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Gout

Gout

Robert Terkeltaub, MD; N. Lawrence Edwards, MD, MACP, MACR; Puja Khanna, MD, MPH 
Reviewed on July 16, 2024
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Introduction

Gout is a disease recognized since antiquity and has been termed the “disease of kings, and king of diseases.” Gout has long been associated, in the public’s eye, with wealth and power in affected middle-aged men. However, the disease is now underestimated in impact due to this outdated caricature of the average patient, and the obsolete impression that the clinical problem is simply self-limited, narrow in reach within the population and easy to control with straightforward temperance in diet and alcohol intake. Over the last few decades, gout has markedly increased in prevalence and clinical complexity and it has recently been estimated that gout prevalence is as high as 3.9% of adults in the United States.

  • Gout has markedly increased in prevalence and increased overall in clinical complexity over the last 2 decades.
  • Dietary trends, increased longevity, comorbidities and iatrogenic factors have shaped the changing epidemiology and clinical landscape of…

Introduction

Gout is a disease recognized since antiquity and has been termed the “disease of kings, and king of diseases.” Gout has long been associated, in the public’s eye, with wealth and power in affected middle-aged men. However, the disease is now underestimated in impact due to this outdated caricature of the average patient, and the obsolete impression that the clinical problem is simply self-limited, narrow in reach within the population and easy to control with straightforward temperance in diet and alcohol intake. Over the last few decades, gout has markedly increased in prevalence and clinical complexity and it has recently been estimated that gout prevalence is as high as 3.9% of adults in the United States.

  • Gout has markedly increased in prevalence and increased overall in clinical complexity over the last 2 decades.
  • Dietary trends, increased longevity, comorbidities and iatrogenic factors have shaped the changing epidemiology and clinical landscape of gout.
  • The diagnostic criteria and imaging tools for gout are evolving.
  • Treatment-refractory gouty arthritis and hyperuricemia are growing challenges.
  • Safe and cost-effective treatment is built on a foundation of attention to therapeutic benchmarks that achieve the best outcomes, with patient education and treatment adherence, the cornerstones of gout and hyperuricemia therapy.
  • New treatments are emerging and available for difficult gouty arthritis and hyperuricemia.

We see increasing numbers of more severe and treatment-refractory cases with iatrogenic factors, multiple comorbidities and advanced age, and increasingly often, patients require hospital admission and inpatient treatment for gout flare. The good news is that genetic, translational, and clinical research advances in gout continue to spawn improved and novel evidence-based strategies and new Food and Drug Administration (FDA)-approved treatments (and other compelling treatments in advanced clinical trials) to safely and more effectively treat gouty arthritis and hyperuricemia. These measures are summarized here for the busy clinician, as are highly valuable diagnostic modalities that have emerged in the last decade, such as high resolution ultrasound (done in-office in many rheumatology practices) and dual-energy computed tomography (DECT) imaging.

This module discusses outcome measures that allow physicians to better assess therapeutic targets for improved quality of care and health-related quality of life (HRQOL) in gout. In addition, we review how to best educate patients to encourage their adherence to the gout therapeutic program, a key aspect of the success of management. In doing so, we summarize diet, lifestyle and other nonpharmacologic measures that most patients ask and care about and that are so vital to an effective and comprehensive management program. Clearly, management should improve the gout patient’s overall health, since gout and hyperuricemia are at the very least biomarkers for increased cardiovascular (CV), metabolic, and renal disease and CV mortality.

Collectively, gout has been redefined at the levels of the subjects affected, diagnosis, treatment, and definition of appropriate therapeutic targets and outcomes. Novel approaches to diagnosis and management of gouty arthritis and hyperuricemia make it exciting to treat gout patients now and in the future. This is particularly so for cases in the past in which available treatment would have failed.

Disease Definition and Overview of Pathogenesis

The development of supersaturation of a variety of solutes in tissue extracellular fluids can result in deposition of a variety of crystals (or stones, alternatively termed “calculi”). Pathologic deposition of crystalline salts can manifest clinically in the biliary tract and urinary tract, and also in the extracellular matrix of connective tissues of the artery wall (as calcification in atherosclerosis). Crystal deposition diseases that manifest as joint disease include calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (which can cause an acute inflammatory arthritis commonly known as “pseudogout”), hydroxyapatite (HA) crystal deposition disease, and the articular manifestations of oxalate crystal deposition. Gout serves as a prime example of a systemic crystal deposition disorder that causes arthritis and is the subject of this module.

In gout, an elevation in the concentration of urate beyond its solubility threshold (experimentally defined as >6.8 mg/dL in vitro in physiologic buffer) promotes deposition of crystals of the monosodium salt of uric acid (monosodium urate [MSU] crystals) in joint fluid and on the articular cartilage surface, and into larger structures containing aggregated crystals that are termed tophi. Sites where urate crystal deposits and tophi typically first develop have relatively low core temperature, which decreases urate solubility and a connective tissue matrix that may not be well vascularized. Such sites include the synovium and cartilage of peripheral joints (particularly occurring first in the more distal, cooler joints), the olecranon bursa and the helix of the ear.

Definitions

Gout

Gout is defined as a disorder resulting from tissue deposition of MSU crystals (in joints, bursae, bone and certain other soft tissues, such as ligaments, tendons, and, occasionally, skin) and/or crystallization of uric acid within the renal collecting system (tubules and renal pelvis) that typically occurs in acid urine (Table 1-1). Gout manifests clinically as arthritis due to inflammatory reactions related to microscopic and macroscopic soft tissue deposits of MSU crystals, including those aggregated in tophi. The urate crystals often exist silently in tissues for long periods between symptoms.

Urate crystal deposits can trigger intense but self-limited bouts of acute arthritis (“flares”), characteristically with excruciating pain and articular and periarticular inflammation. Tissue urate crystal deposits occur in a substantial fraction of asymptomatic hyperuricemia, as detected by advanced imaging (dual energy CT [DECT] and ultrasound, Diagnosis of Gout and Use of Laboratory and Imaging), but the volume of the crystal deposits is less than that in patients who have had symptomatic gouty arthritis. This suggests that a threshold of crystal deposits is needed for gout to develop in most people. However, the clinical phenotype of the gouty inflammatory response is variable, even with comparable volumes of tissue urate crystal deposits.

Classic triggers of gout flares are cited in Table 1-2 and include trauma, alcohol and diet indiscretion, concurrent medical or surgical illness and dehydration. Seasonal factors are significant, likely in large part via dehydration, since gout flares are more frequent in spring and summer than in other seasons (Prophylaxis of Acute Gout Flares). Chronic inflammatory and erosive arthritis also can develop in gout. In some patients, gout also manifests as urolithiasis, promoted in part by urine acidity, and increased urine uric acid can promote both uric acid and calcium oxalate urolithiasis.

In more severe cases, clinically significant interstitial nephropathy develops, mediated by deposition of MSU crystals in the physiologic pH milieu of the renal medullary interstitium (a condition termed “gouty nephropathy,” which impairs renal function). However, clinically significant gouty nephropathy is uncommon, although the prevalence and extent of anatomic urate crystal deposition in the renal interstitium in gout is not currently defined. In the past, recognition of gouty interstitial nephropathy was driven by histopathologic evaluation, but it is possible, subject to future testing, that more sensitive advanced imaging approaches than those currently available could be employed to help recognize this condition noninvasively.

There is abundant evidence that an expanded disease definition of gout should include a strong association of the disease (and of hyperuricemia alone) with increased cardiovascular (CV) disease and CV mortality. Essentially, gout (and hyperuricemia) are biomarkers for increased CV disease, hypertension and new-onset and progressive kidney disease (see: Who Gets Gout?). Hyperuricemia may be an independent and possibly causal risk factor for such diseases due to reported effects of soluble urate on vascular cells and possibly indirect effects of gouty inflammation. Moreover, birefringent deposits highly suggestive of monosodium urate crystals have been detected in the coronary arteries, as well as prostate, and tophi can develop in cardiac valves. The important issue of comorbidities of gout is discussed in more detail in Who Gets Gout?

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Hyperuricemia

Uric acid is the physiologic end product of purine metabolism. At physiologic pH (such as in serum and joint tissues), uric acid (which is a weak acid) exists as the anion urate, and plasma protein binding is quite low for urate. A marked increase in total body uric acid stores, reflected as hyperuricemia, is fundamental to the development of gout. Serum urate levels rise with puberty, and total-body miscible stores of uric acid reach ~1.2 g in the average adult man (range 800-1600 mg), with lower levels in adult women. Serum urate levels in women remain relatively stable overall until menopause, at which time serum urate rises in association with loss of the natural uricosuric effect of estrogen (i.e., loss of the promotion by estrogen of renal excretion of uric acid, which is likely mediated in large part by sex hormone effects on one or more major urate transporters). Therefore, gout in premenopausal women should trigger a search for renal disease, in particular analgesic-abuse nephropathy or other interstitial nephropathies.

In the past, hyperuricemia was defined as serum urate at least two standard deviations above the community average established by individual laboratories according to gender (Figure 1-1). Along those lines, hyperuricemia had previously been most widely defined as >7.0 mg/dL in adult men and >6.0 in premenopausal women. However, serum urate levels, such as those for obesity, vary among communities. Moreover, the limit of solubility of urate in physiologic solutions is 6.7 to 7.0 in vitro at 37oC. The solubility of urate declines progressively at cooler temperatures, such as those in the distal peripheral joints (e.g., first metatarsophalangeal [MTP] joint) where urate crystals typically first deposit in gout.

The current, and more medically and chemically appropriate, definition of hyperuricemia is a serum urate >6.8 mg/dL, whether in adult men or women (Figure 1-1). As discussed in this module, the NHANES III 2008 survey recorded the average serum urate in adults in the United States to be ~5.5 mg/dL, and ~21% of US adults have had recorded hyperuricemia. Clearly, in humans, “normal” serum urate concentrations provide only a narrow safety window against potential deposition of urate crystals in the most susceptible tissue sites. The risk of developing gout in those with asymptomatic hyperuricemia increases with higher serum urate level, and has suggested to be ~20% at 5 years in those with a serum urate of 9 mg/dL.

In this context, ultrasound survey of joints in subjects with asymptomatic hyperuricemia, discussed in Diagnosis of Gout and Use of Laboratory and Imaging, has noted evidence of articular surface urate crystal deposits in ~17% to 25% (of knees and toes) and intra-articular subclinical tophi in ~16%, with none in normouricemic controls. Moreover, DECT has also detected a similar frequency of deposits of urate crystals in the feet of subjects with asymptomatic hyperuricemia. Hence, there is the tantalizing possibility that advanced imaging might allow us to better predict which patients with hyperuricemia are likely to develop symptomatic gouty arthritis, and thereby inform earlier intervention strategies. Nevertheless, at the time of writing and as discussed elsewhere in this module, asymptomatic hyperuricemia is not a sufficient evidence-based indication for urate-lowering drug therapy.

Enlarge  Figure 1-1: Distribution of Serum Urate Values and Definition of Hyperuricemia. The physicochemical definition of hyperuricemia is a concentration of serum urate >6.8 mg/dL. At this value, urate loses solubility in physiologic solutions and crystallization can occur. When examining the distribution of urate in men and women from 1965 data and using this physicochemical definition of hyperuricemia, it is evident that many men and a smaller percentage of women in the general population have hyperuricemia.1) Because men tend to have higher serum urate levels than women, most laboratories utilize a normative range of serum urate for men and a normative range of serum urate for women. However, regardless of the patient’s gender and the serum urate cutoffs assigned by individual laboratories, serum urate crystallizes >6.8 mg/dL, and this level defines hyperuricemia. Source: Mikkelsen WM, et al. Am J Med. 1965;39:242-251.
Figure 1-1: Distribution of Serum Urate Values and Definition of Hyperuricemia. The physicochemical definition of hyperuricemia is a concentration of serum urate >6.8 mg/dL. At this value, urate loses solubility in physiologic solutions and crystallization can occur. When examining the distribution of urate in men and women from 1965 data and using this physicochemical definition of hyperuricemia, it is evident that many men and a smaller percentage of women in the general population have hyperuricemia.1) Because men tend to have higher serum urate levels than women, most laboratories utilize a normative range of serum urate for men and a normative range of serum urate for women. However, regardless of the patient’s gender and the serum urate cutoffs assigned by individual laboratories, serum urate crystallizes >6.8 mg/dL, and this level defines hyperuricemia. Source: Mikkelsen WM, et al. Am J Med. 1965;39:242-251.

Uric Acid Metabolism and Pathogenesis of Hyperuricemia

Uric acid is produced as the final end product of degradation of purines in humans and undergoes renal elimination as the dominant excretion mechanism. Figure 1-2 provides an overview of key facets of uric acid metabolism, highlighting target points for therapeutic drugs. Humans and other apes lost expression of uric acid oxidase (uricase) in evolution. Uricase oxidizes uric acid, leading to generation of the much more soluble compound allantoin (Figure 1-2), which undergoes renal excretion. Significantly, genetically engineered uricase knockout mice demonstrate marked increase in serum urate (from a normal level of ~1-2 mg/dL to ~10 mg/dL), highlighting the importance of the loss of uricase in human evolution.

Figure 1-3A schematically summarizes normal sources and elimination of uric acid in humans and illuminates the delicate balance of uric acid metabolism that facilitates hyperuricemia. Impaired renal uric acid elimination is the abnormality that causes hyperuricemia in the majority of gout patients, but it is not the sole or dominant cause of hyperuricemia in all cases of gout. Therefore, clinicians should always consider what the cause of hyperuricemia is in the individual patient.

Uric acid synthesis averages ~750 mg/day in adult men, but increased dietary purine intake stimulates higher production of uric acid. Gut elimination of uric acid, which couples transport into the small intestinal lumen and colonic bacterial urate oxidation by uricase, normally removes ~200 mg of uric acid daily in humans (Figure 1-3A), but this elimination pathway has limited potential for adaptive increases in capacity beyond ~100 mg more daily. Renal uric acid excretion in normal adult men on a low-purine diet is ~400 mg/day, but the normal amount cleared by the kidneys is up to ~750 mg/day on a typical Western diet. In adaptation to higher levels of uric acid generation, renal uric acid excretion increases substantially (as allowed by renal filtration and tubular urate anion reabsorption and secretion). Physiologic limits to renal uric acid excretion promote hyperuricemia. Excessive urate filtration can promote urolithiasis, which can be obstructive and nephrotoxic.

Importantly, most of the total-body miscible urate stores are normally turned over every day. This circumstance leads to the potential for substantial expansion of total-body urate stores over time, even with a relatively moderate increase in uric production or decrease in uric acid elimination, as schematized in Figure 1-3B. The many genetic, dietary, comorbid, iatrogenic and environmental factors that influence uric acid generation and removal to cause hyperuricemia are cited in Table 1-3, and often many of these factors act in concert.

Enlarge  Figure 1-2: Final Pathways of Uric Acid Metabolism and Renal Elimination and Primary Therapeutic Sites of Action of Allopurinol, Febuxostat, Uricases (e.g., Pegloticase), and Uricosurics. As depicted in this schematic, xanthine oxidase generates uric acid as the end product of purine metabolism. Allopurinol (pictured) and its major active metabolite oxypurinol (which has a much longer half-life than allopurinol and is primarily eliminated by renal excretion) inhibit xanthine oxidase, and also suppress uric acid generation upstream by additional mechanisms. Febuxostat (pictured), is a selective xanthine oxidase inhibitor and, in further distinction to allopurinol and oxypurinol, does not have a purine-like backbone. Uricase (pictured) oxidizes sparingly soluble uric acid to generate oxidative intermediates that in humans are converted nonenzymatically to highly soluble allantoin. Uricase expression was lost in apes (including humans) during evolution, promoting baseline serum urate levels several higher than in other mammals. Importantly, a PEGylated uricase (pegloticase) is FDA approved for use in gout. Almost all circulating urate is filtered by the glomeruli, with only a small fraction (~10%) normally excreted in the urine as uric acid. The proximal tubule serves as the major locus for both urate reabsorption and secretion, and uricosurics (e.g., probenecid, benzbromarone [outside the United States]) primarily act by suppressing urate anion reabsorption by the proximal tubule epithelial cell. Source: Terkeltaub R. Nat Rev Rheumatol. 2010;6(1):30-38.
Figure 1-2: Final Pathways of Uric Acid Metabolism and Renal Elimination and Primary Therapeutic Sites of Action of Allopurinol, Febuxostat, Uricases (e.g., Pegloticase), and Uricosurics. As depicted in this schematic, xanthine oxidase generates uric acid as the end product of purine metabolism. Allopurinol (pictured) and its major active metabolite oxypurinol (which has a much longer half-life than allopurinol and is primarily eliminated by renal excretion) inhibit xanthine oxidase, and also suppress uric acid generation upstream by additional mechanisms. Febuxostat (pictured), is a selective xanthine oxidase inhibitor and, in further distinction to allopurinol and oxypurinol, does not have a purine-like backbone. Uricase (pictured) oxidizes sparingly soluble uric acid to generate oxidative intermediates that in humans are converted nonenzymatically to highly soluble allantoin. Uricase expression was lost in apes (including humans) during evolution, promoting baseline serum urate levels several higher than in other mammals. Importantly, a PEGylated uricase (pegloticase) is FDA approved for use in gout. Almost all circulating urate is filtered by the glomeruli, with only a small fraction (~10%) normally excreted in the urine as uric acid. The proximal tubule serves as the major locus for both urate reabsorption and secretion, and uricosurics (e.g., probenecid, benzbromarone [outside the United States]) primarily act by suppressing urate anion reabsorption by the proximal tubule epithelial cell. Source: Terkeltaub R. Nat Rev Rheumatol. 2010;6(1):30-38.
Enlarge  Figure 1-3: Sources and Distribution of Uric Acid in an Adult Man Without Gout vs an Adult Mane With Gout. Driven by Uric Acid Underexcretion. (A) Sources and distribution of uric acid in an adult man without gout. (B)Examples of distribution of uric acid in an adult man with gout driven by uric acid underexcretion.
Figure 1-3: Sources and Distribution of Uric Acid in an Adult Man Without Gout vs an Adult Mane With Gout. Driven by Uric Acid Underexcretion. (A) Sources and distribution of uric acid in an adult man without gout. (B)Examples of distribution of uric acid in an adult man with gout driven by uric acid underexcretion.

Overall Effects of Inherited Genetic Variants on Hyperuricemia and Gout and Response to Allopurinol

The heritability of serum urate levels has been estimated at 45% to 73%, and the heritability of the fractional excretion of urate is estimated to be 46–96%. The heritability of gout also is robust, estimated at ~30% in people of European descent. Both hyperuricemia and renal disposition of uric acid are polygenic traits and multiple haplotypes of renal urate transporters are increasingly recognized as significant factors. These include SLC2A9, which encodes GLUT9 (Figure 1-4A); ABCG2, which encodes the renal and small intestinal ABCG2; and SLC22A12, which encodes URAT1 (Figure 1-4B). Data suggests that all transporter variants lead to loss of function, with variants related to secretion increasing the risk of gout, and variants related to reabsorption protecting against gout. Heritable variants in different urate transporters also affect serum urate responses to dietary challenges such as fructose and potentially some medications, but with mixed results for diuretics. There is variability between races and ethnic groups in the heritable factors promoting hyperuricemia. Development of gout is clearly under genetic influence of certain inflammation genes, but with stronger influence of environmental factors.

Larger studies have looked at genetic loci linked to hyperuricemia, as compared to gout, which optimally requires robust clinical validation of the diagnosis. In the limited analyses of gout subjects to date in genome-wide association studies (GWAS), ABCG2 (ATP-binding cassette, subfamily G, 2) and SLC2A9 had the strongest disease association. Evidence suggests that ABCG2 variants may play a role in the pathogenesis of gout by potentially influencing crystal formation and the inflammatory response to crystals. Several GWAS of diverse populations (including Icelandic, Korean, Han Chinese and Japanese participants) investigated genetic associations with gout, and identified several loci, including ALDH16A1, BCAS3, RFX3, KCNQ1 and ATXN2. These loci had varying levels of significance and included population-specific variants. For example, ALDH16A1 in Icelanders and BCAS3, RFX3 and KCNQ1 in Han Chinese populations were identified as significant for their associations with both gout and serum urate levels. Smaller GWAS in Japanese men identified three loci (ABCG2, SLC2A9 and CUX2) associated with renal urate overload and four loci (ABCG2, SLC2A9, CUX2 and GCKR) associated with renal urate underexcretion. Another study and subsequent meta-analysis in the Japanese population identified CNIH2, NIPAL1 and FAM35A as novel gout-associated loci; NIPAL1 and FAM35A (genes whose protein products are expressed in the distal renal tubule) were found to be associated with gout caused by reduced renal urate excretion in particular. A GWAS in male Chinese participants revealed four loci (MSX2, CXCR5, PRKCE and MARCKS) associated with the presence of tophi, introducing novel and currently insufficiently explored genetic associations with gout.

The largest GWAS of serum urate levels in major populations were in Europeans, East Asians, and African Americans. The study of East Asian populations detected SLC2A9, ABCG2, SLC22A12 and MAF loci as significantly associated with serum urate levels, and the study of the African-American population detected SLC2A9, SLC22A12 and SLC2A12 loci. In studies combining data for >140,000 individuals of European ancestry, 28 significant loci were linked to serum urate concentrations, including all of the loci detected in the studies of the African-American population and the East Asian population, excluding SLC2A12. Associations were strongest for urate transporters, particularly SLC2A9 and ABCG2, accounting respectively for 2-3% and 1% of the variance in serum urate levels in Europeans and to a lesser degree, SLC22A12, SLC22A11 (which encodes OAT4, a transporter involved in renal urate reabsorption) (Figure 1-4-A), and SLC17A1 (which encodes NPT1, a transporter mediating renal urate secretion (Figure 1-4-B). Out of all urate associated loci, only three (INHBB, HNF4G and UBE2Q2) are not formally associated with gout. Analyses of loci and networks also implicated numerous genes involved in glucose metabolism (including inhibins and activins) and metabolic regulation of glucose generation (AMPKg chain); these loci presumably act in part by regulating uric acid production and, in some cases, renal urate disposition. The GCKR locus, responsible for encoding the glucokinase regulatory protein, might contribute to urate production through glycolysis, while several hyperuricemia-associated loci contain genes which encode transcription factors, growth factors and regulators of purine synthesis. The PDZK1 gene, located in another locus associated with elevated serum urate, is expressed in the kidney and encodes a product containing the PDZ domain, which acts as a scaffolding protein for a variety of subcellular transport proteins, potentially contributing to the regulation of urate levels within the body.

Enlarge  Figure 1-4: Urate Reabsorption Pathways in Renal Proximal Tubule Epithelial Cell. Transport pathways for urate in proximal tubule cells. Urate reabsorption (a) is quite dominant over urate secretion into the proximal tubule lumen, (a) Urate anion reabsorption. Na+-dependent anion transport by SLC5A8 and SLC5A12 increases intracellular concentrations of anions that exchange with luminal urate (URAT1/OAT10) at the apical membrane. URAT1 anion exchange with monocarboxylates is the major deriver of urate reabsorption from the tubule lumen, with lactate (modulated by exercise and alcohol), butyrate, nicotinamide (niacin) and salicylate being major triggers of URAT1-driven urate reabsorption. OAT4 appears to exchange urate with divalent anions at the apical membrane. GLUT9 acts as the exit pathway for urate at the basolateral membrane to re-enter the circulation. PZA denotes pyrazinoate, a monocarboxylate metabolite of the anti-TB drug pyrazinamide. As depicted in the Figure, URAT1 is a major drug target of potent uricosurics, with the now-discontinued drug lesinurad also inhibiting OAT4, a transporter that appears involved in diuretic-induced hyperuricemia. Moreover, certain loss of function mutants of URAT1 and GLUT9 cause renal-mediated hyperuricemia, which can present as exercise-induced renal failure medicated by uric acid urolithiasis. (b) Urate secretion. Urate enters the cell at the basolateral membrane in exchange with α-ketoglutarate (α-KG), mediated by OAT1 and OAT3, or in exchange with unknown anions via OAT2; see text for details. At the apical membrane, urate is secreted via MRP4, ABCG2, NPT1, and/or NPT4. Source: Adapted from Mandal AK, Mount DB. Annu Rev Physiol. 2015;77:323-345.
Figure 1-4: Urate Reabsorption Pathways in Renal Proximal Tubule Epithelial Cell. Transport pathways for urate in proximal tubule cells. Urate reabsorption (a) is quite dominant over urate secretion into the proximal tubule lumen, (a) Urate anion reabsorption. Na+-dependent anion transport by SLC5A8 and SLC5A12 increases intracellular concentrations of anions that exchange with luminal urate (URAT1/OAT10) at the apical membrane. URAT1 anion exchange with monocarboxylates is the major deriver of urate reabsorption from the tubule lumen, with lactate (modulated by exercise and alcohol), butyrate, nicotinamide (niacin) and salicylate being major triggers of URAT1-driven urate reabsorption. OAT4 appears to exchange urate with divalent anions at the apical membrane. GLUT9 acts as the exit pathway for urate at the basolateral membrane to re-enter the circulation. PZA denotes pyrazinoate, a monocarboxylate metabolite of the anti-TB drug pyrazinamide. As depicted in the Figure, URAT1 is a major drug target of potent uricosurics, with the now-discontinued drug lesinurad also inhibiting OAT4, a transporter that appears involved in diuretic-induced hyperuricemia. Moreover, certain loss of function mutants of URAT1 and GLUT9 cause renal-mediated hyperuricemia, which can present as exercise-induced renal failure medicated by uric acid urolithiasis. (b) Urate secretion. Urate enters the cell at the basolateral membrane in exchange with α-ketoglutarate (α-KG), mediated by OAT1 and OAT3, or in exchange with unknown anions via OAT2; see text for details. At the apical membrane, urate is secreted via MRP4, ABCG2, NPT1, and/or NPT4. Source: Adapted from Mandal AK, Mount DB. Annu Rev Physiol. 2015;77:323-345.

ABCG2 Gene Variants Are Particularly Common and Are Frequently Functionally Significant

It is clear that variants in ABCG2 on chromosome 4q are quite common, and functionally significant on a frequent basis (Table 1-4). Specifically, the mutation Q141K encoded by the common SNP (single nucleotide polymorphism) rs2231142 reduces urate transport rates by ~50% (half-functional ABCG2) compared to wild-type ABCG2. ABCG2 rs2231142 has been significantly linked in two studies with decreased serum urate lowering response to allopurinol. This association likely reflects the capacity of ABCG2 to transport allopurinol in the liver (and possibly other sites).

The Q126X mutation in ABCG2 (encoded by SNP rs72552713) encodes an entirely nonfunctional ABCG2, and carriage of this allele is a major factor in intestinal (extra-renal) underexcretion of urate with renal uric acid overload (without uric acid overproduction) (Figure 1-5). The Q141K mutation is also linked with this phenotype of renal uric acid overload, both in patients who are homozygous for Q141K and those who are heterozygous for Q126X and Q141K. This phenotype of hyperuricemia with renal uric acid overload driven by the decreased intestinal disposal of urate has changed the way we classify gout. In essence, gout used to be divided up simply between uric acid underexcretors and uric acid overproducers, predicated in large part, in those with intact renal function, by the amount of uric acid excreted in a 24-hour urine collection. However, some gout patients with elevated 24-hour urine uric acid, as described in Japanese cohorts, have renal uric overload due to intestinal ABCG2 dysfunction without uric acid overproduction (Figure 1-5). Q126X is common in Japanese people (~2-3% allele frequency in the population, and higher in Japanese gout patients). It has also been reported in Han Chinese and Korean populations, but not in people of White or Black descent.

The ABCG2 rs2231142 SNP encoding Q141K may represent a substantial contribution to hyperuricemia in at least 10% of White patients. The prevalence of this allele is several times greater in Japanese patients, but lower in Black patients. In Japanese patients with hyperuricemia who were studied in detail, heritable ABCG2 dysfunction was observed in up to half of the study population investigated, and its population-attributable contribution to hyperuricemia was as high as 30%, much higher than the contribution of non-genetic factors such as overweight/obesity, heavy alcohol consumption and aging. Patients of Western Polynesian descent have also been reported to have markedly elevated allele frequency (~28%) of ABCG2 Q141K, and Q141K allele frequency in Han Chinese gout patients is 49.6% (compared to 30.9% in controls). In people of European descent, a much smaller but still significant fraction of the population (up to ~10-15%) carry the ABCG2 Q141K allele that causes renal urate transport functional impairment via ABCG2 dysfunction.

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Enlarge  Figure 1-5: Small Intestinal (Extra-Renal) ABCG2 in Classification of Hyperuricemia in Gout. Pathophysiological model in the classification of hyperuricemia in gout patents. Hyperuricemia has previously been classified into urate ‘overproduction type’ (A), ‘renal underexcretion type’ (B), and combined type. Taking extra-renal urate excretion into account, the newer classification defines ‘renal overload type’ (A), into two subtypes, genuine ‘uric overproduction’ (A1) and ‘extra-renal urate underexcretion’ (A2). Source: Adapted from Ichida K, et al. Nat Commun. 2012;3:764.
Figure 1-5: Small Intestinal (Extra-Renal) ABCG2 in Classification of Hyperuricemia in Gout. Pathophysiological model in the classification of hyperuricemia in gout patents. Hyperuricemia has previously been classified into urate ‘overproduction type’ (A), ‘renal underexcretion type’ (B), and combined type. Taking extra-renal urate excretion into account, the newer classification defines ‘renal overload type’ (A), into two subtypes, genuine ‘uric overproduction’ (A1) and ‘extra-renal urate underexcretion’ (A2). Source: Adapted from Ichida K, et al. Nat Commun. 2012;3:764.

Impaired Renal Elimination of Uric Acid

It has been estimated that decreased renal uric acid elimination is the primary driver of hyperuricemia in gout in ~90% of cases. Almost all plasma urate is filtered at the glomerulus and most of the filtered load undergoes proximal tubular reabsorption, with secretion and postsecretory reabsorption also regulating the ultimate uric acid elimination of normally ~10% of the filtered load (Figure 1-6). The most common gross defect that promotes hyperuricemia in patients with gout without chronic kidney disease (CKD) is marked renal underexcretion of uric acid over broad ranges of serum urate levels (Figure 1-7). The identification of key renal urate anion transporters promoting reabsorption or secretion into the lumen has markedly increased our understanding of the physiology and genetics of hyperuricemia (Figure 1-4).

The organic anion exchanger URAT1 is localized at the apical (tubule lumen-facing) membrane of renal proximal tubule epithelial cells (Figure 1-4-A). URAT1-transduced urate anion reabsorption is stimulated by intracellular organic anions, including lactate and other monocarboxylates (e.g., salicylate, butyrate, nicotinamide [niacin], and the anti-TB drug pyrazinamide metabolite pyrazinoate). URAT1 is a target for estrogen and probenecid uricosuric effects, as well as effects of several other uricosurics. The balance between proximal tubular secretion and reabsorption of filtered urate (mediated in a major way at the basolateral membrane by GLUT9/SLC2A9) ultimately determines net renal uric acid excretion (Figure 1-4).

Decreased glomerular filtration, as well as the effects on tubular handling of uric acid of hydration, certain organic acids, drugs (in particular thiazide and loop diuretics) and exogenous toxins (e.g., lead), all impair renal excretion of uric acid (Table 1-3). Alcohol acts in part to stimulate hyperuricemia by decreasing renal uric acid excretion. The same is the case for obesity (likely in part via leptin). Patients with gout frequently have comorbid conditions that predispose to renal dysfunction and increased urate reabsorption, including hypertension and metabolic syndrome (insulin resistance) (see: Who Gets Gout?) Impaired urinary alkalinization in metabolic syndrome likely contributes to elevated risks of uric acid urolithiasis in the gout patient population.

Enlarge  Figure 1-6: Uric Acid and Urate Anion Disposition in the Nephron. Once produced, uric acid is eliminated predominantly through the kidney. Despite nearly free filtration at the glomerulus, renal clearance of uric acid is equivalent to only about 10% of that filtered. Studies in humans and experimental animals indicate that the proximal convoluted tubule of the nephron is the site of complex urate anion handling processes strongly favoring net reabsorption of 90% or more of filtered urate. Source: Adapted from Becker M, Koopman WJ, eds. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2291.
Figure 1-6: Uric Acid and Urate Anion Disposition in the Nephron. Once produced, uric acid is eliminated predominantly through the kidney. Despite nearly free filtration at the glomerulus, renal clearance of uric acid is equivalent to only about 10% of that filtered. Studies in humans and experimental animals indicate that the proximal convoluted tubule of the nephron is the site of complex urate anion handling processes strongly favoring net reabsorption of 90% or more of filtered urate. Source: Adapted from Becker M, Koopman WJ, eds. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2291.
Enlarge  Figure 1-7: Uric Acid Excretion Kinetics of Patients With and Without Gout. The relationship between plasma urate concentration and the rate of urinary uric acid excretion is depicted in this graph for both subjects with and without gout. Using patients without gout at a serum urate concentration of 8 mg/dL as an example, it is apparent that they are excreting uric acid at a rate ~0.9 mg/min. For patients with gout at this same concentration, they are excreting uric acid at a slower rate of ~0.5 mg/min. As another example, patients without gout (with a serum urate concentration of 10 mg/dL) are excreting uric acid at a rate of ~1.3 mg/min, whereas patients with gout are excreting uric acid at a rate of ~0.75 mg/min at the same urate concentration. It is evident from this depiction that both patients with and without gout have similar sigmoidal relationships between serum urate concentrations and the rate of urinary excretion of uric acid. However, patients with primary gout have excretion kinetics that “shift to the right,” since they excrete less uric acid (approximately half as much) at the same plasma urate concentration as those patients with gout. Insufficient excretion kinetics seen in primary gout1: the cause of 90% of primary hyperuricemia and gout. ~41% less uric acid is excreted in patients with gout, compared to those without gout. Source: Becker M, Koopman WJ, eds. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2316. 2) Simkin PA. Adv Exp Med Biol. 1977;76B:41-45.
Figure 1-7: Uric Acid Excretion Kinetics of Patients With and Without Gout. The relationship between plasma urate concentration and the rate of urinary uric acid excretion is depicted in this graph for both subjects with and without gout. Using patients without gout at a serum urate concentration of 8 mg/dL as an example, it is apparent that they are excreting uric acid at a rate ~0.9 mg/min. For patients with gout at this same concentration, they are excreting uric acid at a slower rate of ~0.5 mg/min. As another example, patients without gout (with a serum urate concentration of 10 mg/dL) are excreting uric acid at a rate of ~1.3 mg/min, whereas patients with gout are excreting uric acid at a rate of ~0.75 mg/min at the same urate concentration. It is evident from this depiction that both patients with and without gout have similar sigmoidal relationships between serum urate concentrations and the rate of urinary excretion of uric acid. However, patients with primary gout have excretion kinetics that “shift to the right,” since they excrete less uric acid (approximately half as much) at the same plasma urate concentration as those patients with gout. Insufficient excretion kinetics seen in primary gout1: the cause of 90% of primary hyperuricemia and gout. ~41% less uric acid is excreted in patients with gout, compared to those without gout. Source: Becker M, Koopman WJ, eds. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2316. 2) Simkin PA. Adv Exp Med Biol. 1977;76B:41-45.
Enlarge  Figure 1-4: Urate Reabsorption Pathways in Renal Proximal Tubule Epithelial Cell. Transport pathways for urate in proximal tubule cells. Urate reabsorption (a) is quite dominant over urate secretion into the proximal tubule lumen, (a) Urate anion reabsorption. Na+-dependent anion transport by SLC5A8 and SLC5A12 increases intracellular concentrations of anions that exchange with luminal urate (URAT1/OAT10) at the apical membrane. URAT1 anion exchange with monocarboxylates is the major deriver of urate reabsorption from the tubule lumen, with lactate (modulated by exercise and alcohol), butyrate, nicotinamide (niacin) and salicylate being major triggers of URAT1-driven urate reabsorption. OAT4 appears to exchange urate with divalent anions at the apical membrane. GLUT9 acts as the exit pathway for urate at the basolateral membrane to re-enter the circulation. PZA denotes pyrazinoate, a monocarboxylate metabolite of the anti-TB drug pyrazinamide. As depicted in the Figure, URAT1 is a major drug target of potent uricosurics, with the now-discontinued drug lesinurad also inhibiting OAT4, a transporter that appears involved in diuretic-induced hyperuricemia. Moreover, certain loss of function mutants of URAT1 and GLUT9 cause renal-mediated hyperuricemia, which can present as exercise-induced renal failure medicated by uric acid urolithiasis. (b) Urate secretion. Urate enters the cell at the basolateral membrane in exchange with α-ketoglutarate (α-KG), mediated by OAT1 and OAT3, or in exchange with unknown anions via OAT2; see text for details. At the apical membrane, urate is secreted via MRP4, ABCG2, NPT1, and/or NPT4. Source: Adapted from Mandal AK, Mount DB. Annu Rev Physiol. 2015;77:323-345.
Figure 1-4: Urate Reabsorption Pathways in Renal Proximal Tubule Epithelial Cell. Transport pathways for urate in proximal tubule cells. Urate reabsorption (a) is quite dominant over urate secretion into the proximal tubule lumen, (a) Urate anion reabsorption. Na+-dependent anion transport by SLC5A8 and SLC5A12 increases intracellular concentrations of anions that exchange with luminal urate (URAT1/OAT10) at the apical membrane. URAT1 anion exchange with monocarboxylates is the major deriver of urate reabsorption from the tubule lumen, with lactate (modulated by exercise and alcohol), butyrate, nicotinamide (niacin) and salicylate being major triggers of URAT1-driven urate reabsorption. OAT4 appears to exchange urate with divalent anions at the apical membrane. GLUT9 acts as the exit pathway for urate at the basolateral membrane to re-enter the circulation. PZA denotes pyrazinoate, a monocarboxylate metabolite of the anti-TB drug pyrazinamide. As depicted in the Figure, URAT1 is a major drug target of potent uricosurics, with the now-discontinued drug lesinurad also inhibiting OAT4, a transporter that appears involved in diuretic-induced hyperuricemia. Moreover, certain loss of function mutants of URAT1 and GLUT9 cause renal-mediated hyperuricemia, which can present as exercise-induced renal failure medicated by uric acid urolithiasis. (b) Urate secretion. Urate enters the cell at the basolateral membrane in exchange with α-ketoglutarate (α-KG), mediated by OAT1 and OAT3, or in exchange with unknown anions via OAT2; see text for details. At the apical membrane, urate is secreted via MRP4, ABCG2, NPT1, and/or NPT4. Source: Adapted from Mandal AK, Mount DB. Annu Rev Physiol. 2015;77:323-345.
Enlarge 

Increased Uric Acid Production

In ~10% of patients with gout, excess uric acid generation can be documented by excretion of >800 to 1000 mg/day of uric acid in a 24-hour urine collection (while on a Western diet). However, renal uric acid excretion can mask the fact that up to ~20% to 25% of gout patients have, as one component of their hyperuricemia, elevated generation of uric acid. For example, alcohol consumption promotes hyperuricemia in part by increasing uric acid production (Table 1.-3). Alcohol-induced accelerated hepatic breakdown of adenosine triphosphate (ATP), and also the high content of the readily absorbable dietary purine guanosine in beer, promote increased uric acid production; fructose metabolism also consumes ATP and promotes increased uric acid production (Approach to Diet, Alcohol, and Other Lifestyle Factors). Clearly, increased alcohol consumption and fructose intake (particularly seen via ingestion of sweetened sodas and energy beverages sweetened with high-fructose corn syrup) promote increased uric acid production; hereditary fructose intolerance is rare as a cause of clinically significant uric acid overproduction.

Importantly, overproduction of uric acid is seen in several acquired and genetic disorders with excessive rates of cell (and purine) turnover (Table 1-3). Inherited errors in mechanisms regulating purine metabolism (principally X-linked deficiency of hypoxanthine guanine phosphoribosyl transferase (HPRT) activity and superactivity of phosphoribosyl pyrophosphate (PRPP) synthetase account for a very small fraction of patients with uric acid overproduction. Nevertheless, inborn errors of purine metabolism should be excluded in patients with uric acid overproduction, particularly in men with disease onset under the age of 25 to 30 years and in women with gout onset in the early menopause and not due to other defined etiology such as CKD or thiazide or loop diuretic use.

Enlarge 

Uric Acid Production as a Target of Therapy in Patients With Gout

In the catabolism of purines, uric acid generation by the enzyme xanthine oxidase (that also has xanthine dehydrogenase activity) (Figure 1-2) highlights the key therapeutic mechanisms of action of the xanthine oxidase inhibitors allopurinol and febuxostat (Pharmacologic Urate-Lowering Therapy). Allopurinol and its major longer-lived active metabolite oxypurinol not only inhibit xanthine oxidase but also lower overall purine production. Allopurinol and oxypurinol affect pyrimidine metabolism and have a purine-like backbone.

Febuxostat is a selective xanthine oxidase inhibitor that is not structurally related to allopurinol, oxypurinol, or purines (Figure 1-2), which allows it to be used in patients with prior allopurinol hypersensitivity. Allopurinol and oxypurinol differ from febuxostat in their capacity for inhibition of the oxidized and reduced forms of the xanthine oxidase/xanthine dehydrogenase enzyme, but the clinical pharmacologic ramifications in typical medical practice of such differences are not yet clear. Direct induction of uric acid degradation using enzymes such as the recombinant PEGylated uricase pegloticase is an alternative approach to hyperuricemia that targets excess body urate burden irrespective of its etiology and is particularly useful for severe tophaceous gout (Difficult Gout and Hyperuricemia).

Enlarge  Figure 1-2: Final Pathways of Uric Acid Metabolism and Renal Elimination and Primary Therapeutic Sites of Action of Allopurinol, Febuxostat, Uricases (e.g., Pegloticase), and Uricosurics. As depicted in this schematic, xanthine oxidase generates uric acid as the end product of purine metabolism. Allopurinol (pictured) and its major active metabolite oxypurinol (which has a much longer half-life than allopurinol and is primarily eliminated by renal excretion) inhibit xanthine oxidase, and also suppress uric acid generation upstream by additional mechanisms. Febuxostat (pictured), is a selective xanthine oxidase inhibitor and, in further distinction to allopurinol and oxypurinol, does not have a purine-like backbone. Uricase (pictured) oxidizes sparingly soluble uric acid to generate oxidative intermediates that in humans are converted nonenzymatically to highly soluble allantoin. Uricase expression was lost in apes (including humans) during evolution, promoting baseline serum urate levels several higher than in other mammals. Importantly, a PEGylated uricase (pegloticase) is FDA approved for use in gout. Almost all circulating urate is filtered by the glomeruli, with only a small fraction (~10%) normally excreted in the urine as uric acid. The proximal tubule serves as the major locus for both urate reabsorption and secretion, and uricosurics (e.g., probenecid, benzbromarone [outside the United States]) primarily act by suppressing urate anion reabsorption by the proximal tubule epithelial cell. Source: Terkeltaub R. Nat Rev Rheumatol. 2010;6(1):30-38.
Figure 1-2: Final Pathways of Uric Acid Metabolism and Renal Elimination and Primary Therapeutic Sites of Action of Allopurinol, Febuxostat, Uricases (e.g., Pegloticase), and Uricosurics. As depicted in this schematic, xanthine oxidase generates uric acid as the end product of purine metabolism. Allopurinol (pictured) and its major active metabolite oxypurinol (which has a much longer half-life than allopurinol and is primarily eliminated by renal excretion) inhibit xanthine oxidase, and also suppress uric acid generation upstream by additional mechanisms. Febuxostat (pictured), is a selective xanthine oxidase inhibitor and, in further distinction to allopurinol and oxypurinol, does not have a purine-like backbone. Uricase (pictured) oxidizes sparingly soluble uric acid to generate oxidative intermediates that in humans are converted nonenzymatically to highly soluble allantoin. Uricase expression was lost in apes (including humans) during evolution, promoting baseline serum urate levels several higher than in other mammals. Importantly, a PEGylated uricase (pegloticase) is FDA approved for use in gout. Almost all circulating urate is filtered by the glomeruli, with only a small fraction (~10%) normally excreted in the urine as uric acid. The proximal tubule serves as the major locus for both urate reabsorption and secretion, and uricosurics (e.g., probenecid, benzbromarone [outside the United States]) primarily act by suppressing urate anion reabsorption by the proximal tubule epithelial cell. Source: Terkeltaub R. Nat Rev Rheumatol. 2010;6(1):30-38.

Pathogenesis of Tissue Deposition of Urate Crystals Into Tophi

Besides tissue supersaturation with urate and the effects of decreased temperature and decreased tissue pH to promote decreased urate solubility, other factors promote the transformation of soluble urate into urate crystals deposited in tophi (Figure 1-6). Tophi resemble granulomas and demonstrate leukocyte traffic, consistent with a role of inflammation in promoting tophus formation and remodeling. Tophi commonly develop in osteoarthritic toe and hand joints, suggesting roles of trauma, altered hydration (swelling) and connective tissue matrix structure and turnover (Figure 1-8).

Microscopic tophi are often present in the synovial membrane at the time of the first gouty attack and may also be detected within cartilage, and macroscopic tophi can be seen on arthroscopy (Figure 1-8). Abrupt rises and declines in serum urate levels, as stimulated by diuretics, alcohol use, and with initiation of therapy with antihyperuricemic drugs, may promote release of urate crystals from tophi and other crystal aggregates, via changes in packing of crystals in deposits. Free urate crystals have considerable pro-inflammatory potential, via the ability to activate synovial lining cells and leukocytes, to induce cleavage of C5 and subsequent activation of the membrane attack complex of complement, and to trigger certain other inflammatory cascades.48-50

However, in many individuals with gout, urate crystals can be found in asymptomatic joints never previously affected by an acute attack or in non-inflamed joints between acute attacks of gout (intercritical gout) at those sites (Figure 1-9). Such findings reinforce that urate crystal deposition in tissues can be asymptomatic, but without appropriate management, the process can progress to destructive tophaceous disease (Figure 1-10) over varying periods of several years to a decade or more.

Enlarge  Figure 1-6: Uric Acid and Urate Anion Disposition in the Nephron. Once produced, uric acid is eliminated predominantly through the kidney. Despite nearly free filtration at the glomerulus, renal clearance of uric acid is equivalent to only about 10% of that filtered. Studies in humans and experimental animals indicate that the proximal convoluted tubule of the nephron is the site of complex urate anion handling processes strongly favoring net reabsorption of 90% or more of filtered urate. Source: Adapted from Becker M, Koopman WJ, eds. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2291.
Figure 1-6: Uric Acid and Urate Anion Disposition in the Nephron. Once produced, uric acid is eliminated predominantly through the kidney. Despite nearly free filtration at the glomerulus, renal clearance of uric acid is equivalent to only about 10% of that filtered. Studies in humans and experimental animals indicate that the proximal convoluted tubule of the nephron is the site of complex urate anion handling processes strongly favoring net reabsorption of 90% or more of filtered urate. Source: Adapted from Becker M, Koopman WJ, eds. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2291.
Enlarge  Figure 1-8: Factors That Promote MSU Crystal Deposition in Tissues (Tophus Formation) Source: Espejo-Baena A, et al. J Rheumatol. 2006;33:193-195.
Figure 1-8: Factors That Promote MSU Crystal Deposition in Tissues (Tophus Formation) Source: Espejo-Baena A, et al. J Rheumatol. 2006;33:193-195.
Enlarge  Figure 1-9: Progression of Gout From Asymptomatic and Episodic Disease to Chronic Disease in Distinct Stages
Figure 1-9: Progression of Gout From Asymptomatic and Episodic Disease to Chronic Disease in Distinct Stages
Enlarge  Figure 1-10: Destructive Tophaceous Gout
Figure 1-10: Destructive Tophaceous Gout

Pathogenesis of Acute Gouty Inflammation

Understanding gouty inflammation provides a rationale for the therapeutic approaches (Management of Acute Gouty Arthritis and Prophylaxis of Acute Gout Flares) that suppress endothelial activation, neutrophil adhesion to endothelium, macrophage activation and neutrophil activation and expression and release of inflammatory cytokines, such as IL-1β, TNF-α, and IL-8 (CXCL8). Gout, as well as other crystal-induced diseases, is mediated by host and diet and lifestyle factors that modulate inflammation (Pharmacologic Urate-Lowering Therapy), and is driven by activation of innate immune inflammatory responses by tissue deposits of crystals. In acute gout, MSU crystals, liberated from tissue deposits by remodeling effects or microtrauma, stimulate inflammatory cascades that involve complement activation and assembly of the C5b-9 membrane attack complex, and release of multiple inflammatory cytokines, including IL-1β and the chemokines IL-8 (CXCL8) and GRO-α (CXCL1). These final inflammation execution pathways turn on neutrophils via the receptor CXCR2 and other pathways (Figure 1-11). The process culminates in acute neutrophil-driven inflammation (Figure 1-11). The clinical picture encompasses all elements of the acute inflammatory response (Figure 1-12).

At the cellular level, a fundamental mechanism that promotes and orchestrates urate crystal–induced inflammation is NLRP3 inflammasome activation. Importantly, the process involves two sets of signals, with the urate crystal providing the “second signal” to build on one or more “first signals” that prime NLRP3 (cryopyrin) inflammasome activation and pro-IL-1β mRNA expression. The first signals are provided by macrophage lineage cell activation through factors including C5a, GM-CSF and ligands of certain Toll-like receptors (e.g., TLR2, TLR4), exemplified by dietary long chain fatty acid palmitate, or generation of high circulating levels of the short chain fatty acid acetate, such as by alcohol intake. Additionally, the rs2043211 variant of CARD8 and the G allele of IL1B rs1143623 have been linked to gout, with an epistatic interaction between these variants suggesting a mechanism involving increased NLRP3 inflammasome activity and IL-1β production in response to MSU crystals. Furthermore, the T allele of APOA1 rs670 is associated with gout but not increased serum urate levels, suggesting that APOA1 is involved in the progression from hyperuricemia to gout. These effects of the T allele of APOA1 rs670 may be mediated by changes in apolipoprotein A1 expression (encoded by APOA1) or by the inhibitory effects of apolipoprotein A1 on IL-1β production, which may contribute to the initiation and resolution of gout attacks.

In macrophage lineage cells, second signal urate crystal uptake is followed by phagolysosome destabilization with intracellular protease release, reactive oxygen species generation and decreased intracellular potassium, via cell swelling and potassium efflux. These events promote the activation of the NLRP3 inflammasome, and a cascade of proteolytic cleavage and activation of caspase-1, cleavage and maturation of pro-IL-1β and secretion of mature IL-1β (Figure 1-13). The capacity of synovial lining cell IL-1β to promote initiation and perpetuation of gouty arthritis appears promoted by synovial mast cells, and is amplified in evolving acute gout by neutrophil-derived proteinases, such as elastase and proteinase 3, with macrophage-derived proteinases, including caspase-1, playing a role in all phases of the disease. In model gouty inflammation in mice, IL-1α release is also increased via an alternative NLRP3 inflammasome-mediated pathway, with major effects on the responses seen. However, it is not yet clear what the role of IL-1α is in human gouty inflammation, since off-label IL-1β inhibition alone with the monoclonal antibody canakinumab is remarkably effective in humans with acute gouty arthritis (Management of Acute Gouty Arthritis).

Acute gouty attacks are often spontaneously self-limited within 7 to 10 days in most patients, primarily due to changes in the balance between pro-inflammatory mediators and anti-inflammatory pathways. The latter include uptake of apoptotic neutrophils and urate crystals by macrophages of the M2 macrophage subtype, with consequent induction of anti-inflammatory mediators, such as TGF-β in affected joints. Moreover, neutrophil extracellular trap formation (termed NETosis) and neutrophil vesicle release promote limitation of experimental gouty inflammation. However, synovitis may persist at a low-to-substantial level in affected joints in patients with gout. The inflammatory mechanisms driving gout can lead to chronic synovial proliferation, erosion of bone as well as cartilage and destruction of joint architecture with functional incapacity. Therefore, appropriate management of gout with early intervention is critical, including adequate control of hyperuricemia and ultimate and permanent resolution of tophi that must be maintained by lifelong normalization of the serum urate.

Enlarge  Figure 1-11: Inflammatory Cascade That Triggers Acute Gouty Arthritis
Figure 1-11: Inflammatory Cascade That Triggers Acute Gouty Arthritis
Enlarge  Figure 1-12: Acute Gout: Acute, Very Painful, but Self-Limited Inflammatory Response. MSU Crystals Trigger Multiple Aspects of the Acute Inflammatory Response. Source: Lawrence T, et al. Nat Rev Immunol. 2002;2:787-795.
Figure 1-12: Acute Gout: Acute, Very Painful, but Self-Limited Inflammatory Response. MSU Crystals Trigger Multiple Aspects of the Acute Inflammatory Response. Source: Lawrence T, et al. Nat Rev Immunol. 2002;2:787-795.
Enlarge  Figure 1-13: Urate Crystal–Induced IL-1β Release: A Core Event in Gouty Inflammation. Urate crystal uptake by phagocytes, NLRP3 (Nacht Domain, Leucine-Rich Repeat-, and PYD-Containing Protein) inflammasome activation, and IL-1β secretion in promotion of gouty inflammation. The schematic depicts consequences of urate crystal uptake by phagocytes, which is driven by engagement of crystals at the cell surface mediated by innate immune mechanisms. In this model, uptake of urate crystals is followed by phagolysosome destabilization with protease release, reactive oxygen species generation, and lowering of cytosolic K+, and these events have the capacity to synergistically promote activation of the NLRP3 (cryopyrin) inflammasome. Consequently, endoproteolytic activation of caspase-1 and cleavage and maturation of IL-1β promote the secretion of IL-1β, which plays a central role in driving experimental urate crystal–induced inflammation. IL-1β also has been identified as a therapeutic target in human gouty arthritis, as discussed in the text. Source: Terkeltaub R. Nat Rev Rheumatol. 2010;6:30-38.
Figure 1-13: Urate Crystal–Induced IL-1β Release: A Core Event in Gouty Inflammation. Urate crystal uptake by phagocytes, NLRP3 (Nacht Domain, Leucine-Rich Repeat-, and PYD-Containing Protein) inflammasome activation, and IL-1β secretion in promotion of gouty inflammation. The schematic depicts consequences of urate crystal uptake by phagocytes, which is driven by engagement of crystals at the cell surface mediated by innate immune mechanisms. In this model, uptake of urate crystals is followed by phagolysosome destabilization with protease release, reactive oxygen species generation, and lowering of cytosolic K+, and these events have the capacity to synergistically promote activation of the NLRP3 (cryopyrin) inflammasome. Consequently, endoproteolytic activation of caspase-1 and cleavage and maturation of IL-1β promote the secretion of IL-1β, which plays a central role in driving experimental urate crystal–induced inflammation. IL-1β also has been identified as a therapeutic target in human gouty arthritis, as discussed in the text. Source: Terkeltaub R. Nat Rev Rheumatol. 2010;6:30-38.

Take-Away Messages

  • Hyperuricemia is defined as serum urate above the in vitro solubility threshold of 6.8 mg/dL.
  • MSU crystals deposit into tophi typically in cool, poorly vascularized peripheral connective tissues.
  • Classic triggers of gout flares include trauma, alcohol and diet indiscretion, concurrent medical or surgical illness and dehydration.
  • Gout is not simply an acute illness. Chronic inflammatory and erosive arthritis also can develop in gout, particularly with poorly controlled hyperuricemia.
  • In some patients, gout also manifests as uric acid and/or calcium oxalate urolithiasis, promoted in part by acidic urine pH.
  • Gout and hyperuricemia are biomarkers for increased cardiovascular (CV) disease and death.
  • Loss of uricase in evolution predisposes humans to hyperuricemia.
  • Most of the total-body miscible urate stores are normally turned over every day. Hence, even moderate decrease in renal uric acid elimination or increase in uric production can cause hyperuricemia over time.
  • Clinicians should always consider what the cause of hyperuricemia is in the individual patient.
  • Decreased renal uric acid elimination is the primary driver of hyperuricemia in gout in ~90% of cases. Many medications and medical conditions, and alcohol, inhibit renal uric acid excretion.
  • The organic anion exchanger URAT1 is a target for multiple uricosurics.
  • Certain, particularly common ABCG2 variants cause renal uric acid underexcretion, extra-renal (small intestinal uric acid underexcretion with renal uric acid overload (and not mediated by uric acid overproduction), an earlier age of onset of gout and decreased urate-lowering response to allopurinol (mediated by altered allopurinol intestinal transport).
  • Gout used to be divided up simply between uric acid underexcretors and uric acid overproducers, predicated in large part, in those with intact renal function, by the amount of uric acid excreted in a 24-hour urine collection. We now recognize that many gout patients with elevated 24-hour urine uric acid have renal uric overload due to intestinal ABCG2 dysfunction, without uric acid overproduction.
  • Overproduction of uric acid is seen in several acquired and genetic disorders with excessive rates of cell (and purine) turnover.
  • Inherited errors in purine metabolism account for very few patients with gout but should be excluded with uric acid overproduction, particularly in men with disease onset under ages 25 to 30, and women with gout onset in the early menopause and not due to renal disease and/or diuretics.
  • IL-1β is a major mediator of urate crystal–induced inflammation.
  • Inflammatory mechanisms driving gout can lead to chronic synovial proliferation and erosion of bone and cartilage, with destruction of joint architecture and functional incapacity. Therefore, appropriate management of gout with early intervention is critical, including adequate control of hyperuricemia and ultimate, permanent resolution of tophi with lifelong maintenance of a normal serum urate.

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