Mednotes

L22 Metabolism The metabolism and genetics of gout

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tagsmetabolism, lecture, gout, genetics
aliasesMetabolism and genetics of gout

22 min read

Overview

This lecture covers Gout from clinical presentation through to underlying biochemistry and genetics. It opens with the epidemiology, staged disease progression, and clinical features of gout, then covers diagnosis and current treatment (anti-inflammatory, urate-lowering, lifestyle, and patient education). It then explains the biochemistry of urate production and excretion, the two-signal inflammatory pathway that triggers a gout flare, and dietary/other flare triggers. The final section covers how genetic studies have identified the pathways causing hyperuricaemia, the progression from hyperuricaemia to gout, and variability in drug response/adverse events, closing with a summary and a look at gaps between guideline treatment and real-world practice in New Zealand.

Disease Overview and Epidemiology

Gout (gout arthritis) is the second most common arthritis in New Zealand (osteoarthritis 56%, gout 27%, rheumatoid arthritis 14%, other 3%), affecting ~210,000 New Zealanders (~140,000 European/Asian, ~41,000 Māori, ~30,000 Pacific). It is more frequent in men and older people. It is a treatable form of arthritis but is associated with poor health and reduced life expectancy, and has many comorbidities — diabetes, cardiovascular disease, renal disease, hypertension — which complicate treatment through contraindications and higher risk.

Māori prevalence of gout rises highest with age (to ~35% by age 70–80), followed by Pacific peoples, with Total Population/European/Asian clustering lower (~10–15% peak).

Disease progression (stages, in order):

  1. Elevated serum urate levels
  2. Deposition of monosodium urate (MSU) crystals
  3. Inflammatory response (acute flare)
  4. Bone erosion and tophi formation (parallel/overlapping)
  5. Chronic gouty inflammation (persistent joint pain)

The period spanning from acute flare through to bone erosion/tophi is termed “intercritical gout”. The earlier stages (elevated urate through inflammatory response) produce no early clinical symptoms — disease can be silently progressing before it becomes symptomatic. Progression depends on genetics, environment, ethnicity, hormones, age, and other clinical conditions.

Clinical Presentation

Gout flare: acute pain within a joint, most commonly the metatarsophalangeal joint (termed podagra), though any joint (sometimes more than one) may be affected. The joint is tender, red, swollen, and difficult to move. Onset is sudden with no obvious cause; pain is >7/10, peaking at 12–24 hours after onset, and slowly resolves within a week even without treatment.

Advanced gout (in the presence of persistent hyperuricaemia):

  • Recurrent flares continue.
  • Persistent joint pain may develop, resembling other arthritic diseases.
  • Tophi may form: chronic foreign-body granuloma-like structures containing urate crystals surrounded by inflammatory cells and connective tissue, forming within joints, skin, and cartilage; they can ulcerate.
  • Bone erosion may occur near intra-articular or peri-articular tophi, typified by an “overhanging rim” appearance on imaging, radiographically distinct from rheumatoid arthritis erosions.

Severe/tophaceous gout can be profoundly disabling and distressing — patient accounts in the lecture described pain severe enough to affect the will to live and to prevent normal daily functioning.

Diagnosis

  • Gold standard: presence of monosodium urate crystals in synovial fluid, obtained via joint aspirate during a flare. Crystals can also be present in asymptomatic individuals.
  • Hyperuricaemia test: serum urate ≥ 0.42 mmol/L (≥ 7 mg/dL). Urate levels can appear normal during a flare.
  • Imaging (X-ray, ultrasound, or dual-energy computed tomography, DECT): useful when presentation is atypical or deep structures (e.g. spine) are involved.
  • Septic arthritis must be excluded.

Treatment

Medications

Anti-inflammatory (treat acute flare as early as possible):

  • Colchicine or NSAIDs — contraindicated in renal disease, cardiovascular disease, and gastro disease.
  • Ice can be applied for additional relief.
  • Low-dose anti-inflammatory prophylaxis is prescribed at urate-lowering therapy (ULT) initiation, because sudden drops in urate levels can induce flares (“mobilisation flares”).

Urate-lowering therapy (ULT):

  • Initiate for patients with tophi, radiographic damage, or ≥2 flares per year.
  • Do not initiate at first flare unless the patient has CKD stage >3, urolithiasis, or urate levels >0.54 mmol/L (9 mg/dL).
  • Treat-to-target: reduce serum urate to < 0.36 mmol/L (6 mg/dL).
  • Allopurinol is first-line: a xanthine oxidase inhibitor (XOI), started at low dose and titrated up to the dose required to maintain the urate target. Febuxostat (also an XOI) and probenecid (a uricosuric) are also available.

Lifestyle

Guidelines conditionally recommend limiting alcohol, purine intake, sugar/high-fructose corn syrup intake, and losing weight if overweight/obese. However, evidence for effectiveness is limited, patient expectations need managing, and lifestyle advice is often emphasised at the expense of more effective (drug) treatment by both patients and doctors; providers are cautioned that lifestyle advice should not be misinterpreted as “patient-blaming”.

Patient education

Key messages for patients and whānau: gout is not the patient’s fault; it is a serious, long-term disease (not “just a pain in the toe”) caused by deposits of urate crystals; long-term allopurinol can stop flares; allopurinol is a safe and highly effective medicine. GPs, nurses, and pharmacists all play a role in gout education.

Urate Metabolism

What causes gout — the known and unknown:

  • Gout is caused by monosodium urate crystals in the joints, which form when urate is high (hyperuricaemia, ≥0.42 mmol/L), determined by the balance of production and excretion.
  • Gout flares are an immune response to urate crystals, but only 13–30% of people with hyperuricaemia develop gout, and ~40% of people with hyperuricaemia develop tophi and/or bone erosions without ever having a gout flare.
  • What is not understood: what changes a person’s urate production/excretion balance, and why only some people mount an immune response.

Urate production:

  • Urate (uric acid) is produced in the liver as the end product of purine catabolism.
  • In humans, the uricase enzyme is non-functional, so uric acid cannot be converted to the more soluble compound allantoin.

Purine catabolism pathway (ordered):

  1. Purines enter from dietary purines and endogenous purines (from ATP depletion or nucleic acid degradation).
  2. Dietary purines and the ATP-depletion route feed into AMP; nucleic acid degradation feeds into GMP.
  3. AMP branch: AMP → IMP → Inosine (via Adenosine ↔ Inosine interconversion) → Hypoxanthine → (via xanthine oxidase/xanthine dehydrogenase, XO/XDH) → Xanthine.
  4. GMP branch: GMP → Guanosine → Guanine → (via XO/XDH) → Xanthine, converging with the AMP branch.
  5. Xanthine → (via XDH/XO) → Uric acid.
  6. In species with functional uricase, uric acid → allantoin → allantoate → urea + glyoxylate — but uricase is non-functional in humans.

Metabolic end-products differ by species: uric acid (humans, great apes, birds, reptiles), allantoin (other mammals), urea + glyoxylate (fish).

Because human uricase is non-functional, uric acid — rather than the more soluble allantoin — is the metabolic end point, predisposing humans to crystal formation at high urate levels.

Evolutionary loss of uricase activity:

  • The uricase gene carries multiple independent disruptive mutations across the great-ape/gibbon lineage (e.g. CAAT-box disruption, nonsense mutations at codons 33 and 187, a splice-site disruption in intron 2, a missense mutation at codon 18, and a deletion spanning codons 72–76), each arising separately across different branches.
  • Gibbon variations occurred separately from the great-ape mutations, but at a similar evolutionary time.
  • Lowered uricase activity preceded pseudogenisation (i.e. activity declined before the gene was fully disabled).
  • High uric acid may have conferred an evolutionary advantage [slide does not elaborate on the mechanism of this advantage].

Hyperuricaemia / serum urate balance:

  • Urate levels reflect a balance of production and excretion; more cases of hyperuricaemia are due to under-excretion than over-production.
  • The kidneys are responsible for the majority of urate excretion.
  • Circulating urate is produced by the liver and reabsorbed from the kidney back into circulation. Of total excretion, the kidney handles 70% and the intestine handles 30%.
  • Urate-lowering drugs act at different points in this balance: allopurinol and febuxostat act at the liver production step (inhibiting xanthine oxidase); probenecid acts at the kidney (reducing reabsorption/promoting excretion, a uricosuric).

Urate levels over the lifespan:

  • Children have low urate levels (~0.20 mmol/L).
  • At puberty, urate rises — to much higher levels in males (~0.35–0.37 mmol/L, plateauing through adulthood) than in females (rising only slightly to ~0.26 mmol/L).
  • At menopause, female urate levels rise again, increasing steadily from ~0.27 to ~0.32 mmol/L by old age, but remaining below male levels throughout life.
  • Higher average urate in men is reflected in higher gout prevalence in men.

Urate levels across populations:

  • Average urate levels vary substantially across ethnic groups.
  • Polynesian and Micronesian populations have the highest average urate, with some populations averaging above the hyperuricaemia/crystal-formation threshold (≥0.42 mmol/L) — reflecting the high prevalence of gout in these populations.

Inflammatory Pathway (Gout Flare Mechanism)

Gout flares are an inflammatory response to urate crystals, but only 20–30% of people with hyperuricaemia experience a flare. Initiation requires two signals: urate crystals, plus “something else” (e.g. a dietary trigger) [slide does not elaborate further on the identity of the second signal]. The process of flare resolution can itself lead to tophi forming.

Three-stage flare mechanism (ordered):

  1. Flare initiation. Hyperuricaemia leads to MSU (monosodium urate) crystal formation. Two signals converge on monocytes:

    • Priming signal: LPS/PAMPs bind TLR2/TLR4 receptors on the monocyte, signalling via MyD88 → NF-κB/MAPK → production of inflammasome components.
    • Assembly signal: phagocytosis of MSU crystals by the monocyte triggers assembly of the NLRP3 inflammasome, which activates caspase-1.
    • Separately, MSU crystal deposition in tissue causes chronic inflammatory tissue response, with clustering of crystals and inflammatory cells forming a tophus.

  2. Inflammatory amplification. Active caspase-1 cleaves pro-IL-1β to IL-1β; the monocyte produces and releases pro-inflammatory mediators (IL-1β, IL-6), which recruit and activate neutrophils. Neutrophils engulf MSU crystals; neutrophil lysis by engulfed crystals causes further neutrophil recruitment.

  3. Flare resolution. Neutrophils undergo NETosis, releasing neutrophil extracellular traps (NETs), which aggregate. Resolution is associated with increased anti-inflammatory mediators (IL-37, IL-10) and reduced pro-inflammatory mediators (IL-1RA, TGFβ1).

Diet and Flare Triggers

Food has been anecdotally linked to gout flares since Hippocrates first described the disease.

  • Alcohol, purines, and caffeine are associated with a higher risk of flare onset.
  • Cherries are associated with a reduced risk of flare onset.
  • Non-food triggers also associate with flare risk: e.g. diuretics, infection, weather.
  • Avoidance of triggers complicates treatment.

[The lecture noted a large, largely anecdotal word-cloud of implicated foods — most prominently red meat, seafood, fish, oranges, meat, shellfish, alcohol, tomatoes, beef, fizzy drinks, mussels, wine, oysters, and pork; the transcript does not give quantified risk data for individual foods beyond alcohol, purines, caffeine, and cherries above.]

Genetics

Why genetics matters here

Genetics helps explain: why some people have high urate, why some populations have high urate, and why only some people with hyperuricaemia develop gout. Genetics can explain variability between people and populations, identify important biological pathways of disease, and — sometimes — lead to new drug targets or predict poor drug response/adverse events.

Basics of genetic analysis: everyone has genetic variants (differences in DNA). Comparing genetic differences between people/groups helps understand diseases and traits. The easiest variants to compare are SNPs (single nucleotide polymorphisms, single-letter changes) — the most common form of human variation (~1 in every 300 bases); SNPs can be beneficial, harmful, or neutral.

Genetics of urate

  • The first genome-wide association study (GWAS) of urate, published in 2007, found one significant hit: SLC2A9 (GLUT9).
    • GLUT9 was originally thought to be only a glucose/fructose transporter; follow-on analyses confirmed it is important in the reabsorption of urate.
    • The urate-raising variant in SLC2A9 has higher prevalence in Māori and Pacific populations, and this evidence contributed to successful lobbying for changes to funding of urate-lowering drugs in NZ.
  • A 2019 GWAS of 457,690 people linked 183 loci to urate, 147 of which were previously unknown.

Slide 25 included a circular (Circos-style) genome-wide association plot ("1 dot = 1 SNP"); the individual gene labels around the outer edge were too small/low-resolution to transcribe.

Genetics of gout

Gout genetics is less well studied than urate genetics — fewer studies ask about gout specifically, and very few studies examine the progression from hyperuricaemia to gout (most gout-genetics studies actually find urate-related genes). The inflammatory portion of gout is very poorly understood both genetically and biologically. Conceptually, the population funnels from General Population → High Urate (subset) → Gout (smaller subset).

Largest gout GWAS (decade-long project):

  • 120,295 people with gout vs. 2,503,087 people without gout.
  • Identified 377 genetic loci associated with gout, containing 1,764 candidate gout genes, implicating urate metabolism, type 2 diabetes, and chromatin modification as important pathways in gout.
  • 108 genes were “prioritised” for follow-up based on likely involvement in the progression from hyperuricaemia to gout, involved in epigenetic remodelling, cell osmolarity, and regulation of the NLRP3 inflammasome.

Slide 27's chromosome ideogram plot listed many densely-packed gene labels across all autosomes; only a representative sample was transcribed as the full list was not fully legible.

Candidate gene example — IL-37:

  • IL-37 (Interleukin 37) binds the alpha chain of the IL-18 receptor and inhibits production of pro-inflammatory cytokines in urate-crystal-induced inflammation.
  • Mechanistically: IL-18 binding IL-18Rα causes TIR domains to dimerize with two MyD88 adaptor proteins, producing a strong pro-inflammatory signal. IL-37 instead binds the SIGIRR/IL-1R8 receptor via a distinct “TIR-b” domain that engages MyD88 less effectively (weaker/incomplete dimerization), producing a weak or absent pro-inflammatory signal.
  • Sequencing identified four predicted dysfunctional IL-37 variants, all located in exon 5 (which codes for the functional domain).
    • rs752113534 (p.Asn182Ser): ~4% prevalence in Māori/Pacific (Polynesian) populations vs. <0.01% in other populations; shows strong association with gout risk (overall effect OR 1.81 [95% CI 1.05–3.12], z=2.14, p=0.03; East Polynesian OR 1.90, West Polynesian OR 1.68).

Genetics of drug response

  • Allopurinol (first-line, lowers urate by inhibiting xanthine oxidase) shows substantial variation in response between individuals, especially in the dose required to reach target.
    • The ABCG2 (Q141K) variant reduces ABCG2 transport function by one-quarter and is associated with a smaller change in urate after allopurinol initiation and poorer response (GWAS peak for ABCG2 exceeded genome-wide significance; forest plot showed increased odds of poor response, OR > 1).
  • Allopurinol hypersensitivity / SCAR (severe cutaneous adverse reactions) is a rare but potentially fatal side effect of allopurinol initiation.
    • Starts as flu-like fever, then a spreading rash of diffuse red/purple spots, progressing to loose blisters that merge into sheets of detached skin.
    • Sub-forms range from mild to severe: Stevens–Johnson syndrome (SJS, skin detachment <10% body surface area) and toxic epidermal necrolysis (TEN, skin detachment >30%).
    • Low incidence (~0.5 cases per million) but high mortality (SJS 5–10%, TEN 30–40%).
    • HLA-B*5801 is a genetic marker for allopurinol-induced SCAR, first identified in a 2005 study of Han Chinese individuals that searched 823 SNPs in drug-metabolism/immune-response genes.
      • Allele frequency ranges from ~0.5% to ~9% across populations (highest in East/Southeast Asia).
      • In a case series: allele frequency was 100% in allopurinol-SCAR patients (n=51) vs. 15% in tolerant controls (OR 580.3, Pc 4.7×10⁻²⁴) and 20% in general population controls (OR 393.5, Pc 8.1×10⁻¹⁸).
      • HLA-B*5801 testing is conditionally recommended before allopurinol initiation for patients of Southeast Asian or African American descent.

HLA-B*5801 testing before starting allopurinol is a concrete example of genetics guiding a therapeutic decision in gout care.

Summary

  • Gout is the second most common arthritis in NZ, characterised by flares of acute pain.
  • Treatment must both relieve pain and prevent future flares/joint damage; urate-lowering treatment can effectively “cure” gout.
  • Flares are an inflammatory response to monosodium urate crystals; urate is the end product of purine metabolism in humans, and crystals form when urate is high, which is determined by the balance of production and excretion.
  • Genetic studies have helped identify the pathways leading to hyperuricaemia, are beginning to explain progression from hyperuricaemia to gout, and can explain differences in drug response and side-effects.

Current State of Gout Treatment (NZ)

  • Urate-lowering therapy (ULT) is prescribed to ~60% of patients, but only ~40% regularly receive it.
  • Allopurinol is commonly prescribed at 300 mg/day, which is not a high enough dose for most people.
  • Serum urate levels are not commonly re-measured after allopurinol initiation; only ~30% of people on ULT achieve the target.
  • By ethnicity, “regular dispensing” of ULT is lower than “any dispensing” across all groups (Māori ~38%, Pacific peoples ~33%, Non-Māori/non-Pacific ~43% regular dispensing, vs. ~55–60% any dispensing for all three groups).

Pacific peoples are 9x, and Māori 5x, more likely to be admitted to hospital for gout than non-Māori/non-Pacific people, despite similar rates of any ULT dispensing — reflecting a gap between treatment initiation and effective, sustained treat-to-target management.

Self-test

  1. Where does gout rank among arthritis types in New Zealand by prevalence, and which ethnic groups have the highest gout prevalence with age?
  2. List, in order, the stages of gout disease progression from elevated serum urate to chronic gouty inflammation.
  3. Describe the classic clinical presentation of an acute gout flare, including which joint is most commonly affected and the time course of pain.
  4. What is a tophus, and where can tophi form?
  5. What is the gold-standard diagnostic test for gout, and what is the serum urate threshold used to define hyperuricaemia?
  6. Why can serum urate levels appear normal even during an acute flare, and what does this mean for diagnosis?
  7. Outline the anti-inflammatory and urate-lowering treatment strategies for gout, including which patients should start urate-lowering therapy and the treat-to-target urate level.
  8. Why is low-dose anti-inflammatory prophylaxis given when starting urate-lowering therapy?
  9. What is allopurinol’s mechanism of action, and what other urate-lowering drugs were mentioned along with their targets?
  10. What caveats apply to lifestyle-based gout treatment recommendations?
  11. Explain why humans, unlike most mammals, accumulate uric acid rather than allantoin as the end product of purine catabolism.
  12. Describe the purine catabolism pathway from AMP and GMP through to uric acid, naming the key enzyme(s) involved.
  13. What evolutionary evidence suggests uricase was lost independently multiple times in the great-ape/gibbon lineage?
  14. Explain the balance of production and excretion that determines serum urate levels, including where allopurinol, febuxostat, and probenecid act.
  15. Describe how urate levels change across the lifespan and between sexes, and how this relates to the sex difference in gout prevalence.
  16. Why do only some people with hyperuricaemia develop gout flares, according to the “two-signal” model of flare initiation?
  17. Describe, in order, the three stages of the inflammatory pathway underlying a gout flare, from monocyte activation to flare resolution.
  18. What role does the NLRP3 inflammasome play in gout flare initiation?
  19. List dietary and non-dietary factors associated with increased or decreased risk of a gout flare.
  20. What was found by the first GWAS of urate (2007), and how did this finding change scientific understanding of GLUT9?
  21. Why is the genetics of gout itself less well understood than the genetics of urate?
  22. Summarise the scale and key findings of the largest gout GWAS described in the lecture (cohort size, loci identified, and implicated pathways).
  23. Describe the mechanism by which the IL-37 variant rs752113534 is thought to affect inflammatory signalling, and its population distribution.
  24. What is the effect of the ABCG2 (Q141K) variant on allopurinol response, and why is this clinically relevant?
  25. Distinguish Stevens–Johnson syndrome from toxic epidermal necrolysis in terms of severity and mortality.
  26. What is HLA-B*5801, and in which patients is testing for it recommended before starting allopurinol?
  27. Close the note. From memory, write out the three-stage inflammatory pathway of a gout flare (initiation, amplification, resolution), including the key molecular players at each stage, then check against Inflammatory Pathway (Gout Flare Mechanism).
  28. Integrative: A Māori patient presents with a first gout flare and a serum urate of 0.58 mmol/L. Using what you know about urate-lowering therapy initiation criteria, ethnic differences in urate genetics, and drug-response genetics, outline the treatment decisions and any genetic testing considerations relevant to this patient.

Answers

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