Wilson’s Disease
Overview
Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutation in the ATP7B gene. It is a classic board favorite because it combines hepatology, neurology, psychiatry, genetics, and ophthalmology. For the PANCE, you must recognize the age group, key physical findings, diagnostic labs, and first-line treatment.
Pathophysiology
As mentioned above, Wilson’s Disease is a rare autosomal recessive mutation causing the accumulation of free copper within the liver, brain, kidneys, and cornea. This accumulation is due to a mutation of the ATP7B gene on chromosome 13. Normally copper ingested into the body is absorbed in the small intestine where it is then bound to ceruloplasmin in the liver and excreted back into GI circulation as bile.
The ATP7B gene provides the liver with instructions to create a protein for copper transport to then be bound to ceruloplasmin which is then excreted into the bile. When this gene is mutated copper is not properly bound to ceruloplasmin leading to inadequate excretion of copper in the bile and an increase in circulating copper in the blood which in turn leads to copper deposition into tissues leading to cellular damage. This buildup of copper in tissues tends to accumulate and cause oxidative stress in vital structures including the liver, brain, kidneys, and cornea.
Clinical Manifestation
Signs and symptoms of copper buildup can very based on the location of the accumulation.
-Hepatic copper deposits may cause hepatitis, hepatosplenomegaly, hemolytic anemia, cirrhosis, and liver failure.
-CNS deposits have an affinity for the basal ganglia and can lead to Parkinson-like symptoms like bradykinesia, tremors, and rigidity. Personality changes and dysarthria can also be caused as a result.
-Corneal deposits commonly cause Kayser-Fleischer rings which are brown or green pigmented rings along the edges of the cornea can be seen in a proper ophthalmologic exam and using a slit lamp is availible.
-Kidney deposits may lead to tubular dysfunction, acute kidney disease, hematuria, and renal tubular acidosis.
Diagnosis
In Wilson’s disease is suspected in patients initial lab work should include serum Ceruloplasmin levels and 24-hour urinary copper excretion. Typically patients with Wilson’s disease will have a low serum ceruloplasmin level and an increase is urinary copper excretion. Further diagnostic testing can be obtained via a liver biopsy which would show high copper concentrations within the liver tissue.
Treatment
First line treatment is D-Pencillamin, which chelates the excess circulating copper, orTrientene as an alternative chelating agent. Pyridoxine or vitamin B6 may also be given to prevent depletion. Zinc may also be given which decreased copper absorption by the small intestine leading to increased fecal excretion of free copper and is used as second line for patient who are intolerant of copper chelating agents. Ammonium tetrathiomolybdate is used to increase urinary excretion of copper if necessary. For severe cases of copper related liver failure a liver transplant can be curative.
Quiz Question
A 17-year-old boy is brought to the clinic by his mother due to progressive behavioral changes over the past 6 months. She reports increased irritability, declining school performance, and social withdrawal. Over the past 2 months, he has developed a tremor in both hands and difficulty speaking clearly.
On physical examination, he has mild jaundice and a coarse, wing-beating tremor when his arms are extended. Slit-lamp examination reveals brownish discoloration at the periphery of both corneas. Laboratory studies show elevated AST and ALT. Hemoglobin is mildly decreased with evidence of hemolysis.
Which of the following is the most appropriate next step in confirming the diagnosis?
A. Measure serum ferritin level
B. Order hepatitis B surface antigen
C. Measure serum ceruloplasmin level
D. Order anti–smooth muscle antibody
E. Obtain abdominal ultrasound
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The correct answer is: C. Measure serum ceruloplasmin level