Intermediate hepatobiliary cells predict an increased risk of hepatocarcinogenesis in patients with hepatitis C virus-related cirrhosis.
OBJECTIVE
The expression of biliary lineage markers such as cytokeratin (K) 7 by hepatocytes is thought to reflect an altered regeneration pathway recruiting a stem cell compartment, more prone to carcinogenesis. We aimed to investigate the presence of these so-called intermediate hepatobiliary cells (IHC) in liver biopsies of patients with hepatitis C-related cirrhosis and their potential influence on the subsequent occurrence of hepatocellular carcinoma (HCC).


METHODS
From a cohort of patients with hepatitis C-related cirrhosis, prospectively screened for HCC, we retrospectively selected those with a liver biopsy performed for the initial diagnosis of cirrhosis. Presence of IHC was recorded when foci of K7-positive, intermediate-sized hepatocytes were detected.


RESULTS
A total of 150 patients were included (87 men; mean age, 57 y; range, 19-84 y; body mass index, 25 kg/m(2)). After a median follow-up period of 4.85 years, HCC was diagnosed in 36 patients (24%). Baseline liver biopsy showed intermediate hepatobiliary cell foci in 61 patients (41%). Intermediate cells co-expressed both hepatocytes markers and the progenitor cell markers Ep-CAM and K19. The presence of intermediate hepatobiliary cells was associated independently with HCC occurrence (Fine and Gray model; hazard ratio, 2.48; 95% confidence interval, 1.24-4.96; P = .01). Other predictors of HCC were diabetes and low platelet count. The HCC annual incidence rate was significantly higher in patients with IHC compared with patients without (8.14% vs 3.12%, Gray's test, P = .003).


CONCLUSIONS
The aberrant expression of biliary K by hepatocytes in patients with hepatitis C virus-related cirrhosis is related independently to HCC occurrence.
Ziol
Marianne
M
Pathology Department, CHU Jean Verdier, Assistance Publique, Hôpitaux de Paris (AP-HP), Bondy and Paris 13 University, Bobigny, France. marianne.ziol@jvr.aphp.fr
Nault
Jean-Charles
JC
Aout
Mounir
M
Barget
Nathalie
N
Tepper
Maryline
M
Martin
Antoine
A
Trinchet
Jean-Claude
JC
Ganne-Carrié
Nathalie
N
Vicaut
Eric
E
Beaugrand
Michel
M
N'Kontchou
Gisele
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000032:analysis; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D053552:Keratin-7