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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1996 Aug;149(2):389–398.

Chronic iron overload in rats induces oval cells in the liver.

P G Smith 1, G C Yeoh 1
PMCID: PMC1865311  PMID: 8701979

Abstract

Liver damage induced by a variety of agents including hepatocarcinogens, alcohol, and virus induces proliferation of oval cells. In this study, iron overloading of the liver is used as a means of inducing liver damage over an extended period to ascertain whether it promotes the appearance of oval cells. Rats were fed a 2% carbonyl-iron-supplemented diet for 3 or 6 months. Extensive iron deposits appeared periportally in hepatocytes and some Kupffer cells. Iron deposition was less pronounced pericentrally. Small oval-like cells, morphologically and immunocytochemically similar to CDE-derived oval cells, were identified and quantified. They first emerged periportally and subsequently in small tracts or foci nearer central regions and stained positively for alpha-fetoprotein, pi-class glutathione S-transferase, and the embryonic form of pyruvate kinase. They contained very few iron deposits and were classified as iron free. The major difference between CDE- and iron-overload-derived oval cells was that the latter were negative for transferrin. This study shows that cellular changes occurring in iron-overloaded rat liver are similar to those observed in rats placed on a hepatocarcinogenic diet and in rats chronically exposed to alcohol.

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  1. Adams P. C., Chau L. A. Hepatic ferritin uptake and hepatic iron. Hepatology. 1990 May;11(5):805–808. doi: 10.1002/hep.1840110514. [DOI] [PubMed] [Google Scholar]
  2. Andrews S. C., Brady M. C., Treffry A., Williams J. M., Mann S., Cleton M. I., de Bruijn W., Harrison P. M. Studies on haemosiderin and ferritin from iron-loaded rat liver. Biol Met. 1988;1(1):33–42. doi: 10.1007/BF01128015. [DOI] [PubMed] [Google Scholar]
  3. Bacon B. R., Britton R. S. The pathology of hepatic iron overload: a free radical--mediated process? Hepatology. 1990 Jan;11(1):127–137. doi: 10.1002/hep.1840110122. [DOI] [PubMed] [Google Scholar]
  4. Bacon B. R. Causes of iron overload. N Engl J Med. 1992 Jan 9;326(2):126–127. doi: 10.1056/NEJM199201093260208. [DOI] [PubMed] [Google Scholar]
  5. Bacon B. R., Fried M. W., DiBisceglie A. M. A 39-year-old man with chronic hepatitis, elevated serum ferritin values, and a family history of hemochromatosis. Semin Liver Dis. 1993 Feb;13(1):101–105. doi: 10.1055/s-2007-1007342. [DOI] [PubMed] [Google Scholar]
  6. Bacon B. R., Park C. H., Brittenham G. M., O'Neill R., Tavill A. S. Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload. Hepatology. 1985 Sep-Oct;5(5):789–797. doi: 10.1002/hep.1840050514. [DOI] [PubMed] [Google Scholar]
  7. Bacon B. R., Tavill A. S., Brittenham G. M., Park C. H., Recknagel R. O. Hepatic lipid peroxidation in vivo in rats with chronic iron overload. J Clin Invest. 1983 Mar;71(3):429–439. doi: 10.1172/JCI110787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Baynes R. D., Cook J. D., Bothwell T. H., Friedman B. M., Meyer T. E. Serum transferrin receptor in hereditary hemochromatosis and African siderosis. Am J Hematol. 1994 Apr;45(4):288–292. doi: 10.1002/ajh.2830450404. [DOI] [PubMed] [Google Scholar]
  9. Bonkovsky H. L. Iron and the liver. Am J Med Sci. 1991 Jan;301(1):32–43. doi: 10.1097/00000441-199101000-00006. [DOI] [PubMed] [Google Scholar]
  10. Borecki I. B., Rao D. C., Le Mignon L., Yaouanq J., Simon M., Lalouel J. M. Genetic hemochromatosis: distribution analysis of six laboratory measures of iron metabolism. Am J Med Genet. 1989 Nov;34(3):435–441. doi: 10.1002/ajmg.1320340321. [DOI] [PubMed] [Google Scholar]
  11. Braun L., Mikumo R., Fausto N. Production of hepatocellular carcinoma by oval cells: cell cycle expression of c-myc and p53 at different stages of oval cell transformation. Cancer Res. 1989 Mar 15;49(6):1554–1561. [PubMed] [Google Scholar]
  12. Britton R. S., Ferrali M., Magiera C. J., Recknagel R. O., Bacon B. R. Increased prooxidant action of hepatic cytosolic low-molecular-weight iron in experimental iron overload. Hepatology. 1990 Jun;11(6):1038–1043. doi: 10.1002/hep.1840110620. [DOI] [PubMed] [Google Scholar]
  13. Britton R. S., O'Neill R., Bacon B. R. Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes [corrected]. Gastroenterology. 1991 Sep;101(3):806–811. doi: 10.1016/0016-5085(91)90543-t. [DOI] [PubMed] [Google Scholar]
  14. Britton R. S., O'Neill R., Bacon B. R. Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload. Hepatology. 1990 Jan;11(1):93–97. doi: 10.1002/hep.1840110116. [DOI] [PubMed] [Google Scholar]
  15. Deugnier Y. M., Charalambous P., Le Quilleuc D., Turlin B., Searle J., Brissot P., Powell L. W., Halliday J. W. Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients. Hepatology. 1993 Dec;18(6):1363–1369. [PubMed] [Google Scholar]
  16. Deugnier Y. M., Guyader D., Crantock L., Lopez J. M., Turlin B., Yaouanq J., Jouanolle H., Campion J. P., Launois B., Halliday J. W. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases. Gastroenterology. 1993 Jan;104(1):228–234. doi: 10.1016/0016-5085(93)90856-8. [DOI] [PubMed] [Google Scholar]
  17. Deugnier Y. M., Loréal O., Turlin B., Guyader D., Jouanolle H., Moirand R., Jacquelinet C., Brissot P. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology. 1992 Jun;102(6):2050–2059. doi: 10.1016/0016-5085(92)90331-r. [DOI] [PubMed] [Google Scholar]
  18. Deugnier Y., Battistelli D., Jouanolle H., Guyader D., Gueguen M., Loréal O., Jacquelinet C., Bourel M., Brissot P. Hepatitis B virus infection markers in genetic haemochromatosis. A study of 272 patients. J Hepatol. 1991 Nov;13(3):286–290. doi: 10.1016/0168-8278(91)90070-r. [DOI] [PubMed] [Google Scholar]
  19. Di Bisceglie A. M., Axiotis C. A., Hoofnagle J. H., Bacon B. R. Measurements of iron status in patients with chronic hepatitis. Gastroenterology. 1992 Jun;102(6):2108–2113. doi: 10.1016/0016-5085(92)90339-z. [DOI] [PubMed] [Google Scholar]
  20. Dunsford H. A., Maset R., Salman J., Sell S. Connection of ductlike structures induced by a chemical hepatocarcinogen to portal bile ducts in the rat liver detected by injection of bile ducts with a pigmented barium gelatin medium. Am J Pathol. 1985 Feb;118(2):218–224. [PMC free article] [PubMed] [Google Scholar]
  21. Evarts R. P., Nagy P., Marsden E., Thorgeirsson S. S. In situ hybridization studies on expression of albumin and alpha-fetoprotein during the early stage of neoplastic transformation in rat liver. Cancer Res. 1987 Oct 15;47(20):5469–5475. [PubMed] [Google Scholar]
  22. Evarts R. P., Nagy P., Nakatsukasa H., Marsden E., Thorgeirsson S. S. In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res. 1989 Mar 15;49(6):1541–1547. [PubMed] [Google Scholar]
  23. FARBER E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res. 1956 Feb;16(2):142–148. [PubMed] [Google Scholar]
  24. Fargion S., Mandelli C., Piperno A., Cesana B., Fracanzani A. L., Fraquelli M., Bianchi P. A., Fiorelli G., Conte D. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology. 1992 Apr;15(4):655–659. doi: 10.1002/hep.1840150417. [DOI] [PubMed] [Google Scholar]
  25. Fargion S., Piperno A., Fracanzani A. L., Cappellini M. D., Romano R., Fiorelli G. Iron in the pathogenesis of hepatocellular carcinoma. Ital J Gastroenterol. 1991 Dec;23(9):584–588. [PubMed] [Google Scholar]
  26. Germain L., Noël M., Gourdeau H., Marceau N. Promotion of growth and differentiation of rat ductular oval cells in primary culture. Cancer Res. 1988 Jan 15;48(2):368–378. [PubMed] [Google Scholar]
  27. Hauser S. C. Hemochromatosis and the heart. Heart Dis Stroke. 1993 Nov-Dec;2(6):487–491. [PubMed] [Google Scholar]
  28. Hayner N. T., Braun L., Yaswen P., Brooks M., Fausto N. Isozyme profiles of oval cells, parenchymal cells, and biliary cells isolated by centrifugal elutriation from normal and preneoplastic livers. Cancer Res. 1984 Jan;44(1):332–338. [PubMed] [Google Scholar]
  29. Hsia C. C., Evarts R. P., Nakatsukasa H., Marsden E. R., Thorgeirsson S. S. Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology. 1992 Dec;16(6):1327–1333. doi: 10.1002/hep.1840160604. [DOI] [PubMed] [Google Scholar]
  30. Irving M. G., Booth C. J., Devlin C. M., Halliday J. W., Powell L. W. The effect of iron and ethanol on rat hepatocyte collagen synthesis. Comp Biochem Physiol C. 1991;100(3):583–590. doi: 10.1016/0742-8413(91)90044-t. [DOI] [PubMed] [Google Scholar]
  31. Kew M. D. Pathogenesis of hepatocellular carcinoma in hereditary hemochromatosis: occurrence in noncirrhotic patients. Hepatology. 1990 Jun;11(6):1086–1087. doi: 10.1002/hep.1840110629. [DOI] [PubMed] [Google Scholar]
  32. Kiel D. P., Baron J. A., Plymate S. R., Chute C. G. Sex hormones and lipoproteins in men. Am J Med. 1989 Jul;87(1):35–39. doi: 10.1016/s0002-9343(89)80480-2. [DOI] [PubMed] [Google Scholar]
  33. Loréal O., Deugnier Y., Moirand R., Lauvin L., Guyader D., Jouanolle H., Turlin B., Lescoat G., Brissot P. Liver fibrosis in genetic hemochromatosis. Respective roles of iron and non-iron-related factors in 127 homozygous patients. J Hepatol. 1992 Sep;16(1-2):122–127. doi: 10.1016/s0168-8278(05)80104-7. [DOI] [PubMed] [Google Scholar]
  34. Lévy P., Dumont M., Brissot P., Letreut A., Favier A., Deugnier Y., Erlinger S. Acute infusions of bile salts increase biliary excretion of iron in iron-loaded rats. Gastroenterology. 1991 Dec;101(6):1673–1679. doi: 10.1016/0016-5085(91)90407-c. [DOI] [PubMed] [Google Scholar]
  35. Marleen P., Hendrik R., van Oostveldt P. Early liver cell lesions in rats induced by thioacetamide. An ultrastructural, cytophotometric and autoradiographic study. Pathol Res Pract. 1988 Dec;184(1):69–76. doi: 10.1016/S0344-0338(88)80193-6. [DOI] [PubMed] [Google Scholar]
  36. Niederau C., Fischer R., Sonnenberg A., Stremmel W., Trampisch H. J., Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med. 1985 Nov 14;313(20):1256–1262. doi: 10.1056/NEJM198511143132004. [DOI] [PubMed] [Google Scholar]
  37. Palazzo J. P., Lundquist K., Mitchell D., Mittal K. R., Hann H. W., Munoz S., Moritz M. J., Jacobs J. M., Martin P. Rapid development of lymphoma following liver transplantation in a recipient with hepatitis B and primary hemochromatosis. Am J Gastroenterol. 1993 Jan;88(1):102–104. [PubMed] [Google Scholar]
  38. Piperno A., Fargion S., D'Alba R., Roffi L., Fracanzani A. L., Vecchi L., Failla M., Fiorelli G. Liver damage in Italian patients with hereditary hemochromatosis is highly influenced by hepatitis B and C virus infection. J Hepatol. 1992 Nov;16(3):364–368. doi: 10.1016/s0168-8278(05)80671-3. [DOI] [PubMed] [Google Scholar]
  39. Roberts F. D., Charalambous P., Fletcher L., Powell L. W., Halliday J. W. Effect of chronic iron overload on procollagen gene expression. Hepatology. 1993 Sep;18(3):590–595. [PubMed] [Google Scholar]
  40. Seglen P. O. Preparation of rat liver cells. I. Effect of Ca 2+ on enzymatic dispersion of isolated, perfused liver. Exp Cell Res. 1972 Oct;74(2):450–454. doi: 10.1016/0014-4827(72)90400-4. [DOI] [PubMed] [Google Scholar]
  41. Sell S., Leffert H. L. An evaluation of cellular lineages in the pathogenesis of experimental hepatocellular carcinoma. Hepatology. 1982 Jan-Feb;2(1):77–86. doi: 10.1002/hep.1840020113. [DOI] [PubMed] [Google Scholar]
  42. Sharma B. K., Bacon B. R., Britton R. S., Park C. H., Magiera C. J., O'Neill R., Dalton N., Smanik P., Speroff T. Prevention of hepatocyte injury and lipid peroxidation by iron chelators and alpha-tocopherol in isolated iron-loaded rat hepatocytes. Hepatology. 1990 Jul;12(1):31–39. doi: 10.1002/hep.1840120107. [DOI] [PubMed] [Google Scholar]
  43. Smith P. G., Tee L. B., Yeoh G. C. Appearance of oval cells in the liver of rats after long-term exposure to ethanol. Hepatology. 1996 Jan;23(1):145–154. doi: 10.1002/hep.510230120. [DOI] [PubMed] [Google Scholar]
  44. Stremmel W., Riedel H. D., Niederau C., Strohmeyer G. Pathogenesis of genetic haemochromatosis. Eur J Clin Invest. 1993 Jun;23(6):321–329. doi: 10.1111/j.1365-2362.1993.tb02031.x. [DOI] [PubMed] [Google Scholar]
  45. Tee L. B., Smith P. G., Yeoh G. C. Expression of alpha, mu and pi class glutathione S-transferases in oval and ductal cells in liver of rats placed on a choline-deficient, ethionine-supplemented diet. Carcinogenesis. 1992 Oct;13(10):1879–1885. doi: 10.1093/carcin/13.10.1879. [DOI] [PubMed] [Google Scholar]
  46. Yaswen P., Hayner N. T., Fausto N. Isolation of oval cells by centrifugal elutriation and comparison with other cell types purified from normal and preneoplastic livers. Cancer Res. 1984 Jan;44(1):324–331. [PubMed] [Google Scholar]
  47. von Herbay A., de Groot H., Hegi U., Stremmel W., Strohmeyer G., Sies H. Low vitamin E content in plasma of patients with alcoholic liver disease, hemochromatosis and Wilson's disease. J Hepatol. 1994 Jan;20(1):41–46. [PubMed] [Google Scholar]

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