Wilson Disease
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Direct answer
Wilson disease — an autosomal recessive ATP7B mutation on chromosome 13 that blocks copper transport into bile and caeruloplasmin — should come to mind for anyone under 40 with unexplained liver disease, movement disorder or behaviour change, and it is diagnosed by combining Kayser-Fleischer rings, a caeruloplasmin below 20 mg/dL and a 24-hour urinary copper above 100 micrograms, formalised in the eight-point Leipzig score where 4 or more makes the diagnosis. Chelation is lifelong: D-penicillamine with pyridoxine supplementation or the better-tolerated trientine, with zinc as maintenance or presymptomatic therapy. Stopping treatment is how Wilson disease converts itself into acute liver failure. A fulminant presentation with Coombs-negative haemolysis, a low alkaline phosphatase and an AST:ALT ratio below 2.2 is a transplant emergency, because no chelator rescues a dying liver — only a new one does.
What you must remember
- Genetics: ATP7B on chromosome 13, autosomal recessive, population frequency near 1 in 30,000; siblings of an index case carry a 25 per cent risk and must be screened.
- Ocular sign: Kayser-Fleischer rings are copper in Descemet's membrane, seen at slit lamp — present in about 95 per cent of neurological but only around half of hepatic presentations, so their absence never excludes hepatic Wilson disease.
- Biochemistry: caeruloplasmin below 20 mg/dL (falsely low in nephrotic syndrome and advanced liver failure, falsely normal with acute inflammation); 24-hour urinary copper above 100 micrograms; liver copper above 250 micrograms per gram dry weight.
- Penicillamine challenge: a fivefold rise in 24-hour urinary copper after a standard dose supports the diagnosis in borderline cases.
- Fulminant clues: Coombs-negative haemolysis with an alkaline phosphatase-to-bilirubin ratio below 4 and AST:ALT below 2.2 — a combination worth memorising for the emergency stem.
- Neuropsychiatric face: wing-beating tremor, dysarthria, dystonia, drooling, and personality or school-performance change in a teenager; the psychiatric presentation is under-recognised in Indian practice.
- Leipzig score: rings 2, neurological features 2, typical biochemistry up to 2 each, haemolysis with high copper 1, mutation analysis 4 — total 4 or more diagnoses.
- Drugs: D-penicillamine (add pyridoxine 25 mg daily; watch marrow, nephrotic proteinuria, and early neurological worsening), trientine (fewer adverse effects), zinc acetate (blocks intestinal absorption, useful in maintenance and pre-symptomatic disease); ammonium tetrathiomolybdate is available in India as second-line per local experience.
A typical viva case
A 16-year-old boy has two years of declining school performance, a coarse tremor and slurring speech; transaminases are mildly raised, caeruloplasmin is 8 mg/dL and slit-lamp examination shows golden-brown rings at the corneal limbus. Walk it: the Leipzig score accrues rings 2, neurological signs 2 and biochemistry 2 — 6, diagnosis made; confirm with 24-hour urinary copper and ATP7B sequencing if available. Start trientine (or low-dose penicillamine) and zinc; warn the family that early neurological deterioration in the first weeks of chelation is recognised and usually recovers. Screen every sibling with liver profile, caeruloplasmin and slit-lamp examination, and haplotype or sequencing where possible. Contrast: a 19-year-old girl with the same copper chemistry arriving with haemoglobin of 6, INR 3, bilirubin 30 and an alkaline phosphatase of 40 IU/L does not belong to the chelation pathway — the ratios mark fulminant Wilson disease and she needs listing now; the biochemical rule of thumb (alkaline phosphatase divided by bilirubin under 4) exists precisely for this decision.
How the exam frames it
Wilson disease appears as three photographs: the teenager with tremor, the child with cryptogenic cirrhosis, and the young woman with fulminant failure and haemolysis. The first asks for the diagnostic pair (slit lamp plus caeruloplasmin), the second for the Leipzig score, the third for the transplant decision. The negative-markers matter: absent rings do not exclude it, a normal caeruloplasmin does not exclude it (the acutely ill, inflamed liver raises it), and a low caeruloplasmin alone never diagnoses it, since it is an acute-phase-negative protein that falls in any severe failure.
Frequently asked questions
Which investigations confirm Wilson disease?
Slit-lamp for Kayser-Fleischer rings, serum caeruloplasmin, 24-hour urinary copper and hepatic copper quantification, consolidated in the Leipzig score.
What suggests fulminant Wilson disease?
Coombs-negative haemolysis with alkaline phosphatase-to-bilirubin ratio below 4 and AST:ALT ratio below 2.2 — proceed directly to transplant assessment.
What monitoring does penicillamine require?
Full blood counts and urinalysis (marrow suppression, proteinuria), pyridoxine 25 mg daily supplementation, and awareness of early neurological worsening.
When is zinc used instead of chelation?
As maintenance after de-coppering, in pre-symptomatic siblings, and when chelators are intolerable — it blocks intestinal copper absorption.
Can Wilson disease be cured by transplant?
Yes — the hepatic defect sits in the liver, so a graft normalises copper metabolism; neurological recovery after transplant is variable.