Alpha-1-Antitrypsin Deficiency Initially Presenting in an Adult Surgical Patient: A Case Report and Review of Current Understanding of Disease Process

摘要

Alpha-1-antitrypsin (AAT) is one of several serpin molecules which functions to balance the action of various endogenous proteolytic enzymes. A deficiency of functional levels of this enzyme is most commonly inherited in an autosomal recessive fashion. Greater than 95% of AAT-deficient persons are homozygous for the non-functional Z-variant of the enzyme. ZZ-homozygosity is relatively common, affecting 1 in 2500 persons of northern European decent. Known complications of AAT-deficiency include early-onset emphysema, childhood liver disease, cirrhosis, and increased incidence of hepatocellular carcinoma1. Although AAT-deficiency is frequently diagnosed in early childhood, it is not uncommon for persons to go undiagnosed for many years until otherwise unexplained lung or liver disease become evident. We report a case of AAT-deficiency in a 44-year-old female which became evident post-operatively after unexplained, uncontrollable ascites and respiratory failure. Introduction Alpha-1-antitrypsin (AAT) is produced primarily in hepatocytes and functions to counteract neutrophil elastase and various other proteolytic enzymes in the lung. The discovery of early emphysematous changes in young, non-smoking individuals and subsequent elucidation of the disease process served as the foundation of the protease-protease-inhibitor theory of chronic lung disease. The normal M-variant of the AAT protein is encoded for on chromosome 14q and undergoes post-translational modification within the endoplasmic reticulum (ER) of hepatocytes before being released into the serum. The functional molecule consists of a mobile reactive center loop and a β-pleated sheet. These sites serve as a decoy substrate for protease binding. After cleavage by the protease, AAT undergoes a conformational change which disrupts the catalytic site of the protease, thus rendering it inactive2,3,4,5. The most common manifestation of AAT-deficiency occurs in individuals homozygous for the Z-variant of the AAT gene. This mutation causes a single amino acid substitution which alters the secondary and tertiary structure of the normal β-pleated sheet-reactive center interaction. The Z form of AAT allows for insertion of the reactive loop of one molecule into the β-sheet of another. This process may be repeated ad infinitum resulting in large polymers of Z-AAT. These polymers are too large to be transported out of the ER and result in intracytoplasmic, PAS-positive inclusions which are classically seen in the hepatocytes of AAT-deficient patients6. In addition to being largely secluded and subsequently degraded within hepatocytes, Z-AAT protein which does reach the serum has approximately half the functionality of the wild-type M-AAT7. Approximately 85% of the Z-AAT produced in homozygous individuals remains within the ER of hepatocytes8. The exact mechanism by which the these polymer-inclusions cause liver dysfunction is not well understood.Liver dysfunction in AAT-deficiency frequently becomes evident early in life and may present as persistently elevated bilirubin and transaminase levels. Of these AAT-deficient neonates with evidence of liver injury, population-based studies show that 80% will show only mild evidence of hepatic disease which typically resolves in late adolescence. The remaining 20% will experience more severe liver disease and many patients from this cohort require early liver transplantation9. Still, other patients will show virtually normal liver function throughout childhood and develop liver injury later in life. What eventually tips the balance and causes manifestations of liver disease in these patients remains largely undiscovered, although various environmental factors and physiologic stressors have been implicated10, 12-16. Case Report The patient was a 44-year-old female with a past medical history significant for gastric bypass complicated by the development of volvulus and subsequent necrotic bowel leading to small bowel resection 3 months prior to