Expression of bcl-2 in ductular proliferation is related to periportal hepatic stellate cell activation and fibrosis progression in patients with autoimmune cholestasis

Abstract

Aim: To study bcl-2 expression in ductular proliferation cholangiocytes and hepatic stellate cell activation in liver biopsies from patients with autoimmune cholangitis and primary biliary cirrhosis.

Materials and methods: Twenty-four primary biliary cirrhosis patients and 11 autoimmune cholangitis patients were included. Thirty-four females, average age: 52.5+/-12.6 years. We studied the presence of ductular proliferation, cholestasis, florid ductal lesion, granulomata, ductopenia and histologic stage. Patients were classified in primary biliary cirrhosis or autoimmune cholangitis according to antimitochondrial antibodies, antinuclear antibodies, smooth muscle antibody, antiGP210 and antiSP100 autoantibodies. We studied the presence of bcl-2 by monoclonal antibcl-2 antibody (clon 100, BioGenex). The presence of activated (specific antialpha-actin antibodies) and independent lobular, periportal and portal hepatic stellate cell was assessed using a semiquantitative scale.

Results: Interlobular ducts bcl-2 was seen in 18 (51.4%) patients. Activated periportal hepatic stellate cell correlated with Ludwig's stage (r=0.43; n=35; p=0.01). Ten out of 15 (66.6%) patients with ductular proliferation showed positive interlobular ducts bcl-2 while bcl-2 was negative in 8 out of 20 (40%) patients without ductular proliferation; p<0.05. Bcl-2 positive patients in ductular proliferation showed a more advanced Ludwig's stage (2.33+/-0.77 versus 1.26+/-1.05; p<0.05) and a higher periportal hepatic stellate cell activation index (0.83+/-0.78 versus 0.23+/-0.43; p=0.009). No relationship was found among periportal hepatic stellate cell activation and the presence of florid ductal lesion, cholestasis, granulomata or biliary erosive necrosis. Hepatic stellate cell activation was similar in patients with either autoimmune cholangitis or primary biliary cirrhosis.

Conclusions: Periportal hepatic stellate cell activation seems to play a main role in fibrosis progression in patients with autoimmune cholestasis. Bcl-2 expression in ductular proliferation may promote hepatic stellate cell activation and fibrosis.