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Summary of an AASLD Single Topic Conference SPECIAL ARTICLE Nonalcoholic Steatohepatitis: Summary of an AASLD Single Topic Conference Brent A. Neuschwander-Tetri and Stephen H. Caldwell Fatty liver disease that develops in the absence of alcohol abuse is recognized increasingly as a major health burden. This report summarizes the presentations and discussions at a Single Topic Conference held September 20-22, 2002, and sponsored by the American Association for the Study of Liver Diseases. The conference focused on fatty liver disorders. Estimates based on imaging and autopsy studies suggest that about 20% to 30% of adults in the United States and other Western countries have excess fat accumulation in the liver. About 10% of these individ- uals, or fully 2% to 3% of adults, are estimated to meet current diagnostic criteria for nonalco- holic steatohepatitis (NASH). Sustained liver injury leads to progressive fibrosis and cirrhosis in a fraction, possibly up to one third, of those with NASH, and NASH may be a cause of crypto- genic cirrhosis. NASH is now a significant health issue for obese children as well, leading to cirrhosis in some. The diagnostic criteria for NASH continue to evolve and rely on the histologic findings of steatosis, hepatocellular injury (ballooning, Mallory bodies), and the pattern of fibrosis. Generally recognized indications for biopsy include establishing the diagnosis and staging of the injury, but strict guidelines do not exist. Liver enzymes are insensitive and cannot be used reliably to confirm the diagnosis or stage the extent of fibrosis. Older age, obesity, and diabetes are predictive of fibrosis. The pathogenesis of NASH is multifactorial. Insulin resistance may be an important factor in the accumulation of hepatocellular fat, whereas excess intracellular fatty acids, oxidant stress, adenosine triphosphate (ATP) depletion, and mitochondrial dysfunc- tion may be important causes of hepatocellular injury in the steatotic liver. Efforts are underway to refine the role of insulin resistance in NASH and determine whether improving insulin sensitivity pharmacologically is an effective treatment. An altered lifestyle may be a more effective means of improving insulin sensitivity. The research agenda for the future includes establishing the role of insulin resistance and abnormal lipoprotein metabolism in NASH, determining the pathogenesis of cellular injury, defining predisposing genetic abnormalities, identifying better noninvasive predictors of disease, and defining effective therapy. (HEPATOLOGY 2003;37: 1202-1219.) he following is a summary of talks presented at Atlanta, Georgia on September 20-22, 2002. The syllabus the American Association for the Study of Liver and lecture materials prepared by the conference’s 25 pre- TDiseases (AASLD) Clinical Single Topic Confer- senters form the basis of this summary. As course organiz- ence on Nonalcoholic Steatohepatitis (NASH) held in ers, the authors of this summary would like to acknowledge the presenters for their substantial contribu- Abbreviations: AASLD, American Association for the Study of Liver Diseases; tions. These individuals are listed in the Appendix. NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; AST, The objectives of AASLD Single Topic Conferences aspartate aminotransferase; ALT, alanine aminotransferase; IRS-1, insulin receptor are to bring together researchers and practitioners with a substrate 1; TNF-␣, tumor necrosis factor ␣, VLDL, very low density lipoprotein; apoE, apolipoprotein E; MTTP, microsomal triglyceride transfer protein; SREBP, focused interest in a specific area of liver disease to review sterol regulatory element binding protein; ATP, adenosine triphosphate; UCP, un- current thinking and identify areas needing further dis- coupling protein. covery. The objective of this particular conference was to From the Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO and the Division of GI/Hepatology, University bring together active clinical and basic science researchers of Virginia Health Sciences Center, Charlottesville, VA. in the field of fatty liver disease to critically analyze the Received December 12, 2002; accepted February 21, 2003. latest developments and share ideas with respect to patho- Address reprint requests to: Brent A. Neuschwander-Tetri, M.D., Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, 3635 genesis, diagnosis, and treatment. A focus of the meeting Vista Ave., St. Louis, MO 63110. E-mail: [email protected]; fax: 314-577-8125. was the role of insulin resistance and hyperinsulinemia in Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3705-0031$30.00/0 the pathogenesis of nonalcoholic fatty liver disease doi:10.1053/jhep.2003.50193 (NAFLD) and NASH. Because of the focused nature of 1202 HEPATOLOGY, Vol. 37, No. 5, 2003 NEUSCHWANDER-TETRI AND CALDWELL 1203 the conference, many key aspects of fatty liver disease Table 1. Histopathologic Abnormalities in NASH could not be discussed in depth. The purpose of this re- Necessary components port is to provide an overview of the conference and not Steatosis, macro Ͼ micro; accentuated in zone 3 Mixed, mild lobular inflammation; scattered polymorphonuclear leukocytes as summarize all aspects of NAFLD and NASH. well as mononuclear cells Hepatocellular ballooning; most apparent near steatotic liver cells, typically in Defining NAFLD, NASH, and the Meaning of zone 3 “Nonalcoholic” Usually present; but not necessary for diagnosis Zone 3 perisinusoidal fibrosis The term NASH, coined by Ludwig et al.1 in 1980 to Zone 1 hepatocellular glycogenated nuclei describe the biopsy findings in patients with steatohepa- Lipogranulomas in the lobules; of varying size, but usually small Occasional acidophil bodies or periodic acid-Schiff–stained Kupffer cells titis in the absence of significant alcohol consumption, Fat cysts has served the field well by bringing attention to this May be present but not necessary for diagnosis entity and promoting further research. However, this in- Mallory’s hyaline in ballooned hepatocytes Usually zone 3 in NASH, may be zone 1 in diabetes, amiodarone clusive term has become problematic because it requires a Typically poorly formed, may require immunostaining for ubiquitin, p62, or pathologist to make a clinical statement about alcohol cytokeratins 7, 18, 19 to confirm consumption. As recently proposed,2,3 an alternative Mild (1ϩ) granular periportal (zone 1) hepatocellular iron or scattered iron name—metabolic steatohepatitis—was discussed but not granules in sinusoidal lining cells (best detected by Prussian blue stain) uniformly accepted. Another alternative under consider- Megamitochondria in hepatocytes ation by pathologists is to further simplify the nomencla- Unusual for NASH; recommend consideration of other causes of liver test ture by reporting only steatohepatitis using specific abnormalities Macrovesicular steatosis: Ͻ30% of parenchyma involved or nonzonal criteria (see later) and leaving it up to the clinicians to distribution assign causality and risk factors. Purely or predominantly microvesicular steatosis NAFLD is defined currently as fat accumulation in the Sclerosing hyaline necrosis, veno-occlusive lesions, perivenular fibrosis, phlebosclerosis liver exceeding 5% to 10% by weight, but it is estimated Portal inflammation greater than lobular inflammation, lymphoid aggregates, practically as the percentage of fat-laden hepatocytes ob- numerous plasma cells served by light microscopy.4 Whether NAFLD with the Significant eosinophils in portal or lobular inflammation; epithelioid minimum amount of fat is truly a disease, hence the D in granulomata Portal/periportal fibrosis in absence of, or markedly greater than, zone 3 the acronym, or simply a benign condition, was debated. perisinusoidal fibrosis; portal-based bridging fibrosis without concurrent Progression to cirrhosis is rare in mild NAFLD, yet pro- perisinusoidal fibrosis gression has been observed and any amount of fat may Lobular disarray, marked inflammation or confluent or bridging necrosis, endophlebitis sensitize the liver to injury from other causes. Clearly, Acute cholestasis: bile plugs there is wide agreement on the need for a consensus re- Chronic cholestasis ϩ/Ϫ bile duct lesions (florid duct lesions), bile duct garding the precise criteria for classifying, grading, and loss, ductular proliferation; copper granules in periportal hepatocytes Periodic acid-Schiff–stained globules (␣1AT) in periportal hepatocytes staging histologic injury in these disorders collectively Significant granular iron in hepatocytes ϩ/Ϫ zone 1 to zone 3 gradient known as NAFLD (see later). Inherent to defining NAFLD and NASH is the thresh- old at which steatohepatitis becomes alcohol related. This injury) and NASH as its more extreme forms. How is not a sharply demarcated distinction. Many centers NASH is best defined remains unsettled because there is accept up to 14 to 28 units of ethanol per week (up to significant diversity of opinion among expert pathologists 20-40 g/d in men and 20 g/d in women) whereas other regarding the necessity and character of specific findings. investigators have used a cut-off level of 7 units/wk (10 These include the amount and types of fat (macrovesicu- g/d) or less. One report has suggested that limited alcohol lar and microvesicular), lobular inflammation (acute intake is protective against NASH (as well as diabetes).5 and/or chronic), and fibrosis (zone 3 and portal). In ad-
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