A 24-year-old man is brought to the office by his parents due to hand shaking and involuntary movements, which have progressively worsened over the last 6 months. A year ago, he was diagnosed with depression and treated with fluoxetine for 5 months but stopped the medication and did not follow up with his psychiatrist. His medical history is otherwise unremarkable. The patient has smoked cigarettes intermittently in the past but does not drink alcohol or use illicit drugs. He dropped out of college and has worked as a delivery man for the last several years. Blood pressure is 122/82 mm Hg supine and 120/84 mm Hg standing. Physical examination reveals clear breath sounds and no cardiac murmurs. The liver is enlarged, firm, and nontender, and the spleen is not palpable. There is tremor of both hands that increases with activity. Occasional rapid, jerky contractions of the distal extremities are also seen. Laboratory results are as follows:
| Total bilirubin | 1.9 mg/dL |
| Direct bilirubin | 0.9 mg/dL |
| Alkaline phosphatase | 31 U/L |
| Aspartate aminotransferase | 276 U/L |
| Alanine aminotransferase | 130 U/L |
| Prothrombin time | 12.0 sec |
Viral hepatitis panel is negative. Which of the following is the most likely diagnosis?
Wilson disease | |
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The combination of liver disease (eg, elevated liver enzyme results) and neuropsychiatric symptoms (eg, tremors, involuntary movements) in a young adult is highly suggestive of Wilson disease (WD, hepatolenticular degeneration), a rare, autosomal recessive disease most often identified in individuals age 5-35. It results from impaired copper transportation with resultant accumulation in tissues, including the liver and brain. In younger patients, liver disease predominates, whereas neurologic symptoms are more prominent in older patients.
Liver dysfunction ranges from asymptomatic liver function abnormalities to hepatitis to cirrhosis. Neuropsychiatric symptoms include parkinsonism, dysarthria, choreoathetosis, ataxia, personality changes, and depression. Tremors can occur with activity or at rest. The diagnosis is suggested by low serum ceruloplasmin with increased urinary copper excretion or Kayser-Fleischer rings (golden brown or greenish rings due to copper deposits in the cornea).
Treatment focuses on removing accumulated copper and preventing re-accumulation. First-line medications include copper chelators (eg, D-penicillamine, trientine). Oral zinc, which interferes with copper absorption, may be used for maintenance therapy. For patients with fulminant hepatic failure or drug-resistant disease, liver transplantation is curative.
(Choice A) Alpha-1-antitrypsin deficiency (AATD) can result in obstructive lung disease, liver dysfunction (eg, cirrhosis), and skin disease. Patients who smoke are at very high risk of early onset emphysema, but this patient lacks any evidence of lung involvement, and AATD would not explain the neuropsychiatric symptoms.
(Choice B) Hemochromatosis is characterized by iron overload. Common clinical manifestations include liver disease, hyperpigmentation, diabetes mellitus, arthropathy, and cardiac enlargement.
(Choice C) Huntington disease is a genetic disorder with marked neuropsychiatric manifestations such as chorea, parkinsonism, dementia, and personality changes; however, there is no association with liver disease. Moreover, symptom onset usually occurs in midlife.
(Choice D) Multiple system atrophy describes a series of neuromotor disorders that share a common set of symptoms, including parkinsonism, urogenital dysfunction (eg, erectile dysfunction), autonomic dysfunction (eg, orthostatic hypotension), and ataxia.
(Choice E) Serotonin syndrome most commonly occurs within the first 24 hours of starting or adjusting the dose of a medication with serotonergic activity. It is associated with autonomic instability, agitation, diaphoresis, hyperreflexia, and clonus.
Educational objective:
Wilson disease is characterized by the combination of liver disease and neuropsychiatric symptoms that present in patients age 5-35. Liver dysfunction ranges from asymptomatic liver function abnormalities to cirrhosis. Neuropsychiatric symptoms include parkinsonism, dysarthria, choreoathetosis, ataxia, personality changes, and depression.