Inhibition of URAT1 (63, 90) Inhibition of URAT1 (63, 90) Inhibition of URAT1 (63) Inhibition of URAT1 (63) May inhibit URAT1 Increased renal urate excretion (86) Inhibition of xanthine oxidase Inhibition of xanthine oxidase Oxidation of urate to allantoin

* Numbers in parentheses are reference numbers. URAT1 ⫽ urate transporter-1.

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 urate transport is typically explained by a 4-component model: glomerular filtration, a near-complete reabsorption of filtered urate, subsequent secretion, and postsecretory reabsorption in the remaining proximal tubule (see Glossary) (76, 77). This model evolved from an interpretation of the effects of “uricosuric” and “antiuricosuric” agents; drugs and compounds known to affect serum urate levels are summarized in the Table. The urate secretion step was incorporated into the model to explain the potent antiuricosuric effect of pyrazinamide (91). However, direct inhibition of proximal tubular urate secretion 506 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

by pyrazinoate, the relevant metabolite, has never been demonstrated. Indeed, pyrazinamide has no effect in animal species that eliminate urate through net secretion (92), and direct effects of the drug on human urate secretion are largely unsubstantiated (91). Rather, studies utilizing renal brush-border membrane vesicles (see Glossary) (93, 94) have shown that pyrazinoate activates the reabsorption of urate through indirect stimulation of apical urate exchange (Figure 5). Similar mechanisms underlie the clinically relevant hyperuricemic effects of lactate (45), ketoacids (95), and nicotinate (96), as shown in the Table. Recent advances in the understanding of the relevant physiology are reviewed in the following sections. The Renal Urate–Anion Exchanger URAT1

Enomoto and colleagues (63) recently identified the molecular target for uricosuric agents (see Glossary), an anion exchanger responsible for the reabsorption of filtered urate by the renal proximal tubule (Table). The authors searched the human genome database for novel gene sequences within the organic anion transporter (OAT) gene family and identified URAT1 (SLC22A12) (see Glossary), a novel transporter expressed at the apical brush border of the proximal nephron (63). Urate–anion exchange activity similar to that of URAT1 was initially described in brushborder membrane vesicles from urate-reabsorbing species, such as rats and dogs (97–100), and was subsequently confirmed in human kidneys (101). Frog eggs (Xenopus oocytes) injected with URAT1-encoding RNA transport urate and exhibit pharmacologic properties consistent with data from human brush-border membrane vesicles (63,

Pathogenesis of Gout

101). These and other experiments indicate that uricosuric compounds (for example, probenecid, benzbromarone, sulfinpyrazone, and losartan) directly inhibit URAT1 from the apical side of tubular cells (“cis-inhibition” [see Glossary]). Conversely, antiuricosuric substances (for example, pyrazinoate, nicotinate, and lactate) serve as the exchanging anion from inside cells (Figure 6 and Table), thereby stimulating anion exchange and urate reabsorption (“transstimulation” [see Glossary]) (9, 63). In addition to urate, URAT1 has particular affinity for aromatic organic anions, such as nicotinate and pyrazinoate, followed by lactate, ␤-hydroxybutyrate, acetoacetate, and inorganic anions, such as chloride and nitrate (63). Enomoto and colleagues (63) provided unequivocal genetic proof that URAT1 is crucial for urate homeostasis: A handful of patients with “familial renal hypouricemia” (OMIM [Online Mendelian Inheritance in Man] accession number 220150; see Glossary) were shown to carry lossof-function mutations in the human SLC22A12 gene encoding URAT1, indicating that this exchanger is essential for proximal tubular reabsorption. Furthermore, pyrazinamide, benzbromarone, and probenecid failed to affect urate clearance in patients with homozygous loss-of-function mutations in SLC22A12, indicating that URAT1 is


essential for the effect of both uricosuric and antiuricosuric agents (see Glossary) (90). Secondary Sodium Dependency of Urate Reabsorption

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 (102–104), 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

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, ␤-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 ␣-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.

4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 507


Pathogenesis of Gout

Figure 7. Dual effects of pyrazinoate on urate transport.

110), and parathyroid hormone (111); URAT1 and the sodium-dependent anion cotransporter or cotransporters may be targets for these stimuli. Dose-Dependent Dual Response in Urate Excretion

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.)

brush-border urate exchange; urate itself is not a substrate for the sodium–anion transporter. The molecular identity of the relevant sodium-dependent anion cotransporter or cotransporters remains unclear; however, a leading candidate gene is SLC5A8 (see Glossary), which encodes a sodium-dependent lactate and butyrate cotransporter (105). Preliminary data indicate that the SLC5A8 protein can also transport both pyrazinoate and nicotinate, potentiating urate transport in Xenopus oocytes that co-express URAT1 (106). The antiuricosuric mechanism explains the longstanding clinical observation that hyperuricemia is induced by increased ␤-hydroxybutyrate and acetoacetate levels in diabetic ketoacidosis (95), increased lactic acid levels in alcohol intoxication (45), or increased nicotinate and pyrazinoate levels in niacin and pyrazinamide therapy, respectively (96). Urate retention is also known to be provoked by a reduction in extracellular fluid volume (107) and by excesses of angiotensin II (108, 109), insulin (62, 508 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

A conundrum in the pathophysiology of gout has been how certain anions can exhibit either uricosuric or antiuricosuric properties, depending on the dose administered. Monovalent anions that interact with URAT1 have the dual potential to increase or decrease renal urate excretion (93, 112) because they can both trans-stimulate and cisinhibit apical urate exchange in the proximal tubule (101). For example, a low concentration of pyrazinoate stimulates urate reabsorption as a consequence of trans-stimulation, whereas a higher concentration reduces urate reabsorption through extracellular cis-inhibition of URAT1 (63, 93, 113) (Figure 7). Dissenting opinions notwithstanding (114), these observations remain consistent with the basic scheme of apical urate transport shown in Figure 6. Biphasic effects on urate excretion (that is, antiuricosuria at low doses and uricosuria at high doses) are particularly well described for salicylate (115). Salicylate cis-inhibits URAT1 (63, 116), explaining the high-dose uricosuric effect; low antiuricosuria reflects a trans-stimulation of URAT1 by intracellular salicylate, which is evidently a substrate for the sodium–pyrazinoate transporter (103). Minimal doses of salicylate—75, 150, and 325 mg daily—were shown to increase serum uric acid levels by 16, 12, and 2 ␮mol/L, respectively (78). However, the effect on the risk for gout of this salicylate-induced increase in the serum uric acid level has not been determined. Other Renal Urate Transporters

At the basolateral membrane of proximal tubular cells, the entry of urate from the surrounding interstitium appears to be driven by sodium-dependent uptake of divalent anions, such as ␣-ketoglutarate, rather than monovalent carboxylates, such as pyrazinoate and lactate (117, 118) (Figure 6). Candidate proteins for this basolateral urate exchange activity include both OAT1 (119) and OAT3 (120,⫺ 121) (see Glossary), each of which function as an⫺ ion1 – dicarboxylate2 exchangers (121–123) at the basolateral membrane of the proximal tubule. These proteins (or similar transporters) conceivably facilitate the basolateral influx or efflux of urate. As mentioned previously, the quantitative role of human urate secretion remains unclear. Nonetheless, several molecular candidates have been proposed for the electrogenic urate secretion pathway across the apical membrane of proximal tubules, including the urate transporter/channel (UAT, also known as galectin-9) (124) and the voltagedriven organic anion transporter-1 (OATV1) (125). The apical ATP-driven anion transporter multidrug resistance protein 4 (MRP4) (see Glossary) has also been shown to mediate urate efflux (126).

Pathogenesis of Gout


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-␣ ⫽ 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.

URATE CRYSTAL–INDUCED INFLAMMATION Urate crystals are directly able to 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 (Figure 8). Urate Crystal–Induced Cell Activation and Signaling

Urate crystals interact with the phagocyte through 2 broad mechanisms. First, they activate the cells through the conventional route as opsonized and phagocytosed particles, eliciting the stereotypical phagocyte response of lysosomal fusion, respiratory burst, and release of inflammatory mediators. The other mechanism involves the

ticular properties of the urate crystal to interact directly with lipid membranes and proteins through cell membrane perturbation and cross-linking of membrane glycoproteins in the phagocyte. This interaction leads to the activation of several signal transduction pathways, including G proteins, phospholipase C and D, Src tyrosine kinases, the mitogenactivated protein kinases ERK1/ERK2, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase (see Glossary) (127–130). These steps are critical for crystalinduced interleukin (IL)– 8 (see Glossary) expression in monocytic cells (130 –132), which plays a key role in the neutrophil accumulation that is discussed later in this review (133). 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 509


Pathogenesis of Gout

Crystal-Induced Cellular Response

Cellular kinetic analyses using experimental animal models of gout (134, 135) indicate that monocytes and mast cells participate during the early phase of inflammation, whereas neutrophil infiltrates occur later during inflammation (Figure 8). Phagocytes from noninflamed joints may contain urate crystals (136), and most of these phagocytes are macrophages (137). The state of differentiation of mononuclear phagocytes determines whether the crystals will trigger an inflammatory response. In less differentiated cell lines, synthesis of tumor necrosis factor–␣ (TNF-␣) (see Glossary) and endothelial cell activation occurred after urate crystal phagocytosis, whereas well-differentiated macrophages failed to induce TNF-␣ synthesis or to activate endothelial cells (137). Similarly, freshly isolated human monocytes lead to a vigorous response by induction of TNF-␣, IL-1␤, IL-6, IL-8, and cyclooxygenase-2 secretion (see Glossary), whereas human macrophages differentiated in vitro for 7 days failed to secrete cytokines (see Glossary) or to induce endothelial cell activation (138). These findings indicate that monocytes play a central role in stimulating an acute attack of gout, whereas differentiated macrophages play an anti-inflammatory role in terminating an acute attack and preserving the asymptomatic state (Figure 8). Experimental animal models suggest that mast cells are involved in the early phase of crystal-induced inflammation (134), and they also release inflammatory mediators, such as histamine (139), in response to C3a, C5a, and IL-1. The vasodilatation, increased vascular permeability, and pain are also mediated by kinins, complement cleavage peptides, and other vasoactive prostaglandins (see Glossary) (140). Neutrophilic Influx and Amplification

Neutrophilic synovitis (see Glossary) is the hallmark of an acute gouty attack (Figure 8). Neutrophilic– endothelial cell interaction leading to neutrophilic influx appears to be an important event in this inflammation and represents a major locus for the pharmacologic effect of colchicine. Neutrophil influx is believed to be promoted by the endothelial–neutrophil adhesion that is triggered by IL-1, TNF-␣, and several chemokines (see Glossary), such as IL-8 and neutrophil chemoattractant protein-1 (MCP1). Neutrophil migration involves neutrophilic– endothelial interaction mediated by cytokine-induced clustering of E-selectin (see Glossary) on endothelial cells. Colchicine interferes with the interactions by altering the number and distribution of selectins on endothelial cells and neutrophils in response to IL-1 or TNF-␣ (141). Once in the synovial tissue, the neutrophils follow concentration gradients of chemoattractants such as C5a, leukotriene B4 (see Glossary), platelet-activating factor, IL-1, and IL-8 (142). Among these factors, IL-8 and growth-related gene chemokines play a central role in neutrophil invasion in experimental models of acute gout (143–147). For example, IL-8 alone accounts for approxi510 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

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).




The self-limited nature of acute gout is thought to involve several mechanisms (151), as shown in Figure 8. Clearance of urate crystals by differentiated macrophages in vitro has been linked to inhibition of leukocyte and endothelial activation (137, 138, 152). Neutrophil apoptosis (see Glossary) and other apoptotic cell clearance represent a fundamental mechanism in the resolution of acute inflammation. Furthermore, transforming growth factor–␤ (see Glossary) becomes abundant in acute gouty synovial fluid and inhibits IL-1 receptor expression and IL-1– driven cellular inflammatory responses (153, 154). Upregulation of IL-10 expression has been shown to limit experimental urate-induced inflammation and may function as a native inhibitor of gouty inflammation (155). Similarly, urate crystals induce peroxisome proliferator–activated receptor-␥ (PPAR-␥) (see Glossary) expression in human monocytes and promote neutrophil and macrophage apoptosis (156). Research has yet to determine if the PPAR-␥– based therapy currently available for type 2 diabetes would also be useful in gout management. Inactivation of inflammatory mediators by proteolytic cleavage, cross-desensitization of receptors for chemokines, release of lipoxins (see Glossary), IL-1 receptor antagonist, and other anti-inflammatory mediators all facilitate the resolution of acute gout. As shown in Figure 8, increased vascular permeability allows the entry of large molecules (such as apolipoproteins B and E [see Glossary]) and other plasma proteins into the synovial cavity, which also contributes to the spontaneous resolution of acute flares (157, 158).

CHRONIC GOUTY ARTHRITIS Chronic gouty arthritis typically develops in patients who have had gout for years (Figure 9). Cytokines, chemokines, proteases, and oxidants involved in acute urate crystal–induced inflammation also contribute to the chronic inflammation, leading to chronic synovitis, cartilage loss, and bone erosion. Even during remissions of acute flares, low-grade synovitis in involved joints may persist with ongoing intra-articular phagocytosis of crystals by leukocytes (136). Tophi on the cartilage surface, which can be observed through arthroscopy (159), may contribute to chondrolysis despite adequate treatment of both

Pathogenesis of Gout


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.

hyperuricemia and acute gouty attacks (160). Adherent chondrocytes phagocytize microcrystals and produce active metalloproteinases. Furthermore, crystal– chondrocyte cell membrane interactions can trigger chondrocyte activation, gene expression of IL-1␤ and inducible nitric oxide synthase, nitric oxide release, and the overexpression of matrix metalloproteinases (see Glossary) that leads to cartilage destruction (161). The crystals can also suppress the 1,25-dihydroxycholecalciferol–induced activity of alkaline phosphatase and osteocalcin (see Glossary). Thus, crystals can reduce the anabolic effects of osteoblasts, thereby contributing to damage to the juxta-articular bone (162) (Figure 9).

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.

Weight control, limits on red meat consumption, and daily exercise are important foundations of lifestyle modification recommendations for patients with gout or hyperuricemia and parallel recommendations related to prevention of coronary heart disease, diabetes, and certain types of cancer. Patients with gout could consider using plantderived ␻-3 fatty acids or supplements of eicosapentaenoic acid and docosahexanoic acid instead of consuming fish for cardiovascular benefits. The recent recommendation on dairy consumption for the general public would also be applicable for most patients with gout or hyperuricemia and may offer added benefit to individuals with hypertension, diabetes, and cardiovascular disorders. Further risk– benefit assessments in each specific clinical context would be helpful. Daily consumption of nuts and legumes as recommended by the Harvard Healthy Eating Pyramid (32) may also provide important health benefits without increasing the risk for gout. Similarly, a daily glass of wine may benefit health without imposing an elevated risk for gout, especially in contrast to beer or liquor consumption. These lifestyle modifications are inexpensive and safe and, when combined with drug therapy, may result in better control of gout. Effective management of gout risk factors (for example, hypertension) and the strategic choice of certain therapies for comorbid conditions may also aid gout care. For example, antihypertensive agents with uricosuric properties (for example, losartan [165] or amlodipine [86]) could 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 511


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 patient’s 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 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, [email protected]

Current author addresses are available at 512 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

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, O’Fallon 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 diet—insights 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

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 (McArdle’s 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


Dis. 1998;57:509-10. [PMID: 9849306] 55. Lee J, Sparrow D, Vokonas PS, Landsberg L, Weiss ST. Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol. 1995;142: 288-94. [PMID: 7631632] 56. Rathmann W, Funkhouser E, Dyer AR, Roseman JM. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Coronary Artery Risk Development in Young Adults. Ann Epidemiol. 1998;8:25061. [PMID: 9590604] 57. Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC. Incidence and risk factors for gout in white men. JAMA. 1991;266:3004-7. [PMID: 1820473] 58. Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis. 2000;59:539-43. [PMID: 10873964] 59. Yamashita S, Matsuzawa Y, Tokunaga K, Fujioka S, Tarui S. Studies on the impaired metabolism of uric acid in obese subjects: marked reduction of renal urate excretion and its improvement by a low-calorie diet. Int J Obes. 1986;10: 255-64. [PMID: 3771090] 60. Emmerson BT. Alteration of urate metabolism by weight reduction. Aust N Z J Med. 1973;3:410-2. [PMID: 4519128] 61. Ter Maaten JC, Voorburg A, Heine RJ, Ter Wee PM, Donker AJ, Gans RO. Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. Clin Sci (Lond). 1997;92:51-8. [PMID: 9038591] 62. Muscelli E, Natali A, Bianchi S, Bigazzi R, Galvan AQ, Sironi AM, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens. 1996;9:746-52. [PMID: 8862220] 63. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002;417:447-52. [PMID: 12024214] 64. Bedir A, Topbas M, Tanyeri F, Alvur M, Arik N. Leptin might be a regulator of serum uric acid concentrations in humans. Jpn Heart J. 2003;44: 527-36. [PMID: 12906034] 65. Fruehwald-Schultes B, Peters A, Kern W, Beyer J, Pfutzner A. Serum leptin is associated with serum uric acid concentrations in humans. Metabolism. 1999; 48:677-80. [PMID: 10381138] 66. Bakker SJ, Gans RO, ter Maaten JC, Teerlink T, Westerhoff HV, Heine RJ. The potential role of adenosine in the pathophysiology of the insulin resistance syndrome. Atherosclerosis. 2001;155:283-90. [PMID: 11254897] 67. Balakrishnan VS, Coles GA, Williams JD. Effects of intravenous adenosine on renal function in healthy human subjects. Am J Physiol. 1996;271:F374-81. [PMID: 8770169] 68. Balakrishnan VS, Coles GA, Williams JD. A potential role for endogenous adenosine in control of human glomerular and tubular function. Am J Physiol. 1993;265:F504-10. [PMID: 8238379] 69. Fransen R, Koomans HA. Adenosine and renal sodium handling: direct natriuresis and renal nerve-mediated antinatriuresis. J Am Soc Nephrol. 1995;6: 1491-7. [PMID: 8589328] 70. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-7. [PMID: 12365955] 71. Freedman DS, Khan LK, Serdula MK, Galuska DA, Dietz WH. Trends and correlates of class 3 obesity in the United States from 1990 through 2000. JAMA. 2002;288:1758-61. [PMID: 12365960] 72. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-9. [PMID: 11790215] 73. Wyngaarden JB, Kelley WN. Gout and Hyperuricemia. New York: Grune & Stratton; 1976. 74. Prebis JW, Gruskin AB, Polinsky MS, Baluarte HJ. Uric acid in childhood essential hypertension. J Pediatr. 1981;98:702-7. [PMID: 7229748] 75. Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med. 1980;93:817-21. [PMID: 7447188] 76. Diamond HS, Paolino JS. Evidence for a postsecretory reabsorptive site for uric acid in man. J Clin Invest. 1973;52:1491-9. [PMID: 4703233] 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 513


Pathogenesis of Gout

77. Giebisch G, Windhager E. Transport of urea, glucose, phosphate, calcium, magnesium, and organic solutes. In: Boron W, Boulpaep E, eds. Medical Physiology. Philadelphia: WB Saunders; 2003:790-813. 78. Caspi D, Lubart E, Graff E, Habot B, Yaron M, Segal R. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum. 2000;43:103-8. [PMID: 10643705] 79. Steele TH. Evidence for altered renal urate reabsorption during changes in volume of the extracellular fluid. J Lab Clin Med. 1969;74:288-99. [PMID: 5799512] 80. Steele TH, Oppenheimer S. Factors affecting urate excretion following diuretic administration in man. Am J Med. 1969;47:564-74. [PMID: 4309843] 81. Lin HY, Rocher LL, McQuillan MA, Schmaltz S, Palella TD, Fox IH. Cyclosporine-induced hyperuricemia and gout. N Engl J Med. 1989;321:28792. [PMID: 2664517] 82. Gupta AK, Rocher LL, Schmaltz SP, Goldfarb MT, Brown MD, Ellis CN, et al. Short-term changes in renal function, blood pressure, and electrolyte levels in patients receiving cyclosporine for dermatologic disorders. Arch Intern Med. 1991;151:356-62. [PMID: 1992963]. 83. Hansen JM, Fogh-Andersen N, Leyssac PP, Strandgaard S. Glomerular and tubular function in renal transplant patients treated with and without ciclosporin A. Nephron. 1998;80:450-7. [PMID: 9832645] 84. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol. 2000;11:974-9. [PMID: 10770978] 85. Ahn KJ, Kim YS, Lee HC, Park K, Huh KB. Cyclosporine-induced hyperuricemia after renal transplant: clinical characteristics and mechanisms. Transplant Proc. 1992;24:1391-2. [PMID: 1496597] 86. Chanard J, Toupance O, Lavaud S, Hurault de Ligny B, Bernaud C, Moulin B. Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients. Nephrol Dial Transplant. 2003;18:2147-53. [PMID: 13679494] 87. Starzl TE, Fung J, Jordan M, Shapiro R, Tzakis A, McCauley J, et al. Kidney transplantation under FK 506. JAMA. 1990;264:63-7. [PMID: 1693970] 88. Boots JM, van Duijnhoven EM, Christiaans MH, Nieman FH, van Suylen RJ, van Hooff JP. Single-center experience with tacrolimus versus cyclosporineNeoral in renal transplant recipients. Transpl Int. 2001;14:370-83. [PMID: 11793034] 89. Reyes AJ. Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther. 2003;17:397-414. [PMID: 15107595] 90. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, 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;15:164-73. [PMID: 14694169] 91. Roch-Ramel F, Guisan B. Renal transport of urate in humans. News Physiol Sci. 1999;14:80-84. [PMID: 11390825] 92. Simmonds HA, Hatfield PJ, Cameron JS, Cadenhead A. Uric acid excretion by the pig kidney. Am J Physiol. 1976;230:1654-61. [PMID: 7142] 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. [PMID: 4031062] 94. Roch-Ramel F, Guisan B, Schild L. Indirect coupling of urate and p-aminohippurate transport to sodium in human brush-border membrane vesicles. Am J Physiol. 1996;270:F61-8. [PMID: 8769823] 95. Padova J, Bendersky G. Hyperuricemia in diabetic ketoacidosis. N Engl J Med. 1962;267:530-4. [PMID: 14483098] 96. Gershon SL, Fox IH. Pharmacologic effects of nicotinic acid on human purine metabolism. J Lab Clin Med. 1974;84:179-86. [PMID: 4367231] 97. Blomstedt JW, Aronson PS. pH gradient-stimulated transport of urate and p-aminohippurate in dog renal microvillus membrane vesicles. J Clin Invest. 1980;65:931-4. [PMID: 7358852] 98. Guggino SE, Martin GJ, Aronson PS. Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am J Physiol. 1983;244:F61221. [PMID: 6859253] 99. Kahn AM, Aronson PS. Urate transport via anion exchange in dog renal microvillus membrane vesicles. Am J Physiol. 1983;244:F56-63. [PMID: 6849384] 100. Kahn AM, Branham S, Weinman EJ. Mechanism of urate and p-aminohippurate transport in rat renal microvillus membrane vesicles. Am J Physiol. 1983;245:F151-8. [PMID: 6309010] 514 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

101. Roch-Ramel F, Werner D, Guisan B. Urate transport in brush-border membrane of human kidney. Am J Physiol. 1994;266:F797-805. [PMID: 8203564] 102. Garcia ML, Benavides J, Valdivieso F. Ketone body transport in renal brush border membrane vesicles. Biochim Biophys Acta. 1980;600:922-30. [PMID: 7407151] 103. Manganel M, Roch-Ramel F, Murer H. Sodium-pyrazinoate cotransport in rabbit renal brush border membrane vesicles. Am J Physiol. 1985;249:F400-8. [PMID: 4037092] 104. Boumendil-Podevin EF, Podevin RA. Nicotinic acid transport by brush border membrane vesicles from rabbit kidney. Am J Physiol. 1981;240:F185-91. [PMID: 7212065] 105. Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, et al. The human tumour suppressor gene SLC5A8 expresses a Na⫹-monocarboxylate cotransporter. J Physiol. 2004;557:719-31. [PMID: 15090606] 106. Zandi-Nejad K, Plata C, Enck AH, Mercado A, Romero MF, Mount DB. Slc5a8 functions as a sodium-dependent pyrazinoate and nicotinate cotransporter; implications for renal urate transport. J Am Soc Nephrol. 2004;15:89A. 107. Weinman EJ, Eknoyan G, Suki WN. The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J Clin Invest. 1975;55: 283-91. [PMID: 1127100] 108. Ferris TF, Gorden P. Effect of angiotensin and norepinephrine upon urate clearance in man. Am J Med. 1968;44:359-65. [PMID: 4295950] 109. Moriwaki Y, Yamamoto T, Tsutsumi Z, Takahashi S, Hada T. Effects of angiotensin II infusion on renal excretion of purine bases and oxypurinol. Metabolism. 2002;51:893-5. [PMID: 12077737] 110. Quinones Galvan A, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995;268: E1-5. [PMID: 7840165] 111. Mintz DH, Canary JJ, Carreon G, Kyle LH. Hyperuricemia in hyperparathyroidism. N Engl J Med. 1961;265:112-5. [PMID: 13771118] 112. Kahn AM, Weinman EJ. Urate transport in the proximal tubule: in vivo and vesicle studies. Am J Physiol. 1985;249:F789-98. [PMID: 3000189] 113. Fanelli GM Jr, Weiner IM. Pyrazinoate excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs. J Clin Invest. 1973;52:1946-57. [PMID: 4719671] 114. Steele TH. Hyperuricemic nephropathies. Nephron. 1999;81 Suppl 1:45-9. [PMID: 9873214] 115. Yu TF, Gutman AB. Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man. J Clin Invest. 1959;38:1298-315. [PMID: 13673086] 116. Roch-Ramel F, Guisan B, Diezi J. Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles. J Pharmacol Exp Ther. 1997;280:839-45. [PMID: 9023298] 117. Kahn AM, Shelat H, Weinman EJ. Urate and p-aminohippurate transport in rat renal basolateral vesicles. Am J Physiol. 1985;249:F654-61. [PMID: 4061653] 118. Werner D, Roch-Ramel F. Indirect Na⫹ dependency of urate and paminohippurate transport in pig basolateral membrane vesicles. Am J Physiol. 1991;261:F265-72. [PMID: 1877650] 119. Ichida K, Hosoyamada M, Kimura H, Takeda M, Utsunomiya Y, Hosoya T, et al. Urate transport via human PAH transporter hOAT1 and its gene structure. Kidney Int. 2003;63:143-55. [PMID: 12472777] 120. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, et al. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001;59:1277-86. [PMID: 11306713] 121. Bakhiya A, Bahn A, Burckhardt G, Wolff N. Human organic anion transporter 3 (hOAT3) can operate as an exchanger and mediate secretory urate flux. Cell Physiol Biochem. 2003;13:249-56. [PMID: 14586168] 122. Sweet DH, Chan LM, Walden R, Yang XP, Miller DS, Pritchard JB. Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na⫹ gradient. Am J Physiol Renal Physiol. 2003;284:F763-9. [PMID: 12488248] 123. Aslamkhan A, Han YH, Walden R, Sweet DH, Pritchard JB. Stoichiometry of organic anion/dicarboxylate exchange in membrane vesicles from rat renal cortex and hOAT1-expressing cells. Am J Physiol Renal Physiol. 2003;285:F77583. [PMID: 12837685] 124. Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG.

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, O’Connell 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]


141. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest. 1995;96:994-1002. [PMID: 7543498] 142. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76:301-14. [PMID: 7507411] 143. Terkeltaub R, Baird S, Sears P, Santiago R, Boisvert W. The murine homolog of the interleukin-8 receptor CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model of acute urate crystal-induced gouty synovitis. Arthritis Rheum. 1998;41:900-9. [PMID: 9588743] 144. Fujiwara K, Ohkawara S, Takagi K, Yoshinaga M, Matsukawa A. Involvement of CXC chemokine growth-related oncogene-alpha in monosodium urate crystal-induced arthritis in rabbits. Lab Invest. 2002;82:1297-304. [PMID: 12379764] 145. Matsukawa A, Miyazaki S, Maeda T, Tanase S, Feng L, Ohkawara S, et al. Production and regulation of monocyte chemoattractant 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; 78:973-85. [PMID: 9714185] 146. Matsukawa A, Yoshimura T, Maeda T, Takahashi T, Ohkawara S, Yoshinaga M. Analysis of the cytokine network among tumor necrosis factor alpha, interleukin-1beta, interleukin-8, and interleukin-1 receptor antagonist in monosodium urate crystal-induced rabbit arthritis. Lab Invest. 1998;78:559-69. [PMID: 9605181] 147. Jaramillo M, Godbout M, Naccache PH, Olivier M. Signaling events involved in macrophage chemokine expression in response to monosodium urate crystals. J Biol Chem. 2004;279:52797-805. [PMID: 15471869] 148. Nishimura A, Akahoshi T, Takahashi M, Takagishi K, Itoman M, Kondo H, et al. Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol. 1997;62:444-9. [PMID: 9335313] 149. Rouleau P, Vandal K, Ryckman C, Poubelle PE, Boivin A, Talbot M, et al. The calcium-binding protein S100A12 induces neutrophil adhesion, migration, and release from bone marrow in mouse at concentrations similar to those found in human inflammatory arthritis. Clin Immunol. 2003;107:46-54. [PMID: 12738249] 150. Ryckman C, McColl SR, Vandal K, de Medicis R, Lussier A, Poubelle PE, et al. Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis. Arthritis Rheum. 2003;48:2310-20. [PMID: 12905486] 151. Ortiz-Bravo E, Sieck MS, Schumacher HR Jr. Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. Immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model. Arthritis Rheum. 1993;36: 1274-85. [PMID: 8216421] 152. Haskard DO, Landis RC. Interactions between leukocytes and endothelial cells in gout: lessons from a self-limiting inflammatory response. Arthritis Res. 2002;4 Suppl 3:S91-7. [PMID: 12110127] 153. Liote F, Prudhommeaux F, Schiltz C, Champy R, Herbelin A, OrtizBravo E, et al. Inhibition and prevention of monosodium urate monohydrate crystal-induced acute inflammation in vivo by transforming growth factor beta1. Arthritis Rheum. 1996;39:1192-8. [PMID: 8670330] 154. Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest. 2002;109:41-50. [PMID: 11781349] 155. Murakami Y, Akahoshi T, Kawai S, Inoue M, Kitasato H. Antiinflammatory effect of retrovirally transfected interleukin-10 on monosodium urate monohydrate crystal-induced acute inflammation in murine air pouches. Arthritis Rheum. 2002;46:2504-13. [PMID: 12355499] 156. Akahoshi T, Namai R, Murakami Y, Watanabe M, Matsui T, Nishimura A, et al. Rapid induction of peroxisome proliferator-activated receptor gamma expression in human monocytes by monosodium urate monohydrate crystals. Arthritis Rheum. 2003;48:231-9. [PMID: 12528124] 157. Terkeltaub R, Curtiss LK, Tenner AJ, Ginsberg MH. Lipoproteins containing apoprotein B are a major regulator of neutrophil responses to monosodium urate crystals. J Clin Invest. 1984;73:1719-30. [PMID: 6725556] 158. Terkeltaub RA, Dyer CA, Martin J, Curtiss LK. Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo. J Clin Invest. 1991;87:20-6. [PMID: 1985096] 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 515


Pathogenesis of Gout

159. Yu KH. Intraarticular tophi in a joint without a previous gouty attack. J Rheumatol. 2003;30:1868-70. [PMID: 12913949] 160. McCarthy GM, Barthelemy CR, Veum JA, Wortmann RL. Influence of antihyperuricemic therapy on the clinical and radiographic progression of gout. Arthritis Rheum. 1991;34:1489-94. [PMID: 1747133] 161. Liu R, Liote F, Rose DM, Merz D, Terkeltaub R. Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes. Arthritis Rheum. 2004;50:247-58. [PMID: 14730623] 162. Bouchard L, de Medicis R, Lussier A, Naccache PH, Poubelle PE. Inflammatory microcrystals alter the functional phenotype of human osteoblast-like cells

516 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7

in vitro: synergism with IL-1 to overexpress cyclooxygenase-2. J Immunol. 2002; 168:5310-7. [PMID: 11994489] 163. August P. Initial treatment of hypertension. N Engl J Med. 2003;348: 610-7. [PMID: 12584370] 164. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2004. 165. Tokahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis. 2003;62:572-5. [PMID: 12759298]

Annals of Internal Medicine Current Author Addresses: Dr. Choi: Division of Rheumatology, De-

partment 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.

4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 W-121


Review - American Physiological Society

PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE Physiology in Medicine: Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD,...

2MB Sizes 1 Downloads 31 Views

Recommend Documents

No documents