• Prevalence: ~1–4% in developed countries; prevalence is rising globally, partly driven by increasing metabolic syndrome, ageing population, and dietary westernisation ^[3].
• Hong Kong: Gout is one of the most common inflammatory arthropathies encountered in medical practice. The prevalence in HK is estimated at ~2–3%, with a notable increase attributed to high seafood consumption, alcohol intake, and an ageing population.
• Sex ratio: M:F ≈ 5–9:1 — the striking male predominance is because oestrogen is uricosuric (promotes renal urate excretion). Post-menopausal women lose this protective effect, so gout incidence in females rises from the 6th–7th decade, whereas in males it rises from the 4th–5th decade ^[2][3].
• Age: Rare before puberty (low urate levels in childhood: ~3–4 mg/dL). Peak incidence in men is 40–60 years; in women, 60+ years ^[3].
• Racial/ethnic factors: Higher prevalence in Polynesian/Pacific Islander populations (genetic predisposition via SLC2A9 variants). In Hong Kong's Han Chinese population, the HLA-B5801 carrier frequency is ~8%*, which is critically relevant because this allele confers a dramatically increased risk of severe cutaneous adverse reactions (SJS/TEN) to allopurinol ^[4].

• Prevalence has roughly doubled in developed countries over the past 30 years.
• Reasons: obesity epidemic, increased diuretic use (for hypertension and heart failure), ageing population, dietary changes.

Purines (adenine, guanine) come from three sources:

1. Dietary intake (~one-third): purine-rich foods
2. De novo purine synthesis in the liver
3. Cellular turnover/catabolism: breakdown of nucleic acids from dying cells

The degradation pathway:

Purines (adenine, guanine)
    ↓ (hypoxanthine → xanthine → uric acid)
    ↓ Catalysed by XANTHINE OXIDASE
    → Uric acid (end product in humans)

Why is uric acid a problem in humans but not most other mammals? Most mammals possess the enzyme uricase (urate oxidase) which further converts uric acid to the highly soluble allantoin. Humans (and great apes) lost the functional uricase gene during evolution (~15 million years ago), probably because uric acid is a potent antioxidant that conferred a survival advantage. The trade-off is susceptibility to hyperuricaemia and gout.

~70% of urate is excreted by the kidneys; ~30% is eliminated via the GI tract (intestinal uricolysis by gut bacteria).

Renal handling follows a four-component model:

1. Glomerular filtration: virtually all serum urate is freely filtered
2. Proximal tubular reabsorption (~90%): via URAT1 (SLC22A12) and GLUT9 (SLC2A9) on the apical membrane
3. Tubular secretion: via ABCG2, OAT1/3, MRP4 on the basolateral membrane
4. Post-secretory reabsorption

Net result: only ~10% of filtered urate is excreted in the final urine.

This is why > 90% of gout is due to relative underexcretion — even a small impairment in this tightly regulated system tips the balance ^[2][3].

Gout progresses through a well-defined clinical spectrum:

Mnemonic: "Needle-shaped, Negatively birefringent = gout (two N's)" vs. "Pseudogout = Positively birefringent, Pyrophosphate" ^[1][2]

Why must you aspirate the joint? Because the clinical features alone cannot reliably distinguish gout from septic arthritis. Both can present with an explosive, exquisitely tender, red, hot, swollen joint with fever and raised inflammatory markers. The only way to definitively differentiate is joint aspiration for Gram stain, culture, AND crystal analysis. Crucially, gout and septic arthritis can coexist — finding crystals does NOT exclude infection ^[1][8][9].

Microbiology of septic arthritis ^[8][10]:

• S. aureus is the most common organism in adults and children > 2 years
• N. gonorrhoeae in sexually active young adults (disseminated gonococcal infection — often polyarticular, associated with tenosynovitis, dermatitis)
• Group B Streptococcus and Gram-negative bacilli in neonates
• H. influenzae type B in unvaccinated children <2 years
• Salmonella in sickle cell disease

Why does pseudogout affect different joints? CPPD crystals deposit preferentially in fibrocartilage (menisci, triangular fibrocartilage of the wrist, labrum) and hyaline cartilage of larger joints. Unlike MSU, CPPD crystal formation is less temperature-dependent and more related to local cartilage matrix factors (proteoglycan degradation in OA, ATP release from damaged chondrocytes) ^[3].

From Ryan Ho Rheumatology: "tophi can be confused with rheumatoid nodules, but gout typically associated with asymmetrical and asynchronous involvement + urate crystal in joint fluid" ^[3]. In chronic tophaceous gout, polyarticular involvement can genuinely mimic RA clinically and radiologically. The key differentiator is crystal analysis on aspiration.

Ryan Ho: "Dactylitis in spondyloarthritis" is a key differential for chronic gout affecting digits ^[3]. Psoriasis itself is also a risk factor for hyperuricaemia (increased skin cell turnover → increased purine catabolism), so gout and psoriatic arthritis can coexist.

Why can OA predispose to crystal deposition? Damaged cartilage in OA releases matrix fragments and alters local pH/ionic milieu, promoting both MSU and CPPD crystal nucleation. OA-affected joints are a common site for pseudogout flares ^[3].

Haemarthrosis is characterised by bloody joint aspirate. In the context of a patient on warfarin or with known haemophilia who develops an acutely swollen joint, haemarthrosis is the primary concern. However, always send fluid for Gram stain and crystal analysis because infection and crystals should still be excluded.

• Previous similar attacks with complete resolution (recurrent monoarthritis with symptom-free intervals is classical) ^[1]
• Involvement of the 1st MTPJ (podagra)
• Rapid time to peak severity (≤12–24 hours) ^[3]
• Nocturnal onset ^[3]
• Known risk factors: male, metabolic syndrome, CKD, purine-rich diet, alcohol, relevant medications
• Identifiable precipitant: dietary, surgical, drug change, dehydration ^[2]
• Self-resolution over 5–14 days even without treatment ^[3]
• Pruritus and desquamation of overlying skin during resolution ^[1]

Joint aspiration is the single most important investigation for differentiating the causes of acute monoarthritis ^[1][2][8]. Every aspirated fluid should be sent for:

1. Gross appearance (colour, turbidity, viscosity)
2. Cell count with differential (WBC, % PMNs)
3. Compensated polarised light microscopy (crystal identification)
4. Gram stain and culture (to exclude infection)
5. Additional: AFB smear/culture if TB suspected

Synovial fluid analysis reference table ^[11]:

Key exam point: Gout produces an inflammatory synovial fluid (WBC typically 10,000–100,000/mm³, > 90% PMNs) ^[3][11]. This overlaps significantly with the septic range. The WBC count alone cannot distinguish gout from septic arthritis — you need Gram stain, culture, AND crystal analysis. And remember: finding crystals does NOT rule out concurrent infection ^[1][8].

At least 1 episode of swelling, pain, or tenderness in a peripheral joint or bursa

→ If this is NOT met, the criteria cannot be applied.

Demonstration of MSU crystals in a symptomatic joint/bursa (synovial fluid) or tophus

→ If MSU crystals are demonstrated, the patient is classified as having gout regardless of the scoring below. No further scoring needed.

If joint aspiration has not been performed or crystals were not identified, a point-based scoring system is used across 8 domains. A score of ≥8 out of 23 classifies the patient as having gout.

Total threshold: ≥ 8 points = classified as gout ^[3]

Why can serum urate be normal or low during a flare?

1. Acute-phase proteins (released during inflammation) have uricosuric properties — they promote renal urate excretion
2. IL-6 (elevated in acute gout) directly increases renal urate clearance
3. Urate is being consumed — shifting from solution into crystalline form within the joint
4. Volume expansion from IV fluids (if hospitalised) dilutes serum urate

Plain XR is often the first imaging performed but is insensitive in early/acute gout (may be completely normal). Its value is in chronic disease and excluding other pathology.

Key XR distinction from RA: In RA, erosions are marginal (at the "bare area" of bone not covered by cartilage), with early joint space narrowing and periarticular osteopenia. In gout, erosions are punched-out with overhanging margins and joint space is preserved until late disease ^[2][3].

From Ryan Ho Fundamentals: "Arthritic changes, eg. joint space narrowing, periarticular erosion, chondrocalcinosis (pseudogout), tophaceous erosion" ^[13] — these are the key XR findings to look for in the approach to any arthritis.

Musculoskeletal ultrasound is increasingly used as a bedside, non-invasive tool for gout diagnosis.

The double contour sign is included in the 2015 ACR/EULAR criteria (scores 4 points) ^[3]. It is caused by MSU crystals depositing as a thin layer on the surface of hyaline cartilage, creating a second echogenic line parallel to the subchondral bone echo — hence "double contour."

DECT is an advanced imaging modality that can specifically identify and colour-code urate deposits in tissues.

• RICE: Rest, Ice, Compression, Elevation ^[2]
• Rehydration: Dehydration is a common precipitant; IV/oral fluids correct this and promote renal urate excretion
• Offload the joint: Avoid weight-bearing; use a bed cradle to keep bedsheets off the affected joint

From Maksim Medicine Notes: "Lifestyle modification: avoid triggers" ^[2]:

Protective foods: Low-fat dairy, cherries, coffee, vitamin C — promote urate excretion or have anti-inflammatory effects. These are not strong enough to replace pharmacotherapy but are helpful adjuncts.

This is the end-stage of untreated or inadequately treated gout, typically developing after ≥10 years of recurrent attacks.

Pathophysiology from first principles:

• Persistent hyperuricaemia → ongoing MSU crystal deposition in cartilage, synovium, periarticular bone, and soft tissues
• These deposits organise into tophi — collections of solid MSU crystals surrounded by granulomatous inflammation (macrophages, multinucleated giant cells, fibroblasts)
• Tophi behave like slow-growing erosive masses:
  • They erode bone from outside-in (periarticular erosion) → producing the characteristic "punched-out" erosions with overhanging sclerotic margins on XR ^[2]
  • They destroy cartilage → eventual joint space narrowing and loss of function
  • They destroy tendons and ligaments → instability, subluxation, deformity

Clinical manifestations of tophaceous complications ^[3]:

From Ryan Ho Rheumatology: "Surgical treatment: primarily limited to complications of tophaceous disease, e.g., infection, local compression (nerve, spinal cord), joint deformity, intractable pain" ^[3]. Surgery is reserved for these structural complications that medical ULT alone cannot address — but systemic ULT should always take precedence and can dissolve tophi over 6–24 months if the target urate (< 0.30 mmol/L for tophaceous gout) is achieved.

From Ryan Ho Rheumatology: "In untreated patients, 2nd flare occurs within ≤1 year (62%), ≤2 years (78%), ≤10 years (93%)" ^[3].

Over time, the pattern of disease changes:

• Intercritical periods become progressively shorter ^[3]
• Flares become increasingly prolonged, disabling, and polyarticular ^[3]
• Flares may be accompanied by fever — mimicking sepsis ^[3]
• Eventually, there is no symptom-free interval at all → continuous chronic arthritis

This progression is driven by the expanding crystal burden: each flare deposits more crystals, each deposit serves as a nidus for further crystal growth, and the cumulative burden eventually overwhelms the body's resolution mechanisms.

From Maksim Medicine Notes: "Urolithiasis (urate stone)" ^[2]. From MBBS Final MB (Surgery): "Gout (hyperuricemia and hyperuricosuria)" is listed as a cause of uric acid stone formation ^[7].

Prevalence: ~10–25% of patients with gout develop kidney stones.

Pathophysiology:

• Hyperuricaemia → hyperuricosuria (increased urate in urine)
• Uric acid is poorly soluble at acidic urine pH (< 5.5). At pH 5.0, uric acid solubility is only ~60 mg/L; at pH 7.0, it rises to ~1,580 mg/L
• Factors promoting stone formation:
  1. Low urine pH (the dominant factor) — metabolic syndrome, insulin resistance, and chronic diarrhoea all promote acidic urine
  2. High urinary uric acid concentration — from high purine intake, high cell turnover, or uricosuric drugs
  3. Low urine volume — dehydration concentrates urate

Clinical features: Renal colic (severe colicky flank pain radiating to groin), haematuria, dysuria, urinary obstruction.

Key imaging point: Uric acid stones are radiolucent on plain XR — they are invisible on standard kidney-ureter-bladder (KUB) film. They ARE visible on CT KUB (non-contrast CT), which is the investigation of choice for suspected nephrolithiasis ^[7].

Prevention:

• Adequate hydration (urine output > 2L/day)
• Urine alkalinisation (potassium citrate, sodium bicarbonate) — raising urine pH to 6.0–6.5 dramatically increases uric acid solubility
• Low purine diet
• ULT (allopurinol/febuxostat) to reduce both serum and urinary urate
• Note: Uricosuric agents (probenecid) are contraindicated in patients with urate stones because they increase urinary urate and promote further stone formation ^[3][17]

From Ryan Ho Rheumatology: "Chronic UAN: a form of CKD due to deposition of urate crystals in medullary interstitium" ^[3].

Pathophysiology:

• MSU crystals deposit in the renal medullary interstitium (the medulla is cooler and more acidic than the cortex → favours crystal precipitation — same principle as why peripheral joints are affected)
• Crystal deposits induce a chronic inflammatory response → macrophage infiltration → cytokine release → progressive interstitial fibrosis and tubular atrophy → CKD ^[3]

Clinical features ^[3]:

• Non-specific: progressive renal impairment (rising creatinine, declining eGFR), bland urinary sediment, mild proteinuria
• Typically seen in patients with chronic tophaceous gout
• Diagnostic challenge: Many gout patients also have hypertension and diabetes, which independently cause CKD — making it difficult to attribute CKD specifically to urate nephropathy ^[3]
• One clue: Serum urate concentration is higher than expected for the degree of renal impairment (controversial, difficult to define precisely) ^[3]

Bidirectional relationship:

This creates a vicious cycle: CKD → ↓ urate excretion → ↑ hyperuricaemia → more crystal deposition → more renal damage → worse CKD. Breaking this cycle with ULT is essential.

From Ryan Ho Rheumatology: "Acute UAN: acute oliguric/anuric renal failure due to distal tubule/collecting duct deposition" ^[3].

Pathophysiology:

• Massive, sudden hyperuricaemia → overwhelming precipitation of uric acid crystals in the distal renal tubules and collecting ducts → tubular obstruction → obstructive AKI
• Think of it like a "crystal traffic jam" in the renal tubules

Causes ^[3]:

• Tumour lysis syndrome (TLS) — the most common cause: rapid lysis of tumour cells (esp. haematological malignancies — lymphoma, leukaemia) after chemotherapy/radiotherapy releases massive amounts of intracellular purines → rapid conversion to uric acid → overwhelms renal excretion
• Other causes: status epilepticus (rhabdomyolysis + massive ATP turnover), severe exercise, Lesch-Nyhan syndrome, Fanconi syndrome

Distinguishing features ^[3]:

• Marked hyperuricaemia (> 15 mg/dL) — compared with typically < 12 mg/dL in AKI from other causes
• Uric acid crystals visible in urinalysis
• Urinary urate:creatinine ratio > 1 (in other causes of AKI, this ratio is typically < 1)

Management ^[3][20]:

• Rasburicase (recombinant urate oxidase) — first-line for TLS-associated acute urate nephropathy. Converts urate to allantoin (≥5× more soluble). Contraindicated in G6PD deficiency (byproduct H₂O₂ causes haemolysis) ^[17][20]
• Allopurinol/febuxostat — for prevention or lower-risk cases
• IV fluids + loop diuretics → increase urine output to flush crystals
• Haemodialysis if refractory AKI
• Prognosis: excellent — majority completely recover with prompt treatment ^[3]

From pharmacogenomics lecture: "Allopurinol and carbamazepine — always [check HLA before prescribing]" ^[19]. From Learning Points: "HLA-B*5801 screening before allopurinol initiation, particularly important in Han Chinese populations with 8% carrier frequency. This genetic variant dramatically increases severe cutaneous adverse reaction risk including Stevens-Johnson syndrome" ^[4].

STOPP criteria: Long-term colchicine for chronic gout if CrCl < 10 mL/min — risk of fatal accumulation ^[16].

From Gen Clerk Microbiology: "Pyrazinamide can precipitate or cause gouty attack. All patients taking pyrazinamide will have hyperuricaemia, but not all patients with hyperuricaemia develop gout → no point measuring blood urate" ^[6].

Prevention: If the patient has severe pre-existing gout, avoid pyrazinamide and use an alternative TB regimen (consult infectious disease specialist) ^[6].