A 43-year-old man comes to the office due to yellowing of the skin over the past several days. He has had no fever or abdominal pain and has not traveled recently or received blood transfusions. The patient has also experienced increased shortness of breath with exercise over the past few months. He has no other medical conditions and takes no medications. The patient drinks 1 or 2 glasses of wine on social occasions and does not use tobacco or illicit drugs. His father died of liver cirrhosis attributed to alcohol use. On physical examination, expiration is prolonged and there are scattered bilateral wheezes. Laboratory results show total bilirubin of 4.1 mg/dL and alanine aminotransferase of 90 U/L. Viral hepatitis serology is negative. Chest x-ray shows hyperlucency of lung fields and flattening of the diaphragm. Abdominal ultrasound reveals increased liver span and echogenicity of the liver parenchyma but no masses. Which of the following is the most likely underlying cause of this patient's symptoms?

Question

A 43-year-old man comes to the office due to yellowing of the skin over the past several days.  He has had no fever or abdominal pain and has not traveled recently or received blood transfusions.  The patient has also experienced increased shortness of breath with exercise over the past few months.  He has no other medical conditions and takes no medications.  The patient drinks 1 or 2 glasses of wine on social occasions and does not use tobacco or illicit drugs.  His father died of liver cirrhosis attributed to alcohol use.  On physical examination, expiration is prolonged and there are scattered bilateral wheezes.  Laboratory results show total bilirubin of 4.1 mg/dL and alanine aminotransferase of 90 U/L.  Viral hepatitis serology is negative.  Chest x-ray shows hyperlucency of lung fields and flattening of the diaphragm.  Abdominal ultrasound reveals increased liver span and echogenicity of the liver parenchyma but no masses.  Which of the following is the most likely underlying cause of this patient's symptoms?

Quizplus · Accepted Answer

11ec160b_392c_a10d_9249_eb8c68e20a85_MD0001_00 This patient with signs of liver dysfunction (ie, jaundice, transaminitis) and evidence of emphysema on chest x-ray (eg, hyperlucency, diaphragmatic flattening) likely has alpha-1 antitrypsin deficiency (AATD). Alpha-1 antitrypsin is a serine protease inhibitor that regulates the activity of a number of tissue-destructive proteases, most importantly neutrophil elastase. Deficiency is inherited in an autosomal codominant fashion. AATD leads to unchecked elastase activity in the lungs, resulting in alveolar destruction and lung hyperinflation; the panacinar emphysema tends to favor the basilar lung regions and typically develops prior to age 50. In addition, some patients can develop liver disease due to accumulation of improperly folded alpha-1 antitrypsin proteins in hepatocytes. Liver disease is of greatest concern in the first 2 decades of life, but it can present in any decade. Patients can experience hepatomegaly, hyperbilirubinemia, elevated transaminases, and eventual cirrhosis and end-stage liver disease. Hepatocellular carcinoma may also develop. (Choice A) Autoimmune injury of intrahepatic bile ducts occurs in primary biliary cholangitis (PBC, formerly primary biliary cirrhosis). PBC predominantly affects women and is characterized by positive antimitochondrial antibodies. It is not associated with emphysema. (Choice B) UDP-glucuronosyltransferase is an enzyme that converts unconjugated bilirubin to its conjugated form, and inherited deficiency can exist in varying degrees. Mild deficiency results in benign elevations in unconjugated bilirubin during periods of stress (ie, Gilbert syndrome), while severe deficiency can be fatal during infancy (ie, Crigler-Najjar syndrome type I). (Choice C) Defective epithelial chloride transport occurs in cystic fibrosis. Patients typically develop obstructive lung disease in the form of bronchiectasis and can have pancreatic insufficiency leading to malabsorption. In addition, cirrhosis can sometimes occur. Cystic fibrosis usually presents during childhood; onset of disease manifestations at age >40 would be highly unusual. (Choice D) Defective copper transport resulting in accumulation of intracellular copper occurs in Wilson disease. Patients can develop cirrhosis as well as brain degeneration leading to neurologic (eg, dysarthria, gait abnormalities) and psychiatric (eg, impulsivity) manifestations. (Choice F) Unregulated gastrointestinal iron absorption occurs in hemochromatosis. Patients can develop cirrhosis due to iron overload. The joints (arthritis), pancreas (diabetes mellitus), and heart (cardiomyopathy) are also commonly affected, but lung involvement is not typical. Educational objective: Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that regulates the activity of elastase in the lung. Inherited deficiency of AAT leads to alveolar destruction and panacinar emphysema; in addition, accumulation of improperly folded AAT proteins in hepatocytes can lead to liver dysfunction and cirrhosis in some patients. __________ References: Diagnosis and management of patients with a1-antitrypsin (A1AT) deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/22200689) An update on laboratory diagnosis of liver inherited diseases. (http://www.ncbi.nlm.nih.gov/pubmed/24222913)

A 43-Year-Old Man Comes to the Office Due to Yellowing