202 Spontaneous Iron Accumulation in a Young Rat Fig. 4. a. Irregular bodies filled with electron-opaque aggregates are apparent in hepatocytes. b. Very fine particles (ferritin) are distributed diffusely, without any enveloping membrane in the cytosol, as well as in single membrane-limited bodies. observed. They varied in density and had irregular-shaped d e p o s i t s , s o m e t i m e s i n c l u d i n g f i n e p a r t i c l e s , a n d corresponded to pigmented granules on light microscopy. Furthermore, very fine particles were also observed diffusely, not enveloped by any membrane in the cytosol. These particles were considered to be ferittin based on morphological criteria including a size of around 5–7 nm2. Other organelles and the bile canaliculi were normal. According to a previous report on spontaneous iron overload in SD rats3, onset involves only hepatocyte pigmentation, the degree of iron overload increases with age and there is no relation to spleen hemosiderin deposition. The authors described iron accumulation as beginning in the pericanalicular siderosomes of periportal hepatocytes and extending the progressively to the entire lobule and non- hepatocytic cells, like Kupffer cells in the sinusoids and other macrophages around the bile ducts in portal tracts. In addition, no significant inflammatory cell infiltration, degeneration, necrosis or fibrosis were noted. In humans, primary or genetic hemochromatosis is an inherited disease characterized by excessive absorption of iron from a diet with normal iron content and progressive iron loading of parenchymal tissues such as the liver. The changes in humans are irreversible, and liver cell iron overload leads to cirrhosis and eventual hepatocellular carcinomas in some cases. However, in the early stages, only iron accumulation in hepatocytes is apparent, with a pericanalicular polarization, along with a diminishing periportal-to-centrilobular gradient2, almost the same as our female rat. In experimental animals, there have been other reports of iron overload in the liver4–7. However, almost all examples of experimentally induced hemochromatosis differed from our case because early iron deposition occurs primarily in non-hepatocytic cells and may involve other organs4. Only with dietary iron overload, in the very early s t a g e s , i r o n a c c u m u l a t i o n b e g i n i n h e p a t o c y t e s predominantly5. The origin of the spontaneous iron overload observed in our animal is not clear but might be related to an increase of duodenal iron absorption or an imbalance between iron absorption and excretion capacity at the level of the cell. A l t h o u g h t h e l i v e r i r o n c o n c e n t r a t i o n , b l o o d i r o n concentration, transferrin and ferritin were not examined, t h e r e i s a s i m i l a r i t y w i t h h u m a n h e r e d i t a r y hemochromatosis. The pathogenesis of different iron overloading in hepatocytes between and within lobes, is also unclear, but strongly suggests that the iron deposition is attributable to altered metabolism rather than an underlying genetic defect. IL-1beta, IL-6 and TNF-alfa stimulate transferrin-bound iron uptake by parenchymal cells of the liver8, and heterogenic iron deposition cases have been reported in chronic hepatitis or cirrhosis patients. An absence of iron accumulation in preneoplastic and neoplastic lesions has been described in the rat liver with chemical induced hemosiderosis6. In some human biopsy specimens from patients with chronic viral hepatitis, unusual foci of irregular h e p a t o c e l l u l a r i r o n s t o r a g e h a v e b e e n d e s c r i b e d 9 . Furthermore, interpretation of hepatic iron content in small biopsy samples is particularly difficult, such as in case of t h a l a s s e m i a p a t i e n t s w i t h a n u n e v e n h e p a t i c i r o n distribution10. In conclusion, the histological features of the present case of uncertain pathogenesis, point to similarities in the typical hemochromatosis in humans. Acknowledgements: We wish to thank the members of the Kansai Conference of Toxicologic Pathology (KCTP) for their advice.