Clinical Review: Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications.

CONTEXT Nonalcoholic fatty liver disease (NAFLD) is increasingly diagnosed worldwide and is the most common chronic liver disease in Western countries. In this review, we discuss the role of NAFLD as a novel cardiometabolic risk factor for the development of type 2 diabetes (T2DM) and for the development of major chronic complications and poor glycemic control in people with established T2DM. EVIDENCE ACQUISITION This is a clinical, narrative review and not a systematic review and meta-analysis. PubMed was extensively searched for articles using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "diabetes risk," "cardiovascular risk," "cardiovascular mortality," "chronic kidney disease," or "diabetic nephropathy" between 1990 and 2012. Articles published in languages other than English were excluded from the analysis. EVIDENCE SYNTHESIS NAFLD exacerbates hepatic insulin resistance and increases the risk of developing T2DM. Growing evidence also indicates that NAFLD may worsen glycemic control in people with T2DM and may contribute to the development and progression of the most important chronic complications of diabetes, such as cardiovascular disease and chronic kidney disease. CONCLUSIONS The adverse impact of NAFLD on risk for T2DM and its major chronic vascular complications deserves particular attention among endocrinologists/cardiologists/hepatologists, in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD. Clinicians who manage patients with NAFLD should not only focus on liver disease, but should also recognize the increased risk of developing T2DM and its chronic vascular complications and undertake early, aggressive risk factor modification.

[1]  Enrico Barbieri,et al.  Nonalcoholic Fatty Liver Disease Is Associated With Left Ventricular Diastolic Dysfunction in Patients With Type 2 Diabetes , 2012, Diabetes Care.

[2]  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.

[3]  M. Chonchol,et al.  Relationship between serum gamma-glutamyltransferase and chronic kidney disease in the United States adult population. Findings from the National Health and Nutrition Examination Survey 2001-2006. , 2010, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[4]  J. Girard,et al.  Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. , 2008, The Journal of clinical investigation.

[5]  Sarah A. Moore,et al.  Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss , 2011, Gut.

[6]  Fang-Chi Hsu,et al.  Hepatic Steatosis and Subclinical Cardiovascular Disease in a Cohort Enriched for Type 2 Diabetes: The Diabetes Heart Study , 2008, The American Journal of Gastroenterology.

[7]  I. G. Fantus,et al.  Mechanisms of the Free Fatty Acid-induced Increase in Hepatic Glucose Production Ffa and Gluconeogenesis Hepatic Insulin Signaling , 2022 .

[8]  Z. Yamagata,et al.  The Association of Fatty Liver and Diabetes Risk , 2007, Journal of epidemiology.

[9]  Sun Woo Kim,et al.  Combined Effect of Nonalcoholic Fatty Liver Disease and Impaired Fasting Glucose on the Development of Type 2 Diabetes , 2011, Diabetes Care.

[10]  G. Lippi,et al.  Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients , 2008, Diabetologia.

[11]  S. Srinivasan,et al.  Elevated Liver Function Enzymes Are Related to the Development of Prediabetes and Type 2 Diabetes in Younger Adults , 2011, Diabetes Care.

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

[13]  Fritz Schick,et al.  Identification and characterization of metabolically benign obesity in humans. , 2008, Archives of internal medicine.

[14]  James E. Nelson,et al.  Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and toll‐like receptor activation , 2012, Hepatology.

[15]  F. Anania,et al.  Glucagon‐like peptide‐1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway , 2010, Hepatology.

[16]  B. Staels,et al.  Roles of PPARs in NAFLD: potential therapeutic targets. , 2012, Biochimica et biophysica acta.

[17]  Enzo Bonora,et al.  Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. , 2010, The New England journal of medicine.

[18]  N. Chalasani,et al.  An assessment of statin safety by hepatologists. , 2006, The American journal of cardiology.

[19]  A. Hakkarainen,et al.  Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. , 2008 .

[20]  B. Teusink,et al.  Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice. , 2003, Endocrinology.

[21]  K-U. Lee,et al.  Fatty liver is an independent risk factor for the development of Type 2 diabetes in Korean adults , 2008, Diabetic medicine : a journal of the British Diabetic Association.

[22]  J. Cercueil,et al.  Nonalcoholic fatty liver is not associated with carotid intima-media thickness in type 2 diabetic patients. , 2009, The Journal of clinical endocrinology and metabolism.

[23]  S. Morini,et al.  Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes , 2011, BMC medicine.

[24]  T. Saheki,et al.  Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. , 2008, Journal of hepatology.

[25]  N. Barzilai,et al.  Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. , 2007, American journal of physiology. Endocrinology and metabolism.

[26]  D. Kim,et al.  Association between nonalcoholic fatty liver disease and carotid intima-media thickness according to the presence of metabolic syndrome. , 2009, Atherosclerosis.

[27]  P. Whincup,et al.  Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. , 2005, Diabetes care.

[28]  T. Lehtimäki,et al.  Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. , 2006, American journal of physiology. Endocrinology and metabolism.

[29]  S. Kahn,et al.  Review: The role of insulin resistance in nonalcoholic fatty liver disease. , 2006, The Journal of clinical endocrinology and metabolism.

[30]  G. Targher,et al.  Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. , 2007, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[31]  Khosrow Adeli,et al.  Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. , 2002, Endocrine reviews.

[32]  K. Sung,et al.  Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. , 2011, The Journal of clinical endocrinology and metabolism.

[33]  D. Reijngoud,et al.  Increased de novo Lipogenesis and Delayed Conversion of Large VLDL into Intermediate Density Lipoprotein Particles Contribute to Hyperlipidemia in Glycogen Storage Disease Type 1a , 2008, Pediatric Research.

[34]  P. Hayes,et al.  Prevalence of and Risk Factors for Hepatic Steatosis and Nonalcoholic Fatty Liver Disease in People With Type 2 Diabetes: the Edinburgh Type 2 Diabetes Study , 2011, Diabetes Care.

[35]  Scott Harmsen,et al.  Nonalcoholic Fatty Liver Disease Increases Risk of Death Among Patients With Diabetes: A Community-Based Cohort Study , 2010, The American Journal of Gastroenterology.

[36]  Catriona A. Burdon,et al.  Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. , 2012, Journal of hepatology.

[37]  W. Goessling,et al.  Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. , 2008, Gastroenterology.

[38]  M. Prentki,et al.  Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart. , 2005, American journal of physiology. Endocrinology and metabolism.

[39]  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.

[40]  L. Adams,et al.  Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment , 2011, Nature Reviews Endocrinology.

[41]  H. Lamb,et al.  Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. , 2010, Journal of the American College of Cardiology.

[42]  L. Poston,et al.  Maternal high‐fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression , 2009, Hepatology.

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

[44]  柴田 道彦 Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men , 2008 .

[45]  H. Ginsberg,et al.  Regulation of plasma triglycerides in insulin resistance and diabetes. , 2005, Archives of medical research.

[46]  Manisha Talim,et al.  Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With Cardiovascular Disease Among Type 2 Diabetic Patients , 2007, Diabetes Care.

[47]  V. de Lédinghen,et al.  Screening for liver fibrosis by using FibroScan(®) and FibroTest in patients with diabetes. , 2012, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[48]  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.

[49]  C. Lewis,et al.  γ-Glutamyltransferase Is a Predictor of Incident Diabetes and Hypertension: The Coronary Artery Risk Development in Young Adults (CARDIA) Study , 2003 .

[50]  B. Neuschwander‐Tetri,et al.  Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[51]  G. Zoppini,et al.  Non-alcoholic fatty liver disease is associated with carotid artery wall thickness in diet-controlled Type 2 diabetic patients , 2006, Journal of endocrinological investigation.

[52]  D. Jacobs,et al.  γ-Glutamyltransferase, Obesity, and the Risk of Type 2 Diabetes: Observational Cohort Study among 20,158 Middle-Aged Men and Women , 2004 .

[53]  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.

[54]  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.

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

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

[57]  G. Targher Elevated serum γ-glutamyltransferase activity is associated with increased risk of mortality, incident type 2 diabetes, cardiovascular events, chronic kidney disease and cancer – a narrative review , 2010, Clinical chemistry and laboratory medicine.

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

[59]  D. Klonoff,et al.  Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. , 2008, Current medical research and opinion.

[60]  S. Wild,et al.  Fatty Liver, Insulin Resistance, and Features of Metabolic Syndrome , 2012, Diabetes Care.

[61]  C. Byrne,et al.  The metabolic syndrome: common origins of a multifactorial disorder , 2009, Postgraduate Medical Journal.

[62]  M. Cnop,et al.  The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments. , 2002, Diabetes.

[63]  C. Lipina,et al.  Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance , 2011, Diabetologia.

[64]  G. Bedogni,et al.  Epidemiology of Non-Alcoholic Fatty Liver Disease , 2010, Digestive Diseases.

[65]  E. Bonora,et al.  Increased risk of cardiovascular disease and chronic kidney disease in NAFLD , 2012, Nature Reviews Gastroenterology &Hepatology.

[66]  Christian Thoma,et al.  Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. , 2012, Journal of hepatology.

[67]  E. Bonora,et al.  Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? , 2011, Journal of hepatology.

[68]  S. McCall,et al.  Diacylglycerol acyltranferase 1 anti‐sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis , 2007, Hepatology.

[69]  A. Häkkinen,et al.  Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. , 2000, Diabetes.

[70]  A. Häkkinen,et al.  Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. , 2002, The Journal of clinical endocrinology and metabolism.

[71]  Jian-Gao Fan,et al.  Effects of nonalcoholic fatty liver disease on the development of metabolic disorders , 2007, Journal of gastroenterology and hepatology.

[72]  J. Adams,et al.  Update in vitamin D. , 2010, The Journal of clinical endocrinology and metabolism.

[73]  Chao-Long Chen,et al.  Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. , 2011, Journal of hepatology.

[74]  Beverley Balkau,et al.  articleNine-year incident diabetes is predicted by fatty liver indices : the French D . E . S . I . R . study , 2015 .

[75]  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.

[76]  Y. Iwamoto,et al.  Prevalence of non‐alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[77]  M. Vivarelli,et al.  Glucagon‐like peptide‐1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high‐fat diet in nonalcoholic steatohepatitis , 2011, Liver international : official journal of the International Association for the Study of the Liver.

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

[79]  S. O’Rahilly,et al.  Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. , 2009, The Journal of clinical investigation.

[80]  Amalia Gastaldelli,et al.  Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. , 2007, Gastroenterology.

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

[82]  M. Beaugrand,et al.  Transient elastography in non-alcoholic fatty liver disease. , 2012, Annals of hepatology.

[83]  G. Lippi,et al.  Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease. , 2008, Journal of the American Society of Nephrology : JASN.

[84]  S. Wild,et al.  Predicting incident fatty liver using simple cardio-metabolic risk factors at baseline , 2012, BMC Gastroenterology.

[85]  B. S. Mohammed,et al.  Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity , 2009, Proceedings of the National Academy of Sciences.

[86]  J. Ix,et al.  Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. , 2010, Journal of the American Society of Nephrology : JASN.

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

[88]  Won-Young Lee,et al.  Impact of non‐alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes , 2010, Internal medicine journal.

[89]  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.

[90]  S. Wild,et al.  Combined Influence of Insulin Resistance, Overweight/Obesity, and Fatty Liver as Risk Factors for Type 2 Diabetes , 2012, Diabetes Care.

[91]  Christopher D Byrne,et al.  Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? , 2012, European heart journal.

[92]  G. Lippi,et al.  Relationship of Serum γ‐Glutamyltransferase to Atherogenic Dyslipidemia and Glycemic Control in Type 2 Diabetes , 2009, Obesity.

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

[94]  G. Lippi,et al.  Vitamin D, Thrombosis, and Hemostasis: More than Skin Deep , 2012, Seminars in Thrombosis & Hemostasis.

[95]  G. Silecchia,et al.  Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus , 2012, Hepatology.

[96]  F. Anania,et al.  Exendin‐4, a glucagon‐like protein‐1 (GLP‐1) receptor agonist, reverses hepatic steatosis in ob/ob mice , 2006, Hepatology.

[97]  Q. Anstee,et al.  How big a problem is non-alcoholic fatty liver disease? , 2011, BMJ : British Medical Journal.