NASH

Zusammenfassung

Eine Leberschädigung mit den typischen Veränderungen einer alkoholischen Pathogenese, ohne dass eine solche vorliegt, wurde erstmals 1962 beschrieben und im Jahr 1980 durch Ludwig et al. als nichtalkoholische Steatohepatitis (NASH) definiert. Viele Arbeitsgruppen erforschten seitdem diese Erkrankung. Sie gilt als Syndrom multifaktorieller Ätiologie, das die hepatische Manifestation des Syndroms X darstellt. Die Pathogenese findet als „two-hit”-Phänomen statt, bei dem der „first hit” zu einer Steatosis hepatis führt und die Leber den Noxen des „second hit” gegenüber vulnerabel macht. Zentrale Faktoren des „second hit” sind Sauerstoff-Radikale, oxidativer Stress, Lipid-Peroxidation und Zytokine. Die genauen pathogenetischen Mechanismen der NASH sind jedoch noch nicht endgültig geklärt. Die NASH ist eine Lebererkrankung, die bis zur Zirrhose mit Leberfunktionsstörung fortschreiten kann. Einen medikamentösen kurativen Therapieansatz gibt es bisher noch nicht. Die Gefahr des Progresses der Erkrankung, ihre Zunahme als typische Wohlstandserkrankung und der Mangel an therapeutischen Optionen machen NASH zu einer der wichtigen und somit forschungsrelevanten Erkrankungen unserer Zeit. Ziel dieses Artikels ist es, den aktuellen Wissensstand über diese Erkrankung, speziell die Pathogenese, anhand der Literatur von 1979 bis zum aktuellen Zeitpunkt darzustellen.

Abstract

Nonalcoholic steatohepatitis describes a hepatic disorder with the typical characteristics of an alcoholic pathogenesis without alcohol consumption. It was first described in 1962 and named NASH by Ludwig et al. 1980. Many researchers worked on this disease since this time. It represents the hepatic manifestation of the syndrome X. The pathogenesis is a two-hit phenomenon. The first hit leads to steatosis hepatis and makes the liver vulnerable to the second hit. Central factors of the second hit are oxygen-radicals, oxidative stress, lipid-peroxidation and cytokines. The exact pathogenic mechanisms are still unknown. NASH is a hepatic disease which can end up in liver cirrhosis and liver failure. Up to now a curative drug therapy does not exist. The poor prognosis in some cases, the increasing incidence in western populations and the lack of therapeutic options renders NASH to a serious problem. The aim of this article is to show the actual knowledge of this disease, especially focussed on the pathogenesis, by review of the literature from 1979 up to the present time.

Schlüsselwörter

NASH - NAFL - Leberzellschädigung - oxidativer Stress

Key words

NASH - NAFLD - hepatocyte damage - oxidative stress

Literatur

• 1 Diehl A M. Nonalcoholic steatohepatitis.  Semin Liver Dis. 1999;  19 221-229
• 2 Chitturi S, Farrel G C. Ethiopathogenesis of nonalcoholic steatohepatitis.  Semin Liver Dis. 2001;  21 27-41
• 3 Adler M, Shaffner F. Fatty liver hepatitis and cirrhosis in obese patients.  Am J Med. 1979;  67 811-816
• 4 Falchuk K R, Fiske S C, Haggitt R C. et al . Pericentral hepatic fibrosis and intracellular hyaline in diabetes mellitus.  Gastroenterology. 1980;  78 835-841
• 5 Ludwig J, Viggiano T R, McGill D B. et al . Nonalcoholic steatohepatitis. Mayo clinic experience with a hitherto unnamed disease.  Mayo Clin Proc. 1980;  55 434-438
• 6 Batman P A, Scheuer P J. Diabetic hepatitis preceding the onset of glucose intolerance.  Histopathology. 1985;  9 237-243
• 7 Diehl A M, Goodman Z, Ishak K G. Alcohol-like liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury.  Gastroenterology. 1988;  95 1056-1062
• 8 Lee R G. Nonalcoholic steatohepatitis: a study of 49 patients.  Hum Pathol. 1989;  20 594-598
• 9 Sheth S G, Gordon F D, Chopra S. Nonalcoholic steatohepatitis.  Ann Intern Med. 1997;  126 137-145
• 10 Wanless I R, Lentz J S. Fatty liver hepatitis (stetatohepatitis) and obesity: an autopsy study with analysis of risk factors.  Hepatology. 1990;  12 1106-1110
• 11 Luyckx F H, Lefebvre P J, Scheen A J. Non-alcoholic steatohepatitis: association with obesity and insulin resistence, and influence of weight reduction.  Diabetes Metab. 2000;  26 98-106
• 12 Pagano G, Pacini G, Musso G. et al . Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association.  Hepatology. 2002;  35 367-372
• 13 Basaranoglu M, Sonsuz A, Senturk H, Akin P. The low incidence of primary liver disease in patients with nonalcoholic steatohepatitis.  J Hepatol. 2001;  35 684-685
• 14 Marchesini G, Brizi M, Bianchi G. et al . Nonalcoholic fatty liver disease. A feature of the metabolic syndrome.  Diabetes. 2001;  50 1844-1850
• 15 Willner I R, Waters B, Patil S R. et al . Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.  Am J Gastroenterol. 2001;  96 2957-2961
• 16 Powell E E, Cooksley W GE, Hanson R. et al . The natural history of nonalcoholic steatohepatitis: a follow-up study of fourty-two patients for up to 21 years.  Hepatology. 1990;  11 74-80
• 17 Bacon B R, Farahvash M J, Janney C G. et al . Nonalcoholic steatohepatitis: an expanded clinical entity.  Gastroenterology. 1994;  107 1103-1109
• 18 Grimm I S, Schindler W, Haluszka O. Steatohepatitis and fatal hepatic failure after biliopancreatic diversion.  Am J Gastroenterology. 1992;  87 775-779
• 19 Matteoni C A, Younossi Z M, Gramlich T. et al . Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.  Gastroenterology. 1999;  116 1413-1419
• 20 Pinto C H, Baptista A, Camilo M E. et al . Nonalcoholic steatohepatitis: clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients.  Dig Dis and Science. 1996;  41 172-179
• 21 Flegal K M, Carrol M D, Kuczmarski R J. et al . Overweight and obesity in the United States: prevalence and trends, 1960-1994.  Int J Obes. 1998;  22 39-47
• 22 Kopelman P G. Obesity as a medical problem.  Nature. 2000;  404 635-643
• 23 Wilding J. Science, medicine and the future: obesity treatment.  BMJ. 1997;  315 997-1000
• 24 Loguercio C, De Girolamo V, De Sio I. et al . Non-alcoholic fatty liver disease in an area of southern Italy: main clinical, histological, and pathophysiological aspects.  J Hepatol. 2001;  35 568-574
• 25 Valenti L, Fracanzani A L, Dongiovanni P. et al . Tumor necrosis factor α promotor polymorphisms and insulin resistance in nonalcoholic fatty liver disease.  Gastroenterology. 2002;  122 274-280
• 26 Garcia-Monzon C, Martin-Perez E, Lo I acono O. et al . Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity.  J Hepatol. 2000;  33 716-724
• 27 James O FW, Day C P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.  J Hepatol. 1998;  29 495-501
• 28 Angulo P, Keach J C, Batts K P, Lindor K D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.  Hepatology. 1999;  30 1356-1362
• 29 Eriksson S, Eriksson K, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition.  Acta Med Scand. 1986;  220 83-88
• 30 Tankurt E, Biberoglu S, Ellidokuz E. et al . Hyperinsulinemia and insulin resistance in non-alcoholic steatohepatitis.  Hepatol. 1999;  31 963-968
• 31 Neuschwander-Tetri B A. Evolving pathophysiologic concepts in nonalcoholic steatohepatitis.  Curr Gastroenterol Rep. 2002;  4 31-36
• 32 Chitturi S, Abeygunasekera S, Farrell G C. et al . NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome.  Hepatology. 2002;  35 373-379
• 33 Comert B, Mas M R, Erdem H. et al . Insulin resistance in non-alcoholic steatohepatitis.  Dig Liver Dis. 2001;  33 353-358
• 34 Nehra V, Angulo P, Buchman A L, Lindor K D. Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.  Dig Dis Sci. 2001;  46 2347-2352
• 35 Cortez-Pinto H, Camilo M E, Baptista A. et al . Nonalcoholic fatty liver: another feature of the metabolic syndrome?.  Clin Nutr. 1999;  18 353-835
• 36 Fiatarone J R, Coverdale S A, Batey R G. et al . Non-alcoholic stetaohepatitis: impaired antipyrine metabolism and hypertriglyceridaemia may be clues to its pathogenesis.  J Gastroenterol Hepatol. 1991;  6 585-590
• 37 Sorbi D, McG ill D B, Thistle J L, Therneau T M. et al . An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities.  Am J Gastroenterol. 2000;  95 3206-3210
• 38 DeWind L T, Payne J H. Intestinal bypass surgery for morbid obesity. Long term results.  JAMA. 1976;  236 2298-2301
• 39 Peters R L. Hepatic morphologic changes after jejunoileal bypass.  Prog Liver Dis. 1979;  6 581-594
• 40 Hocking M P, Davis G L, Franzini D A. et al . Long-term consequences after jejunoileal bypass for morbid obesity.  Dig Dis Sci. 1998;  43 2493-2499
• 41 Peters R L, Gay T, Reynolds T B. Post-jejunoileal bypass hepatic disease.  J Clin Pathol. 1975;  63 318-331
• 42 Hamilton D L, Vest T K, Brown B S. et al . Liver injury with alcoholic like hyalin after gastroplasty for morbid obesity.  Gastroenterology. 1983;  85 722-726
• 43 Bowyer B A, Fleming C R, Ludwig J. et al . Does long-term home parenteral nutrition in adult patients cause chronic liver disease?.  J Parenter Nutr. 1985;  9 11-17
• 44 Craig R M, Neumann T, Jeejeebhoy K N. et al . Severe hepatocellular reaction resembling alcoholic hepatitis with cirrhosis after massive small bowel resection and prolonged total parenteral nutrition.  Gastroenterology. 1980;  79 131-137
• 45 Quigley E M, Marsh M N, Shaffer J L. et al . Hepatobiliary complications of total parenteral nutrition.  Gastroenterology. 1993;  104 286-301
• 46 Fleming C R. Hepatobiliary complications in adults receiving nutrition support.  Dig Dis. 1994;  12 191-198
• 47 Nazim M, Stamp G, Hodgson H J. Non-alcoholic steatohepatitis associated with small intestinal diverticulosis and bacterial overgrowth.  Hepatogastroenterology. 1989;  36 349-351
• 48 Falck-Ytter Y, Younossi Z M, Marchesini G. et al . Clinical features and natural history of nonalcoholic steatosis syndromes.  Semin Liver Dis. 2001;  21 17-26
• 49 Day C P, James O FW. Steatohepatitis: a tale of two ‘hits’?.  Gastroenterology. 1998;  114 842-845
• 50 Rashid A, Wu T C, Huang C C. et al . Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver.  Hepatology. 1999;  29 1131-1138
• 51 Chavin K, Yang S Q, Lin H Z. et al . Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.  J Biol Chem. 1999;  274 5692-5700
• 52 Cortez-Pinto H, Chatham J, Chacko V P. et al . Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis. A pilot study.  JAMA. 1999;  282 1659-1664
• 53 Letteron P, Fromenty B, Terris B. et al . Acute and chronic steatosis lead to in vivo lipid peroxidation in mice.  J Hepatol. 1996;  24 200-208
• 54 Yang S Q, Lin H Z, Lane M D. et al . Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis.  Proc Natl Acad. 1997;  94 2557-2562
• 55 Fromenty B, Berson A, Pessayre D. Microvesicular steatosis and steatohepatitis: a role of mitochondrial dysfunction and lipid peroxidation.  J Hepatol. 1997;  26 13-22
• 56 Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines.  J Hepatol. 1997;  26 Suppl. 2 43-53
• 57 Pessayre D, Berson A, Fromenty B. et al . Mitochondria in steatohepatitis.  Semin Liver Dis. 2001;  21 57-69
• 58 Marchesini G, Brizi M, Morselli-Labate A M. et al . Association of nonalcoholic fatty liver disease with insulin resistence.  Am J Med. 1999;  107 450-455
• 59 Sanyal A J, Campbell-Sargent C, Mirshahi F. et al . Nonalcoholic steatohepatitis: association of insulin resistence and mitochondrial abnormalities.  Gastroenterology. 2001;  120 1183-1192
• 60 Angulo P, Lindor K D. Insulin resistance and mitochondrial abnormalities in NASH: a cool look into a burning issue.  Gastroenterology. 2001;  120 1281-1285
• 61 Rao M S, Reddy J K. Peroxisomal ß-oxidation and steatohepatitis.  Semin liver dis. 2001;  21 43-55
• 62 Shigenaga M, Hagen T M, Ames B. Oxidative damage and mitochondrial decay in aging.  Proc Natl Acad Sci. 1994;  91 10771-10778
• 63 Cassader M, Gambino R, Musso G. et al . Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients.  Lipids. 2001;  36 1117-1124
• 64 Acosta D, Wenzel D G. Injury produced by free fatty acids to lysosomes and mitochondria in cultured heart muscle and endothelial cells.  Atherosclerosis. 1974;  20 417-426
• 65 Wenzel D G, Hale T W. Toxicity of free fatty acids for cultured rat heart muscle and endothelial cells.  Toxicology. 1978;  11 109-117
• 66 Drenick E J, Fisler J, Johnson D. Hepatic steatosis after intestinal bypass. Prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition.  Gastroenterology. 1982;  82 535-548
• 67 Esterbauer H. Cytotoxicity and genotoxicity of lipid-oxidation products.  Am J Clin Nutr. 1996;  57 779S-785S
• 68 Pappo I, Becovier H, Berry E M. et al . Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in rat.  J Clin Res. 1991;  51 106-112
• 69 Weltman M D, Farrell G C, Hall P. et al . Hepatic cytochrome P450 2E1 is increased in patients with non-alcoholic steatohepatitis.  Hepatology. 1998;  27 128-133
• 70 Weltman M D, Farrell G C Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation.  Gastroenterology. 1996;  111 1645-1653
• 71 Zhang B -H, Weltman M, Farrell G C. Does steatohepatitis impair liver regeneration? A study in a dietary model of non-alcoholic steatohepatitis in rats?.  J Gastroenterol Hepatol. 1999;  14 133-137
• 72 Leclercq I A, Farrell G C, Field J. et al . CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine non-alcoholic steatohepatitis.  J Clin Invest. 2000;  105 1067-1075
• 73 Maher J. The CYP2E1 knockout delivers another punch: first ASH, now NASH. Alcoholic steatohepatitis. Nonalcoholic steatohepatitis.  Hepatology. 2001;  33 311-312
• 74 Jaeschke H, Gores G J, Cederbaum A I. et al . Mechanisms of hepatotoxicity.  Toxicol Sci. 2002;  65 166-176
• 75 Robertson G, Leclercq I, Farrell G C. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress.  Am J Physiol Gastrointest Liver Physiol. 2001;  281 G1135-1139
• 76 Fong D G, Nehra V, Lindor K D. et al . Metabolic and nutritional considerations in nonalcoholic fatty liver.  Hepatology. 2000;  32 3-10
• 77 Pessayre D, Mansouri A, Fromenty B. Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.  Am J Physiol Gastrointest Liver Physiol. 2002;  282 G193-199
• 78 Pessayre D, Mansouri A, Haouzi D. et al . Hepatotoxicity due to mitochondrial dysfunction.  Cell Biol Toxicol. 1999;  15 367-373
• 79 Hruszkewycz E M. Evidence for mitochondrial DNA damage by lipid peroxidation.  Biochem Biophys Res Commun. 1988;  153 191-197
• 80 Curzio M, Esterbauer H, Dianzani M U. Possible role of aldehydic lipid peroxidation products as chemoattractants.  Int J Tissue React. 1987;  9 295-306
• 81 Curzio M, Esterbauer H, Dianzani M U. Chemotactic activity of hydroxyalkenals on rats neutrophils.  Int J Tissue React. 1985;  7 137-142
• 82 Garcia-Ruiz C, Collel A, Morales A. et al . Role of oxidative stress generated from mitochondrial electron transport chain and mitochondrial electron status in loss of mitochondrial function and activation of transcription factor nuclear factor-(B: studies with isolated mitochondria and rat hepatocytes.  Mol Pharmacol. 1995;  48 825-834
• 83 Bedossa P, Houglum K, Trautwein C. et al . Stimulation of collagen α-1 (I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis?.  Hepatology. 1994;  19 1262-1271
• 84 Kamimura S, Gaal K, Britton R S. et al . Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis.  Hepatology. 1992;  16 448-453
• 85 Leonarduzzi G, Scavazza A, Biasi F. et al . The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor ß1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis.  FASEB. 1997;  11 851-857
• 86 Esterbauer H, Schaur R J, Zollner H. Chemistry and biochemistry of 4hydroxynonenal, malondialdehyde and related aldehydes.  Free Radic Biol Med. 1991;  11 81-128
• 87 Wigg A J, Roberts-Thomson I C, Dymock R B. et al . The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis.  Gut. 2001;  48 148-149
• 88 Crespo J, Cayon A, Fernandez-Gil P. et al . Gene expression of tumor necrosis factor ( and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients.  Hepatology. 2001;  34 1158-1163
• 89 Yamakawa T, Tanaka S, Yamakawa Y. et al . Augmented production of tumor necrosis factor-alpha in obese mice.  Clin Immunol Immunopathol. 1995;  75 51-56
• 90 Kern P A, Saghizadeh M, Ong J M. et al . The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase.  J Clin Invest. 1995;  95 2111-2119
• 91 Lee K S, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression.  J Clin Invest. 1995;  96 2461-2468
• 92 Olaso E, Friedman S L. Molecular regulation of hepatic fibrogenesis.  J Hepatol. 1998;  29 836-347
• 93 Farrel G C. Is bacterial ash the flash that ignites NASH?.  Gut (Editorial). 2001;  48 148-149
• 94 Angulo P, Lindor K D. Treatment of nonalcoholic fatty liver: present and emerging therapies.  Seminar Liver Dis. 2001;  21 81-88
• 95 Pequignot G, Tuyns A S, Berta J L. Ascitic cirrhosis in relationship to alcohol consumption.  Int J Epidemiol. 1978;  7 113-120
• 96 Yoshimura T, Matsushima K, Tanaka S. et al . Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines.  Proc Natl Acad Sci USA. 1987;  84 9233-9237
• 97 Hammond M E, Lapointe G R, Feicht P H. et al . IL-8 induces neutrophil chemotaxis predominantly via type 1 IL-8 receptors.  J Immunol. 1995;  155 1428-1434
• 98 Poli G. Pathogenesis of liver fibrosis: role of oxidative stress.  Mol Aspects Med. 2000;  21 49-98
• 99 Paradis V, Perlemuter G, Bonvoust F. et al . High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis.  Hepatology. 2001;  34 738-744
• 100 Casini A, Pinzani M, Milani S. et al . Regulation of extracellular matrix synthesis by by transforming growth factor-ß1 in human fat storing cells.  Gastroenterology. 1993;  105 245-253
• 101 Everett L, Galli A, Crabb D. The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease.  Liver. 2000;  20 191-199
• 102 Lee S S, Pineau T, Drago J. et al . Targeted disruption of the alpha isoform of the peroxisome proliferator activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.  Mol Cell Biol. 1995;  15 3012-3022
• 103 Reddy J K. Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis.  Am J Physiol Gastrointest Liver Physiol. 2002;  281 G1333-1339
• 104 Abraham B H, Furth E E. Receiver operating characteristic analysis of glycogenated nuclei in liver biopsy specimen: quantitative evaluation of their relationship with diabetes and obesity.  Hum Pathol. 1994;  25 1063-1068
• 105 George D K, Goldwurm S, MacDonald G A. et al . Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology. 1998;  114 311-318
• 106 Angulo P. Nonalcoholic fatty liver disease.  N Engl J Med. 2002;  346 1221-1231
• 107 Caldwell S H, Swerdlow R H, Khan E M. et al . Mitochondrial abnormalities in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 430-434
• 108 Teli M R, James O FW, Burt A D. et al . The naturel history of nonalcoholic fatty liver: a follow-up study.  Hepatology. 1995;  22 1714-1719
• 109 Nagore N, Scheuer P J. The pathology of diabetic hepatitis.  J Pathol. 1988;  156 155-160
• 110 Silverman J F, O`Brian K F, Long S. et al . Liver pathology in morbidly obese patients with and without diabetes.  Am J Gastroenterology. 1990;  85 1349-1355
• 111 Van Thiel D H, Stone B G. Diabetes mellitus and the liver.  Semin Liver Dis. 1985;  5 8-28
• 112 Buchwald H, Lober P H, Varco R L. Liver biopsy findings in seventy-seven consecutive patients undergoing jejunoileal bypass for morbid obesity.  Am J Surg. 1974;  127 48-52
• 113 Kern W H, Heger A H, Payne J H. et al . Fatty metamorphosis of the liver in morbid obesity.  Arch Pathol. 1973;  96 342-346
• 114 Lee R G. Nonalcoholic steatohepatitis: tightening the morphological screws on a hepatic rambler.  Hepatology. 1995;  21 1742-1743
• 115 Contos M J, Sanyal A J. The clinicopathologic spectrum and management of nonalcoholic fatty liver disease.  Adv Anat Pathol. 2002;  9 37-51
• 116 Brunt E M, Janney C G, Di Bisceglie A M. et al . Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.  Am J Gastroenterol. 1999;  94 2467-2474
• 117 Kumar K S, Malet P F. Nonalcoholic Steatohepatitis.  Mayo Clin Proc. 2000;  75 733-739
• 118 Lelbach W K. Epidemiology of alcoholic liver disease.  Prog Liver Dis. 1976;  5 494-513
• 119 Sorbi D, Boynton J, Lindor K D. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease.  Am J Gastroenterol. 1999;  94 1018-1022
• 120 Van Ness M M, Diehl A M. Is liver biopsy useful in the evaluation of patients with chronically elevated enzymes?.  Ann Intern Med. 1989;  111 473-478
• 121 Lumeng L. New diagnostic markers of alcohol abuse.  Hepatology. 1986;  6 42-47
• 122 Sanson-Fischer R. The measurement of alcohol consumption and alcohol related problems.  Aust Drug Alcohol Rev. 1986;  5 309-313
• 123 Storey E, Anderson G J, Mack U. et al . Desialylated transferrin as a serological marker of chronic excessive alcohol ingestion.  Lancet. 1987;  1 1292-1294
• 124 Fletcher L M, Kwoh-Gain L, Powell E E. et al . Markers of chronic alcohol ingestion in nonalcoholic steatohepatitis: An aid to diagnosis.  Hepatology. 1991;  13 455-459
• 125 Rogers D W, Lee C H, Pound D C. et al . Hepatitis C virus does not cause nonalcoholic steatohepatitis.  Dig Dis Sci. 1992;  37 1644-1647
• 126 Bonkovsky H L, Jawaid Q, Tortorelli K. et al . Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 421-429
• 127 George D K, Powell L W, Losowsky M S. The haemochromatosis gene: a co-factor for chronic liver diseases?.  J Gastroenterol Hepatol. 1999;  14 745-749
• 128 Quinn S F, Gosink B B. Characteristic sonographic signs of hepatic fatty infiltration.  AJR. 1985;  145 753-755
• 129 Celle G, Savarino V, Picciotto A. et al . Is hepatic ultrasonography a valid alternative tool to liver biopsy? Report on 507 cases studied with both techniques.  Dig Dis Sci. 1988;  33 467-471
• 130 Needleman L, Kurtz A B, Rifkin M D. et al . Sonography of diffuse benign liver disease: accuracy of pattern recognition and grading.  AJR. 1986;  146 1011-1015
• 131 Sanford N L, Walsh P, Matis C. et al . Is ultrasonography useful in the assessment of diffuse parenchymal liver disease?.  Gastroenterology. 1985;  89 186-191
• 132 Siegelman E S, Rosen M A. Imaging of hepatic steatosis.  Seminar Liver Dis. 2001;  21 71-80
• 133 Jacobs J E, Birnbaum B A, Shapiro M A. et al . Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT.  AJR. 1998;  171 659-664
• 134 Piekarski J, Goldberg H I, Royal S A. et al . Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease.  Radiology. 1980;  137 727-729
• 135 Herlong H F. Approach to the patient with abnormal liver enzymes.  Hosp Pract. 1994;  11 32-38
• 136 Berasain C, Betes M, Panizo A. et al . Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology.  Gut. 2000;  47 429-435
• 137 Sorrell M F, Mukherjee S. Non-alcoholic stetatohepatitis (NASH).  Current treatment options in gastroenterology. 1999;  2 447-450
• 138 Itoh S, Yougel T, Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis.  Am J Gastroenterol. 1987;  82 650-654
• 139 Charlton M, Kasparova P, Weston S. et al . Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease.  Liver Transpl. 2001;  7 608-614
• 140 Dixon J B, Bhathal P S, O`Brien P E. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese.  Gastroenterology. 2001;  121 91-100
• 141 Propst A, Propst T, Judmaier G, Vogel W. Prognosis in nonalcoholic steatohepatitis.  Gastroenterology. 1995;  108 1607
• 142 Caldwell S H, Oelsner D H, Iezzoni J C. et al . Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.  Hepatology. 1999;  29 664-669
• 143 Ong J, Younossi Z M, Reddy V. et al . Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease.  Liver Transpl. 2001;  7 797-801
• 144 Struben V MD, Hespenheide E E, Caldwell S H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds.  Am J Med. 2000;  108 9-13
• 145 Lieber C S. Alcohol and the liver: update 1994.  Gastroenterology. 1994;  106 1085-1105
• 146 Zen Y, Katayanagi K, Tsuneyama K. et al . Hepatocellular carcinoma arising in non-alcoholic steatohepatitis.  Pathol International. 2001;  51 127-131
• 147 Andersen T, Gluud C, Franzmann M B. et al . Hepatic effects of dietary weight loss in morbidly obese patients.  J Hepatol. 1991;  12 224-229
• 148 Capron J P, Delamarre M, Dupas J L. et al . Fasting in obesity: Another cause of liver injury with alcoholic hyaline?.  Dig Dis Sci. 1982;  54 374-377
• 149 Rozental P, Biava C, Spencer H, Zimmerman H J. Liver morphology and function tests in obesity and during total starvation.  Am J Dig. 1967;  12 198-208
• 150 Lin H Z, Yang S Q, Chuckaree C. et al . Metformin reverses fatty liver disease in obese, leptin-deficient mice.  Nat Med. 2000;  6 998-1003
• 151 Caldwell S H, Hespenheide E E, Redick J A. et al . A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.  Am J Gastroenterol. 2001;  96 274-276
• 152 Battle E H, Hespenheiden E E, Caldwell S H. Pilot study of troglitazone (Rezulin) for nonalcoholic steatohepatitis.  Hepatology. 1998;  28 304A
• 153 Watkins P B, Whitcomb R W. Hepatic dysfunction associated with troglitazone.  N Engl J Med. 1998;  338 908-909
• 154 Menon K VN, Angulo P, Lindor K D. Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus.  Am J Gastroenterol. 2001;  96 1631-1634
• 155 Laurin J, Lindor K D, Crippin J S. et al . Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.  Hepatology. 1996;  23 1464-1467
• 156 Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis.  J Hepatol. 1999;  31 384
• 157 Ceriani R, Bunati S, Morini L. et al . Effect of ursodeoxycholic acid plus diet in patients with non-alcoholic steatohepatitis.  Hepatology. 1998;  28 386A
• 158 Guma G, Viola L, Thome M. et al . Ursodeoxycholic acid in the treatment of nonalcoholic stetaohepatitis: results of a prospective clinical controlled trial.  Hepatology. 1997;  26 387A
• 159 Neumann M G, Cameron R G, Shear N H. et al . Effect of taurodeoxycholic and ursodeoxycholic acid on ethanol-induced cell injuries in the human Hep-G2 cell line.  Gastroenterology. 1995;  109 555-563
• 160 Peterson T C, Slysz G, Isbrucker R. The inhibitory effect of ursodeoxycholic acid and pentoxifylline on platelet derived growth factor-stimulated proliferation is distinct froman effect by cyclic AMP.  Immunpharmacology. 1998;  39 181-191
• 161 Trauner M, Graziadei W. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver disease.  Aliment Pharmacol Ther. 1999;  13 979-995
• 162 Vendemiale G, Grattagliano I, Signorile A. et al . Ethanol-induced changes of intracellular thiol compartmentation and protein redox status in the rat liver: effect of taurodeoxycholate.  J Hepatol. 1998;  28 46-53
• 163 Abdelmalek M, Angulo P, Jorgensen R A. et al . Betaine for patients with nonalcoholic steatoheaptitis: a promising new agent.  Gastroenterology. 2000;  118 A973
• 164 Abdelmalek M, Angulo P, Jorgensen R A. et al . Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study.  Am J Gastroenterol. 2001;  96 2711-2717
• 165 Miglio F, Rovati L C, Santoro A. et al . Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study.  Arzneimittelforschung. 2000;  50 722-727
• 166 Barak A J, Beckenhauer H C, Junnila M. et al . Dietary betaine promotes generation of hepatitic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration.  Alcohol Clin Exp Res. 1993;  17 552-555
• 167 Gulbahar O, Karasu Z A, Ersoz G. et al . Treatment of nonalcoholic steatohepatitis with N-acetylcysteine.  Gastroenterology. 2000;  118 A1444
• 168 Hasegawa T, Yoneda M, Nakamura K. et al . Long- and short-term d-alpha-tocopherol supplementation inhibits liver collagen alpha-1(I) gene expression.  Hepatology. 1997;  26 250A
• 169 Lavine J E. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study.  Pediatr. 2000;  136 734-738
• 170 Freund H R, Muggia-Sullam M, LaFrance R. et al . A possible benficial effect of metronidazole in reducing TPN-associated liver function derangements.  J Surg Res. 1985;  38 356-363
• 171 Younossi Z M, Gramlich T, Bacon B R. et al . Hepatic iron and nonalcoholic fatty liver disease.  Hepatology. 1999;  30 847-850
• 172 Desai T K. Phlebotomy reduces transaminase levels in patients with non-alcoholic steatohepatitis.  Gastroenterology. 2000;  118 A975
• 173 Nitecki J, Jackson F W, Allen M L. et al . Effect of phlebotomy on non-alcoholic steatohepatitis (NASH).  Gastroenterology. 2000;  118 A1474
• 174 Cauble M S, Gilroy R, Sorrell M F. et al . Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation.  Transplantation. 2001;  71 892-895
• 175 Contos M J, Cales W, Sterling R K. et al . Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis.  Liver Transpl. 2001;  7 363-373
• 176 Poucell S, Ireton J, Valencia-Mayoral P. et al . Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical and electron microscopic studies.  Gastroenterology. 1984;  86 926-936
• 177 Seki K, Minami Y, Nishikawa M. et al . Nonalcoholic steatohepatitis induced by massive doses of synthetic estrogen.  Gastroenterol Jpn. 1983;  18 197-203
• 178 Pessayre D, Bichara M, Degott C. et al . Perhexiline maleate-induced cirrhosis.  Gastroenterology. 1979;  76 170-177
• 179 Babany G, Uzzan F, Larrey D. et al . Alcoholic-like liver lesions induced by nifedipine.  J Hepatol. 1989;  9 252-255
• 180 Itoh S, Igarashi M, Tsukada Y. et al . Nonalcoholic fatty liver with alcoholic hyalin after long term glucocorticoid therapy.  Acta Hepatogastroenterol. 1977;  24 415-418
• 181 Tarugi P, Lonardo A, Ballarini G. et al . Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B.  Gastroenterology. 1996;  111 1125-1133
• 182 Tilg H, Diehl A M. Cytokines in alcoholic and nonalcoholic steatohepatitis.  N Engl J Med. 2000;  343 1467-1476
• 183 Kimura H, Kako M, Yo K, Oda T. Alcoholic hyalins (Mallory bodies) in a case of Weber-Christian disease: electron microscopic observations of liver involvement.  Gastroenterology. 1980;  78 807-812
• 184 Partin J S, Partin J C, Schubert W K. et al . Liver ultrastructure in abetalipoproteinemia: evolution of micronodular cirrhosis.  Gastroenterology. 1974;  67 107-118
• 185 Pratt D S, Knox T A, Erban J. Tamoxifen-induced steatohepatitis.  Annals of Internal Medicine. 1995;  123 236
• 186 Reid A E. Nonalcoholic steatohepatitis.  Gastroenterology. 2001;  121 710-723
• 187 Berson A, DeBeco V, Letteron P. et al . Steatohepatitis-induced drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes.  Gastroenterology. 1998;  114 764-774
• 188 Abdelmalek M, Ludwig M, Lindor K D. Two cases from the spectrum of nonalcoholic steatohepatitis.  J Clin Gastroenterol. 1995;  20 127-130
• 189 Brunt E M. Nonalcoholic steatohepatitis: definition and pathology.  Semin Liver Dis. 2001;  21 3-16