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Nonalcoholic Fatty Liver Disease: Review of Management for Primary Care Providers

      Abstract

      Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the United States and worldwide. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplant. Comorbidities associated with NAFLD development and NASH include type 2 diabetes, obesity, metabolic syndrome, and dyslipidemia. Extrahepatic morbidity and mortality are considerable as NAFLD is associated with an increased risk of cardiovascular disease and chronic kidney disease. Once NAFLD is diagnosed, the presence of liver fibrosis is the central determinant of hepatic prognosis. Severe liver fibrosis requires aggressive clinical management. No pharmacologic agents have regulatory approval in the United States for the treatment of NAFLD or NASH. Management is centered on efforts to reduce underlying obesity (lifestyle, medications, surgical or endoscopic interventions) and metabolic derangements (prediabetes, type 2 diabetes, hypertension, hyperlipidemia, and others). Current pharmacologic therapy for NAFLD is limited mainly to the use of vitamin E and pioglitazone, although other agents are being investigated in clinical trials. Cardiovascular and metabolic risk factors must also be assessed and managed. Here, NAFLD evaluation, diagnosis, and management are considered in the primary care setting and endocrinology clinics.

      Abbreviations and Acronyms:

      AASLD (American Association for the Study of Liver Diseases), BMI (body mass index), CKD (chronic kidney disease), 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), FIB-4 (Fibrosis-4 index), GLP-1 RA (glucagon-like peptide 1 receptor agonist), HCC (hepatocellular carcinoma), MetS (metabolic syndrome), MRI (magnetic resonance imaging), NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), T2D (type 2 diabetes), VCTE (vibration-controlled transient elastography)
      Article Highlights
      • Primary care providers can expect to see growing numbers of patients with nonalcoholic fatty liver disease (NAFLD), given its increasing prevalence—fueled by the global epidemics of obesity and type 2 diabetes.
      • A significant risk of cardiovascular morbidity and mortality is associated with NAFLD. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplant.
      • The presence of liver fibrosis (NASH fibrosis) is the central determinant of liver-related mortality; the presence of advanced fibrosis (stage ≥F3) requires aggressive clinical management.
      • Clinical action is necessary if NAFLD is suspected, even with normal liver biochemistry or an absence of symptoms. Prompt diagnosis of NAFLD and determination of liver fibrosis risk are critical to improve patient outcomes.
      • Liver biopsy is the “gold standard” for diagnosis of NASH but has several disadvantages; thus, noninvasive biomarkers (serum and imaging) are used more frequently.
      Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease globally and in the United States.
      • 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.
      • 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.
      It is characterized by the development of hepatic steatosis (triglyceride accumulation in hepatocytes) in the absence of secondary causes, including significant alcohol consumption (US standard drink, 14 g of alcohol: >2 drinks/day for men, >1 drink/day for women).
      • 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.
      ,
      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.
      Nonalcoholic fatty liver disease encompasses the full spectrum of histopathologic changes (simple steatosis to extensive fibrosis to cirrhosis),
      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.
      ,
      • Brunt E.M.
      • Kleiner D.E.
      • Carpenter D.H.
      • et al.
      NAFLD: reporting histologic findings in clinical practice.
      whereas nonalcoholic steatohepatitis (NASH) is characterized by inflammation and hepatocyte injury (ballooning) with or without fibrosis.
      • 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.
      Disease progression from steatosis to cirrhosis may not be linear, and periods of stability or regression can occur.
      • Wong T.
      • Wong R.J.
      • Gish R.G.
      Diagnostic and treatment implications of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
      Liver fibrosis may progress to cirrhosis with all of its resulting complications, including end-stage liver disease, risk of hepatocellular cancer, and possible need for liver transplant.
      • 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.
      Fibrosis progression occurs in approximately 40% of individuals 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 severity of liver fibrosis is a key predictor of the long-term outcomes in people with NASH, including overall mortality.
      • Taylor R.S.
      • Taylor R.J.
      • Bayliss S.
      • et al.
      Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      The main features of NAFLD are presented in Figure 1.
      • 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.
      ,
      • 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.
      ,
      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.
      ,
      • Estes C.
      • Razavi H.
      • Loomba R.
      • Younossi Z.
      • Sanyal A.J.
      Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.
      Figure thumbnail gr1
      Figure 1Main features of nonalcoholic fatty liver disease (NAFLD). Disease progression is not linear; periods of stability or regression may occur. Steatosis: triglyceride accumulation in hepatocytes (fatty liver); must be present in more than 5% of hepatocytes as assessed by histology or imaging. Hepatocyte ballooning: enlargement of hepatocyte, indicative of injury/degeneration. F0, no fibrosis; F1, mild fibrosis; F2, significant fibrosis; F3, advanced (bridging) fibrosis; F4, cirrhosis; NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis; PCOS, polycystic ovary syndrome. Data sources: prevalence
      • 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.
      ; projected prevalence.
      • Estes C.
      • Razavi H.
      • Loomba R.
      • Younossi Z.
      • Sanyal A.J.
      Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.
      Liver histology/histopathology images courtesy of Zobair M. Younossi, MD, MPH, FACP, FACG, AGAF, FAASLD; President, Inova Medicine Services; Chairman, Clinical Research, Inova Health System; Professor and Chairman, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA.
      Nonalcoholic fatty liver disease is strongly associated with metabolic syndrome (MetS), obesity, type 2 diabetes (T2D), and dyslipidemia.
      • 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.
      Unsurprisingly, cardiovascular disease (CVD) is the most common cause of death in people with NAFLD
      • 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.
      (as it is overall in those with MetS
      • Mottillo S.
      • Filion K.B.
      • Genest J.
      • et al.
      The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis.
      ); NAFLD is associated with disease progression in cardiovascular disease (CVD) and chronic kidney disease (CKD)
      • 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.
      ,
      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.
      and with increased cancer-related mortality.
      • 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.
      • Paik J.M.
      • Henry L.
      • De Avila L.
      • Younossi E.
      • Racila A.
      • Younossi Z.M.
      Mortality related to nonalcoholic fatty liver disease is increasing in the United States.
      • 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.
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      Approximately 20% of people with NAFLD are classified as having 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.
      and 20% of those with NASH have advanced liver disease (category F3/F4 fibrosis).
      • Estes C.
      • Razavi H.
      • Loomba R.
      • Younossi Z.
      • Sanyal A.J.
      Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.
      An estimated 18.2 million American adults have T2D and NAFLD, of whom 6.4 million have NASH; 20-year costs for NAFLD in these patients are almost $56 billion and are projected to increase significantly during the coming 20 years.
      • Younossi Z.M.
      • Tampi R.P.
      • Racila A.
      • et al.
      Economic and clinical burden of nonalcoholic steatohepatitis in patients with type 2 diabetes in the U.S.
      The global epidemic of metabolic disorders related to obesity and diabetes will result in a considerable increase in the clinical and economic burden of NAFLD and NASH.
      The aim of this review is to present current information on the evaluation, diagnosis, and management of NAFLD and NASH in adults in the primary care setting and endocrinology clinics.

      Methods

      Literature was retrieved using Boolean searches for English-language articles in PubMed and Google Scholar and included terms related to NAFLD and NASH. The reference lists from retrieved articles were also considered.

      Pragmatic Approach to Management

      Scientific societies from different regions of the world have developed guidelines for the management of patients with NAFLD. In the United States, the American Association for the Study of Liver Diseases (AASLD) published practice guidance in 2018,
      • 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.
      and combined guidance from 3 European societies was published in 2016 (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]).
      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.
      In addition, guidelines have been published by the Asia-Pacific Working Party on Non-Alcoholic Fatty Liver Disease (2017),
      • Wong V.W.
      • Chan W.K.
      • Chitturi S.
      • et al.
      Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017—Part 1: definition, risk factors and assessment.
      ,
      • Chitturi S.
      • Wong V.W.
      • Chan W.K.
      • et al.
      The Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017—Part 2: management and special groups.
      the Italian Association for the Study of the Liver (2017),
      Italian Association for the Study of the Liver (AISF)
      AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions.
      and the United Kingdom’s National Institute for Health and Care Excellence (2016).
      National Institute for Health and Care Excellence
      Non-alcoholic fatty liver disease (NAFLD): assessment and management.
      A comparison of all 5 sets of guidelines was reported by Leoni et al,
      • Leoni S.
      • Tovoli F.
      • Napoli L.
      • Serio I.
      • Ferri S.
      • Bolondi L.
      Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis.
      and guidelines from the AASLD, the EASL-EASD-EASO, and the National Institute for Health and Care Excellence are summarized in Table 1.
      • 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.
      ,
      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.
      ,
      • Leoni S.
      • Tovoli F.
      • Napoli L.
      • Serio I.
      • Ferri S.
      • Bolondi L.
      Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis.
      Whereas we expect more harmonized guidelines in the future, herein we attempt to provide a pragmatic approach to the management of patients with NAFLD.
      Table 1Comparison of NAFLD Management Guidelines in Adults From the United States (AASLD), Europe (EASL-EASD-EASO), and United Kingdom (NICE)
      • 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.
      ,
      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.
      ,
      National Institute for Health and Care Excellence
      Non-alcoholic fatty liver disease (NAFLD): assessment and management.
      ,
      • Leoni S.
      • Tovoli F.
      • Napoli L.
      • Serio I.
      • Ferri S.
      • Bolondi L.
      Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis.
      GuidelinesDiagnostic criteriaScreening strategy; diagnostic tests and prognostic scoresEvaluation and monitoring of fibrosis; liver biopsyLifestyle interventionsPharmacotherapy
      AASLD 2018
      • 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.
      Evidence of HS (≥5%) by imaging or histology

      Exclusion of secondary causes of HS (no significant alcohol consumption, no existing liver disease)

      Alcohol consumption threshold (weekly): >21 drinks in men or >14 drinks in women (United States standard drink, 14 g of alcohol)
      No systematic screening

      No screening in high-risk groups; but “vigilance” for chronic liver disease in T2D

      HS imaging: US; MRI is better but routine availability limited

      Assess risk of CVD and T2D

      Presence of metabolic disease most potent predictor of adverse outcome
      Serum biomarkers

      Clinical decision aids: NFS or FIB-4

      Imaging: TE or MRE

      Monitoring: no information

      Liver biopsy with advanced liver fibrosis suggested by serum or noninvasive imaging tools

      Liver biopsy with MetS + risk liver inflammation
      Structured programs: weight loss, healthy diet, regular physical activity

      500-1000 kcal deficit; 3%-5% weight loss improves HS; 7%-10% weight loss improves NASH (including fibrosis)

      Moderate-intensity exercise

      Macronutrients/diet: no information
      For NASH + fibrosis

      Metformin: not recommended

      Pioglitazone: may be used in adult T2D + biopsy-proven NASH

      GLP-1 RAs: insufficient data

      Vitamin E: may be used in nondiabetic adult + biopsy-proven NASH

      UCDA: not recommended

      Omega-3 fatty acids: may be used in adult hypertriglyceridemia + NAFLD

      Statins: may be used in adults + dyslipidemia + NAFLD or NASH
      EASL-EASD-EASO 2016
      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.
      HS in >5% hepatocytes by imaging or histology

      Associated with insulin resistance

      Exclusion of secondary causes (no significant alcohol consumption)

      Alcohol consumption threshold (daily): >30 g in men or >20 g in women
      No community screening

      Screening in high-risk groups by US or liver enzymes

      HS imaging: US; MRI is “gold standard,” but availability and cost issues

      HS score: FLI (SteatoTest) or NAFLD liver fat score

      Assess risk of CVD and T2D
      Serum biomarkers

      Clinical decision aids: NFS or FIB-4

      Imaging: TE (in combination with biomarkers/scores, as less reliable with high BMI)

      Monitoring for progression: NASH ± fibrosis, yearly; NASH cirrhosis, every 6 months

      Liver biopsy when medium/high risk of advanced liver fibrosis suggested by serum or noninvasive imaging tools
      Structured programs: weight loss, healthy diet, regular physical activity

      500-1000 kcal deficit; 7%-10% weight loss to improve HS and NASH

      150-200 min/wk moderate-intensity aerobic and resistance training (split into shorter sessions)

      Diet: low to moderate fat + moderate to high carbohydrates; low-carbohydrate ketogenic or high protein
      For NASH + fibrosis

      For early NASH + high risk of progression

      Metformin: insufficient evidence

      Pioglitazone: may be used in adult NASH with T2D (off-label outside T2D)

      GLP-1 RAs: initial data favorable; insufficient evidence

      Vitamin E: may be used in noncirrhotic nondiabetic adult + NASH; more data needed

      UCDA: no effect observed

      Omega-3 fatty acids: insufficient data to support use

      Statins: no benefit or harm to liver disease
      NICE
      National Institute for Health and Care Excellence
      Non-alcoholic fatty liver disease (NAFLD): assessment and management.
      Excessive fat in liver

      Exclusion of secondary causes (no significant alcohol consumption)

      Alcohol consumption threshold (daily): >30 g in men or >20 g in women
      No community screening

      Consider that NAFLD is common in T2D and MetS
      ELF blood test

      Monitoring: ELF negative, reassess every 3 years; ELF positive, referral to hepatologist

      Liver biopsy is the gold standard for diagnosis but impractical to use widely in at-risk patients
      Consider NICE guidelines for obesity excessive weight gainFor NASH + fibrosis

      Metformin: not mentioned

      Pioglitazone: consider use regardless of diabetes status

      GLP-1 RAs: not mentioned

      UCDA: not mentioned

      Omega-3 fatty acids: not recommended

      Statins: continue use if already taking statins; stop if liver enzymes elevate (×2 within 3 months)

      Vitamin E: consider use regardless of diabetes status
      AASLD, American Association for the Study of Liver Diseases; BMI, body mass index; 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; FIB-4, Fibrosis-4; FLI, fatty liver index; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HS, hepatic steatosis; MetS, metabolic syndrome; MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NFS, NAFLD fibrosis score; NICE, National Institute for Health and Care Excellence; T2D, type 2 diabetes; TE, transient elastography; UCDA, ursodeoxycholic acid; US, ultrasound.

      Risk Factors, Comorbidities, and Complications

      The pathogenesis of NAFLD is multifactorial and not yet fully understood (comprehensive reviews have been published
      • Parthasarathy G.
      • Revelo X.
      • Malhi H.
      Pathogenesis of nonalcoholic steatohepatitis: an overview.
      • Tilg H.
      • Adolph T.E.
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      Multiple parallel hits hypothesis in NAFLD—revisited after a decade.
      • Godoy-Matos A.F.
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      NAFLD as a continuum: from obesity to metabolic syndrome and diabetes.
      • Noureddin M.
      • Sanyal A.J.
      Pathogenesis of NASH: the impact of multiple pathways.
      ). Nonalcoholic fatty liver disease is often referred to as the hepatic manifestation of MetS.
      • Cortez-Pinto H.
      • Camilo M.E.
      • Baptista A.
      • De Oliveira A.G.
      • De Moura M.C.
      Non-alcoholic fatty liver: another feature of the metabolic syndrome?.
      ,
      • Marchesini G.
      • Brizi M.
      • Bianchi G.
      • et al.
      Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.
      Briefly, the presence of excess lipid is the primary insult and is followed by the effects of pathogenic drivers, including insulin resistance, lipotoxicity, and immune system activation; these are combined with other modifying factors, such as adverse nutritional intake (eg, foods rich in fructose or saturated fats)
      • Berna G.
      • Romero-Gomez M.
      The role of nutrition in non-alcoholic fatty liver disease: pathophysiology and management.
      ,
      • Lombardi R.
      • Iuculano F.
      • Pallini G.
      • Fargion S.
      • Fracanzani A.L.
      Nutrients, genetic factors, and their interaction in non-alcoholic fatty liver disease and cardiovascular disease.
      and proinflammatory changes to the gut microbiome.
      • Parthasarathy G.
      • Revelo X.
      • Malhi H.
      Pathogenesis of nonalcoholic steatohepatitis: an overview.
      There are also known genetic predispositions to hepatic fat accumulation (eg, polymorphisms in the PNPLA3 gene and variants of the TM6SF2 gene)
      • Krawczyk M.
      • Liebe R.
      • Lammert F.
      Toward genetic prediction of nonalcoholic fatty liver disease trajectories: PNPLA3 and beyond.
      as well as the newly discovered protective genetic polymorphism in the 17β-hydroxysteroid dehydrogenase 13 gene, in which loss of function variants were associated with a reduced risk of chronic liver disease and progression from steatosis to steatohepatitis.
      • Abul-Husn N.S.
      • Cheng X.
      • Li A.H.
      • et al.
      A protein-truncating HSD17B13 variant and protection from chronic liver disease.
      ,
      • Ma Y.
      • Belyaeva O.V.
      • Brown P.M.
      • et al.
      17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease.
      The association between NAFLD and metabolic disorders is well documented, as is the occurrence of NAFLD with CVD or CKD (summarized later and reviewed in a number of publications
      • Godoy-Matos A.F.
      • Silva Junior W.S.
      • Valerio C.M.
      NAFLD as a continuum: from obesity to metabolic syndrome and diabetes.
      ,
      • Mantovani A.
      • Scorletti E.
      • Mosca A.
      • Alisi A.
      • Byrne C.D.
      • Targher G.
      Complications, morbidity and mortality of nonalcoholic fatty liver disease.
      • Kasper P.
      • Martin A.
      • Lang S.
      • et al.
      NAFLD and cardiovascular diseases: a clinical review.
      • Bisaccia G.
      • Ricci F.
      • Mantini C.
      • et al.
      Nonalcoholic fatty liver disease and cardiovascular disease phenotypes.
      • Byrne C.D.
      • Targher G.
      NAFLD as a driver of chronic kidney disease.
      • Targher G.
      • Byrne C.D.
      • Tilg H.
      NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications.
      • Tomah S.
      • Alkhouri N.
      • Hamdy O.
      Nonalcoholic fatty liver disease and type 2 diabetes: where do diabetologists stand?.
      ). Obesity (excessive body mass index [BMI] and visceral obesity) is the most common risk factor for NAFLD and NASH (prevalence of 51% and 82%, respectively
      • 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.
      ) and includes the range from overweight to severely obese.
      • 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.
      The increasing frequency of obesity in American adults—current prevalence of 42% (severe obesity 9%)
      • Hales C.M.
      • Carroll M.D.
      • Fryar C.D.
      • Ogden C.L.
      Prevalence of obesity and severe obesity among adults: United States, 2017-2018. NCHS Data Brief, no 360.
      and anticipated to rise to 49% (severe obesity 24%) by 2030
      • Ward Z.J.
      • Bleich S.N.
      • Cradock A.L.
      • et al.
      Projected U.S. state-level prevalence of adult obesity and severe obesity.
      —can be expected to fuel an increase in NAFLD. Some normal-weight individuals (BMI <25 kg/m2) can exhibit NAFLD with or without exhibiting abnormal levels of liver enzymes; this is so-called lean NAFLD.
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      ,
      • Albhaisi S.
      • Chowdhury A.
      • Sanyal A.J.
      Non-alcoholic fatty liver disease in lean individuals.
      Although generally exhibiting a more favorable metabolic profile than obese individuals, lean NAFLD patients can develop the full spectrum of liver damage associated with “non-lean” NAFLD.
      • Younes R.
      • Bugianesi E.
      NASH in lean individuals.
      This may be due to such individuals’ having dysfunctional adipose tissue or expressing genes associated with obese NAFLD patients (eg, PNPLA3).
      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.
      ,
      • Younes R.
      • Bugianesi E.
      NASH in lean individuals.
      Notably, insulin resistance is also associated with NAFLD in individuals without diabetes or obesity, suggesting that it may play an intrinsic role in the pathogenesis of NAFLD independent of BMI.
      • Bugianesi E.
      • Gastaldelli A.
      • Vanni E.
      • et al.
      Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.
      ,
      • Kim H.J.
      • Kim H.J.
      • Lee K.E.
      • et al.
      Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults.
      All components of MetS correlate with hepatic fat content independently of BMI.
      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.
      Metabolic syndrome is defined as the presence of 3 of the following 5 criteria: impaired fasting glucose level or T2D, hypertriglyceridemia, low high-density lipoprotein cholesterol concentration (sex adjusted), increased waist circumference, and hypertension.
      International Diabetes Federation
      IDF consensus worldwide definition of the metabolic syndrome. 2006.
      A bidirectional association between MetS and NAFLD has been established, and the presence of MetS in an individual should prompt an evaluation for NAFLD risk and vice versa.
      • 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.
      ,
      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.
      The severity of NAFLD was shown to correlate with the number of MetS criteria present in an individual.
      • Jinjuvadia R.
      • Antaki F.
      • Lohia P.
      • Liangpunsakul S.
      The association between nonalcoholic fatty liver disease and metabolic abnormalities in the United States Population.
      The relationship between NAFLD and T2D is also bidirectional, and the 2 conditions can develop concurrently in a patient.
      • 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.
      Both NAFLD and T2D are associated with insulin resistance, obesity, and inflammation, but the precise order of events is not understood.
      • Tomah S.
      • Alkhouri N.
      • Hamdy O.
      Nonalcoholic fatty liver disease and type 2 diabetes: where do diabetologists stand?.
      A 60% prevalence of NAFLD in individuals with T2D was reported (meta-analysis of 24 studies involving T2D; >35,000 patients)
      • Dai W.
      • Ye L.
      • Liu A.
      • et al.
      Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a meta-analysis.
      ; T2D is strongly associated with NAFLD progression to NASH
      • 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.
      ,
      • Gastaldelli A.
      • Cusi K.
      From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options.
      and with the risk of advanced fibrosis.
      • Bril F.
      • Cusi K.
      Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action.
      Dyslipidemia (high serum triglyceride and low high-density lipoprotein levels) is also frequently observed in people with NAFLD (prevalence >50%)
      • 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.
      and often occurs secondary to insulin resistance.
      Given the association between NAFLD and the metabolic disorders described, it is unsurprising that the risk of CVD is also increased in patients with NAFLD. Although it is not yet clear whether there is a causal relationship between the 2 conditions, NAFLD is at least a risk marker for CVD, and NAFLD has been linked with markers of subclinical atherosclerosis, including coronary artery calcification and increased coronary artery calcium score.
      • Kasper P.
      • Martin A.
      • Lang S.
      • et al.
      NAFLD and cardiovascular diseases: a clinical review.
      Therefore, cardiovascular risk assessment should be undertaken in individuals with NAFLD.
      • 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.
      ,
      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.
      ,
      • Kasper P.
      • Martin A.
      • Lang S.
      • et al.
      NAFLD and cardiovascular diseases: a clinical review.
      Evidence indicates that NAFLD increases the risk of hypertension, coronary heart disease, cardiomyopathy, and arrhythmias, resulting in increased cardiovascular morbidity and mortality in patients with NAFLD.
      • Kasper P.
      • Martin A.
      • Lang S.
      • et al.
      NAFLD and cardiovascular diseases: a clinical review.
      The link between NAFLD and CKD has also been examined,
      • Mantovani A.
      • Scorletti E.
      • Mosca A.
      • Alisi A.
      • Byrne C.D.
      • Targher G.
      Complications, morbidity and mortality of nonalcoholic fatty liver disease.
      ,
      • Byrne C.D.
      • Targher G.
      NAFLD as a driver of chronic kidney disease.
      and there is increasing epidemiologic evidence that NAFLD is an independent risk factor for CKD,
      • Byrne C.D.
      • Targher G.
      NAFLD as a driver of 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.
      ,
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • et al.
      Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
      although causality is not yet proven. As with CVD, the occurrence of CKD in NAFLD is not unexpected, given the presence of multiple CKD risk factors in individuals with NAFLD. Individuals with NAFLD should undergo an assessment of kidney function, and a review of any medication that may affect kidney function should be undertaken. The possible mechanisms linking NAFLD with the development of CVD and CKD have been described
      • Lombardi R.
      • Iuculano F.
      • Pallini G.
      • Fargion S.
      • Fracanzani A.L.
      Nutrients, genetic factors, and their interaction in non-alcoholic fatty liver disease and cardiovascular disease.
      ,
      • Kasper P.
      • Martin A.
      • Lang S.
      • et al.
      NAFLD and cardiovascular diseases: a clinical review.
      • Bisaccia G.
      • Ricci F.
      • Mantini C.
      • et al.
      Nonalcoholic fatty liver disease and cardiovascular disease phenotypes.
      • Byrne C.D.
      • Targher G.
      NAFLD as a driver of chronic kidney disease.
      ,
      • Stahl E.P.
      • Dhindsa D.S.
      • Lee S.K.
      • Sandesara P.B.
      • Chalasani N.P.
      • Sperling L.S.
      Nonalcoholic fatty liver disease and the heart: JACC state-of-the-art review.
      ,
      • Niederseer D.
      • Wernly B.
      • Aigner E.
      • Stickel F.
      • Datz C.
      NAFLD and cardiovascular diseases: epidemiological, mechanistic and therapeutic considerations.
      (Supplemental Video, available online at http://www.mayoclinicproceedings.org).
      Nonalcoholic steatohepatitis is now among the top causes of hepatocellular carcinoma (HCC) and the second most common indication for liver transplant in the United States.
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      The risk for HCC is highest among those with NAFLD cirrhosis, such that surveillance is warranted.
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      There is also a risk of HCC with lesser levels of liver fibrosis, but there is no observed increased risk for HCC in those assessed as “low risk” of liver fibrosis measured by noninvasive serum biomarkers (eg, Fibrosis-4 [FIB-4] index).
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.

      Clinical Pathway for Primary Care Providers

      A clinical pathway for assessing individuals with NAFLD and NASH in the primary care setting is presented in Figure 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.
      ,
      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.
      ,
      • Budd J.
      • Cusi K.
      Nonalcoholic fatty liver disease: what does the primary care physician need to know?.
      • Sheka A.C.
      • Adeyi O.
      • Thompson J.
      • Hameed B.
      • Crawford P.A.
      • Ikramuddin S.
      Nonalcoholic steatohepatitis: a review.
      • Jennison E.
      • Patel J.
      • Scorletti E.
      • Byrne C.D.
      Diagnosis and management of non-alcoholic fatty liver disease.
      Figure thumbnail gr2
      Figure 2Management pathway for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
      • 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.
      ,
      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.
      ,
      • Budd J.
      • Cusi K.
      Nonalcoholic fatty liver disease: what does the primary care physician need to know?.
      • Sheka A.C.
      • Adeyi O.
      • Thompson J.
      • Hameed B.
      • Crawford P.A.
      • Ikramuddin S.
      Nonalcoholic steatohepatitis: a review.
      • Jennison E.
      • Patel J.
      • Scorletti E.
      • Byrne C.D.
      Diagnosis and management of non-alcoholic fatty liver disease.
      ALT, alanine aminotransferase; AST, aspartate aminotransferase; CV, cardiovascular; CVD, cardiovascular disease; ELF, enhanced liver fibrosis; FIB-4, Fibrosis-4; GGT, γ-glutamyltransferase; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; NAFL, nonalcoholic fatty liver; NFS, NAFLD fibrosis score; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes; US, ultrasound. aThe enhanced liver fibrosis (ELF) score is expected to be available in the United States in 2022. bBecause of the current lack of efficacy data, the following agents are not recommended to treat steatohepatitis, but their use may be continued as needed for the treatment of hyperglycemia in persons with T2D and NAFLD or NASH: metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin.
      The key questions to be answered are the following: Does the patient have NAFLD or something else? If NAFLD is diagnosed, does the patient have NASH? If NASH is diagnosed, what is the patient’s risk for development of liver fibrosis? Is a liver biopsy necessary? There is no individual diagnostic test for NAFLD, and it is largely a diagnosis of exclusion. Patients with NAFLD may be identified incidentally during investigation for other conditions (eg, abdominal imaging, liver function tests). People with uncomplicated NAFLD are typically asymptomatic, or their symptoms are vague (eg, fatigue, abdominal discomfort). The presence of clinical features of obesity, T2D, MetS, or dyslipidemia increases the clinical suspicion of NAFLD. Clinicians should consider the following individuals to be “at risk” or “high risk”: those with obesity, T2D, or MetS; those with hepatic steatosis on any imaging study; and those with persistently elevated plasma aminotransferases (at least 2 abnormal values within 6 months). These individuals should be screened for NAFLD and advanced fibrosis. Clinical action should be taken if NAFLD is suspected, even in the absence of symptoms or abnormal liver biochemistry. Secondary causes of hepatic steatosis and causes of concurrent liver diseases must be excluded to make a diagnosis of NAFLD, including alcohol and drug use, hepatitis C virus (genotype 3), autoimmune liver disease, Wilson disease, and hemochromatosis.
      • 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.
      ,
      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.
      Liver biochemistry is inadequate in assessing NAFLD (eg, transaminases were within the normal range in 43% of patients with NAFLD who were enrolled in the NASH Clinical Research Network studies
      • Gawrieh S.
      • Wilson L.A.
      • Cummings O.W.
      • et al.
      Histologic findings of advanced fibrosis and cirrhosis in patients with nonalcoholic fatty liver disease who have normal aminotransferase levels.
      ) and is not predictive of liver fat content or fibrosis stage.
      • Mofrad P.
      • Contos M.J.
      • Haque M.
      • et al.
      Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values.
      First-line identification of hepatic steatosis is done by abdominal ultrasound scan, on which increased echogenicity is indicative of steatosis. Ultrasound is an inexpensive and accessible tool. Although it has limitations, an ultrasound scan offers the convenience of enabling complete liver imaging and liver fibrosis assessment to be carried out in the same session. Other imaging techniques are available,
      • Piazzolla V.A.
      • Mangia A.
      Noninvasive diagnosis of NAFLD and NASH.
      including vibration-controlled transient elastography (VCTE), shear wave elastography,
      • Cassinotto C.
      • Boursier J.
      • Paisant A.
      • et al.
      Transient versus two-dimensional shear-wave elastography in a multistep strategy to detect advanced fibrosis in NAFLD.
      and magnetic resonance imaging (MRI). For example, FibroScan (Echosens North America) is a transient elastography device that measures liver fat and fibrosis,
      • Li Q.
      • Dhyani M.
      • Grajo J.R.
      • Sirlin C.
      • Samir A.E.
      Current status of imaging in nonalcoholic fatty liver disease.
      and LiverMultiScan software (Perspectum Ltd) analyzes MRI data,
      • Imajo K.
      • Tetlow L.
      • Dennis A.
      • et al.
      Quantitative multiparametric magnetic resonance imaging can aid non-alcoholic steatohepatitis diagnosis in a Japanese cohort.
      ,
      • Dennis A.
      • Mouchti S.
      • Kelly M.
      • et al.
      A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis.
      including the generation of MRI proton density fat fraction maps.
      • Eddowes P.J.
      • McDonald N.
      • Davies N.
      • et al.
      Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease.
      ,
      • Noureddin M.
      • Lam J.
      • Peterson M.R.
      • et al.
      Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials.
      (Details of imaging modalities are presented in Supplemental Table 1, available online at http://www.mayoclinicproceedings.org.)
      The initial finding of hepatic steatosis is important for the diagnosis of NAFLD, but it is the presence or absence of liver fibrosis (ie, NASH fibrosis) that is the crucial determinant of liver-related mortality. Importantly, if the stage of fibrosis is F3 (severe [bridging] fibrosis) or higher, the clinical action plan must shift from routine monitoring and lifestyle modification to aggressive management. Liver biopsy remains the “gold standard” for the diagnosis of NASH,
      • 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.
      but it is impractical to perform routinely on every patient with NAFLD. Furthermore, the procedure has well-documented limitations; it is invasive, there is a risk of procedural complications and sampling errors, and it has cost implications.
      • 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.
      Nevertheless, liver biopsy should be considered in any individual with NAFLD in whom there is a high suspicion of NASH or if other causes of hepatic steatosis or chronic liver disease need to be excluded.
      • 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.
      ,
      • Gunn N.T.
      • Shiffman M.L.
      The use of liver biopsy in nonalcoholic fatty liver disease: when to biopsy and in whom.
      A range of noninvasive assessments of liver disease in NAFLD are also available to identify individuals at risk of NASH and liver fibrosis
      • Younossi Z.M.
      • Noureddin M.
      • Bernstein D.
      • et al.
      Role of noninvasive tests in clinical gastroenterology practices to identify patients with nonalcoholic steatohepatitis at high risk of adverse outcomes: expert panel recommendations.
      • Ajmera V.
      • Loomba R.
      Imaging biomarkers of NAFLD, NASH, and fibrosis.
      • Castera L.
      • Friedrich-Rust M.
      • Loomba R.
      Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
      ; they are broadly divided into risk indices that use serum biomarkers associated with various types of liver disease and imaging techniques to measure liver steatosis or fibrosis (Supplemental Figure, available online at http://www.mayoclinicproceedings.org). Anthropometric assessments (eg, BMI) and noninvasive biomarkers (eg, liver fibrosis scores) can be used to make an initial assessment of the patient’s risk of NAFLD with liver fibrosis. The preferred noninvasive test is the FIB-4 index
      • 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.
      ,
      • Kanwal F.
      • Shubrook J.H.
      • Adams L.A.
      • et al.
      Clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease.
      ; it is validated and free of charge. Other patented scoring systems are available, such as the enhanced liver fibrosis (ELF) score (available in the United States in 2022).
      • Younossi Z.M.
      • Noureddin M.
      • Bernstein D.
      • et al.
      Role of noninvasive tests in clinical gastroenterology practices to identify patients with nonalcoholic steatohepatitis at high risk of adverse outcomes: expert panel recommendations.
      Most of these noninvasive risk indices are better at identifying advanced stages of fibrosis (≥F3) rather than less advanced stages.
      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.
      Liver imaging by VCTE, shear wave elastography, or magnetic resonance elastography (where available) may be used to further identify persons who need referral to a hepatologist for consideration of a liver biopsy.
      • Castera L.
      • Friedrich-Rust M.
      • Loomba R.
      Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
      ,
      • Younossi Z.M.
      • Corey K.E.
      • Alkhouri N.
      • et al.
      Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices.
      Clinicians should consider doing further work-up if an individual has obesity or T2D and intermediate or high noninvasive liver fibrosis scores. Patients with T2D and a FIB-4 score above 1.3 should be screened by VCTE (if available). In the absence of VCTE, shear wave elastography, or magnetic resonance elastography, clinicians should use risk indices such as the ELF score
      • Lichtinghagen R.
      • Pietsch D.
      • Bantel H.
      • Manns M.P.
      • Brand K.
      • Bahr M.J.
      The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values.
      or other proprietary biomarkers that establish or exclude advanced fibrosis. Similarly, patients with type 1 diabetes should be screened if they have additional risk factors for NAFLD, such as obesity, MetS, elevated alanine aminotransferase or aspartate aminotransferase (≥30 U/L) or FIB-4 score (>1.3), or hepatic steatosis on imaging.
      For an NAFLD patient with liver fibrosis at stage F2 (significant fibrosis) based on biomarkers and the presence of comorbidities, liver imaging (eg, FibroScan) should be carried out with a subsequent referral to a hepatology specialist, and the primary care provider should continue to manage patient care. Patients with liver fibrosis at stage F3 or higher (advanced [bridging] fibrosis) require the involvement of a hepatology specialist. Wherever possible, patients should be encouraged to return to their primary care provider for regular monitoring visits, help with adherence to diets and weight loss programs, and metabolic control (discussed later). If appropriate, patients should be encouraged to consider participating in NAFLD or NASH clinical trials. Ideally, the primary care provider and hepatology specialist should work together closely to manage risk factors and to mitigate disease progression to cirrhosis.
      Optimal follow-up in NAFLD is currently undetermined, but EASL-EASD-EASO guidelines recommend the following: patients who have nonalcoholic fatty liver without worsening metabolic risk factors should be monitored at 2- to 3-year intervals; patients with NASH or fibrosis should be monitored annually; and those with NASH cirrhosis should be monitored at 6-month intervals.
      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.
      Follow-up intervals and criteria for referral to a hepatologist for patients with various stages of liver fibrosis are shown in Table 2. In all cases, monitoring should include routine biochemistry, assessment of metabolic and CVD risk factors (including blood pressure, lipids, and T2D), and noninvasive assessment of fibrosis.
      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.
      For patients with cirrhosis, surveillance for HCC with imaging should be carried out every 6 months.
      • Bruix J.
      • Sherman M.
      American Association for the Study of Liver Disease
      Management of hepatocellular carcinoma: an update.
      Referral to additional specialists (eg, diabetologist, cardiologist, nephrologist, obesity or nutritional specialist) should also be considered, depending on the clinical profile of an individual patient and the comfort level and experience of the primary care provider in managing these conditions.
      Table 2Follow-up Interval and Need for Referral to Hepatologist for Patients With Various Stages of Liver Fibrosis
      Liver fibrosis stageFollow-up intervalReferral to hepatologist
      F0-F1 without comorbidities or risk factors2 to 3 yearsNo
      F0-F1 with comorbidities or risk factors12 monthsNo
      F2 without comorbidities or risk factors12 monthsPossibly
      F2 with comorbidities or risk factors12 monthsYes
      ≥F36 monthsYes
      F0, no fibrosis; F1, mild fibrosis; F2, significant fibrosis; F3, advanced (bridging) fibrosis; F4, cirrhosis.

      Management of Patients With NAFLD

      Standard treatment for NAFLD centers on lifestyle modification leading to weight loss, including calorie reduction, exercise, and healthy food intake.
      • Bischoff S.C.
      • Bernal W.
      • Dasarathy S.
      • et al.
      ESPEN practical guideline: clinical nutrition in liver disease.
      ,
      • Miller E.F.
      Nutrition management strategies for nonalcoholic fatty liver disease: treatment and prevention.
      The EASL-EASD-EASO guidelines recommend using macronutrients per the Mediterranean diet, in which a large fraction of dietary lipid is provided as monounsaturated fatty acids.
      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.
      A diet high in monounsaturated fatty acids was shown to lower liver fat and to improve hepatic and total insulin sensitivity.
      • Errazuriz I.
      • Dube S.
      • Slama M.
      • et al.
      Randomized controlled trial of a MUFA or fiber-rich diet on hepatic fat in prediabetes.
      Data from clinical trials (randomized and nonrandomized) have shown an association between weight loss interventions and improved biomarkers of liver disease in NAFLD
      • Koutoukidis D.A.
      • Astbury N.M.
      • Tudor K.E.
      • et al.
      Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      ,
      • Koutoukidis D.A.
      • Koshiaris C.
      • Henry J.A.
      • et al.
      The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      and NASH.
      • Koutoukidis D.A.
      • Koshiaris C.
      • Henry J.A.
      • et al.
      The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      Loss of at least 5% of body weight improved steatosis, and weight loss of 7% to 9% improved most histopathologic changes, but improvement in fibrosis was observed only with weight loss of more than 10%.
      • 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.
      ,
      • Bischoff S.C.
      • Bernal W.
      • Dasarathy S.
      • et al.
      ESPEN practical guideline: clinical nutrition in liver disease.
      However, these levels of weight loss are extremely difficult to achieve, let alone to sustain.
      • Gulliford M.C.C.J.
      • Booth H.P.
      Costs and outcomes of increasing access to bariatric surgery for obesity: cohort study and cost-effectiveness analysis using electronic health records.
      Intensive behavior-based interventions can induce clinically meaningful weight loss and are recommended by the US Preventive Services Task Force
      US Preventive Services Task Force
      Behavioral weight loss interventions to prevent obesity-related morbidity and mortality in adults: recommendation statement.
      ; measures include counseling, self-monitoring, peer support, and relapse prevention. The involvement of primary care practitioners plus other specialists (such as psychologists, dietitians, fitness coaches) is central in supporting an individual through long-term weight loss management.
      • Durrer Schutz D.
      • Busetto L.
      • Dicker D.
      • et al.
      European practical and patient-centred guidelines for adult obesity management in primary care.
      In individuals in whom these measures are not sufficient, pharmacotherapy is recommended as an adjunct to lifestyle modifications in patients with a BMI above 30 kg/m2 or in patients with a BMI above 27 kg/m2 in the presence of weight-related comorbidities, such as diabetes, hypertension, and dyslipidemia.
      • Garvey W.T.
      • Mechanick J.I.
      • Brett E.M.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for medical care of patients with obesity.
      Five medications are currently approved by the US Food and Drug Administration (FDA) for chronic weight management: orlistat (lipase inhibitor), phentermine/topiramate extended release (sympathomimetic plus anticonvulsant), naltrexone extended release/bupropion extended release (opioid antagonist plus aminoketone antidepressant), and liraglutide and semaglutide (glucagon-like peptide 1 receptor agonists [GLP-1 RAs]).
      • Karam N.
      • Nathan J.S.
      A review of FDA-approved medications for chronic weight management.
      In addition to significant weight loss, semaglutide has been shown to improve NASH, although not fibrosis,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      and it is also associated with significant cardioprotective and nephroprotective effects. Bariatric surgery (discussed later) could also be considered in the treatment of persons with NAFLD or NASH and a BMI of 35 kg/m2 or higher (≥32.5 kg/m2 in Asian populations), particularly if T2D is present, when medical therapy has failed to achieve durable weight loss and improvement of comorbidities.
      Pharmacologic treatments are intended primarily to improve liver disease and should be offered to patients with progressive NASH (biopsy-proven with fibrosis and cirrhosis).
      • 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.
      ,
      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.
      The aim is to interrupt the pathophysiologic processes of NASH, and it is likely that combination drug therapies with different mechanisms of action will be required. Pharmacotherapy may also be used in patients with less severe liver disease but at high risk of disease progression (MetS, diabetes, persistently elevated alanine aminotransferase, high necroinflammatory activity).
      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.
      At the time of writing, no pharmacologic agents have completed phase 3 clinical trials or gained regulatory approval for use in the management of NASH in the United States or Europe.
      • 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.
      ,
      U.S. Department of Health and Human Services, Food and Drug Administration
      Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment guidance for industry. December 2018.
      ,
      European Medicines Agency
      Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH). Draft. November 15, 2018.
      Adjunctive treatment options for NAFLD and NASH are presented in Table 3.
      • 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.
      ,
      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.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      • El Hadi H.
      • Vettor R.
      • Rossato M.
      Vitamin E as a treatment for nonalcoholic fatty liver disease: reality or myth?.
      • Blazina I.
      • Selph S.
      Diabetes drugs for nonalcoholic fatty liver disease: a systematic review.
      • Green C.J.
      • Marjot T.
      • Tomlinson J.W.
      • Hodson L.
      Of mice and men: is there a future for metformin in the treatment of hepatic steatosis?.
      • 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.
      Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis.
      • Bril F.
      • Kalavalapalli S.
      • Clark V.C.
      • et al.
      Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes.
      • Ahsan F.
      • Oliveri F.
      • Goud H.K.
      • et al.
      Pleiotropic effects of statins in the light of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
      • Lv X.
      • Dong Y.
      • Hu L.
      • Lu F.
      • Zhou C.
      • Qin S.
      Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): a systematic review.
      • 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.
      • Mantovani A.
      • Dalbeni A.
      Treatments for NAFLD: state of art.
      • Shao S.C.
      • Kuo L.T.
      • Chien R.N.
      • Hung M.J.
      • Lai E.C.
      SGLT2 inhibitors in patients with type 2 diabetes with non-alcoholic fatty liver diseases: an umbrella review of systematic reviews.
      Treatment recommendations from the NAFLD guidelines are mainly confined to the use of vitamin E (in confirmed NASH; non-diabetes, non-cirrhosis) or pioglitazone (in biopsy-confirmed NASH; off-label use in non-T2D).
      • 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.
      ,
      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.
      ,
      National Institute for Health and Care Excellence
      Non-alcoholic fatty liver disease (NAFLD): assessment and management.
      However, both of these treatments come with additional risks and contraindications. Pioglitazone is associated with weight gain, bone loss in women, and increased risk of bladder cancer and heart failure.
      US Food and Drug Administration
      Prescribing information: pioglitazone tablets. January 1, 2021.
      Long-term vitamin E treatment is associated with an increase in all-cause mortality, hemorrhagic stroke risk, and increased risk of prostate cancer in men.
      National Institutes of Health
      Office of Dietary Supplements. Vitamin E: fact sheet for health professionals. March 26, 2021.
      Limited clinical trials data indicate that GLP-1 RAs and sodium-glucose cotransporter 2 (SGLT2) inhibitors may contribute to improvements in NAFLD and NASH.
      • Athyros V.G.
      • Polyzos S.A.
      • Kountouras J.
      • et al.
      Non-alcoholic fatty liver disease treatment in patients with type 2 diabetes mellitus; new kids on the block.
      The results of longer term randomized controlled trials are awaited with interest, particularly as these agents are associated with risk reduction in cardiovascular events,
      American Diabetes Association
      10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2021.
      which is the leading cause of NAFLD mortality. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA,
      • Rosenstock J.
      • Wysham C.
      • Frias J.P.
      • et al.
      Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.
      is under FDA consideration for use in T2D, but no recommendation can be given for its use in NAFLD or NASH at this time. Several other pharmacologic therapies for NAFLD and NASH are in clinical development
      • Vuppalanchi R.
      • Noureddin M.
      • Alkhouri N.
      • Sanyal A.J.
      Therapeutic pipeline in nonalcoholic steatohepatitis.
      • Shen B.
      • Lu L.G.
      Efficacy and safety of drugs for nonalcoholic steatohepatitis.
      • Guirguis E.
      • Grace Y.
      • Bolson A.
      • DellaVecchia M.J.
      • Ruble M.
      Emerging therapies for the treatment of non-alcoholic steatohepatitis: a systematic review.
      • Ratziu V.
      • Sanyal A.J.
      • Loomba R.
      • et al.
      REGENERATE: design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis.
      Intercept Pharmaceuticals
      Phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter study evaluating the safety and efficacy of obeticholic acid in subjects with nonalcoholic steatohepatitis (REGENERATE).
      Intercept Pharmaceuticals
      Phase 3, double-blind, randomized, placebo-controlled, multicenter study to evaluate the efficacy and safety of obeticholic acid in subjects with compensated cirrhosis due to nonalcoholic steatohepatitis (REVERSE).
      Galmed Pharmaceuticals Ltd
      Phase 3/4 clinical study to evaluate the efficacy and safety of aramchol versus placebo in subjects with NASH (ARMOR).
      Madrigal Pharmaceuticals Inc
      Phase 3 study to evaluate the efficacy and safety of mgl-3196 (resmetirom) in patients with NASH and fibrosis (MAESTRO-NASH).
      Madrigal Pharmaceuticals Inc
      Phase 3 study to evaluate the safety and biomarkers of resmetirom (MGL-3196) in non-alcoholic fatty liver disease (NAFLD) patients (MAESTRO-NAFLD1).
      Galectin Therapeutics Inc
      Phase 2b/3 study evaluating the efficacy and safety of belapectin for the prevention of esophageal varices in NASH cirrhosis (NAVIGATE).
      (Supplemental Table 2, available online at http://www.mayoclinicproceedings.org). The main agents being evaluated are obeticholic acid (Ocaliva),
      • 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.
      a farnesoid X receptor agonist; arachidyl amido cholanoic acid (Aramchol),
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      One-year results of the global phase 2b randomized placebo-controlled arrest trial of aramchol, a stearoyl CoA desaturase inhibitor, in patients with NASH. Presented at: The Liver Meeting 2018: American Association for the Study of Liver Diseases; November 9-13, 2018; San Francisco, CA.
      a stearoyl–coenzyme A desaturase modulator; and resmetirom,
      • Harrison S.A.
      • Bashir M.R.
      • Guy C.D.
      • et al.
      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      a thyroid hormone receptor β agonist. Following the submission of a New Drug Application to the FDA for obeticholic acid in the treatment of NASH, an Incomplete Response letter was issued in June 2020. An FDA re-review based on longer term safety data from the clinical trial is expected in the first half of 2022.
      • Higgins-Dunn N.
      Intercept charts new path to NASH approval for obeticholic acid, as long as safety holds.
      Table 3Adjunctive Treatment Options in NAFLD and NASH
      Drug classDetails
      Antioxidants
       Vitamin E
      • Can be used in patients with biopsy-proven NASH
        • 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.
        ,
        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.
        ,
        • Sanyal A.J.
        • Chalasani N.
        • Kowdley K.V.
        • et al.
        Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
        ,
        • El Hadi H.
        • Vettor R.
        • Rossato M.
        Vitamin E as a treatment for nonalcoholic fatty liver disease: reality or myth?.
      • Not to be used in NASH patients with
        • Diabetes
        • Cirrhosis (because of lack of supporting efficacy data)
      Insulin sensitizers
       Metformin
      • Insufficient data for evidence-based recommendations in NAFLD or NASH treatment
        • 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.
        ,
        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.
        • Rodent study data suggest that metformin reduces liver fat accumulation, but this is not consistently supported by clinical trials data.
          • Blazina I.
          • Selph S.
          Diabetes drugs for nonalcoholic fatty liver disease: a systematic review.
          ,
          • Green C.J.
          • Marjot T.
          • Tomlinson J.W.
          • Hodson L.
          Of mice and men: is there a future for metformin in the treatment of hepatic steatosis?.
       Pioglitazone
      • Can be used in patients with biopsy-proven NASH
        • With or without T2D
          • 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.
          ,
          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.
          ,
          • Blazina I.
          • Selph S.
          Diabetes drugs for nonalcoholic fatty liver disease: a systematic review.
          ,
          • 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.
          Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis.
          • Bril F.
          • Kalavalapalli S.
          • Clark V.C.
          • et al.
          Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes.
          (Use is off-label in the absence of T2D.)
      • Consider adverse effects associated with glitazones:
        • Weight gain, bone fractures (women), heart failure (rare)
      Lipid-lowering agents
       Statins
      • Can be used to treat dyslipidemia in patients with NAFLD or NASH
        • 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.
        ,
        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.
        ,
        • Ahsan F.
        • Oliveri F.
        • Goud H.K.
        • et al.
        Pleiotropic effects of statins in the light of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
      • Not to be used in patients with decompensated cirrhosis
      Newer glycemic control agents
       GLP-1 RAs
      • Insufficient data for evidence-based recommendations in NAFLD or NASH treatment
        • 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.
        • Meta-analysis (24 trials, >6300 participants) reported efficacy in reducing hepatic steatosis and inflammation
          • Lv X.
          • Dong Y.
          • Hu L.
          • Lu F.
          • Zhou C.
          • Qin S.
          Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): a systematic review.
          and the potential to reverse fibrosis.
          • Newsome P.N.
          • Buchholtz K.
          • Cusi K.
          • et al.
          A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
          ,
          • Lv X.
          • Dong Y.
          • Hu L.
          • Lu F.
          • Zhou C.
          • Qin S.
          Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): a systematic review.
          ,
          • 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.
        • Further clinical trials are needed to make a full assessment (ie, longer duration, use of histologic end points).
      • Potentially relevant cardiorenal benefits in large randomized clinical trials enrolling patients with T2D
        • Mantovani A.
        • Dalbeni A.
        Treatments for NAFLD: state of art.
       SGLT2 inhibitors
      • Not mentioned in NAFLD/NASH guidelines
        • Limited clinical trials data indicate potential beneficial effects in NAFLD (improvement in liver enzymes and liver fat; no evidence of liver fibrosis improvement has been reported).
          • Shao S.C.
          • Kuo L.T.
          • Chien R.N.
          • Hung M.J.
          • Lai E.C.
          SGLT2 inhibitors in patients with type 2 diabetes with non-alcoholic fatty liver diseases: an umbrella review of systematic reviews.
        • Further clinical trials are needed to make a full assessment (ie, longer duration, use of histologic end points).
      • Potentially relevant cardiorenal benefits in large randomized clinical trials enrolling patients with and without T2D
        • Mantovani A.
        • Dalbeni A.
        Treatments for NAFLD: state of art.
      GLP-1 RA, glucagon-like peptide 1 receptor agonist; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.
      Comorbidities present in patients with NAFLD should be managed according to current standards of care (obesity, prediabetes, and T2D
      American Diabetes Association
      Standards of Medical Care in Diabetes—2021 abridged for primary care providers.
      ; CVD
      • Arnett D.K.
      • Blumenthal R.S.
      • Albert M.A.
      • et al.
      2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ; hypertension
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Williams B.
      • Mancia G.
      • Spiering W.
      • et al.
      2018 ESC/ESH Guidelines for the management of arterial hypertension.
      • Unger T.
      • Borghi C.
      • Charchar F.
      • et al.
      2020 International Society of Hypertension global hypertension practice guidelines.
      ; dyslipidemia
      Authors/Task Force Members; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ,
      • Handelsman Y.
      • Jellinger P.S.
      • Guerin C.K.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm—2020 executive summary.
      ; renal disease
      Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group
      KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Stevens P.E.
      • Levin A.
      Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members
      Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline.
      ). For patients with hypercholesterolemia, statins should be continued where possible as the leading nonliver cause of mortality in patients with NAFLD is cardiovascular death. For patients with prediabetes, referral to a Centers for Disease Control and Prevention–certified diabetes prevention program or use of metformin is recommended. For patients with T2D, preference should be given to treatments that address insulin resistance (eg, metformin) or to newer agents such as the GLP-1 RAs that have shown promising data for NASH.
      For otherwise eligible obese individuals with NAFLD or NASH, bariatric surgery may be considered if lifestyle measures are unsuccessful or insufficient.
      • 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.
      ,
      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.
      However, the potential benefits should be balanced against the risks from perisurgical and postsurgical complications. Data from randomized controlled trials are needed, but observational study data indicate that bariatric surgery may reverse the pathologic liver changes associated with NAFLD
      • Laursen T.L.
      • Hagemann C.A.
      • Wei C.
      • et al.
      Bariatric surgery in patients with non-alcoholic fatty liver disease—from pathophysiology to clinical effects.
      ,
      • Mummadi R.R.
      • Kasturi K.S.
      • Chennareddygari S.
      • Sood G.K.
      Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis.
      in addition to inducing weight loss and improving the features of MetS and T2D.
      • Laursen T.L.
      • Hagemann C.A.
      • Wei C.
      • et al.
      Bariatric surgery in patients with non-alcoholic fatty liver disease—from pathophysiology to clinical effects.
      A prospective study by Lassailly et al
      • Lassailly G.
      • Caiazzo R.
      • Ntandja-Wandji L.C.
      • et al.
      Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis.
      demonstrated a durable and sustained resolution of NASH in 84% of patients at 1 year after bariatric surgery, with progressive reduction in fibrosis observed during 5 years. Recent data on the use of endoscopic bariatric procedures, including the intragastric balloon and endoscopic sleeve gastrectomy, also suggest that other treatment options will be available in the near future.
      • Bazerbachi F.
      • Vargas E.J.
      • Rizk M.
      • et al.
      Intragastric balloon placement induces significant metabolic and histologic improvement in patients with nonalcoholic steatohepatitis.
      • Abu Dayyeh B.K.
      • Bazerbachi F.
      • Graupera I.
      • Cardenas A.
      Endoscopic bariatric and metabolic therapies for non-alcoholic fatty liver disease.
      • Hajifathalian K.
      • Mehta A.
      • Ang B.
      • et al.
      Improvement in insulin resistance and estimated hepatic steatosis and fibrosis after endoscopic sleeve gastroplasty.
      BioSpace
      Apollo Endosurgery receives FDA breakthrough device designation for the Orbera intragastric balloon for treatment of patients with NASH.

      Conclusion

      Primary care providers are frequently at the front line in identifying and assessing individuals with suspected NAFLD. They can expect to see increasing numbers of patients with this disease, given that the prevalence of NAFLD is increasing—fueled by the global epidemic of obesity and T2D. In addition to the hepatic consequences, NAFLD and NASH are associated with an increased risk of CVD morbidity and mortality as well as CKD and cancer-related mortality. Prompt diagnosis of NAFLD, determination of NASH status, and assessment of liver fibrosis risk are critical to improve patient outcomes. Liver biopsy is the gold standard for diagnosis of NASH but has disadvantages; thus, noninvasive biomarkers are being used more frequently. Current clinical guidelines for the management of NAFLD have many points in common but also diverge in several areas. In the United States, patients with NAFLD or NASH should be treated according to AASLD guidelines. Importantly, comorbid conditions including obesity, prediabetes and T2D, dyslipidemia, and CVD should be treated aggressively, especially in patients with NASH or fibrosis. As new data from clinical trials investigating potential NAFLD and NASH treatments become available, it is anticipated that a greater consensus in clinical practice will occur.

      Acknowledgments

      Medical writing assistance, supported financially by Boehringer Ingelheim Pharmaceuticals, Inc, was provided by Debra Brocksmith, MB ChB, PhD, of Elevate Scientific Solutions during the preparation of this manuscript. Boehringer Ingelheim Pharmaceuticals, Inc was given the opportunity to check the data in this manuscript for factual accuracy only.
      Rajia Arbab, MSc, DO candidate at Lake Erie College of Osteopathic Medicine (Erie, Pennsylvania), research assistant to Dr Basu, provided assistance in developing Figure 1.

      Useful Resources

      Fibrosis Risk Calculators (Serum Biomarkers)

      NAFLD/NASH Resources

      Patient and Caregiver Resources

      Potential Competing Interests

      R.B. has received research support from AstraZeneca and Abbott Diabetes Care . M.N. has been on the advisory board for 89BIO, Gilead , Intercept, Pfizer , Novartis , Novo Nordisk , Allergan , Blade, Echosens, Fractyl, Terns, OWL, Siemens , Roche Diagnostic, and Abbott; M.N. has received research support from Allergan , BMS , Gilead , Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis , Shire , Viking, and Zydus; M.N. is a minor shareholder or has stocks in Anaetos and Viking. J.M.C. has served on a scientific advisory board for Boehringer Ingelheim Pharmaceuticals, Inc, and Novo Nordisk.

      Supplemental Online Material

      Figure thumbnail figs1

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