Presenter Disclosure Information 5 6pm Nonalcoholic Fatty Liver Disease (NAFLD): Another Obesity-Related Epidemic SPEAKER Elliot Tapper, MD The following relationships exist related to this presentation: Dr Tapper had no financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Case 1: Rob Identify the risk factors for and disease spectrum of non-alcoholic fatty liver disease (NAFLD) Apply the latest evidence-based recommendations for the management of NAFLD Understand the indications for liver biopsy and further investigation 42-year-old white male BMI: 29 kg/m 2 Drinks socially Fasting LDL: 160 mg/dl Fasting glucose: 113 mg/dl ALT level: 90 IU/L Viral hepatitis screen: negative ALT=alanine aminotransferase Questions Pertinent to Rob Does he have NAFLD? Should he be concerned? How should he be worked up? Should he stop drinking alcohol completely? Does he need a referral to GI? Does he need a liver biopsy? Is it safe to consider statins to lower his LDL? What is NAFLD?.?
Spectrum of NAFLD: NAFL vs. Spectrum of NAFLD NAFL Simple fatty liver Histologically characterized by macrovesicular steatosis with no additional pathology. Generally considered benign from a hepatic standpoint. Histologically advanced fatty liver. Characterized by steatosis, inflammation, ballooning, fibrosis. Can lead to cirrhosis and liver failure. Normal Steatosis (NAFL) Steatohepatitis () Fibrosis/ cirrhosis NAFLD=nonalcoholic fatty liver disease =nonalcoholic steatohepatitis Risk Factors for NAFLD Major Co-Morbidities Type 2 diabetes Dyslipidemia Obesity Metabolic syndrome Hyperuricemia Emerging Associations Hypothyroidism Sleep apnea Hypopituitarism Hypogonadism Polycystic ovary syndrome Racial Differences in Fatty Liver Disease Prevalence of steatosis ( 1 H-MR Spect) in 2971 multiethnic adults in the Dallas Heart Study 100% Compared to Caucasians, NAFLD is less common among African-Americans 80% and more common among Hispanics 60% and cryptogenic 45% cirrhosis are less common 40% 31% 33% among African-Americans 24% 20% 0% All Hispanic White Black * Blacks had comparable obesity, diabetes, hyper TG, and low HDL. Lonardo A, et al. J Hepatol. 2006; 44: 1196-1207. Vuppalanchi R, Chalasani N. Hepatology. 2009;49:306-317. Adapted from Browning JD, et al. Hepatology. 2004;40(6):1387-1395. The Two Hit Model: Day & James (1998) The One Hit Theory Normal first hit Steatosis Obesity Insulin resistance Normal Hepatitis+ Fibrosis Oxidative Stress Cytokines Steatosis FFA/Glu/Insulin Oxidative stress ER stress Cytokine stress??? Cell death Inflammation Fibrosis Adapted from Day CP & James OFW. Gastroenterology. 1998:114:842-845.
Hepatic Outcomes of NAFLD Should Rob be concerned? Simple Steatosis Cirrhosis Cryptogenic Cirrhosis Largely benign with minimal risk of cirrhosis Progressive with 20% risk of cirrhosis over a 10-yr time horizon Moderate risk for liver cancer (2-4% per year) Likely a burnt-out form of in up to 80% of patients Outcomes in NAFLD Outcomes Overall Mortality Incident CVD Incident Type 2 Diabetes Surrogates NAFLD vs. general population ALT as a surrogate GGT as a surrogate Imaging as a surrogate ALT as a surrogate GGT as a surrogate Imaging as a surrogate OR=odds ratio 95% CI= 95% confidence interval ALT =alanine aminotransferase Musso G, et al. Ann Med. 2011;43(6):413-417. # Studies OR [95% CI] 8 studies 1.57 [1.18-2.10] 6 studies 10 studies 7 studies 17 studies 12 studies 3 studies 1.10 [0.85-1.41] 1.57 [1.42-1.74] 2.05 [1.81-2.31] 1.97 [1.77-2.20] 2.74 [2.39 3.14] 3.51 [2.28-5.41] CVD=cardiovascular disease GGT= γ-glutamyl transferase vs. NAFL Meta-analysis Outcomes # studies OR [95% CI] Overall mortality 5 studies 1.81 [1.24-2.66] Liver-related mortality CVD-related mortality OR=odds ratio for vs steatosis 95% CI= 95% confidence interval Musso G, et al. Ann Med. 2011;43(6):413-417. 5 studies 5.71 [2.31-14.31] 5 Studies 0.91 [0.42-1.98] Key Elements in the Diagnosis How do we evaluate Rob to provide him with an accurate diagnosis? NAFLD No significant alcohol consumption No competing etiologies (eg, autoimmune, HCV, etc), or medications (eg, amiodarone, tamoxifen) Imaging evidence of hepatic steatosis Aminotransferases may or may not be elevated However, only a liver biopsy can establish the presence of
Diagnosis of NAFLD/ Work-Up of Patients with NAFLD Aminotransferases Imaging tests Can be normal in patients with NAFLD and even Currently not able to establish the presence of Meticulous alcohol and medication history Exclusion of co-existing or competing etiologies Auto-antibodies and hyperferritinemia are common Fasting lipid profile and measures of insulin resistance Imaging to establish the presence of steatosis Liver biopsy to establish the presence of NOTE: The upper limits of normal for liver enzymes vary across different laboratories and do not determine the health of your patient s liver Mofrad P, et al. Hepatology. 2003; 37:1286-1292. When to Biopsy? Surrogate Markers/Predictive Models Patients with NAFLD at increased risk for steatohepatitis and advanced fibrosis. Presence of metabolic syndrome and the NAFLD Fibrosis Score may be used to identify patients at risk for steatohepatitis and advanced fibrosis. Consider Liver Biopsy for Patients with suspected NAFLD in whom competing etiologies for hepatic steatosis and co-existing chronic liver diseases cannot be excluded without a liver biopsy. Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-23. Predict Adapted from Musso G, et al. Ann Med. 2011;43(6):413-417. Predict Advanced Fibrosis Metabolic Syndrome CK-18 fragments NAFLD Fibrosis Score CK-18 + sfas Transient elastography Oxidized Fatty acids Fibrotest test BARD score Predictive Index ELF panel Obesity NAFLD score Fibrometer Clinical Score Genomics NAFIC (ferritin, insulin, collagen) IU panel MR elastography CK=Cytokeratin; sfas=soluble FAS; ELF=European Liver Fibrosis Panel; MR=magnetic resonance; BARD=Body-mass index, AST/ALT Ratio, Diabetes (type 2) NAFLD Fibrosis Score (NFS) http://nafldscore.com Transient Elastography NAFLD Fibrosis Score predicts long-term outcomes in individuals with NAFLD Independent predicts advanced fibrosis. Based on six variables: age, BMI, AST/ALT ratio, hyperglycemia/diabetes, platelet count and albumin Noninvasive Safe, Reliable FDA Approved in 2013 Risk Score Calculation -1.675 + 0.037 * age (years) + 0.094 * BMI (kg/m 2 ) + 1.13 * IFG/diabetes (yes=1, no=0) + 0.99 * AST/ALT ratio - 0.013 * platelet (x10 9 /l) - 0.66 * albumin (g/dl) Detects cirrhosis with 99% NPV and 46% PPV PPV and NPV = positive and negative predictive value. Angulo P, et al. Hepatology. 2007;45:846-854./Kim D, et al. Hepatology. 2013;57: 1357-1365;. Angulo P, et al. Gastroenterology. 2013: in press. Tapper EB, Castera L, Afdhal NH. Clinical Gastroenterology and Hepatology. 2014: in press.
How do we use these new tests and when is referral to GI indicated? Now that Rob has a diagnosis, what do are we going to do for him? Treating a Patient with NAFLD Treatment* of Liver Disease in NAFLD If a patient has, attention should be paid to metabolic co-morbidities as well as liver disease However, if a patient has steatosis alone, attention should be paid to metabolic and cardiovascular morbidities Potential Options: Life style modification Bariatric surgery Vitamin E Insulin sensitizers Tested But Do Not Work: UDCA (Ursodiol) Metformin Under Investigation: Pentoxifylline Obeticholic acid Eicosapentaenoic acid Many others *No agents are approved for treating NAFLD/ UDCA=ursodeoxycholic acid Lifestyle Modification for NAFLD Bariatric Surgery* Weight Loss At least 3-5% necessary to improve steatosis Weight loss up to 10% may be needed to improve necroinflammation + Generally reduces hepatic steatosis Achieved either by hypocaloric diet alone or in with increased physical activity. Evidence: A Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-23. Exercise Exercise alone in adults may reduce hepatic steatosis Ability to improve other aspects of liver histology remains unknown. BUT no good data available on specific diets that are most effective. Bariatric surgery improves steatosis and may improve necroinflammation (and possibly fibrosis) in carefully selected patients Meta-analysis by Mummadi et al. showed that steatosis, steatohepatitis, and fibrosis improve following bariatric surgery However, Cochrane review highlights lack of welldesigned studies *Not indicated as a treatment for NAFLD/ Mummadi RR, et al. Clin Gastroenterol Hepatol. 2008;6:1396 1402. Chavez-Tapia NC, et al. Cochrane Database of Syst Rev. 2010 Jan 20;(1):CD007340.
Bariatric Surgery in NAFLD/ Insulin Sensitizers* for Not contraindicated in otherwise eligible obese persons with NAFLD or (without established cirrhosis) Evidence: A Foregut Bariatric Surgery Type, safety and efficacy of this surgery in otherwise eligible obese persons with established cirrhosis due to NAFLD are not established. Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-23. Premature to consider foregut bariatric surgery as established option to specifically treat Metformin Thiazolidinediones Rosiglitazone Pioglitazone *Not approved as a treatment for NAFLD/ No role in either adults or children Improve liver histology but weight gain is a problem Unavailable Role is unclear. Improves histology in non-diabetics with, but is not approved in non-diabetics. Concerns of unfavorable safety Multisociety Practice Guideline: Pioglitazone* & Pioglitazone can be used to treat steatohepatitis in patients with biopsy-proven. However, it should be noted that: Most patients who participated in clinical trials of pioglitazone for were non-diabetic Long term safety and efficacy of pioglitazone in patients with is not established. *Not approved as a treatment for NAFLD/ Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-23. Multisociety Practice Guideline: Vitamin E & Vitamin E (α-tocopherol) 800 IU/day: Improves liver histology in non-diabetic adults with biopsy-proven Should be considered as a first-line pharmacotherapy for this patient population Until further data supporting effectiveness become available, vitamin E is not recommended to treat in: Diabetic patients NAFLD without liver biopsy cirrhosis Cryptogenic cirrhosis Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-23. Evidence: C Alcohol Use in Individuals with NAFLD and While heavy drinking is certainly deleterious, there are evolving data to suggest non-heavy drinking may have hepatic and metabolic benefits -- Liangpunsakul S, Chalasani N. Am J Gastroenterol. 2012;107(7):976-978. Practice Guideline Recommendation Patients with NAFLD should not consume heavy amounts of alcohol No recommendation can be made with regards to non-heavy consumption of alcohol by individuals with NAFLD Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-2023. Cardiovascular Disease in NAFLD NAFLD is heavily enriched with cardiovascular risk factors Increased prevalence of surrogate markers of coronary artery disease Many studies have shown cardiovascular disease as the single most common cause of death in patients with NAFLD Targher G, Day CP, Bonora E. N Engl J Med. 2010;363:1341-1350. Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Hepatology. 2012 Jun;55(6):2005-2023.
General Guidelines for Managing Cardiovascular Risk in NAFLD Diet low in sodium and simple sugars Unsaturated fat Increased fruits and vegetables Foods enriched with omega-3 fatty acids Caloric restriction to achieve and maintain ideal body weight Moderate to vigorous exercise for 30 to 60 minutes per day most days of the week Smoking cessation Avoidance of alcohol Statins Can Be Used Safely In Patients with NAFLD and Patients with NAFLD are important targets for statins Risk of serious hepatotoxicity from statins is very rare Patients with underlying liver disease are not at higher risk for statin hepatotoxicity Case series have shown histological improvement in Fish oil is probably the first choice to treat hypertriglyceridemia Chalasani N. Hepatology. 2005; 41(4):690-695. Lewis JH, et al. Hepatology. 2007;46:1453-63 Take Home Messages Exclude competing etiologies and look for coexisting liver diseases Steatosis is hepatically benign but is progressive and can lead to cirrhosis Patients with NAFLD are at higher risk for incident type 2 diabetes and cardiovascular disease Liver biopsy can establish the diagnosis of Management of NAFLD includes managing underlying metabolic and cardiovascular risks as well as managing the liver disease Questions?