From NAFLD in clinical practice to answers from guidelines.

This review of the literature consists of three sections. First, papers concerning non-alcoholic fatty liver disease (NAFLD) awareness among the general population, general practitioners, and liver and non-liver specialists were retrieved and analyzed to highlight the perception of disease, verify knowledge of current recommendations, and identify the main difficulties experienced in clinical practice. Next, position papers and clinical practice guidelines issued by International and National Hepatological Scientific Societies were identified and critically assessed in order to pinpoint the areas of convergence/difference. Finally, practical suggestions on NAFLD diagnosis and management in daily practice are provided and the open questions highlighted.

[1]  A. Craxì,et al.  Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection , 2011, Liver international : official journal of the International Association for the Study of the Liver.

[2]  R. Hanson,et al.  The natural history of nonalcoholic steatohepatitis: A follow‐up study of forty‐two patients for up to 21 years , 1990, Hepatology.

[3]  H. J. de Silva,et al.  Non‐alcoholic fatty liver disease: Confronting the global epidemic requires better awareness , 2009, Journal of gastroenterology and hepatology.

[4]  P. Thuluvath,et al.  Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: A case‐control study , 2000, Hepatology.

[5]  R. Xu,et al.  Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease , 2008, Hepatology.

[6]  Z. Younossi,et al.  Screening for hepatitis B, C and non‐alcoholic fatty liver disease: a survey of community‐based physicians , 2009, Alimentary pharmacology & therapeutics.

[7]  M. Manos,et al.  Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease , 2005, Hepatology.

[8]  D. van der Poorten,et al.  Liver disease in adolescents: A cohort study of high‐risk individuals , 2007, Hepatology.

[9]  D. Purdie,et al.  Steatosis is a cofactor in liver injury in hemochromatosis. , 2005, Gastroenterology.

[10]  M. Fishbein,et al.  Pediatric Nonalcoholic Fatty Liver Disease Undetected Hepatomegaly in Obese Children by Primary Care Physicians: A Pitfall in the Diagnosis of , 2013 .

[11]  Z. Younossi,et al.  Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. , 2008, Journal of hepatology.

[12]  C. Ahn,et al.  Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. , 2004, Archives of internal medicine.

[13]  V. Wong,et al.  High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis , 2011, Gut.

[14]  Carlo Palombo,et al.  Fatty liver index, gamma‐glutamyltransferase, and early carotid plaques , 2012, Hepatology.

[15]  A. Lonardo,et al.  The wide spectrum of steatohepatitis: a report of four cases and a review of the literature , 2004, European journal of gastroenterology & hepatology.

[16]  L. N. Valenti,et al.  Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes , 2008, Hepatology.

[17]  W. Chan,et al.  Updated thresholds for serum alanine aminotransferase level in a large‐scale population study composed of 34 346 subjects , 2012, Alimentary pharmacology & therapeutics.

[18]  A. Lonardo,et al.  HCV and diabetes. A two-question-based reappraisal. , 2007, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[19]  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.

[20]  N. Unwin,et al.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Detection, Evaluation, and Treatment of High Blood Cholesterol Education Program (NCEP) Expert Panel on Executive Summary of the Third Report of the National , 2009 .

[21]  A. Lonardo,et al.  Hepatitis C and diabetes: the inevitable coincidence? , 2009, Expert review of anti-infective therapy.

[22]  S. Grundy,et al.  Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. , 2005, American journal of physiology. Endocrinology and metabolism.

[23]  Henry Völzke,et al.  Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation. , 2008, Gastroenterology.

[24]  M. Zheng,et al.  Upper Limits of Normal for Serum Alanine Aminotransferase Levels in Chinese Han Population , 2012, PloS one.

[25]  H. Cortez‐Pinto,et al.   Gut microbiota and nonalcoholic fatty liver disease. , 2012, Annals of hepatology.

[26]  T. Asselah,et al.  Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. , 2006, Gastroenterology.

[27]  G. Farrell,et al.  Nonalcoholic fatty liver disease: From steatosis to cirrhosis , 2006, Hepatology.

[28]  A. McCullough,et al.  Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. , 2009, Journal of hepatology.

[29]  P. Portincasa,et al.  Management of chronic liver disease by general practitioners in southern Italy: unmet educational needs. , 2013, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[30]  G. Svegliati-Baroni,et al.  A 360-degree overview of paediatric NAFLD: recent insights. , 2013, Journal of hepatology.

[31]  J. Levitsky,et al.  Diagnosis and therapy of alcoholic liver disease. , 2004, Seminars in liver disease.

[32]  Ross J. Harris,et al.  Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis. , 2009, Diabetes care.

[33]  Samy Suissa,et al.  The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study , 2012, BMJ : British Medical Journal.

[34]  R. Xu,et al.  Suspected Nonalcoholic Fatty Liver Disease and Mortality Risk in a Population-Based Cohort Study , 2008, The American Journal of Gastroenterology.

[35]  T. Poynard,et al.  Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease. , 2011, Clinics and research in hepatology and gastroenterology.

[36]  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.

[37]  Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease , 2001 .

[38]  A. Sanyal,et al.  Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). , 2012, Journal of hepatology.

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

[40]  S. Sookoian,et al.  Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. , 2008, Journal of hepatology.

[41]  S. Caldwell,et al.  Cryptogenic cirrhosis: Clinical characterization and risk factors for underlying disease , 1999, Hepatology.

[42]  T. Joh,et al.  Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup , 2010, Journal of gastroenterology and hepatology.

[43]  G. Musso,et al.  Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity , 2011, Annals of medicine.

[44]  G. Musso,et al.  Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials , 2012, Diabetologia.

[45]  T. Therneau,et al.  Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States , 2013, Hepatology.

[46]  K. Pietiläinen,et al.  Liver fat in the metabolic syndrome. , 2007, The Journal of clinical endocrinology and metabolism.

[47]  C. Sirlin,et al.  Advances in pediatric nonalcoholic fatty liver disease , 2009, Hepatology.

[48]  Y. Chawla,et al.  Asians need different criteria for defining overweight and obesity. , 2005, Archives of internal medicine.

[49]  S. Woolfenden,et al.  Diagnosis and management of childhood obesity: A survey of general practitioners in South West Sydney , 2008, Journal of paediatrics and child health.

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

[51]  P. Hayashi,et al.  The natural history of nonalcoholic fatty liver disease: a clinical histopathological study , 2003, American Journal of Gastroenterology.

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

[53]  M. Holmqvist,et al.  Long‐term follow‐up of patients with NAFLD and elevated liver enzymes , 2006, Hepatology.

[54]  Jonathan C. Cohen,et al.  Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity , 2004, Hepatology.

[55]  G. Lau,et al.  Guidelines for the assessment and management of non‐alcoholic fatty liver disease in the Asia–Pacific region: Executive summary , 2007, Journal of gastroenterology and hepatology.

[56]  G. Salles,et al.  Prevalence and associated factors of non‐alcoholic fatty liver disease in patients with type‐2 diabetes mellitus , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[57]  H. Cortez‐Pinto,et al.  Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. , 2013, Journal of hepatology.

[58]  N. Chalasani,et al.  What Should We Recommend to Our Patients with NAFLD Regarding Alcohol Use? , 2012, The American Journal of Gastroenterology.

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

[60]  N. Chalasani.  Statins and hepatotoxicity: Focus on patients with fatty liver , 2005, Hepatology.

[61]  A. Lonardo,et al.  Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk? , 2011, Archives of medical research.

[62]  A. Tsung,et al.  Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: A case‐control study , 2012, Hepatology.

[63]  R. Cantor,et al.  Heritability of nonalcoholic fatty liver disease. , 2009, Gastroenterology.

[64]  L. N. Valenti,et al.  Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling--a propensity score-adjusted observational study. , 2011, QJM : monthly journal of the Association of Physicians.

[65]  T. Saibara,et al.  Non‐alcoholic fatty liver disease in the Asia–Pacific region: Definitions and overview of proposed guidelines , 2007, Journal of gastroenterology and hepatology.

[66]  J. Stockman.  Underdiagnosis of Pediatric Obesity and Underscreening for Fatty Liver Disease and Metabolic Syndrome by Pediatricians and Pediatric Subspecialists , 2007 .

[67]  M. Holmqvist,et al.  Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease , 2009, Scandinavian journal of gastroenterology.

[68]  V. Paradis,et al.  Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: A pathological analysis , 2009, Hepatology.

[69]  G. Bedogni,et al.  ASH and NASH , 2011, Digestive Diseases.

[70]  D. Harnois.  Nonobese Population in a Developing Country Has a High Prevalence of Nonalcoholic Fatty Liver and Significant Liver Disease , 2010 .

[71]  A. Zanella,et al.  Updated Definitions of Healthy Ranges for Serum Alanine Aminotransferase Levels , 2002, Annals of Internal Medicine.

[72]  J. Ijzermans,et al.  Systematic review and meta‐analysis of steatosis as a risk factor in major hepatic resection , 2010, The British journal of surgery.

[73]  J. Olsen,et al.  Risk of Cancer in Patients Hospitalized With Fatty Liver: A Danish Cohort Study , 2003, Journal of clinical gastroenterology.

[74]  Sang-hun Park.  Expanding the Natural History of Nonalcoholic Steatohepatitis: from Cryptogenic Cirrhosis to Hepatocellular Carcinoma , 2003 .

[75]  S. Caldwell,et al.  Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. , 2000, The American journal of medicine.

[76]  R. Torella,et al.  The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. , 2006, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[77]  Hong Tang,et al.  Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China. , 2009, Hepatobiliary & pancreatic diseases international : HBPD INT.

[78]  D. Houlihan,et al.  Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. , 2010, The New England journal of medicine.

[79]  Anurag Maheshwari,et al.  Cryptogenic Cirrhosis and NAFLD: Are They Related? , 2006, The American Journal of Gastroenterology.

[80]  F. Capron,et al.  Excess weight risk factor for alcoholic liver disease , 1997, Hepatology.

[81]  Lungen Lu,et al.  Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: Update 2010 , 2011, Journal of digestive diseases.

[82]  J. Teckman,et al.  Obese children with steatohepatitis can develop cirrhosis in childhood , 2002, American Journal of Gastroenterology.

[83]  A. Lonardo,et al.  Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD , 2012, Liver international : official journal of the International Association for the Study of the Liver.

[84]  Roberto Pastor-Barriuso,et al.  Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality , 2005 .

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

[86]  A. Gasbarrini,et al.  Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. , 2010, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[87]  A. Clouston,et al.  Awareness and opinions of non‐alcoholic fatty liver disease by hospital specialists , 2013, Internal medicine journal.

[88]  C. Day,et al.  Genetic determinants of susceptibility and severity in nonalcoholic fatty liver disease , 2011, Expert review of gastroenterology & hepatology.

[89]  A. Clouston,et al.  Steatosis: Co‐factor in other liver diseases , 2005, Hepatology.

[90]  S. Rabot,et al.  Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice , 2012, Gut.

[91]  Henry Völzke,et al.  Multicausality in fatty liver disease: is there a rationale to distinguish between alcoholic and non-alcoholic origin? , 2012, World journal of gastroenterology.

[92]  M. Chonchol,et al.  Cardiovascular and systemic risk in nonalcoholic fatty liver disease - atherosclerosis as a major player in the natural course of NAFLD. , 2013, Current pharmaceutical design.

[93]  P. Vereerstraeten,et al.  Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease. , 2011, Acta gastro-enterologica Belgica.

[94]  J. Olsen,et al.  Prognosis of patients with a diagnosis of fatty liver--a registry-based cohort study. , 2003, Hepato-gastroenterology.

[95]  Y. Yılmaz.  Review article: is non‐alcoholic fatty liver disease a spectrum, or are steatosis and non‐alcoholic steatohepatitis distinct conditions? , 2012, Alimentary pharmacology & therapeutics.

[96]  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.

[97]  C. Renou,et al.  A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France. , 2012, Journal of hepatology.

[98]  H. Szajewska,et al.  Pharmacological Interventions for Nonalcoholic Fatty Liver Disease in Adults and in Children: A Systematic Review , 2009, Journal of pediatric gastroenterology and nutrition.

[99]  P. Portincasa,et al.  Improving nonalcoholic fatty liver disease management by general practitioners: a critical evaluation and impact of an educational training program. , 2008, Journal of gastrointestinal and liver diseases : JGLD.

[100]  I. Suh,et al.  Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study , 2004, BMJ : British Medical Journal.

[101]  K. Kaita,et al.  Fatty Infiltration of Liver in Hyperlipidemic Patients , 2000, Digestive Diseases and Sciences.

[102]  E. Brunt,et al.  Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. , 2012, Journal of hepatology.

[103]  V. Wong,et al.  Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease , 2011, Gut.

[104]  A. Feldstein,et al.  Cytokeratin‐18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: A multicenter validation study , 2009, Hepatology.

[105]  H. Cortez‐Pinto,et al.  Hepatic histology in obese patients undergoing bariatric surgery. , 2006, Journal of hepatology.

[106]  A. Lonardo,et al.  'Endocrine NAFLD' a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. , 2006, Journal of hepatology.

[107]  P. Vajro,et al.  Diagnosis of Nonalcoholic Fatty Liver Disease in Children and Adolescents: Position Paper of the ESPGHAN Hepatology Committee , 2012, Journal of pediatric gastroenterology and nutrition.

[108]  Roger Williams,et al.  Calorie and alcohol consumption in nonalcoholic fatty liver disease , 2012, European journal of gastroenterology & hepatology.

[109]  G. Svegliati-Baroni,et al.  From the metabolic syndrome to NAFLD or vice versa? , 2010, Digestive and Liver Disease.

[110]  G. Norman,et al.  SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. , 2010, Gastroenterology.

[111]  G. Bedogni,et al.  Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study , 2005, Hepatology.

[112]  M. Savolainen,et al.  Biochemical markers of alcoholism , 2007, Clinical chemistry and laboratory medicine.

[113]  W. Hui,et al.  Non‐alcoholic fatty liver disease: An expanding problem with low levels of awareness in Hong Kong , 2009, Journal of gastroenterology and hepatology.

[114]  J. Craig,et al.  Pioglitazone and vitamin E for nonalcoholic steatohepatitis: A cost utility analysis , 2012, Hepatology.

[115]  D. Harnois,et al.  Risk of Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease , 2011 .

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

[117]  H. El‐Serag,et al.  Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. , 2008, Journal of hepatology.

[118]  Greger Lindberg,et al.  Decreased survival of subjects with elevated liver function tests during a 28‐year follow‐up , 2010, Hepatology.

[119]  F. Negro,et al.  Nonalcoholic Fatty Liver Disease in Lean Individuals in the United States , 2012, Medicine.

[120]  Roberto Pastor-Barriuso,et al.  Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality , 2005, Annals of Internal Medicine.

[121]  A. Kotronen,et al.  Fatty Liver: A Novel Component of the Metabolic Syndrome , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[122]  H. Tilg,et al.  Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis , 2010, Hepatology.

[123]  S. Grundy,et al.  National Cholesterol Education Program Third Report of the National Cholesterol Education Program ( NCEP ) Expert Panel on Detection , Evaluation , and Treatment of High Blood Cholesterol in Adults ( Adult Treatment Panel III ) Final Report , 2022 .

[124]  濱口 真英.  The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation , 2009 .

[125]  Erland Erdmann,et al.  Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial , 2005, The Lancet.

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

[127]  J. Benson,et al.  The natural history of non-alcoholic fatty liver disease , 2006 .

[128]  Chunhong Bai,et al.  Long-term follow-up of patients with nonalcoholic fatty liver. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[129]  S. Caldwell,et al.  The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. , 2004, Journal of hepatology.

[130]  A. Lonardo,et al.  Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. , 1996, Gastroenterology.

[131]  Jeffrey B. Schwimmer,et al.  Prevalence of Fatty Liver in Children and Adolescents , 2006, Pediatrics.

[132]  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.

[133]  R. Fisher,et al.  Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values , 2003, Hepatology.

[134]  James E. Nelson,et al.  Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease , 2012, Hepatology.

[135]  Paul Zimmet,et al.  The metabolic syndrome—a new worldwide definition , 2005, The Lancet.

[136]  J. Mckenney,et al.  National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) , 2002 .

[137]  Henry Völzke,et al.  Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma‐glutamyl transpeptidase levels , 2009, Hepatology.

[138]  E. Yu,et al.  Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. , 2007, Journal of hepatology.