Regenerative capacity differs between micro- and macrovesicular hepatic steatosis.

INTRODUCTION Independent of etiology, the hepatic microvesicular steatosis has a worse prognosis compared with macrovesicular steatosis. Proliferation compensates for apoptosis and reflects regenerative mechanisms following liver injury. It is unknown whether these two types of fatty liver have differences in regenerative capacity and apoptosis, which could have an impact on their prognosis. METHODS Two groups of pigs were studied for 72 days under a protein-deficient diet. One group received only protein-deficient diet (n=6), the other was treated in addition to the diet with 6g ethanol/kg/day by means of a percutaneous intragastric catheter (n=6). The rate of proliferating and apoptotic hepatocytes was determined, respectively, by proliferation cell nuclear antigen (PCNA) and ISEL/TUNEL staining for apoptosis in liver biopsies with similar steatosis grade in pigs with micro- or macrovesicular fatty liver. RESULTS The ethanol-treated group developed microvesicular steatosis, the other group developed macrovesicular steatosis. Proliferation index was significantly increased in macrovesicular in comparison with microvesicular steatosis (p<0.05). Apoptosis rate was similar in both groups. CONCLUSIONS Regeneration, but not apoptosis rate differs between micro- and macrovesicular steatosis. The reduced regenerative capacity in microvesicular steatosis may contribute to the worse prognosis of this subtype of fatty liver disease.

[1]  G. Labbe,et al.  Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: Possible role in microvesicular steatosis induced by this antibiotic , 1988, Hepatology.

[2]  A. Slomiany,et al.  Chronic ethanol-initiated apoptosis in hepatocytes is induced by changes in membrane biogenesis and intracellular transport. , 1999, Alcoholism, clinical and experimental research.

[3]  D. Pessayre,et al.  Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation. , 1997, Journal of hepatology.

[4]  A. Diehl.  Nonalcoholic fatty liver disease: implications for alcoholic liver disease pathogenesis. , 2001, Alcoholism, clinical and experimental research.

[5]  P. Hall,et al.  In situ end‐labelling detects DNA strand breaks in apoptosis and other physiological and pathological states , 1993, The Journal of pathology.

[6]  C. Trépo,et al.  Fulminant hepatitis with microvesicular steatosis (a histologic comparison of cases occurring in Brazil--Labrea hepatitis--and in central Africa--Bangui hepatitis). , 1992, Revista da Sociedade Brasileira de Medicina Tropical.

[7]  S. J. James,et al.  Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation , 1996, Hepatology.

[8]  C. Sempoux,et al.  Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats. , 2002, Journal of hepatology.

[9]  G. Gores,et al.  Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. , 2003, Gastroenterology.

[10]  G. Poli,et al.  Studies on fatty liver with isolated hepatocytes. I. The action of colchicine, phalloidin, cytochalasin B, and cyclohexamide on protein and triglyceride synthesis and secretion. , 1977, Experimental and molecular pathology.

[11]  U. Apte,et al.  Hepatocyte Proliferation is the Possible Mechanism for the Transient Decrease in Liver Injury During Steatosis Stage of Alcoholic Liver Disease , 2004, Toxicologic pathology.

[12]  R. Rej.  Aminotransferases in disease. , 1989, Clinics in laboratory medicine.

[13]  G. Michalopoulos,et al.  Hepatocyte regeneration in acute fulminant and nonfulminant hepatitis: A study of proliferating cell nuclear antigen expression , 1992, Hepatology.

[14]  F. Gordon,et al.  Steatosis in donor and transplant liver biopsies. , 2000, Human pathology.

[15]  A. Sanyal,et al.  The histologic spectrum of nonalcoholic fatty liver disease. , 2004, Clinics in liver disease.

[16]  K. Nair,et al.  Apolipoprotein synthesis in nonalcoholic steatohepatitis , 2002, Hepatology.

[17]  A. Tannapfel,et al.  Apoptosis and proliferation in relation to histopathological variables and prognosis in hepatocellular carcinoma , 1999, The Journal of pathology.

[18]  A. Rötig,et al.  Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis. , 1995, Gastroenterology.

[19]  P. Angulo,et al.  Nonalcoholic fatty liver disease. , 2002, Revista de gastroenterologia de Mexico.

[20]  V. P. Chacko,et al.  Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition? , 2001, Cancer research.

[21]  S. Sherlock,et al.  Acute cholestasis, hepatic failure, and fatty liver in the alcoholic. , 1978, Scandinavian journal of gastroenterology.

[22]  A. Rashid,et al.  Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver , 1999, Hepatology.

[23]  R. Teschke,et al.  Induction of hepatic microsomal gamma-glutamyltransferase activity following chronic alcohol consumption. , 1977, Biochemical and biophysical research communications.

[24]  D. Vance,et al.  The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. , 1988, The Journal of biological chemistry.

[25]  R. Barouki,et al.  In vitro biosynthesis and membrane insertion of gamma-glutamyl transpeptidase. , 1984, The Journal of biological chemistry.

[26]  A. Burt,et al.  Diagnosis and interpretation of steatosis and steatohepatitis. , 1998, Seminars in diagnostic pathology.

[27]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[28]  M. Fishbein,et al.  The Spectrum of Fatty Liver in Obese Children and The Relationship of Serum Aminotransferases to Severity of Steatosis , 2003, Journal of pediatric gastroenterology and nutrition.

[29]  G. Farrell,et al.  Etiopathogenesis of Nonalcoholic Steatohepatitis , 2001, Seminars in liver disease.

[30]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: an expanded clinical entity. , 1994, Gastroenterology.

[31]  B. Holtmann,et al.  Fulminant hepatic failure after repeated exposure to isoflurane anesthesia: A case report , 1991, Hepatology.

[32]  J. Briceño,et al.  Influence of marginal donors on liver preservation injury , 2002, Transplantation.

[33]  G. Gores,et al.  Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. , 2001, Journal of hepatology.

[34]  B. Portmann,et al.  Acute liver damage and ecstasy ingestion. , 1996, Gut.

[35]  R. Stratta,et al.  FROZEN SECTION EVALUATION OF DONOR LIVERS BEFORE TRANSPLANTATION , 1993, Transplantation.

[36]  R. Fietkau,et al.  Incidence of apoptosis, cell proliferation and P53 expression in renal cell carcinomas. , 1997, Anticancer research.

[37]  H. Cortez‐Pinto,et al.  Hepatocyte Apoptosis, Expression of Death Receptors, and Activation of NF-κB in the Liver of Nonalcoholic and Alcoholic Steatohepatitis Patients , 2004, The American Journal of Gastroenterology.

[38]  T. Fishbein,et al.  Use of livers with microvesicular fat safely expands the donor pool. , 1997, Transplantation.

[39]  E. Krul,et al.  Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthotopic liver transplantation , 1990, Hepatology.

[40]  B. Lombardi.  Considerations on the pathogenesis of fatty liver. , 1966, Laboratory investigation; a journal of technical methods and pathology.

[41]  K. Ishak,et al.  Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. , 1988, Gastroenterology.

[42]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[43]  H. Bonkovsky,et al.  Frequency and distribution of DNA fragmentation as a marker of cell death in chronic liver diseases , 1997, Virchows Archiv.