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EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

  • European Association for the Study of the Liver (EASL)
  • European Association for the Study of Diabetes (EASD)
  • andEuropean Association for the Study of Obesity (EASO)
Published:April 06, 2016DOI:https://doi.org/10.1016/j.jhep.2015.11.004

      Abbreviations:

      ALT (alanine transaminase), BMI (body mass index), CAP (controlled attenuation parameter), CCR (chemokine receptor), CK-18 (cytokeratin-18 fragments), CKD (chronic kidney disease), CT (computed tomography), CVD (cardiovascular disease), EASD (European Association for the Study of Diabetes), EASL (European Association for the Study of the Liver), EASO (European Association for the Study of Obesity), ELF (enhanced liver fibrosis), F (fibrosis stage), FIB-4 (fibrosis 4 calculator), FLI (fatty liver index), HbA1c (glycosylated haemoglobin A1c), HCC (hepatocellular carcinoma), HDL (high-density lipoprotein), HOMA-IR (homeostasis model assessment of insulin resistance), IFG (impaired fasting glucose), IR (Insulin resistance), LDL (low-density lipoprotein), MetS (metabolic syndrome), MRI (magnetic resonance imaging), MRS (magnetic resonance spectroscopy), NAFL (non-alcoholic fatty liver), NAFLD (non-alcoholic fatty liver disease), NFS (NAFLD fibrosis score), NAS (NAFLD Activity Score), NASH (non-alcoholic steatohepatitis), NPV (negative predictive value), OGTT (oral glucose tolerance test), PNHS (paediatric NAFLD histological score), PNPLA3 (patatin-like phospholipase domain containing 3), PPAR (peroxisome proliferator-activated receptor), PPV (positive predictive value), PUFA (polyunsaturated fatty acids), RCT (randomized controlled trials), SAF (steatosis, activity and fibrosis), T2DM (type 2 diabetes mellitus), TM6SF2 (transmembrane 6 superfamily 2), UDCA (urso-deoxycholic acid), US (ultrasound)

      Introduction

      The Clinical Practice Guidelines propose recommendations for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease (NAFLD) patients and are the product of a joint effort by the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO). They update a position statement based on the 2009 EASL Special Conference [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ].
      The data have been retrieved by an extensive PubMed search up to April 2015. The final statements are graded according to the level of evidence and strength of recommendation, which are adjustable to local regulations and/or team capacities (Table 1) [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ]. In particular, screening for NAFLD in the population at risk should be in the context of the available resources, considering the burden for the national health care systems and the currently limited effective treatments. The document is intended both for practical use and for advancing the research and knowledge of NAFLD in adults, with specific reference to paediatric NAFLD whenever necessary. The final purpose is to improve patient care and awareness of the importance of NAFLD, and to assist stakeholders in the decision-making process by providing evidence-based data, which also takes into consideration the burden of clinical management for the healthcare system.
      Table 1Evidence grade used for the EASL–EASD–EASO Clinical Practice Guidelines on NAFLD (adapted from the GRADE system
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ).

      Definition

      NAFLD is characterised by excessive hepatic fat accumulation, associated with insulin resistance (IR), and defined by the presence of steatosis in >5% of hepatocytes according to histological analysis or by a proton density fat fraction (providing a rough estimation of the volume fraction of fatty material in the liver) >5.6% assessed by proton magnetic resonance spectroscopy (1H-MRS) or quantitative fat/water selective magnetic resonance imaging (MRI). NAFLD includes two pathologically distinct conditions with different prognoses: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); the latter covers a wide spectrum of disease severity, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC) (Table 2).
      Table 2The spectrum of NAFLD and concurrent diseases.
      • ⁎
        Also called Primary NAFLD and associated with metabolic risk factors/components of Metabolic Syndrome:
        • 1.
          Waist circumference ⩾94/⩾80 cm for Europid men/women.
        • 2.
          Arterial pressure ⩾130/85 mmHg or treated for hypertension.
        • 3.
          Fasting glucose ⩾100 mg/dl (5.6 mmol/L) or treated for T2DM.
        • 4.
          Serum triacylglycerols >150 mg/dl (>1.7 mmol/L).
        • 5.
          HDL cholesterol <40/50 mg/dl for men/women (<1.0/<1.3 mmol/L).
      °Also called secondary NAFLD. Note that primary and secondary NAFLD may coexist in individual patients. Also NAFLD and AFLD may coexist in subjects with metabolic risk factors and drinking habits above safe limits.
      ^Can occur in the absence of cirrhosis and histological evidence of NASH, but with metabolic risk factors suggestive of “burned-out” NASH.
      The diagnosis of NAFLD requires the exclusion of both secondary causes and of a daily alcohol consumption ⩾30 g for men and ⩾20 g for women [
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      ]. Alcohol consumption above these limits indicates alcoholic liver disease. The relationship between alcohol and liver injury depends on several cofactors (type of alcoholic beverage, drinking patterns, duration of exposure, individual/genetic susceptibility), rendering simple quantitative thresholds at least partly arbitrary. Specifically, patients consuming moderate amounts of alcohol may be still predisposed to NAFLD if they have metabolic risk factors. Of note, the overall impact of metabolic risk factors on the occurrence of steatosis appears to be higher than that of alcohol in these patients [
      • Bellentani S.
      • Saccoccio G.
      • Masutti F.
      • Croce L.S.
      • Brandi G.
      • Sasso F.
      • et al.
      Prevalence of and risk factors for hepatic steatosis in Northern Italy.
      ]. The definitive diagnosis of NASH requires a liver biopsy.

       Recommendations

      Prevalence and incidence

      NAFLD is the most common liver disorder in Western countries, affecting 17–46% of adults, with differences according to the diagnostic method, age, sex and ethnicity [
      • Vernon G.
      • Baranova A.
      • Younossi Z.M.
      Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
      ]. It parallels the prevalence of MetS and its components, which also increases the risk of more advanced disease, both in adults and in children. NAFLD is also present in 7% of normal-weight (lean) persons [
      • Younossi Z.M.
      • Stepanova M.
      • Negro F.
      • Hallaji S.
      • Younossi Y.
      • Lam B.
      • et al.
      Nonalcoholic fatty liver disease in lean individuals in the United States.
      ], more frequently in females, at a younger age and with normal liver enzymes. Their liver disease may nonetheless be progressive [
      • Fracanzani A.L.
      • Valenti L.
      • Bugianesi E.
      • Andreoletti M.
      • Colli A.
      • Vanni E.
      • et al.
      Risk of severe liver disease in NAFLD with normal aminotransferase levels: a role for insulin resistance and diabetes.
      ].
      NAFLD incidence has rarely been measured. It was 20-86/1000 person-years based on elevated liver enzymes and/or on ultrasound (US), and 34/1000 per year by 1H-MRS [
      • Marchesini G.
      • Mazzotti A.
      NAFLD incidence and remission: only a matter of weight gain and weight loss?.
      ].
      The need for NAFLD screening in the community has been questioned given the high direct and indirect costs of testing, the low predictive value of non-invasive tests, the risks of liver biopsy and the lack of effective treatments [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. However, the progressive form of NAFLD (i.e. NASH), particularly when associated with advanced fibrosis, should be identified in patients at risk (age >50 years, type 2 diabetes mellitus [T2DM] or MetS), because of its prognostic implications. Validated cost utility studies on extensive screening programmes are eagerly awaited. Similarly, although familial clustering occurs, family screening is not generally advisable, with the exception of cases with defined inherited diseases (e.g. lysosomal acid lipase deficiency).

       Recommendations

      Pathogenesis: Lifestyle and genes

      A high-calorie diet, excess (saturated) fats, refined carbohydrates, sugar-sweetened beverages, a high fructose intake and a Western diet [
      • Barrera F.
      • George J.
      The role of diet and nutritional intervention for the management of patients with NAFLD.
      ] have all been associated with weight gain and obesity, and more recently with NAFLD. High fructose consumption may increase the risk of NASH and advanced fibrosis, although the association may be confounded by excess calorie intake or by unhealthy lifestyles and sedentary behaviour [
      • Chiu S.
      • Sievenpiper J.L.
      • de Souza R.J.
      • Cozma A.I.
      • Mirrahimi A.
      • Carleton A.J.
      • et al.
      Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
      ], which are more common in NAFLD [
      • Gerber L.
      • Otgonsuren M.
      • Mishra A.
      • Escheik C.
      • Birerdinc A.
      • Stepanova M.
      • et al.
      Non-alcoholic fatty liver disease (NAFLD) is associated with low level of physical activity: a population-based study.
      ].

       Recommendations

      Figure thumbnail fx8
      Several genetic modifiers of NAFLD have been identified [
      • Anstee Q.M.
      • Targher G.
      • Day C.P.
      Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
      ], but a minority have been robustly validated (Supplementary Table 1). The best-characterised genetic association is with PNPLA3, initially identified from genome-wide association studies and confirmed in multiple cohorts and ethnicities as a modifier of NAFLD severity across the entire histological spectrum [
      • Valenti L.
      • Al-Serri A.
      • Daly A.K.
      • Galmozzi E.
      • Rametta R.
      • Dongiovanni P.
      • et al.
      Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.
      ,
      • Liu Y.L.
      • Patman G.L.
      • Leathart J.B.
      • Piguet A.C.
      • Burt A.D.
      • Dufour J.F.
      • et al.
      Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.
      ]. Recently, the TM6SF2 gene has been reported as another disease modifier [
      • Liu Y.L.
      • Reeves H.L.
      • Burt A.D.
      • Tiniakos D.
      • McPherson S.
      • Leathart J.B.
      • et al.
      TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.
      ,
      • Dongiovanni P.
      • Petta S.
      • Maglio C.
      • Fracanzani A.L.
      • Pipitone R.
      • Mozzi E.
      • et al.
      Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.
      ] and may have clinical utility assisting risk stratification for liver-related vs. cardiovascular morbidity.
      The PNPLA3 rs738409 variant also confers susceptibility and affects the histological pattern of NAFLD and fibrosis in obese children and adolescents [
      • Valenti L.
      • Alisi A.
      • Galmozzi E.
      • Bartuli A.
      • Del Menico B.
      • Alterio A.
      • et al.
      I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease.
      ]. A NASH risk score based on four polymorphisms has been validated in obese children with increased liver enzymes [
      • Nobili V.
      • Donati B.
      • Panera N.
      • Vongsakulyanon A.
      • Alisi A.
      • Dallapiccola B.
      • et al.
      A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease.
      ].

       Recommendations

      Liver biopsy

      Liver biopsy is essential for the diagnosis of NASH and is the only procedure that reliably differentiates NAFL from NASH, despite limitations due to sampling variability [
      • Ratziu V.
      • Charlotte F.
      • Heurtier A.
      • Gombert S.
      • Giral P.
      • Bruckert E.
      • et al.
      Sampling variability of liver biopsy in nonalcoholic fatty liver disease.
      ].
      NAFL encompasses: a) steatosis alone, b) steatosis with lobular or portal inflammation, without ballooning, or c) steatosis with ballooning but without inflammation [
      • Kleiner D.E.
      • Brunt E.M.
      Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research.
      ]. The diagnosis of NASH requires the joint presence of steatosis, ballooning and lobular inflammation [
      • Kleiner D.E.
      • Brunt E.M.
      Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research.
      ,
      • Kleiner D.E.
      • Brunt E.M.
      • Van Natta M.
      • Behling C.
      • Contos M.J.
      • Cummings O.W.
      • et al.
      Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      ,
      • Bedossa P.
      FLIP Pathology Consortium
      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.
      ]. Other histological features can be seen in NASH, but are not necessary for the diagnosis: portal inflammation, polymorphonuclear infiltrates, Mallory-Denk bodies, apoptotic bodies, clear vacuolated nuclei, microvacuolar steatosis and megamitochondria. Perisinusoidal fibrosis is also frequent, but not part of the diagnostic criteria; the term “borderline” NASH is confusing, unnecessary and should be abandoned. The prospectively designed FLIP algorithm increases observer agreement and precisely defines the grading of ballooning [
      • Bedossa P.
      FLIP Pathology Consortium
      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.
      ]. “Burned-out NASH” describes regression of advanced disease (steatosis, inflammation or ballooning) in patients exposed to metabolic risk factors.
      The NAFLD Activity Score (NAS) scoring system should not be used for the diagnosis of NASH but rather for the evaluation of disease severity, once the diagnosis has been established by the overall pathological assessment. Although NAS is correlated with aminotransferase and homeostasis model assessment of insulin resistance (HOMA-IR) [
      • Brunt E.M.
      • Kleiner D.E.
      • Wilson L.A.
      • Belt P.
      • Neuschwander-Tetri B.A.
      • Network N.C.R.
      Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings.
      ], they have a low prognostic value [
      • Ekstedt M.
      • Hagstrom H.
      • Nasr P.
      • Fredrikson M.
      • Stal P.
      • Kechagias S.
      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      ]. The steatosis, activity and fibrosis (SAF) score [
      • Bedossa P.
      FLIP Pathology Consortium
      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.
      ] is an alternative with good reproducibility and provides a more accurate and comprehensive description. Fibrosis staging relies on the Kleiner classification [
      • Kleiner D.E.
      • Brunt E.M.
      • Van Natta M.
      • Behling C.
      • Contos M.J.
      • Cummings O.W.
      • et al.
      Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      ] (used in a simplified pattern in SAF) [
      • Bedossa P.
      FLIP Pathology Consortium
      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.
      ].
      In children, NASH displays many of the features observed in adults, even though the distribution of lesions may be different. Portal inflammation is a frequent feature, but can also be seen in adults with more severe disease [
      • Brunt E.M.
      • Kleiner D.E.
      • Wilson L.A.
      • Unalp A.
      • Behling C.E.
      • Lavine J.E.
      • et al.
      Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network.
      ]. Hepatocellular ballooning and Mallory-Denk bodies are only sporadically observed in paediatric NASH, and portal-based chronic inflammation is predominant [
      • Kleiner D.E.
      • Brunt E.M.
      • Van Natta M.
      • Behling C.
      • Contos M.J.
      • Cummings O.W.
      • et al.
      Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      ]. Based on the distinctive histological pattern, a specific histological score (Paediatric NAFLD Histological Score – PNHS) has been validated for better classification of children with/without NASH [
      • Alkhouri N.
      • De Vito R.
      • Alisi A.
      • Yerian L.
      • Lopez R.
      • Feldstein A.E.
      • et al.
      Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease.
      ].

      Non-invasive assessment

      Non-invasive markers should aim to: i) in primary care settings, identify the risk of NAFLD among individuals with increased metabolic risk; ii) in secondary and tertiary care settings, identify those with worse prognosis, e.g. severe NASH; iii) monitor disease progression; iv) predict response to therapeutic interventions. Achieving these objectives could reduce the need for liver biopsy.

       Steatosis

      Rationale. Steatosis should be documented whenever NAFLD is suspected as the primary disease or as a coexisting condition. It also predicts future diabetes mellitus, cardiovascular events and arterial hypertension. In clinical practice, quantification of fat content is not of interest, except as a surrogate of treatment efficacy, and is therefore not generally recommended.
      In individual patients, especially in tertiary care centres, steatosis should be identified by imaging, preferably US, because it is more widely available and cheaper than the gold standard, MRI (Supplementary Table 2). US has limited sensitivity and does not reliably detect steatosis when <20% [
      • Saadeh S.
      • Younossi Z.M.
      • Remer E.M.
      • Gramlich T.
      • Ong J.P.
      • Hurley M.
      • et al.
      The utility of radiological imaging in nonalcoholic fatty liver disease.
      ,
      • Fishbein M.
      • Castro F.
      • Cheruku S.
      • Jain S.
      • Webb B.
      • Gleason T.
      • et al.
      Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound.
      ] or in individuals with high body mass index (BMI) (>40 kg/m2) [
      • 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.
      ]. Despite observer dependency, US (or computed tomography [CT] or MRI) robustly diagnoses moderate and severe steatosis and provides additional hepatobiliary information, hence it should be performed as a first-line diagnostic test. However, for larger scale screening studies, serum biomarkers are preferred, as availability and cost of imaging substantially impact feasibility (Supplementary Table 3). The best-validated steatosis scores are the fatty liver index (FLI), the SteatoTest® and the NAFLD liver fat score; they have all been externally validated in the general population or in grade 3 obese persons and variably predict metabolic, hepatic and cardiovascular outcomes/mortality. These scores are associated with IR and reliably predict the presence, not the severity, of steatosis [
      • Fedchuk L.
      • Nascimbeni F.
      • Pais R.
      • Charlotte F.
      • Housset C.
      • Ratziu V.
      • et al.
      Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease.
      ]. Another imaging technique, the controlled attenuation parameter (CAP) can diagnose steatosis, but has a limited ability to discriminate histological grades and has never been compared with 1H-MRS-measured steatosis. Also, the date from studies comparing CAP with US are inconclusive. Thus more data are needed to define the role of CAP.

       Recommendations

       Steatohepatitis, NASH

      Rationale. The diagnosis of NASH provides important prognostic information and indicates an increased risk of fibrosis progression, cirrhosis and possibly hepatic comorbidities (HCC). It may also prompt a closer follow-up and possibly a greater need for more intensive therapy.
      Clinical, biochemical or imaging measures cannot distinguish NASH from steatosis [
      • Machado M.V.
      • Cortez-Pinto H.
      Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal.
      ,
      European Association for the Study of the Liver, Asociacion Latinoamericana para el Estudio del Higado
      EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
      ]. Cytokeratin-18 fragments (CK-18), which are generated during cell death (M65 fragments) or apoptosis (M30 fragments), have modest accuracy for the diagnosis of NASH (66% sensitivity, 82% specificity) [
      • Cusi K.
      • Chang Z.
      • Harrison S.
      • Lomonaco R.
      • Bril F.
      • Orsak B.
      • et al.
      Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease.
      ,
      • Kwok R.
      • Tse Y.K.
      • Wong G.L.
      • Ha Y.
      • Lee A.U.
      • Ngu M.C.
      • et al.
      Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease–the role of transient elastography and plasma cytokeratin-18 fragments.
      ]. CK-18 changes parallel histological improvement but do not perform better than alanine transaminase (ALT) in identifying histological responders [
      • Vuppalanchi R.
      • Jain A.K.
      • Deppe R.
      • Yates K.
      • Comerford M.
      • Masuoka H.C.
      • et al.
      Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease.
      ]. To date, non-invasive tests are not validated for the diagnosis of NASH.

       Recommendations

       Fibrosis

      Rationale. Fibrosis is the most important prognostic factor in NAFLD and is correlated with liver-related outcomes and mortality [
      • Ekstedt M.
      • Hagstrom H.
      • Nasr P.
      • Fredrikson M.
      • Stal P.
      • Kechagias S.
      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      ]. The presence of advanced fibrosis identifies patients in need of in-depth hepatological investigation, including, on a case-by-case basis, confirmatory biopsy and intensive therapies. Monitoring of fibrosis progression is also necessary at variable time intervals.
      Many serum markers have shown acceptable diagnostic accuracy as defined by an area under the receiver operating characteristic curve (AUROC) >0.8 (Supplementary Table 3) [
      European Association for the Study of the Liver, Asociacion Latinoamericana para el Estudio del Higado
      EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
      ]. NAFLD fibrosis score (NFS) and fibrosis 4 calculator (FIB-4) have been externally validated in ethnically different NAFLD populations, with consistent results. NFS, FIB-4, Enhanced Liver Fibrosis (ELF) and FibroTest® predict overall mortality, cardiovascular mortality and liver-related mortality. NFS predicts incident diabetes, and changes in NFS are associated with mortality. The tests perform best at distinguishing advanced (⩾F3) vs. non-advanced fibrosis but not significant (⩾F2) or any (⩾F1) fibrosis vs. no fibrosis [
      • Guha I.N.
      • Parkes J.
      • Roderick P.
      • Chattopadhyay D.
      • Cross R.
      • Harris S.
      • et al.
      Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers.
      ]. Importantly, the negative predictive values (NPVs) for excluding advanced fibrosis are higher than the corresponding positive predictive values (PPVs) [
      • Guha I.N.
      • Parkes J.
      • Roderick P.
      • Chattopadhyay D.
      • Cross R.
      • Harris S.
      • et al.
      Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers.
      ,
      • McPherson S.
      • Anstee Q.M.
      • Henderson E.
      • Day C.P.
      • Burt A.D.
      Are simple noninvasive scoring systems for fibrosis reliable in patients with NAFLD and normal ALT levels?.
      ]; therefore, non-invasive tests may be confidently used for first-line risk stratification to exclude severe disease. However, predictive values depend on prevalence rates and most of these studies have been conducted in tertiary centres where the pre-test probability of advanced fibrosis is higher than in the community.
      Among imaging techniques, transient elastography performs better for cirrhosis (F4) than for advanced fibrosis (F3). Elastography has a higher rate of false-positive than false-negative results and higher NPV than PPV [
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan H.L.
      • Le Bail B.
      • et al.
      Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.
      ], hence the ability to diagnose bridging fibrosis or cirrhosis is insufficient for clinical decision-making. The main shortcoming of transient elastography is unreliable results in the presence of high BMI and/or thoracic fold thickness. In a large, unselected European series, up to 20% of examinations had unreliable results [
      • Castera L.
      • Foucher J.
      • Bernard P.H.
      • Carvalho F.
      • Allaix D.
      • Merrouche W.
      • et al.
      Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.
      ], mainly in obese NAFLD [
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan H.L.
      • Le Bail B.
      • et al.
      Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.
      ]. The XL probe should be used in these patients to reduce the failure rate, which remains high (35%) [
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan A.W.
      • Chermak F.
      • et al.
      Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease.
      ].
      There is no consensus on thresholds or strategies for use in clinical practice when trying to avoid liver biopsy [
      European Association for the Study of the Liver, Asociacion Latinoamericana para el Estudio del Higado
      EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
      ]. Some data suggest that the combination of elastography and serum markers performs better than either method alone [
      • Petta S.
      • Vanni E.
      • Bugianesi E.
      • Di Marco V.
      • Camma C.
      • Cabibi D.
      • 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.
      ]. Importantly, longitudinal data correlating changes in histological severity and in non-invasive measurements are urgently needed.

       Recommendations

       Non-invasive testing in paediatric NAFLD

      The position paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Hepatology Committee has recently delineated diagnostic criteria for paediatric NAFLD [
      • Vajro P.
      • Lenta S.
      • Socha P.
      • Dhawan A.
      • McKiernan P.
      • Baumann U.
      • et al.
      Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.
      ]. In obese children, NAFLD should always be suspected; elevated aminotransferase levels and liver hyperechogenicity deserve further evaluation and the exclusion of other causes of liver disease. Due to the poor sensitivity of these tests in overweight/obese children, non-invasive markers and imaging techniques are the first diagnostic step [
      • Nobili V.
      • Svegliati-Baroni G.
      • Alisi A.
      • Miele L.
      • Valenti L.
      • Vajro P.
      A 360-degree overview of paediatric NAFLD: recent insights.
      ].

       Recommendations

      Common metabolic disorders related to NAFLD

      NAFLD is tightly associated with IR not only in the liver, but also in muscle and adipose tissues [
      • Gaggini M.
      • Morelli M.
      • Buzzigoli E.
      • DeFronzo R.A.
      • Bugianesi E.
      • Gastaldelli A.
      Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease.
      ], and also with the MetS, defined as the cluster of any three of the following five features associated with IR: impaired fasting glucose (IFG) or T2DM, hypertriglyceridaemia, low high-density lipoprotein (HDL)-cholesterol (gender-adjusted), increased waist circumference (ethnicity adjusted) and high blood pressure [
      • Alberti A.
      • Vario A.
      • Ferrari A.
      • Pistis R.
      Review article: chronic hepatitis C–natural history and cofactors.
      ]. As all components of MetS correlate with liver fat content, independently of BMI, the presence of MetS in any given patient should lead to an evaluation of the risk of NAFLD, and vice versa the presence of NAFLD should lead to an assessment of all components of MetS.
      Hepatic triacylglycerol accumulation is accompanied by abnormal hepatic energy metabolism [
      • Koliaki C.
      • Szendroedi J.
      • Kaul K.
      • Jelenik T.
      • Nowotny P.
      • Jankowiak F.
      • et al.
      Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.
      ] and impaired insulin-mediated suppression of hepatic glucose and very low-density lipoprotein production [
      • Yki-Jarvinen H.
      Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome.
      ], leading to hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. In non-diabetic persons, the product of fasting glucose (in mmol/L) and insulin (in mU/ml), divided by 22.5 (HOMA-IR) can serve as surrogate for IR [
      • Matthews D.R.
      • Hosker J.P.
      • Rudenski A.S.
      • Naylor B.A.
      • Treacher D.F.
      • Turner R.C.
      Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
      ], and is therefore an acceptable alternative to more expensive and time-consuming dynamic testing. Liver disease progression has been associated with persistence or worsening of metabolic abnormalities, including HOMA-IR [
      • McPherson S.
      • Hardy T.
      • Henderson E.
      • Burt A.D.
      • Day C.P.
      • Anstee Q.M.
      Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.
      ,
      • Pais R.
      • Charlotte F.
      • Fedchuk L.
      • Bedossa P.
      • Lebray P.
      • Poynard T.
      • et al.
      A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.
      ]. However, the validity of HOMA-IR depends on the ability of insulin secretion to adapt to IR, questioning its suitability in overt diabetes. Moreover, the assays for insulin measurements vary widely, and there is no agreement on a threshold defining IR using HOMA-IR.

       Recommendations

       Obesity

      BMI and waist circumference, a measure of visceral adiposity, are positively related to the presence of NAFLD [
      • 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.
      ] and predict advanced disease, particularly in the elderly [
      • Frith J.
      • Day C.P.
      • Robinson L.
      • Elliott C.
      • Jones D.E.
      • Newton J.L.
      Potential strategies to improve uptake of exercise interventions in non-alcoholic fatty liver disease.
      ]. A large proportion of patients with cryptogenic cirrhosis have a high prevalence of metabolic risk factors [
      • Caldwell S.H.
      • Crespo D.M.
      The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.
      ], suggesting that the majority of cases of cryptogenic cirrhosis are “burned-out” NASH. Common comorbidities of obesity, such as T2DM, and sleep apnoea [
      • Aron-Wisnewsky J.
      • Minville C.
      • Tordjman J.
      • Levy P.
      • Bouillot J.L.
      • Basdevant A.
      • et al.
      Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese.
      ], polycystic ovary syndrome and other endocrine disorders (hypogonadism), further drive NAFLD prevalence and severity.
      Importantly, patients with BMI <30 kg/m2 (or even <25 kg/m2) but with visceral fat accumulation or dysfunctional adipose tissue can exhibit NAFLD with/without abnormal liver enzymes [
      • Gaggini M.
      • Morelli M.
      • Buzzigoli E.
      • DeFronzo R.A.
      • Bugianesi E.
      • Gastaldelli A.
      Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease.
      ,
      • Gomez-Ambrosi J.
      • Silva C.
      • Galofre J.C.
      • Escalada J.
      • Santos S.
      • Millan D.
      • et al.
      Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity.
      ]. The currently used concept of “metabolically healthy” obese individuals should be considered with caution, given that they may exhibit gene expression similar to those of metabolically altered obese patients, and may have altered liver tests and adverse health outcomes when longitudinally examined [
      • Chang Y.
      • Ryu S.
      • Suh B.S.
      • Yun K.E.
      • Kim C.W.
      • Cho S.I.
      Impact of BMI on the incidence of metabolic abnormalities in metabolically healthy men.
      ,
      • Gomez-Ambrosi J.
      • Catalan V.
      • Rodriguez A.
      • Andrada P.
      • Ramirez B.
      • Ibanez P.
      • et al.
      Increased cardiometabolic risk factors and inflammation in adipose tissue in obese subjects classified as metabolically healthy.
      ].

       Recommendations

       Diabetes mellitus

      T2DM patients are insulin resistant, often obese, dyslipidaemic, display increased liver enzymes [
      • Ghouri N.
      • Preiss D.
      • Sattar N.
      Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data.
      ] and tend to accumulate hepatic fat independently of BMI [
      • Gastaldelli A.
      • Cusi K.
      • Pettiti M.
      • Hardies J.
      • Miyazaki Y.
      • Berria R.
      • et al.
      Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.
      ,
      • Kotronen A.
      • Juurinen L.
      • Hakkarainen A.
      • Westerbacka J.
      • Corner A.
      • Bergholm R.
      • et al.
      Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects.
      ]. The prevalence of NAFLD is also higher in persons at risk of T2DM, defined as a glycosylated haemoglobin A1c (HbA1c) of 5.7–6.4% (38.8–46.4 mmol/mol), IFG (fasting glucose: 100–125 mg/dl [5.55–6.94 mmol/L]) and/or impaired glucose tolerance (IGT; glucose: 140–199 mg/dl [7.77–11.04 mmol/L] at 2 h of the standardized 75 g oral glucose tolerance test [OGTT]). Diabetes risk and T2DM closely associate with the severity of NAFLD, progression to NASH, advanced fibrosis and the development of HCC [
      • Vernon G.
      • Baranova A.
      • Younossi Z.M.
      Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
      ,
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • Wilson L.
      • Lavine J.
      • Doo E.
      • et al.
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      ], independently of liver enzymes [
      • Fracanzani A.L.
      • Valenti L.
      • Bugianesi E.
      • Andreoletti M.
      • Colli A.
      • Vanni E.
      • et al.
      Risk of severe liver disease in NAFLD with normal aminotransferase levels: a role for insulin resistance and diabetes.
      ]. Conversely, US-defined NAFLD is associated with a 2–5-fold risk of developing T2DM after adjustment for several lifestyle and metabolic confounders [
      • Armstrong M.J.
      • Adams L.A.
      • Canbay A.
      • Syn W.K.
      Extrahepatic complications of nonalcoholic fatty liver disease.
      ]. The standardized 75 g OGTT should therefore be performed in persons with increased diabetes risk [
      • American Diabetes Association
      Standards of medical care in diabetes–2014.
      ,
      • Ortiz-Lopez C.
      • Lomonaco R.
      • Orsak B.
      • Finch J.
      • Chang Z.
      • Kochunov V.G.
      • et al.
      Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD).
      ].
      Insulin treatment increases body fat, but it does not appear to promote or worsen NAFLD in diabetes [
      • Juurinen L.
      • Tiikkainen M.
      • Hakkinen A.M.
      • Hakkarainen A.
      • Yki-Jarvinen H.
      Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes.
      ,
      • Llaurado G.
      • Sevastianova K.
      • Sadevirta S.
      • Hakkarainen A.
      • Lundbom N.
      • Orho-Melander M.
      • et al.
      Liver fat content and hepatic insulin sensitivity in overweight patients with type 1 diabetes.
      ]. While acute insulin infusion dose-dependently increases liver fat content in T2DM [
      • Anderwald C.
      • Bernroider E.
      • Krssak M.
      • Stingl H.
      • Brehm A.
      • Bischof M.G.
      • et al.
      Effects of insulin treatment in type 2 diabetic patients on intracellular lipid content in liver and skeletal muscle.
      ], chronic insulin treatment improves adipose tissue IR and therefore reduces non-esterified fatty acids flux and hepatic fat content.

       Recommendations

      Diagnostic algorithm and follow-up

      The incidental discovery of steatosis should lead to comprehensive evaluation of family and personal history of NAFLD-associated diseases and the exclusion of secondary causes of steatosis. Metabolic work-up has to include a careful assessment of all components of MetS [
      • American Diabetes Association
      Standards of medical care in diabetes–2014.
      ]. Similarly, the presence of obesity/T2DM or the incidental finding of raised liver enzymes in patients with metabolic risk factors should prompt non-invasive screening to predict steatosis, NASH and fibrosis (Table 3).
      Table 3Protocol for a comprehensive evaluation of suspected NAFLD patients.
      ∗According to a priori probability or clinical evaluation.
      Surrogate markers of fibrosis (NFS, FIB-4, ELF or FibroTest) should be calculated for every NAFLD patient, in order to rule out significant fibrosis (⩾F2). If significant fibrosis cannot be ruled out, patients should be referred to a Liver Clinic for transient elastography; if significant fibrosis is confirmed, the final diagnosis should be made by liver biopsy (Fig. 1). All cases with diabetes or diabetes risk should be referred to a Diabetes Clinic for optimal management. Those at increased diabetes risk should be included in a structured lifestyle modification program. Obesity should prompt the inclusion of the patient in a structured weight loss program and/or referral to an obesity specialist. Finally, all cases should receive comprehensive cardiovascular disease (CVD) work-up.
      Figure thumbnail gr1
      Fig. 1Diagnostic flow-chart to assess and monitor disease severity in the presence of suspected NAFLD and metabolic risk factors. 1Steatosis biomarkers: Fatty Liver Index, SteatoTest, NAFLD Fat score (see Tables). 2Liver tests: ALT AST, γGT. 3Any increase in ALT, AST or γGT. 4Serum fibrosis markers: NAFLD Fibrosis Score, FIB-4, Commercial tests (FibroTest, FibroMeter, ELF). 5Low risk: indicative of no/mild fibrosis; Medium/high risk: indicative of significant fibrosis or cirrhosis (see Tables).
      The optimal follow-up of patients with NAFLD is as yet undetermined. Risk of progression of both the hepatic disease and the underlying metabolic conditions as well as the cost and workload for healthcare providers need to be considered. Monitoring should include routine biochemistry, assessment of comorbidities and non-invasive monitoring of fibrosis. NAFL patients without worsening of metabolic risk factors, should be monitored at 2–3-year intervals. Patients with NASH and/or fibrosis should be monitored annually, those with NASH cirrhosis at 6-month intervals. If indicated on a case-by-case basis, liver biopsy could be repeated after 5 years.

      Natural history and complications

       Disease progression

      In general, NAFLD is a slowly progressive disease, both in adults and in children, but fibrosis rapidly progresses in 20% of cases [
      • 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.
      ]. The rate of progression corresponds to 1 fibrosis stage every 14 years in NAFL and every 7 years in NASH, and is doubled by arterial hypertension [
      • 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.
      ]. NASH is associated with an increased standardized mortality ratio compared with the general population [
      • Haflidadottir S.
      • Jonasson J.G.
      • Norland H.
      • Einarsdottir S.O.
      • Kleiner D.E.
      • Lund S.H.
      • et al.
      Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease.
      ] and liver disease is the third most common cause of death after CVD and cancer. US-diagnosed NAFLD is not associated with increased mortality [
      • 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.
      ], presumably because progression to NASH and fibrosis is rare for steatosis alone [
      • McPherson S.
      • Hardy T.
      • Henderson E.
      • Burt A.D.
      • Day C.P.
      • Anstee Q.M.
      Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.
      ,
      • Pais R.
      • Charlotte F.
      • Fedchuk L.
      • Bedossa P.
      • Lebray P.
      • Poynard T.
      • et al.
      A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.
      ].

       Recommendations

      Figure thumbnail fx17
      Paediatric NAFLD is of concern because of the potential for severe liver-related complications later in life [
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Diehl A.M.
      • Brunt E.M.
      • Cusi K.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      ]. NASH-related cirrhosis has been reported as early as 8 years of age [
      • Schwimmer J.B.
      • Behling C.
      • Newbury R.
      • Deutsch R.
      • Nievergelt C.
      • Schork N.J.
      • et al.
      Histopathology of pediatric nonalcoholic fatty liver disease.
      ].

       Cardiovascular disease

      The prevalence and incidence of CVD is higher in NAFLD than in matched controls and driven by the association between NAFLD and MetS components ([
      • Oni E.T.
      • Agatston A.S.
      • Blaha M.J.
      • Fialkow J.
      • Cury R.
      • Sposito A.
      • et al.
      A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?.
      ,
      • Targher G.
      • Day C.P.
      • Bonora E.
      Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
      ] (Supplementary Table 4). CVD is a more common cause of death than liver disease in NAFLD [
      • Targher G.
      • Day C.P.
      • Bonora E.
      Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
      ]. In most studies, biochemical markers of atherosclerosis (low HDL cholesterol, high triacylglycerol) or inflammation (high-sensitive C reactive protein [CRP]), and increased levels of procoagulant/prothrombotic factors are more common in NAFLD than in persons without steatosis [
      • Targher G.
      • Day C.P.
      • Bonora E.
      Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
      ]. Pre-atherogenic lesions such as increased carotid intima-media thickness; coronary artery, abdominal aortic and aortic valve calcifications; endothelial dysfunction and functional unresponsiveness of the artery wall are more prevalent in NAFLD and are, in some studies, correlated with histological severity. Other defects such as echocardiographic and ECG abnormalities and altered cardiac energy metabolism have also been demonstrated [
      • Bhatia L.S.
      • Curzen N.P.
      • Calder P.C.
      • Byrne C.D.
      Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?.
      ]. They are largely independent of traditional risk factors, duration of diabetes, glycaemic control, drug treatment and MetS components. In the general population, US-detected steatosis and its surrogate markers (e.g., FLI) are associated with a higher risk of CVD mortality in the long-term [
      • Calori G.
      • Lattuada G.
      • Ragogna F.
      • Garancini M.P.
      • Crosignani P.
      • Villa M.
      • et al.
      Fatty liver index and mortality: the Cremona study in the 15th year of follow-up.
      ], and the risk increases further in NASH and in advanced fibrosis [
      • Targher G.
      • Day C.P.
      • Bonora E.
      Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
      ].
      The overall consensus is that CVD should be identified in NAFLD regardless of the presence of traditional risk factors. Conversely NAFLD screening should be performed in persons at high CVD risk. An association between serum γ-glutamyltransferase (GGT) and CVD incidence has been prospectively established, although it is insufficient for devising follow-up protocols. Notably, CVD and metabolic risk factors are also reported in adolescents and children with NAFLD [
      • Pacifico L.
      • Chiesa C.
      • Anania C.
      • De Merulis A.
      • Osborn J.F.
      • Romaggioli S.
      • et al.
      Nonalcoholic fatty liver disease and the heart in children and adolescents.
      ].

       Recommendations

       Hepatocellular carcinoma

      Large-scale epidemiological studies have repeatedly associated obesity and T2DM with the risk of HCC, and the occurrence of HCC has also been reported in NAFLD/cryptogenic cirrhosis. The cumulative incidence of NAFLD-associated HCC (>10-fold higher in T2DM and obesity) varies according to study population (population-based, natural history vs. clinic-based cohorts with/without fibrosis or cirrhosis) from 7.6% at 5 years in persons with advanced fibrosis or cirrhosis to only 0.25% in a larger series followed for 5.6 years [
      • Dyson J.
      • Jaques B.
      • Chattopadyhay D.
      • Lochan R.
      • Graham J.
      • Das D.
      • et al.
      Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
      ].
      At diagnosis, patients with NAFLD-associated HCC are older than those with non-NAFLD HCC, have more extrahepatic comorbidities, but a lower prevalence of cirrhosis (only 2/3 of cases) (Supplementary Table 5). NAFLD-related HCC may, however, be diagnosed at more advanced stages, due to less systematic surveillance, and receive less treatment. Conflicting data are reported on survival. At present, NAFLD is the second leading indication for HCC-related transplantation in the USA [
      • 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..
      ].
      The large number of NAFLD cases at risk of HCC makes systematic surveillance largely impracticable. The PNPLA3 rs738409 C>G gene polymorphism has been associated with an increased HCC risk and might provide patient-risk stratification for tailored HCC surveillance in NAFLD, but it is not yet considered cost-effective (Supplementary Table 1).

       Recommendations

       Other extrahepatic disorders

      Chronic kidney disease (CKD) can be found in 20-50% of NAFLD patients, particularly in biopsy-proven NASH [
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • Ekstedt M.
      • Kechagias S.
      • Hamaguchi M.
      • et al.
      Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
      ]. US-defined NAFLD carries a 1.5- to 2-fold adjusted risk of incident CKD in Type 1 diabetes mellitus [
      • Targher G.
      • Bertolini L.
      • Chonchol M.
      • Rodella S.
      • Zoppini G.
      • Lippi G.
      • et al.
      Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients.
      ].
      NAFLD is also associated with colorectal cancer [
      • Kim N.H.
      • Park J.
      • Kim S.H.
      • Kim Y.H.
      • Kim D.H.
      • Cho G.Y.
      • et al.
      Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population.
      ], metabolic bone disease (vitamin D deficiency, osteoporosis) [
      • Armstrong M.J.
      • Adams L.A.
      • Canbay A.
      • Syn W.K.
      Extrahepatic complications of nonalcoholic fatty liver disease.
      ,
      • Hazlehurst J.M.
      • Tomlinson J.W.
      Non-alcoholic fatty liver disease in common endocrine disorders.
      ] and rare metabolic diseases (lipodystrophies, glycogen storage diseases).

      Treatment

      Rationale. Successful treatment of NASH should improve outcomes, i.e. decrease NASH-related mortality, reduce progression to cirrhosis or HCC. The resolution of the histological lesions defining NASH is now accepted as a surrogate endpoint, particularly in clinical trials. Only a few properly designed randomized controlled trials (RCTs) are available, with improvement/regression of hepatic necroinflammation and/or fibrosis as primary outcomes [
      • Lindor K.D.
      • Kowdley K.V.
      • Heathcote E.J.
      • Harrison M.E.
      • Jorgensen R.
      • Angulo P.
      • et al.
      Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.
      ,
      • Bugianesi E.
      • Gentilcore E.
      • Manini R.
      • Natale S.
      • Vanni E.
      • Villanova N.
      • et al.
      A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease.
      ,
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • Darland C.
      • Finch J.
      • Hardies J.
      • et al.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      ,
      • Zelber-Sagi S.
      • Kessler A.
      • Brazowsky E.
      • Webb M.
      • Lurie Y.
      • Santo M.
      • et al.
      A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.
      ,
      • Dufour J.F.
      • Oneta C.M.
      • Gonvers J.J.
      • Bihl F.
      • Cerny A.
      • Cereda J.M.
      • et al.
      Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • Charlotte F.
      • Hartemann-Heurtier A.
      • Serfaty L.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.
      ,
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • Lawson A.
      • Ryder S.D.
      • Spendlove I.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      ,
      • Haukeland J.W.
      • Konopski Z.
      • Eggesbo H.B.
      • von Volkmann H.L.
      • Raschpichler G.
      • Bjoro K.
      • et al.
      Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial.
      ,
      • Harrison S.A.
      • Fecht W.
      • Brunt E.M.
      • Neuschwander-Tetri B.A.
      Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial.
      ,
      • Shields W.W.
      • Thompson K.E.
      • Grice G.A.
      • Harrison S.A.
      • Coyle W.J.
      The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial.
      ,
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • Jackvony E.
      • Kearns M.
      • Wands J.R.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • Charlotte F.
      • Bernhardt C.
      • Giral P.
      • Halbron M.
      • Lenaour G.
      • et al.
      Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • McCullough A.
      • Diehl A.M.
      • Bass N.M.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Leuschner U.F.
      • Lindenthal B.
      • Herrmann G.
      • Arnold J.C.
      • Rossle M.
      • Cordes H.J.
      • et al.
      High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.
      ,
      • Zein C.O.
      • Yerian L.M.
      • Gogate P.
      • Lopez R.
      • Kirwan J.P.
      • Feldstein A.E.
      • et al.
      Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
      ,
      • Lavine J.E.
      • Schwimmer J.B.
      • Van Natta M.L.
      • Molleston J.P.
      • Murray K.F.
      • Rosenthal P.
      • et al.
      Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.
      ,
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • Abdelmalek M.F.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ,
      • Valenti L.
      • Fracanzani A.L.
      • Dongiovanni P.
      • Rovida S.
      • Rametta R.
      • Fatta E.
      • et al.
      A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia.
      ,
      • Takeshita Y.
      • Takamura T.
      • Honda M.
      • Kita Y.
      • Zen Y.
      • Kato K.
      • et al.
      The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial.
      ,
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • Cummings O.W.
      • Chojkier M.
      EPE-A Study Group
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ,
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • Bettencourt R.
      • Jain R.
      • Salotti J.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ,
      • Argo C.K.
      • Patrie J.T.
      • Lackner C.
      • Henry T.D.
      • de Lange E.E.
      • Weltman A.L.
      • et al.
      Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial.
      ,
      • Armstrong M.J.
      • Gaunt P.
      • Aithal G.P.
      • Barton D.
      • Hull D.
      • Parker R.
      • et al.
      Liraglutide safety and effi cacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ] (Table 4).
      Table 4Randomized controlled trials with histological outcomes in NAFLD.
      C, control arm; CBT, cognitive-behaviour therapy; E, Experimental arm; EPA, Eicosapentanoic acid; EZE, Ezetimibe; HbA1c, glycosylated haemoglobin; LIRA, liraglutide; MET, metformin; MR, magnetic resonance; MRI, magnetic resonance imaging; NAS, NAFLD activity score; OCA, obeticholic acid; ORL, orlistat; PIO, pioglitazone; PL, placebo; PTX, pentoxifylline; PUFA, polyunsaturated fatty acids; RSG, rosiglitazone.

       Diet and lifestyle changes

      Rationale. Epidemiological evidence suggests a tight relationship between unhealthy lifestyle and NAFLD [
      • Zelber-Sagi S.
      • Ratziu V.
      • Oren R.
      Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence.
      ], which makes lifestyle correction mandatory in all patients (Table 5). Of note, daily alcohol consumption up to 30 g (men) or 20 g (women) is insufficient to induce alcoholic steatosis and might even be protective against NAFLD, NASH and fibrosis as compared with total abstinence.
      Table 5Elements of a comprehensive lifestyle approach to NAFLD treatment.
      Relatively small amounts of weight loss reduce liver fat and improve hepatic IR [
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • Lehrke M.
      • Hendler R.E.
      • Shulman G.I.
      Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.
      ]. In a pilot RCT of cognitive-behaviour therapy, lifestyle intervention resulted in more weight loss, more frequent resolution of NASH and a borderline higher (p = 0.05) reduction in the NAS score [
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • Jackvony E.
      • Kearns M.
      • Wands J.R.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      ]. In a post hoc analysis, a weight loss ⩾7% was associated with histological improvement. In an uncontrolled, 12-month study with 261 paired biopsies, a modest lifestyle-induced weight loss was associated with NASH regression (25% of total cases) without worsening of fibrosis [
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • Torres-Gonzalez A.
      • Gra-Oramas B.
      • Gonzalez-Fabian L.
      • et al.
      Weight loss via lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      ].
      Pragmatic approaches combining dietary restriction and a progressive increase in aerobic exercise/resistance training [
      • Rodriguez B.
      • Torres D.M.
      • Harrison S.A.
      Physical activity: an essential component of lifestyle modification in NAFLD.
      ] are preferable and should be individually tailored. No data are available on their long-term effects on the natural history of NAFLD.

       Recommendations

       Drug treatment

      Rationale. Drug therapy should be indicated for progressive NASH (bridging fibrosis and cirrhosis) but also for early-stage NASH with increased risk of fibrosis progression (age >50 years; diabetes, MetS, increased ALT [
      • Adams L.A.
      • Sanderson S.
      • Lindor K.D.
      • Angulo P.
      The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.
      ]) or active NASH with high necroinflammatory activity [
      • Sanyal A.J.
      • Friedman S.L.
      • McCullough A.J.
      • Dimick-Santos L.
      American Association for the Study of Liver DiseasesUnited States Food and Drug Administration
      Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.
      ]. No drug has currently been tested in phase III trials and is approved for NASH by regulatory agencies. Therefore, no specific therapy can be firmly recommended and any drug treatment would be off-label (for reviews see [
      • Younossi Z.M.
      • Reyes M.J.
      • Mishra A.
      • Mehta R.
      • Henry L.
      Systematic review with meta-analysis: non-alcoholic steatohepatitis – A case for personalised treatment based on pathogenic targets.
      ,
      • Mazzella N.
      • Ricciardi L.M.
      • Mazzotti A.
      • Marchesini G.
      The role of medications for the management of patients with NAFLD.
      ,
      • Ratziu V.
      • Goodman Z.
      • Sanyal A.
      Current efforts and trends in the treatment of NASH.
      ], Table 4). Safety and tolerability are essential prerequisites for drug treatment, because of NASH-associated comorbidities and polypharmacy, a potential source of drug-drug interactions.

       Insulin sensitizers

      There is scarce evidence for a histological efficacy of metformin in NASH [
      • Bugianesi E.
      • Gentilcore E.
      • Manini R.
      • Natale S.
      • Vanni E.
      • Villanova N.
      • 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.
      • von Volkmann H.L.
      • Raschpichler G.
      • Bjoro K.
      • et al.
      Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial.
      ,
      • Shields W.W.
      • Thompson K.E.
      • Grice G.A.
      • Harrison S.A.
      • Coyle W.J.
      The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial.
      ]. The effect of metformin on liver fat is weak, because of its inability to restore serum adiponectin levels in the short-term [
      • Tiikkainen M.
      • Hakkinen A.M.
      • Korsheninnikova E.
      • Nyman T.
      • Makimattila S.
      • Yki-Jarvinen H.
      Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes.
      ]. Some preclinical data support an anti-tumorigenic activity of metformin on liver cancer [
      • Bhalla K.
      • Hwang B.J.
      • Dewi R.E.
      • Twaddel W.
      • Goloubeva O.G.
      • Wong K.K.
      • et al.
      Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis.
      ], while the demonstration of reduced rates of HCC in humans is limited to retrospective studies [
      • 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.
      ] and insufficient for evidence-based recommendations.
      Thiazolidinediones are peroxisome proliferator-activated receptor (PPAR)γ agonists with insulin-sensitizing effects. The PIVENS trial compared low dose pioglitazone vs. vitamin E vs. placebo for 2 years in patients without overt diabetes. Pioglitazone improved all histological features (except for fibrosis) and achieved resolution of NASH more often than placebo [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • McCullough A.
      • Diehl A.M.
      • Bass N.M.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ]. The histological benefit occurred together with ALT improvement and partial correction of IR. Similar results were reported in two smaller and shorter RCTs [
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • Darland C.
      • Finch J.
      • Hardies J.
      • et al.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      ,
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • Lawson A.
      • Ryder S.D.
      • Spendlove I.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      ]. Prolonged therapy with rosiglitazone, up to 2 years, did not result in further histological improvement [
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • Charlotte F.
      • Hartemann-Heurtier A.
      • Serfaty L.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.
      ,
      • Ratziu V.
      • Charlotte F.
      • Bernhardt C.
      • Giral P.
      • Halbron M.
      • Lenaour G.
      • et al.
      Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial.
      ], although this was not formally tested with pioglitazone. Side effects of glitazones are of concern: weight gain, bone fractures in women and, rarely, congestive heart failure. Despite the safety and tolerability profile, pioglitazone can be used for selected patients with NASH, particularly in T2DM where the drug has a registered use.
      Incretin-mimetics, acting on the glucose-insulin interplay have shown favourable results in pre-marketing studies on liver enzymes [
      • Vilsboll T.
      • Christensen M.
      • Junker A.E.
      • Knop F.K.
      • Gluud L.L.
      Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.
      ]. A small pilot trial of daily injections of liraglutide met the histological outcome of NASH remission without worsening of fibrosis [
      • Armstrong M.J.
      • Gaunt P.
      • Aithal G.P.
      • Barton D.
      • Hull D.
      • Parker R.
      • et al.
      Liraglutide safety and effi cacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ].

       Antioxidants, cytoprotective and lipid lowering agents

      In the PIVENS trial, vitamin E (800 IU/day) improved steatosis, inflammation and ballooning and induced resolution of NASH in 36% of patients (21% in the placebo arm) [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • McCullough A.
      • Diehl A.M.
      • Bass N.M.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ]. Reduced ALT correlated with histological improvement and histological non-responders did not reduce ALT [
      • Hoofnagle J.H.
      • Van Natta M.L.
      • Kleiner D.E.
      • Clark J.M.
      • Kowdley K.V.
      • Loomba R.
      • et al.
      Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis.
      ]. In the paediatric TONIC trial [
      • Lavine J.E.
      • Schwimmer J.B.
      • Van Natta M.L.
      • Molleston J.P.
      • Murray K.F.
      • Rosenthal P.
      • et al.
      Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.
      ], vitamin E failed to reduce aminotransferases, steatosis and inflammation but improved ballooning and doubled the rate of NASH clearance vs. placebo. These results contrast with previous trials, which were mostly negative in both adults and children. Concerns about long-term safety of vitamin E exist, mainly an increase in overall mortality [
      • 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.
      ], in haemorrhagic stroke [
      • 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.
      ] and prostate cancer in males older than 50 [
      • Klein E.A.
      • Thompson Jr, I.M.
      • Tangen C.M.
      • Crowley J.J.
      • Lucia M.S.
      • Goodman P.J.
      • et al.
      Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
      ]. Vitamin E may be used in non-cirrhotic non-diabetic NASH patients but further studies are needed before firm recommendations can be made.
      Ursodeoxycholic acid (UDCA) has been investigated in several RCTs, at different doses and for up to 2 years, but only showed some biochemical but no histological improvements [
      • Lindor K.D.
      • Kowdley K.V.
      • Heathcote E.J.
      • Harrison M.E.
      • Jorgensen R.
      • Angulo P.
      • et al.
      Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.
      ,
      • Dufour J.F.
      • Oneta C.M.
      • Gonvers J.J.
      • Bihl F.
      • Cerny A.
      • Cereda J.M.
      • et al.
      Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis.
      ,
      • Leuschner U.F.
      • Lindenthal B.
      • Herrmann G.
      • Arnold J.C.
      • Rossle M.
      • Cordes H.J.
      • et al.
      High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.
      ].
      A synthetic farnesoid X receptor agonist, obeticholic acid, improved IR in T2DM [
      • Mudaliar S.
      • Henry R.R.
      • Sanyal A.J.
      • Morrow L.
      • Marschall H.U.
      • Kipnes M.
      • et al.
      Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.
      ]. In the phase IIb FLINT trial, a 72-week treatment with obeticholic acid in non-cirrhotic NASH patients, improved all NASH lesions while improving fibrosis [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • Abdelmalek M.F.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ]. Main issues with safety and tolerability were increased low-density lipoprotein (LDL)-cholesterol and pruritus.
      Preliminary data from small or uncontrolled studies suggested that n-3 polyunsaturated fatty acids (PUFA) might reduce liver fat [
      • Parker H.M.
      • Johnson N.A.
      • Burdon C.A.
      • Cohn J.S.
      • O’Connor H.T.
      • George J.
      Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      ], but two trials testing PUFA on histological outcomes were negative [
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • Cummings O.W.
      • Chojkier M.
      EPE-A Study Group
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ,
      • Argo C.K.
      • Patrie J.T.
      • Lackner C.
      • Henry T.D.
      • de Lange E.E.
      • Weltman A.L.
      • et al.
      Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial.
      ]. Available data on pentoxifylline and orlistat are limited or inconclusive [
      • Zelber-Sagi S.
      • Kessler A.
      • Brazowsky E.
      • Webb M.
      • Lurie Y.
      • Santo M.
      • et al.
      A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.
      ,
      • Harrison S.A.
      • Fecht W.
      • Brunt E.M.
      • Neuschwander-Tetri B.A.
      Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial.
      ,
      • Zein C.O.
      • Yerian L.M.
      • Gogate P.
      • Lopez R.
      • Kirwan J.P.
      • Feldstein A.E.
      • et al.
      Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
      ]. Also, data on lipid-lowering drugs are poor; recent trials with ezetimibe were negative [
      • Takeshita Y.
      • Takamura T.
      • Honda M.
      • Kita Y.
      • Zen Y.
      • Kato K.
      • et al.
      The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial.
      ,
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • Bettencourt R.
      • Jain R.
      • Salotti J.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ], whereas statins have not been adequately tested. Their use in NAFLD is safe, with no increased risk of hepatotoxicity, and may even significantly reduce aminotransferases [
      • Dongiovanni P.
      • Petta S.
      • Mannisto V.
      • Mancina R.M.
      • Pipitone R.
      • Karja V.
      • et al.
      Statin use and nonalcoholic steatohepatitis in at risk individuals.
      ].
      Promising novel agents with anti-inflammatory, antifibrotic or insulin sensitizing properties (dual PPARα/δ agonists, dual chemokine receptor [CCR]2/CCR5 antagonists and fatty acid/bile acid conjugates) and antifibrotic agents (anti-lysyl oxidase-like [anti-LOXL2] monoclonal antibodies) are also being tested in late-phase RCTs in NASH.

       Recommendations

      Figure thumbnail fx21

       Iron depletion

      Hepatic iron accumulation is associated with IR, and iron depletion improves IR [
      • Valenti L.
      • Fracanzani A.L.
      • Dongiovanni P.
      • Bugianesi E.
      • Marchesini G.
      • Manzini P.
      • et al.
      Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study.
      ]. In NAFLD, high ferritin levels are common, in the presence of variable transferrin saturation, independent of gene polymorphisms of familial hemochromatosis. In these patients, a phlebotomy programme to reduce iron stores to near iron deficiency improved the NAS score, without worsening fibrosis [
      • Valenti L.
      • Fracanzani A.L.
      • Dongiovanni P.
      • Rovida S.
      • Rametta R.
      • Fatta E.
      • et al.
      A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia.
      ], but more data are needed.

       Paediatric NAFLD

      In children, diet and exercise training reduce steatosis, but do not affect ballooning, inflammation and fibrosis [
      • Nobili V.
      • Alisi A.
      • Raponi M.
      Pediatric non-alcoholic fatty liver disease: preventive and therapeutic value of lifestyle intervention.
      ]. Although several drug-based therapies, such as vitamin E and metformin, and dietary supplementation, including probiotics and docosahexaenoic acid, have shown beneficial effects on ballooning, steatosis and inflammation, fibrotic lesions are refractory to treatment [
      • Mitchel E.B.
      • Lavine J.E.
      Review article: the management of paediatric nonalcoholic fatty liver disease.
      ] and the long-term outcome of paediatric NASH remains poor [
      • Feldstein A.E.
      • Charatcharoenwitthaya P.
      • Treeprasertsuk S.
      • Benson J.T.
      • Enders F.B.
      • Angulo P.
      The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.
      ].

       Recommendations

       Bariatric (metabolic) surgery

      In patients unresponsive to lifestyle changes and pharmacotherapy, bariatric surgery is an option for reducing weight and metabolic complications, with stable results in the long-term [
      • Schauer P.R.
      • Bhatt D.L.
      • Kirwan J.P.
      • Wolski K.
      • Brethauer S.A.
      • Navaneethan S.D.
      • et al.
      Bariatric surgery versus intensive medical therapy for diabetes–3-year outcomes.
      ]. Surrogate markers indicate that bariatric surgery is effective on NAFLD-associated liver injury, and there is also initial evidence for improved necroinflammation and fibrosis [
      • Caiazzo R.
      • Lassailly G.
      • Leteurtre E.
      • Baud G.
      • Verkindt H.
      • Raverdy V.
      • et al.
      Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study.
      ]. A recent cohort study with 1-year follow-up confirmed that bariatric surgery-associated weight loss cleared NASH in 85% of patients and improved fibrosis in 34% [
      • Lassailly G.
      • Caiazzo R.
      • Buob D.
      • Pigeyre M.
      • Verkindt H.
      • Labreuche J.
      • et al.
      Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients.
      ], although the possible benefits should be balanced against peri-/postoperative complications. No solid data on the comparative effects of different bariatric procedures on liver fat are available.

       Recommendations

      Liver transplantation

      NAFLD-associated cirrhosis is among the top three indications for liver transplantation. The 3- and 5-year survival is not different in NAFLD vs. no-NAFLD; NAFLD carries a higher risk of death from cardiovascular complications and sepsis, whereas the risk of graft failure is lower [
      • Charlton M.R.
      • Burns J.M.
      • Pedersen R.A.
      • Watt K.D.
      • Heimbach J.K.
      • Dierkhising R.A.
      Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.
      ,
      • 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.
      ]. The overall mortality is associated with BMI and diabetes, with 50% of cases with BMI >35 kg/m2 dying within 1-year of transplantation [
      • Heuer M.
      • Kaiser G.M.
      • Kahraman A.
      • Banysch M.
      • Saner F.H.
      • Mathe Z.
      • et al.
      Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience.
      ]. Transplant failure (10% and 45% at 10 and 20 years, respectively [
      • Sebagh M.
      • Samuel D.
      • Antonini T.M.
      • Coilly A.
      • Degli Esposti D.
      • Roche B.
      • et al.
      Twenty-year protocol liver biopsies: invasive but useful for the management of liver recipients.
      ]) in obese patients is rarely associated with recurrent NASH cirrhosis (≈2%) [
      • 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.
      ].

       Recommendations

      Conflict of interest

      • Giulio Marchesini declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      • Christopher P. Day declares he has been a consultant/advisor for Abbott Laboratories and Genfit and completed sponsored lectures for Abbott Laboratories.
      • Jean-François Dufour declares he has been a consultant/advisor for Intercept and Genfit.
      • Ali Canbay declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      • Valerio Nobili declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      • Vlad Ratziu declares he has been a consultant/advisor for Genfit, in addition has been on the advisory board for Gilead, Genfit, Roche and Galmed Pharmaceuticals.
      • Herbert Tilg declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      • Michael Roden has received research support and been involved in clinical trails for Boehringer Ingelheim, Novartis Pharma and Sanofi-Aventis Germany. He has been a consultant/advisor for GI Dynamics, Sanofi-Aventis Germany and Merck & Co. Inc. He has completed sponsored lectures for Eli Lilly and Novo Nordisk.
      • Amalia Gastaldelli has received research support from Amylin-BMS-AstraZeneca and has been a consultant/advisor for Roche, Eli-Lilly and Sanofi-Aventis.
      • Hannele Yki-Järvinen declares she does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      • Fritz Schick declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      • Roberto Vettor declares that he has been a consultant/advisor as well as received grants/research support from Sanofi-Aventis. In addition he has completed sponsored lectures for Novo Nordisk, Sanofi-Aventis and AstraZeneca.
      • Gema Frühbeck declares that she is on the Novo Nordisk Obesity Scientific Communication Global Advisory Board.
      • Lisbeth Mathus-Vliegen declares she does not have anything to disclose regarding funding and conflict of interest with respect to this manuscript.

      Acknowledgements

      We would like to thank the reviewers of this Clinical Practice Guideline for their time and critical reviewing: Professor Elisabetta Bugianesi (Department of Medical Sciences, University of Turin, Turin, Italy), Professor Helena Cortez-Pinto (Unidade de Nutrição e Metabolismo, Faculdade de Medicina de Lisboa, Lisbon, Portugal) and Dr. Stephen Harrison (Brooke Army Medical Center, San Antonio, Texas, USA).

      Supplementary data

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      Linked Article

      • Response to: Comment to “EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease”
        Journal of HepatologyVol. 66Issue 2
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          We thank Jorge Fonseca et al. for their comments, which give us the opportunity to clarify the controversial issue of dietary approach to NAFLD, an issue that did not receive adequate attention in the Clinical Practice Guidelines (CPG) due to space constraints. They are concerned about the sentence suggesting “low-to-moderate fat and moderate-to-high carbohydrate intake” as a reasonable option for NAFLD cases. Indeed, no recommendation on nutrient composition of the diet was issued within the CPG, but a formal recommendation reads “Dietary recommendations should consider energy restriction and exclusion of NAFLD-promoting components (processed food, and food and beverages high in added fructose).
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      • Comment to: “EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease”
        Journal of HepatologyVol. 66Issue 2
        • Preview
          We had received with great interest the new Clinical Practice Guidelines on NAFLD, a joint consensus from the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) and the paper fulfilled our expectations. Every clinician taking care of liver patients is well aware of the increasing NAFLD epidemic and, also, the importance of the obesity/insulin resistance/diabetes burden growing in Western societies [1].
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