Liver changes in heterozygote alpha 1-antitrypsin deficiency PiZ

Abstract

Whether heterozygotes with alpha-1-antitrypsin (AAT) deficiency type PiZ bear an increased risk for chronic liver disease is controversial. On the basis of liver tissue from 1,030 autopsies (autopsy series), 1,847 biopsies (biopsy series) and 317 primary liver carcinomas (tumor series), we analysed the effect of heterozygous state PiZ for the development of liver diseases. The PiZ status was screened immunohistochemically and verified in selected cases by SSCP analysis and by sequencing DNA extracted from paraffin embedded tissue. The PiZ frequency in the biopsy series (3.4%) and tumor series (5.99%) was significantly higher than in the autopsy series (1.8%). Hepatic PiZ deposits in heterozygotes sometimes were as extensive as in homozygotes. The amount of PiZ deposits correlated positively with the inflammatory activity and stage of fibrosis, as well as with the age of patients. Patients with concurrent liver disease such as hepatitis and alcoholic liver disease showed significantly higher scores of inflammatory activity, stage of fibrosis and amount of PiZ deposits than those without additional liver disease. Cholangiocarcinomas and combined hepato-cholangiocarcinomas were seen significantly more frequently in patients with PiZ-associated liver carcinoma than in genetic healthy individuals (p = 0.004). Three out of 19 PiZ-associated liver carcinomas had developed in cirrhotic liver tissue. Heterozygotes of type PiZ have an enhanced risk for chronic liver disease including primary liver carcinoma. PiZ-associated liver diseases will become clinically manifest in middle or old aged adults. Rarely this genetic defect causes liver cirrhosis even without concurrent liver disease. PiZ-associated liver carcinomas are frequently characterized by cholangiocellular differentiation and may develop often in non-cirrhotic liver tissue. Immunohistochemistry is a specific method to detect hepatic PiZ deposits.