NAFLD incidence and remission: Only a matter of weight gain and weight loss?
Authors: Giulio Marchesini, Arianna Mazzotti
Journal: Journal of Hepatology (2014)

Incidence of non-alcoholic fatty liver disease in Hong Kong: A population study with paired proton-magnetic resonance spectroscopyJournal of HepatologyVol. 62Issue 1PreviewBecause abdominal ultrasonography cannot reliably quantify hepatic steatosis, accurate data on the incidence of non-alcoholic fatty liver disease (NAFLD) are lacking. We aimed to study the population incidence of NAFLD with state-of-the-art non-invasive tests. Full-Text PDF The prevalence of non-alcoholic fatty liver disease (NAFLD) in the community is probably rising, driven by the epidemics of obesity and diabetes. A provocative study on obesity prevalence in the U.S. suggested that, given the trend observed between 1970 and 2004, all American adults would become overweight or obese by 2048, with differences between genders and ethnic ancestry [[1]Wang Y. Beydoun M.A. Liang L. Caballero B. Kumanyika S.K. Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic.Obesity (Silver Spring). 2008; 16: 2323-2330Crossref PubMed Scopus (1063) Google Scholar]. Similar data exist for the prevalence of type 2 diabetes, which is now well above a 10% prevalence rate in several countries, with an estimated total of 382 million cases throughout the world and a prospective rise to 592 million cases in the next 25 years [[2]International Diabetes Federation. IDF Diabetes Atlas: Executive Summary. Available at: <https://wwwidforg/sites/default/files/EN_6E_Atlas_Exec_Sum_0pdf>; 2013.Google Scholar]. From the early description of NAFLD, we know that the disease is intimately connected with obesity, diabetes and the metabolic syndrome, therefore it is not surprising that NAFLD is among the top three causes of liver transplantation. Considering the rapid advances in antiviral therapy, it is expected to become the most common indication in the near future. A correct identification of incident cases may help to determine additional risk factors and program therapeutic interventions.Only a few studies have been available so far on fatty liver or NAFLD incidence (Table 1). The usual method to diagnose NAFLD has been ultrasonography, sometimes coupled with raised liver enzymes [3Hamaguchi M. Kojima T. Takeda N. Nakagawa T. Taniguchi H. Fujii K. et al.The metabolic syndrome as a predictor of non-alcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Scopus (836) Google Scholar, 4Bruno 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: 932-937Crossref PubMed Scopus (172) Google Scholar, 5Suzuki A. Angulo P. Lymp J. St Sauver J. Muto A. Okada T. et al.Chronological development of elevated aminotransferases in a non-alcoholic population.Hepatology. 2005; 41: 64-71Crossref PubMed Scopus (151) Google Scholar, 6Bedogni 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. 2007; 46: 1387-1391Crossref PubMed Scopus (179) Google Scholar, 7Tsuneto A. Hida A. Sera N. Imaizumi M. Ichimaru S. Nakashima E. et al.Fatty liver incidence and predictive variables.Hypertens Res. 2010; 33: 638-643Crossref PubMed Scopus (57) Google Scholar, 8Zelber-Sagi S. Lotan R. Shlomai A. Webb M. Harrari G. Buch A. et al.Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up.J Hepatol. 2012; 56: 1145-1151Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 9Xu C. Yu C. Ma H. Xu L. Miao M. Li Y. Prevalence and risk factors for the development of non-alcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study.Am J Gastroenterol. 2013; 108: 1299-1304Crossref PubMed Scopus (117) Google Scholar, 10Sung K.C. Wild S.H. Byrne C.D. Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension.J Hepatol. 2014; 60: 1040-1045Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. We all know that this method is crude, imprecise, highly insensitive and operator-dependent and cannot provide quantitative data. Overall, data are remarkably different in relation to study population, age, gender and comorbidities (in particular, to the presence/absence of obesity and the method of ascertainment). In the present issue of the Journal, Wong et al. present their analysis of NAFLD incidence based on paired proton-magnetic resonance spectroscopy (MRS) in a community-based Hong-Kong cohort, where also the parameters of metabolic syndrome were recorded [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. In 565 cases without evidence of NAFLD at baseline (intrahepatic triglyceride (IHTG) content <5%), 1H-MRS was repeated after an interval of 3–5 years (median 47 months). All cases had an anthropometric and biochemical assessment for the features of metabolic syndrome, and subjects with incident fatty liver also had liver stiffness measured by transient elastography. The incidence of fatty liver (78 new cases with IHTG >5%) was set at 3.4% per year, after exclusion of two cases with excessive alcohol intake, with 20% of new cases in the range of moderate-severe steatosis and only one patient with liver stiffness indicative of advanced fibrosis. The presence of metabolic syndrome at baseline was the strongest predictor of incident steatosis, which was also associated with incident obesity, incident metabolic syndrome, and no remission of impaired glucose tolerance.Table 1Studies on incident NAFLD in different populations.ALT, alanine aminotransferase; FL, fatty liver; F-U, follow-up; HDL, high density lipoprotein; HOMA, homeostasis model assessment; NMR, nuclear magnetic resonance; SLD, suspected liver disease (high liver enzymes, high mean corpuscular volume, low platelet count); TG, triglycerides; US, ultrasonography; WC, waist circumference. Open table in a new tab In general, these data were largely expected, but the details of the study open a number of important questions for future research. In individual cases with incident fatty liver, IHTG increased from values below 5% to values ranging up to 35%, and more than doubled in 20% of cases. We know that changes in MRS-determined IHTG may rapidly occur in response to dietary intake [[12]Browning J.D. Davis J. Saboorian M.H. Burgess S.C. A low-carbohydrate diet rapidly and dramatically reduces intrahepatic triglyceride content.Hepatology. 2006; 44: 487-488Crossref PubMed Scopus (34) Google Scholar] and weight [[13]Petersen K.F. Dufour S. Befroy D. Lehrke M. Hendler R.E. Shulman G.I. Reversal of non-alcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.Diabetes. 2005; 54: 603-608Crossref PubMed Scopus (658) Google Scholar] modifications. Although a linear trend was observed between baseline and follow-up IHTG levels, incident fatty liver did not result merely from modest fluctuations around the cut-off of 5%, but in selected cases a dramatic increase in IHTG levels occurred. Whether this is due to large modifications in body weight/waist circumference or in the habitual dietary intake/physical activity cannot be determined.Metabolic syndrome was defined according to the specific criteria dictated for the Southeast Asian population by the International Diabetes Federation, using the cut-off point of waist circumference ⩾90 cm for males and ⩾80 for females. The probability to develop incident fatty liver was related to both baseline values and changes in waist circumference, but on average no systematic differences in anthropometric parameters were observed between baseline and follow-up measurements. In a follow-up study of a Japanese cohort with previously elevated liver enzymes – assumed as markers for NAFLD – maintaining weight control after weight loss and habitual exercising were predictive of long-term remission from NAFLD [[14]Suzuki A. Lindor K. St Sauver J. Lymp J. Mendes F. Muto A. et al.Effect of changes on body weight and lifestyle in non-alcoholic fatty liver disease.J Hepatol. 2005; 43: 1060-1066Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar]. However, a body weight within normal limits does not provide any guarantee of keeping free of NAFLD [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. Incident fatty liver developed in 8% of cases with a BMI within the ethnic-specific cut-off of 23 kg/m2 both at baseline and at follow-up, as well as in a small proportion of cases who moved their BMI from the overweight or obese range to normal weight. This confirms that factors independent from anthropometric changes may be operative in selected cases.Considerable attention should be paid to NAFLD development in the absence of obesity, i.e., the improperly called 'lean' NAFLD (more properly, "normal weight" NAFLD). Within the cohort of the National Health and Nutrition Examination Survey III (NHANES III), Younossi et al. identified 2492 individuals (18.8%) with moderate-to-severe NAFLD at ultrasonography [[15]Younossi Z.M. Stepanova M. Negro F. Hallaji S. Younossi Y. Lam B. et al.Non-alcoholic fatty liver disease in lean individuals in the United States.Medicine (Baltimore). 2012; 91: 319-327Crossref PubMed Scopus (345) Google Scholar]. The prevalence was as high as 27.7% in overweight/obese subjects, significantly higher than the 7.4% observed in subjects with normal BMI (<25 kg/m2). Multivariate analysis showed that 'lean' NAFLD was independently associated with diabetes, when compared to lean controls, and with younger age, female sex, insulin resistance and hypercholesterolemia, when compared with overweight/obese NAFLD patients. The authors conclude that 'lean' NAFLD individuals constitute a subgroup of patients relatively free from the components of metabolic syndrome, usually associated with NAFLD. Similar data were reported in a tertiary care liver unit [[16]Vos B. Moreno C. Nagy N. Fery F. Cnop M. Vereerstraeten P. et al.Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease.Acta Gastroenterol Belg. 2011; 74: 389-394PubMed Google Scholar], where 'lean' NAFLD had a reduced likelihood of being associated with the components of metabolic syndrome, but subjects were nonetheless insulin resistant when compared to healthy controls. This intrinsic defect was confirmed in a cohort of subjects with biopsy-proven NAFLD, free of diabetes and obesity, where insulin resistance was maintained, and the metabolic pattern was similar to that observed in obesity, with adipose tissue playing an important role [[17]Bugianesi E. Gastaldelli A. Vanni E. Gambino R. Cassader M. Baldi S. et al.Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.Diabetologia. 2005; 48: 634-642Crossref PubMed Scopus (529) Google Scholar].The key question is whether 'lean' NAFLD carries the same risk of progression as the fatty liver of obesity. Several cross sectional analyses found that the presence of obesity or type 2 diabetes is a risk factor for NAFLD severity. Unexpectedly, an international study, involving several tertiary liver units, published so far only in abstract form, reported a more severe prognosis in 'lean' biopsy-proven NAFLD compared with overweight or obese subjects [[18]Dela Cruz A.C. Bugianesi E. George J. Day C.P. Liaquat H. Charatcharoenwitthaya P. et al.Characteristics and long-term prognosis of lean patients with non-alcoholic fatty liver disease.Gastroenterology. 2014; 146: S-909Google Scholar]. Of 1090 NAFLD cases (mean age, 46), only 125 (11.5%) were classified as 'lean' (BMI <25 kg/m2) at first diagnosis; they were characterized by a lower prevalence of diabetes, hypertension, hypertriglyceridemia, low-HDL cholesterol, central obesity and metabolic syndrome, as well as more frequently normal liver enzymes and a lower prevalence or severity of insulin resistance. At histology, 'lean' NAFLD had a lower grade/stage of steatosis and fibrosis, but more severe lobular inflammation. In a cohort of 483 cases, first observed before 2005, 'lean' vs. 'non-lean' NAFLD patients were compared in a cumulative overall survival analysis over a mean follow-up period of over 11 years. Mortality was significantly higher in 'lean' patients and the Cox model identified 'lean' NAFLD (HR 11.8; 95% CI 2.8–50.1; p = 0.001) and age as prognostic factors, after adjustment for confounders.We also know that subjects with massive fatty liver, related to defects in lipoprotein metabolism, are relatively free of hepatic necroinflammation, fibrosis and disease progression. Why should subjects with 'lean' NAFLD be at higher risk of mortality? In the study by Wong et al. [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar], the presence of the common variant in the patatin-like phospholipase-3 gene (PNPLA3), known to confer susceptibility to NAFLD [[19]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to non-alcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2140) Google Scholar], did not provide any relevant clue for incident NAFLD, but other variants in different loci may be involved in individual cases.The final question is how to manage subjects diagnosed with NAFLD, given the very large number of cases, the difficulty in predicting evolution, and the slow progression and long duration of disease. If the poorer prognosis of 'lean' NAFLD was confirmed, this cohort might deserve more systematic surveillance and treatment. Although several new drugs are under investigations for more progressive disease, weight loss remains the background therapy in all cases with overweight/obesity. The results are generally poor, but a 7% weight loss significantly modifies liver histology. In 'lean' NAFLD patients, where weight loss cannot be a reasonable target of therapy, a psychological program to support patients towards habitual physical activity might also be indicated. There is evidence that habitual physical activity is approximately as effective as a standard weight loss program on liver enzymes and cardiovascular fitness [[20]Montesi L. Caselli C. Centis E. Nuccitelli C. Moscatiello S. Suppini A. et al.Physical activity support or weight loss counseling for non-alcoholic fatty liver disease?.World J Gastroenterol. 2014; 20: 10128-10136Crossref PubMed Scopus (20) Google Scholar]. The study by Wong et al. [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar] provides the framework for future intervention; the evidence that incidence and remission are not solely related to body weight changes must dictate tailored treatment in individual patients.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The prevalence of non-alcoholic fatty liver disease (NAFLD) in the community is probably rising, driven by the epidemics of obesity and diabetes. A provocative study on obesity prevalence in the U.S. suggested that, given the trend observed between 1970 and 2004, all American adults would become overweight or obese by 2048, with differences between genders and ethnic ancestry [[1]Wang Y. Beydoun M.A. Liang L. Caballero B. Kumanyika S.K. Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic.Obesity (Silver Spring). 2008; 16: 2323-2330Crossref PubMed Scopus (1063) Google Scholar]. Similar data exist for the prevalence of type 2 diabetes, which is now well above a 10% prevalence rate in several countries, with an estimated total of 382 million cases throughout the world and a prospective rise to 592 million cases in the next 25 years [[2]International Diabetes Federation. IDF Diabetes Atlas: Executive Summary. Available at: <https://wwwidforg/sites/default/files/EN_6E_Atlas_Exec_Sum_0pdf>; 2013.Google Scholar]. From the early description of NAFLD, we know that the disease is intimately connected with obesity, diabetes and the metabolic syndrome, therefore it is not surprising that NAFLD is among the top three causes of liver transplantation. Considering the rapid advances in antiviral therapy, it is expected to become the most common indication in the near future. A correct identification of incident cases may help to determine additional risk factors and program therapeutic interventions. Only a few studies have been available so far on fatty liver or NAFLD incidence (Table 1). The usual method to diagnose NAFLD has been ultrasonography, sometimes coupled with raised liver enzymes [3Hamaguchi M. Kojima T. Takeda N. Nakagawa T. Taniguchi H. Fujii K. et al.The metabolic syndrome as a predictor of non-alcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Scopus (836) Google Scholar, 4Bruno 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: 932-937Crossref PubMed Scopus (172) Google Scholar, 5Suzuki A. Angulo P. Lymp J. St Sauver J. Muto A. Okada T. et al.Chronological development of elevated aminotransferases in a non-alcoholic population.Hepatology. 2005; 41: 64-71Crossref PubMed Scopus (151) Google Scholar, 6Bedogni 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. 2007; 46: 1387-1391Crossref PubMed Scopus (179) Google Scholar, 7Tsuneto A. Hida A. Sera N. Imaizumi M. Ichimaru S. Nakashima E. et al.Fatty liver incidence and predictive variables.Hypertens Res. 2010; 33: 638-643Crossref PubMed Scopus (57) Google Scholar, 8Zelber-Sagi S. Lotan R. Shlomai A. Webb M. Harrari G. Buch A. et al.Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up.J Hepatol. 2012; 56: 1145-1151Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 9Xu C. Yu C. Ma H. Xu L. Miao M. Li Y. Prevalence and risk factors for the development of non-alcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study.Am J Gastroenterol. 2013; 108: 1299-1304Crossref PubMed Scopus (117) Google Scholar, 10Sung K.C. Wild S.H. Byrne C.D. Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension.J Hepatol. 2014; 60: 1040-1045Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. We all know that this method is crude, imprecise, highly insensitive and operator-dependent and cannot provide quantitative data. Overall, data are remarkably different in relation to study population, age, gender and comorbidities (in particular, to the presence/absence of obesity and the method of ascertainment). In the present issue of the Journal, Wong et al. present their analysis of NAFLD incidence based on paired proton-magnetic resonance spectroscopy (MRS) in a community-based Hong-Kong cohort, where also the parameters of metabolic syndrome were recorded [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. In 565 cases without evidence of NAFLD at baseline (intrahepatic triglyceride (IHTG) content <5%), 1H-MRS was repeated after an interval of 3–5 years (median 47 months). All cases had an anthropometric and biochemical assessment for the features of metabolic syndrome, and subjects with incident fatty liver also had liver stiffness measured by transient elastography. The incidence of fatty liver (78 new cases with IHTG >5%) was set at 3.4% per year, after exclusion of two cases with excessive alcohol intake, with 20% of new cases in the range of moderate-severe steatosis and only one patient with liver stiffness indicative of advanced fibrosis. The presence of metabolic syndrome at baseline was the strongest predictor of incident steatosis, which was also associated with incident obesity, incident metabolic syndrome, and no remission of impaired glucose tolerance. ALT, alanine aminotransferase; FL, fatty liver; F-U, follow-up; HDL, high density lipoprotein; HOMA, homeostasis model assessment; NMR, nuclear magnetic resonance; SLD, suspected liver disease (high liver enzymes, high mean corpuscular volume, low platelet count); TG, triglycerides; US, ultrasonography; WC, waist circumference. In general, these data were largely expected, but the details of the study open a number of important questions for future research. In individual cases with incident fatty liver, IHTG increased from values below 5% to values ranging up to 35%, and more than doubled in 20% of cases. We know that changes in MRS-determined IHTG may rapidly occur in response to dietary intake [[12]Browning J.D. Davis J. Saboorian M.H. Burgess S.C. A low-carbohydrate diet rapidly and dramatically reduces intrahepatic triglyceride content.Hepatology. 2006; 44: 487-488Crossref PubMed Scopus (34) Google Scholar] and weight [[13]Petersen K.F. Dufour S. Befroy D. Lehrke M. Hendler R.E. Shulman G.I. Reversal of non-alcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.Diabetes. 2005; 54: 603-608Crossref PubMed Scopus (658) Google Scholar] modifications. Although a linear trend was observed between baseline and follow-up IHTG levels, incident fatty liver did not result merely from modest fluctuations around the cut-off of 5%, but in selected cases a dramatic increase in IHTG levels occurred. Whether this is due to large modifications in body weight/waist circumference or in the habitual dietary intake/physical activity cannot be determined. Metabolic syndrome was defined according to the specific criteria dictated for the Southeast Asian population by the International Diabetes Federation, using the cut-off point of waist circumference ⩾90 cm for males and ⩾80 for females. The probability to develop incident fatty liver was related to both baseline values and changes in waist circumference, but on average no systematic differences in anthropometric parameters were observed between baseline and follow-up measurements. In a follow-up study of a Japanese cohort with previously elevated liver enzymes – assumed as markers for NAFLD – maintaining weight control after weight loss and habitual exercising were predictive of long-term remission from NAFLD [[14]Suzuki A. Lindor K. St Sauver J. Lymp J. Mendes F. Muto A. et al.Effect of changes on body weight and lifestyle in non-alcoholic fatty liver disease.J Hepatol. 2005; 43: 1060-1066Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar]. However, a body weight within normal limits does not provide any guarantee of keeping free of NAFLD [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. Incident fatty liver developed in 8% of cases with a BMI within the ethnic-specific cut-off of 23 kg/m2 both at baseline and at follow-up, as well as in a small proportion of cases who moved their BMI from the overweight or obese range to normal weight. This confirms that factors independent from anthropometric changes may be operative in selected cases. Considerable attention should be paid to NAFLD development in the absence of obesity, i.e., the improperly called 'lean' NAFLD (more properly, "normal weight" NAFLD). Within the cohort of the National Health and Nutrition Examination Survey III (NHANES III), Younossi et al. identified 2492 individuals (18.8%) with moderate-to-severe NAFLD at ultrasonography [[15]Younossi Z.M. Stepanova M. Negro F. Hallaji S. Younossi Y. Lam B. et al.Non-alcoholic fatty liver disease in lean individuals in the United States.Medicine (Baltimore). 2012; 91: 319-327Crossref PubMed Scopus (345) Google Scholar]. The prevalence was as high as 27.7% in overweight/obese subjects, significantly higher than the 7.4% observed in subjects with normal BMI (<25 kg/m2). Multivariate analysis showed that 'lean' NAFLD was independently associated with diabetes, when compared to lean controls, and with younger age, female sex, insulin resistance and hypercholesterolemia, when compared with overweight/obese NAFLD patients. The authors conclude that 'lean' NAFLD individuals constitute a subgroup of patients relatively free from the components of metabolic syndrome, usually associated with NAFLD. Similar data were reported in a tertiary care liver unit [[16]Vos B. Moreno C. Nagy N. Fery F. Cnop M. Vereerstraeten P. et al.Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease.Acta Gastroenterol Belg. 2011; 74: 389-394PubMed Google Scholar], where 'lean' NAFLD had a reduced likelihood of being associated with the components of metabolic syndrome, but subjects were nonetheless insulin resistant when compared to healthy controls. This intrinsic defect was confirmed in a cohort of subjects with biopsy-proven NAFLD, free of diabetes and obesity, where insulin resistance was maintained, and the metabolic pattern was similar to that observed in obesity, with adipose tissue playing an important role [[17]Bugianesi E. Gastaldelli A. Vanni E. Gambino R. Cassader M. Baldi S. et al.Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.Diabetologia. 2005; 48: 634-642Crossref PubMed Scopus (529) Google Scholar]. The key question is whether 'lean' NAFLD carries the same risk of progression as the fatty liver of obesity. Several cross sectional analyses found that the presence of obesity or type 2 diabetes is a risk factor for NAFLD severity. Unexpectedly, an international study, involving several tertiary liver units, published so far only in abstract form, reported a more severe prognosis in 'lean' biopsy-proven NAFLD compared with overweight or obese subjects [[18]Dela Cruz A.C. Bugianesi E. George J. Day C.P. Liaquat H. Charatcharoenwitthaya P. et al.Characteristics and long-term prognosis of lean patients with non-alcoholic fatty liver disease.Gastroenterology. 2014; 146: S-909Google Scholar]. Of 1090 NAFLD cases (mean age, 46), only 125 (11.5%) were classified as 'lean' (BMI <25 kg/m2) at first diagnosis; they were characterized by a lower prevalence of diabetes, hypertension, hypertriglyceridemia, low-HDL cholesterol, central obesity and metabolic syndrome, as well as more frequently normal liver enzymes and a lower prevalence or severity of insulin resistance. At histology, 'lean' NAFLD had a lower grade/stage of steatosis and fibrosis, but more severe lobular inflammation. In a cohort of 483 cases, first observed before 2005, 'lean' vs. 'non-lean' NAFLD patients were compared in a cumulative overall survival analysis over a mean follow-up period of over 11 years. Mortality was significantly higher in 'lean' patients and the Cox model identified 'lean' NAFLD (HR 11.8; 95% CI 2.8–50.1; p = 0.001) and age as prognostic factors, after adjustment for confounders. We also know that subjects with massive fatty liver, related to defects in lipoprotein metabolism, are relatively free of hepatic necroinflammation, fibrosis and disease progression. Why should subjects with 'lean' NAFLD be at higher risk of mortality? In the study by Wong et al. [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar], the presence of the common variant in the patatin-like phospholipase-3 gene (PNPLA3), known to confer susceptibility to NAFLD [[19]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to non-alcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2140) Google Scholar], did not provide any relevant clue for incident NAFLD, but other variants in different loci may be involved in individual cases. The final question is how to manage subjects diagnosed with NAFLD, given the very large number of cases, the difficulty in predicting evolution, and the slow progression and long duration of disease. If the poorer prognosis of 'lean' NAFLD was confirmed, this cohort might deserve more systematic surveillance and treatment. Although several new drugs are under investigations for more progressive disease, weight loss remains the background therapy in all cases with overweight/obesity. The results are generally poor, but a 7% weight loss significantly modifies liver histology. In 'lean' NAFLD patients, where weight loss cannot be a reasonable target of therapy, a psychological program to support patients towards habitual physical activity might also be indicated. There is evidence that habitual physical activity is approximately as effective as a standard weight loss program on liver enzymes and cardiovascular fitness [[20]Montesi L. Caselli C. Centis E. Nuccitelli C. Moscatiello S. Suppini A. et al.Physical activity support or weight loss counseling for non-alcoholic fatty liver disease?.World J Gastroenterol. 2014; 20: 10128-10136Crossref PubMed Scopus (20) Google Scholar]. The study by Wong et al. [[11]Wong V.W.-S. Wong G.L.-H. Yeung D.K.-W. Lau T.K.-T. Chan C.K.-M. Chim A.M.-L. et al.Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.J Hepatol. 2015; 62: 182-189Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar] provides the framework for future intervention; the evidence that incidence and remission are not solely related to body weight changes must dictate tailored treatment in individual patients. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.