Is heterozygous alpha-1-antitrypsin deficiency type PiZ a risk factor for primary liver carcinoma?

BACKGROUND. It is well known that homozygotes with alpha-1-antitrypsin defi ciency type PiZ are associated with an increased risk of chronic liver dise ase and liver carcinoma. The aim of this study was to determine whether het erozygous PiZ status is a risk factor for liver carcinoma development. METHODS. Three hundred seventeen consecutive primary liver carcinomas and t he tumor-bearing liver tissue (tumor series) from adult patients were scree ned immunohistochemically for hepatocellular PiZ deposits. Liver specimens from 1663 consecutive adult patients (biopsy series) and liver tissue from 1030 consecutive adult autopsies (autopsy series) served as controls, The z ygosity status of alpha-1-antitrypsin was verified by analysis of single st rand conformational polymorphism and by sequencing DNA extracted from paraf fin embedded tissue. RESULTS. The PiZ frequency in the tumor series (5.99%) was significantly hi gher than in the biopsy series (3.43%) or the autopsy series (1.84%). Chola ngiocarcinomas and/or combined hepatocholangiocarcinomas were seen signific antly more frequently in PiZ-associated liver carcinomas (57.9%) than in no n-PiZ-associated carcinomas (27.2%). Cirrhosis was found in only 3 of the 1 9 PiZ-associated carcinomas. The remaining 16 livers showed varying stages of fibrosis or normal tissue. All nine cases with PiZ-associated liver carc inoma suitable for genetic analysis showed heterozygous PiZ mutations. CONCLUSIONS. Heterozygotes of type PiZ are associated with an increased ris k of primary liver carcinoma. PiZ-associated carcinoma may develop in nonci rrhotic liver tissue and without concurrent liver disease, and is frequentl y characterized by cholangiocellular differentiation. The site specific ant ibody ATZ11 is a reliable morphologic tool for detecting PiZ individuals. ( C) 2000 American Cancer Society.