Alpha-1-antitrypsin deficiency (PiZ): Clinical studies with special regard to hepatic and vasculitic disorders

Sammanfattning: Homozygous alpha-1-antitrypsin (AAT)deficiency (PiZZ) is known to predispose to emphysema and chronic liver disease (CLD). The overall aim of the studies upon which this thesis is based was to investigate extra-pulmonary disease manifestations of AAT deficiency with special reference to hepatic and vasculitic disorders. Both men and women with homozygous AAT deficiency were shown to be at increased risk of cirrhosis (OR=8.3, 42%) and hepatocellular carcinoma (HCC) (OR=5.0, 16%). The risk of HCC was more manifest in men. The risk of cirrhosis or HCC was unrelated to the presence of such environmental factors as alcohol consumption or chronic hepatitis B or C infection. No increased prevalence of viral hepatitis could be found in heterozygous AAT-deficients (PiZ) with CLD, but 63% (5/8) of heterozygotes with hepatitis C infection had severe liver dysfunction. In contrast, a high prevalence of HCV infection was found in patients with low plasma alpha-1-antichymotrypsin (ACT) levels. Among patients with genetic hemochromatosis, 4.5% were found to be homozygous for the PiZ gene, a proportion more than 80-fold greater than that expected in the general population (1/1700) (p<0.0001). The presence of the PiZ gene in these patients contributed to an earlier onset of cirrhosis. A strong correlation was found to exist between systemic necrotizing small-vessel vasculitides and both heterozygous and homozygous AAT deficiency. Vasculitic patients with AAT deficiency were characterized by a more disseminated disease and a worse prognosis. These observations suggest that: 1) although the high risk of cirrhosis and HCC in homozygous AAT-deficients was unrelated to the presence of environmental factors such as alcohol abuse and chronic viral hepatitis, the coexistence of other genetic traits could influence the course of CLD in such individuals; 2) the role of partial ACT deficiency (acquired or hereditary) in hepatitis C is unknown but the protein may have an important defense function; 3) the correlation between AAT deficiency and PR3-ANCA-positive systemic vasculitis suggests AAT to be an important protective protein in vasculitis. When PR3 is exposed on the surface of neutrophils, lack of AAT might cause persistent proteolytic activity and subsequent endothelial cell injury. Vasculitic processes seem to be facilitated by low plasma concentrations of AAT.