α 1 -Antitrypsin Deficiency

Introduction

α ₁ -Antitrypsin (α ₁ AT) deficiency is an autosomal codominant disorder associated with premature development of pulmonary emphysema, chronic liver disease, and hepatocellular carcinoma. A point mutation results in a protein that is misfolded and retained in the endoplasmic reticulum (ER) of liver cells rather than secreted into the blood and body fluids. The misfolded mutant protein is also prone to polymerization within the ER. Loss of function permits uninhibited proteolytic destruction of the connective tissue matrix of the lung, ultimately leading to emphysema. Cigarette smoking exacerbates the development of emphysema because residual α ₁ AT molecules are functionally inactivated by the increased load of active oxygen intermediates that are produced by smokers' alveolar macrophages. In contrast, liver disease results from a gain-of-toxic function mechanism whereby the retention of mutant α ₁ AT in liver cells somehow triggers a series of events that lead to liver injury and a predilection for hepatocellular carcinoma. Although it is the most common genetic cause of liver disease in children, clinically significant liver disease appears to affect a subgroup of homozygotes during the first 3 decades of life, an observation that has provided the basis for the notion that genetic modifiers and environmental factors play a role in susceptibility to and/or protection from liver disease in α ₁ AT deficiency. Recent observations suggest that liver disease affects more adults with α ₁ AT deficiency than previously recognized and that adults with pulmonary emphysema may also be affected by liver disease. Although liver transplantation is the only effective treatment available for the liver disease caused by α ₁ AT deficiency, there are several attractive new concepts for chemoprophylaxis and treatment of this liver disease.