The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology

Podcast interview: . Also available on iTunes. These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines;1Eddy D.M. A manual for assessing health practices and designing practice guidelines.in: American College of Physicians, Philadelphia1996: 1-126Google Scholar (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1) .2Guyatt G.H. Oxman A.D. Vist G.E. Kunz R. Falck-Ytter Y. Alonso-Coello P. Schunemann H.J. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C).2Guyatt G.H. Oxman A.D. Vist G.E. Kunz R. Falck-Ytter Y. Alonso-Coello P. Schunemann H.J. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.3Vuppalanchi R. Chalasani N. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis: selected practical issues in their management.Hepatology. 2009; 49: 306-317Crossref PubMed Scopus (0) Google Scholar, 4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar, 5Neuschwander-Tetri B.A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.Hepatology. 2010; 52: 774-788Crossref PubMed Scopus (627) Google Scholar, 6Targher G. Day C.P. Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.N Engl J Med. 2010; 363: 1341-1350Crossref PubMed Scopus (1259) Google Scholar, 7Gambino R. Cassader M. Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.Annals of Medicine. 2011; 43 (G): 617-649Crossref PubMed Scopus (0) Google Scholar, 8Musso G. Gambino R. Cassader M. Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease.Hepatology. 2010; 52: 79-104Crossref PubMed Scopus (415) Google ScholarTable 1Grading of Recommendations, Assessment, Development and Evaluation (GRADE)CriteriaStrength of Recommendation Strong [1]Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost Weak [2]Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumptionQuality of Evidence High [A]Further research is unlikely to change confidence in the estimate of the clinical effect Moderate [B]Further research may change confidence in the estimate of the clinical effect Low [C]Further research is very likely to impact confidence on the estimate of clinical effect Open table in a new tab The definition of nonalcoholic fatty liver disease (NAFLD) requires that (a) there is evidence of hepatic steatosis, either by imaging or by histology and (b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders (Table 2) . In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) (Table 3) . NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis.Table 2Common Causes of Secondary Hepatic Steatosis- Macrovesicular steatosis - Excessive alcohol consumption - Hepatitis C (genotype 3) - Wilson's disease - Lipodystrophy - Starvation - Parenteral nutrition - Abetalipoproteinemia - Medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids)- Microvesicular steatosis - Reye's syndrome - Medications (valproate, anti-retroviral medicines) - Acute fatty liver of pregnancy - HELLP syndrome - Inborn errors of metabolism (e.g., LCAT deficiency, cholesterol ester storage disease, Wolman disease) Open table in a new tab Table 3Nonalcoholic Fatty Liver Disease and Related DefinitionsNonalcoholic Fatty Liver Disease (NAFLD)Encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from fatty liver to steatohepatitis and cirrhosis.Nonalcoholic Fatty Liver (NAFL)Presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes or no evidence of fibrosis. The risk of progression to cirrhosis and liver failure is minimal.Nonalcoholic steatohepatitis (NASH)Presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. This can progress to cirrhosis, liver failure and rarely liver cancer.NASH CirrhosisPresence of cirrhosis with current or previous histological evidence of steatosis or steatohepatitisCryptogenic CirrhosisPresence of cirrhosis with no obvious etiology. Patients with cryptogenic cirrhosis are heavily enriched with metabolic risk factors such as obesity and metabolic syndrome.NAFLD Activity Score (NAS)An unweighted composite of steatosis, inflammation, and ballooning scores. It is a useful tool to measure changes in liver histology in patients with NAFLD in clinical trials. Open table in a new tab The incidence of NAFLD has been investigated in a limited number of studies. Two Japanese studies9Suzuki A. Angulo P. Lymp J. St Sauver J. Muto A. Okada T. Lindor K. Chronological development of elevated aminotransferases in a nonalcoholic population.Hepatology. 2005; 41: 64-71Crossref PubMed Scopus (0) Google Scholar, 10Hamaguchi M. Kojima T. Takeda N. et al.The metabolic syndrome as a predictor of non-alcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Google Scholar reported an incidence rate of 31 and 86 cases of suspected NAFLD per 1,000 person-years respectively, whereas another study from England showed a much lower incidence rate of 29 cases per 100,000 person-years.11Whalley S. Puvanachandra P. Desai A. Kennedy H. Hepatology outpatient service provision in secondary care: a study of liver disease incidence and resource costs.Clin Med. 2007; 7: 119-124Crossref PubMed Google Scholar More studies are needed to better understand the incidence of NAFLD across different age, ethnic, and geographic groups. The reported prevalence of NAFLD varies widely depending on the population studied and the definition used. The prevalence of histologically-defined NAFLD was 20% and 51% in two different studies comprised of potential living liver donors.12Lee J.Y. Kim K.M. Lee S.G. Yu E. Lim Y.S. Lee H.C. Chung Y.H. Lee Y.S. Suh D.J. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center.J Hepatol. 2007; 47: 239-244Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 13Marcos A. Fischer R.A. Ham J.M. Olzinski A.T. Shiffman M.L. Sanyal A.J. Luketic V.A. Sterling R.K. Olbrisch M.E. Posner M.P. Transplantation. 2000; 69: 2410-2415Crossref PubMed Google Scholar The reported prevalence of NAFLD when defined by liver ultrasound ranged between 17% and 46% depending on the population studied.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar In a study consisting of nearly 400 middle aged individuals, the prevalence of NAFLD defined by ultrasonography was 46% and the prevalence of histologically confirmed NASH was 12.2%.14Williams C.D. Stenger J. Asike M.I. Torres D.M. Shaw J. Contreras M. Landt C.L. Harrison S.A. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.Gastroenterology. 2011; 140: 124-131Abstract Full Text Full Text PDF PubMed Scopus (1388) Google Scholar In the Dallas Heart Study, when assessed by MR spectroscopy the prevalence of NAFLD in the general population was 31%.15Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2727) Google Scholar The prevalence of suspected NAFLD when estimated using aminotransferases alone without imaging or histology ranged between 7% and 11%, but aminotransferases can be normal in individuals with NAFLD.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar In summary, estimates of the worldwide prevalence of NAFLD ranges from 6.3% to 33% with a median of 20% in the general population, based on a variety of assessment methods.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar On the other hand, the estimated prevalence of NASH is lower, ranging from 3 to 5%.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar The prevalence of NASH cirrhosis in the general population is not known. Obesity is a common and well documented risk factor for NAFLD. Both excessive BMI and visceral obesity are recognized risk factors for NAFLD. In patients with severe obesity undergoing bariatric surgery, the prevalence of NAFLD can exceed 90% and up to 5% of patients may have unsuspected cirrhosis.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar, 16Boza C. Riquelme A. Ibañez L. Duarte I. Norero E. Viviani P. Soza A. Fernandez J.I. Raddatz A. Guzman S. Arrese M. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass.Obes Surg. 2005; 15: 1148-1153Crossref PubMed Scopus (99) Google Scholar, 17Haentjens P. Massaad D. Reynaert H. Peeters E. Van Meerhaeghe A. Vinken S. Poppe K. Velkeniers B. Identifying non-alcoholic fatty liver disease among asymptomatic overweight and obese individuals by clinical and biochemical characteristics.Acta Clin Belg. 2009; 64: 483-493Crossref PubMed Scopus (24) Google Scholar, 18Machado M. Marques-Vidal P. Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery.J Hepatol. 2006; 45: 600-606Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 19Colicchio P. Tarantino G. del Genio F. Sorrentino P. Saldalamacchia G. Finelli C. Conca P. Contaldo F. Pasanisi F. Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy.Ann Nutr Metab. 2005; 49: 289-295Crossref PubMed Scopus (0) Google Scholar, 20Beymer C. Kowdley K.V. Larson A. Edmonson P. Dellinger E.P. Flum D.R. Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery.Arch Surg. 2003; 138: 1240-1244Crossref PubMed Scopus (143) Google Scholar There is a very high prevalence of NAFLD in individuals with type 2 diabetes mellitus (T2DM).4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar An ultrasonographic study of patients with T2DM showed a 69% prevalence of NAFLD.21Leite N.C. Salles G.F. Araujo A.L. Villela-Nogueira C.A. Cardoso C.R. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus.Liver Int. 2009; 29: 113-119Crossref PubMed Scopus (332) Google Scholar In another study, 127 of 204 diabetic patients displayed fatty infiltration on ultrasound, and 87% of the patients with fatty infiltration who consented to biopsy had histologic confirmation of NAFLD.22Prashanth M. Ganesh H.K. Vima M.V. John M. Bandgar T. Joshi S.R. Shah S.R. Rathi P.M. Joshi A.S. Thakkar H. Menon P.S. Shah N.S. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus.J Assoc Physicians India. 2009; 57: 205-210PubMed Google Scholar High serum triglyceride levels and low serum HDL levels are very common in patients with NAFLD. The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics was estimated to be 50%.23Assy N. Kaita K. Mymin D. Levy C. Rosser B. Minuk G. Fatty infiltration of liver in hyperlipidemic patients.Dig Dis Sci. 2000; 45: 1929-1934Crossref PubMed Scopus (285) Google ScholarTable 4Risk Factors Associated with NAFLDConditions with established associationConditions with emerging association⁎Few studies suggested that individuals with type1 diabetes have increased prevalence of hepatic steatosis based on liver imaging, but there is limited histological evidence.ObesityPolycystic ovary syndromeType 2 diabetes mellitusHypothyroidismDyslipidemiaObstructive Sleep apneaMetabolic syndrome⁎⁎The Adult Treatment Panel III clinical definition of the metabolic syndrome requires the presence of three or more of the following features: (1) waist circumference greater than 102 cm in men or greater than 88 cm in women; (2) triglyceride level 150 mg/dL or greater; (3) high-density lipoprotein (HDL) cholesterol level less than 40 mg/dL in men and less than 50 mg/dL in women; (4) systolic blood pressure 130 mm Hg or greater or diastolic pressure 85 mm Hg or greater; and (5) fasting plasma glucose level 110 mg/dL or greater.198HypopituitarismHypogonadismPancreato-duodenal resection Few studies suggested that individuals with type1 diabetes have increased prevalence of hepatic steatosis based on liver imaging, but there is limited histological evidence. The Adult Treatment Panel III clinical definition of the metabolic syndrome requires the presence of three or more of the following features: (1) waist circumference greater than 102 cm in men or greater than 88 cm in women; (2) triglyceride level 150 mg/dL or greater; (3) high-density lipoprotein (HDL) cholesterol level less than 40 mg/dL in men and less than 50 mg/dL in women; (4) systolic blood pressure 130 mm Hg or greater or diastolic pressure 85 mm Hg or greater; and (5) fasting plasma glucose level 110 mg/dL or greater.198Grundy S.M. Cleeman J.I. Daniels S.R. Donato K.A. Eckel R.H. Franklin B.A. Gordon D.J. Krauss R.M. Savage P.J. Smith Jr, S.C. Spertus J.A. Costa F. American Heart AssociationNational Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.Circulation. 2005 Oct 25; 112: 2735-2752Crossref PubMed Scopus (8159) Google Scholar Open table in a new tab Age, gender and ethnicity are also associated with a differential prevalence for NAFLD.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar A number of studies have shown that the prevalence of NAFLD increases with age.24Li H. Wang Y.J. Tan K. Zeng L. Liu L. Liu F.J. Zhou T.Y. Chen E.Q. Tang H. Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China.Hepatobiliary Pancreat Dis Int. 2009; 8: 377-382PubMed Google Scholar, 25Amarapurkar D. Kamani P. Patel N. Gupte P. Kumar P. Agal S. Baijal R. Lala S. Chaudhary D. Deshpande A. Prevalence of non-alcoholic fatty liver disease: population based study.Ann Hepatol. 2007; 6: 161-163Crossref PubMed Google Scholar, 26Park S.H. Jeon W.K. Kim S.H. Kim H.J. Park D.I. Cho Y.K. Sung I.K. Sohn C.I. Keum D.K. Kim B.I. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults.J Gastroenterol Hepatol. 2006; 21: 138-143Crossref PubMed Scopus (236) Google Scholar, 27Frith J. Day C.P. Henderson E. Burt A.D. Newton J.L. Non-alcoholic fatty liver disease in older people.Gerontology. 2009; 55: 607-613Crossref PubMed Scopus (130) Google Scholar, 28Chen C.H. Huang M.H. Yang J.C. Nien C.K. Yang C.C. Yeh Y.H. Yueh S.K. Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan.J Gastroenterol Hepatol. 2007; 22: 1482-1489Crossref PubMed Scopus (110) Google Scholar The likelihood of disease progression to advanced fibrosis or mortality increases in older patients with NAFLD.29Ong J.P. Pitts A. Younossi Z.M. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease.J Hepatol. 2008; 49: 608-612Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 30Hashimoto E. Yatsuji S. Kaneda H. Yoshioka Y. Taniai M. Tokushige K. Shiratori K. The characteristics and natural history of Japanese patients with nonalcoholic fatty liver disease.Hepatol Res. 2005; 33: 72-76Crossref PubMed Scopus (0) Google Scholar, 31Adams L.A. Lymp J.F. St Sauver J. Sanderson S.O. Lindor K.D. Feldstein A. Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (2085) Google Scholar Many recent studies have reported that male gender is a risk factor for fatty liver disease.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar For example, in a study of 26,527 subjects undergoing medical checkups, the prevalence of NAFLD was 31% in men and 16% in women.32Chen Z.W. Chen L.Y. Dai H.L. Chen J.H. Fang L.Z. Relationship between alanine aminotransferase levels and metabolic syndrome in nonalcoholic fatty liver disease.J Zhejiang Univ Sci B. 2008; 9: 616-622Crossref PubMed Scopus (0) Google Scholar Compared to non-Hispanic whites, Hispanic individuals have significantly higher and non-Hispanic blacks have significantly lower prevalence of NAFLD.15Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2727) Google Scholar, 33Clark J.M. Brancati F.L. Diehl A.M. The prevalence and etiology of elevated aminotransferase levels in the United States.Am J Gastroenterol. 2003; 98: 960-967Crossref PubMed Scopus (1037) Google Scholar, 34Kallwitz E.R. Kumar M. Aggarwal R. Berger R. Layden-Almer J. Gupta N. Cotler S.J. Ethnicity and nonalcoholic fatty liver disease in an obesity clinic: the impact of triglycerides.Dig Dis Sci. 2008; 53: 1358-1363Crossref PubMed Scopus (0) Google Scholar, 35Wagenknecht L.E. Scherzinger A.L. Stamm E.R. Hanley A.J. Norris J.M. Chen Y.D. Bryer-Ash M. Haffner S.M. Rotter J.I. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort.Obesity. 2009; 17: 1240-1246Crossref PubMed Scopus (0) Google Scholar The prevalence of NAFLD in American-Indian and Alaskan-Native populations appears lower, ranging from 0.6% to 2.2%, although the lack of histologic definition makes it likely that is an underestimate.36Fischer G.E. Bialek S.P. Homan C.E. Livingston S.E. McMahon B.J. Chronic liver disease among Alaska-Native people, 2003–2004.Am J Gastroenterol. 2009; 104: 363-370Crossref PubMed Scopus (0) Google Scholar, 37Bialek S.R. Redd J.T. Lynch A. Vogt T. Lewis S. Wilson C. Bell B.P. Chronic liver disease among two American Indian patient populations in the southwestern United States, 2000–2003.J Clin Gastroenterol. 2008; 42: 949-954Crossref PubMed Scopus (0) Google Scholar There are data to suggest that hypothyroidism, hypopituitarism, hypogonadism, sleep apnea, and polycystic ovary syndrome independent of obesity are important risk factors for the presence of NAFLD (Table 4).3Vuppalanchi R. Chalasani N. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis: selected practical issues in their management.Hepatology. 2009; 49: 306-317Crossref PubMed Scopus (0) Google Scholar The evolution of hepatic histologic changes in patients with NAFL and NASH has been investigated by several studies, but these generally included smaller number of patients and had relatively modest duration of follow-up.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar, 7Gambino R. Cassader M. Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.Annals of Medicine. 2011; 43 (G): 617-649Crossref PubMed Scopus (0) Google Scholar Nonetheless, it is generally agreed that patients with simple steatosis have very slow, if any, histological progression, while patients with NASH can exhibit histological progression to cirrhotic-stage disease.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar, 7Gambino R. Cassader M. Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.Annals of Medicine. 2011; 43 (G): 617-649Crossref PubMed Scopus (0) Google Scholar The long term outcomes of patients with NAFLD and NASH have been reported in several studies.31Adams L.A. Lymp J.F. St Sauver J. Sanderson S.O. Lindor K.D. Feldstein A. Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (2085) Google Scholar, 38Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999 Jun; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2648) Google Scholar, 39Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sørensen T.I. Becker U. Bendtsen F. Long term prognosis of fatty liver: risk of chronic liver disease and death.Gut. 2004 May; 53: 750-755Crossref PubMed Scopus (403) Google Scholar, 40Ekstedt M. Franzén L.E. Mathiesen U.L. Thorelius L. Holmqvist M. Bodemar G. Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (1639) Google Scholar, 41Dunn W. Xu R. Wingard D. Rogers C. Angulo P. Younossi Z.M. Schwimmer J.B. Suspected Nonalcoholic Fatty Liver Disease and Mortality Risk in a Population-based Cohort Study.Am J of Gastroenterology. 2008; 103: 2263-2271Crossref PubMed Scopus (0) Google Scholar, 42Rafiq N. Bai C.H. Fang Y. Srishord M. McCullough A. Gramlich T. Younossi Z.M. Long-Term Follow-Up of Patients with Non-Alcoholic Fatty Liver.Clinical Gastro and Hepatology. 2009; 7: 234-238Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Dam-Larsen S. Becker U. Franzmann M.B. Larsen K. Christoffersen P. Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients.Scand J Gastroenterol. 2009; 44: 1236-1243Crossref PubMed Scopus (0) Google Scholar, 44Stepanova M. Rafiq N. Younossi Z.M. Components of metabolic syndrome as independent predictors of mortality in chronic liver disease: A population-based study.Gut. 2010; 59: 1410-1415Crossref PubMed Scopus (0) Google Scholar, 45Söderberg C. Stål P. Askling J. Glaumann H. Lindberg G. Marmur J. Hultcrantz R. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up.Hepatology. 2010; 51: 595-602Crossref PubMed Scopus (527) Google Scholar Their detailed discussion is beyond the scope of this guideline, but their findings can be summarized as follows; (a) patients with NAFLD have increased overall mortality compared to matched control populations, (b) the most common cause of death in patients with NAFLD, NAFL and NASH is cardiovascular disease, and (c) patients with NASH (but not NAFL) have an increased liver-related mortality rate. Another piece of indirect evidence that supports the progressive nature of NASH is in the features of cryptogenic cirrhosis which is closely related to NAFLD.46Caldwell S.H. Crespo D.M. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.J Hepatol. 2004; 40: 578-584Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 47Browning J.D. Kumar K.S. Saboorian M.H. Thiele D.L. Ethnic differences in the prevalence of cryptogenic cirrhosis.Am J Gastroenterol. 2004; 99: 292-298Crossref PubMed Scopus (177) Google Scholar Patients with cryptogenic cirrhosis have disproportionately high prevalence of metabolic risk factors (T2DM, obesity, metabolic syndrome) typical of patients with NAFLD, their liver biopsies frequently show one or more features of NASH, and studies have demonstrated the loss of histological features of NASH with the development of cirrhosis.4Vernon G. Baranova A. Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther. 2011; 34: 274-285Crossref PubMed Scopus (1984) Google Scholar, 7Gambino R. Cassader M. Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.Annals of Medicine. 2011; 43 (G): 617-649Crossref PubMed Scopus (0) Google Scholar, 46Caldwell S.H. Crespo D.M. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.J Hepatol. 2004; 40: 578-584Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 47Browning J.D. Kumar K.S. Saboorian M.H. Thiele D.L. Ethnic differences in the prevalence of cryptogenic cirrhosis.Am J Gastroenterol. 2004; 99: 292-298Crossref PubMed Scopus (177) Google Scholar Patients with NAFLD are at increased risk for HCC, but this risk is likely limited to those with advanced fibrosis and cirrhosis.48Bugianesi E. Leone N. Vanni E. Marchesini G. Brunello F. Carucci P. Musso A. De Paolis P. Capussotti L. Salizzoni M. Rizzetto M. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1211) Google Scholar, 49Hashimoto E. Yatsuji S. Tobari M. Taniai M. Torii N. Tokushige K. Shiratori K. hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.J Gastroenterol. 2009; 44: 89-95Crossref PubMed Scopus (215) Google Scholar, 50Smedile A. Bugianesi E. Steatosis and hepatocellular carcinoma risk.Eur Rev Med Pharmacol Sci. 2005; 9: 291-293PubMed Google Scholar, 51Takuma Y. Nouso K. Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our