Background
Focal hepatic necrosis is a relatively rare lesion observed in a variety of inbred strains of mice at The Jackson Laboratory not exposed to any pathogens or chemical irritants (Table 1). Focal hepatic necrosis is also a nonspecific lesion associated with mouse hepatitis virus, 3,7 Bacillus piliformis (Tyzzer's disease) 3, a new Helicobacter-like organism, 1,6 chemical agents 2,5 and ischemia. Hepatic necrosis may be associated with extensive metastasis or multicentric involvement of a variety of spontaneous neoplastic diseases that spread to the liver.
Gross necropsy findings
In colonies maintained at The Jackson Laboratory, focal hepatic necrosis is diagnosed as an incidental finding at the time of necropsy. Livers have solitary or multiple small, irregular, light brown foci that may coalesce. No pathogenic bacteria have been isolated, nor have antibodies to mouse pathogens been detected in routine serological surveys of colonies or evaluation of individuals with hepatic lesions.
Histologic findings
Microscopically the liver lesions present as single or multiple foci of clusters of hepatocytes undergoing necrosis. The foci are sharply demarcated. Scattered individual hepatocellular necrosis may also be seen in livers with prominent foci of necrosis. Affected cells are usually swollen, have rounded edges, bright eosinophilic cytoplasm, pycnotic or karyorrhectic nuclei or no nuclear remnants. Cytoplasmic borders are evident. Inflammation is absent in acute lesions. Sub-acute lesions have mild infiltrations of neutrophils and some lymphocytes. Chronic lesions exhibit various degrees of peripheral fibrosis. Thrombi can occasionally be identified in adjacent vessels, but extensive serial sectioning may be necessary to identify vascular lesions. No pathogenic organisms have been identified in any of the cases diagnosed at The Jackson Laboratory using a variety of special stains including Warthin-Starry, tissue Gram, Gomori's methenamine silver, Steiner's, or Giemsa stains.
Pathogenesis
The pathogenesis of focal hepatic necrosis in inbred laboratory mice appears to be ischemia secondary to vascular occlusion, usually a thrombus in a vessel supplying blood to the affected area. Several strains of mice have a propensity for developing auricular mural thrombi, 2-4 which may be the source of emboli that ultimately lodge in the liver.
Comparison to Helicobacter-associated liver lesions
Scientists at NIH have recently reported infection in their colonies with a new Helicobacter-like organism that causes focal hepatic necrosis, mild nonsuppurative inflammation, oval cell hyperplasia, hepatomegaly, bile duct hyperplasia and peribiliary leukocyte infiltrates. 1,6 The disease is transmissible, and some strains, such as A/JCr, had liver tumors associated with the disease process. The agent can be demonstrated in tissue sections using the Steiner's stain (M.R. Anver, personal communication, 24 August 1993). The sporadic, low incidence, focal hepatic necrosis observed in mice at The Jackson Laboratory is different from that described at NIH, and we have found no evidence of the Helicobacter-like agent in our mice with hepatic lesions in Steiner's stained sections.
Table 1
Strains maintained at The Jackson Laboratory diagnosed with focal or multifocal hepatic necrosis with no microbiological etiology between 1990-1992.
- BALB/cByJ
- BALB/cJ
- B10.A/SgSnJ
- B10.D2/nSnJ
- B10.RIII(71NS)/SnJ
- BXSB/MpJ
- C3H/HeJ
- C57BL/6J
- C57BL/10J
- C57BL/10SnJ
- C58/J
- DBA/2J
- DW/J
- MRL/MpJ
- NON/Lt
- NU/JRIIIS/J
- Rb(5.17)7Rma
- SJL/J
References
1. Anver MR, Haines DC, Tully JG, Collins MJ, Gorelick PL, Anderson LM, Rice JM, Russell RJ, Ward JM. Hepatitis in mice associated with a helical bacterium. Vet Pathol 30:476, 1993 (Abstract).
2. Clapp NK. An Atlas of RF Mouse Pathology: Disease Descriptions and Incidences. United States Atomic Energy Commission, Springfield, Virginia, pp. 9, 1973.
3. Frith CH, Ward JM. Color Atlas of Neoplastic and Non-neoplastic Lesions in Aging Mice. Elsevier, Amsterdam, pp. 3, 11, 1988.
4. Meier H, Hoag WG. Blood coagulation. In: Biology of the Laboratory Mouse. Green EL, ed., Dover Publications, New York, pp. 373-376, 1975.
5. Ward JM. Cirrhosis, Mouse. In: Monographs on Pathology of Laboratory Animals Digestive System. Jones TC, Mohr U, Hunt RD, eds., Springer-Verlag, Heidelberg, ppp. 107-110, 1985.
6. Ward JM, Anver MR, Rice JM, Russell RJ. A unique hepatitis in mice assocated with a helical bacterium. Society of Toxcological Pathologists, 12th Internatl Meeting, 1993 (Abstract).
7. Ward JM, Coolins MJ Jr., Parker JC. Naturally occurring mouse hepatitis virus infection in the nude mouse. Lab Anim Sci 27:372-376, 1977.