Hepatocyte proliferation in primary biliary cirrhosis as assessed by proliferating cell nuclear antigen and Ki-67 antigen labelling

Expression of the proliferating cell nuclear antigen and Ki-67 antigen by hepatocytes was investigated in liver tissue specimens of 29 patients with primary biliary cirrhosis (stage I 13, stage II 6, stage III 5 and stage IV 5 patients) prior to treatment with ursodeoxycholic acid and of five control subjects using immunocytochemical methods. Proliferating cell nuclear antigen and Ki-67 expression were reevaluated in seven patients after 3 years of treatment with ursodeoxycholic acid. Proliferating cell nuclear antigen labelling indices were significantly higher in primary biliary cirrhosis (stage I, 6.4% to 32.4%, median, 10.9%; stage II, 9.6% to 21.6%, median 11.4%; stage III, 5.2% to 12.5%, median, 7.6%; stage IV, 3.8% to 8.9%, median, 5.6%) than in controls (0% to 0.5%, median, 0.1%; p<0.005). Ki-67 antigen labelling counts were lower than proliferating cell nuclear antigen indices but elevated in all stages of primary biliary cirrhosis (stage I, 0.5% to 3.5%, median 2.0%; stage II, 1.8% to 3.6%, median 2.6%; stage III, 1.3% to 2.5%, median 1.9%; stage IV, 0.4% to 1.7%, median 1.0%) compared with controls (0% to 0.5%, median 0.3%; p<0.005). After ursodeoxycholic acid treatment, mean proliferating cell nuclear antigen and Ki-67 labelling indices decreased from a median of 9.0% (range, 3.8% to 32.4%) to a median of 7.8% (range, 4.5% to 17.2%; p=0.045) for proliferating cell nuclear antigen and from a median of 2.5% (range, 0.8% to 3.6%) to a median of 2.1% (range, 0.9% to 3.1%; p=0.031) for Ki-67 antigen. It is concluded that hepatocyte proliferation is markedly increased in primary biliary cirrhosis, particularly in the early stages of the disease, and that ursodeoxycholic acid treatment reduces proliferative activity in primary biliary cirrhosis.