Wilson Disease: Symptoms, Diagnosis and Treatment in India

Wilson disease is an inherited inability to excrete copper, caused by mutations in the ATP7B gene. Copper builds up in the liver, brain and eyes. Found early, it is controlled for life with chelating drugs or zinc. Presenting as acute liver failure, it is fatal without an urgent transplant — and a simple blood ratio, alkaline phosphatase to bilirubin below 4, is one of the fastest bedside clues.
— Dr Chetan Kalal, DM Hepatology, Gleneagles Hospital Mumbai

Picture a 16-year-old girl brought in from a district hospital with jaundice that has deepened over ten days. Her liver enzymes are oddly modest for how ill she looks. Her haemoglobin has dropped. Her bilirubin is high, her alkaline phosphatase almost normal, and her INR is climbing by the day. She was treated for “viral hepatitis” and sent home once already. This is how Wilson disease often announces itself in India — not as a rare genetic curiosity, but as a teenager in liver failure whose diagnosis was missed at the first visit.

Wilson disease is uncommon. Symptomatic disease affects roughly one person in 30,000, and specialists suspect it is under-diagnosed in South Asia, where consanguineous marriage is more frequent. Yet it is one of the very few causes of chronic liver disease that is genuinely, completely controllable with tablets — if someone thinks of it. As a hepatologist who has spent most of a career managing acute and acute-on-chronic liver failure, from the ICU at ILBS New Delhi to the transplant programme at Gleneagles Hospital Mumbai, I have learnt to keep Wilson disease on the list for any young patient with unexplained liver disease, unexplained haemolysis, or a neurological or psychiatric illness that does not quite fit. This guide explains how the disease behaves, how we prove it, how it is treated, and when it becomes an emergency.

What goes wrong: copper that the body cannot get rid of

We absorb copper from food every day — nuts, shellfish, chocolate, liver, mushrooms and legumes all contain it. A healthy liver loads surplus copper onto a carrier protein called ceruloplasmin and pushes the excess out into bile. The protein that does this work is coded by the ATP7B gene.

In Wilson disease both copies of ATP7B are faulty. Copper cannot leave through bile, so it piles up inside liver cells. For years the liver absorbs the damage quietly: fatty change, then inflammation, then scarring. Eventually the liver can hold no more and free copper spills into the bloodstream, depositing in the brain (particularly the basal ganglia, which control movement), the cornea of the eye, the kidneys, and red blood cells, which it can burst.

Because the defect is recessive, parents are usually healthy carriers. Each child of two carriers has a one-in-four chance of having the disease. That arithmetic is the reason sibling screening matters so much, and why a family history of a young relative who “died of jaundice” should always prompt the question.

The disease is a spectrum rather than a single picture. Most patients present between about 5 and 35 years of age, although diagnoses well outside that range are documented, and age alone should never be used to exclude it. Children tend to present with liver disease; adolescents and young adults are more likely to show neurological or psychiatric features, often with liver disease that nobody has yet noticed.

Symptoms: liver, brain, eyes — and the ones that get missed

Liver presentations range from nothing at all (a raised ALT found on a routine test) through fatty liver, chronic hepatitis and silent cirrhosis, to acute liver failure. Raised liver enzymes in a lean child or young adult with no alcohol, no viral hepatitis and no metabolic risk factors should lead to a Wilson work-up. So should cirrhosis diagnosed before the age of 40 without an obvious cause.

Neurological presentations include a tremor (classically coarse, “wing-beating” when the arms are held out), slurred speech, drooling, clumsiness, stiffness, dystonic postures and a fixed, vacant smile. Handwriting often deteriorates first, and parents notice it before doctors do.

Psychiatric presentations are the cruellest, because they are the easiest to misread: falling school performance, irritability, depression, impulsive behaviour, and occasionally psychosis. A teenager treated for months for “behaviour problems” who later develops a tremor is a story hepatologists and neurologists both recognise.

The eyes may show Kayser-Fleischer rings — a golden-brown ring at the edge of the cornea, made of copper. They are best seen on slit-lamp examination by an ophthalmologist; a torch examination misses many. In a Bangladeshi cohort of 40 children with Wilsonian acute liver failure, Kayser-Fleischer rings were present in 72.5%, which means more than a quarter of those children did not have them. Absent rings never exclude the disease, especially when the presentation is purely hepatic.

Other clues include haemolytic anaemia (red cells breaking down) without another explanation, kidney tubular problems, early-onset arthritis, and, in women, recurrent miscarriage.

How Wilson disease is diagnosed

No single test settles it. That is the honest answer, and it is why guidelines from both the American Association for the Study of Liver Diseases (AASLD, 2022) and the European Association for the Study of the Liver (EASL, 2012) combine several results.

Serum ceruloplasmin is the usual first test. A low level supports the diagnosis, but ceruloplasmin is an acute-phase protein, so inflammation can push it into the normal range; and it is low in other conditions, including protein malnutrition and severe liver failure of any cause. 24-hour urinary copper is more useful than most doctors realise. A level above 100 µg in 24 hours is the usual threshold in adults; in children a lower cut-off, above 40 µg, is used. The collection must be done in copper-free containers.

Slit-lamp examination looks for Kayser-Fleischer rings. Liver biopsy with measurement of copper content in the tissue remains valuable when the other results conflict; a hepatic copper above 250 µg per gram of dry liver is strongly supportive. Genetic testing of ATP7B confirms the diagnosis when two disease-causing variants are found, and once a family’s variants are known, siblings can be tested quickly and definitively. MRI of the brain is done in anyone with neurological symptoms.

Clinicians often combine these into the Leipzig score, which awards points for each finding. A score of 4 or more establishes the diagnosis. The practical point for patients is simpler: if your doctor orders three or four different copper tests, that is not over-investigation. It is how this disease has to be proved.

The emergency: Wilsonian acute liver failure

When Wilson disease first declares itself as acute liver failure, the timeline compresses from years into days. These patients — typically adolescents and young women — arrive jaundiced, with a rising INR, often with confusion, and frequently with haemolysis that drops their haemoglobin and drives their bilirubin very high. The pattern of the blood tests is distinctive: liver enzymes are only moderately raised, and alkaline phosphatase is disproportionately low.

That pattern is diagnostically useful precisely because conventional copper tests perform badly in this setting. In a landmark US study of 140 patients with acute liver failure, 16 of whom had Wilson disease, Korman and colleagues found that a serum ceruloplasmin below 20 mg/dL by the oxidase method detected only 21% of the Wilson cases. Serum copper was above 200 µg/dL in every Wilson patient tested — but it was also raised in patients whose liver failure had other causes. Two simple ratios did far better. An alkaline phosphatase-to-total bilirubin ratio below 4 was 94% sensitive and 96% specific; an AST:ALT ratio above 2.2 was 94% sensitive and 86% specific; together, they identified every Wilson case.

Here is the caveat that matters for Indian patients. When Yasmin and colleagues tested the same ratios in 60 children with acute liver failure in Dhaka, 40 of them Wilsonian, the ALP:bilirubin ratio below 4 was 100% specific but only 32.5% sensitive, and the AST:ALT ratio was 70% sensitive. Mortality among the Wilson children was 60%. The lesson is not that the ratios are useless. It is that in South Asian children a positive result should trigger immediate transplant assessment, while a negative result must not reassure anyone.

Medical treatment alone rarely rescues fulminant Wilson disease; the Korman group described it as invariably fatal without emergency transplantation. To decide who needs a transplant, specialists use the revised King’s Wilson Index, developed by Dhawan and colleagues in 88 children. It scores bilirubin, INR, AST and white cell count at presentation; a score of 11 or more predicted death without transplant with 93% sensitivity and 98% specificity. It was derived in children, and its use in adults is an extrapolation — one reason our group has been working on a refinement of the index, which is currently under peer review and not yet published. For the patient and family, the message is blunt: a young person with Wilsonian liver failure belongs in a centre with a liver ICU and an active liver transplant programme, today rather than tomorrow. My own randomised trial work in acute liver failure — the MAHAL study, comparing mannitol with hypertonic saline for raised brain pressure — came out of exactly that kind of ICU, where hours decide outcomes.

Treatment: lifelong, and it works

Outside the emergency, Wilson disease is one of the most treatable conditions in hepatology. Two families of medicine are used, and the choice depends on how the disease presented, how advanced it is, and how the patient tolerates the drug.

Chelating agents — penicillamine and trientine — bind copper and remove it through the urine. They are usually the first treatment for patients with symptoms, to strip out the accumulated load. Penicillamine has a well-known list of side effects, and some patients with neurological disease can worsen temporarily when it is started, so the drug and its introduction are chosen and monitored by a specialist. Zinc salts work differently: they block copper absorption from the gut. Zinc is often used for maintenance once copper levels are controlled, and for siblings diagnosed before any symptoms develop.

I am deliberately not giving doses here. Doses depend on weight, age, kidney function, the stage of disease and urine copper results over time, and getting them wrong in either direction causes harm — too little lets copper reaccumulate, too much can cause copper deficiency. Treatment is monitored with periodic liver tests, blood counts and 24-hour urinary copper.

Three rules matter more than any dose. First, treatment is for life. Stopping it, even after years of feeling well, can precipitate acute liver failure, and that scenario is well documented. Second, women with Wilson disease can have healthy pregnancies, but treatment should continue through pregnancy with specialist adjustment rather than being stopped. Third, a low-copper diet helps in the early phase (avoiding shellfish, organ meats, nuts, chocolate and mushrooms in quantity), but diet alone never controls the disease. Families sometimes check their household water too, particularly if it runs through copper pipes or is stored in copper vessels, a common practice in many Indian homes.

Liver transplantation is curative because the new liver carries normal ATP7B. It is used for acute liver failure and for decompensated cirrhosis that does not respond to medicine. After transplant, Wilson-specific medicines are no longer required, although lifelong transplant follow-up is.

Screening the family

When one person is diagnosed, every brother and sister should be tested, whatever their age and however well they feel. Each sibling has a one-in-four chance of having the disease, and a sibling caught before symptoms has the best prognosis of anyone with Wilson disease. Children of a patient should also be checked, as should cousins in consanguineous families.

Screening starts with a clinical examination, liver tests, ceruloplasmin, 24-hour urinary copper and a slit-lamp examination. Once the index patient’s ATP7B variants are known, targeted genetic testing gives a clear yes or no. A diagnosed but symptom-free sibling usually starts maintenance treatment straight away. This is prevention in its purest form: a few tablets a day in exchange for avoiding cirrhosis, liver failure or brain injury.

If you have a young relative with unexplained liver disease or a movement disorder, or a family history of a young person who died of “jaundice”, ask your doctor whether Wilson disease has been excluded. It is a simple question, and it has saved lives. A specialist hepatology review can organise the full work-up in one visit, with slit-lamp examination and genetic testing arranged alongside.

References

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