A 15-year-old girl is hospitalized due to confusion and hematemesis for 2 days. Medical history is notable for depression over the past year. Temperature is 37.2 C (99 F), blood pressure is 86/56 mm Hg, pulse is 112/min, and respirations are 20/min; BMI is 23 kg/m². She is oriented to person but disoriented to time and place. The patient quickly deteriorates and dies during hospitalization. Autopsy examination reveals a nodular liver, esophageal varices, splenomegaly, and atrophy of the basal ganglia with increased copper content. The most likely cause of this patient's condition is an abnormality in which of the following physiologic processes?

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11ec160b_3aea_561c_9249_9bdb7f20fe1b_MD0001_00 This patient has evidence of cirrhosis (eg, nodular liver, splenomegaly, esophageal varices) with acute liver failure (ie, encephalopathy) in addition to copper deposition in the basal ganglia. These findings are consistent with Wilson disease, an autosomal recessive disorder characterized by accumulation of copper due to a defective copper transport protein, ATP7B. In general, dietary copper is absorbed in the stomach and duodenum and bound to circulating albumin. It is then transported to the liver and taken up by hepatocytes. Excessive intracellular copper levels normally cause ATP7B to transfer the excess copper into the bile canaliculi. This process is essential for biliary excretion of copper, which accounts for the majority of total body copper excretion. In Wilson disease, defective ATP7B results in impaired biliary excretion of copper. The accumulation of hepatocellular copper results in oxidative stress and apoptosis. Upon cell death, free copper is released into the bloodstream and deposited into extrahepatic tissues (eg, basal ganglia, cornea), causing the classic triad of hepatic, neurologic, and psychiatric (eg, depression) symptoms. ATP7B is also required for the hepatic production of ceruloplasmin, which is apoceruloplasmin bound to copper. The inability to create and secrete ceruloplasmin in Wilson disease results in low serum ceruloplasmin. This abnormality does not account for the clinical manifestations of Wilson disease but is an important diagnostic finding. (Choice B) Autoimmune hepatitis due to production of autoantibodies can cause cirrhosis and acute liver failure but not copper accumulation. (Choice C) Hereditary hemochromatosis is an autosomal recessive disorder that can cause cirrhosis due to increased intestinal absorption of iron, not copper. (Choice D) Niemann-Pick disease and Gaucher disease are lipid storage disorders that cause hepatosplenomegaly. Symptoms usually present in early childhood, and copper deposition is not seen in either condition. (Choice E) Renal copper deposition in Wilson disease can cause Fanconi syndrome (eg, proximal tubular dysfunction). However, this occurs as a result of impaired biliary excretion of copper; it is not the cause of copper accumulation in Wilson disease. Educational objective: Wilson disease is caused by defective copper transport within hepatocytes, which leads to impaired biliary excretion of copper. Hepatic copper accumulation eventually results in the release of free copper into the bloodstream and copper deposition into extrahepatic tissues (eg, basal ganglia, cornea). __________ References: Wilson disease. (http://www.ncbi.nlm.nih.gov/pubmed/28723019)

A 15-Year-Old Girl Is Hospitalized Due to Confusion and Hematemesis