Primary biliary cirrhosis: modalities of injury and death in biliary epithelium

Background/Aim. Despite the number of studies on primary biliary cirrhosis, contrasting data remain concerning modalities of cholangiocyte death. Live r biopsies obtained from 40 patients with anti mitochondrial antibody-posit ive primary biliary cirrhosis, at various stages of the disease, were exami ned, and special attention was paid to the expression of subcellular damage and evidence of apoptosis. Methods. Liver sections were stained with haematoxylin/eosin or Sirius red. Ductular mass was evaluated on sections after cytokeratin 7 staining. Apop tosis was evaluated on haematoxylin/eosin stained material or after process ing for terminal deoxynucleotidyl transferase-mediated dUTP nick end-labell ing assay In 16 patients, part of the biopsy was processed for electron mic roscopy. Twenty histologically normal liver biopsies were used for control purposes. Results. According to Scheuer's classification, 29 patients were classified as stage I-II, and 11 as stage III-IV A strong staining of bile ducts was evident after immunohistochemistry for cytokeratin 7, often associated with ductular metaplasia in lobular zone 1. Cytokeratin 7-positive cells occupi ed 3.0+/-1.3% of liver mass as compared to 0.25+/-0.03% in controls. Ductul ar metaplasia accounted for 1.4+/-0.07% of all cytokeratin 7-positive cells . Regardless of staging, apoptotic bodies were seen only exceptionally in e pithelial wall of bile ducts, whereas cholangiocyte damage leading to exten sive lytic necrosis appeared responsible for most of the bile duct mass los s, as also confirmed by ultrastructural studies. A few terminal deoxynucleo tidyl transferase-mediated dUTP nick end-labelling-positive nuclei were occ asionally associated with the inflammatory infiltrate and evidence of apopt osis in hepatocytes was frequent, especially in zone 1. Conclusion. Regardless of staging, lytic necrosis and not apoptosis account s for most of the bile duct loss in primary biliary cirrhosis, Furthermore, ductular metaplasia appears as a late event with highly variable pattern b eing observed between patients.