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Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

  • Erin K. Spengler
    Affiliations
    Division of Gastroenterology, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City
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  • Rohit Loomba
    Correspondence
    Correspondence: Address to Rohit Loomba, MD, MHSc, University of California at San Diego, 9500 Gilman Dr, MC 0063, La Jolla, CA 92093.
    Affiliations
    NAFLD Translational Research Unit, Division of Gastroenterology, Department of Medicine, and Division of Epidemiology, Department of Family and Preventive Medicine, University of California San Diego School of Medicine, La Jolla, CA
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      Abstract

      Nonalcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease in the United States, afflicting an estimated 80 to 100 million Americans. Nonalcoholic fatty liver disease is a spectrum of liver diseases composed of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Although nonalcoholic fatty liver has a negligible risk of progression, patients with NASH often develop cirrhosis or hepatocellular carcinoma. Although liver biopsy is required to diagnose NASH, only patients with a high risk of NASH or advanced fibrosis require this evaluation. Despite the high prevalence of NAFLD, well-defined screening recommendations are currently lacking. In this review, suggestions for screening, diagnosis, and initial work-up of NAFLD are given on the basis of established guidelines and recent publications. Proposed drug treatments of NASH are also discussed, highlighting the study outcomes, as well as proposed uses and limitations of these drugs. The literature was searched in PubMed using search terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, with filters of “English language.” A date range of January 1, 2000, to May 1, 2015, was used for the search. The bibliographies of key references were also searched manually, and seminal publications before the year 2000 were included.

      Abbreviations and Acronyms:

      ALT (alanine aminotransferase), AST (aspartate aminotransferase), BMI (body mass index), EGD (esophagoduodenoscopy), FXR (farnesoid X receptor), HCC (hepatocellular carcinoma), LDL (low-density lipoprotein), MRE (magnetic resonance elastography), NAFL (nonalcoholic fatty liver), NAFLD (nonalcoholic fatty liver disease), NAS (nonalcoholic fatty liver disease activity score), NASH (nonalcoholic steatohepatitis), PTX (pentoxifylline), RCT (randomized controlled trial), RR (relative risk)
      Article Highlights
      • Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases composed of nonalcoholic fatty liver, which has a negligible risk of progression, and nonalcoholic steatohepatitis (NASH), which has a higher risk of liver disease progression. Nonalcoholic steatohepatitis is histologic diagnosis based on liver biopsy findings of steatosis, ballooning, and lobular inflammation; this disease is associated with an increased risk of cardiovascular death, cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
      • Patients with suspected or known NAFLD and a high risk of NASH or advanced fibrosis should be referred for consideration of liver biopsy.
      • Lifestyle modifications, including weight loss and exercise, form the cornerstone of NAFLD treatment and should be strongly encouraged. Vitamin E and pioglitazone have been shown to benefit select patients with biopsy-proven NASH.
      • Statins and metformin therapy are not indicated for the treatment of NASH, but are safe and effective in patients with NASH with other clinical indications for their use, such as dyslipidemia and diabetes.
      Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States, and its prevalence and clinical importance is increasing worldwide.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      • Loomba R.
      • Sanyal A.J.
      The global NAFLD epidemic.
      Recent studies estimate that between 30% and 40% of the population in the United States (80 to 100 million Americans) is affected by NAFLD.
      • 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.
      • Fraser A.
      • Longnecker M.P.
      • Lawlor D.A.
      Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004.
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      • Wong V.W.
      • Wong G.L.
      • Choi P.C.
      • et al.
      Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
      The number of people at risk for NAFLD is even greater, given the increasing prevalence of obesity, diabetes, and metabolic syndrome.
      • Wong V.W.
      • Wong G.L.
      • Choi P.C.
      • et al.
      Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
      Nonalcoholic steatohepatitis (NASH) is a frequently progressive subset of NAFLD that can be complicated by cardiovascular disease, cirrhosis, and hepatocellular carcinoma (HCC).
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      • Bhala N.
      • Angulo P.
      • van der Poorten D.
      • et al.
      The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study.
      Although there are no Food and Drug Administration–approved medications for NASH, there are several medications that have shown benefits in clinical trials. The uses and limitations of these medications will be discussed in detail (Table 1). Prompt diagnosis, timely referrals, and effective treatments are necessary to improve the long-term outcomes of patients with NAFLD and NASH in the setting of primary care and general gastroenterology practices. This review will focus on these important aspects of patient care.
      Table 1Medications for Use in Patients With NAFLD
      MedicationIndicationsContraindicationsLimitationsAdverse effects
      PioglitazonePrimary treatment of biopsy-proven NASH in diabetic and nondiabetic patients

      Treatment of diabetes in patients with NAFLD
      Symptomatic heart failureMay increase risk of bladder cancerWeight gain, bone loss, GI upset, fatigue, and lower extremity edema
      Vitamin EPrimary treatment of biopsy-proven NASH in nondiabetic patientsHistory of prostate cancer and bleeding disorderMay increase all-cause mortality, risk of prostate cancer

      Not tested in diabetic patients
      Increased risk of bleeding and hemorrhagic stroke
      MetforminTreatment of diabetes and insulin resistance in patients with NAFLDRenal failureNot a primary treatment of NASHDiarrhea, lactic acidosis, and GI upset
      Obeticholic acidPrimary treatment of biopsy-proven NASH in diabetic and nondiabetic patientsNot currently commercially availableNot FDA approved or available outside of clinical trials

      Long-term safety is not known
      Pruritus and hypercholesterolemia
      StatinTreatment of hyperlipidemia in patients with NAFLDExcessive alcohol use and hypersensitivity to statin classNot a primary treatment of NASHMyalgia, GI upset, mild transaminitis, rare liver injury, and myopathy
      GI = gastrointestinal; FDA = Food and Drug Administration; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis.
      The content of this review is based on a search of the literature performed in PubMed using the following search terms: nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Studies published in the non-English scientific literature were excluded. A date range of January 1, 2000, to May 1, 2015, was used for the search. The bibliographies of key references were also searched manually, and seminal publications before the year 2000 were included.

      Histology, Epidemiology, and Disease Course

      Nonalcoholic fatty liver disease is characterized by hepatic steatosis, without a history of excessive alcohol use, in the absence of other known liver diseases.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      Nonalcoholic fatty liver disease is categorized into 2 subtypes: nonalcoholic fatty liver (NAFL), which is usually nonprogressive, and NASH, which is often progressive and can lead to cirrhosis and 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.
      Nonalcoholic fatty liver and NASH have traditionally been considered 2 separate clinical entities, rather than 2 points on a disease continuum.
      • Teli M.R.
      • James O.F.
      • Burt A.D.
      • Bennett M.K.
      • Day C.P.
      The natural history of nonalcoholic fatty liver: a follow-up study.
      Recent studies evaluating sequential liver biopsies are challenging this notion.
      • 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.
      • Matteoni C.A.
      • Younossi Z.M.
      • Gramlich T.
      • Boparai N.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
      • 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.
      A systematic review and meta-analysis of paired biopsy studies found that both patients with NAFL and NASH have the potential to develop progressive liver disease.
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      The fibrosis progression rate from stage 0 to stage 1 for NAFL vs NASH is 14 years vs 7 years, providing suggestive evidence that NAFL, NASH, and fibrosis progression are a continuum rather than separate diagnoses.
      • 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.
      Patients with NAFL and mild lobular inflammation, without ballooning, had an increased risk of disease progression as compared with those without inflammation.
      • 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.
      Another retrospective study evaluated serial liver biopsies in 108 patients and found no significant difference in the proportion of fibrosis progression between patients with NAFL and those with NASH at index biopsy (37% vs 43%; P=.65).
      • 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.
      Similarly, a recent study analyzing paired liver biopsies over time found that even patients with bland steatosis can progress to NASH, especially in the setting of metabolic risk factors.
      • Pais R.
      • Charlotte F.
      • Fedchuk L.
      • et al.
      LIDO Study Group
      A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.
      Establishing an accurate diagnosis of NASH is of major clinical importance. A histologic diagnosis of NASH is associated with cardiovascular disease

      Arulanandan A, Ang B, Bettencourt R, et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis [published online ahead of print February 3, 2015]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2015.01.027.

      and more rapid progression of liver disease.
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      To accurately distinguish NASH from NAFL requires liver biopsy. Nonalcoholic fatty liver is defined as bland steatosis with minimal or no inflammation, whereas NASH is characterized by macrovesicular steatosis, ballooning, and mixed lobular inflammation with or without zone 3 perisinusoidal fibrosis
      • Yeh M.M.
      • Brunt E.M.
      Pathological features of fatty liver disease.
      (Figure 1). Steatosis and ballooning in adults with NASH are most commonly zone 3 predominant or panacinar.
      • Kleiner D.E.
      • Brunt E.M.
      Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research.
      • Chalasani N.
      • Wilson L.
      • Kleiner D.E.
      • Cummings O.W.
      • Brunt E.M.
      • Unalp A.
      NASH Clinical Research Network. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease.
      When advanced fibrosis develops, the zonal distribution of steatosis and ballooning is often lost.
      • Kleiner D.E.
      • Brunt E.M.
      Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research.
      • Chalasani N.
      • Wilson L.
      • Kleiner D.E.
      • Cummings O.W.
      • Brunt E.M.
      • Unalp A.
      NASH Clinical Research Network. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease.
      Acidophil bodies (compact eosinophilic cells representing apoptotic hepatocytes) and Mallory-Denk bodies (ropey intracytoplasmic inclusions composed of damaged intermediate filaments) are also frequently seen on biopsies from patients with NASH but are not required for the diagnosis.
      • Yeh M.M.
      • Brunt E.M.
      Pathological features of fatty liver disease.
      Figure thumbnail gr1
      Figure 1Histopathology of NAFLD. A, Image of NAFL (H&E, original magnification 40×). Note the severe fatty change, numerous glycogenated nuclei (arrow), and lack of inflammation or balloon degeneration. B, Image of NASH (H&E, original magnification 60×). In addition to significant steatosis, there is evidence of ballooned hepatocytes (long arrow) and mixed inflammation including neutrophils (short arrow). C, Image of NASH (Klatskin trichrome stain, original magnification 40×). On this Klatskin stain, the sinusoidal fibrosis characteristic of NASH is evident (zone 3). H&E = hematoxylin and eosin; NAFL = nonalcoholic fatty liver; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis.
      In the Western world, NAFLD is most commonly associated with obesity, metabolic syndrome, and diabetes.
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      As with other metabolic conditions, NAFLD appears to have a strong genetic component. Both family history of diabetes and Hispanic ethnicity have been identified as risk factors.
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      The first genome-wide association study of NAFLD identified that the variant I148M (rs738409) located in human patatin-like phospholipase domain–containing protein 3 gene (PNPLA3) was associated with increased hepatic fat content and hepatic inflammation.
      • Pirazzi C.
      • Adiels M.
      • Burza M.A.
      • et al.
      Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro.
      This allele was found at a higher frequency in Hispanic patients, providing one possible reason for increased susceptibility in this population. Metabolic syndrome, diabetes, and advanced age have all been shown to increase the risk of liver disease progression in patients with NAFLD.
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      • Grundy S.M.
      • Cleeman J.I.
      • Daniels S.R.
      • et al.
      American Heart Association; National Heart, Lung, and Blood Institute
      Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.
      • Noureddin M.
      • Yates K.P.
      • Vaughn I.A.
      • et al.
      NASH CRN
      Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients.
      It is estimated that NASH occurs in 20% of patients with NAFLD (3%-12% of the US population).
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      • Wong V.W.
      • Wong G.L.
      • Choi P.C.
      • et al.
      Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
      Approximately 30% to 40% of patients with NASH will develop fibrosis
      • 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.
      • 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.
      • Fassio E.
      • Alvarez E.
      • Domínguez N.
      • Landeira G.
      • Longo C.
      Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies.
      • Argo C.K.
      • Northup P.G.
      • Al-Osaimi A.M.
      • Caldwell S.H.
      Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.
      (Figure 2).
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      • 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.
      • 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.
      • Ascha M.S.
      • Hanouneh I.A.
      • Lopez R.
      • Tamimi T.A.
      • Feldstein A.F.
      • Zein N.N.
      The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      • Takuma Y.
      • Nouso K.
      Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review.
      • Marrero J.A.
      • Fontana R.J.
      • Su G.L.
      • Conjeevaram H.S.
      • Emick D.M.
      • Lok A.S.
      NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.
      Although fibrosis regresses in some patients,
      • Wong V.W.
      • Wong G.L.
      • Choi P.C.
      • et al.
      Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
      • 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.
      • Hamaguchi E.
      • Takamura T.
      • Sakurai M.
      • et al.
      Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis.
      others progress to advanced fibrosis or cirrhosis.
      • 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.
      • Neuschwander-Tetri B.A.
      • Caldwell S.H.
      Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.
      In fact, NASH is the third leading cause of cirrhosis in the United States and the third most common indication for liver transplant.
      • 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.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      In addition to cirrhosis, and the complications that accompany it, NASH places patients at risk for HCC.
      • Hashimoto E.
      • Yatsuji S.
      • Tobari M.
      • et al.
      Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      There have been recent reports of HCC developing in patients with NASH without cirrhosis; however, the risk appears to be low and routine surveillance for HCC in patients with NASH without cirrhosis is not recommended until further evidence is available.
      • Takuma Y.
      • Nouso K.
      Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review.
      • Marrero J.A.
      • Fontana R.J.
      • Su G.L.
      • Conjeevaram H.S.
      • Emick D.M.
      • Lok A.S.
      NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.
      Figure thumbnail gr2
      Figure 2Epidemiology of NAFLD. It is estimated that 3% to 12% of the US population is affected by NASH.
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      Although patients with NASH have a higher risk of progression, some patients may progress directly from NAFL to advanced fibrosis.
      • 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.
      • 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.
      Approximately 2% to 3% of patients with NASH cirrhosis will develop HCC each year.
      • Ascha M.S.
      • Hanouneh I.A.
      • Lopez R.
      • Tamimi T.A.
      • Feldstein A.F.
      • Zein N.N.
      The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      Some patients with NASH without cirrhosis may develop HCC, but the magnitude of risk is not clear.
      • Takuma Y.
      • Nouso K.
      Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review.
      • Marrero J.A.
      • Fontana R.J.
      • Su G.L.
      • Conjeevaram H.S.
      • Emick D.M.
      • Lok A.S.
      NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.
      HCC = hepatocellular carcinoma; NAFL = nonalcoholic fatty liver; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis.

      Pathogenesis

      Nonalcoholic fatty liver can be seen in any setting in which there is an excess of energy intake and increased hepatic lipid storage in the form of triglycerides.
      • Day C.P.
      • James O.F.
      Steatohepatitis: a tale of two “hits”?.
      Steatosis may be worsened by de novo lipogenesis in the liver and decreased export of triglycerides from the liver in the form of very low density lipoproteins.
      • Dowman J.K.
      • Tomlinson J.W.
      • Newsome P.N.
      Pathogenesis of non-alcoholic fatty liver disease.
      Nonalcoholic steatohepatitis occurs in only a subset of patients with NAFLD. The “two-hit” hypothesis of NAFLD suggests that an increase in oxidative stress leads to overwhelming lipid peroxidation and resultant necroinflammatory injury to the fat-laden hepatocytes.
      • Day C.P.
      • James O.F.
      Steatohepatitis: a tale of two “hits”?.
      • Tariq Z.
      • Green C.J.
      • Hodson L.
      Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)?.
      A more recent view of NAFLD pathogenesis identifies lipotoxicity as the primary driver of cellular injury and death in NASH.
      • Neuschwander-Tetri B.A.
      Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
      In the lipotoxicity model of NASH, free fatty acid metabolites cause endoplasmic reticular stress, hepatocyte apoptosis, necrosis, and inflammation, leading to the histologic findings that characterize this disease.
      • Feldstein A.E.
      Novel insights into the pathophysiology of nonalcoholic fatty liver disease.
      • Loomba R.
      • Quehenberger O.
      • Armando A.
      • Dennis E.A.
      Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis.
      The hepatocellular injury, in turn, triggers fibrogenesis and inflammation, hastening disease progression.
      • Schuppan D.
      • Schattenberg J.M.
      Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches.
      In this model, triglyceride accumulation may actually be protective against hepatocellular injury.
      • Neuschwander-Tetri B.A.
      Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
      Like most chronic medical conditions, NASH involves a complex interplay between genetics and the environment. There are strong correlations among NASH, obesity, diabetes, and metabolic syndrome,
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      suggesting a mechanistic link between these diseases. Recent investigations have revealed an interplay between the liver, innate immune system, gut, and adipose tissue. As a result, the farnesoid X receptor (FXR) has become a target of interest.
      • Trauner M.
      • Claudel T.
      • Fickert P.
      • Moustafa T.
      • Wagner M.
      Bile acids as regulators of hepatic lipid and glucose metabolism.
      The FXR plays an important role in modulating metabolism and insulin sensitivity through the binding of lipophilic bile acids.
      • Trauner M.
      • Claudel T.
      • Fickert P.
      • Moustafa T.
      • Wagner M.
      Bile acids as regulators of hepatic lipid and glucose metabolism.
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • et al.
      NASH Clinical Research Network
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      Dysregulation of the gut-liver axis has also been implicated as a contributor to NASH pathogenesis through derangement of the intestinal microbiome, production of gut-derived endotoxin, and altered intestinal permeability.
      • Mouzaki M.
      • Comelli E.M.
      • Arendt B.M.
      • et al.
      Intestinal microbiota in patients with nonalcoholic fatty liver disease.
      • Raman M.
      • Ahmed I.
      • Gillevet P.M.
      • et al.
      Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.
      • Wigg A.J.
      • Roberts-Thomson I.C.
      • Dymock R.B.
      • McCarthy P.J.
      • Grose R.H.
      • Cummins A.G.
      The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis.
      Chemokines, such as adiponectin
      • Musso G.
      • Gambino R.
      • De Michieli F.
      • Durazzo M.
      • Pagano G.
      • Cassader M.
      Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH.
      • Musso G.
      • Gambino R.
      • Durazzo M.
      • et al.
      Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease.
      and tumor necrosis factor α,
      • Li Z.
      • Soloski M.J.
      • Diehl A.M.
      Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.
      • Maher J.J.
      • Leon P.
      • Ryan J.C.
      Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis.
      may be mediators of some of these systemic changes. A thorough discussion of NAFLD pathogenesis is outside the scope of this review, but is addressed in several recent publications.
      • Schuppan D.
      • Schattenberg J.M.
      Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches.
      • Cusi K.
      Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.

      Clinical Presentation

      Nonalcoholic fatty liver disease is most commonly asymptomatic, although some patients have nonspecific symptoms, such as fatigue, right upper quadrant discomfort, or epigastric fullness. In the absence of advanced liver disease, hepatomegaly may be the only physical finding. Once cirrhosis develops, splenomegaly, spider angiomata, palmar erythema, or ascites may be identified. Nonalcoholic fatty liver disease is most commonly recognized through abnormal liver chemistries or incidental ultrasound findings and should be considered in the differential of any patient with elevated transaminase levels.
      • Dowman J.K.
      • Tomlinson J.W.
      • Newsome P.N.
      Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
      • Pratt D.S.
      • Kaplan M.M.
      Evaluation of abnormal liver-enzyme results in asymptomatic patients.
      Most commonly, patients have a mildly elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) level, with an AST/ALT ratio of less than 1.
      • Dowman J.K.
      • Tomlinson J.W.
      • Newsome P.N.
      Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
      In later stages of the disease this ratio may reverse, so AST/ALT greater than 1 does not exclude NAFLD.
      • Sorbi D.
      • Boynton J.
      • Lindor K.D.
      The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease.
      Although patients with NASH commonly come to medical attention because of an elevated ALT level, a normal or near-normal ALT level does not exclude NASH.
      • Yan E.
      • Durazo F.
      • Tong M.
      • Hong K.
      Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management.
      The alkaline phosphatase and/or gamma-glutamyltransferase level may be mildly elevated, but the bilirubin level typically remains normal unless advanced disease is present. Increased international normalized ratio, hypoalbuminemia, or thrombocytopenia often indicate cirrhosis or portal hypertension and may be the primary laboratory findings in patients with advanced fibrosis.

      Screening, Diagnosis, and Initial Management

      The prevalence of NAFLD and NASH is high in the general population, but there are no accepted screening regimens, even in high-risk patients. Despite poor sensitivity and specificity, serum ALT and AST levels are the most readily available and commonly used tests to evaluate for asymptomatic liver disease. Obtaining a random ALT and AST level in patients with metabolic syndrome or diabetes may be reasonable, given the high disease burden in this population. Although 50% of patients with NAFLD have normal liver chemistries, up to 80% of patients with NASH may be identified on the basis of elevated transaminase levels.
      • Yan E.
      • Durazo F.
      • Tong M.
      • Hong K.
      Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management.
      There are several noninvasive scoring systems designed to increase the detection of NAFLD and advanced fibrosis,
      • Angulo P.
      • Bugianesi E.
      • Bjornsson E.S.
      • et al.
      Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease.
      • Angulo P.
      • Hui J.M.
      • Marchesini G.
      • et al.
      The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.
      but the best way to incorporate these into a screening model is not clear. The fatty liver index, for example, uses triglycerides, waist circumference, body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared), and gamma-glutamyltransferase to improve the sensitivity and specificity of diagnosing NAFLD,
      • Koehler E.M.
      • Schouten J.N.
      • Hansen B.E.
      • Hofman A.
      • Stricker B.H.
      • Janssen H.L.
      External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study.
      but there is no consensus on which, or if, patients should be screened using this or similar models. Biomarkers, such as cytokeratin 18, currently lack the sensitivity needed to be clinically useful screening tests.
      • Cusi K.
      • Chang Z.
      • Harrison S.
      • et al.
      Limited value of plasma cytokeratin-18 as a biomarker for nash and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).
      A recent study from the NASH Clinical Research Network proposed and validated a model designed to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients using routinely available clinical variables and laboratories.
      • Bazick J.
      • Donithan M.
      • Neuschwander-Tetri B.A.
      • et al.
      Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD.
      The model for NASH identification included white race, BMI, waist circumference, ALT level, AST level, albumin level, hemoglobin A1c level, homeostasis model assessment of insulin resistance, and ferritin level. Although sensitivity was poor (56.8%), the model exhibited excellent specificity (90.0%) and had a positive predictive value of 93.2%, making it a helpful clinical tool to predict the presence of NASH in adult diabetic patients. Despite improvements in predictive models, screening is not recommended at this time in any population.
      Baseline liver evaluation and cardiovascular risk assessment should be considered in all patients who have a presumptive diagnosis of NAFLD (Table 2).
      • Bazick J.
      • Donithan M.
      • Neuschwander-Tetri B.A.
      • et al.
      Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD.
      A liver ultrasound, full liver chemistry panel, international normalized ratio, creatinine level, and complete blood cell count should be obtained to characterize the pattern of liver injury and to assess the severity of disease. Other causes of liver disease should be investigated and excluded, and medications known to worsen steatosis should be discontinued.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology
      The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.
      Common comorbidities, such as diabetes and dyslipidemia, should be identified and treated. A higher amount of fat in the liver is associated with an increased risk of cardiovascular disease

      Arulanandan A, Ang B, Bettencourt R, et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis [published online ahead of print February 3, 2015]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2015.01.027.

      but there is no consensus on routine cardiovascular screening in this population. Patients with cirrhosis should be screened for HCC and esophageal varices according to the current American Association of Liver Disease guidelines.
      • Neuschwander-Tetri B.A.
      • Caldwell S.H.
      Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.
      There are no current HCC screening guidelines for patients with NASH without cirrhosis.
      • White D.L.
      • Kanwal F.
      • El-Serag H.B.
      Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.
      Table 2Recommended Management of Patients With NAFLD
      AASLD = American Association of Liver Disease; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CBC = complete blood cell; EGD = esophagoduodenoscopy; HCC = hepatocellular carcinoma; INR = international normalized ratio; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis.
      1. Recommend lifestyle modification:
      • a.
        Weight loss of at least 5%-10% of the total body weight
      • b.
        Aerobic exercise 3-5 times/wk
      • c.
        Minimization of alcohol use (no more than 1 drink/d for women or 2 drinks/d for men)
      2. Assess cardiovascular risks using lipid profile, fasting glucose and/or hemoglobin A1c level, waist circumference, and BMI
      3. Manage comorbidities, including diabetes, dyslipidemia, hypertension, and cardiovascular disease
      4. Discontinue medications that may worsen steatosis, including corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid
      5. Obtain baseline liver evaluation, including liver ultrasound, CBC count, liver panel (AST, ALT, bilirubin, and alkaline phosphatase levels), INR, and creatinine level
      6. Consider referral for liver biopsy, if
      • a.
        Patient has risk factors for NASH and advanced fibrosis, including diabetes
        Biopsy should be considered in diabetic patients with other risk factors for advanced fibrosis.58
        and/or metabolic syndrome
      • b.
        Patient has findings concerning for cirrhosis, such as thrombocytopenia, AST level > ALT level, or hypoalbuminemia
      • c.
        Patients is undergoing cholecystectomy or bariatric surgery and intraoperative biopsy is low risk
      7. Consider pharmacotherapy if patient has biopsy-proven NASH without cirrhosis and no absolute contraindications
      8. Obtain appropriate screening if patient has known cirrhosis:
      • a.
        Right upper quadrant ultrasound every 6 mo for HCC screening (refer to AASLD guidelines)
      • b.
        EGD screening for esophageal varices (refer to AASLD guidelines)
      • c.
        Referral to a transplant center when appropriate (refer to AASLD guidelines)
      a AASLD = American Association of Liver Disease; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CBC = complete blood cell; EGD = esophagoduodenoscopy; HCC = hepatocellular carcinoma; INR = international normalized ratio; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis.
      b Biopsy should be considered in diabetic patients with other risk factors for advanced fibrosis.
      • Bazick J.
      • Donithan M.
      • Neuschwander-Tetri B.A.
      • et al.
      Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD.

      Imaging

      Ultrasonography is the most inexpensive and widely available imaging test for NAFLD.
      • Dowman J.K.
      • Tomlinson J.W.
      • Newsome P.N.
      Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
      • Festi D.
      • Schiumerini R.
      • Marzi L.
      • et al.
      Review article: the diagnosis of non-alcoholic fatty liver disease—availability and accuracy of non-invasive methods.
      Typical sonographic findings of NAFLD are hepatomegaly and increased echogenicity. Unfortunately, ultrasonography is not sensitive if less than 30% of the liver is involved by steatosis.
      • Hernaez R.
      • Lazo M.
      • Bonekamp S.
      • et al.
      Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis.
      Variability in operator skill and the limiting body habitus of the typical patient with NAFLD can lead to inadequate or inconsistent results.
      • Bohte A.E.
      • van Werven J.R.
      • Bipat S.
      • Stoker J.
      The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis.
      Although changes of cirrhosis and portal hypertension may be identified on ultrasound, it is neither a sensitive nor a specific modality for this diagnosis.
      • Festi D.
      • Schiumerini R.
      • Marzi L.
      • et al.
      Review article: the diagnosis of non-alcoholic fatty liver disease—availability and accuracy of non-invasive methods.
      Given these limitations, other imaging studies are being investigated for the diagnosis and risk stratification of patients with NAFLD. Magnetic resonance imaging, including magnetic resonance spectroscopy, has shown good sensitivity and specificity in detecting and quantifying steatosis,

      Idilman IS, Keskin O, Celik A, et al. A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease [published online ahead of print April 8, 2015]. Acta Radiol. doi:10.1177/0284185115580488.

      but it is expensive and not widely used for this purpose.
      • Tang A.
      • Desai A.
      • Hamilton G.
      • et al.
      Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease.
      • Tang A.
      • Tan J.
      • Sun M.
      • et al.
      Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis.
      • Permutt Z.
      • Le T.A.
      • Peterson M.R.
      • et al.
      Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD.
      Transient elastography has been used with moderate success to evaluate the degree of fibrosis and cirrhosis in patients with NAFLD, but is limited by body habitus and degree of steatosis.
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • et al.
      Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.
      • Naveau S.
      • Lamouri K.
      • Pourcher G.
      • et al.
      The diagnostic accuracy of transient elastography for the diagnosis of liver fibrosis in bariatric surgery candidates with suspected NAFLD.
      Magnetic resonance elastography (MRE) provides an accurate noninvasive measure of fibrosis in NAFLD and may be particularly helpful in identifying patients with advanced fibrosis.
      • Loomba R.
      • Wolfson T.
      • Ang B.
      • et al.
      Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study.
      • Cui J.
      • Ang B.
      • Haufe W.
      • et al.
      Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study.
      Among all noninvasive imaging modalities, MRE appears to be the most accurate test for fibrosis assessment in NAFLD.
      • Cui J.
      • Ang B.
      • Haufe W.
      • et al.
      Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study.
      • Singh S.
      • Venkatesh S.K.
      • Wang Z.
      • et al.
      Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data.
      Despite growing evidence of its potential clinical utility, MRE is not widely available and data are needed to show its performance and cost-effectiveness as a fibrosis screening test in routine clinical practice. If validated in prospective studies, MRE may be used to screen for advanced fibrosis in high-risk patients, such as older diabetic patients. A novel quantitative ultrasound technique using ultrasound imaging–based biomarkers is being developed for the diagnosis and quantification of hepatic steatosis.
      • Lin S.C.
      • Heba E.
      • Wolfson T.
      • et al.
      Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat using a new quantitative ultrasound technique.
      Although not yet commercially available, in the future this could provide a low-cost method of identifying patients with probable NAFLD. As with all diagnostic modalities, advanced imaging studies should be ordered in a facility equipped to accurately perform and interpret the test. With the development of more specialized and complex testing, it is important that the ordering physician understand the indications for the study as well as the clinical application of specific results.

      Referral for Consideration of Liver Biopsy

      Liver biopsy is the criterion standard for diagnosing NAFL and NASH, but is not indicated in all patients with suspected diseases. It is invasive, expensive, and not without risk. Liver biopsy should be considered in all patients with persistently elevated aminotransferase levels in whom the diagnosis remains uncertain.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology
      The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.
      Biopsy is also important in ruling out the presence of other concomitant liver diseases, such as in the setting of elevated serum ferritin levels or the presence of autoantibodies. Furthermore, biopsy has prognostic value in NAFLD because the presence of NASH and/or fibrosis provides information on the future risk of progression to cirrhosis and the risk of liver-related mortality.
      The American Association of Liver Disease practice guidelines for NAFLD recommend considering liver biopsy in patients with NAFLD who are at an increased risk of NASH and advanced fibrosis. These guidelines suggest that the presence of metabolic syndrome and the NAFLD fibrosis score be used to identify these high-risk patients.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      A recent study by the NASH Clinical Research Network used data on 435 patients with NAFLD and diabetes to develop and verify a model to predict the presence of NASH and advanced fibrosis in diabetic patients with NAFLD.
      • Bazick J.
      • Donithan M.
      • Neuschwander-Tetri B.A.
      • et al.
      Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD.
      Among this large cohort of patients, 69.2% were found to have NASH and 41.0% were found to have advanced fibrosis,
      • Bazick J.
      • Donithan M.
      • Neuschwander-Tetri B.A.
      • et al.
      Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD.
      highlighting the high risk of progressive disease in this population. The model used to predict advanced fibrosis in diabetic patients included age, BMI, waist-to-hip ratio, Hispanic ethnicity, hypertension, ALT/AST ratio, bilirubin (total and direct) level, alkaline phosphatase level, isolated abnormal alkaline phosphatase level, globulin level, albumin level, serum insulin level, hematocrit, international normalized ratio, and platelet count.
      • Bazick J.
      • Donithan M.
      • Neuschwander-Tetri B.A.
      • et al.
      Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD.
      This proposed model predicted advanced fibrosis better than did the NAFLD fibrosis score, and it may be used to guide liver biopsy referral in patients with type 2 diabetes. New evidence suggests that advanced age or a strong family history of NASH may also be associated with a more aggressive disease course,
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      but there are not adequate data to support biopsy in all patients with these risk factors. Patients undergoing bariatric surgery have a high prevalence of NASH and should strongly consider having intraoperative liver biopsy for diagnosis and staging.
      • Chavez-Tapia N.C.
      • Tellez-Avila F.I.
      • Barrientos-Gutierrez T.
      • Mendez-Sanchez N.
      • Lizardi-Cervera J.
      • Uribe M.
      Bariatric surgery for non-alcoholic steatohepatitis in obese patients.
      Laboratory parameters suggesting cirrhosis, such as thrombocytopenia, hypoalbuminemia, and AST level > ALT level, should also prompt consideration of liver biopsy referral.
      • Ratziu V.
      • Bellentani S.
      • Cortez-Pinto H.
      • Day C.
      • Marchesini G.
      A position statement on NAFLD/NASH based on the EASL 2009 special conference.
      In addition to proving a definitive diagnosis, liver biopsy is useful in NAFLD to identify the stage of liver disease and assess the likelihood of progression. Liver biopsies are subject to substantial sampling error that may lead to inaccurate staging or disease classification,
      • Ratziu V.
      • Charlotte F.
      • Heurtier A.
      • et al.
      LIDO Study Group
      Sampling variability of liver biopsy in nonalcoholic fatty liver disease.
      but liver biopsy remains the criterion standard for diagnosis and staging. Patients with bland steatosis without necroinflammation on biopsy are unlikely to develop cirrhosis, assuming metabolic parameters remain unchanged. The severity of steatosis, however, may correlate with the development of metabolic syndrome and the risk of cardiovascular disease independent of the presence of NASH.

      Arulanandan A, Ang B, Bettencourt R, et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis [published online ahead of print February 3, 2015]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2015.01.027.

      The presence of NASH on index biopsy predicts a more aggressive disease course with a higher rate of progression to cirrhosis.
      • Matteoni C.A.
      • Younossi Z.M.
      • Gramlich T.
      • Boparai N.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
      In addition to informing patient discussions on prognosis, this information helps identify which patients should be considered for more aggressive therapy. All currently recommended pharmacologic treatments of NASH require histologic diagnosis before the initiation of therapy.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.

      Lifestyle Interventions

      Weight loss is the cornerstone of NAFLD treatment. Clinical trials have shown that weight loss reduces hepatic steatosis
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      and that exercise itself may improve histology regardless of weight change.
      • Sullivan S.
      • Kirk E.P.
      • Mittendorfer B.
      • Patterson B.W.
      • Klein S.
      Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease.
      Even resistance training led to improvements in hepatic steatosis in a recent randomized controlled trial (RCT).
      • Bacchi E.
      • Negri C.
      • Zanolin M.E.
      • et al.
      Metabolic effects of aerobic training and resistance training in type 2 diabetic subjects: a randomized controlled trial (the RAED2 study).
      A weight loss of at least 3% to 5% of the total body weight has been found to improve steatosis, and a weight loss of more than 7% of the total body weight is associated with a decrease in necroinflammation.
      • Lazo M.
      • Solga S.F.
      • Horska A.
      • et al.
      Fatty Liver Subgroup of the Look AHEAD Research Group
      Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes.
      A small RCT of 31 patients reported that an intensive weight loss program led to more weight loss, elevated ALT level, and histology as compared to general education alone.
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      Two-thirds of the patients in the intervention group no longer met the definition of NASH after the 48-week study period. This suggests that patients may reap more benefit from a structured weight loss regimen than from physician education alone. Encouraging patients to seek additional training and assistance with weight loss may be worthwhile.

      Bariatric Surgery

      Although bariatric surgery has been shown to help morbidly obese patients lose weight, there are limited data supporting its use as a treatment of NASH. A Cochrane review of 21 prospective and retrospective studies reported an improvement in steatosis and/or inflammation scores after bariatric surgery, but the authors were unable to recommend its use for this indication because none of the studies were adequately randomized or controlled.
      • Chavez-Tapia N.C.
      • Tellez-Avila F.I.
      • Barrientos-Gutierrez T.
      • Mendez-Sanchez N.
      • Lizardi-Cervera J.
      • Uribe M.
      Bariatric surgery for non-alcoholic steatohepatitis in obese patients.
      A recent study from France examined prospectively 109 obese patients with biopsy-proven NASH who underwent bariatric surgery.

      Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients [published online ahead of print April 25, 2015]. Gastroenterology. doi:10.1053/j.gastro.2015.04.014.

      Nearly 85% of patients had histologic resolution of NASH at 1 year. Histologic resolution was most common in patients with mild NASH before surgery and in patients who underwent gastric bypass rather than vertical gastric banding.

      Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients [published online ahead of print April 25, 2015]. Gastroenterology. doi:10.1053/j.gastro.2015.04.014.

      The study suggests that bariatric surgery may be a promising treatment of NASH, but is limited by the lack of randomization or a control group.
      In a large Cochrane review, 4 studies found worsening fibrosis in patients with NAFLD who underwent bariatric surgery.
      • Chavez-Tapia N.C.
      • Tellez-Avila F.I.
      • Barrientos-Gutierrez T.
      • Mendez-Sanchez N.
      • Lizardi-Cervera J.
      • Uribe M.
      Bariatric surgery for non-alcoholic steatohepatitis in obese patients.
      The finding of worsening disease was seen primarily in patients with high BMI or advanced fibrosis,
      • Chavez-Tapia N.C.
      • Tellez-Avila F.I.
      • Barrientos-Gutierrez T.
      • Mendez-Sanchez N.
      • Lizardi-Cervera J.
      • Uribe M.
      Bariatric surgery for non-alcoholic steatohepatitis in obese patients.
      indicating that this surgery may not be safe in all patients. Other studies evaluating the risk of bariatric surgery in patients with NAFLD have found no increase in postoperative complications.
      • Ribeireiro T.
      • Swain J.
      • Sarr M.
      • et al.
      NAFLD and insulin resistance do not increase the risk of postoperative complications among patients undergoing bariatric surgery–a prospective analysis.
      • Weingarten T.N.
      • Swain J.M.
      • Kendrick M.L.
      • et al.
      Nonalcoholic steatohepatitis (NASH) does not increase complications after laparoscopic bariatric surgery.
      Mayo Clinic published a review of 14 patients with compensated cirrhosis who underwent bariatric surgery at their center.
      • Pestana L.
      • Swain J.
      • Dierkhising R.
      • Kendrick M.L.
      • Kamath P.S.
      • Watt K.D.
      Bariatric surgery in patients with cirrhosis with and without portal hypertension: a single-center experience.
      Although there was no increase in perioperative complications, the authors
      • Pestana L.
      • Swain J.
      • Dierkhising R.
      • Kendrick M.L.
      • Kamath P.S.
      • Watt K.D.
      Bariatric surgery in patients with cirrhosis with and without portal hypertension: a single-center experience.
      noted that the results apply only to well-compensated cirrhotic patients treated in a large referral center. Patients with NAFLD who meet other medical criteria for surgery should be referred for bariatric procedures,
      • Mechanick J.I.
      • Youdim A.
      • Jones D.B.
      • et al.
      American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery
      Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery.
      but data to support bariatric surgery as a specific treatment of NASH remain limited.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      A prospective RCT is needed to further investigate the safety and efficacy of this promising intervention.

      Pioglitazone

      Although the pathogenesis of NASH has not been fully elucidated, there is a clear association with insulin resistance and sensitization of the liver to metabolic injury and inflammation. Several insulin-sensitizing medications have been tested for the treatment of NASH, with mostly limited success. Although no medications are Food and Drug Administration approved for NASH treatment, pioglitazone appears to have a beneficial effect on steatosis, necroinflammation, and possibly even fibrosis.
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      • Bell L.N.
      • Wang J.
      • Muralidharan S.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study.
      Pioglitazone and other thiazolidinediones are selective peroxisome proliferator–activated receptor-gamma agonists. They modify the adipocytokine profile by stimulating adipocyte maturation. This, in turn, increases β-oxidation of fatty acids and reduces proinflammatory cytokines. Peroxisome proliferator–activated receptor-gamma agonists also work at the level of the muscle, liver, and adipose tissue to improve insulin sensitivity.
      The largest RCT of pioglitazone use in NASH is the PIVENS trial. This trial included 247 nondiabetic patients with biopsy-proven NASH randomized to treatment with 96 weeks of placebo, pioglitazone 30 mg, or vitamin E 800 IU.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      NASH CRN
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      The primary end point was histologic improvement, which required increase by 1 or more points in the hepatocellular ballooning score, no increase in the fibrosis score, and either a decrease in the nonalcoholic fatty liver disease activity score (NAS) to a score of 3 points or less or a decrease in the NAS of at least 2 points, with at least a 1-point decrease in either lobular inflammation or steatosis score.
      • Sanyal A.J.
      • Brunt E.M.
      • Kleiner D.E.
      • et al.
      Endpoints and clinical trial design for nonalcoholic steatohepatitis.
      The NAS is calculated using the grade of steatosis (grade 0-3), ballooning (grade 0-2), and lobular inflammation (grade 0-3)
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.
      and serves as a relatively objective manner of standardizing NASH histology and allowing a comparison of biopsies in clinical trials. Although the pioglitazone arm did not meet the primary end point (P=.04), there was a significant reduction in steatosis (P<.001) and lobular inflammation in this group (P=.004).
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      NASH CRN
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      The most common adverse events were gastrointestinal upset, lower extremity edema, and fatigue.
      A meta-analysis by Boettcher et al
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      reviewed 4 good quality RCTs, including the PIVENS trial, addressing treatment of NASH with thiazolidinediones. When both rosiglitazone and pioglitazone were included in the analysis, there was a statistically significant improvement in necroinflammation as compared with the use of placebo, but again with no improvement in fibrosis. A subgroup analysis of pioglitazone vs placebo, however, did show an improvement in fibrosis.
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      Although pioglitazone treatment has been associated with histologic improvement in NASH, there are drawbacks to its use. Thiazolidinediones commonly cause a significant increase in body weight with an average increase of 4 kg.
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      Rosiglitazone is no longer available in the United States because of an association with coronary events and decompensation of heart failure. Because of similar concerns about pioglitazone, a large meta-analysis including 16,390 patients with type 2 diabetes was performed.
      • Lincoff A.M.
      • Wolski K.
      • Nicholls S.J.
      • Nissen S.E.
      Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.
      Although pioglitazone was associated with a statistically significant increase in congestive heart failure, from 1.8% to 2.3% (P=.002), all-cause mortality, myocardial infarction, and stroke were reduced in patients taking pioglitazone.
      • Lincoff A.M.
      • Wolski K.
      • Nicholls S.J.
      • Nissen S.E.
      Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.
      Unfortunately, because only diabetic patients were included in these safety studies, it is not known if these findings are applicable to all patients with NASH. Considering only diabetic patients with NASH for treatment with this agent may be overly restrictive, because all the studies that investigated histologic improvement were performed in nondiabetic patients. However, only patients with biopsy-proven NASH should be considered for treatment with pioglitazone because these are the patients who are at the highest risk of progression and thus most likely to benefit from a pharmacologic intervention.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology
      The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.
      This medication should be avoided in patients with known heart failure, a history of bladder cancer, or an increased risk of bone loss, because its use may increase the risk of these conditions.

      Vitamin E

      The pathogenesis of NASH is felt to be at least in part due to damage from oxidative stress induced by reactive oxygen species. Vitamin E (α-tocopherol) is a naturally occurring antioxidant thought to mitigate oxidative stress and reactive oxygen species formation through suppression of lipid peroxidation and has been investigated as a possible therapy for NASH. In the TONIC trial, 173 children and adolescents with biopsy-proven NASH were randomized to treatment with vitamin E 800 IU, metformin, or placebo.
      • Lavine J.E.
      • Schwimmer J.B.
      • Van Natta M.L.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.
      At the end of the 96-week trial, the vitamin E group had achieved a significant improvement in NAS (P=.02) and hepatocellular ballooning score (P=.006) but no significant change in ALT level (P=.07) as compared with the placebo group. The PIVENS trial, which included only nondiabetic patients with biopsy-proven NASH and no evidence of cirrhosis, remains the largest RCT to investigate the effect of vitamin E on NASH.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      NASH CRN
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      After 96 weeks of treatment, patients in the vitamin E arm achieved a significant improvement in NASH histology (P=.001). Furthermore, both vitamin E and pioglitazone led to resolution of NASH in approximately one-third of the patients. Vitamin E use was also associated with a decrease in ALT (P=.001) and NAS (P≤.001), but fibrosis scores were not changed as compared with placebo use (P=.24).
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      NASH CRN
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      Vitamin E is well-tolerated with minimal adverse effects, but the safety of long-term use is not known.
      • Bjelakovic G.
      • Nikolova D.
      • Gluud C.
      Meta-regression analyses, meta-analyses, and trial sequential analyses of the effects of supplementation with beta-carotene, vitamin A, and vitamin E singly or in different combinations on all-cause mortality: do we have evidence for lack of harm?.
      A large meta-analysis of randomized trials of antioxidant supplements suggested an increase in all-cause mortality in patients taking vitamin E (relative risk [RR], 1.04; 95% CI, 1.01-1.07) or other antioxidant supplements.
      • 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.
      Vitamin E use is also associated with an increased risk of prostate cancer with an absolute risk of 1.6 per 1000 person-year.
      • Klein E.A.
      • Thompson Jr., I.M.
      • Tangen C.M.
      • et al.
      Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
      A meta-analysis investigating the effect of vitamin E on stroke subtypes found a decrease in ischemic stroke (RR, 0.9; P=.02), but an increase in hemorrhagic stroke (RR, 1.2; P=.05).
      • Schürks M.
      • Glynn R.J.
      • Rist P.M.
      • Tzourio C.
      • Kurth T.
      Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.
      Although the increase in absolute risk of these conditions remains low, it is recommended that these potential health concerns be discussed with patients before initiating the treatment. At this time, there is no evidence for use in patients with diabetes, cirrhosis, or NAFLD without biopsy-proven NASH. Given the promising study results and lack of alternative therapies, it is reasonable to begin 800 IU of vitamin E in nondiabetic, noncirrhotic patients with biopsy-proven NASH.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology
      The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.
      It is not recommended to treat with vitamin E unless the patient has a biopsy-proven diagnosis of NASH.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.

      Emerging Therapies

      Obeticholic acid, a synthetic derivative of the naturally occurring bile salt chenodeoxycholic acid, is an FXR agonist that has recently been evaluated as a potential therapy for NASH.
      • Cariou B.
      The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis.
      When bound to the FXR, lipophilic bile acids such as obeticholic acid have been shown to decrease hepatic gluconeogenesis and improve insulin sensitivity.
      • Cariou B.
      • van Harmelen K.
      • Duran-Sandoval D.
      • et al.
      The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice.
      In the FLINT trial, 283 patients were randomized to receive obeticholic acid or placebo with biopsies performed at baseline and after 72 weeks of treatment.
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • et al.
      NASH Clinical Research Network
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      After a planned interim analysis of histologic changes revealed benefit from treatment, the decision was made to complete the 72-week biopsy in only 200 patients. The final analysis revealed a statistically significant improvement in histologic features of NASH, including ballooning, inflammation, steatosis, and fibrosis.
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • et al.
      NASH Clinical Research Network
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      This study included both diabetic and nondiabetic patients, as well as nonresponders to vitamin E who were randomized to either obeticholic acid or placebo. Although nearly a quarter of patients treated with obeticholic acid developed pruritus, only 1 patient had to discontinue therapy owing to severe pruritus. Because of its effect on bile acid synthesis and cholesterol disposal, obeticholic acid was predictably associated with a significant increase in total cholesterol and low-density lipoprotein (LDL) levels, with a decrease in high-density lipoprotein. Future studies are needed to examine the long-term effects of these alterations on the cardiovascular risk in patients with NASH. Mechanistic studies are underway to better understand the pathogenesis of obeticholic acid–induced pruritus and LDL increase and determine whether cotreatment with other pharmacologic agents can modify the pruritus or risks of LDL increase. It is important to note that ursodeoxycholic acid, a bile acid derivative that is currently in clinical use, failed to show convincing benefit in NASH.
      • Ratziu V.
      • de Ledinghen V.
      • Oberti F.
      • et al.
      FRESGUN
      A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis.
      • Lindor K.D.
      • Kowdley K.V.
      • Heathcote E.J.
      • et al.
      Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.
      However, unlike obeticholic acid, ursodeoxycholic acid is not an effective FXR agonist.
      Pentoxifylline (PTX) is a phosphodiesterase inhibitor that has been shown to inhibit the proinflammatory cytokine tumor necrosis factor α.
      • Ward A.
      • Clissold S.P.
      Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy.
      Tumor necrosis factor α has been implicated in the pathogenesis of NASH in animal models,
      • Wigg A.J.
      • Roberts-Thomson I.C.
      • Dymock R.B.
      • McCarthy P.J.
      • Grose R.H.
      • Cummins A.G.
      The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis.
      although its specific contribution in human NASH is not entirely clear.
      • Zein C.O.
      • Lopez R.
      • Fu X.
      • et al.
      Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism.
      Pentoxifylline also increases hepatic glutathione production, which may contribute to its hepatoprotective effect. Human studies investigating PTX therapy in NASH are limited. Only 2 RCTs to date have investigated histologic end points of treatment.
      • Van Wagner L.B.
      • Koppe S.W.
      • Brunt E.M.
      • et al.
      Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial.
      • Zein C.O.
      • Yerian L.M.
      • Gogate P.
      • et al.
      Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
      Zein et al
      • Zein C.O.
      • Yerian L.M.
      • Gogate P.
      • et al.
      Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
      conducted a placebo-controlled trial including 55 patients with biopsy-proven NASH who were randomized to either PTX 400 mg 3 times daily orally or placebo for 12 months. Liver histology was assessed at the end of the treatment. The PTX group exhibited significant improvement in serum ALT level, histologic features of NASH, and fibrosis. There was histologic resolution of NASH in 25% of the treatment arm as compared with 3.9% of those receiving placebo.
      • Zein C.O.
      • Yerian L.M.
      • Gogate P.
      • et al.
      Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
      Cirrhotic patients were excluded from the study, and less than 10% of the study group had diabetes. A smaller RCT including 26 patients who were randomized to either PTX or placebo did not show improvement in histology or ALT.
      • Van Wagner L.B.
      • Koppe S.W.
      • Brunt E.M.
      • et al.
      Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial.
      Although the dosing and treatment duration were the same as in the other RCT, this study included patients with cirrhosis, which may account for some of the differences in outcomes. Nausea and vomiting were the most common adverse effects in those receiving PTX. Although these studies indicate that PTX may have therapeutic potential, there are insufficient data to recommend its use in NASH at this time. Additional studies investigating the use of PTX are underway.
      Metformin increases peripheral glucose and fatty acid uptake while inhibiting lipogenesis and gluconeogenesis. It has been shown to improve insulin resistance and transaminitis while inducing weight loss.
      Diabetes Prevention Program (DPP) Research Group
      The Diabetes Prevention Program (DPP): description of lifestyle intervention.
      In 2 pilot studies metformin improved liver histology,
      • Nair S.
      • Diehl A.M.
      • Wiseman M.
      • Farr G.H.
      • Perrillo R.P.
      Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial.
      • Loomba R.
      • Lutchman G.
      • Kleiner D.E.
      • et al.
      Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis.
      but subsequent RCTs did not support this finding.
      • Lavine J.E.
      • Schwimmer J.B.
      • Van Natta M.L.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.
      • Loomba R.
      • Lutchman G.
      • Kleiner D.E.
      • et al.
      Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis.
      • Garinis G.A.
      • Fruci B.
      • Mazza A.
      • et al.
      Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study.
      • 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.
      Metformin has been shown to be effective in treating diabetes and insulin resistance and is safe for use in patients with NAFLD. Physicians are encouraged to use metformin for the management of prediabetes or diabetes in those who have coexisting NAFLD. Recent case-control and cohort studies have shown the benefit of metformin in reducing the risk of liver decompensation, death, and HCC in patients with cirrhosis.
      • Zhang X.
      • Harmsen W.S.
      • Mettler T.A.
      • et al.
      Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes.
      Further RCTs are needed to assess the effect of metformin in reducing the risk of hepatic decompensation and HCC in patients with NASH cirrhosis. There are several other therapies outside the scope of this review that are in clinical trials for the treatment of NAFLD and NASH.
      • Pearlman M.
      • Loomba R.
      State of the art: treatment of nonalcoholic steatohepatitis.
      Descriptions of ongoing trials are available through the National Institutes of Health website at ClinicalTrials.gov.

      Referral for Consideration of Liver Transplant

      Despite optimal medical management, many patients with NASH will develop cirrhosis. In fact, NASH often goes unrecognized until patients present with symptoms of decompensated liver disease. Cirrhosis due to NASH is currently the third most common indication for liver transplant in the United States and the second most common indication for liver transplant listing.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      United Network for Organ Sharing data have shown that the number of patients with NASH listed for liver transplant has tripled in the past 10 years.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      Nonalcoholic steatohepatitis is also the most rapidly growing etiology of liver disease in patients transplanted for HCC.
      • 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.
      Despite their increased BMIs and medical comorbidities, patients transplanted for NASH cirrhosis have no worse 90-day survival than do those transplanted for hepatitis C or alcoholic liver disease.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      Studies evaluating long-term posttransplant survival in patients with NASH found that survival is similar, or even superior, to that in those transplanted for other etiologies.
      • Wong R.J.
      • Chou C.
      • Bonham C.A.
      • Concepcion W.
      • Esquivel C.O.
      • Ahmed A.
      Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data.
      • 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.
      Although graft loss is significantly lower (OR, 0.21; 95% CI, 0.05-0.89; P=.03) in patients with NASH, risk of cardiovascular death is higher (OR, 1.65; 95% CI, 1.01-2.70; P=.05),
      • 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.
      highlighting the importance of excellent preventive care after transplant. Patients transplanted for NASH cirrhosis also have a higher rate of chronic kidney disease after transplant.
      • Fussner L.A.
      • Charlton M.R.
      • Heimbach J.K.
      • et al.
      The impact of gender and NASH on chronic kidney disease before and after liver transplantation.
      Any patient developing signs of decompensated cirrhosis, such as ascites, hepatic encephalopathy, or variceal bleeding, and/or a model for end-stage liver disease score of 10 or more should be referred to a transplant center for evaluation.
      • Murray K.F.
      • Carithers Jr., R.L.
      AASLD
      AASLD practice guidelines: evaluation of the patient for liver transplantation.

      Future Directions and Conclusion

      Nonalcoholic fatty liver disease is one of the leading causes of chronic liver disease worldwide. The obesity epidemic has led to an ever-increasing number of patients at risk for NAFLD and NASH. Liver biopsy is expensive and invasive, but it remains the only definitive means to diagnose NASH. Therefore, the development of noninvasive methods of diagnosing NASH is a major unmet need in the field. Although weight loss and other lifestyle modifications remain the foundation of treatment, there are now good data to support the use of pioglitazone and vitamin E in specific patients. Unfortunately, fewer than 50% of patients with NASH respond to current therapies, which underlines the importance of continued research and the need for improved therapies for NASH and NASH-related fibrosis. There are several promising therapeutic modalities and targets currently under investigation. The field is at a tipping point of discovery and innovation. With continued interest in research efforts, improvements in the diagnosis and management of NAFLD and NASH will continue in coming years.

      Acknowledgment

      We thank Leana Guerin, MD, Department of Pathology, University of Iowa Hospitals and Clinics, for preparing the histology figures.

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      Linked Article

      • Diet and Activity Programs Are Ineffective in Nonalcoholic Steatohepatitis
        Mayo Clinic ProceedingsVol. 91Issue 5
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          With the continued international increase in the prevalence of overweight and obese individuals, the recent review by Spengler and Loomba1 of nonalcoholic fatty liver disease (NAFLD) and the subset of individuals with nonalcoholic steatohepatitis (NASH), as defined by liver histology, is a very important topic. In the United States, NASH is the second most common indication for liver transplant,2 and the rate of liver transplant procedures is increasing. Prevention and treatment to reduce the rate of liver transplant is therefore a major issue in this field.
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