Chronic liver disease in heterozygous α1-antitrypsin deficiency PiZ

Background/Aims: The contribution of the heterozygous state PiZ of α1-antitrypsin deficiency (AATD) to the pathogenesis of chronic liver disease is debated. We analyzed whether patients with this genetic defect carrying a single PiZ gene are at increased risk for developing chronic liver disease. Methods: 1847 consecutive biopsy cases and 1030 autopsy cases of Caucasian adults were screened immunohistochemically for PiZ deposits. The zygosity status was analyzed by single-strand conformational polymorphism (SSCP) and by sequencing DNA extracted from paraffin-embedded tissue. Results: All analyzed biopsy cases were heterozygous for the PiZ mutation. The biopsy group revealed a significantly higher rate of PiZ-positive cases (3.4%) than the autopsy group (1.8%) (p=0.019). PiZ deposits ranged from scarce granules to extensive globular inclusions as in homozygous AATD of PiZ type. The extent of PiZ deposits correlated well with the inflammatory activity and stage of fibrosis. Cirrhotic livers contained globular PiZ deposits significantly more often than the biopsies with minor fibrosis. PiZ-positive biopsies from patients without concurrent liver disease (n=26) revealed only minor fibrosis in the age group between 20 and 39 years, but significantly more severe fibrosis and significantly more PiZ deposits in the older age groups. Biopsies with concurrent liver disease (n=28) presented with significantly more severe inflammation and fibrosis, and more PiZ deposits than the cases without concurrent liver disease. Conclusions: Patients with heterozygous AATD of PiZ type bear an increased risk for chronic liver disease. If at all, this genetic defect will become clinically relevant only in middle-aged or old adults. It rarely causes liver cirrhosis even without concurrent liver disease. It can aggravate or can be aggravated by advanced coexistent chronic liver diseases. PiZ immunohistochemistry is an easy, highly specific method to detect this metabolic defect on liver biopsies.