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From NAFLD in clinical practice to answers from guidelines

Open AccessPublished:June 10, 2013DOI:https://doi.org/10.1016/j.jhep.2013.05.044

      Summary

      This review of the literature consists of three sections.
      First, papers concerning non-alcoholic fatty liver disease (NAFLD) awareness among the general population, general practitioners, and liver and non-liver specialists were retrieved and analyzed to highlight the perception of disease, verify knowledge of current recommendations, and identify the main difficulties experienced in clinical practice.
      Next, position papers and clinical practice guidelines issued by International and National Hepatological Scientific Societies were identified and critically assessed in order to pinpoint the areas of convergence/difference.
      Finally, practical suggestions on NAFLD diagnosis and management in daily practice are provided and the open questions highlighted.

      Abbreviations:

      NAFLD (non-alcoholic fatty liver disease), MS (metabolic syndrome), NASH (non-alcoholic steatohepatitis), HCC (hepatocellular carcinoma), T2D (type 2 diabetes), CLD (chronic liver disease), GPs (general practitioners), EASL (European Association for the Study of the Liver), APWP (Asian-Pacific Working Party), CLDA (Chinese Liver Disease Association), IASL (Italian Association for the Study of the Liver), AGA (American Gastroenterological Association), AASLD (American Association for the Study of Liver Disease), ACG (American College of Gastroenterology), ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology and Nutrition), LB (liver biopsy), US (ultrasonography), IR (insulin resistance), MRFs (metabolic risk factors), AFLD (alcoholic fatty liver disease), LTs (liver tests), CVD (cardiovascular disease)

      Keywords

      Introduction

      Non-alcoholic fatty liver disease (NAFLD), the hepatic counterpart of the metabolic syndrome (MS) [
      • Kotronen A.
      • Yki-Järvinen H.
      Fatty liver: a novel component of the metabolic syndrome.
      ,
      • Vanni E.
      • Bugianesi E.
      • Kotronen A.
      • De Minicis S.
      • Yki-Järvinen H.
      • Svegliati-Baroni G.
      From the metabolic syndrome to NAFLD or vice versa?.
      ], encompasses a disease spectrum spanning steatosis through non-alcoholic steatohepatitis (NASH) with/without cirrhosis, and hepatocellular carcinoma (HCC) [
      • Farrell G.C.
      • Larter C.Z.
      Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
      ]. The obesity and type 2 diabetes (T2D) pandemic and the improved management of chronic viral hepatitis have resulted in NAFLD becoming a leading cause of chronic liver disease (CLD) [
      • 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.
      ] and a major health concern owing to hepatic and extrahepatic morbidity/mortality [
      • Musso G.
      • Gambino 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.
      ,
      • Ekstedt 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.
      ,
      • Soderberg 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.
      ].
      Such a shift in the epidemiology of CLD has left practicing clinicians somewhat puzzled in identifying and treating this NAFLD “epidemic” [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ,
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ,
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ,
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ,
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ]. Moreover, an ever increasing number of practice guidelines on NAFLD diagnosis and management issued by eminent Scientific Societies may probably add to the uncertainties concerning the best conduct to follow in clinical practice.
      Our paper aims at (1) highlighting the perception of NAFLD among practicing physicians, (2) providing a critical, comparative analysis of the statements on NAFLD diagnosis and management, issued by clinical practice guidelines and technical reviews of Scientific Societies, (3) offering practical suggestions on the controversial topics and defining the unsettled questions.

      Methods

      We conducted a PubMed database search (keywords: general practice and/or primary care and/or specialists and/or physicians and/or awareness and/or perception and/or liver steatosis and/or fatty liver and/or NAFLD and/or NASH and/or guidelines and/or recommendations. Limits: December 2012 and English language) aimed at ascertaining: (a) the awareness/perception of the importance of NAFLD-NASH among potential patients and practicing physicians [both general practitioners (GPs) and specialists] and (b) guidelines/consensus/recommendations for NAFLD diagnosis and management issued by Medical Societies.
      Six studies meeting the inclusion and exclusion criteria investigated current beliefs and practices of NAFLD among the general population, GPs and liver and non-liver specialists [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ,
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ,
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ,
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ,
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ,
      • Leung C.M.
      • Lai L.S.
      • Wong W.H.
      • Chan K.H.
      • Luk Y.W.
      • Lai J.Y.
      • et al.
      Non-alcoholic fatty liver disease: an expanding problem with low levels of awareness in Hong Kong.
      ]. Moreover, three further studies [
      • Sivertsen L.M.
      • Woolfenden S.R.
      • Woodhead H.J.
      • Lewis D.
      Diagnosis and management of childhood obesity: a survey of general practitioners in South West Sydney.
      ,
      • Fishbein M.
      • Mogren J.
      • Mogren C.
      • Cox S.
      • Jennings R.
      Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease.
      ,
      • Riley M.R.
      • Bass N.M.
      • Rosenthal P.
      • Merriman R.B.
      Underdiagnosis of pediatric obesity and underscreening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists.
      ] addressing the clinical approach of practicing physicians towards pediatric NAFLD were identified (Table 1).
      Table 1Analysis of reports from real-life clinical practice.
      Five position papers and clinical practice guidelines, issued by the European Association for the Study of the Liver (EASL) [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ], Asian-Pacific Working Party for NAFLD (APWP-NAFLD) [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ], Chinese Liver Disease Association (CLDA) [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ], Italian Association for the Study of the Liver (IASL) [
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ] and American Gastroenterological Association (AGA)-American Association for the Study of Liver Disease (AASLD)-American College of Gastroenterology (ACG) [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ], were identified. Three out of five such reports are evidence-based [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. A single position paper on diagnosis of NAFLD in pediatrics was found (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition [ESPGHAN]) [
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ].
      The “real world” reports were analyzed to highlight the actual perception of NAFLD, verify the awareness of current recommendations, and identify the main difficulties experienced in clinical practice [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ,
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ,
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ,
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ,
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ,
      • Leung C.M.
      • Lai L.S.
      • Wong W.H.
      • Chan K.H.
      • Luk Y.W.
      • Lai J.Y.
      • et al.
      Non-alcoholic fatty liver disease: an expanding problem with low levels of awareness in Hong Kong.
      ,
      • Sivertsen L.M.
      • Woolfenden S.R.
      • Woodhead H.J.
      • Lewis D.
      Diagnosis and management of childhood obesity: a survey of general practitioners in South West Sydney.
      ,
      • Fishbein M.
      • Mogren J.
      • Mogren C.
      • Cox S.
      • Jennings R.
      Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease.
      ,
      • Riley M.R.
      • Bass N.M.
      • Rosenthal P.
      • Merriman R.B.
      Underdiagnosis of pediatric obesity and underscreening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists.
      ].
      The recommendations issued by Scientific Societies were critically assessed in order to pinpoint the areas of convergence/difference.
      The single position paper for pediatric medicine [
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ] was also examined in order to provide information useful to those involved in pediatric care.
      Finally, prompted by the analysis of the reports of practicing physicians [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ,
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ,
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ,
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ,
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ,
      • Leung C.M.
      • Lai L.S.
      • Wong W.H.
      • Chan K.H.
      • Luk Y.W.
      • Lai J.Y.
      • et al.
      Non-alcoholic fatty liver disease: an expanding problem with low levels of awareness in Hong Kong.
      ,
      • Sivertsen L.M.
      • Woolfenden S.R.
      • Woodhead H.J.
      • Lewis D.
      Diagnosis and management of childhood obesity: a survey of general practitioners in South West Sydney.
      ,
      • Fishbein M.
      • Mogren J.
      • Mogren C.
      • Cox S.
      • Jennings R.
      Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease.
      ,
      • Riley M.R.
      • Bass N.M.
      • Rosenthal P.
      • Merriman R.B.
      Underdiagnosis of pediatric obesity and underscreening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists.
      ] and the systematic analysis/comparison of guidelines [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ,
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ], we provide practical suggestions on NAFLD diagnosis and management in daily practice and highlight the open questions and future research.

      Results and comments

      Analysis of reports concerning issues from “real-life” practice and selected guidelines disclosed the following major topics regarding NAFLD diagnosis and management that remain a matter of dispute (Table 1, Table 2):
      • (1)
        Definition and initial assessment of suspected NAFLD patients;
      • (2)
        Screening strategies for NAFLD;
      • (3)
        Diagnostic strategies: non-invasive assessment and liver biopsy (LB);
      • (4)
        Management of NAFLD patients;
      • (5)
        Follow-up strategies of NAFLD patients;
      • (6)
        Pediatric NAFLD.
      Table 2Analysis of guidelines.
      +, recommended; -, not recommended; /, not mentioned.

      What is the definition of NAFLD and which is the initial assessment of suspected NAFLD patients?

      Analysis of reports from real-life clinical practice

      The single study evaluating the awareness of NAFLD in the general population demonstrated that the vast majority of people (83%) had never come across the term NAFLD; knowledge about NAFLD diagnosis and risk factors was also inadequate among those who had ever heard of it [
      • Leung C.M.
      • Lai L.S.
      • Wong W.H.
      • Chan K.H.
      • Luk Y.W.
      • Lai J.Y.
      • et al.
      Non-alcoholic fatty liver disease: an expanding problem with low levels of awareness in Hong Kong.
      ].
      Similarly, several studies showed that knowledge about NAFLD diagnosis and assessment is relatively poor among GPs. An American study showed that GPs were less likely to consider NAFLD as a common cause of liver disease than Hepato-Gastroenterologists [
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ]. These findings are consistent with an Italian survey: only 4.7% of GPs indicated a metabolic cause as the first determinant of an “undefined” persistent hypertransaminasemia. Moreover, a great variability in diagnostic approach to NAFLD was described [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ]. In Loguercio’s retrospective analysis involving 104 GPs, alcohol consumption, BMI, transaminases, and ultrasonography (US) were assessed only in a minority of patients with liver steatosis; no additional tests [markers of insulin resistance (IR), lipid profile, viral hepatitis serologies] were recorded [
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ].
      In a recent survey of 100 hospital non-liver specialists, >90% appreciated that traditional cardiovascular risk factors predicted NAFLD and acknowledged these to be common in non-liver patients. Moreover, 57% considered alcohol consumption to be strongly associated with NAFLD [
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ].
      A French survey among 352 Hepato-Gastroenterologists showed that two-thirds would diagnose NAFLD irrespective of the co-existence of other CLD, as long as metabolic risk factors (MRFs) were present. There was no agreement on the threshold of daily alcohol consumption that ruled out the diagnosis of NAFLD. In the initial assessment of NAFLD patients, a large majority of surveyed specialists collected information on BMI, blood pressure, and glucose or lipid parameters; nonetheless, a sizeable proportion never assessed surrogate markers of IR or measurements of regional adiposity [
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ].

      Analysis of guidelines

      All guidelines agree that diagnosis of NAFLD relies on both imaging or histological evidence of hepatic steatosis and exclusion of causes of secondary hepatic fat accumulation; there is full agreement that NAFLD is strictly associated with MRFs. All Scientific Societies state that, because of the high prevalence of MRFs, NAFLD can co-exist with other CLDs. There is universal consensus that the metabolic profile should be assessed, competing etiologies of steatosis and co-existing CLD should be ruled out, and alcohol consumption should be estimated [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].
      Regarding metabolic assessment, the majority of guidelines [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ] highlight the importance of testing insulin sensitivity. However, there seems to be no consensus on how this should be done. All societies agree that presence of overweight/obesity should be evaluated through anthropometric measures (BMI, waist circumference) and that blood pressure and serum lipids measurement should be performed as a minimal initial assessment [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. Regarding the criteria to adopt for the diagnosis of MS, the American guideline [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ] recommends the Adult Treatment Panel III definition [
      • Adult Treatment Panel III
      Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report.
      ,
      • Grundy S.M.
      • Cleeman J.I.
      • Daniels S.R.
      • Donato K.A.
      • Eckel R.H.
      • Franklin B.A.
      • et al.
      American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement [published corrections appear in Circulation 2005; 112:e297 and Circulation 2005;112:e298].
      ], whereas Asian-Pacific Societies [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ] recommend the International Diabetes Federation criteria [
      • Alberti K.G.
      • Zimmet P.
      • Shaw J.
      • IDF Epidemiology Task Force Consensus Group
      The metabolic syndrome: a new worldwide definition.
      ].
      All guidelines concur that all NAFLD patients should undergo a careful familial and medical history, viral hepatitis and autoimmune serology, alpha1-antitrypsin, iron and copper status measurement. The common association between chronic HCV infection and hepatic steatosis and its implications for fibrosis progression and/or treatment response rate are mentioned by all guidelines [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].
      The threshold for hepatotoxic alcohol consumption to rule out alcoholic liver disease varies as a function of local drinking culture/habits. European Associations [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ] maintain a threshold of 30 and 20 g of alcohol daily for men and women, respectively. Similarly, the American guideline [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ] suggests 210/140 g (=21/14 drinks) of alcohol weekly, whereas Asian-Pacific countries [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ] restrict to 140/70 g of alcohol weekly for men and women, respectively. Moreover, the American guideline specifically recommends a 2-year alcohol withdrawal for NASH clinical trials candidate eligibility purposes [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. This point is not discussed in other guidelines.

      Comments

      In recent years, the diagnostic strategy for NAFLD has evolved from a diagnosis of exclusion towards a chiefly positive approach based on the recognition of the underlying dysmetabolic milieu [
      • Kotronen A.
      • Yki-Järvinen H.
      Fatty liver: a novel component of the metabolic syndrome.
      ,
      • Vanni E.
      • Bugianesi E.
      • Kotronen A.
      • De Minicis S.
      • Yki-Järvinen H.
      • Svegliati-Baroni G.
      From the metabolic syndrome to NAFLD or vice versa?.
      ]. In patients with suspected NAFLD, exclusion of competing etiologies for steatosis is essential. To this end, endocrine disorders [
      • Lonardo A.
      • Carani C.
      • Carulli N.
      • Loria P.
      ‘Endocrine NAFLD’ a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis.
      ], familial hypobetalipoproteinemia [
      • Tarugi P.
      • Lonardo A.
      • Ballarini G.
      • Grisendi A.
      • Pulvirenti M.
      • Bagni A.
      • et al.
      Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B.
      ], alcohol abuse, and, particularly, HCV infection, given that HCV infection, diabetes and steatosis are closely linked to one another [
      • White D.L.
      • Ratziu V.
      • El-Serag H.B.
      Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis.
      ,
      • Lonardo A.
      • Carulli N.
      • Loria P.
      HCV and diabetes. A two-question-based reappraisal.
      ,
      • Lonardo A.
      • Adinolfi L.E.
      • Petta S.
      • Craxì A.
      • Loria P.
      Hepatitis C and diabetes: the inevitable coincidence?.
      ], need to be ruled out. Moreover, it is also necessary to carefully assess for MRFs and the cardiovascular risk profile. Furthermore, NAFLD can occur together with other CLD, which may accelerate the progression of liver injury [
      • Naveau S.
      • Giraud V.
      • Borotto E.
      • Aubert A.
      • Capron F.
      • Chaput J.C.
      Excess weight risk factor for alcoholic liver disease.
      ,
      • Powell E.E.
      • Jonsson J.R.
      • Clouston A.D.
      Steatosis: co-factor in other liver diseases.
      ,
      • 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.
      ,
      • Leandro G.
      • Mangia A.
      • Hui J.
      • Fabris P.
      • Rubbia-Brandt L.
      • Colloredo G.
      • et al.
      HCV Meta-Analysis (on) Individual Patients’ Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data.
      ,
      • Petta S.
      • Cammà C.
      • Di Marco V.
      • Macaluso F.S.
      • Maida M.
      • Pizzolanti G.
      • et al.
      Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection.
      ]. Accordingly, in liver patients with MRFs, the presence of concurrent NAFLD should be evaluated. Conversely, when steatosis is detected in patients with CLD due to non-NAFLD etiology, a metabolic assessment is needed. It is critical to define the appropriate standard anthropometric, biochemical and imaging protocol to be followed to detect NAFLD in clinical practice.
      Figure thumbnail fx5

      Who and how to screen for NAFLD?

      Analysis of reports from real-life clinical practice

      Grattagliano’s survey showed that 70% of Italian GPs underestimated the prevalence of NAFLD among the general adult population, only 36.6% would screen for NAFLD diabetic subjects and a substantial subset of hypertransaminasemic patients were not considered for NAFLD even in the presence of MRFs. Specific training significantly improved GPs’ ability in screening at-risk patients [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ]. The underestimation of the NAFLD problem by GPs was confirmed by another Italian study, in which an extremely low prevalence of fatty liver was reported, and a high proportion of patients were considered as affected by “undefined” CLD despite a high rate of overweight/obesity and an incomplete diagnostic work-up [
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ]. GPs are reported to be less familiar with current recommendations and to use appropriate screening strategies less frequently than hepato-gastroenterologists unless they are fully aware of guidelines [
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ].
      An Australian survey showed that also non-liver Specialists underestimated the prevalence of NAFLD both in the general population and in high-risk patients, thus reflecting a low grade of referrals to Hepatology services [
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ]. Accordingly, a French study reported that only 20% of NAFLD patients seen in gastroenterology practice were referred by specialists in the metabolic field. This survey stressed that among liver specialists there was an over-reliance on transaminases instead of MRFs or US steatosis, when considering the diagnosis of NAFLD [
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ].

      Analysis of guidelines

      The majority of guidelines [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ] explicitly suggest the opportunity to implement a screening policy in individuals at high risk of NAFLD identified by the presence of MRFs and/or IR. Two guidelines either fail to mention [
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ] or discourage any screening policies [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. Indeed, the most recent American guideline [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ] states that systematic screening for NAFLD is not recommended not only in the general population but also in high-risk patients, in family members and in obese children, due to paucity of evidence.
      All Scientific Societies who support screening suggest that it should be done through both US and Liver Tests (LTs).

      Comments

      The prevalence of NAFLD in the general population ranges from 6.3% to 51% depending on the method used to assess liver steatosis and the population/ethnicity studied [
      • Vernon 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.
      ,
      • 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.
      ,
      • Bedogni 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.
      ,
      • Lee J.Y.
      • Kim K.M.
      • Lee S.G.
      • Yu E.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      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.
      ,
      • Li H.
      • Wang Y.J.
      • Tan K.
      • Zeng L.
      • Liu L.
      • Liu F.J.
      • et al.
      Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China.
      ]. This prevalence can be significantly higher in individuals with MRFs [
      • Assy N.
      • Kaita K.
      • Mymin D.
      • Levy C.
      • Rosser B.
      • Minuk G.
      Fatty infiltration of liver in hyperlipidemic patients.
      ,
      • Machado M.
      • Marques-Vidal P.
      • Cortez-Pinto H.
      Hepatic histology in obese patients undergoing bariatric surgery.
      ,
      • Leite 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.
      ]. Moreover, familial aggregation and heritability of NAFLD have been consistently reported [
      • Struben V.M.
      • Hespenheide E.E.
      • Caldwell S.H.
      Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds.
      ,
      • Lonardo A.
      • Bagni A.
      • Tarugi P.
      • Loria P.
      The wide spectrum of steatohepatitis: a report of four cases and a review of the literature.
      ,
      • Willner I.R.
      • Waters B.
      • Patil S.R.
      • Reuben A.
      • Morelli J.
      • Riely C.A.
      Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.
      ,
      • Schwimmer J.B.
      • Celedon M.A.
      • Lavine J.E.
      • Salem R.
      • Campbell N.
      • Schork N.J.
      • et al.
      Heritability of nonalcoholic fatty liver disease.
      ].
      There are important differences concerning the definitions of overweight/obesity and MS between Western and Asia-Pacific patients. In the Asian population, morbidity and mortality occur at lower BMIs and smaller waist circumferences than in Caucasians, justifying specific criteria for overweight/obesity and MS representative of people living in the Asia-Pacific region [
      • Alberti K.G.
      • Zimmet P.
      • Shaw J.
      • IDF Epidemiology Task Force Consensus Group
      The metabolic syndrome: a new worldwide definition.
      ,
      • Dhiman R.K.
      • Duseja A.
      • Chawla Y.
      Asians need different criteria for defining overweight and obesity.
      ,
      • Chitturi S.
      • Farrell G.C.
      • Hashimoto E.
      • Saibara T.
      • Lau G.K.
      • Sollano J.D.
      • Asia-Pacific Working Party on NAFLD
      Non-alcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines.
      ,
      • World Health Organization
      Definition, diagnosis and classification of diabetes mellitus and its complications-part 1: diagnosis and classification of diabetes mellitus.
      ].
      Although the majority of NAFLD cases are strongly associated with overweight/obesity and T2D, different studies reported a prevalence of NAFLD in the normal-weight population between 7% and 16% [
      • 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.
      ,
      • Kim H.J.
      • Kim H.J.
      • Lee K.E.
      • Kim D.J.
      • Kim S.K.
      • Ahn C.W.
      • et al.
      Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Negro F.
      • Hallaji S.
      • Younossi Y.
      • Lam B.
      • et al.
      Nonalcoholic fatty liver disease in lean individuals in the United States.
      ,
      • Vos B.
      • Moreno C.
      • Nagy N.
      • Féry F.
      • Cnop M.
      • Vereerstraeten P.
      • et al.
      Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease.
      ,
      • Das K.
      • Das K.
      • Mukherjee P.S.
      • Ghosh A.
      • Ghosh S.
      • Mridha A.R.
      • et al.
      Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.
      ]. These studies invariably demonstrated that NAFLD is closely associated with metabolic disorders, particularly IR, even in lean patients. NAFLD should be considered an early predictor of metabolic derangements, thus suggesting that IR, rather than frank diabetes or obesity, is the alteration to be detected when screening for NAFLD. Therefore, methods and thresholds to define subtle IR are strongly needed in order to detect those patients at increased risk of hepatic complications.
      Compared to the general population, NAFLD is independently associated with a significantly higher all-cause mortality [
      • Musso G.
      • Gambino 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.
      ,
      • Ekstedt 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.
      ,
      • Soderberg 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.
      ,
      • Jepsen P.
      • Vilstrup H.
      • Mellemkjaer L.
      • Thulstrup A.M.
      • Olsen J.H.
      • Baron J.A.
      • et al.
      Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study.
      ,
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • Sanderson S.O.
      • Lindor K.D.
      • Feldstein A.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      ,
      • Ong J.P.
      • Pitts A.
      • Younossi Z.M.
      Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease.
      ,
      • Dunn W.
      • Xu R.
      • Wingard D.L.
      • Rogers C.
      • Angulo P.
      • Younossi Z.M.
      • et al.
      Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study.
      ,
      • Haring R.
      • Wallaschofski H.
      • Nauck M.
      • Dorr M.
      • Baumeister S.E.
      • Volzke H.
      Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels.
      ,
      • Rafiq N.
      • Bai C.
      • Fang Y.
      • Srishord M.
      • McCullough A.
      • Gramlich T.
      • et al.
      Long-term follow-up of patients with nonalcoholic fatty liver.
      ], and cancer incidence [
      • Sørensen H.T.
      • Mellemkjaer L.
      • Jepsen P.
      • Thulstrup A.M.
      • Baron J.
      • Olsen J.H.
      • et al.
      Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study.
      ,
      • Wong V.W.
      • Wong G.L.
      • Tsang S.W.
      • Fan T.
      • Chu W.C.
      • Woo J.
      • et al.
      High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis.
      ], principally HCC [
      • Bugianesi E.
      • Leone N.
      • Vanni E.
      • Marchesini G.
      • Brunello F.
      • Carucci P.
      • et al.
      Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
      ,
      • Baffy G.
      • Brunt E.M.
      • Caldwell S.H.
      Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace.
      ], increased incident T2D risk [
      • Ekstedt 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.
      ,
      • Fraser A.
      • Harris R.
      • Sattar N.
      • Ebrahim S.
      • Davey Smith G.
      • Lawlor D.A.
      Alanine transaminase, gamma-glutamyltransferase, and incident diabetes: the British women’s heart and health study and meta-analysis.
      ,
      • Yamada T.
      • Fukatsu M.
      • Suzuki S.
      • Wada T.
      • Yoshida T.
      • Joh T.
      Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup.
      ], greater prevalence/incidence of cardiovascular disease (CVD) [
      • Sookoian S.
      • Pirola C.J.
      Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review.
      ,
      • Targher G.
      • Day C.P.
      • Bonora E.
      Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
      ,
      • Wong V.W.
      • Wong G.L.
      • Yip G.W.
      • Lo A.O.
      • Limquiaco J.
      • Chu W.C.
      • et al.
      Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease.
      ,
      • Kozakova M.
      • Palombo C.
      • Eng M.P.
      • Dekker J.
      • Flyvbjerg A.
      • Mitrakou A.
      • et al.
      RISC Investigators. Fatty liver index, gamma-glutamyltransferase, and early carotid plaques.
      ], and a higher rate of major complications and death after surgery [
      • de Meijer V.E.
      • Kalish B.T.
      • Puder M.
      • Ijzermans J.N.
      Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection.
      ,
      • Reddy S.K.
      • Marsh J.W.
      • Varley P.R.
      • Mock B.K.
      • Chopra K.B.
      • Geller D.A.
      • et al.
      Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: a case-control study.
      ,
      • Lonardo A.
      • Sookoian S.
      • Chonchol M.
      • Loria P.
      • Targher G.
      Cardiovascular and systemic risk in nonalcoholic fatty liver disease – atherosclerosis as a major player in the natural course of NAFLD.
      ].
      Based on the above reasons, detection of NAFLD should be considered as a major task in the management of patients with features of IR. Nevertheless, due to uncertainties surrounding the best diagnostic and management strategy, unequivocal indications in NAFLD screening policies are lacking.
      US, being safe, inexpensive, widely available, and having a good performance when steatosis is present in at least 20–30% of hepatocytes is an acceptable first-line screening procedure for NAFLD in clinical practice. However, the relatively low acuity for mild steatosis, the low accuracy in morbid obesity, and its operator-dependency are the main limitations [
      • Palmentieri B.
      • de Sio I.
      • La Mura V.
      • Masarone M.
      • Vecchione R.
      • Bruno S.
      • et al.
      The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.
      ,
      • Dasarathy S.
      • Dasarathy J.
      • Khiyami A.
      • Joseph R.
      • Lopez R.
      • McCullough A.J.
      Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study.
      ]. Interestingly, although not so sensitive as magnetic resonance spectroscopy [
      • Szczepaniak L.S.
      • Nurenberg P.
      • Leonard D.
      • Browning J.D.
      • Reingold J.S.
      • Grundy S.
      • et al.
      Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.
      ,
      • Kotronen A.
      • Westerbacka J.
      • Bergholm R.
      • Pietiläinen K.H.
      • Yki-Järvinen H.
      Liver fat in the metabolic syndrome.
      ], US can nevertheless have a lower threshold for fat detection than previously appreciated [
      • Dasarathy S.
      • Dasarathy J.
      • Khiyami A.
      • Joseph R.
      • Lopez R.
      • McCullough A.J.
      Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study.
      ]. Criteria used to define US steatosis need to be standardized and semi-quantitated. Once such semi-quantitation is performed through simple scores, US is able to predict metabolic derangements and liver histology changes [
      • Hamaguchi M.
      • Kojima T.
      • Itoh Y.
      • Harano Y.
      • Fujii K.
      • Nakajima T.
      • et al.
      The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation.
      ,
      • Ballestri S.
      • Lonardo A.
      • Romagnoli D.
      • Carulli L.
      • Losi L.
      • Day C.P.
      • et al.
      Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD.
      ].
      Figure thumbnail fx6

      How to non-invasively assess inflammation and fibrosis and when to obtain an LB?

      Analysis of reports from real-life clinical practice

      Grattagliano reported that the majority of GPs indicated hypertransaminasemia or none as the best reason to ask for LB in NAFLD subjects. Only 2.3% of GPs chose over 50 year-old diabetic patients as potential candidates for LB. However, after attending a tailored workshop, 80.9% indicated the latter as good candidates for LB and a substantial proportion reconsidered a fraction of their previously diagnosed NAFLD patients at potential risk of NASH [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ].
      The Australian survey among non-liver Specialists reported that 98% correctly identified that NASH can be diagnosed on LB, about three-quarters agreed that LTs are not sufficiently sensitive to detect NASH, but 66% deemed that a diagnosis of NASH can be based on imaging [
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ].
      Ratziu showed that about two-thirds of Hepato-Gastroenterologists considered important the identification of steatohepatitis or the staging of fibrosis. However, the main indication for LB was to gauge the fibrosis stage. In fact, given the invasive nature of LB, 38% would not perform this procedure to estimate hepatic inflammation. Confirming that transaminases levels impact on the decision to perform an LB, 43% of hypertransaminasemic vs. 6% of normotransaminasemic NAFLD patients would be asked to undergo an LB. Non-invasive fibrosis markers were used by 90% of the surveyed physicians in clinical practice: the majority used both serum markers and elastometry [
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ].

      Analysis of guidelines

      Initial non-invasive assessment of inflammation and fibrosis is suggested in clinical practice by some [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ] but not all guidelines. CLDA and APWP restrict non-invasive assessment of NASH and fibrosis to research purposes alone [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ]. European and Italian guidelines suggest the combined use of clinical and laboratory parameters, serum markers, composite scores (particularly the NAFLD fibrosis score) and imaging methods (transient elastography – FibroScan) in order to reduce the number of NAFLD patients requiring LB [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ]. The American guideline confirms the clinical utility of NAFLD fibrosis score in identifying NAFLD patients with higher likelihood of having advanced fibrosis and highlights the importance of MS as strong predictor of NASH [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].
      There is universal agreement that LB should not be performed in all patients. All guidelines recommend LB in NAFLD patients presenting an increased risk for NASH or advanced fibrosis [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. LB is considered in suspected NAFLD patients in whom there is diagnostic uncertainty due to difficulties in excluding competing etiologies for hepatic steatosis and co-existing CLD by the majority of guidelines [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. The European guideline recommends performing LB to assess concurrent NAFLD in patients with other CLD, MRFs, and US steatosis [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ]. Asian-Pacific and European guidelines suggest the opportunity to perform LB in NAFLD patients subjected to surgical procedures for other purposes [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ]. All guidelines (implicitly or explicitly) recommend LB in NALFD patients enrolled in clinical trials [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].

      Comments

      Simple steatosis is associated with a normal life expectancy and its progression is limited to anecdotal case reports [
      • Tilg H.
      • Moschen A.R.
      Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.
      ,
      • Pais R.
      • Pascale A.
      • Fedchuck L.
      • Charlotte F.
      • Poynard T.
      • Ratziu V.
      Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease.
      ,
      • Yilmaz Y.
      Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions?.
      ]. Conversely, NASH worsens in up to 30% of cases, evolving in cirrhosis in a substantial fraction of cases [
      • Farrell G.C.
      • Larter C.Z.
      Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
      ,
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • Sanderson S.O.
      • Lindor K.D.
      • Feldstein A.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      ,
      • Harrison S.A.
      • Torgerson S.
      • Hayashi P.H.
      The natural history of nonalcoholic fatty liver disease: a clinical histopathological study.
      ]. Moreover, 30–75% of cases of cryptogenic cirrhosis can be attributed to previously unrecognized NASH [
      • Bugianesi E.
      • Leone N.
      • Vanni E.
      • Marchesini G.
      • Brunello F.
      • Carucci P.
      • et al.
      Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
      ,
      • Powell E.E.
      • Cooksley W.G.
      • 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.
      ,
      • 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.
      ,
      • Poonawala A.
      • Nair S.P.
      • Thuluvath P.J.
      Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.
      ,
      • Caldwell S.H.
      • Crespo D.M.
      The spectrum expanded: cryptogenic cirrhosis and the natural history of nonalcoholic fatty liver disease.
      ,
      • Maheshwari A.
      • Thuluvath P.J.
      Cryptogenic cirrhosis and NAFLD: are they related?.
      ]. Given that the presence of inflammation at the initial LB is the strongest predictor of NAFLD progression and that the degree of fibrosis is the most important prognostic factor, efforts of practicing physicians should be oriented towards identification of those patients with steatohepatitis and/or advanced fibrosis.
      Figure thumbnail fx7

      How to treat NAFLD patients?

      Analysis of reports from real-life clinical practice

      In the Italian survey, 78% and 91% of GPs, before and after the workshop, respectively, indicated diet as the first and best approach to NAFLD. 34.1% stated that statins should be avoided in NAFLD patients [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ].
      In Bergqvist’s study, 95% of non-hepatologists agreed that management of NAFLD involves weight loss, physical exercise, and treatment of concurrent MRFs. Further to lifestyle changes, drugs to lose weight and bariatric surgery were included in NAFLD management, whereas 75% of respondents excluded specific liver-directed drug therapy [
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ].
      The French survey among hepatologists showed that 72% of patients were treated with lifestyle changes only, while 28% were treated with drugs further to non-pharmacological interventions. The most frequently prescribed regimens were: metformin, ursodesoxycholic acid, phlebotomy, glitazones, and vitamin E. 42% recommended total abstinence from alcohol; about 50% allowed daily alcohol consumption of 10–30 g in male and 10–20 g in female patients [
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ].

      Analysis of guidelines (Table 3)

      There is universal consensus that all patients should undergo interventions aimed at promoting healthier lifestyles and strict control of MRFs associated with NAFLD. All guidelines agree that lifestyle changes including weight loss, dietary changes, and physical exercise should always be implemented as first-line option in all NAFLD patients [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].
      Table 3How to manage NAFLD patients?
      +, recommended; −, not recommended; /, not mentioned.
      With regard to the entity of weight loss, the Italian guideline simply states that 0.5 kg/week weight loss should be considered in overweight individuals [
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ], whereas the Chinese guideline recommends more than 5% weight reduction in 6–12 months [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ]. The European guideline suggests that a weight loss of 7% should be reasonable in overweight and mildly obese patients [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ]. Finally, American societies provide more specific indications: loss of at least 3–5% of body weight to improve steatosis, and up to 10% to improve necroinflammation [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].
      All societies concur in recommending a hypocaloric diet to promote weight-loss [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. However, while the Chinese guideline provides quantitative details (intake of 500–1000 kcal daily for obese adults) [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ], almost all guidelines identify qualitative directions (low carbohydrate and saturated fat intake, avoidance of fructose-enriched soft drinks and increased consumption of fibers and antioxidants-rich fruits and vegetables) [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ].
      All guidelines agree that heavy alcohol consumption should be avoided in NAFLD patients. However, no guidelines encourage mild-moderate intake [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].
      All guidelines strongly recommend avoidance of sedentariness and implementation of physical activity. The European guideline is more accurate in suggesting at least 150 min per week of moderate-intensity physical activity and at least 75 min per week of vigorous-intensity physical activity, further to muscle strengthening twice a week [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ]. Similarly, the Chinese guideline recommends moderate aerobic exercise at least 4 times weekly, with a minimum cumulated exercise time of 150 min [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ]. Moreover, European societies [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ] and the Chinese guideline [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ] highlight behavior therapy as important in accomplishing weight loss.
      Pharmacologic therapy should be reserved only to NASH. The more conservative suggestion is to limit the use of drugs to randomized controlled trials [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ]. However, EASL suggests a 1–2 year course of therapy with glitazones or vitamin E, preferably associated with high-dose UDCA [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ]; the AGA-AASLD-ACG guideline advocates pioglitazone and vitamin E in non-diabetic biopsy-proven NASH [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]; and the Chinese guideline proposes liver protective and anti-inflammatory drugs, including Chinese traditional and western medicines, in biopsy-proven NASH [
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ].
      All guidelines agree that the underlying MRFs should be managed as clinically required in NAFLD patients and drugs (particularly statins for dyslipidemia) given as needed [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. Bariatric surgery, if otherwise indicated, is considered a valid option for obese patients with NAFLD/NASH by all but one guideline [
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ].

      Comments

      The management of NAFLD patients is based on treatment of liver disease alongside the associated MRFs [
      • Maurantonio M.
      • Ballestri S.
      • Odoardi M.R.
      • Lonardo A.
      • Loria P.
      Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk?.
      ,
      • Musso G.
      • Cassader M.
      • Rosina F.
      • Gambino R.
      Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials.
      ]. Data on this topic are many and perhaps confusing. Guidelines are influenced by the year of publication. There are no medications specifically approved for NASH, therefore drug treatments specifically aimed at liver disease should be reserved to randomized trials with histological end points. Interestingly, there is increasing evidence for a beneficial effect of pioglitazone and vitamin E on liver outcomes in non-diabetic patients with biopsy-proven NASH [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • McCullough A.
      • Diehl A.M.
      • Bass N.M.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ], and a recent cost-utility analysis indicated that, in subjects with NASH and advanced fibrosis, treatment with either pioglitazone or vitamin E further to standard lifestyle changes is likely cost-effective [
      • Mahady S.E.
      • Wong G.
      • Craig J.C.
      • George J.
      Pioglitazone and vitamin E for nonalcoholic steatohepatitis: a cost utility analysis.
      ]. However, pioglitazone, vitamin E, and UDCA are not free of side and toxic effects. Pioglitazone is associated with weight gain and an increased risk of congestive heart failure, bone fractures, and bladder cancer [
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.
      • Erdmann E.
      • Massi-Benedetti M.
      • Moules I.K.
      • et al.
      Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
      ,
      • Azoulay L.
      • Yin H.
      • Filion K.B.
      • Assayag J.
      • Majdan A.
      • Pollak M.N.
      • et al.
      The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study.
      ]. High-dose vitamin E has been linked to increased all-cause mortality and an excess hemorrhagic stroke and prostate cancer [
      • Miller 3rd, E.R.
      • Pastor-Barriuso R.
      • Dalal D.
      • Riemersma R.A.
      • Appel L.J.
      • Guallar E.
      Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.
      ,
      • Klein E.A.
      • Thompson Jr., I.M.
      • Tangen C.M.
      • Crowley J.J.
      • Lucia M.S.
      • Goodman P.J.
      • et al.
      Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT).
      ]. High-dose UDCA determines diarrhea and abdominal discomfort [
      • Ratziu V.
      • de Ledinghen V.
      • Oberti F.
      • Mathurin P.
      • Wartelle-Bladou C.
      • Renou C.
      • et al.
      A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis.
      ].
      From a practical perspective, ameliorating cardiometabolic risk profile and histological disease activity, lifestyle-induced weight loss should be recommended in all NAFLD patients, but clear targets and suggestions on how to reach them are needed. It should be highlighted that the common pharmacological treatment of MRFs (particularly statins) is not contraindicated in NAFLD [
      • Chalasani N.
      Statins and hepatotoxicity: focus on patients with fatty liver.
      ].
      As far as alcohol intake concerns, on the one hand, heavy consumption is harmful to the liver [
      • Ekstedt M.
      • Franzén L.E.
      • Holmqvist M.
      • Bendtsen P.
      • Mathiesen U.L.
      • Bodemar G.
      • et al.
      Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease.
      ] and should be discouraged. On the other hand, light-moderate alcohol consumption might well exert favorable effects on MRFs and, perhaps, on liver outcomes [
      • Dunn W.
      • Xu R.
      • Schwimmer J.B.
      Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease.
      ,
      • Moriya A.
      • Iwasaki Y.
      • Ohguchi S.
      • Kayashima E.
      • Mitsumune T.
      • Taniguchi H.
      • et al.
      Alcohol consumption appears to protect against non-alcoholic fatty liver disease.
      ,
      • Dunn W.
      • Sanyal A.J.
      • Brunt E.M.
      • Unalp-Arida A.
      • Donohue M.
      • McCullough A.J.
      • et al.
      Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD).
      ,
      • Liangpunsakul S.
      • Chalasani N.
      What should we recommend to our patients with NAFLD regarding alcohol use?.
      ]. However, in the absence of randomized controlled trials, all guidelines discourage from prescribing low-moderate alcohol consumption as preventive/therapeutic strategy against NAFLD.

      How to follow-up NAFLD patients?

      Analysis of reports from real-life clinical practice

      Two-thirds and 22% of the surveyed Australian non-liver Specialists considered semi-annual LTs and 5 yearly LB as the most effective method for monitoring NAFLD patients [
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
      ]. The majority of French Hepatologists stated to monitor their NAFLD patients with a mean number of two annual visits. LTs and US were the most frequently performed procedures. 57% did not perform follow-up LB. With regards to MRFs, the majority of surveyed specialists monitored glycemic and lipid profile, and half of those who assessed these parameters did so twice a year. However, surrogate markers of IR were never monitored by at least 50% [
      • Ratziu V.
      • Cadranel J.F.
      • Serfaty L.
      • Denis J.
      • Renou C.
      • Delassalle P.
      • et al.
      A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.
      ].

      Analysis of guidelines

      There is universal consensus on the opportunity to perform hepatological and cardiovascular follow-up in NAFLD patients [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. In NAFLD patients, semi-annual to annual hepatic monitoring (non-invasive follow-up of fibrosis, liver US, transaminases and LTs, markers of IR) is warranted [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ]. Routine repetition of LB is not indicated [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. LB may be repeated not earlier than 5 years after baseline LB in those patients in whom fibrosis progression is suspected [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ]. Surveillance for esophago-gastric varices [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ] and HCC [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ] in patients with NASH-cirrhosis is advocated by the majority of societies.
      All societies agree that a thorough assessment of MRFs and a risk stratification for CVD should be done in all NAFLD patients [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. These evaluations should be repeated every 6 months–1 or 2 years [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ]; the interval between check-ups should be modulated on an individual basis, mirroring the severity of liver disease and clustering of MRFs [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ]. Generalized cancer screening programs cannot be proposed to all NAFLD patients [
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ]. Three out of five guidelines support the practice of oncologic follow-up on individual basis [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ]. Four scientific societies specifically mention HCC among the cancer types to which NAFLD patients may be prone [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ,
      • Fan J.G.
      • Jia J.D.
      • Li Y.M.
      • Wang B.Y.
      • Lu L.G.
      • Shi J.P.
      • et al.
      Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010 (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).
      ,
      • Loria P.
      • Adinolfi L.E.
      • Bellentani S.
      • Bugianesi E.
      • Grieco A.
      • Fargion S.
      • et al.
      Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.
      ,
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. The guideline of the Asia-Pacific region suggests to extend screening to those “cancers whose incidence is increased by MS” [
      • Farrell G.C.
      • Chitturi S.
      • Lau G.K.
      • Sollano J.D.
      Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary.
      ].

      Pediatric NAFLD

      Analysis of reports from real-life clinical practice

      A survey among American primary pediatric care providers showed that, in obese children with NAFLD, clinicians detected hepatomegaly in only 1.4% and requested LTs in 12.5% of encounters, thus increasing the likelihood of a delayed or omitted diagnosis [
      • Fishbein M.
      • Mogren J.
      • Mogren C.
      • Cox S.
      • Jennings R.
      Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease.
      ]. An Australian survey described that only 9% of GPs used BMI charts to correctly diagnose childhood obesity and only 30% assessed for fatty liver in overweight/obese children [
      • Sivertsen L.M.
      • Woolfenden S.R.
      • Woodhead H.J.
      • Lewis D.
      Diagnosis and management of childhood obesity: a survey of general practitioners in South West Sydney.
      ].
      Another survey among general pediatricians and pediatric endocrinologists and gastroenterologists at two American academic hospitals confirmed the underdiagnosis of obesity and the underscreening for MS and NAFLD in children [
      • Riley M.R.
      • Bass N.M.
      • Rosenthal P.
      • Merriman R.B.
      Underdiagnosis of pediatric obesity and underscreening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists.
      ].

      Analysis of guidelines

      Among adult NAFLD guidelines, only the American one deals with specific aspects of pediatric NAFLD [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]; a single position paper is specifically devoted to diagnosis of NAFLD in children and adolescents [
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ]. The American guideline and ESPGHAN statement disagree with regard to screening for NAFLD in overweight/obese children. American societies suggest that a formal recommendation cannot be made [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ], whereas ESPGHAN states that NAFLD should be suspected in all overweight/obese children and adolescents older than 3 years especially if familiarity for NAFLD is present [
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ].
      According to ESPGHAN, abdominal US and LTs should be the first diagnostic step in suspected NAFLD children, followed by exclusion of other liver diseases [
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ]. The two guidelines agree that very young or lean children with liver steatosis should be tested for monogenic metabolic disorders as causes of fatty liver [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ,
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ].
      Both documents suggest similar indications for LB: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ,
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ]. Only the American guideline discusses treatment of pediatric NAFLD. According to AGA-AASLD-ACG, intensive lifestyle modification is recommended as the first-line treatment in pediatric NAFLD. Metformin should be avoided. Vitamin E offers histological benefits to children with NASH, but confirmatory studies are needed before its use can be recommended in clinical practice [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ].

      Comments

      The rising incidence of obesity is paralleled by the increasing recognition of NAFLD also in children and adolescents [
      • Schwimmer J.B.
      • Deutsch R.
      • Kahen T.
      • Lavine J.E.
      • Stanley C.
      • Behling C.
      Prevalence of fatty liver in children and adolescents.
      ,
      • Loomba R.
      • Sirlin C.B.
      • Schwimmer J.B.
      • Lavine J.E.
      Advances in pediatric nonalcoholic fatty liver disease.
      ]. Due to its potential progressive nature also in childhood [
      • Molleston J.P.
      • White F.
      • Teckman J.
      • Fitzgerald J.F.
      Obese children with steatohepatitis can develop cirrhosis in childhood.
      ,
      • Feldstein A.E.
      • Charatcharoenwitthaya P.
      • Treeprasertsuk S.
      • Benson J.T.
      • Enders F.B.
      • Angulo P.
      The natural history of nonalcoholic fatty liver disease in children: a follow-up study for up to 20 years.
      ], early diagnosis and treatment are important in all age-groups [
      • Socha P.
      • Horvath A.
      • Vajro P.
      • Dziechciarz P.
      • Dhawan A.
      • Szajewska H.
      Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review.
      ]. Therefore, shared standards to be used by physicians caring pediatric NAFLD are needed. Non-invasive diagnostic strategy represents a key issue in pediatric practice. However, contrasting with adult medicine, relatively scarce data are available in pediatric patients [
      • Machado M.V.
      • Cortez-Pinto H.
      Non-invasive diagnosis of non-alcoholic fatty liver disease–a critical appraisal.
      ,
      • Nobili V.
      • Svegliati-Baroni G.
      • Alisi A.
      • Miele L.
      • Valenti L.
      • Vajro P.
      A 360-degree overview of paediatric NAFLD: recent insights.
      ].

      Discussion

      Given that NAFLD epidemic poses a heavy health-related costs burden [
      • Baumeister S.E.
      • Völzke 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.
      ], an effort is justified to improve our medical ability in clinical practice. A successful management plan requires a motivated public, competent primary care doctors and specialists, and the implementation of multidisciplinary collaborative networks [
      • de Silva H.J.
      • Dassanayake A.S.
      Non-alcoholic fatty liver disease: confronting the global epidemic requires better awareness.
      ]. However, studies in “real-life” practice have shown that: (1) awareness of NAFLD is low in the general population [
      • Leung C.M.
      • Lai L.S.
      • Wong W.H.
      • Chan K.H.
      • Luk Y.W.
      • Lai J.Y.
      • et al.
      Non-alcoholic fatty liver disease: an expanding problem with low levels of awareness in Hong Kong.
      ]; (2) knowledge of NAFLD and its complications is not properly diffused among GPs who thus may fail to approach some aspects of diagnosis and management [
      • Grattagliano I.
      • D’Ambrosio G.
      • Palmieri V.O.
      • Moschetta A.
      • Palasciano G.
      • Portincasa P.
      “Steatostop Project” Group. Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program.
      ,
      • Kallman J.B.
      • Arsalla A.
      • Park V.
      • Dhungel S.
      • Bhatia P.
      • Haddad D.
      • et al.
      Screening for hepatitis B, C and non-alcoholic fatty liver disease: a survey of community-based physicians.
      ,
      • Loguercio C.
      • Tiso A.
      • Cotticelli G.
      • Blanco Cdel V.
      • Arpino G.
      • Laringe M.
      • et al.
      Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs.
      ,
      • Sivertsen L.M.
      • Woolfenden S.R.
      • Woodhead H.J.
      • Lewis D.
      Diagnosis and management of childhood obesity: a survey of general practitioners in South West Sydney.
      ,
      • Fishbein M.
      • Mogren J.
      • Mogren C.
      • Cox S.
      • Jennings R.
      Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease.
      ]; (3) specialists other than hepatologists may miss a high proportion of high-risk NAFLD patients and under-appreciate the overlap between NAFLD and other MRFs [
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.