CHRONIC ACTIVE HEPATITIS AND ASSOCIATED LIVER-TUMORS IN MICE CAUSED BY A PERSISTENT BACTERIAL-INFECTION WITH A NOVEL HELICOBACTER SPECIES

Background: In the autumn of 1992, a novel form of chronic, active hep atitis of unknown etiology was discovered in mice at the National Canc er Institute-Frederick Cancer Research and Development Center (NCI-FCR DC), Frederick, Md. A high incidence of hepatocellular tumors occurred in affected animals. The disease entity was originally identified in A/JCr mice that were untreated controls in a long-term toxicologic stu dy. Purpose: Our original purpose was to determine the origin and etio logy of the chronic hepatitis and to quantify its association with hep atocellular tumors in mice of low liver tumor incidence strains. After a helical microorganism was discovered in hepatic parenchyma of disea sed mice, we undertook characterization of the organism and investigat ion of its relationship to the disease process. Methods: Hepatic histo pathology of many strains of mice and rats, as well as guinea pigs and Syrian hamsters, in our research and animal production facilities was reviewed. Steiner's modification of the Warthin-Starry stain and tran smission electron microscopy were used to identify bacteria in the liv er. We transmitted the hepatitis with liver suspensions from affected mice and by inoculation with bacterial cultures. Bacteria were cultiva ted on blood agar plates maintained under anaerobic or microaerophilic conditions and characterized morphologically, biochemically, and by 1 6S rRNA sequence. Results: We report here the isolation of a new speci es of Helicobacter (provisionally designated Helicobacter hepaticus sp . nov.) that selectively and persistently colonizes the hepatic bile c analiculi of mice (and possibly the intrahepatic biliary system and la rge bower), causing a morphologically distinctive pattern of chronic, active hepatitis and associated with a high incidence of hepatocellula r neoplasms in infected animals. Conclusions: The novel Helicobacter i s a likely candidate for the etiology of hepatocellular tumors in our mice. The Helicobacter-associated chronic active hepatitis represents a new model to study mechanisms of carcinogenesis by this genus of bac teria. Implications: Adenocarcinoma of the stomach, the second most pr evalent of all human malignancies worldwide, is associated with infect ion at an early age with Helicobacter pylori. Infection leads to sever al distinctive forms of gastritis, including chronic atrophic gastriti s, which is a precursor of adenocarcinoma. H. hepaticus infection in m ice constitutes the only other parallel association between a persiste nt bacterial infection and tumor development known to exist naturally. Study of the H. hepaticus syndrome of chronic active hepatitis and li ver tumors in mice may yield insights into the role of H. pylori in hu man stomach cancer and gastric lymphoma.