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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO)

Open AccessPublished:December 15, 2021DOI:https://doi.org/10.1016/j.numecd.2021.04.028

      Abstract

      Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell’Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l’Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources.
      Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.

      Keywords

      1. Introduction

      The present report is a summary of Clinical Practice Guidelines resulting from a cooperative work of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell’Obesità (SIO). Current knowledge on the diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD) is translated into relevant practical recommendations for management following the rules and the methodology suggested in Italy by the Centro Nazionale per l’Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). In this summary, we report the outline of disease burden and the risks associated with disease progression, followed by PICO questions and recommendations. The review of the literature at the basis of individual recommendations is uploaded as supplementary material.

      2. Burden of disease and risk factors

      The natural history of nonalcoholic fatty liver disease (NAFLD) has been extensively investigated in the past 20 years [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      . Steatosis is the hallmark of NAFLD and has been identified as an independent risk factor for the full spectrum of liver damage including inflammation, ballooning and fibrosis [
      • Dongiovanni P.
      • Stender S.
      • Pietrelli A.
      • et al.
      Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.
      ]. The diagnosis of NAFLD requires the exclusion of both secondary causes and of alcohol consumption ≥30 g per day for men and ≥20 g per day for women [
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ]. Recently, a consensus of experts proposed to overcome the current nomenclature “NAFLD” and adopt for a “positive” definition the acronym Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD) using metabolic dysfunctions as diagnostic criteria independently of the presence of other causes of chronic liver disease [
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      ]. The mean prevalence of NAFLD worldwide is 24.1%, ranging from 13.5% in Africa to 31.8% in Middle East, with differences among studies also related to diagnostic methods, age, gender and ethnicity [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ]. Italian studies indicate a prevalence of 22.5–27.0% in the general population [
      • 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.
      ,
      • Pendino G.M.
      • Mariano A.
      • Surace P.
      • et al.
      Prevalence and etiology of altered liver tests: a population-based survey in a Mediterranean town.
      ,
      • Caserta C.A.
      • Mele A.
      • Surace P.
      • et al.
      Association of non-alcoholic fatty liver disease and cardiometabolic risk factors with early atherosclerosis in an adult population in Southern Italy.
      • Petta S.
      • Di Marco V.
      • Pipitone R.M.
      • et al.
      Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population.
      , with a 2% prevalence of noninvasively-assessed advanced fibrosis due to NAFLD [
      • Petta S.
      • Di Marco V.
      • Pipitone R.M.
      • et al.
      Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population.
      ]. The prevalence increases in patients with metabolic comorbidities and the metabolic syndrome (MetS), defined by the presence of at least three metabolic alterations among elevated waist circumference (≥94 cm in males; ≥80 cm in females in Europids), elevated triglycerides (≥150 mg/dL), reduced HDL-C (≤40 mg/dL in males; ≤50 mg/dL in females), elevated blood pressure (systolic pressure ≥130 mmHg and/or diastolic pressure ≥85 mm or antihypertensive drug treatment) and elevated fasting glucose (≥100 mg/dL antihyperglycemic treatment) [
      • Alberti K.G.
      • Eckel R.H.
      • Grundy S.M.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; World heart federation; international atherosclerosis society; and international association for the study of obesity.
      ]. NAFLD is observed in 54–90% [
      • Petta S.
      • Di Marco V.
      • Pipitone R.M.
      • et al.
      Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population.
      ,
      • Colicchio P.
      • Tarantino G.
      • del Genio F.
      • et al.
      Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy.
      and 78.8% [
      • Soresi M.
      • Noto D.
      • Cefalu A.B.
      • et al.
      Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society.
      ] of cases with obesity or with MetS, respectively. In the Dionysos study, the presence of steatosis was closely associated with obesity [
      • Bellentani S.
      • Saccoccio G.
      • Masutti F.
      • et al.
      Prevalence of and risk factors for hepatic steatosis in Northern Italy.
      ] and in the Dionysos and Nutrition Liver Study the risk of NAFLD was 9-fold increased by the presence of BMI ≥ 30 kg/m2 and 6-fold by abdominal obesity (waist circumference ≥102 cm in males, ≥88 in females) [
      • 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.
      ], independently of altered liver enzymes. Raised liver enzymes, assumed as surrogate indexes of NAFLD, were reported in 21% of cases with obesity and did not increase systematically with obesity class [
      • Marchesini G.
      • Avagnina S.
      • Barantani E.G.
      • et al.
      Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome.
      ]. In a more recent analysis of 890 subjects of the community-based ABCD (“Alimentazione, Benessere Cardiovascolare e Diabete”) study, Petta et al. reported a NAFLD prevalence of 48%, with a relative risk for obesity of 4.02 (95% confidence interval, 2.77–5.84) [
      • Petta S.
      • Di Marco V.
      • Pipitone R.M.
      • et al.
      Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population.
      ], but the various diagnostic tools and/or settings may provide slightly different results.
      The prevalence of NAFLD is as high as 70–80% in patients with type 2 diabetes mellitus (T2DM) [
      • Lonardo A.
      • Bellentani S.
      • et al.
      Non-alcoholic Fatty Liver Disease Study Group
      Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups.
      ,
      • Younossi Z.M.
      • Golabi P.
      • de Avila L.
      • et al.
      The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis.
      , who are also more likely to have nonalcoholic steatohepatitis (NASH) and cirrhosis, even in the presence of fairly normal serum aminotransferase levels [
      • Younossi Z.M.
      • Golabi P.
      • de Avila L.
      • et al.
      The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      • Anstee Q.M.
      • Targher G.
      • Day C.P.
      Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
      . In Italian patients with diabetes NAFLD is reported in 59.0–73.2% [
      • Forlani G.
      • Giorda C.
      • Manti R.
      • et al.
      The burden of NAFLD and its characteristics in a nationwide population with type 2 diabetes.
      ,
      • Targher G.
      • Mantovani A.
      • Pichiri I.
      • et al.
      Non-alcoholic fatty liver disease is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes.
      , with about 13%-18% of them experiencing advanced fibrosis [
      • Giorda C.B.
      • Forlani G.
      • Manti R.
      • et al.
      Trend over time in hepatic fibrosis score in a cohort of type 2 diabetes patients.
      ]. A bidirectional association exists between NAFLD and T2DM [
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      ,
      • Targher G.
      • Marchesini G.
      • Byrne C.D.
      Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: causal association or epiphenomenon?.
      , worsening the course of both diseases; the presence of T2DM increases the risk of NAFLD progression to advanced fibrosis and cirrhosis, as well as also of incident hepatocellular carcinoma (HCC), liver-related hospital admissions and liver-related deaths [
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      ,
      • Porepa L.
      • Ray J.G.
      • Sanchez-Romeu P.
      • Booth G.L.
      Newly diagnosed diabetes mellitus as a risk factor for serious liver disease.
      ,
      • Wild S.H.
      • Morling J.R.
      • McAllister D.A.
      • et al.
      Type 2 diabetes and risk of hospital admission or death for chronic liver diseases.
      • Zoppini G.
      • Fedeli U.
      • Gennaro N.
      • Saugo M.
      • Targher G.
      • Bonora E.
      Mortality from chronic liver diseases in diabetes.
      , whereas the presence of NAFLD in T2DM is associated with a reduced probability of achieving good glycemic control, and exacerbates atherogenic dyslipidemia, further increasing the risk of chronic kidney disease and adverse CV outcomes [
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      ,
      • Anstee Q.M.
      • Targher G.
      • Day C.P.
      Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
      , particularly in the presence of NASH-fibrosis [
      • Sun D.Q.
      • Ye F.Z.
      • Kani H.T.
      • et al.
      Higher liver stiffness scores are associated with early kidney dysfunction in patients with histologically proven non-cirrhotic NAFLD.
      ].
      The lifetime costs of all NASH patients in the United States in 2017 is estimated at $222.6 billion, and the cost of the advanced NASH population at $95.4 billion [
      • Younossi Z.M.
      • Tampi R.
      • Priyadarshini M.
      • Nader F.
      • Younossi I.M.
      • Racila A.
      Burden of illness and economic model for patients with nonalcoholic steatohepatitis in the United States.
      ]. Data from Italian local Health Units, based on administrative data and resources utilization, calculated an average direct cost for NAFLD/NASH progressively increasing from the non-advanced stage, to advanced NAFLD disease, compensated cirrhosis, liver transplant, and hepatocellular carcinoma (HCC), also driven by comorbidities, up to over € 65.000/year [
      • Petta S.
      • Ting J.
      • Saragoni S.
      • et al.
      Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.
      ]. Considering the projections calculated by disease modeling for the next decades, the total costs is likely to become very challenging for the National Health system [
      • Petta S.
      • Ting J.
      • Saragoni S.
      • et al.
      Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.
      ].

      3. NAFLD mortality and morbidity

      Patients with NAFLD have an increased overall mortality compared to matched control populations [
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      ,
      • Younossi Z.
      • Henry L.
      Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality.
      . According to a meta-analysis, overall mortality was reported to be 15.4 per 1,000 person-years (range, 11.7–20.3) for patients with NAFLD and 25.6 (range, 6.3–103.8) for the cohort with NASH [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ]. The presence of NASH (adjusted hazard ratioadjHR], 9.16), age (adjHR, 1.06), and the presence of T2DM (adjHR, 2.09) increased all-cause and liver-related mortality, after controlling for other variables. Liver-specific mortality was estimated as 0.8 (range, 0.3–1.8) in NAFLD and 11.8 (range, 7.1–19.5) in NASH [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ]. Cardiovascular (CV) disease (CVD) remains the most common cause of death, independent of other metabolic comorbidities [
      • Spahillari A.
      • Mukamal K.J.
      • DeFilippi C.
      • et al.
      The association of lean and fat mass with all-cause mortality in older adults: the cardiovascular health study.
      ,
      • Stepanova M.
      • Younossi Z.M.
      Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.
      , driven by the atherogenic profile and widespread CV complications [
      • Stepanova M.
      • Younossi Z.M.
      Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.
      ,
      • Bhatia L.S.
      • Curzen N.P.
      • Calder P.C.
      • Byrne C.D.
      Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?.
      • Lonardo A.
      • Nascimbeni F.
      • Mantovani A.
      • Targher G.
      Hypertension, diabetes, atherosclerosis and NASH: cause or consequence?.
      , independently of other known risk factors [
      • Kim D.
      • Kim W.R.
      • Kim H.J.
      • Therneau T.M.
      Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States.
      ,
      • Targher G.
      • Byrne C.D.
      • Lonardo A.
      • Zoppini G.
      • Barbui C.
      Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
      . Fibrosis stage is the strongest predictor for mortality from CVD and liver-related disease in a cohort of biopsy-proven NAFLD after up to 33 years of follow-up [
      • Ekstedt M.
      • Hagstrom H.
      • Nasr P.
      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      ].
      NAFLD is also associated with an approximate 2-fold increased risk of incident T2DM, ranging from a 35% to a 5.5-fold increase, independent of overweight/obesity and other common risk factors [
      • Bhatia L.S.
      • Curzen N.P.
      • Calder P.C.
      • Byrne C.D.
      Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?.
      ,
      • Ballestri S.
      • Zona S.
      • Targher G.
      • et al.
      Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis.
      . The risk of incident T2DM appears to diminish over time following the improvement or resolution of NAFLD [
      • Sung K.C.
      • Wild S.H.
      • Byrne C.D.
      Resolution of fatty liver and risk of incident diabetes.
      ,
      • Yamazaki H.
      • Tsuboya T.
      • Tsuji K.
      • Dohke M.
      • Maguchi H.
      Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes.
      . Patients with NAFLD also have a nearly 40% increase in the long-term risk of incident chronic kidney disease [
      • Mantovani A.
      • Zaza G.
      • Byrne C.D.
      • et al.
      Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis.
      ], as well as other recognized associations with sleep apnea, osteoporosis, psoriasis and endocrinopathies [
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      ].
      The presence of NASH increases liver-related mortality [
      • Sayiner M.
      • Koenig A.
      • Henry L.
      • Younossi Z.M.
      Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world.
      ,
      Global Burden of Disease 2015
      Mortality and causes of death collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the global burden of disease study 2015.
      , but the most important driver of mortality is fibrosis at histology, specifically, zone 3 sinusoidal fibrosis plus periportal fibrosis (stage 2), advanced fibrosis (bridging fibrosis [stage 3] or cirrhosis [stage 4]) [
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      , associated with the multiple component of MetS [
      • Younossi Z.M.
      Non-alcoholic fatty liver disease - a global public health perspective.
      ]. Patients with stage 4 fibrosis (cirrhosis) had a nearly 10-fold risk of liver-related complications [
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ], with liver-related events occurring in 8.9 per 100 person-years (95% CI, 6.7–11.7]. The reported annual incidence of hepatic decompensation was 3.3 and 15.6 per 100 person-years among patients with Child Pugh (CP)-A5 and CP-A6 cirrhosis, respectively [
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wai-Sun Wong V.
      • et al.
      Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
      ].

      4. Hepatocellular carcinoma and extrahepatic cancers

      NAFLD is the third-most common cause of HCC in the United States, after hepatitis C and alcohol-related disease, accounting for 14.1% of all cases [
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      ]. The cumulative incidence of NAFLD-associated HCC has been reported to range from 2.4% to 12.8% over a median follow-up period of 3.2–7.2 years [
      • Younes R.
      • Bugianesi E.
      Should we undertake surveillance for HCC in patients with NAFLD?.
      ], corresponding to 0.44 (range, 0.29–0.66) per 1000 person-years and increasing at a 9% annual rate [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      ,
      • Ioannou G.N.
      • Green P.
      • Kerr K.F.
      • Berry K.
      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      . Patients with NAFLD fibrosis stages F3 and F4 have an almost 7-fold increased risk of HCC compared to people without liver disease [
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      ] and the risk is >10 folds higher in association with T2DM and obesity [
      • Dyson J.
      • Jaques B.
      • Chattopadyhay D.
      • et al.
      Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
      ], making NAFLD the second leading cause of liver transplantation (LT) due to HCC in U.S and the most rapidly increasing indication [
      • Wong R.J.
      • Cheung R.
      • Ahmed A.
      Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S..
      ]. At diagnosis, patients with NAFLD-related HCC are older, have higher prevalence of extrahepatic comorbidities but lower prevalence of cirrhosis (absence of cirrhosis in up to 1/3 of cases), and shorter survival time [
      • Younes R.
      • Bugianesi E.
      Should we undertake surveillance for HCC in patients with NAFLD?.
      ], being more likely to die from their primary liver cancer than other HCC patients [
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      ]. These conditions may be driven by less systematic surveillance, leading to diagnosis at later stage and less treatment [
      • Piscaglia F.
      • Svegliati-Baroni G.
      • Barchetti A.
      • et al.
      Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
      ].
      Other extra-hepatic cancers are similarly increased, namely cancers of the uterus (IRR=2.3; 95%CI 1.4, 4.1), stomach (IRR=2.3; 95%CI 1.3, 4.1), pancreas (IRR=2.0; 95%CI 1.2, 3.3) and colon (IRR=1.8; 95%CI 1.1, 2.8) [
      • Piscaglia F.
      • Svegliati-Baroni G.
      • Barchetti A.
      • et al.
      Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
      ]. The association with cancer risk is stronger in NAFLD than in obesity [
      • Allen A.M.
      • Hicks S.B.
      • Mara K.C.
      • Larson J.J.
      • Therneau T.M.
      The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - a longitudinal cohort study.
      ].

      5. Lean NAFLD

      The term ‘lean’ NAFLD refers to patients with a BMI within the ethnic-specific cut-off of normalweight, but frequently extended to the area of overweight (30 kg/m2 in Caucasian and 27 kg/m2 in Asian subjects). It is conceivable that ‘lean’ NAFLD comprises an heterogeneous NAFLD cohort associated with environmental and genetic factors, as well as differences in fat distribution and body composition [
      • Younes R.
      • Bugianesi E.
      NASH in lean individuals.
      ], accounting for 5–26% of total NAFLD cases in the Asian population and 7–20% in the Western areas [
      • Younes R.
      • Bugianesi E.
      NASH in lean individuals.
      ]. A recent meta-analysis of 33 observational studies from 14 countries concluded for a global prevalence of NAFLD in lean individuals (BMI ≤ 23 kg/m2 for Asian subjects and BMI ≤ 25 kg/m2 for non-Asian subjects) of 9.7% (95% CI: 7.7–11.8%), with an upward trend between 1988 and 2017[
      • Lu F.B.
      • Zheng K.I.
      • Rios R.S.
      • Targher G.
      • Byrne C.D.
      • Zheng M.H.
      Global epidemiology of lean non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      ]. Their rate of comorbidity is lower compared to obese patients, but higher compared to healthy controls [
      • Feldman A.
      • Eder S.K.
      • Felder T.K.
      • et al.
      Clinical and metabolic characterization of lean caucasian subjects with non-alcoholic fatty liver.
      ,
      • Younossi Z.M.
      • Otgonsuren M.
      • Venkatesan C.
      • Mishra A.
      In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not.
      . Data on histological severity are controversial; they can develop the full spectrum of liver disease associated with NASH [
      • Fracanzani A.L.
      • Valenti L.
      • Bugianesi E.
      • et al.
      Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity.
      ] and similar adverse health outcomes when longitudinally examined [
      • Dela Cruz A.C.
      • Bugianesi E.
      • George J.
      • et al.
      Characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease.
      ,
      • Hagstrom H.
      • Nasr P.
      • Ekstedt M.
      • et al.
      Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: a long-term follow-up study.
      .

      6. Methods for guideline development

      Following the needs of an updated guidance upon clinical management of the Non Alcoholic Fatty Liver Disease, the Scientific Societies whose members are primarily involved in its management (Italian Association for the Study of the Liver - AISF; Italian Society of Diabetology - SID; Italian Society of Obesity - SIO) commissioned to an experts panel the drafting of a new dedicated document to outline the updated clinical practice guidelines. The present document was made according to the rules dictated by the Italian Center for the Cure Excellence (Centro Nazionale per l’Eccellenza delle Cure - CNEC), an institution recently set up by the Italian National Institute of Health (Istituto Superiore di Sanità - ISS) to outline the methodologies needed to provide evidence-based clinical, diagnostic and therapeutic guidelines in Italy [
      CNEC - Centro Nazionale per l’Eccellenza delle Cure
      Manuale metodologco per la Produzione di Linee Guida di Pratica Clinica. Roma: ISS - Istituto Superiore di Sanità.
      ]. According to these rules, a “multi-societary” and “multi-disciplinary” committee of experts was selected by the abovementioned Scientific Societies. The committee defined the objectives, the key issues and retrieved the relevant evidences by performing a systematic review of literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines’ key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes) [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 2. Framing the question and deciding on important outcomes.
      ]. The most relevant questions were chosen by voting among the whole committee. The mean agreement among panel members on recommendations was 98.15%, as reported in supplementary Table 1. For each PICO question, a systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase) by performing both a free-text research and by a BOOLEAN research string formulated on purpose (see Appendix 1). The profiles of evidence were developed by applying the GRADE-Evidence to Decision (EtD) frameworks as per CNEC manual indications [
      CNEC - Centro Nazionale per l’Eccellenza delle Cure
      Manuale metodologco per la Produzione di Linee Guida di Pratica Clinica. Roma: ISS - Istituto Superiore di Sanità.
      ,
      • Moberg J.
      • Oxman A.D.
      • Rosenbaum S.
      • et al.
      The GRADE Evidence to Decision (EtD) framework for health system and public health decisions.
      . In particular, all aspects regarding the questions, the assessment of evidence and the conclusions drawings were discussed between the panel members and voted to obtain a final decision. The GRADEpro GDT online tool was used to develop the questions and make the decisions [
      GRADE
      GRADEpro guideline development tool.
      ]. The quality of evidence was evaluated by applying the “Quality Assessment of Diagnostic Accuracy Studies version 2” (QUADAS-2) checklist for the diagnostic accuracy questions [
      • Whiting P.F.
      • Rutjes A.W.
      • Westwood M.E.
      • et al.
      QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.
      ], the “revised tool for Risk of Bias in randomized trials” (RoB 2) [
      • Sterne J.A.C.
      • Savovic J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ] and the “Risk Of Bias in Non-randomized Studies - of Interventions” tool (ROBINS-I) [
      • Sterne J.A.
      • Hernan M.A.
      • Reeves B.C.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ] for randomized clinical trials and non-randomized studies where applicable.
      The final draft was submitted for advice and revision to EpaC (Liver Patients’ Association). Their comments were considered in the final version.

      7. Strength and limits

      The present report is a summary of Clinical Practice Guidelines resulting from a cooperative multi-society work and by using rigorous methodology suggested in Italy by the Centro Nazionale per l’Eccellenza delle cure and Istituto Superiore di Sanità. Lack of awareness for NAFLD and obstacles to apply and implement guidelines could limit their utility.

      8. What is already known on this subject?

      NAFLD is an emerging liver disease with a growing epidemiological and clinical burden.
      National guidelines for the management of NAFLD patients are not still available.

      9. What this study adds?

      The present document is the first effort to provide multi-society national guidelines on NAFLD aimed to a multidisciplinary and shared management of NAFLD patients.

      10. PICO Questions and recommendations

      • (A)
        Assessment of disease severity
      PICO 1 - In adult patients with NAFLD, should non-invasive scores, serum markers, liver stiffness, and imaging methods be used as replacement for liver biopsy for the diagnosis of NASH?
      Recommendation
      • In patients with NAFLD non-invasive tests do not have acceptable accuracy for the diagnosis of NASH, and liver biopsy remains the reference standard (B,2).
      References: [
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ,
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      ,
      • Castera L.
      • Friedrich-Rust M.
      • Loomba R.
      Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
      ,
      • Verhaegh P.
      • Bavalia R.
      • Winkens B.
      • Masclee A.
      • Jonkers D.
      • Koek G.
      Noninvasive tests do not accurately differentiate nonalcoholic steatohepatitis from simple steatosis: a systematic review and meta-analysis.
      ,
      • Zheng K.I.
      • Liu W.Y.
      • Pan X.Y.
      • et al.
      Combined and sequential non-invasive approach to diagnosing non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease and persistently normal alanine aminotransferase levels.
      ,
      • Brunt E.M.
      • Janney C.G.
      • Di Bisceglie A.M.
      • Neuschwander-Tetri B.A.
      • Bacon B.R.
      Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.
      • Bedossa P.
      • Pathology Consortium F.
      Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
      PICO 2 - In adult patients with NAFLD, should non-invasive scores, serum markers, liver stiffness, and imaging methods be used as replacement for liver biopsy for the diagnosis of advanced fibrosis?
      Recommendations
      • In patients with NAFLD, simple noninvasive scores, namely the Fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS), as well as liver stiffness measurement (LSM), using transient elastography, have acceptable accuracy to identify NAFLD cases at low risk of advanced fibrosis (A, 1).
      • A two-tier sequential combination of simple noninvasive scores like FIB-4 or NFS with imaging techniques such as LSM by transient elastography is recommended as a triage test for ruling out advanced fibrosis sparing further testing (B, 2).
      • Magnetic resonance elastography (MRE) is the most accurate noninvasive method for estimation of liver fibrosis. This technique can be preferred in clinical trials, but it is not recommended in clinical practice, being expensive and very rarely available (B, 2).
      References: [
      • Vilar-Gomez E.
      • Chalasani N.
      Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers.
      ,
      • Wong V.W.
      • Adams L.A.
      • de Ledinghen V.
      • Wong G.L.
      • Sookoian S.
      Noninvasive biomarkers in NAFLD and NASH - current progress and future promise.
      ,
      • Angulo P.
      • Hui J.M.
      • Marchesini G.
      • et al.
      The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.
      ,
      • Sterling R.K.
      • Lissen E.
      • Clumeck N.
      • et al.
      Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
      ,
      • Lin Z.H.
      • Xin Y.N.
      • Dong Q.J.
      • et al.
      Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis.
      ,
      • Harrison S.A.
      • Oliver D.
      • Arnold H.L.
      • Gogia S.
      • Neuschwander-Tetri B.A.
      Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease.
      ,
      • Xiao G.
      • Zhu S.
      • Xiao X.
      • Yan L.
      • Yang J.
      • Wu G.
      Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis.
      ,
      • Sun W.
      • Cui H.
      • Li N.
      • et al.
      Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: a meta-analysis study.
      ,
      • McPherson S.
      • Hardy T.
      • Dufour J.F.
      • et al.
      Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis.
      ,
      • Petta S.
      • Wai-Sun Wong V.
      • Bugianesi E.
      • et al.
      Impact of obesity and alanine aminotransferase levels on the diagnostic accuracy for advanced liver fibrosis of noninvasive tools in patients with nonalcoholic fatty liver disease.
      ,
      • Joo S.K.
      • Kim W.
      • Kim D.
      • et al.
      Steatosis severity affects the diagnostic performances of noninvasive fibrosis tests in nonalcoholic fatty liver disease.
      ,
      • Bertot L.C.
      • Jeffrey G.P.
      • de Boer B.
      • et al.
      Diabetes impacts prediction of cirrhosis and prognosis by non-invasive fibrosis models in non-alcoholic fatty liver disease.
      ,
      • Bril F.
      • McPhaul M.J.
      • Caulfield M.P.
      • et al.
      Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes.
      ,
      • Anstee Q.M.
      • Lawitz E.J.
      • Alkhouri N.
      • et al.
      Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials.
      ,
      • Guillaume M.
      • Moal V.
      • Delabaudiere C.
      • et al.
      Direct comparison of the specialised blood fibrosis tests fibrometer(V2G) and enhanced liver fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres.
      ,
      • Wong V.W.
      • Irles M.
      • Wong G.L.
      • et al.
      Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease.
      ,
      • Boursier J.
      • Zarski J.P.
      • de Ledinghen V.
      • et al.
      Determination of reliability criteria for liver stiffness evaluation by transient elastography.
      ,
      • Eddowes P.J.
      • Sasso M.
      • Allison M.
      • et al.
      Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease.
      ,
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • et al.
      The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease.
      ,
      • Petta S.
      • Wong V.W.
      • Camma C.
      • et al.
      Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values.
      ,
      • Karlas T.
      • Petroff D.
      • Sasso M.
      • et al.
      Impact of controlled attenuation parameter on detecting fibrosis using liver stiffness measurement.
      ,
      • Hsu C.
      • Caussy C.
      • Imajo K.
      • et al.
      Magnetic resonance vs transient elastography analysis of patients with nonalcoholic fatty liver disease: a systematic review and pooled analysis of individual participants.
      ,
      • Cassinotto C.
      • Boursier J.
      • de Ledinghen V.
      • et al.
      Liver stiffness in nonalcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy.
      ,
      • Petta S.
      • Wong V.W.
      • Camma C.
      • et al.
      Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD.
      ,
      • Petta S.
      • Vanni E.
      • Bugianesi E.
      • et al.
      The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease.
      ,
      • Boursier J.
      • de Ledinghen V.
      • Leroy V.
      • et al.
      A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis.
      • Srivastava A.
      • Gailer R.
      • Tanwar S.
      • et al.
      Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.
      Fig. 1 depicts a two-step algorithm, based on FIB-4 or NAFLD fibrosis score as first step followed by LSM, proposed for the assessment of fibrosis severity in patients with NAFLD.
      Fig 1
      Fig. 11NAFLD is defined by ultrasound; in case of difficult access to ultrasound, clinicians can directly screen patients with features of metabolic syndrome by liver enzymes and noninvasive scores of fibrosis.
      2AST, ALT, GGT
      Note that in patients referred to specialists (right side) follow-up will depend on disease severity/available therapeutic protocols; timing of follow-up in negative patients (left side) will depend on the presence of metabolic factors and comorbid conditions.
      PICO 3 - In adult patients with NAFLD, should non-invasive scores, liver stiffness and imaging methods be used as replacement for liver biopsy for predicting liver-related outcomes?
      Recommendations
      • In patients with NAFLD, non-invasive tools might acceptably rule out fibrosis progression (C, 2).
      • In patients with NAFLD, noninvasive tools might acceptably predict the risk of occurrence of overall and liver-related events and mortality (C, 2).
      References: [
      • Kim D.
      • Kim W.R.
      • Kim H.J.
      • Therneau T.M.
      Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States.
      ,
      • Siddiqui M.S.
      • Yamada G.
      • Vuppalanchi R.
      • et al.
      Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage.
      ,
      • Angulo P.
      • Bugianesi E.
      • Bjornsson E.S.
      • et al.
      Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease.
      ,
      • Hagstrom H.
      • Nasr P.
      • Ekstedt M.
      • Stal P.
      • Hultcrantz R.
      • Kechagias S.
      Accuracy of noninvasive scoring systems in assessing risk of death and liver-related endpoints in patients with nonalcoholic fatty liver disease.
      ,
      • Sebastiani G.
      • Alshaalan R.
      • Wong P.
      • et al.
      Prognostic value of non-invasive fibrosis and steatosis tools, hepatic venous pressure gradient (HVPG) and histology in nonalcoholic steatohepatitis.
      ,
      • Onnerhag K.
      • Hartman H.
      • Nilsson P.M.
      • Lindgren S.
      Non-invasive fibrosis scoring systems can predict future metabolic complications and overall mortality in non-alcoholic fatty liver disease (NAFLD).
      ,
      • Boursier J.
      • Vergniol J.
      • Guillet A.
      • et al.
      Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.
      ,
      • Munteanu M.
      • Pais R.
      • Peta V.
      • et al.
      Long-term prognostic value of the FibroTest in patients with non-alcoholic fatty liver disease, compared to chronic hepatitis C, B, and alcoholic liver disease.
      ,
      • Kawamura Y.
      • Arase Y.
      • Ikeda K.
      • et al.
      Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma.
      ,
      • Shili-Masmoudi S.
      • Wong G.L.
      • Hiriart J.B.
      • et al.
      Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.
      ,
      • Petta S.
      • Sebastiani G.
      • Vigano M.
      • et al.
      Monitoring occurrence of liver-related events and survival by transient elastography in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease.
      • Hagstrom H.
      • Talback M.
      • Andreasson A.
      • Walldius G.
      • Hammar N.
      Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease.
      PICO 4 - In adult patients with NAFLD, should genetic testing be used as an add on after usual testing in predicting the severity of histologically-assessed liver damage and liver-related outcomes?
      Recommendations
      • Clinicians in referral centers might consider the genetic risk profile for stratification of individual NAFLD-HCC risk, but the effectiveness of such strategy requires larger prospective studies (C, 2).
      • We suggest that genetic risk variants be evaluated in clinical studies for stratification of disease risk progression and sub-phenotyping of NAFLD (B, 2).
      References: [
      • Dongiovanni P.
      • Stender S.
      • Pietrelli A.
      • et al.
      Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.
      ,
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ,
      • Eslam M.
      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      ,
      • Hyysalo J.
      • Mannisto V.T.
      • Zhou Y.
      • et al.
      A population-based study on the prevalence of NASH using scores validated against liver histology.
      ,
      • Mancina R.M.
      • Dongiovanni P.
      • Petta S.
      • et al.
      The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent.
      ,
      • Abul-Husn N.S.
      • Cheng X.
      • Li A.H.
      • et al.
      A protein-truncating HSD17B13 variant and protection from chronic liver disease.
      ,
      • Valenti L.V.
      • Baselli G.A.
      Genetics of nonalcoholic fatty liver disease: a 2018 update.
      ,
      • Grimaudo S.
      • Pipitone R.M.
      • Pennisi G.
      • et al.
      Association between PNPLA3 rs738409 C>G variant and liver-related outcomes in patients with nonalcoholic fatty liver disease.
      ,
      • Liu Y.L.
      • Patman G.L.
      • Leathart J.B.
      • et al.
      Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.
      ,
      • Anstee Q.M.
      • Liu Y.L.
      • Day C.P.
      • Reeves H.L.
      Reply to: HCC and liver disease risk in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance.
      ,
      • Pelusi S.
      • Baselli G.
      • Pietrelli A.
      • et al.
      Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease.
      ,
      • Pillai S.
      • Duvvuru S.
      • Bhatnagar P.
      • et al.
      The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro.
      • Liu W.Y.
      • Zheng K.I.
      • Pan X.Y.
      • et al.
      Effect of PNPLA3 polymorphism on diagnostic performance of various noninvasive markers for diagnosing and staging nonalcoholic fatty liver disease.
      Supplementary Table 2
      • (B)
        Weight loss and behavioral intervention for NAFLD
      PICO 5 - In adult patients with NAFLD, what is the efficacy of weight loss on histologically-assessed liver damage and liver-related outcomes in comparison with no intervention?
      Recommendations
      • All subjects with NAFLD, including lean (non-obese) NAFLD, should be involved in lifestyle programs aimed at healthy diet and habitual physical activity to a ≥7–10% weight loss target, repeatedly associated with improved histology, including fibrosis (B, 1).
      • The dietary approach to NAFLD should favor adherence to the principles of the Mediterranean diet, including a reduced intake of refined and industrial sugars, associated with reduced hepatic fat content and decreased cardiovascular risk (B, 1).
      • Low-modest alcohol intake in noncirrhotic NAFLD patients should not be encouraged (C, 2) and total abstinence in NAFLD-cirrhosis is recommended (B, 1).
      • In patients with NAFLD, any types of physical activity, as well as reduced sedentariness, should be counseled, in order to reduce liver fat, independently of changes in body weight (B, 1).
      • Clinicians should recommend weight loss by intensive, structured lifestyle programs delivered under specialist control and/or pharmacotherapy and/or bariatric surgery in NAFLD subjects with obesity to reduce liver disease severity (A, 1).
      References: [
      • Petta S.
      • Di Marco V.
      • Pipitone R.M.
      • et al.
      Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population.
      ,
      • Marchesini G.
      • Bugianesi E.
      • Forlani G.
      • et al.
      Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.
      ,
      • Berentzen T.L.
      • Gamborg M.
      • Holst C.
      • Sorensen T.I.
      • Baker J.L.
      Body mass index in childhood and adult risk of primary liver cancer.
      ,
      • Zimmermann E.
      • Gamborg M.
      • Holst C.
      • Baker J.L.
      • Sorensen T.I.
      • Berentzen T.L.
      Body mass index in school-aged children and the risk of routinely diagnosed non-alcoholic fatty liver disease in adulthood: a prospective study based on the Copenhagen school health records register.
      ,
      • Hagstrom H.
      • Stal P.
      • Hultcrantz R.
      • Hemmingsson T.
      • Andreasson A.
      Overweight in late adolescence predicts development of severe liver disease later in life: a 39years follow-up study.
      ,
      • Suzuki A.
      • Angulo P.
      • Lymp J.
      • et al.
      Chronological development of elevated aminotransferases in a nonalcoholic population.
      ,
      • Wong V.W.
      • Wong G.L.
      • Yeung D.K.
      • et al.
      Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy.
      ,
      • Tsuneto A.
      • Hida A.
      • Sera N.
      • et al.
      Fatty liver incidence and predictive variables.
      ,
      • Zelber-Sagi S.
      • Lotan R.
      • Shlomai A.
      • et al.
      Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up.
      ,
      • Moscatiello S.
      • Di Luzio R.
      • Bugianesi E.
      • et al.
      Cognitive-behavioral treatment of non-alcoholic fatty liver disease: a propensity score-adjusted observational study.
      ,
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      ,
      • Bellentani S.
      • Dalle Grave R.
      • Suppini A.
      • Marchesini G.
      Fatty Liver Italian N. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach.
      ,
      • Marchesini G.
      • Petta S.
      • Dalle Grave R.
      Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice.
      ,
      • Mazzotti A.
      • Caletti M.T.
      • Brodosi L.
      • et al.
      An internet-based approach for lifestyle changes in patients with NAFLD: two-year effects on weight loss and surrogate markers.
      ,
      • Romero-Gomez M.
      • Zelber-Sagi S.
      • Trenell M.
      Treatment of NAFLD with diet, physical activity and exercise.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis.
      ,
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      ,
      • Armstrong M.J.
      • Gaunt P.
      • Aithal G.P.
      • et al.
      Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ,
      • Wong V.W.
      • Chan R.S.
      • Wong G.L.
      • et al.
      Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial.
      ,
      • Neuschwander-Tetri B.A.
      Lifestyle modification as the primary treatment of NASH.
      ,
      • Marchesini G.
      • Mazzella N.
      • Forlani G.
      Weight loss for a healthy liver.
      ,
      • Petroni M.L.
      • Brodosi L.
      • Barbanti F.L.
      • Di Domizio S.
      • Petta S.
      • Marchesini G.
      Lifestyle changes for the treatment of nonalcoholic fatty liver disease – a 2015-19 update.
      ,
      • Vilar-Gomez E.
      • Athinarayanan S.J.
      • Adams R.N.
      • et al.
      Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study.
      ,
      • Wong V.W.
      • Wong G.L.
      • Chan R.S.
      • et al.
      Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease.
      ,
      • Kontogianni M.D.
      • Tileli N.
      • Margariti A.
      • et al.
      Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease.
      ,
      • Ryan M.C.
      • Itsiopoulos C.
      • Thodis T.
      • et al.
      The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.
      ,
      • Gepner Y.
      • Shelef I.
      • Komy O.
      • et al.
      The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content.
      ,
      • Abid A.
      • Taha O.
      • Nseir W.
      • Farah R.
      • Grosovski M.
      • Assy N.
      Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome.
      ,
      • Zelber-Sagi S.
      • Nitzan-Kaluski D.
      • Goldsmith R.
      • et al.
      Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study.
      ,
      • Ryu S.
      • Chang Y.
      • Jung H.S.
      • et al.
      Relationship of sitting time and physical activity with non-alcoholic fatty liver disease.
      ,
      • St George A.
      • Bauman A.
      • Johnston A.
      • Farrell G.
      • Chey T.
      • George J.
      Independent effects of physical activity in patients with nonalcoholic fatty liver disease.
      ,
      • Hashida R.
      • Kawaguchi T.
      • Bekki M.
      • et al.
      Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review.
      ,
      • Keating S.E.
      • George J.
      • Johnson N.A.
      The benefits of exercise for patients with non-alcoholic fatty liver disease.
      ,
      • Sookoian S.
      • Castano G.O.
      • Pirola C.J.
      Modest alcohol consumption decreases the risk of non-alcoholic fatty liver disease: a meta-analysis of 43 175 individuals.
      ,
      • Dunn W.
      • Sanyal A.J.
      • Brunt E.M.
      • et al.
      Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD).
      ,
      • Chang Y.
      • Cho Y.K.
      • Kim Y.
      • et al.
      Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study.
      ,
      • Chang Y.
      • Ryu S.
      • Kim Y.
      • et al.
      Low levels of alcohol consumption, obesity, and development of fatty liver with and without evidence of advanced fibrosis.
      ,
      • Ajmera V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
      ,
      • Xu L.
      • Xie J.
      • Chen S.
      • et al.
      Light-to-moderate alcohol consumption is associated with increased risk of type 2 diabetes in individuals with nonalcoholic fatty liver disease: A nne-year cohort study.
      ,
      • VanWagner L.B.
      • Ning H.
      • Allen N.B.
      • et al.
      Alcohol use and cardiovascular disease risk in patients with nonalcoholic fatty liver disease.
      ,
      • Aberg F.
      • Puukka P.
      • Salomaa V.
      • et al.
      Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts.
      ,
      • Hajifathalian K.
      • Torabi Sagvand B.
      • McCullough A.J.
      Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study.
      ,
      • Ascha M.S.
      • Hanouneh I.A.
      • Lopez R.
      • Tamimi T.A.
      • Feldstein A.F.
      • Zein N.N.
      The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      ,
      The Diabetes Prevention Program Research Group
      The Diabetes Prevention Program (DPP): description of lifestyle intervention.
      ,
      • RR W.
      • Bolin P.
      • et al.
      Look AHEAD Research Group
      Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
      ,
      • Burza M.A.
      • Romeo S.
      • Kotronen A.
      • et al.
      Long-term effect of bariatric surgery on liver enzymes in the Swedish obese subjects (SOS) study.
      ,
      • Sjostrom L.
      • Peltonen M.
      • Jacobson P.
      • et al.
      Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications.
      ,
      • Lassailly G.
      • Caiazzo R.
      • Buob D.
      • et al.
      Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.
      ,
      • Lassailly G.
      • Caiazzo R.
      • Ntandja-Wandji L.C.
      • et al.
      Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis.
      ,
      • Sjostrom L.
      • Peltonen M.
      • Jacobson P.
      • et al.
      Bariatric surgery and long-term cardiovascular events.
      ,
      • Mingrone G.
      • Panunzi S.
      • De Gaetano A.
      • et al.
      Bariatric surgery versus conventional medical therapy for type 2 diabetes.
      ,
      • Sjoholm K.
      • Pajunen P.
      • Jacobson P.
      • et al.
      Incidence and remission of type 2 diabetes in relation to degree of obesity at baseline and 2 year weight change: the Swedish Obese Subjects (SOS) study.
      • Klebanoff M.J.
      • Corey K.E.
      • Chhatwal J.
      • Kaplan L.M.
      • Chung R.T.
      • Hur C.
      Bariatric surgery for nonalcoholic steatohepatitis: a clinical and cost-effectiveness analysis.
      • (C)
        Pharmacologic treatment for NAFLD
      The epidemic of NAFLD and its complications, and the discovery of different potential therapeutic targets for NASH treatment led to start an impressive number of clinical trials. International guidelines recommend that pharmacological therapy for NAFLD/NASH should be reserved to patients presenting an active disease and the presence of liver fibrosis ≥ stage 2 [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American association for the study of liver diseases.
      ,
      • Rinella M.E.
      • Tacke F.
      • Sanyal A.J.
      • Anstee Q.M.
      participants of the AASLD EASL Workshop
      Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.
      . Moreover, the FDA (US Food and Drug Administration) and the EMA (European Medicines Agency) identified two endpoints for the conditional approval of drugs in patients with noncirrhotic NASH: (1) resolution of NASH without worsening of liver fibrosis, and (2) at least one stage improvement in liver fibrosis without worsening of NASH fibrosis [
      • Rinella M.E.
      • Tacke F.
      • Sanyal A.J.
      • Anstee Q.M.
      participants of the AASLD EASL Workshop
      Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.
      ]. Consistently, most of the phase 2b and phase 3 trials enrolled patients with NASH plus fibrosis stage F2-F3. However, in spite of a large number of published or ongoing clinical trials, to date neither FDA, nor EMA or AIFA have approved any pharmacological treatment for patients with NASH.
      PICO 6 - In adult patients with NAFLD, what is the efficacy of pharmacological treatment on histologically-assessed liver damage and liver-related outcomes in comparison with no pharmacological intervention?
      Recommendations
      • In patients with NASH pioglitazone may be used to improve NASH and fibrosis, although the drug is off-label and the risk/benefit balance related to pioglitazone side-effects should be discussed with each patient (B, 2).
      • In patients with NASH vitamin E may be used to improve NASH and fibrosis, even if risks and benefits should be discussed with each patient (B, 2).
      • In patients with NASH standard or high-dose ursodeoxycholic acid (UDCA) should not be used to treat NASH and fibrosis, because ineffective (B, 2).
      • In patients with NASH obeticholic acid may improve fibrosis without worsening of NASH, but its use is waiting for approval by regulatory agencies, based on additional safety and efficacy data (B, 2).
      References for pioglitazone: [
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • et al.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      ,
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Torres D.M.
      • Jones F.J.
      • Shaw J.C.
      • Williams C.D.
      • Ward J.A.
      • Harrison S.A.
      Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial.
      ,
      • Sharma B.C.
      • Kumar A.
      • Garg V.
      • Reddy R.S.
      • Sakhuja P.
      • Sarin S.K.
      A randomized controlled trial comparing efficacy of pentoxifylline and pioglitazone on metabolic factors and liver histology in patients with non-alcoholic steatohepatitis.
      ,
      • Razavizade M.
      • Jamali R.
      • Arj A.
      • Matini S.M.
      • Moraveji A.
      • Taherkhani E.
      The effect of pioglitazone and metformin on liver function tests, insulin resistance, and liver fat content in nonalcoholic fatty liver disease: a randomized double blinded clinical trial.
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ,
      • Musso G.
      • Cassader M.
      • Paschetta E.
      • Gambino R.
      Pioglitazone for advanced fibrosis in nonalcoholic steatohepatitis: new evidence, new challenges.
      ,
      • Yen F.S.
      • Yang Y.C.
      • Hwu C.M.
      • et al.
      Liver-related long-term outcomes of thiazolidinedione use in persons with type 2 diabetes.
      ,
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.
      • 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.
      ,
      • Kernan W.N.
      • Viscoli C.M.
      • Furie K.L.
      • et al.
      Pioglitazone after ischemic stroke or transient ischemic attack.
      ,
      • Lewis J.D.
      • Habel L.A.
      • Quesenberry C.P.
      • et al.
      Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes.
      ,
      • Billington E.O.
      • Grey A.
      • Bolland M.J.
      The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis.
      ,
      • Liao H.W.
      • Saver J.L.
      • Wu Y.L.
      • Chen T.H.
      • Lee M.
      • Ovbiagele B.
      Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis.
      • Mahady S.E.
      • Wong G.
      • Craig J.C.
      • George J.
      Pioglitazone and vitamin E for nonalcoholic steatohepatitis: a cost utility analysis.
      References for vitamin E: [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Hoofnagle J.H.
      • Van Natta M.L.
      • Kleiner D.E.
      • et al.
      Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis.
      ,
      • Sato K.
      • Gosho M.
      • Yamamoto T.
      • et al.
      Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials.
      ,
      • Xu R.
      • Tao A.
      • Zhang S.
      • Deng Y.
      • Chen G.
      Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis.
      ,
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • et al.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ,
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Gawrieh S.
      • et al.
      Vitamin E improves transplant-free survival and hepatic decompensation among patients with nonalcoholic steatohepatitis and advanced fibrosis.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Gluud L.L.
      • Simonetti R.G.
      • Gluud C.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ,
      • Schurks M.
      • Glynn R.J.
      • Rist P.M.
      • Tzourio C.
      • Kurth T.
      Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.
      • Klein E.A.
      • Thompson I.M.
      • Tangen C.M.
      • et al.
      Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT).
      References for ursodeoxycholic acid: [
      • Dufour J.F.
      • Oneta C.M.
      • Gonvers J.J.
      • et al.
      Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis.
      ,
      • Lindor K.D.
      • Kowdley K.V.
      • Heathcote E.J.
      • et al.
      Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.
      ,
      • Leuschner U.F.
      • Lindenthal B.
      • Herrmann G.
      • et al.
      High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.
      • Ratziu V.
      • de Ledinghen V.
      • Oberti F.
      • et al.
      A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis.
      References for obeticholic acid: [
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ,
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      Intercept pharmaceuticals: update on intercept’s NDA submission to the FDA.
      PICO 7 - In adult patients with NAFLD and type 2 diabetes mellitus, what is the efficacy of glucose-lowering treatment on histologically-assessed liver damage and liver-related outcomes?
      Recommendations
      • In T2DM patients with NAFLD/NASH, pioglitazone is specifically recommended to treat liver disease (B, 2).
      • In T2DM patients with NAFLD/NASH, metformin use is safe for the liver, but it is not specifically recommended to treat liver disease (B, 2).
      • In T2DM patients with NAFLD/NASH, DPP-4 inhibitors are safe for the liver, but their use is not specifically recommended to treat liver disease (C, 2).
      • In T2DM patients with NAFLD/NASH, GLP-1 receptor agonists are safe for the liver, but, despite preliminary evidence that may decrease liver damage, their use is not specifically approved to treat liver disease (B, 2).
      • In T2DM patients with NAFLD/NASH, SGLT-2 inhibitors are safe for the liver, but their use is not specifically recommended to treat liver disease (C, 2).
      References for metformin: [
      • Razavizade M.
      • Jamali R.
      • Arj A.
      • Matini S.M.
      • Moraveji A.
      • Taherkhani E.
      The effect of pioglitazone and metformin on liver function tests, insulin resistance, and liver fat content in nonalcoholic fatty liver disease: a randomized double blinded clinical trial.
      ,
      • Bugianesi E.
      • Gentilcore E.
      • Manini R.
      • et al.
      A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease.
      ,
      • Haukeland J.W.
      • Konopski Z.
      • Eggesbo H.B.
      • et al.
      Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial.
      ,
      • Lavine J.E.
      • Schwimmer J.B.
      • Van Natta M.L.
      • et al.
      Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.
      ,
      • Omer Z.
      • Cetinkalp S.
      • Akyildiz M.
      • et al.
      Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease.
      ,
      • Rana H.
      • Yadav S.S.
      • Reddy H.D.
      • Singhal S.
      • Singh D.K.
      • Usman K.
      Comparative effect of insulin sensitizers and statin on metabolic profile and ultrasonographical score in non alcoholic fatty liver disease.
      • Zhang Z.J.
      • Zheng Z.J.
      • Shi R.
      • Su Q.
      • Jiang Q.
      • Kip K.E.
      Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis.
      References for DPP-4 inhibitors: [
      • Cui J.
      • Philo L.
      • Nguyen P.
      • et al.
      Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial.
      ,
      • Macauley M.
      • Hollingsworth K.G.
      • Smith F.E.
      • et al.
      Effect of vildagliptin on hepatic steatosis.
      ,
      • Deng X.L.
      • Ma R.
      • Zhu H.X.
      • Zhu J.
      Short article: a randomized-controlled study of sitagliptin for treating diabetes mellitus complicated by nonalcoholic fatty liver disease.
      ,
      • Yan J.
      • Yao B.
      • Kuang H.
      • et al.
      Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease.
      American Diabetes Association
      Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019.
      References for GLP-1 receptor agonists: [
      • Armstrong M.J.
      • Gaunt P.
      • Aithal G.P.
      • et al.
      Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ,
      • Yan J.
      • Yao B.
      • Kuang H.
      • et al.
      Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease.
      ,
      • Armstrong M.J.
      • Houlihan D.D.
      • Rowe I.A.
      • et al.
      Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program.
      ,
      • Shao N.
      • Kuang H.Y.
      • Hao M.
      • Gao X.Y.
      • Lin W.J.
      • Zou W.
      Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes.
      ,
      • Dutour A.
      • Abdesselam I.
      • Ancel P.
      • et al.
      Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy.
      ,
      • Frossing S.
      • Nylander M.
      • Chabanova E.
      • et al.
      Effect of liraglutide on ectopic fat in polycystic ovary syndrome: a randomized clinical trial.
      ,
      • Feng W.
      • Gao C.
      • Bi Y.
      • et al.
      Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease.
      ,
      • Newsome P.
      • Francque S.
      • Harrison S.
      • et al.
      Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      • Kristensen S.L.
      • Rorth R.
      • Jhund P.S.
      • et al.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      References for SGLT-2 inhibitors: [
      • Sattar N.
      • Fitchett D.
      • Hantel S.
      • George J.T.
      • Zinman B.
      Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME(R) trial.
      ,
      • Ito D.
      • Shimizu S.
      • Inoue K.
      • et al.
      Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial.
      ,
      • Kuchay M.S.
      • Krishan S.
      • Mishra S.K.
      • et al.
      Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial).
      ,
      • Eriksson J.W.
      • Lundkvist P.
      • Jansson P.A.
      • et al.
      Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study.
      ,
      • Bolinder J.
      • Ljunggren O.
      • Kullberg J.
      • et al.
      Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.
      ,
      • Cusi K.
      • Bril F.
      • Barb D.
      • et al.
      Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes.
      ,
      • Leiter L.A.
      • Forst T.
      • Polidori D.
      • Balis D.A.
      • Xie J.
      • Sha S.
      Effect of canagliflozin on liver function tests in patients with type 2 diabetes.
      ,
      • Wilding J.P.
      • Charpentier G.
      • Hollander P.
      • et al.
      Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.
      ,
      • Shimizu M.
      • Suzuki K.
      • Kato K.
      • et al.
      Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease.
      ,
      • Bolinder J.
      • Ljunggren O.
      • Johansson L.
      • et al.
      Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.
      • Kluger A.Y.
      • Tecson K.M.
      • Lee A.Y.
      • et al.
      Class effects of SGLT2 inhibitors on cardiorenal outcomes.
      • (D)
        NAFLD and liver transplantation
      PICO 8 - In adult patients with NASH candidate for liver transplantation, should the evaluation of cardiometabolic comorbidities in the pre- and post-transplant phase be different from that of patients with liver disease of other etiology in order to reduce cardiovascular complications?
      Recommendations
      • In liver transplant candidates with NASH-related decompensated cirrhosis or NASH-HCC, both at particularly high risk of developing cardiovascular events, cardiovascular risk factors should be assessed by a multidisciplinary team, which includes a transplant cardiologist and a transplant anesthesiologist, but no universally validated algorithms are available for a comprehensive evaluation (C, 1).
      • Thorough screening for hypertension, diabetes, and dyslipidemia is recommended in patients with NASH undergoing evaluation for liver transplantation and appropriate medical treatment in wait-listed patients is mandatory to reduce events and de-listing (B, 1).
      • Obesity alone does not constitute a contraindication for liver transplantation. Patients with decompensated NASH-cirrhosis or NASH-HCC and morbid obesity (body mass index > 40 kg/m2 should be listed on a highly individualized basis, especially in the presence of diabetes (B, 2).
      References: [
      • Targher G.
      • Byrne C.D.
      • Lonardo A.
      • Zoppini G.
      • Barbui C.
      Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
      ,
      • Piscaglia F.
      • Svegliati-Baroni G.
      • Barchetti A.
      • et al.
      Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
      ,
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European liver transplant registry study.
      ,
      • Wang X.
      • Li J.
      • Riaz D.R.
      • Shi G.
      • Liu C.
      • Dai Y.
      Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis.
      ,
      • Tsochatzis E.
      • Coilly A.
      • Nadalin S.
      • et al.
      International Liver Transplantation consensus statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation.
      ,
      • Stine J.G.
      • Wentworth B.J.
      • Zimmet A.
      • et al.
      Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.
      ,
      • Kulik L.
      • El-Serag H.B.
      Epidemiology and management of hepatocellular carcinoma.
      ,
      • An J.
      • Shim J.H.
      • Kim S.O.
      • et al.
      Prevalence and prediction of coronary artery disease in patients with liver cirrhosis: a registry-based matched case-control study.
      ,
      • Patel S.S.
      • Nabi E.
      • Guzman L.
      • et al.
      Coronary artery disease in decompensated patients undergoing liver transplantation evaluation.
      ,
      • Konerman M.A.
      • Fritze D.
      • Weinberg R.L.
      • Sonnenday C.J.
      • Sharma P.
      Incidence of and risk assessment for adverse cardiovascular outcomes after liver transplantation: a systematic review.
      ,
      • Yotti R.
      • Ripoll C.
      • Bermejo J.
      • Banares R.
      Cardiac function, a key component in evaluation for liver transplant.
      ,
      • Carey W.D.
      • Dumot J.A.
      • Pimentel R.R.
      • et al.
      The prevalence of coronary artery disease in liver transplant candidates over age 50.
      ,
      • Plotkin J.S.
      • Scott V.L.
      • Pinna A.
      • Dobsch B.P.
      • De Wolf A.M.
      • Kang Y.
      Morbidity and mortality in patients with coronary artery disease undergoing orthotopic liver transplantation.
      ,
      • Hayes S.W.
      • De Lorenzo A.
      • Hachamovitch R.
      • et al.
      Prognostic implications of combined prone and supine acquisitions in patients with equivocal or abnormal supine myocardial perfusion SPECT.
      ,
      • Senzolo M.
      • Bassanello M.
      • Graziotto A.
      • et al.
      Microvascular autonomic dysfunction may justify false-positive stress myocardial perfusion imaging in patients with liver cirrhosis undergoing liver transplantation.
      ,
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      • Fleisher L.A.
      • Fleischmann K.E.
      • Auerbach A.D.
      • et al.
      2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American college of cardiology/American heart association task force on practice guidelines.
      PICO 9 - In adult patients with NASH and morbid obesity, candidate for liver transplantation, what is the efficacy of bariatric surgery on pre- and post-transplant outcomes in comparison with no bariatric surgery?
      Recommendation
      • Bariatric surgery may improve outcomes in patients with morbid obesity in the setting of liver transplantation, however in decompensated cirrhosis it is associated with higher risk of morbidity and mortality; too few data are available to recommend the procedure before, during or after transplantation (C, 2).
      References: [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • 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.
      ,
      • Nair S.
      • Verma S.
      • Thuluvath P.J.
      Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States.
      ,
      • Ratziu V.
      • Ghabril M.
      • Romero-Gomez M.
      • Svegliati-Baroni G.
      Recommendations for management and treatment of nonalcoholic steatohepatitis.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Saab S.
      • et al.
      The impact of type 2 diabetes and obesity on the long-term outcomes of more than 85 000 liver transplant recipients in the US.
      ,
      • Mosko J.D.
      • Nguyen G.C.
      Increased perioperative mortality following bariatric surgery among patients with cirrhosis.
      ,
      • Lin M.Y.
      • Tavakol M.M.
      • Sarin A.
      • et al.
      Laparoscopic sleeve gastrectomy is safe and efficacious for pretransplant candidates.
      ,
      • Takata M.C.
      • Campos G.M.
      • Ciovica R.
      • et al.
      Laparoscopic bariatric surgery improves candidacy in morbidly obese patients awaiting transplantation.
      ,
      • Dziodzio T.
      • Biebl M.
      • Ollinger R.
      • Pratschke J.
      • Denecke C.
      The role of bariatric surgery in abdominal organ transplantation-the next big challenge?.
      • Heimbach J.K.
      • Watt K.D.
      • Poterucha J.J.
      • et al.
      Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease.
      • (E)
        NAFLD ascertainment in the general population
      PICO 10 - In the adult population are non-invasive scores and imaging methods useful for the diagnosis of NAFLD?
      Recommendations
      • Non-invasive scores (Fatty Liver Index – FLI) may be useful in population studies for the diagnosis of steatosis (A, 1).
      • Ultrasonography (US) is the first-line diagnostic procedure for detecting NAFLD, as it has high accuracy for moderate-severe steatosis and also provides additional diagnostic information (A, 1).
      • 1H-Magnetic Resonance Spectroscopy (MRS) is the reference standard for a quantitative estimation of liver fat. This technique should be preferred in clinical trials, but it is not recommended in clinical practice because expensive and not largely available (A, 2).
      • Controlled Attenuation Parameter (CAP) is an alternative tool for non-invasive assessment and follow-up of steatosis but more data are needed to definitively define its role (B,2).
      References: [
      • Bedogni G.
      • Bellentani S.
      • Miglioli L.
      • et al.
      The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.
      ,
      • Fedchuk L.
      • Nascimbeni F.
      • Pais R.
      • et al.
      Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease.
      ,
      • Hernaez R.
      • Lazo M.
      • Bonekamp S.
      • et al.
      Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis.
      ,
      • Ajmera V.
      • Park C.C.
      • Caussy C.
      • et al.
      Magnetic resonance imaging proton density fat fraction associates with progression of fibrosis in patients with nonalcoholic fatty liver disease.
      ,
      • Ryan C.K.
      • Johnson L.A.
      • Germin B.I.
      • Marcos A.
      One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation.
      ,
      • Lee S.S.
      • Park S.H.
      Radiologic evaluation of nonalcoholic fatty liver disease.
      ,
      • Gu J.
      • Liu S.
      • Du S.
      • et al.
      Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis.
      ,
      • Loomba R.
      Role of imaging-based biomarkers in NAFLD: recent advances in clinical application and future research directions.
      ,
      • Pu K.
      • Wang Y.
      • Bai S.
      • et al.
      Diagnostic accuracy of controlled attenuation parameter (CAP) as a non-invasive test for steatosis in suspected non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      ,
      • Petroff D.
      • Blank V.
      • Newsome P.N.
      • et al.
      Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis.
      ,
      • Caussy C.
      • Alquiraish M.H.
      • Nguyen P.
      • et al.
      Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.
      • Chan W.K.
      • Nik Mustapha N.R.
      • Mahadeva S.
      • Wong V.W.
      • Cheng J.Y.
      • Wong G.L.
      Can the same controlled attenuation parameter cut-offs be used for M and XL probes for diagnosing hepatic steatosis?.
      ,
      • Karlas T.
      • Petroff D.
      • Sasso M.
      • et al.
      Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.
      PICO 11 - In adult population with metabolic risk factors are non-invasive scores, liver stiffness and imaging methods useful for the diagnosis of advanced fibrosis?
      Recommendation
      • In adult individuals with one or more features of the metabolic syndrome, a combination of non-invasive fibrosis markers may help improve referral of patients with advanced liver fibrosis from primary care to specialist setting, also reducing the cost of management (B, 2).
      References: [
      • Younossi Z.M.
      • Golabi P.
      • de Avila L.
      • et al.
      The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wai-Sun Wong V.
      • et al.
      Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
      ,
      • Wilson J.M.G.
      • Jungner G.
      Principles and practice of screening for disease.
      ,
      • Nascimbeni F.
      • Pais R.
      • Bellentani S.
      • et al.
      From NAFLD in clinical practice to answers from guidelines.
      ,
      • Kanwal F.
      • Kramer J.
      • Li L.
      • et al.
      Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in non-alcoholic fatty liver disease.
      ,
      • Usher-Smith J.A.
      • Sharp S.J.
      • Griffin S.J.
      The spectrum effect in tests for risk prediction, screening, and diagnosis.
      ,
      • Harris R.
      • Harman D.J.
      • Card T.R.
      • Aithal G.P.
      • Guha I.N.
      Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review.
      ,
      • Standing H.C.
      • Jarvis H.
      • Orr J.
      • et al.
      GPs’ experiences and perceptions of early detection of liver disease: a qualitative study in primary care.
      • Srivastava A.
      • Jong S.
      • Gola A.
      • et al.
      Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease.

      11. Conclusion

      In the past few years NAFLD emerged as a common liver disease in adults frequently associated with metabolic alterations, and as a leading cause of HCC and liver decompensation, finally impacting resource utilization and costs of the Healthcare systems. Also in Italy, the cost associated with NAFLD for the National Health System is rapidly increasing [
      • Petta S.
      • Ting J.
      • Saragoni S.
      • et al.
      Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.
      ]. The growing interest for NAFLD lead to the development of new diagnostic tools and algorithms to identify and refer patients at high risk of liver damage to liver specialists for assessment and treatment. The implementation of lifestyle programs aimed at weight loss and ongoing clinical trials with drugs targeting pathogenic pathways responsible for necroinflammation and fibrosis open new scenario in the management of NAFLD patients [
      • Petroni M.L.
      • Brodosi L.
      • Bugianesi E.
      • Marchesini G.
      Management of non-alcoholic fatty liver disease.