Paediatrics chapters
Wilson disease
An inherited disorder of copper excretion: the ATP7B gene, liver disease in younger children and neurological and psychiatric disease in older ones, the tests (ceruloplasmin, urine copper, KF rings, liver copper) and lifelong chelation or zinc.
- Wilson disease is an autosomal recessive defect of the ATP7B copper pump (chromosome 13), so copper cannot be excreted into bile and builds up in the liver, basal ganglia, cornea (Descemet membrane), kidney and bone.
- Children over 3 years usually present with liver disease (acute hepatitis, acute liver failure with Coombs-negative haemolysis, chronic hepatitis, cirrhosis); older children and teenagers (usually over 10) show dystonia, dysarthria, drooling, tremor, deteriorating handwriting and school performance, and psychiatric change.
- Diagnose with low ceruloplasmin (under 20 mg/dL), high 24-hour urine copper, Kayser-Fleischer rings on slit lamp and raised liver copper (over 250 micrograms/g dry weight); treat for life with penicillamine or trientine (plus pyridoxine with penicillamine), then zinc, a low-copper diet, screening of siblings, and liver transplant for liver failure.
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Overview
Wilson disease (hepatolenticular degeneration) is a treatable inherited cause of liver disease and movement disorder. Because copper cannot leave the body through the bile, it accumulates first in the liver, then spills into the brain, eyes, kidneys and red cells. In children it should be considered in any unexplained liver disease after 3 years of age, in acute liver failure with haemolysis, and in older children with new neurological or psychiatric symptoms. Early treatment gives an excellent outlook; untreated disease is fatal.
Aetiology and genetics
- Autosomal recessive; Akbar quotes about 1 in 30,000 live births. A family history and consanguinity are often present.
- Mutations in ATP7B on chromosome 13, which codes for an ATP-driven copper-transporting pump in liver cells.
- Normal role of ATP7B: moves copper into bile for excretion and loads copper onto ceruloplasmin for release into blood.
- Result: copper builds up in hepatocytes; when the liver is saturated, unbound copper is released into blood and deposited in the basal ganglia (lenticular nucleus), Descemet membrane of the cornea, kidneys and bone.
- Tissue damage comes from copper toxicity with oxidant injury.
Ceruloplasmin is low in most patients (Akbar: 80 to 95%) because copper is not loaded onto it, but serum non-ceruloplasmin copper and urine copper are high.
Clinical manifestations
Age pattern
| Presentation | Typical age |
|---|---|
| Hepatic | Over 3 years, rarely clinically evident before 5 years; commonest presentation in children |
| Neurological / psychiatric | Usually over 10 years (older children and adolescents) |
Akbar notes girls more often present with liver disease.
Hepatic
- Asymptomatic hepatomegaly or raised transaminases on routine testing
- Acute hepatitis resembling viral hepatitis
- Acute (fulminant) liver failure, often with severe Coombs-negative haemolysis, very high bilirubin and kidney injury
- Chronic active hepatitis
- Cirrhosis with portal hypertension: splenomegaly, varices, ascites, spider naevi
A child with acute liver failure plus haemolytic anaemia (Coombs negative) should be presumed to have Wilson disease until proved otherwise.
Neurological
- Deteriorating school performance and handwriting
- Dysarthria (loss of clear speech), drooling
- Dystonia (abnormal posturing of limbs and trunk), tremor, rigidity
- Gait disturbance, incoordination
- Seizures (later)
Psychiatric
- Behaviour change, mood disturbance, depression, irritability, psychosis
- Often mistaken for adolescent behaviour problems
Other organs
| Organ | Feature |
|---|---|
| Eye | Kayser-Fleischer (KF) rings: a brown band where the iris meets the cornea, from copper in Descemet membrane |
| Blood | Coombs-negative haemolytic anaemia (may be the first sign) |
| Kidney | Fanconi-like proximal tubular dysfunction |
| Bone | Copper is also deposited in bone |
"Liver, Lenticular, Limbus": copper hits the liver, the lenticular nucleus and the corneal limbus (KF ring).
Diagnostic investigations
| Test | Finding in Wilson disease |
|---|---|
| Serum ceruloplasmin | Low, usually under 20 mg/dL; over 30 mg/dL practically excludes it (Akbar) |
| 24-hour urine copper | Raised (Akbar: over 100 micrograms per 24 hours) |
| Penicillamine challenge | Large rise in 24-hour urine copper after oral penicillamine (Akbar: over 1000 micrograms per 24 hours is diagnostic) |
| Slit-lamp examination | KF rings: present in about 90% with neurological disease, but absent in up to half of young children with liver disease only |
| Liver biopsy copper | Over 250 micrograms per gram dry weight (the most reliable single test) |
| Liver function tests | Raised transaminases and bilirubin |
| CBC, reticulocytes, Coombs test | Coombs-negative haemolysis |
| Genetic testing (ATP7B) | Confirms diagnosis and allows family screening |
- Nelson stresses that any one test can be normal in a single patient, so diagnosis rests on a combination (ceruloplasmin, urine copper, KF rings, haemolysis, liver copper).
Absent KF rings do not exclude Wilson disease in a young child with liver disease. They are almost always present once the brain is involved.
Differential diagnosis
- Acute viral hepatitis
- Autoimmune hepatitis
- Drug-induced hepatitis
- Alpha-1 antitrypsin deficiency
- Indian childhood cirrhosis (copper-associated, in infants)
- For neurological features: other causes of dystonia and tremor, drug-induced movement disorders, and psychiatric illness
Management
Diet
- Avoid high-copper foods: chocolate, nuts, dried fruits, mushrooms (Akbar).
Drugs (lifelong)
| Drug | Action | Notes |
|---|---|---|
| D-penicillamine | Chelates copper and increases urinary excretion | Lifelong first-line chelator (Akbar gives 20 mg/kg/day); give pyridoxine (vitamin B6) with it (Akbar: to prevent optic neuritis) |
| Trientine | Chelator | Alternative when penicillamine is not tolerated (Akbar: 20 mg/kg/day) |
| Zinc acetate | Reduces copper absorption from the gut | Maintenance after chelation has reduced copper stores (Nelson), and for presymptomatic siblings |
- Monitor 24-hour urine copper, liver tests and blood counts at intervals (Nelson).
- Never stop treatment: stopping can cause fatal acute liver failure.
Surgical / transplant
- Liver transplantation for acute liver failure (fulminant Wilson disease) or decompensated cirrhosis not responding to drugs. It cures the metabolic defect because the new liver has normal ATP7B.
Family screening
- All siblings must be screened (ceruloplasmin, urine copper, LFTs, slit lamp, genetics).
- Affected siblings (homozygotes or compound heterozygotes) are treated even without symptoms, with chelation or zinc (Akbar).
- Genetic counselling: each sibling has a 1 in 4 chance of being affected.
Complications
- Cirrhosis, portal hypertension, acute liver failure, hepatic coma
- Haemolytic crisis with acute kidney injury and deep jaundice
- Progressive neurological disability; some damage is permanent
- Death if untreated
Prognosis and long-term follow-up
- Excellent with early diagnosis and lifelong adherence to treatment.
- Poor if untreated; fulminant presentation has a poor outlook without transplant.
- Established neurological damage may not reverse; Akbar describes it as permanent.
- Follow-up: adherence (especially in adolescence), 24-hour urine copper, liver function, blood counts, growth and school performance, and eye examination for KF rings.
Expect: autosomal recessive ATP7B on chromosome 13; failure of biliary copper excretion; liver presentation after 3 years versus neurological and psychiatric features after 10 years; dysarthria, drooling, dystonia and falling school performance; KF rings in Descemet membrane (almost always with neurological disease, often absent in young hepatic cases); low ceruloplasmin, high urine copper, liver copper over 250 micrograms/g; Coombs-negative haemolysis with liver failure; penicillamine with pyridoxine, trientine, zinc to block absorption; low-copper diet; transplant for fulminant disease; and screening of siblings.
Quick revision
- Autosomal recessive; ATP7B, chromosome 13; copper not excreted in bile.
- Liver disease after 3 years (rare before 5); brain and psychiatric disease usually after 10.
- Dysarthria, drooling, dystonia, tremor, worse handwriting and school work.
- KF rings: Descemet membrane; nearly always with neurological signs.
- Ceruloplasmin under 20 mg/dL; urine copper up; liver copper over 250 micrograms/g.
- Acute liver failure + Coombs-negative haemolysis = think Wilson.
- Penicillamine (with B6) or trientine, then zinc; low-copper diet; never stop.
- Transplant for liver failure; screen and treat siblings.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Why is ceruloplasmin low if copper is high?
The faulty ATP7B pump cannot load copper onto ceruloplasmin, so less of the protein circulates even though unbound copper rises in blood and urine.
Can a child have Wilson disease without Kayser-Fleischer rings?
Yes. Up to half of young children with liver-only disease lack them; they are nearly always present once neurological signs appear.
Why is pyridoxine given with penicillamine?
Akbar advises vitamin B6 with penicillamine to prevent optic neuritis caused by the drug.
Should a healthy brother of a patient be tested?
Yes. Each sibling has a one in four chance of being affected, and treating before symptoms prevents liver and brain damage.