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

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.

[1]  B. Neuschwander‐Tetri,et al.  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 , 2012, Hepatology.

[2]  M. Trauner,et al.  Bile Acids as Regulators of Hepatic Lipid and Glucose Metabolism , 2010, Digestive Diseases.

[3]  Xiaofei Wang,et al.  Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[4]  J. Crowley,et al.  Vitamin E and the Risk of Prostate Cancer The Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) , 2011 .

[5]  A. Feldstein,et al.  Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial , 2011, Hepatology.

[6]  M. Yeh,et al.  Pathological features of fatty liver disease. , 2014, Gastroenterology.

[7]  Masoumeh Sikaroodi,et al.  Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. , 2013, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[8]  Joel Z Stengel,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. , 2011, Gastroenterology.

[9]  Zhen Wang,et al.  Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. , 2015, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[10]  R. Idilman,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 , 2016, Acta radiologica.

[11]  L. Hodson,et al.  Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non‐alcoholic steatohepatitis (NASH)? , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[12]  D. Reboussin,et al.  Effect of a 12-Month Intensive Lifestyle Intervention on Hepatic Steatosis in Adults With Type 2 Diabetes , 2010, Diabetes Care.

[13]  Aijaz Ahmed,et al.  Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. , 2014, Hepatology.

[14]  L. Burgart,et al.  Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: Results of a randomized trial , 2004, Hepatology.

[15]  K. Cusi,et al.  Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. , 2014, Journal of hepatology.

[16]  M. Kaplan,et al.  Evaluation of abnormal liver-enzyme results in asymptomatic patients. , 2000, The New England journal of medicine.

[17]  T. Therneau,et al.  The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD , 2007, Hepatology.

[18]  E. Jackvony,et al.  Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis , 2010, Hepatology.

[19]  Michael Charlton,et al.  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. , 2012, Gastroenterology.

[20]  A. Lincoff,et al.  Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. , 2007, JAMA.

[21]  Vincent Wai-Sun Wong,et al.  Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years , 2010, Gut.

[22]  H. Cortez‐Pinto,et al.  Erratum: Nonalcoholic steatohepatitis: Summary of an AASLD single topic conference (Hepatology (2003) 37 (1202-1219)) , 2003 .

[23]  C. Gluud,et al.  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? , 2013, PloS one.

[24]  S. Kaneko,et al.  Histological Course of Nonalcoholic Fatty Liver Disease in Japanese Patients , 2009, Diabetes Care.

[25]  T. Barrientos-Gutiérrez,et al.  Bariatric surgery for non-alcoholic steatohepatitis in obese patients. , 2010, The Cochrane database of systematic reviews.

[26]  R. Green,et al.  Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. , 2011, Annals of hepatology.

[27]  Rocio Lopez,et al.  The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis , 2010, Hepatology.

[28]  Eliseo Guallar,et al.  Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta‐analysis , 2011, Hepatology.

[29]  A. Diehl,et al.  Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease , 2005, Hepatology.

[30]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. , 1999, Gastroenterology.

[31]  M. Taniai,et al.  Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis , 2009, Journal of Gastroenterology.

[32]  C. Sirlin,et al.  Association Between Quantity of Liver Fat and Cardiovascular Risk in Patients With Nonalcoholic Fatty Liver Disease Independent of Nonalcoholic Steatohepatitis. , 2015, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[33]  A. Burt,et al.  Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. , 2015, Journal of hepatology.

[34]  P. Newsome,et al.  Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis , 2010, Alimentary pharmacology & therapeutics.

[35]  C. Sirlin,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 , 2015, Alimentary pharmacology & therapeutics.

[36]  R. Krauss,et al.  Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement , 2005, Current opinion in cardiology.

[37]  D. Schuppan,et al.  Non‐alcoholic steatohepatitis: Pathogenesis and novel therapeutic approaches , 2013, Journal of gastroenterology and hepatology.

[38]  N. Chalasani,et al.  Erratum: 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 (Gastroenterology (2012) 142 (1592-1609)) , 2012 .

[39]  Anthony Gamst,et al.  Magnetic Resonance Elastography Predicts Advanced Fibrosis in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Study , 2014, Hepatology.

[40]  P. Giral,et al.  Sampling variability of liver biopsy in nonalcoholic fatty liver disease. , 2005, Gastroenterology.

[41]  Rohit Loomba,et al.  The global NAFLD epidemic , 2013, Nature Reviews Gastroenterology &Hepatology.

[42]  T. Therneau,et al.  Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes , 2014, Hepatology.

[43]  P. Rosenthal,et al.  Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents , 2017 .

[44]  V. Ventura,et al.  Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study , 2010, International Journal of Obesity.

[45]  The Diabetes Prevention Program (DPP): description of lifestyle intervention. , 2002, Diabetes care.

[46]  K. Nouso,et al.  Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. , 2010, World journal of gastroenterology.

[47]  B. Neuschwander‐Tetri,et al.  Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial , 2015, The Lancet.

[48]  Christophe Tzourio,et al.  Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials , 2010, BMJ : British Medical Journal.

[49]  E. Bjornsson,et al.  Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. , 2013, Gastroenterology.

[50]  J. Maher,et al.  Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis , 2008, Hepatology.

[51]  K. Cusi,et al.  Corrigendum: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 , 2012, The American Journal of Gastroenterology.

[52]  Julien Vergniol,et al.  Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease , 2010, Hepatology.

[53]  Fernando Costa,et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. , 2005, Circulation.

[54]  N. Chalasani,et al.  Endpoints and clinical trial design for nonalcoholic steatohepatitis , 2011, Hepatology.

[55]  Aijaz Ahmed,et al.  Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. , 2015, Gastroenterology.

[56]  S. Caldwell,et al.  Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. , 2009, Journal of hepatology.

[57]  A. Gamst,et al.  Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease. , 2015, Radiology.

[58]  Anthony Gamst,et al.  Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique. , 2015, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[59]  A. Gamst,et al.  Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis. , 2013, Radiology.

[60]  S. Klein,et al.  Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease , 2012, Hepatology.

[61]  S. Sanderson,et al.  The natural history of nonalcoholic fatty liver disease: a population-based cohort study. , 2005, Gastroenterology.

[62]  W. Coyle,et al.  The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial , 2009, Therapeutic advances in gastroenterology.

[63]  B. Neuschwander‐Tetri,et al.  Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients , 2013, Hepatology.

[64]  S. Sanderson,et al.  The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. , 2005, Journal of hepatology.

[65]  F. Pattou,et al.  Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. , 2015, Gastroenterology.

[66]  E. Comelli,et al.  Intestinal microbiota in patients with nonalcoholic fatty liver disease , 2013, Hepatology.

[67]  Chris Day,et al.  A position statement on NAFLD/NASH based on the EASL 2009 special conference. , 2010, Journal of hepatology.

[68]  B. Neuschwander‐Tetri Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites , 2010, Hepatology.

[69]  Federico Schena,et al.  Metabolic Effects of Aerobic Training and Resistance Training in Type 2 Diabetic Subjects , 2012, Diabetes Care.

[70]  B. Neuschwander‐Tetri,et al.  Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD , 2015, Diabetes Care.

[71]  G. Farr,et al.  Metformin in the treatment of non‐alcoholic steatohepatitis: a pilot open label trial , 2004, Alimentary pharmacology & therapeutics.

[72]  J. Heimbach,et al.  The impact of gender and NASH on chronic kidney disease before and after liver transplantation , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[73]  Folkert Kuipers,et al.  The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice* , 2006, Journal of Biological Chemistry.

[74]  B. Cariou The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis. , 2008, Diabetes & metabolism.

[75]  S. Sanderson,et al.  NAFLD and Insulin Resistance Do Not Increase the Risk of Postoperative Complications Among Patients Undergoing Bariatric Surgery—A Prospective Analysis , 2011, Obesity surgery.

[76]  A. Feldstein,et al.  Novel Insights into the Pathophysiology of Nonalcoholic Fatty Liver Disease , 2010, Seminars in liver disease.

[77]  D. Harnois The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study , 2011 .

[78]  P. Bedossa,et al.  A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. , 2013, Journal of hepatology.

[79]  G. Pacini,et al.  Adipokines in NASH: Postprandial lipid metabolism as a link between adiponectin and liver disease , 2005, Hepatology.

[80]  D. Kleiner,et al.  Nonalcoholic Fatty Liver Disease: Pathologic Patterns and Biopsy Evaluation in Clinical Research , 2012, Seminars in Liver Disease.

[81]  O. Cummings,et al.  Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease. , 2008, Journal of hepatology.

[82]  Rohit Loomba,et al.  Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis1 , 2015, Journal of Lipid Research.

[83]  M. Bennett,et al.  The natural history of nonalcoholic fatty liver: A follow‐up study , 1995, Hepatology.

[84]  R. Loomba,et al.  State of the art: treatment of nonalcoholic steatohepatitis , 2014, Current opinion in gastroenterology.

[85]  I. Dagher,et al.  The Diagnostic Accuracy of Transient Elastography for the Diagnosis of Liver Fibrosis in Bariatric Surgery Candidates with Suspected NAFLD , 2014, Obesity Surgery.

[86]  張維君 Patatin-like phospholipase domain containing 3基因多型性與第二型糖尿病的巨量白蛋白尿之關聯性 , 2009 .

[87]  Mohammad Hassan Murad,et al.  Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data. , 2015, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[88]  K. Cusi,et al.  Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. , 2012, Gastroenterology.

[89]  J. Stoker,et al.  The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis , 2010, European Radiology.

[90]  E. Fassio,et al.  Natural history of nonalcoholic steathepatitis: A longitudinal study of repeat liver biopsies , 2004, Hepatology.

[91]  D. Lawlor,et al.  Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004. , 2007, Gastroenterology.

[92]  J. Hoofnagle,et al.  Clinical trial: pilot study of metformin for the treatment of non‐alcoholic steatohepatitis , 2009, Alimentary pharmacology & therapeutics.

[93]  D. Brenner,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 , 2012, Alimentary pharmacology & therapeutics.

[94]  D. Schroeder,et al.  Nonalcoholic Steatohepatitis (NASH) Does Not Increase Complications After Laparoscopic Bariatric Surgery , 2011, Obesity surgery.

[95]  K. Lindor,et al.  The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease , 1999, American Journal of Gastroenterology.

[96]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[97]  P. Rosenthal,et al.  Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. , 2011, JAMA.

[98]  A. Hofman,et al.  External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study. , 2013, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[99]  H. El‐Serag,et al.  Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. , 2012, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[100]  I. Roberts-Thomson,et al.  The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis , 2001, Gut.

[101]  J. Marrero,et al.  NAFLD may be a common underlying liver disease in patients with hepatocellular Carcinoma in the United States , 2002, Hepatology.

[102]  F. Durazo,et al.  Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management. , 2007, Nutrition reviews.

[103]  S. Hazen,et al.  Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: New evidence on the potential therapeutic mechanism , 2012, Hepatology.

[104]  Fernando Costa,et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. , 2006, Current opinion in cardiology.

[105]  Aijaz Ahmed,et al.  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 , 2014, Clinical transplantation.

[106]  R. Loomba,et al.  Meta‐analysis: pioglitazone improves liver histology and fibrosis in patients with non‐alcoholic steatohepatitis , 2012, Alimentary pharmacology & therapeutics.

[107]  R. Carithers,et al.  Practice Guidelines : Evaluation of the Patient for Liver Transplantation , 2005 .

[108]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference , 2003, Hepatology.

[109]  J. Borén,et al.  Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. , 2012, Journal of hepatology.

[110]  Zhao-chun Chi Pathogenesis of non-alcoholic fatty liver disease , 2017 .

[111]  G. Musso,et al.  Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH , 2008, Hepatology.

[112]  M. Kendrick,et al.  Bariatric surgery in patients with cirrhosis with and without portal hypertension: a single-center experience. , 2015, Mayo Clinic proceedings.

[113]  Christian Gluud,et al.  Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. , 2007, JAMA.

[114]  B. Neuschwander‐Tetri,et al.  Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. , 2010, The New England journal of medicine.

[115]  R. Schiumerini,et al.  Review article: the diagnosis of non‐alcoholic fatty liver disease – availability and accuracy of non‐invasive methods , 2013, Alimentary pharmacology & therapeutics.

[116]  V. de Lédinghen,et al.  A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. , 2011, Journal of hepatology.

[117]  M. Abraham,et al.  Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis , 2012, Hepatology.

[118]  A Ward,et al.  Pentoxifylline , 1987, Drugs.

[119]  A. Baranova,et al.  Systematic review: the epidemiology and natural history of non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis in adults , 2011, Alimentary pharmacology & therapeutics.