SN1 SHORT NOTE 5M ★ High-yield

Define gout. Describe its biochemical basis, causes and treatment.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Gout = a disorder of purine metabolism characterised by hyperuricaemia and deposition of monosodium urate crystals in joints and soft tissues.

Hyperuricaemia — serum urate above 7 mg/dL in men, 6 mg/dL in women
Most people with hyperuricaemia never develop gout; it is necessary but not sufficient

Classification and Causes

Type	Mechanism	Causes
Primary — overproduction (10%)	↑ De novo purine synthesis	PRPP synthetase over-activity; partial HGPRT deficiency; glucose-6-phosphatase deficiency
Primary — underexcretion (90%)	↓ Renal urate clearance	Idiopathic; genetic transporter variants
Secondary — overproduction	Excess cell turnover	Leukaemia, lymphoma, psoriasis, haemolysis, tumour lysis syndrome
Secondary — underexcretion	Competition or renal disease	Thiazides, low-dose aspirin, alcohol, lactic acidosis, ketosis, chronic kidney disease, lead

WHY Crystals Form and Where

Urate is least soluble at low temperature and low pH
Hence the classical first attack in the first metatarsophalangeal joint (podagra) — the coolest, most peripheral joint
Crystals are needle-shaped and negatively birefringent under polarised light — the diagnostic finding
They are phagocytosed by neutrophils → inflammasome activation → IL-1β → acute inflammation

Clinical Features

Acute gouty arthritis — sudden, exquisitely painful, red, swollen joint, often at night
Intercritical period — symptom-free between attacks
Chronic tophaceous gout — tophi in the ear cartilage, olecranon bursa and tendons; joint destruction
Renal — uric acid stones (radiolucent), urate nephropathy
Associated with the metabolic syndrome, hypertension and cardiovascular disease

Treatment

Phase	Drug	Mechanism
Acute attack	NSAIDs, colchicine, steroids	Colchicine binds tubulin → blocks neutrophil migration
Long term — underexcretors	Probenecid (uricosuric)	↑ Renal urate excretion
Long term — overproducers	Allopurinol, febuxostat	Inhibit xanthine oxidase
Refractory	Rasburicase (recombinant uricase)	Converts urate to soluble allantoin

Applied Aspects

Never start or stop allopurinol during an acute attack — any sudden change in urate level can precipitate or prolong it
Allopurinol with azathioprine or 6-mercaptopurine is dangerous — xanthine oxidase normally inactivates them, so the dose must be cut drastically
Tumour lysis syndrome — massive cell breakdown after chemotherapy → hyperuricaemia, hyperkalaemia, hyperphosphataemia and renal failure. Prevented by hydration and allopurinol or rasburicase
Low-dose aspirin raises urate (it competes for the tubular transporter) while high doses are uricosuric

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