Also known as: Wilson disease, hepatolenticular degeneration
Overview
Autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13, encoding a hepatocyte copper-transporting ATPase. Loss of function impairs biliary excretion of copper and incorporation of copper into ceruloplasmin, resulting in pathologic copper accumulation in liver, brain, cornea, and other tissues.
Epidemiology
Prevalence ~1 in 30,000 worldwide. Symptoms typically present between ages 5 and 35; hepatic manifestations dominate in children and adolescents, neuropsychiatric in young adults. Higher prevalence in populations with founder mutations.
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Question 1GastrointestinalMedium
A 19-year-old man is brought in by his parents for 3 months of worsening hand tremor, slurred speech, and a recent personality change with irritability and falling grades. On exam he has scleral icterus, a coarse "wing-beating" tremor, and drooling. Vitals are normal. Labs show AST 180 U/L, ALT 95 U/L, total bilirubin 4.2 mg/dL, hemoglobin 9.1 g/dL with a Coombs-negative hemolytic picture, and a low haptoglobin. Serum ceruloplasmin is 12 mg/dL and 24-hour urinary copper is markedly elevated. Slit-lamp examination reveals brownish deposits at the corneal limbus. Which of the following is the most likely diagnosis?
AHereditary hemochromatosis
BAlpha-1 antitrypsin deficiency
CAlcohol-associated hepatitis
DWilson disease
EAutoimmune hepatitis
Reveal answer & full explanation
Correct answer: D — Wilson disease
AHereditary hemochromatosis
BAlpha-1 antitrypsin deficiency
CAlcohol-associated hepatitis
DWilson disease✓
EAutoimmune hepatitis
Why Wilson disease is correct
ATP7B dysfunction impairs biliary copper excretion and copper incorporation into ceruloplasmin, so copper accumulates in liver, brain (basal ganglia), and cornea.
This vignette is the classic triad: a patient under 40 with hepatitis, Coombs-negative (non-immune) hemolytic anemia, and a movement/neuropsychiatric disorder.
Low ceruloplasmin (<20 mg/dL), high 24-hour urinary copper, and Kayser-Fleischer rings (brownish limbic corneal deposits on slit lamp) clinch it; a Leipzig score >=4 is diagnostic.
Why the others are wrong
Autoimmune hepatitis: young patients can present with hepatitis, but you expect positive ANA/ASMA and elevated IgG, not low ceruloplasmin, high urinary copper, or Kayser-Fleischer rings; the wing-beating tremor and corneal findings point away from it.
Hereditary hemochromatosis: iron (not copper) overload from HFE mutations causes high ferritin/transferrin saturation with bronze skin, diabetes, and cardiomyopathy, typically presenting later in life, without a movement disorder or low ceruloplasmin.
Alpha-1 antitrypsin deficiency: produces liver disease and early panacinar emphysema with a low A1AT level (ZZ phenotype); it has no neuropsychiatric component, no Coombs-negative hemolysis, and normal copper studies.
Alcohol-associated hepatitis — an AST:ALT ratio near 2:1, jaundice, tremor, and a personality change with falling grades can suggest alcohol misuse, but alcohol-associated hepatitis does not explain the combination of low ceruloplasmin, markedly elevated 24-hour urinary copper, and Kayser-Fleischer rings, and the wing-beating tremor and drooling reflect basal ganglia copper deposition.
Question 2GastrointestinalMedium
A 19-year-old man is evaluated for 3 months of fatigue, mild jaundice, and a new resting tremor of both hands. He has had worsening school performance and irritability. Examination shows scleral icterus and a wing-beating tremor. Laboratory studies show AST 180 U/L, ALT 70 U/L, total bilirubin 4.2 mg/dL, and a Coombs-negative anemia. Serum ceruloplasmin is low at 12 mg/dL. Which of the following is the most appropriate next diagnostic test to confirm the diagnosis?
ATwenty-four-hour urinary copper level
BSerum total copper concentration
CSerum anti-smooth muscle antibody titer
DSerum alpha-1 antitrypsin phenotyping
ESerum ferritin and transferrin saturation
Reveal answer & full explanation
Correct answer: A — Twenty-four-hour urinary copper level
ATwenty-four-hour urinary copper level✓
BSerum total copper concentration
CSerum anti-smooth muscle antibody titer
DSerum alpha-1 antitrypsin phenotyping
ESerum ferritin and transferrin saturation
Why Twenty-four-hour urinary copper level is correct
This young patient has the classic Wilson disease triad: hepatitis, Coombs-negative hemolytic anemia, and a movement disorder (wing-beating tremor), with a low serum ceruloplasmin already pointing to the diagnosis.
Ceruloplasmin is only a screening test (neither sensitive nor specific alone). The appropriate next step is a 24-hour urinary copper, which is elevated (>100 mcg/24 h in symptomatic disease) and is a core component of the Leipzig diagnostic criteria.
Combined with a slit-lamp exam for Kayser-Fleischer rings and, if needed, hepatic copper quantification on biopsy, urinary copper confirms the diagnosis.
Why the others are wrong
Serum ferritin and transferrin saturation test for hereditary hemochromatosis (iron overload), which causes bronze skin, diabetes, and cardiomyopathy, not a tremor or Coombs-negative hemolysis in a teenager.
Serum alpha-1 antitrypsin phenotyping screens for A1AT deficiency, a real cause of young-adult liver disease, but it produces emphysema rather than a movement disorder and does not lower ceruloplasmin.
Serum anti-smooth muscle antibody titer screens for autoimmune hepatitis; although it can coexist with Wilson, the low ceruloplasmin plus neurologic and hemolytic findings make copper studies the confirmatory next step.
Serum total copper concentration — measuring blood copper seems the direct way to prove copper overload, but most circulating copper is bound to ceruloplasmin, so total serum copper is usually low in proportion to the ceruloplasmin and can shift with hemolysis or liver injury; it neither confirms nor excludes Wilson disease, whereas the 24-hour urine captures the excess free copper.
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More than 700 ATP7B mutations described — compound heterozygosity common
Pathophysiology
Dietary copper is absorbed in the duodenum and delivered to hepatocytes. ATP7B normally transports copper into bile and onto apoceruloplasmin to form ceruloplasmin. With ATP7B dysfunction, copper accumulates in hepatocytes (causing oxidative injury, steatosis, fibrosis, and eventually cirrhosis), is released into blood as free (non-ceruloplasmin-bound) copper, and deposits in brain (basal ganglia), cornea (Descemet membrane → Kayser-Fleischer rings), kidneys, and joints.
Kayser-Fleischer rings: brownish corneal deposits at the limbus; present in ~95% with neurologic disease, ~50% with hepatic disease; require slit-lamp exam
Sunflower cataracts
Jaundice, ascites, splenomegaly in advanced hepatic disease
Neurologic signs as above; risus sardonicus (fixed grin) in advanced cases
Classic findings
Adolescent with hepatitis, hemolytic anemia, and a movement disorder — think Wilson.
Differential diagnosis
Viral hepatitis — Positive serologies, no neuropsychiatric findings, normal ceruloplasmin
Autoimmune hepatitis — Positive ANA, ASMA, elevated IgG; can coexist with Wilson — copper studies still needed
Alpha-1 antitrypsin deficiency — Low A1AT level/activity, ZZ phenotype, often with emphysema
Nonalcoholic fatty liver disease — Metabolic syndrome, imaging steatosis, no neuro findings or Kayser-Fleischer rings
Drug-induced parkinsonism / Huntington / early-onset dystonia (neuropsychiatric Wilson) — No hepatic abnormalities, normal copper studies; family history for HD
Slit-lamp exam by ophthalmology for Kayser-Fleischer rings
Liver biopsy with hepatic copper quantification (>250 mcg/g dry weight is diagnostic)
Genetic testing for ATP7B mutations (confirmatory; useful for family screening)
Imaging
Brain MRI — bilateral basal ganglia (putamen, globus pallidus) and brainstem T2 hyperintensities; 'face of giant panda' sign
Abdominal imaging — features of chronic liver disease in advanced cases
Treatment
First-line
Dietary counseling to limit high-copper foods (shellfish, liver/organ meats, nuts, chocolate, mushrooms) complements, but never replaces, lifelong drug therapy
Symptomatic patients — chelation: penicillamine (with pyridoxine supplementation; risk of neurologic worsening early, autoimmune reactions, nephrotoxicity) OR trientine (better tolerated, often first-line in many centers, especially for neurologic disease)
Asymptomatic / maintenance after chelation: zinc acetate (induces metallothionein, blocking GI copper absorption)
Combination chelation + zinc may be used in severe disease
Monitor 24-h urinary copper, free copper, LFTs to guide therapy
Complications
Progression to cirrhosis with portal hypertension, varices, ascites
Acute liver failure
Hepatocellular carcinoma (lower risk than other cirrhosis etiologies but possible)
Permanent neurologic deficits if treatment delayed
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.