A position statement on NAFLD/NASH based on the EASL 2009 special conference
Authors: Vlad Ratziu, Stefano Bellentani, Helena Cortez-Pinto, Chris Day, Giulio Marchesini
Journal: Journal of Hepatology (2010)

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are increasingly relevant public health issues owing to their close association with the worldwide epidemics of diabetes and obesity. NAFLD/NASH is one of the most common chronic liver diseases and increases the 5-year direct and indirect health care costs by an estimated 26% [[1]Baumeister S.E. Volzke H. Marschall P. John U. Schmidt C.O. Flessa S. et al.Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation.Gastroenterology. 2008; 134: 85-94Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Although evidence-based clinical practice guidelines for this condition are badly needed, currently not enough evidence is available to formulate guidelines in an unbiased, responsible, and unequivocal way. This position statement summarizes the proceedings of the 2009 EASL Special Conference on NAFLD/NASH and proposes expert opinion for different aspects of the clinical care of these patients. NAFLD designates a condition characterized by excessive fat accumulation (steatosis). NASH defines a subgroup of NAFLD where steatosis coexists with liver-cell injury and inflammation (steatohepatitis). Primary NAFLD/NASH is associated with insulin resistance (IR) and its phenotypic manifestations. Secondary NAFLD/NASH is rare in adults, is unrelated to insulin resistance or the metabolic syndrome, and is due to a number of medical or surgical conditions or drug intake. Historically, primary NAFLD/NASH required the exclusion of other causes of liver disease (viral, autoimmune, genetic, etc.) and a daily alcohol consumption ⩽20 g in women and 30 g in men, based on epidemiological studies showing that alcohol-induced steatosis can occur above these thresholds [[2]Bellentani S. Saccoccio G. Masutti F. Croce L.S. Brandi G. Sasso F. et al.Prevalence of and risk factors for hepatic steatosis in Northern Italy.Ann Intern Med. 2000; 132: 112-117Crossref PubMed Google Scholar]. Owing to its increasing prevalence and strong association with the metabolic syndrome [[3]Marchesini G. Brizi M. Bianchi G. Tomassetti S. Bugianesi E. Lenzi M. et al.Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.Diabetes. 2001; 50: 1844-1850Crossref PubMed Google Scholar], it is now recognized that NAFLD/NASH can occur together with other chronic liver diseases and that in some cases (chronic hepatitis C [[4]Moucari R. Asselah T. Cazals-Hatem D. Voitot H. Boyer N. Ripault M.P. et al.Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis.Gastroenterology. 2008; 134: 416-423Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar], hemochromatosis [[5]Powell E.E. Ali A. Clouston A.D. Dixon J.L. Lincoln D.J. Purdie D.M. et al.Steatosis is a cofactor in liver injury in hemochromatosis.Gastroenterology. 2005; 129: 1937-1943Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], alcoholic liver disease [[6]Naveau S. Giraud V. Borotto E. Aubert A. Capron F. Chaput J.C. Excess weight is a risk factor for alcoholic liver disease.Hepatology. 1997; 25: 108-111Crossref PubMed Google Scholar]) this can exacerbate liver damage [[7]Powell E.E. Jonsson J.R. Clouston A.D. Steatosis: co-factor in other liver diseases.Hepatology. 2005; 42: 5-13Crossref PubMed Scopus (254) Google Scholar]. This strongly argues for a change in nomenclature (such as metabolic fatty liver disease and metabolic steatohepatitis) which would drop the "negative" definition of "nonalcoholic" and would recognize the likely causal role of IR in NAFLD/NASH. The prevalence of NAFLD in the general population assessed by ultrasonography is 20–30% in Europe [8Bedogni G. Miglioli L. Masutti F. Tiribelli C. Marchesini G. Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study.Hepatology. 2005; 42: 44-52Crossref PubMed Scopus (529) Google Scholar, 9Lonardo A. Bellini M. Tartoni P. Tondelli E. The bright liver syndrome. Prevalence and determinants of a "bright" liver echopattern.Ital J Gastroenterol Hepatol. 1997; 29: 351-356PubMed Google Scholar] and the Middle East [[10]Zelber-Sagi S. Nitzan-Kaluski D. Halpern Z. Oren R. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures.Liver Int. 2006; 26: 856-863Crossref PubMed Scopus (97) Google Scholar], 15% in the Far East [11Fan J.G. Zhu J. Li X.J. Chen L. Li L. Dai F. et al.Prevalence of and risk factors for fatty liver in a general population of Shanghai, China.J Hepatol. 2005; 43: 508-514Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 12Nomura H. Kashiwagi S. Hayashi J. Kajiyama W. Tani S. Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan.Jpn J Med. 1988; 27: 142-149Crossref PubMed Google Scholar], and 16% in some studies of normal weight subjects without metabolic risk factors [[2]Bellentani S. Saccoccio G. Masutti F. Croce L.S. Brandi G. Sasso F. et al.Prevalence of and risk factors for hepatic steatosis in Northern Italy.Ann Intern Med. 2000; 132: 112-117Crossref PubMed Google Scholar]. A similar prevalence of 15–25% was documented histologically by older, post-mortem studies [13Hilden M. Christoffersen P. Juhl E. Dalgaard J.B. Liver histology in a 'normal' population – examinations of 503 consecutive fatal traffic casualties.Scand J Gastroenterol. 1977; 12: 593-597Crossref PubMed Scopus (176) Google Scholar, 14Ground K.E. Liver pathology in aircrew.Aviat Space Environ Med. 1982; 53: 14-18PubMed Google Scholar]. A surprisingly high prevalence of histological NAFLD has been described in apparently healthy living liver donors: 12–18% in Europe [15Minervini M.I. Ruppert K. Fontes P. Volpes R. Vizzini G. de Vera M.E. et al.Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests.J Hepatol. 2009; 50: 501-510Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 16Nadalin S. Malago M. Valentin-Gamazo C. Testa G. Baba H.A. Liu C. et al.Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits.Liver Transpl. 2005; 11: 980-986Crossref PubMed Scopus (57) Google Scholar] and 27–38% in the US [15Minervini M.I. Ruppert K. Fontes P. Volpes R. Vizzini G. de Vera M.E. et al.Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests.J Hepatol. 2009; 50: 501-510Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 17Ryan C.K. Johnson L.A. Germin B.I. Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation.Liver Transpl. 2002; 8: 1114-1122Crossref PubMed Scopus (149) Google Scholar, 18Tran T.T. Changsri C. Shackleton C.R. Poordad F.F. Nissen N.N. Colquhoun S. et al.Living donor liver transplantation: histological abnormalities found on liver biopsies of apparently healthy potential donors.J Gastroenterol Hepatol. 2006; 21: 381-383Crossref PubMed Scopus (40) Google Scholar]. With sensitive technique such as MR spectroscopy, 34% of US adults have NAFLD [[19]Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (1492) Google Scholar]. Interestingly, 39% of newly identified cases of chronic liver disease in a US survey had NAFLD [[20]Weston S.R. Leyden W. Murphy R. Bass N.M. Bell B.P. Manos M.M. et al.Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease.Hepatology. 2005; 41: 372-379Crossref PubMed Scopus (195) Google Scholar] which makes NAFLD/NASH one of the top causes of liver disease in Western countries. Recent studies in tertiary-care centers, using current histological definitions, have shown a surprisingly high prevalence of NASH among NAFLD cases: 43–55% in patients with increased aminotransferases [21de Ledinghen V. Ratziu V. Causse X. Le Bail B. Capron D. Renou C. et al.Diagnostic and predictive factors of significant liver fibrosis and minimal lesions in patients with persistent unexplained elevated transaminases: a prospective multicenter study.J Hepatol. 2006; 45: 592-599Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 22Soderberg C. Stal P. Askling J. Glaumann H. Lindberg G. Marmur J. et al.Decreased survival of subjects with elevated liver function tests during a 28-year follow-up.Hepatology. 2010; 51: 595-602Crossref PubMed Scopus (218) Google Scholar], as high as 49% in morbidly obese patients [23Campos G.M. Bambha K. Vittinghoff E. Rabl C. Posselt A.M. Ciovica R. et al.A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.Hepatology. 2008; 47: 1916-1923Crossref PubMed Scopus (61) Google Scholar, 24Machado M. Marques-Vidal P. Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery.J Hepatol. 2006; 45 (Epub 2006 Jul 25): 600-666Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar], and 67% in a subset of patients with incident chronic liver disease [[20]Weston S.R. Leyden W. Murphy R. Bass N.M. Bell B.P. Manos M.M. et al.Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease.Hepatology. 2005; 41: 372-379Crossref PubMed Scopus (195) Google Scholar]. In apparently healthy, living liver donors, the prevalence of NASH ranges from 3% to 16% in Europe [15Minervini M.I. Ruppert K. Fontes P. Volpes R. Vizzini G. de Vera M.E. et al.Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests.J Hepatol. 2009; 50: 501-510Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 16Nadalin S. Malago M. Valentin-Gamazo C. Testa G. Baba H.A. Liu C. et al.Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits.Liver Transpl. 2005; 11: 980-986Crossref PubMed Scopus (57) Google Scholar] and from 6% to 15% in the US [15Minervini M.I. Ruppert K. Fontes P. Volpes R. Vizzini G. de Vera M.E. et al.Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests.J Hepatol. 2009; 50: 501-510Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 17Ryan C.K. Johnson L.A. Germin B.I. Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation.Liver Transpl. 2002; 8: 1114-1122Crossref PubMed Scopus (149) Google Scholar, 18Tran T.T. Changsri C. Shackleton C.R. Poordad F.F. Nissen N.N. Colquhoun S. et al.Living donor liver transplantation: histological abnormalities found on liver biopsies of apparently healthy potential donors.J Gastroenterol Hepatol. 2006; 21: 381-383Crossref PubMed Scopus (40) Google Scholar]. The incidence of primary NAFLD in Italy was estimated at 2/100/year [[25]Bedogni G. Miglioli L. Masutti F. Castiglione A. Croce L.S. Tiribelli C. et al.Incidence and natural course of fatty liver in the general population: the Dionysos study.Hepatology (Baltimore, MD). 2007; 46: 1387-1391Crossref PubMed Scopus (55) Google Scholar]; a Japanese study in a selected population reported 10/100/year [[26]Hamaguchi M. Kojima T. Takeda N. Nakagawa T. Taniguchi H. Fujii K. et al.The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Google Scholar]. Secondary NASH due to tamoxifen use was estimated at 0.2/100 women/year [[27]Bruno S. Maisonneuve P. Castellana P. Rotmensz N. Rossi S. Maggioni M. et al.Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial.BMJ. 2005; 330: 932Crossref PubMed Scopus (83) Google Scholar]. The prevalence of NAFLD increases with age, is highest in males between 40 and 65 years [28el-Hassan A.Y. Ibrahim E.M. al-Mulhim F.A. Nabhan A.A. Chammas M.Y. Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and influence on patient management.Br J Radiol. 1992; 65: 774-778Crossref PubMed Google Scholar, 29Bacon B.R. Farahvash M.J. Janney C.G. Neuschwander-Tetri B.A. Nonalcoholic steatohepatitis: an expanded clinical entity.Gastroenterology. 1994; 107: 1103-1109Abstract PubMed Scopus (1019) Google Scholar, 30Powell E.E. Cooksley W.G. Hanson R. Searle J. Halliday R.W. Powell L.W. The natural history of nonalcoholic steatohepatitis: a follow-up study of 42 patients follow for up to 21 years.Hepatology (Baltimore, MD). 1990; 11: 74-80Crossref PubMed Google Scholar, 31Frith 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 (53) Google Scholar] and is higher in Hispanics and lower in African-Americans [19Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (1492) Google Scholar, 20Weston S.R. Leyden W. Murphy R. Bass N.M. Bell B.P. Manos M.M. et al.Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease.Hepatology. 2005; 41: 372-379Crossref PubMed Scopus (195) Google Scholar]. Family members of subjects with NAFLD are also at increased risk, independent of age and BMI [32Schwimmer J.B. Celedon M.A. Lavine J.E. Salem R. Campbell N. Schork N.J. et al.Heritability of nonalcoholic fatty liver disease.Gastroenterology. 2009; 136: 1585-1592Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 33Wagenknecht L.E. Scherzinger A.L. Stamm E.R. Hanley A.J. Norris J.M. Chen Y.D. et al.Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort.Obesity (Silver Spring). 2009; 17: 1240-1246PubMed Google Scholar]. The commonest cause of NAFLD/NASH is primary NAFLD, associated with IR and its phenotypic manifestations, mainly overweight/obesity, visceral adiposity, type 2 diabetes, hypertriglyceridemia and arterial hypertension [3Marchesini G. Brizi M. Bianchi G. Tomassetti S. Bugianesi E. Lenzi M. et al.Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.Diabetes. 2001; 50: 1844-1850Crossref PubMed Google Scholar, 34Marchesini G. Brizi M. Morselli-Labate A.M. Bianchi G. Bugianesi E. McCullough A.J. et al.Association of nonalcoholic fatty liver disease with insulin resistance.Am J Med. 1999; 107: 450-455Abstract Full Text Full Text PDF PubMed Scopus (864) Google Scholar, 35Marchesini G. Bugianesi E. Forlani G. Cerrelli F. Lenzi M. Manini R. et al.Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.Hepatology. 2003; 37: 917-923Crossref PubMed Scopus (1333) Google Scholar]. A causal association has been suggested by longitudinal studies showing a chronological association between the progression of the metabolic syndrome and the occurrence of NAFLD [36Suzuki A. Angulo P. Lymp J. St Sauver J. Muto A. Okada T. et al.Chronological development of elevated aminotransferases in a nonalcoholic population.Hepatology. 2005; 41: 64-71Crossref PubMed Scopus (85) Google Scholar, 37Hamaguchi M. Kojima T. Takeda N. Nakagawa T. Taniguchi H. Fujii K. et al.The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Google Scholar]. In retrospective series from tertiary referral centers, bridging fibrosis is seen in 25–33% of NASH patients at diagnosis, including cirrhosis in 10–15% [[38]Argo C.K. Caldwell S.H. Epidemiology and natural history of non-alcoholic steatohepatitis.Clin Liver Dis. 2009; 13: 511-531Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar]. NASH is by far the commonest cause of fibrosis and cirrhosis in patients with unexplained increased ALT [[21]de Ledinghen V. Ratziu V. Causse X. Le Bail B. Capron D. Renou C. et al.Diagnostic and predictive factors of significant liver fibrosis and minimal lesions in patients with persistent unexplained elevated transaminases: a prospective multicenter study.J Hepatol. 2006; 45: 592-599Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. A micromorphometry study has suggested that NASH has a fibrotic potential similar to that of chronic hepatitis C after adjustment for fibrotic confounders [[39]Charlotte F, Le Naour G, Bernhardt C, Poynard T, Ratziu V. A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C. Hum Pathol 2010 [Epub ahead of print].Google Scholar]. Independent predictors of fibrosis are mainly age >45–50 and diabetes but also BMI >28–30 kg/m2, hypertension, and the degree of IR [40Ratziu V. Giral P. Charlotte F. Bruckert E. Thibault V. Theodorou I. et al.Liver fibrosis in overweight patients.Gastroenterology. 2000; 118: 1117-1123Abstract Full Text Full Text PDF PubMed Google Scholar, 41Angulo P. Keach J.C. Batts K.P. Lindor K.D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.Hepatology. 1999; 30: 1356-1362Crossref PubMed Google Scholar, 42Dixon 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: 91-100Abstract Full Text PDF PubMed Google Scholar]. Advanced fibrosis can coexist with normal aminotransferases [43Fracanzani A.L. Valenti L. Bugianesi E. Andreoletti M. Colli A. Vanni E. et al.Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes.Hepatology. 2008; 48: 792-798Crossref PubMed Scopus (225) Google Scholar, 44Mofrad P. Contos M.J. Haque M. Sargeant C. Fisher R.A. Luketic V.A. et al.Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values.Hepatology. 2003; 37: 1286-1292Crossref PubMed Scopus (515) Google Scholar]. Progression of fibrosis has been demonstrated in retrospective series, raising significant methodological issues [[45]Ratziu V. Poynard T. NASH: a hidden and silent fibroser finally revealed?.J Hepatol. 2005; 42: 12-14Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar], in particular whether the observed changes are within the range of what can be expected from mere sampling variability [[46]Ratziu V. Bugianesi E. Dixon J. Fassio E. Ekstedt M. Charlotte F. et al.Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.Aliment Pharmacol Ther. 2007; 26: 821-830Crossref PubMed Scopus (43) Google Scholar]. Pooled data [47Adams L.A. Sanderson S. Lindor K.D. Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.J Hepatol. 2005; 42: 132-138Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar, 48Fassio E. Alvarez E. Dominguez N. Landeira G. Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies.Hepatology. 2004; 40: 820-826Crossref PubMed Scopus (285) Google Scholar, 49Harrison S.A. Torgerson S. Hayashi P.H. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study.Am J Gastroenterol. 2003; 98: 2042-2047Crossref PubMed Scopus (283) Google Scholar, 50Hui A.Y. Wong V.W. Chan H.L. Liew C.T. Chan J.L. Chan F.K. et al.Histological progression of non-alcoholic fatty liver disease in Chinese patients.Aliment Pharmacol Ther. 2005; 21: 407-413Crossref PubMed Scopus (52) Google Scholar, 51Ekstedt M. Franzen L.E. Mathiesen U.L. Thorelius L. Holmqvist M. Bodemar G. et al.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (845) Google Scholar] have shown that improvement occurs in only 21% of patients with progression in 38% (with some progressing by two stages or more or towards cirrhosis). The strongest predictor of fibrosis progression is necroinflammation on the initial biopsy [[52]Argo C.K. Northup P.G. Al-Osaimi A.M. Caldwell S.H. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.J Hepatol. 2009; 51: 371-379Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar]. Rarely, progression of fibrosis may occur in steatosis only [51Ekstedt M. Franzen L.E. Mathiesen U.L. Thorelius L. Holmqvist M. Bodemar G. et al.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (845) Google Scholar, 53Matteoni 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; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (1812) Google Scholar], presumably due either to concurrent non-specific inflammation (insufficient for a steatohepatitis diagnosis) [[38]Argo C.K. Caldwell S.H. Epidemiology and natural history of non-alcoholic steatohepatitis.Clin Liver Dis. 2009; 13: 511-531Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar] or to missed lesions of steatohepatitis due to sampling variability. End-stage NASH is an underecognized cause of cryptogenic cirrhosis [[54]Caldwell S.H. Oelsner D.H. Iezzoni J.C. Hespenheide E.E. Battle E.H. Driscoll C.J. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.Hepatology. 1999; 29: 664-669Crossref PubMed Google Scholar] mainly because steatosis and liver-cell injury can disappear at this stage [39Charlotte F, Le Naour G, Bernhardt C, Poynard T, Ratziu V. A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C. Hum Pathol 2010 [Epub ahead of print].Google Scholar, 55Powell E.E. Cooksley W.G.E. Hanson R. Searle J. Halliday J.W. Powell L.W. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.Hepatology. 1990; 11: 74-80Crossref PubMed Google Scholar]. Past exposure to metabolic risk factors (Table 1) is the key to diagnosis: at least one major risk factor, being overweight or having diabetes, should be present together with hypertension, dyslipidemia, or atheromatosis. Using these criteria 30–75% of cryptogenic cirrhosis can be attributed to burned-out NASH [54Caldwell S.H. Oelsner D.H. Iezzoni J.C. Hespenheide E.E. Battle E.H. Driscoll C.J. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.Hepatology. 1999; 29: 664-669Crossref PubMed Google Scholar, 56Ayata G. Gordon F.D. Lewis W.D. Pomfret E. Pomposelli J.J. Jenkins R.L. et al.Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation.Hum Pathol. 2002; 33: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 57Ong J. Younossi Z.M. Reddy V. Price L.L. Gramlich T. Mayes J. et al.Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease.Liver Transpl. 2001; 7: 797-801Crossref PubMed Scopus (161) Google Scholar, 58Poonawala A. Nair S.P. Thuluvath P.J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.Hepatology. 2000; 32: 689-692Crossref PubMed Google Scholar, 59Marrero J.A. Fontana R.J. Su G.L. Conjeevaram H.S. Emick D.M. Lok A.S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.Hepatology. 2002; 36: 1349-1354Crossref PubMed Scopus (362) Google Scholar].Table 1Metabolic risk factors.•Body mass index >25 kg/m2 and/or•Waist circumference >94 cm in men, 80 cm in women (Caucasians)•Arterial hypertension >135/85 mmHg•Fasting serum glucose >6.1 mmol/L•Serum triglycerides >1.7 mmol/L•HDL-cholesterol <1 mmol/L (men); <1.3 mmol/L (women)•Serum ferritin >350 μg/L•First degree relatives of individuals with obesity and/or diabetes Open table in a new tab Cirrhosis complications. Liver failure is often (30–51%) the first presentation of patients with cirrhotic NASH [60Ratziu V. Bonyhay L. Di Martino V. Charlotte F. Cavallaro L. Sayegh-Tainturier M.H. et al.Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis.Hepatology. 2002; 35: 1485-1493Crossref PubMed Scopus (336) Google Scholar, 61Sanyal A.J. Banas C. Sargeant C. Luketic V.A. Sterling R.K. Stravitz R.T. et al.Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.Hepatology. 2006; 43: 682-689Crossref PubMed Scopus (218) Google Scholar] and occurs after 7–10 years in 38–45% of cirrhotic cases [61Sanyal A.J. Banas C. Sargeant C. Luketic V.A. Sterling R.K. Stravitz R.T. et al.Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.Hepatology. 2006; 43: 682-689Crossref PubMed Scopus (218) Google Scholar, 62Hui J.M. Kench J.G. Chitturi S. Sud A. Farrell G.C. Byth K. et al.Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C.Hepatology. 2003; 38: 420-427Crossref PubMed Scopus (284) Google Scholar] although available data, all retrospective, are subject to lead-time bias. Causes of death are liver failure, sepsis and variceal hemorrhage, or hepatocellular carcinoma (HCC) [60Ratziu V. Bonyhay L. Di Martino V. Charlotte F. Cavallaro L. Sayegh-Tainturier M.H. et al.Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis.Hepatology. 2002; 35: 1485-1493Crossref PubMed Scopus (336) Google Scholar, 61Sanyal A.J. Banas C. Sargeant C. Luketic V.A. Sterling R.K. Stravitz R.T. et al.Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.Hepatology. 2006; 43: 682-689Crossref PubMed Scopus (218) Google Scholar]. The latter is often diagnosed at a late stage [51Ekstedt M. Franzen L.E. Mathiesen U.L. Thorelius L. Holmqvist M. 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