Etiology and pathogenesis of gout

Key Points

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Gout is a chronic disease of monosodium urate crystal deposition, which typically presents as recurrent episodes of severe, painful inflammatory arthritis. Monosodium urate crystals form from extracellular fluids saturated with urate, the endproduct of human purine metabolism.
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The gout flare is a severe but self-limited arthritis caused by an inflammatory response to monosodium urate crystals. Repeated gout flares and persistent crystal deposition can lead to chronic gouty arthritis, tophi, and erosive gout.
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Hyperuricemia (elevated serum urate concentration) is the central biochemical precursor for gout. It is generally classified as a serum urate concentration exceeding about 6.8 mg/dL (≈400 μM).
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Hyperuricemia results from an imbalance between urate production and excretion. In most patients with gout, hyperuricemia results from impairment of renal and gut excretion.
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Phagocytes from the synovial fluid of people with asymptomatic hyperuricemia and gout often contain monosodium urate crystals, without any overt inflammation, indicating crystals in the synovial compartment do not always elicit an inflammatory response.
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The gout flare is initiated by resident synovial cells, including phagocytes, which secrete chemokines and cytokines to attract and activate the neutrophils that predominate in the synovial cavity of acutely inflamed joints.
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Activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome by monosodium urate crystals, leading to release of mature interleukin-1β, is central to initiation of the gout flare.
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Termination of the gout flare is regulated by macrophage differentiation, release of antiinflammatory soluble mediators, and formation of aggregated neutrophil extracellular traps (NETs) that degrade proinflammatory cytokines. Aggregated NETs may also play a role in tophus formation.
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Joint damage in advanced gout is strongly linked to intraarticular tophi, with activation of catabolic pathways leading to focal cartilage and bone degradation.
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Defects in purine metabolic enzymes (e.g., hypoxanthine-guanine phosphoribosyltransferase and 5-phosphoribosyl 1-pyrophosphate synthetase 1) that result in urate overproduction are well-characterized causes of gout but account for fewer than 1% of cases.
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Large genetic studies have revealed many candidate genes associated with hyperuricemia and gout. These include genes involved in urate transport, metabolic pathways, regulation of inflammation, and regulation of gene expression. Genetic variations in the urate transporters SLC2A9 and ABCG2 are consistently and strongly associated with hyperuricemia and gout.

Gout is a chronic disease of monosodium urate (MSU) crystal deposition presenting as a painful and potentially destructive arthritis arising in the setting of hyperuricemia. Urate is the obligatory endproduct of human purine metabolism. The clinical manifestations of gout arise as a consequence of monosodium urate crystal deposition and include the gout flare, chronic gouty arthritis, and tophi. This chapter focuses on the pathophysiology of articular manifestations of gout, detailing the various “checkpoints” necessary in developing clinically evident gout ( Fig. 193.1 ).

Urate Physiology

The clinical features of gout occur as the result of inflammatory responses to monosodium urate crystals deposited because of one or more derangements in the physiology of urate. In contrast to the case in most mammals, urate is the final product of purine metabolism in humans and higher primate species, in which the gene encoding the enzyme uricase (urate oxidase) has been silenced by loss-of-function genetic variants.

Urate is the most abundant natural antioxidant in the human body ( Box 193.1 ). The traditional view has been that a major physiologic role of urate is to remove reactive oxygen species (ROS), possibly providing protection against oxidant-induced neurologic and cardiovascular degenerative processes. However, pegloticase, which leads to dramatic reductions in serum urate concentrations, did not show increased lipid or protein oxidation, suggesting that urate is not a major factor controlling oxidative stress in vivo.

Box 193.1

Physiologic Functions of Purines

Antioxidation (urate)
Nucleotide building blocks for nucleic acids (DNA and RNA)
Nucleotide components of coenzymes (e.g., coenzyme A, FAD, NAD)
High-energy phosphate donors in enzyme reactions (e.g., ATP)
Metabolic regulators (e.g., cyclic AMP, cyclic GMP)
Neurotransmitters
Extracellular messengers (e.g., adenosine, ATP)
Intracellular second messengers (e.g., G protein–coupled receptors)
Immunologic adjuvants, endogenous “danger” signal for innate immunity
Maintenance of extracellular volume, vascular tone (urate) (hypothesized)

AMP , Adenosine monophosphate; ATP , adenosine triphosphate; FAD , flavin adenine dinucleotide; GMP , guanosine monophosphate; NAD , nicotinamide adenine dinucleotide.

Urate may also have an important role in immune surveillance. Distressed and dying cells produce locally high urate concentrations as a “danger” signal, which acts as an endogenous adjuvant to help trigger inflammatory and both innate and specific immune responses (discussed in more detail later). Urate may also have had an evolutionary role in maintenance of blood pressure and intravascular volume.

Forms of Urate

Urate exists in biologic systems in two forms with limited solubility, the ionized form (uric acid) and the unionized form (urate; Fig. 193.2 ). Uric acid (C ₅ H ₄ N ₄ O ₃ ; 2, 6, 8-trioxypurine) is a weak organic acid ionized at position 9 with a functional pK _a1 in serum of 5.75. At the physiologic pH of most body fluids (pH of 7.4), urate ion levels exceed those of unionized uric acid in a ratio of about 50 to 1. In acidic body fluids (such as urine, pH of 5.0), unionized uric acid predominates. Because of the high concentration of sodium in extracellular fluid, urate mainly functions as monosodium urate (MSU). As a consequence, the high solubility of the urate ion (≈120 mg/dL or 7.1 mM) is replaced by the much lower solubility of monosodium urate (≈6.8 mg/dL or 400 μM). Similarly, the solubility of uric acid is only about 10 to 15 mg/dL (≈600–900 μM).

Fig. 193.2, At physiologic pH (7.4), urate predominates at about 50 : 1 over unionized uric acid. Urate ion solubility is functionally reduced at the high sodium concentration of extracellular fluids, so monosodium urate and uric acid have relatively low solubilities in biologic fluids.

Serum urate concentrations exceeding 6.8 mg/dL are saturating, a condition referred to as hyperuricemia. Persistent hyperuricemia reflects extracellular fluid urate saturation. At these saturated levels, monosodium urate monohydrate crystals are able to form and deposit in the joints and other tissues. In the acidic environment of the urine, uric acid crystals and stones (distinct from monosodium urate crystals) form in the urinary tract. Increasing levels of hyperuricemia impart increasing risk for monosodium urate crystal deposition and the associated clinical consequences.

Hyperuricemia is very common, affecting more than 20% of adult White men in the United States, and is even more common among certain ethnicities. Although hyperuricemia most often does not evolve into clinical gout, it is associated with several highly prevalent chronic disorders, as discussed in Chapter 192 .

Urate Production and Excretion

Urate Balance

Urate levels are maintained through a delicate balance between production and excretion. This balance can be altered by many factors, including genetics, environment, other clinical conditions, and medications (see Fig. 193.3 and Box 193.2 ). These factors alter both production and excretion, with some having much larger influence than others.

Fig. 193.3, The systemic urate pool and the likelihood of gout are determined by the dynamic balance between endogenous synthesis and recycling of purines and excretion by the kidney and gut. ABCG2 , ATP-binding cassette subfamily G member 2; ATP , adenosine triphosphate; GLUT9 , glucose transporter 9; MRP4 , multidrug resistance protein 4; NPT1 , sodium phosphate transport protein 1; URAT1 , urate transporter 1.

Box 193.2

Factors Associated with Urate Variation

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

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

The bulk of urate usually derives from endogenous synthesis of purines from small-molecule nonpurine precursors, breakdown of dietary purines, and reutilization of preformed body purine compounds, as diet contains little urate, and dietary urate is poorly absorbed. Urate production occurs largely in the liver and to a minimal degree the small intestine. Urate released from cells circulates relatively free (<4%) of serum protein binding so that all or nearly all circulating urate is filtered at the glomerulus. Under steady-state conditions, urate production is balanced by excretion, largely through renal excretion of uric acid (equivalent to about two thirds of daily production). Urate secretion into the small intestine, with breakdown of urate by gut bacteria (intestinal uricolysis), accounts for nearly all the rest of urate excretion. The body pool of urate is expanded in hyperuricemic states resulting from impaired urate excretion or urate overproduction.

Urate pools in normal men range from about 800 to 1500 mg and in women from 500 to 1000 mg. Daily turnover of the body’s urate pool (balanced production and excretion) is considerable, averaging 0.6 to 0.7 pools (≈0.5 to 1 g) every day.

Serum urate concentrations in children are lower than those in adults. During male puberty, values increase into the adult male range. Serum urate levels remain lower in women of reproductive age than in their male counterparts. This gender difference results mostly from the action of estrogens, which alter the activity of key urate transporter proteins in the kidney. This results in less renal tubular uric acid reabsorption and thus increased uric acid clearance in women. With the onset of menopause, serum urate values in women increase and approach or equal those of men.

Urate saturation of extracellular fluids (for which hyperuricemia is a surrogate marker) predisposes to monosodium urate crystal formation and deposition, events required for clinical expression of gout. The natural differences in serum urate levels between men and women explain the greater prevalence of gout in men. Additionally, the increase in serum urate levels in postmenopausal women is accompanied by increases in the incidence of hyperuricemia and, over the succeeding 2 to 3 decades, gout.

Purine Metabolism and Urate Production

Urate is the endproduct of purine metabolism in humans and other great apes, as well as birds and reptiles. Purines are compounds possessing the nine-member purine nucleus composed of fused pyrimidine and imidazole rings. Purines fulfill essential functions in all living cells (see Box 193.1 ). Most functions of purines are carried out by nucleotide and nucleoside derivatives of the purine bases adenine, hypoxanthine, and guanine. Representative structures of purine bases, nucleosides, and nucleotides are shown in Fig. 193.4 .

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

The biochemical pathways of purine metabolism and their regulation are discussed in more detail elsewhere. The only endogenous pathway of net purine production is called purine synthesis de novo and involves 10 steps ( Fig. 193.5 ). The purine ring is synthesized on a backbone of ribose-5-phosphate donated by the key regulatory substrate, 5-phosphoribosyl 1-pyrophosphate (PRPP) from the pentose phosphate sugar pathway. The endproduct of this pathway is the nucleotide inosine monophosphate (IMP). IMP serves as a branch point in the conversion of new purines into the adenylate and guanylate classes of purine nucleotides or, alternatively, into the purine degradation pathway, culminating in urate formation.

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

Purine synthesis de novo is an energy costly process. Considerable saving in cellular energy expenditure is achieved by an extensive network of reactions that interconvert and salvage purine nucleotides, nucleosides, and bases. This saves energy and provides flexibility in the provision of specific purines to a wide array of cellular functions.

Degradation of purine nucleotides and nucleosides to purine bases culminates in the key urate precursors, hypoxanthine and guanine. These are mostly reused in salvage reactions with PRPP, catalyzed by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The remainder of guanine is deaminated to xanthine. Unsalvaged hypoxanthine is oxidized to xanthine, which undergoes further oxidation to urate. The enzyme xanthine oxidoreductase (XOR) catalyzes both the conversions of hypoxanthine to xanthine and xanthine to urate.

Xanthine oxidoreductase is a molybdopterin cofactor and iron sulfide cluster-containing flavoprotein that exists in interconvertible forms: an oxidase form (xanthine oxidase [XO]) that uses oxygen (O ₂ ) to convert hypoxanthine and xanthine to urate and a dehydrogenase form (XDH) that uses the nucleotide NAD ⁺ . Inhibition of XOR activity is the major action of the most common class of agents used for urate lowering in patients with gout. Other roles for xanthine oxidoreductase have been proposed, including protection from infection and tissue injury (caused by the generation of unstable oxygen radicals) during and after ischemia.

Purine nucleotide synthesis and degradation are both carefully regulated processes ( Fig. 193.6 ). Malfunctions in this regulatory process lead to increased cellular levels of PRPP, resulting in accelerated purine nucleotide and urate production. This occurs in two rare X chromosome–linked disorders (discussed later). Similarly, excessive cellular adenosine triphosphate (ATP) depletion (e.g., in tissue hypoxia or acute alcohol intoxication) can lead to reduced inhibitory nucleotide concentrations and consequent urate overproduction. Other states of excessive urate production among patients with gout are not as well characterized at the pathway level.

Fig. 193.6, The major purine synthetic steps targeted by regulation are (1) the synthesis of PRPP in the PRPP synthetase (PRS) reaction and (2) the utilization of PRPP in the first step of purine synthesis de novo. Rates of the 10-step de novo pathway of purine nucleotide synthesis (vertical arrows) are regulated by the activity of the enzyme AmidoPRT, which catalyzes the first step. AmidoPRT activity is allosterically controlled by the antagonistic interaction of pathway purine nucleotide products that inhibit (−) the enzyme and the regulatory substrate 5-phosphoribosyl 1-pyrophosphate (PRPP) that activates (+) AmidoPRT. Purine nucleotides also inhibit (−) PRPP synthetase, the enzyme-catalyzing synthesis of PRPP. Regulation directed at these sequential reactions provides a flexible means to control purine nucleotide production in an economical manner, a process potentiated by preferential single-step salvage of preformed purine bases in reactions with PRPP catalyzed by the phosphoribosyltransferase enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and APRT (depicted by the curved arrows ). APT , Adenosine triphosphate; Rib-5-P , ribose-5-phosphate.

Urate Excretion

Urate excretion is mediated by multiple transporter proteins in the renal proximal tubule and the intestinal mucosa. The majority of urate is disposed of through the renal pathway (~60%), with the remaining ~30% being disposed of via the intestinal pathway. The sum of urate excretion via these two pathways almost makes up the total urate clearance, and each pathway can compensate, to a small extent, for underexcretion by the other pathway.

Extrarenal urate excretion

Urate excretion in the intestines is primarily mediated by ABCG2, an ATP-binding cassette (ABC) transporter, encoded by the gene ABCG2 . ABCG2 functions in both the kidney and intestine, and dysfunction is associated with hyperuricemia and gout. Analysis of the role of ABCG2 in intestinal handling of urate has challenged the conventional concept of hyperuricemia caused by urate overproduction. Abcg2 knockout mice have reduced intestinal urate excretion, leading to higher serum urate levels. Despite also lacking Abcg2 in the kidneys, renal uric acid excretion in this situation is still higher than normal, indicating that other transporters in the kidney can partially compensate.

Reduced extrarenal urate excretion leads to an increase in the renal excretion load, which gives the appearance of urate overproduction. Thus it has been suggested that urate overproduction may be better described as “renal overload,” consisting in turn of “extrarenal underexcretion” and “genuine urate overproduction” subtypes.

Renal urate excretion

Despite nearly complete filtration of urate at the glomerulus, renal uric acid clearance in adults averages only 5% to 10% that of creatinine clearance, reflecting net renal tubular reabsorption of about 90% of filtered uric acid. Within the renal tubule, uric acid reabsorption and secretion are regulated by a series of transporter proteins that ultimately regulate serum urate concentrations.

Most people with hyperuricemia resulting from impaired renal uric acid excretion show normal amounts of uric acid in the urine but have selectively reduced uric acid clearance. Excretion of “normal” amounts of uric acid is accomplished by patients with gout only when serum urate levels are 2 to 3 mg/dL (120 to 180 μM) higher than in healthy people excreting the same amounts of uric acid. The hyperuricemia that results from this is the prime risk factor for developing gout.

Many mechanisms contribute to net uric acid excretion. Molecular and genomic approaches have identified several transporters involved in renal uric acid excretion, including some with substantial specificity for uric acid. Alterations in uric acid movement may be caused by changes in these urate transporters, changes in associated proteins or ion cotransporters, or regulation of transport function. Two of these urate transporters, glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), have strong effects on serum urate levels ( Fig. 193.7 ).

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

Urate transporters

Glucose transporter 9

Glucose transporter 9 (GLUT9) is the product of the SLC2A9 gene. It is a voltage-driven urate transporter that mediates uric acid reabsorption from the tubular cell to the circulation. Glucose transporter 9 also transports the sugars glucose and fructose. In humans, GLUT9 exists in two isoforms: GLUT9L, identified on the basolateral aspects (“blood” side) of the proximal renal tubular epithelial cell, and GLUT9S on the apical (“urine”) side.

Glucose transporter 9 is also expressed in the basolateral membrane of hepatocytes and regulates serum urate concentrations through dual roles in uric acid handling in the kidney and uptake in the liver. Mice with systemic knockout of Slc2a9 (Glut9) have moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy. In contrast, specific inactivation of the Slc2a9 gene in the livers of adult mice leads to severe hyperuricemia and hyperuricosuria, without renal disease.

Urate transporter 1

Urate transporter 1 (URAT1) is encoded by the SLC22A12 gene and has a typical organic anion transporter structure. URAT1 is highly specific for uric acid. URAT1 mediates the exchange of uric acid for a variety of endogenous and drug anions known to affect renal uric acid transport. Similar to GLUT9S, URAT1 localizes to the apical brush border membrane of proximal tubular epithelial cells and is involved in the reabsorption of uric acid from the lumen. The uricosuric drugs probenecid, benzbromarone, and lesinurad increase uric acid excretion by inhibiting URAT1 and other OATs.

URAT1 interacts with the scaffolding protein PDZK1. PDZ motifs are typically involved in protein–protein interactions that support intracellular signaling and are also present in other urate transporters, including OAT4 and sodium phosphate transport protein 1 (NPT1, discussed below). This suggests that a more extensive multiprotein complex, the “urate transportasome” (containing transporters, transport regulatory molecules, hormone receptors, and intracellular signaling elements), may be involved in regulating bidirectional uric acid transport across the renal tubular epithelial cell. The fractional renal excretion of Uric acid (FEua = uric acid clearance/creatinine clearance × 100%) in Slc22a12 (Urat1) knockout mice remains substantially less than 100%. This confirms that there are multiple mechanisms of uric acid reabsorption.

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