Write a short note on Wilson's disease.

Definition

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive disorder of copper metabolism caused by mutation of the ATP7B gene on chromosome 13, which encodes a copper-transporting ATPase in hepatocytes. The result is impaired biliary excretion of copper and impaired incorporation of copper into caeruloplasmin, leading to progressive copper accumulation — first in the liver, then, once hepatic capacity is exceeded, released into the circulation and deposited in the brain (especially basal ganglia), cornea, kidneys and other tissues.

Prevalence is about 1 in 30 000, higher where consanguinity is common — making it a significant consideration in Indian practice.

It is critically important because it is one of the few genetic metabolic diseases that is fully treatable — and untreated it is fatal.

Clinical Features

Presentation depends on age: hepatic disease predominates in children and adolescents (5–20 years), and neuropsychiatric disease in older adolescents and young adults (> 20 years).

Hepatic (40–50%):

• Asymptomatic transaminase elevation or hepatomegaly detected incidentally
• Acute hepatitis, often mistaken for viral hepatitis
• Chronic hepatitis and cirrhosis with portal hypertension
• ACUTE LIVER FAILURE — with a highly characteristic profile: Coombs-negative haemolytic anaemia (from sudden release of copper), markedly raised bilirubin with a LOW or normal alkaline phosphatase (an ALP:bilirubin ratio < 4 is highly suggestive), relatively modest transaminase rise with an AST:ALT ratio > 2.2, and renal failure. This picture in a young patient is Wilson's disease until proved otherwise, and carries near-100% mortality without transplantation.

Neurological (40–50%) — always with hepatic involvement, though it may be subclinical:

• Movement disorders: tremor (classically a coarse "wing-beating" tremor), dystonia, parkinsonism with rigidity and bradykinesia, chorea, athetosis.
• Dysarthria (often the earliest neurological sign) and dysphagia; drooling.
• "Risus sardonicus" — a fixed vacuous smile from facial dystonia.
• Ataxia and gait disturbance; micrographia.
• Cognition is relatively preserved until late, in contrast to the movement disorder.

Psychiatric (up to a third, and may be the presenting feature): personality and behavioural change, irritability, impulsivity, depression, anxiety, and psychosis. Adolescents presenting with deteriorating school performance and behavioural change plus abnormal liver tests must be screened.

Ophthalmic:

• KAYSER–FLEISCHER RINGS — golden-brown copper deposition in Descemet's membrane at the corneal limbus. Present in almost all patients with neurological disease but in only about half of those with purely hepatic disease. They require SLIT-LAMP examination — they are frequently invisible to the naked eye, especially in brown irides, and their absence never excludes the diagnosis.
• Sunflower cataract — a less common but characteristic finding.

Other: Coombs-negative haemolytic anaemia, renal tubular acidosis and Fanconi syndrome with nephrolithiasis, arthropathy, osteoporosis, cardiomyopathy and arrhythmia, hypoparathyroidism, and amenorrhoea or recurrent miscarriage.

Investigations

Diagnosis is made using the Leipzig score, combining Kayser–Fleischer rings, neurological features, caeruloplasmin, urinary and hepatic copper, haemolysis and genetic testing.

Management

Treatment is lifelong and must never be interrupted.

1. Chelation therapy — removes accumulated copper

• D-penicillamine — the classic agent; effective but with significant toxicity: hypersensitivity, nephrotic syndrome, marrow suppression, drug-induced lupus, myasthenia, and pyridoxine deficiency (so pyridoxine is co-prescribed). Importantly, it can cause paradoxical initial worsening of neurological symptoms, so it is introduced gradually.
• Trientine — better tolerated, increasingly preferred as first-line, particularly with neurological disease.

2. Zinc — induces intestinal metallothionein, which binds dietary copper and prevents its absorption, and is excreted in shed enterocytes. Used for maintenance therapy, in presymptomatic patients, and in pregnancy; well tolerated. It must be given separately from chelators, which would otherwise bind it.

3. Dietary measures — avoid copper-rich foods: liver, shellfish, nuts, chocolate, mushrooms and dried fruit, particularly in the first year of treatment. Check the copper content of drinking water where copper vessels are used — relevant in Indian households.

4. Liver transplantation — curative, as it replaces the defective hepatic transport protein. Indicated for acute liver failure due to Wilson's disease and for decompensated cirrhosis unresponsive to chelation.

5. Monitoring — clinical assessment, liver function, 24-hour urinary copper (to confirm adherence and adequacy of chelation), serum free copper, CBC and urinalysis for drug toxicity.

• 6. FAMILY SCREENING — mandatory and often neglected.
• All first-degree relatives, particularly siblings, must be screened with caeruloplasmin, urinary copper, liver tests, slit-lamp examination and, where available, genetic testing.
• Presymptomatic siblings identified and treated before organ damage occurs have an entirely normal life expectancy — which makes screening one of the highest-yield actions in the whole of clinical genetics.