Late manifestations of a₁-antitrypsin deficiency
Prof. Dr. med. J. Reichen

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For the molecular basis of liver injury in a₁-antitrypsin deficiency the reader is referred to a recent review (1) and my pathophysiology syllabus (in German). The natural history in affected neonates and adolescents has been described by Sveger's landmark papers (2-4).

In the pre-hepatitis C era, a small series from the Mayo clinic showed chronic liver disease to occur at age 58, 66 and 72 years in ZZ, SZ and MZ phenotypes; liver disease was advanced in most of them (5). In autopsy series of identified cases, cirrhosis and HCC were frequent, but these patients actually lived longer than patients with a₁-antitrypsin deficiency without liver disease (6). The risk of liver disease in PiZZ appears particularly high in men over age 50 (7). In a cohort of transplant candidates, heterozygotes PiZ carriers were overrepresented (9.2 % vs 2-4 % in the normal population (8). Similar data were found in a Swedish cohort  of patients with chronic liver disease (7.6 vs 4. 8 %); of note was that in this study - where screening was performed with a monoclonal antibody specific for Z - only 50 % of affected patients had lowered a₁-antitrypsin levels (9). A similar conclusion was reached by Iezzoni et al. in a study on explants: PAS positive globules were found in 10 % of patients, but a₁-antitrypsin deficiency had been recognized pre-OLT in only 3/17 (10). Also, cryptogenic liver disease is overrepresented in heterozygotes (8;9;11). Non-cirrhotic portal hypertension has been described in an adult with MZ (19).

PiZZ leading to cirrhosis is clearly at increased risk to develop hepatocellular carcinoma (6;11;12) with hepatitis viruses playing no role (12). In the 19 patients from the Mayo clinic, two presented with hepatocellular cancer, both in patients with ZZ (5). Six cases of hepatoma in heterozygotes were found as opposed to only 1 in control patients (9). The risk of HCC appears to be attributable to cirrhosis (13) but an interesting hypothesis linking carcinogenesis to the metabolic defect has recently been forwarded (20). Interestingly, large cell dysplasia occurs in patients with inclusion globules (14). The significance of an old study reporting copper storage and Mallory bodies in patients with HCC associated with a₁-antitrypsin deficiency remains unclear (15). Immunohistochemistry is reported to be superior to PAS/diastase staining (16, 17). The degree of fibrosis increases with increasing age in heterozygotes (17); in this series, one case of HCC and three of cholangiocarcinoma were found. In a series of hepatic tumors, heterozygosity for Z was also markedly overrepresented (18); this was particularly true for cholangiocarcinoma and combined cholangia- and hepatocellular cancers.

Reference List
 

1. Teckman JH, Qu DF, Perlmutter DH. Molecular pathogenesis of liver disease in ?1-antitrypsin deficiency. Hepatology 1996; 24(6):1504-1516.
2. Sveger T. Liver disease in alpha-1-antitrypsin deficiency detected by screening of 200-000 infants. N Engl J Med 1976; 294:1316-1321.
3. Sveger T. The natural history of liver disease in alpha1-antitrypsin deficient children. Acta Paed Scand 1988; 77:847-851.
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19. Lee FI, Kelly JK, Vasudev KS (1983). Hepatic changes in a patient with alpha-1-antitrypsin deficiency (MZ phenotype. Portal tract elastosis and noncirrhotic portal hypertension. Arch Pathol Lab Med 107: 453-455.
20. Rudnick DA, Perlmutter DH (2005). Alpha-1-antitrypsin deficiency: A new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 42: 514-521.