Your next patient has a hand tremor, and his liver tests have been abnormal for 2 years. Here's how the Wilson's disease case unfolds and what to pick up on the way.

This wilson's disease case is easy to miss because the liver story and the brain story often sit in different clinics. Your next patient has a hand tremor and liver tests that have been abnormal for 2 years, and he says: "A tremor in his hands, and liver blood tests that have been abnormal for a couple of years." The history keeps getting split: two years of unexplained abnormal liver tests, a coarse wing-beating tremor with shrinking handwriting, slurred quiet speech with drooling, two years of personality change, leaving university, a cousin who died of liver failure in his twenties, and self-limiting jaundice with dark urine last year. This page walks through how the case presents, what to pick up in the history, the tests, including slit-lamp examination for Kayser, fleischer rings that are almost never requested, and the teaching points.

How the case presents

Your next patient has a hand tremor, and his liver tests have been abnormal for 2 years. In their own words: "A tremor in his hands, and liver blood tests that have been abnormal for a couple of years."

Observations on arrival:

Observation	On arrival
Heart rate	76 beats per minute
Blood pressure	118/70 mmHg
Respiratory rate	14 breaths per minute
Oxygen saturation	99%
Temperature	36.7 °C

What to pick up in the history

These are the findings the case is built around. Each one moves you towards or away from Wilson's disease, and the scorecard checks whether you found it.

Two years of unexplained abnormal liver tests: unexplained liver disease under 40 with negative screens mandates considering Wilson's disease.
Coarse wing-beating tremor and shrinking handwriting: the wing-beating postural tremor is the neurological signature of Wilson's disease.
Slurred, quiet speech with drooling: dysarthria and dystonia indicate basal ganglia copper deposition.
Two years of personality change; left university: psychiatric decline alongside liver disease in a young man unites the two systems.
Cousin died of liver failure in his twenties: fits autosomal recessive inheritance and strengthens the case for Wilson's disease.
Self-limiting jaundice with dark urine a year ago: A prior haemolytic episode is a well-recognised Wilson's clue.

Red flags you must not miss

The case marks these as must-elicit. They only come out if you ask.

Two years of unexplained abnormal liver tests.
Coarse wing-beating tremor and shrinking handwriting.
Slurred, quiet speech with drooling.
Two years of personality change; left university.
The liver problem and the low mood have been looked after by separate teams, and nobody has linked them.
He is only 24, and a doctor told him it is unusual to have liver problems this young with no clear reason.

Investigations and what they showed

Caeruloplasmin: Low, the classic screening abnormality in Wilson's disease. Why it helps: the standard screening test, but beware: it is an acute-phase protein that can be falsely normal with inflammation or oestrogens, and low levels occur in other liver disease, so it must be interpreted alongside urinary copper.
Copper: 24-hour urinary copper markedly raised; serum total copper is low but free (non-caeruloplasmin-bound) copper is high. Why it helps: raised 24-hour urinary copper excretion is a key diagnostic criterion, note total serum copper can be misleadingly low because most circulating copper is normally carried on caeruloplasmin.
Liver function tests: Persistently raised transaminases with a raised bilirubin; ALP may be disproportionately low. Why it helps: A low alkaline phosphatase with a high bilirubin (a low ALP:bilirubin ratio) in acute liver failure is highly suggestive of Wilson's disease.
Full blood count: Anaemia with evidence of haemolysis; thrombocytopenia if portal hypertension is present. Why it helps: coombs-negative haemolytic anaemia (from copper release) alongside liver disease in a young person is a classic Wilson's combination.
Direct antiglobulin test: Negative, a Coombs-negative haemolytic anaemia. Why it helps: distinguishes the copper-induced haemolysis of Wilson's disease from autoimmune haemolytic anaemia.
Prothrombin time / INR: Mildly prolonged, assessing synthetic function.
Albumin: Low-normal, reflecting impaired synthetic function. Why it helps: assesses chronic liver synthetic capacity.
Liver autoantibody panel: Negative, excluding autoimmune hepatitis. Why it helps: autoimmune hepatitis is the main alternative cause of unexplained hepatitis in a young person, and Wilson's can mimic it closely.
Hepatitis B serology: Negative, excluding viral hepatitis. Why it helps: standard exclusion in any unexplained chronic liver disease.
Slit-lamp examination: Kayser, fleischer rings, golden-brown copper deposition at the corneal limbus, present in nearly all patients with neurological Wilson's disease. Why it helps: A simple, decisive bedside/ophthalmology test that virtually clinches the diagnosis in a patient with neuropsychiatric features, and it is almost never requested, which is why the diagnosis is delayed for years.
MRI brain: The face of the giant panda sign in the midbrain (red nuclei = eyes, substantia nigra pars reticulata = ears, superior colliculi = chin around a dark aqueduct). Also bilateral symmetric T2/FLAIR hyperintensity in the basal ganglia (putamen and globus pallidus), thalamus and brainstem; a 'miniature panda' in the pons; and in advanced disease generalised cortical and cerebellar atrophy with enlarged ventricles.
Histology / biopsy: Liver biopsy with quantitative hepatic copper markedly raised; rhodanine staining shows copper granules, with steatosis, inflammation and fibrosis/cirrhosis. Why it helps: the gold standard when biochemistry is equivocal, quantitative hepatic copper is the most definitive test, and it also stages the fibrosis.
Ultrasound abdomen: Early on, a bright echogenic liver of hepatic steatosis (brighter than the renal cortex, with posterior attenuation). Later, a coarse nodular cirrhotic liver with splenomegaly and ascites from portal hypertension. Why it helps: assesses the degree of chronic liver damage and portal hypertension already present in this young man.
Inspect the cornea: A golden-brown ring of pigment in the periphery of the cornea, densest at the upper and lower limbus, a Kayser-Fleischer ring. Why it helps: KF rings are present in virtually every patient with neurological Wilson's disease. This is the cheap, decisive test that is almost never requested, a slit-lamp examination joins his liver problem and his 'psychiatric' problem into one diagnosis.
Inspect the sclera: A faint yellow tinge to the sclerae. Why it helps: he has a persistently raised bilirubin and a past self-limiting jaundiced episode from Coombs-negative haemolysis, a classic Wilson's clue. A low alkaline phosphatase with a high bilirubin is another.
Inspect the hands: When he holds his arms out to the sides with elbows bent, a coarse, slow, large-amplitude flapping tremor develops at the shoulders and elbows, the wing-beating tremor. Why it helps: A coarse proximal postural tremor in a 24-year-old is not benign essential tremor and is not a drug side-effect, with abnormal liver tests it is Wilson's disease until proven otherwise.
Inspect the face: A fixed, rather vacuous open-mouthed smile with reduced facial expression and mild dystonic grimacing.
Inspect the mouth and oral cavity: Saliva pools at the corners of the mouth and he drools, with slurred, indistinct speech. Why it helps: drooling and dysarthria are bulbar features of the extrapyramidal syndrome, and they carry a real aspiration risk, they are neurological signs, not poor self-care or sedation.
Inspect the bedside and surroundings: The consent form and the diary on his locker show cramped, tremulous, deteriorating handwriting compared with his signature from a year ago. Why it helps: deteriorating handwriting is a cheap objective record of a progressive movement disorder, and comparing it with old writing dates the onset better than any history.
Inspect the patient's gait: He walks slowly and stiffly with reduced arm swing and slightly dystonic posturing of one arm. Why it helps: A parkinsonian-dystonic gait in a young adult is never age-related, combined with liver disease it points straight at the basal ganglia changes (and the 'face of the giant panda' sign) of Wilson's.

Imaging findings

OGD / gastroscopy: Screens for oesophageal varices if cirrhosis with portal hypertension is confirmed.
CT abdomen and pelvis: Established cirrhosis with portal hypertension, a shrunken liver with an irregular nodular contour, massive splenomegaly, and free ascites with bowel floating centrally.

Why the diagnosis is Wilson's disease

The decisive diagnosis is wilson's disease, an autosomal recessive disorder of copper transport (ATP7B) causing copper accumulation in the liver, brain, cornea and kidneys. the rule: consider Wilson's disease in any patient under 40 with unexplained liver disease, and in any young person with a movement disorder or unexplained psychiatric/behavioural decline. The neurological signature is a coarse wing-beating tremor, dysarthria, dystonia, drooling and deteriorating handwriting, with kayser, fleischer rings on slit-lamp examination in virtually all patients who have neurological involvement. Screen with a low caeruloplasmin and a high 24-hour urinary copper (caeruloplasmin is an acute-phase protein and can be falsely normal); confirm with liver biopsy quantitative copper or ATP7B genetics. Two extra clues: coombs-negative haemolytic anaemia, and a low alkaline phosphatase with a high bilirubin in acute liver failure.

Wilson's disease at a glance

What it is

Wilson's disease is a rare, autosomal recessive disorder of copper metabolism in which mutations in the ATP7B gene prevent the liver from excreting excess copper into bile. It is easily missed because the liver disease goes to hepatology and the neuropsychiatric disease goes to psychiatry, the diagnosis lives in joining the two together, in any patient under 40 with unexplained liver disease or a movement disorder.

Pathogenesis

Without functioning ATP7B, copper cannot be excreted into bile or properly incorporated into caeruloplasmin, so it accumulates first in the liver, causing hepatitis, fibrosis and eventually cirrhosis. Once hepatic storage capacity is exceeded, copper spills into the bloodstream and deposits in the brain (especially the basal ganglia), the cornea, and other tissues, producing the movement disorder and psychiatric change that can dominate the presentation in some patients.

Who it affects

Rare, roughly 1 in 30,000 people, autosomal recessive, so it typically presents in children, teenagers or young adults, most often before age 40.

How serious it is

Untreated, Wilson's disease progresses to cirrhosis, liver failure, and progressive, disabling neurological disease.

Causes and risk factors

The disease is caused by inherited mutations in both copies of the ATP7B gene (autosomal recessive), so a family history of unexplained liver disease or early movement disorder in a sibling is an important clue. There is no acquired or lifestyle cause, and dietary copper restriction alone does not prevent the disease in a genetically affected individual.

Investigations and lab tests

Screen with a low caeruloplasmin and a high 24-hour urinary copper, but never exclude the diagnosis on caeruloplasmin alone since it is an acute-phase protein and can be falsely normal. Kayser-Fleischer rings on slit-lamp examination are present in virtually all patients with neurological involvement. Confirm with liver biopsy quantitative hepatic copper (the gold standard) or ATP7B genetic testing. Two extra clues: Coombs-negative haemolytic anaemia, and a low alkaline phosphatase with a high bilirubin in acute liver failure.

At a glance: Screen: low caeruloplasmin + high 24-hour urinary copper. Decisive and cheap: slit-lamp for Kayser-Fleischer rings. Confirm: liver biopsy copper or ATP7B genetics.

Teaching points

Consider wilson's disease in any patient under 40 with unexplained liver disease, and in any young person with a movement disorder or unexplained psychiatric/behavioural decline.
It is missed because the liver goes to hepatology and the brain goes to psychiatry, the diagnosis lives in joining the two together.
The neurological signature is a coarse wing-beating postural tremor, dysarthria, dystonia, drooling and deteriorating handwriting.
Kayser, fleischer rings on slit-lamp examination are present in virtually all patients with neurological involvement, it is a cheap, decisive test that is almost never requested.
Screen with a low caeruloplasmin and a high 24-hour urinary copper, but caeruloplasmin is an acute-phase protein and can be falsely normal, so never exclude the diagnosis on it alone.
Confirm with liver biopsy quantitative hepatic copper (the gold standard) or ATP7B genetic testing.
Two powerful extra clues: coombs-negative haemolytic anaemia, and a low alkaline phosphatase with a high bilirubin in acute liver failure.
MRI brain shows basal ganglia signal change and the midbrain 'face of the giant panda' sign.

Practise a similar case

Reading a case is safe and tidy, but it is not the same as shaping the questions yourself when the clock is ticking. Would you have asked about shrinking handwriting, or picked up the coarse wing-beating tremor while keeping the liver story in mind? Try another gastro history and feel that bit of pressure.

Here's one from the same specialty, with the diagnosis left for you to find. Your next patient is 55 with episodes of facial flushing and loose stools for 2 years. Take this patient's history in Diagnosica. It's free to start, no card needed.

Wilson's disease case presentation: history, findings and tests