BACKGROUND: It is well known that homozygotes with alpha-1-antitrypsin deficiency type PiZ are associated with an increased risk of chronic liver disease and liver carcinoma. The aim of this study was to determine whether heterozygous PiZ status is a risk factor for liver carcinoma development. METHODS: Three hundred seventeen consecutive primary liver carcinomas and the tumor-bearing liver tissue (tumor series) from adult patients were screened 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 zygosity status of alpha-1-antitrypsin was verified by analysis of single strand conformational polymorphism and by sequencing DNA extracted from paraffin embedded tissue. RESULTS: The PiZ frequency in the tumor series (5.99%) was significantly higher than in the biopsy series (3.43%) or the autopsy series (1.84%). Cholangiocarcinomas and/or combined hepatocholangiocarcinomas were seen significantly more frequently in PiZ-associated liver carcinomas (57.9%) than in non-PiZ-associated carcinomas (27.2%). Cirrhosis was found in only 3 of the 19 PiZ-associated carcinomas. The remaining 16 livers showed varying stages of fibrosis or normal tissue. All nine cases with PiZ-associated liver carcinoma suitable for genetic analysis showed heterozygous PiZ mutations. CONCLUSIONS: Heterozygotes of type PiZ are associated with an increased risk of primary liver carcinoma. PiZ-associated carcinoma may develop in noncirrhotic liver tissue and without concurrent liver disease, and is frequently characterized by cholangiocellular differentiation. The site specific antibody ATZ11 is a reliable morphologic tool for detecting PiZ individuals. Copyright 2000 American Cancer Society.
BACKGROUND: It is well known that homozygotes with alpha-1-antitrypsindeficiency type PiZ are associated with an increased risk of chronic liver disease and liver carcinoma. The aim of this study was to determine whether heterozygous PiZ status is a risk factor for liver carcinoma development. METHODS: Three hundred seventeen consecutive primary liver carcinomas and the tumor-bearing liver tissue (tumor series) from adult patients were screened 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 zygosity status of alpha-1-antitrypsin was verified by analysis of single strand conformational polymorphism and by sequencing DNA extracted from paraffin embedded tissue. RESULTS: The PiZ frequency in the tumor series (5.99%) was significantly higher than in the biopsy series (3.43%) or the autopsy series (1.84%). Cholangiocarcinomas and/or combined hepatocholangiocarcinomas were seen significantly more frequently in PiZ-associated liver carcinomas (57.9%) than in non-PiZ-associated carcinomas (27.2%). Cirrhosis was found in only 3 of the 19 PiZ-associated carcinomas. The remaining 16 livers showed varying stages of fibrosis or normal tissue. All nine cases with PiZ-associated liver carcinoma suitable for genetic analysis showed heterozygous PiZ mutations. CONCLUSIONS: Heterozygotes of type PiZ are associated with an increased risk of primary liver carcinoma. PiZ-associated carcinoma may develop in noncirrhotic liver tissue and without concurrent liver disease, and is frequently characterized by cholangiocellular differentiation. The site specific antibody ATZ11 is a reliable morphologic tool for detecting PiZ individuals. Copyright 2000 American Cancer Society.