Enterically transmitted non-A, non-B hepatitis in cynomolgus monkeys: morphology and probable mechanism of hepatocellular necrosis.

Two cynomolgus monkeys were inoculated with a stool extract originally derived from patients suffering from enterically transmitted non-A, non-B hepatitis. Subsequently, the primates developed self-limiting acute hepatitis and their liver tissues were obtained sequentially by needle biopsy or at sacrifice. Histologically, the liver tissues exhibited necroinflammation which appeared in parallel, both in time and magnitude, with elevation in serum aminotransferases. Necroinflammation was characterized by focal dropout of hepatocytes with accumulation of lymphocytes and macrophages. These lymphocytes were positive for a cytotoxic/suppressor immunophenotype. The hepatocytes surrounding these focal necroses showed depletion of glycogen granules and decrease in glucose-6-phosphatase and succinic dehydrogenase activities. Ultrastructurally, damaged hepatocytes around the focal necroses revealed marked dilatation of both rough and smooth endoplasmic reticula, swelling and disruption of the mitochondria and leakage of nuclear materials into the cytoplasm. Frequently, direct contact between the damaged hepatocytes and lymphocytes was noted. Virus-like particles measuring about 27 nm in diameter were observed singly or in small groups within the cytoplasm of damaged hepatocytes. Primary hepatocyte culture of a cynomolgus monkey, inoculated with a transmissible stool extract did not show any cytopathic change, although similar virus-like particles were recognized ultrastructurally in the cultured hepatocytes. Morphological analysis of in vitro and in vivo transmission studies in cynomolgus monkeys strongly supported the hypothesis of immune-mediated hepatocytolysis rather than a direct cytopathic effect of this hepatitis virus.