Gout & Pseudogout

Crystal-induced arthropathies are a favourite NEET PG theme because the entire diagnosis can pivot on a single line of synovial fluid microscopy. Gout is caused by monosodium urate (MSU) crystals, while pseudogout (calcium pyrophosphate deposition disease, CPPD) is caused by calcium pyrophosphate dihydrate (CPPD) crystals. Master the crystal shape, birefringence, joint distribution and drugs, and you have locked in 2-3 near-guaranteed marks.

Definition & Classification

Gout is a disorder of purine metabolism characterised by hyperuricaemia and recurrent attacks of acute inflammatory monoarthritis due to deposition of MSU crystals in joints and soft tissues. It progresses through four classic stages:

1. Asymptomatic hyperuricaemia → raised serum urate, no symptoms (does NOT mandate treatment).
2. Acute gouty arthritis → sudden, exquisitely painful monoarthritis.
3. Intercritical gout → symptom-free interval between attacks.
4. Chronic tophaceous gout → tophi, chronic arthropathy, deformity.

Serum urate cut-off: > 6.8 mg/dL is the physiological saturation point of urate at 37°C (above this, crystals precipitate). Clinically, hyperuricaemia is often defined as > 7 mg/dL in men and > 6 mg/dL in women.

Pseudogout / CPPD is deposition of calcium pyrophosphate dihydrate crystals in fibrocartilage and hyaline cartilage, producing chondrocalcinosis radiologically and acute or chronic arthritis clinically. CPPD has multiple presentations: asymptomatic chondrocalcinosis, acute CPP crystal arthritis (the classic "pseudogout"), chronic CPP arthritis, and an osteoarthritis-like or rheumatoid-like pattern.

High-yield: Urate is the end product of purine metabolism in humans because we lack uricase (urate oxidase), the enzyme that converts uric acid to soluble allantoin in most other mammals.

Etiology & Pathophysiology

Gout

Hyperuricaemia arises from overproduction (10%) or, far more commonly, underexcretion (90%) of urate.

Overproduction causes:

• Increased cell turnover: myeloproliferative/lymphoproliferative disorders, haemolysis, psoriasis, tumour lysis syndrome.
• Enzyme defects: HGPRT deficiency — complete deficiency = Lesch-Nyhan syndrome (X-linked; self-mutilation, choreoathetosis, intellectual disability, hyperuricaemia); partial = Kelley-Seegmiller syndrome. Also PRPP synthetase overactivity and glucose-6-phosphatase deficiency (von Gierke, GSD type I).
• High purine diet: red meat, organ meat, seafood, beer (rich in guanosine).

Underexcretion causes:

• Chronic kidney disease.
• Drugs — remember mnemonic "CANT LEAP": Cyclosporine, Alcohol, Nicotinic acid, Thiazides, Loop diuretics, Ethambutol, Aspirin (low dose), Pyrazinamide.
• Lead nephropathy (saturnine gout), lactic/keto-acidosis (compete with urate for tubular secretion).

The acute attack: MSU crystals are coated by IgG and complement, phagocytosed by neutrophils, and activate the NLRP3 inflammasome → caspase-1 → IL-1β release, driving the intense neutrophilic inflammation. This IL-1β axis is the rationale for IL-1 inhibitors in refractory gout.

Pseudogout / CPPD

CPPD crystal formation is favoured by metabolic and ageing-related changes in cartilage. Secondary causes are tested through the mnemonic "4 H's" (Hyperparathyroidism, Haemochromatosis, Hypophosphatasia, Hypomagnesaemia) plus hypothyroidism and Wilson disease.

High-yield: If you see CPPD/chondrocalcinosis in a young patient (<55 years), screen for an underlying metabolic disease — especially haemochromatosis and hyperparathyroidism.

Clinical Features

Gout

• Podagra — acute monoarthritis of the first metatarsophalangeal (1st MTP) joint is the classic and most common site (~50% of first attacks; involved in 90% over time).
• Onset is rapid, often nocturnal, reaching peak intensity within 12-24 hours. The joint is red, hot, swollen, and exquisitely tender (even bed-sheet weight is intolerable).
• Other joints: midfoot, ankle, knee, wrist, fingers. Polyarticular in chronic disease.
• Tophi — chalky, firm deposits of MSU in the helix of the ear, olecranon bursa, Achilles tendon, finger pads, develop in chronic untreated gout. Tophi may discharge white pasty material.
• More common in men and postmenopausal women; oestrogen is uricosuric (protective premenopausally).

Pseudogout

• Knee is the commonest joint (also wrist, MCP joints, shoulder, hip).
• Acute attacks mimic gout but are often less explosive; affects the elderly.
• Can be precipitated by trauma, surgery, or severe medical illness.
• Wrist/MCP involvement and a "pseudo-rheumatoid" pattern may mimic RA.

High-yield: Acute gout/pseudogout can present with fever and leukocytosis, closely mimicking septic arthritis — always aspirate and culture before attributing it to crystals. Crystals and infection can coexist.

Diagnosis & Investigation of Choice

Synovial fluid aspiration with polarised light microscopy is the gold standard / investigation of choice. Both diagnoses are confirmed by identifying the crystal — serum urate alone is neither sensitive nor specific (urate can be normal during an acute attack).

Feature	Gout (MSU)	Pseudogout (CPPD)
Crystal	Monosodium urate	Calcium pyrophosphate dihydrate
Shape	Needle-shaped	Rhomboid / rod-shaped
Birefringence	Negative (strongly)	Positive (weakly)
Colour under polariser (crystal parallel to slow ray of red compensator)	Yellow when parallel	Blue when parallel
Commonest joint	1st MTP (podagra)	Knee
X-ray hallmark	Punched-out erosions, overhanging edge (Martel sign), soft-tissue tophi	Chondrocalcinosis (linear cartilage calcification)
Age/sex	Middle-aged men	Elderly

High-yield mnemonic for polarised microscopy: "ABC" — Negative birefringent crystals appear Blue when Bottom (perpendicular) ... simplest reliable pearl: Gout = Needle + Negative birefringent + Yellow when parallel. Pseudogout is the opposite (Rhomboid + Positive + Blue when parallel).

Synovial fluid in crystal arthritis is inflammatory: WBC typically 2,000-50,000/µL (can exceed 50,000, overlapping with septic). Always send Gram stain and culture.

Other investigations:

• Serum uric acid (interpret cautiously; may fall acutely).
• 24-hour urinary uric acid: distinguishes overproduction (> 800 mg/day on normal diet, or >1000 mg/day) from underexcretion — guides choice between allopurinol and uricosurics.
• Renal function, glucose, lipids (gout clusters with metabolic syndrome).
• For CPPD in the young: serum calcium, PTH, ferritin/transferrin saturation, magnesium, TSH.
• Dual-energy CT (DECT) can non-invasively detect urate deposits; ultrasound double-contour sign (hyperechoic band over cartilage) supports gout.

ACR/EULAR 2015 classification criteria for gout use a point system (joint involvement, characteristics, urate level, imaging, crystal proof). MSU crystal demonstration is the definitive entry criterion.

Diagnostic flow

Acute hot joint → aspirate synovial fluid → Gram stain + culture (rule out sepsis) → polarised microscopy → needle-shaped negatively birefringent = gout; rhomboid positively birefringent = pseudogout → if no crystals & infection suspected, treat as septic arthritis.

Management & Drug of Choice

Acute attack (same principles for gout and pseudogout)

First-line options (do NOT change urate-lowering therapy during an acute attack):

1. NSAIDs — e.g. naproxen, indomethacin; rapid, effective; avoid in renal impairment, peptic ulcer, heart failure.
2. Colchicine — best if started within 24 hours of onset. Low-dose regimen (1.2 mg then 0.6 mg one hour later, then 0.6 mg daily) is as effective as high-dose with far less GI toxicity. Inhibits microtubule polymerisation → blocks neutrophil migration. Toxicity: diarrhoea (earliest, dose-limiting), myopathy, neuropathy, bone marrow suppression. Interacts dangerously with clarithromycin, statins, cyclosporine (CYP3A4/P-gp).
3. Corticosteroids — oral prednisolone or intra-articular steroid (preferred when 1-2 joints involved and infection excluded); ideal in renal failure where NSAIDs/colchicine are contraindicated.
4. IL-1 inhibitors (anakinra, canakinumab) — for refractory cases or when all above are contraindicated.

High-yield: In a patient with renal impairment or on anticoagulants, the safest acute gout drug is an intra-articular or oral corticosteroid, not NSAIDs.

Urate-lowering therapy (ULT) — chronic gout

Indications: ≥2 attacks/year, tophi, chronic gouty arthropathy, gout with CKD/urate stones, very high urate.

• Xanthine oxidase inhibitors (drug of choice for chronic gout):
  • Allopurinol — first-line. Start low (100 mg, or 50 mg in CKD), titrate to target. Risk of allopurinol hypersensitivity syndrome (SJS/TEN) — strongly linked to HLA-B*5801 (screen in high-risk Han Chinese, Thai, Korean). Active metabolite is oxypurinol.
  • Febuxostat — non-purine XO inhibitor; useful in allopurinol allergy or CKD; carries a cardiovascular mortality warning (CARES trial).
• Uricosurics: probenecid (less effective if GFR low; contraindicated in urate overproducers/stone formers — increases stone risk). Lesinurad (URAT1 inhibitor, with XO inhibitor).
• Pegloticase — recombinant uricase; converts urate to allantoin; for severe refractory tophaceous gout.

Treatment target: serum urate < 6 mg/dL (< 5 mg/dL if tophi present).

High-yield: When starting ULT, give prophylaxis with low-dose colchicine (or NSAID) for 3-6 months because abruptly lowering urate can paradoxically mobilise crystals and precipitate flares.

Drug pearls:

• Allopurinol + azathioprine/6-mercaptopurine = dangerous — XO inhibition blocks their metabolism → marrow toxicity (reduce thiopurine dose markedly).
• Losartan and fenofibrate are mildly uricosuric — preferred antihypertensive/lipid agents in gout.
• Pseudogout has no urate-lowering equivalent; management is symptomatic (NSAIDs/colchicine/steroids), treat the underlying metabolic cause, and low-dose colchicine can reduce recurrent attacks.

Drug	Mechanism	Key use / caution
Colchicine	Microtubule inhibition → ↓ neutrophil migration	Acute & prophylaxis; diarrhoea, statin/macrolide interaction
Allopurinol	Xanthine oxidase inhibitor	1st-line ULT; HLA-B*5801 SJS, avoid with azathioprine
Febuxostat	Non-purine XO inhibitor	CKD-friendly; CV mortality signal
Probenecid	↑ renal urate excretion (URAT1)	Underexcretors; avoid in stones/CKD
Pegloticase	Recombinant uricase → allantoin	Refractory tophaceous gout

Complications

• Chronic tophaceous gout with joint destruction and deformity.
• Urate nephrolithiasis (radiolucent stones) and chronic urate nephropathy; acute urate nephropathy in tumour lysis.
• Secondary osteoarthritis in CPPD-affected joints; severe destructive arthropathy ("pseudo-neuropathic").
• Strong association with metabolic syndrome, hypertension, CKD, and cardiovascular disease.

Key Differentials

• Septic arthritis — the must-exclude; aspirate and culture.
• Rheumatoid arthritis — symmetrical small-joint, RF/anti-CCP positive; CPPD can mimic it.
• Osteoarthritis — chronic, mechanical; CPPD accelerates it.
• Reactive/psoriatic arthritis — psoriasis also causes hyperuricaemia.
• Cellulitis — overlying erythema in podagra can mislead.

Recently asked / exam angle

• Image-based: a polarised micrograph showing needle-shaped negatively birefringent yellow crystals → answer gout; rhomboid positively birefringent blue → pseudogout.
• "Best/confirmatory investigation in acute monoarthritis" → synovial fluid polarised microscopy, not serum urate.
• Drug interaction questions: allopurinol + azathioprine, colchicine + clarithromycin/statin.
• HLA-B*5801 with allopurinol hypersensitivity (SJS/TEN).
• CANT LEAP drug-induced hyperuricaemia (especially thiazides, low-dose aspirin, pyrazinamide, ethambutol).
• Enzyme defects: HGPRT deficiency → Lesch-Nyhan; G6Pase → von Gierke.
• "Young patient with chondrocalcinosis" → screen for haemochromatosis / hyperparathyroidism.
• X-ray: overhanging edge (rat-bite/Martel) erosions = gout; linear chondrocalcinosis of knee menisci = CPPD.
• "Do not start/stop allopurinol during an acute flare."
• Target serum urate < 6 mg/dL.

Rapid revision

1. Gout = MSU, needle-shaped, negatively birefringent, yellow when parallel to red compensator; 1st MTP = podagra.
2. Pseudogout = CPPD, rhomboid, positively birefringent, blue when parallel; knee, chondrocalcinosis.
3. Synovial fluid polarised microscopy is the investigation of choice — always Gram stain/culture to exclude sepsis.
4. Urate saturation point = 6.8 mg/dL; ULT target < 6 mg/dL (< 5 with tophi).
5. 90% of gout = underexcretion; drug causes via CANT LEAP.
6. Acute attack: NSAID / colchicine (within 24 h) / steroid; colchicine toxicity = diarrhoea.
7. Chronic gout DOC = allopurinol (XO inhibitor); active metabolite oxypurinol.
8. Allopurinol + azathioprine → marrow toxicity; HLA-B*5801 → SJS/TEN.
9. Febuxostat for CKD/allopurinol allergy but carries CV mortality warning; pegloticase for refractory tophaceous gout.
10. Lesch-Nyhan = complete HGPRT deficiency, X-linked, self-mutilation.
11. Young CPPD → screen haemochromatosis, hyperparathyroidism, hypomagnesaemia, hypophosphatasia.
12. Losartan and fenofibrate are uricosuric — preferred in hypertensive/dyslipidaemic gout patients.