Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Abstract

Erythropoietic protoporphyria (EPP) is an inherited disease of haem synthesis caused by a mutation in one of the alleles of the enzyme ferrochelatase. This mutation leads to partial deficiency of the enzyme, resulting in increased concentrations of protoporphyrin (PP) in blood, liver, and faeces. Five to ten per cent of patients with EPP develop severe liver disease characterized by the presence of PP deposits. This study used histochemistry and immunohistochemistry to investigate the histopathological features present in the livers of 44 mice with a heterozygous or homozygous point mutation in the ferrochelatase gene (fch/+ and fch/fch mice, respectively). Some fch/+ mouse livers showed mixed steatosis and large cell dysplasia. The livers of fch/fch mice showed periportal or septal fibrosis accompanied by an atypical ductular reaction. These findings suggest that the obstruction and damage of a proportion of large and small bile ducts by PP deposits cause an accumulation of PP in the parenchyma, which leads to damage and loss of hepatocytes due to the toxic effects of PP. The classical stages of hepatocarcinogenesis were observed and hepatic progenitor cells appear to be involved in this process. PP acts as the promoting agent and is probably also the initiating agent.

Immune Suppression Uncovers Endogenous Cytopathic Effects of the Hepatitis B Virus

“…The monoclonal mouse anti-human antibody Ki67 (clone Mib-1, dilution 1/100; Dako) was used to assess the proliferative status of human hepatocytes (20). To evaluate both human and mouse cells, polyclonal rabbit antibodies against human cytokeratins (dilution 1/20; Dako) and CEA (dilution 1/300; Dako) were used (15,36). The polyclonal antibody to CEA is a marker for canaliculi (33).…”

Hepatic Gene Expression in Protoporphyic Fech Mice Is Associated with Cholestatic Injury but Not a Marked Depletion of the Heme Regulatory Pool

“…By 32 to 52 weeks livers became so enlarged that they accounted for up to 25% of body weight with large eosinophilic and clear cell foci, adenomas, and adenocarcinomas as reported by Libbrecht and colleagues. 15 …”

“…Accepted for publication December 20, 2004. leads to biliary fibrosis and neoplastic development 13,15 but whether the liver is suffering from heme deficiency and how the toxicity arises are not clear. A proposal has been made for the involvement of cytotoxic bile containing high concentrations of bile salts and protoporphyrin that might damage bile duct epithelium and cause biliary fibrosis.…”

Oxidative Stress and Oval Cell Accumulation in Mice and Humans with Alcoholic and Nonalcoholic Fatty Liver Disease

“…[1][2][3][4] Similar oval cell accumulation has also been described in human liver, close to hepatitis B-associated hepatocellular carcinoma, 5 in hepatoblastoma, 6 in regenerating liver, 7 and in cholestatic liver diseases. 8 We recently showed that putative progenitor cells accumulate in the livers of patients with chronic hepatitis C, an acknowledged risk factor for hepatocellular carcinoma.…”