A 33-year-old man presents to the hospital complaining of dyspnea. Over the past year he has had increasing shortness of breath while running that limits the distance he can run. In addition, he has a persistent cough that is bothering him, and during the past few days he has had increasing sputum production that was previously white and is now yellow. He has not visited a doctor yet because he does not have medical insurance. The patient denies any significant medical history but has a positive family history of emphysema. He smokes half a pack of cigarettes daily and drinks alcohol moderately. On examination, he has a temperature of 37.9°C, blood pressure of 122/76 mmHg, heart rate of 93 beats per minute, respiratory rate of 24 breaths per minute, and oxygen saturation of 92% on room air. He has scattered wheezes throughout both lung fields with a normal cardiac examination. A chest x-ray shows loss of interstitial lung markings primarily at the lung bases.
Which of the following is the mechanism by which this disease produces liver disease?
A. Failure to inhibit the destruction of connective tissue by elastaseAccumulation of abnormal proteins within hepatocytes. For a young patient presenting with symptoms and signs of COPD, always consider α1-antitrypsin deficiency as the cause. Although this autosomal recessive disease usually presents in patients after the age of 40, it can present earlier if the patient is a smoker. α1-Antitrypsin is a protease inhibitor that is produced in the liver and inhibits elastase in the lungs. During acute inflammation, neutrophils release elastase in the lungs that can degrade elastin, an important structural protein that helps tissues maintain their shape. Normally this is inhibited by α1-antitrypsin; however, patients with α1-antitrypsin deficiency will develop panacinar emphysema due to unopposed destruction of elastin in the lung parenchyma. If a patient is exposed to greater than average amounts of toxins (e.g., smoking) that produce lung injury and inflammation, they will develop manifestations of emphysema at a younger age. The clues to the diagnosis in this case are the fact that the patient is very young, has a family history of emphysema, and has emphysema that is predominantly affecting the lung bases (seen on chest x-ray).
Another clue is that the question stem states that liver disease is associated with the condition. Not all mutations cause liver disease, but some genotypes lead to the production of an abnormal protein within hepatocytes that polymerizes and causes cell apoptosis. (A) Therefore, the mechanism of liver disease is different from the mechanism of lung disease, with connective tissue destruction not being a prominent feature. When the liver is biopsied, the cytoplasmic inclusions are periodic acid-Schiff positive. Skin findings (e.g., necrotizing panniculitis) are another extrapulmonary manifestation that may be associated with this disease. Diagnosis of α1-antitrypsin deficiency is made by finding low serum levels of α1-antitrypsin as well as genotyping the patient. Treatments include smoking cessation, IV supplementation of α1-antitrypsin, standard treatments for COPD based on severity of disease, and lung or liver transplant if end-stage disease is present.
(B) Emphysema causes pulmonary vascular destruction, which can lead to increased pulmonary artery pressure and eventually cor pulmonale. Congestive hepatopathy as a result of elevated venous pressure would exacerbate the liver disease, but it is not the primary cause of the liver disease in α1-antitrypsin deficiency. (C) Mallory bodies are cytoplasmic inclusions seen within hepatocytes in alcoholic liver disease. They are not 100% specific to alcoholic liver disease and may rarely be seen on histology in α1-antitrypsin deficiency. However, this is not the best explanation for the mechanism of liver disease in these patients.