Non-Alcoholic Fatty Liver Disease (NAFLD)

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Non-Alcoholic Fatty Liver Disease (NAFLD)

Transcript of Non-Alcoholic Fatty Liver Disease (NAFLD)


2. DEFINITION Nonalcoholic Fatty Liver Disease (NAFLD) (a) there is evidence of hepatic steatosis, either by imaging or by histology and (b) (b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders Histologically further categorized into Nonalcoholic Fatty Liver (NAFL) Nonalcoholic Steatohepatitis (NASH) 3. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) Most common of All liver Disorders Most frequent cause of chronic liver disease most common cause of End stage Liver Disorder Needing liver transplantation. Present in up to 75% of individuals with obesity and type 2 Diabetes Present in 3% of children and > 50%obese children. 4. Nonalcoholic Fatty Liver (NAFL) Evidence of Hepatic steatosis either by imaging or Histology (> 5% of hepatocytes histologically) without any other Cause for secondary Fat Accumulation with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes or no evidence of fibrosis. The risk of progression to cirrhosis and liver failure is minimal. Nonalcoholic steatohepatitis (NASH) Presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. This can progress to cirrhosis, liver failure and rarely liver cancer 5. METABOLIC SYNDROME ; ALARMING FIGURES 6. NFLD : A BURDEN WORLDWIDE 7. ENVIRONMENTAL FACTORS FOR A FATTY WORLD 8. ETHNIC FACTORS AND NAFLD 9. PREVALENCE OF NAFLD IN HIGH RISK GROUPS Population studied prevalence of NAFLD excessive BMI and visceral obesity are recognized risk factors Severe obesity undergoing bariatric surgery 90% NAFLD 5% of patients may have unsuspected cirrhosis An ultrasonographic study of patients with T2DM 69% prevalence of NAFLD Another study 127 of 204 diabetic patients displayed fatty infiltration on ultrasound, 62% fatty infiltration and 87% those who consented to biopsy had histologic confirmation of NAFLD Individuals with dyslipidemia attending lipid clinics prevalence of NAFLD estimated to be 50%. 10. PATHOGENESIS AND RISK FACTORS Insulin resistance is related to obesity and is central to the pathogenesis of NAFLD. In addition, oxidative stress and cytokines are important contributing factors, together resulting in steatosis and progressive liver damage in genetically susceptible individuals. Key histologic components of NASH are steatosis, hepatocellular ballooning, and lobular inflammation 11. MULTI-HIT HYPOTHESIS 12. RISK FACTORS AND ASSOCIATED CONDITIONS 13. NASH SCORING SYSTEM IN MORBID OBESITY 14. PROGNOSIS AND COMPLICATIONS Disease progression from NAFLD to NASH to cirrhosis/liver failure and HCC. Concurrence of NAFLD with hepatitis C or human immunodeficiency virus (HIV) worsens their prognoses and decreases their responses to therapy. Liver biopsy may indicate the severity of disease, but only fibrosis, and not inflammation or necrosis, has been confirmed to predict the disease prognosis. End-stage NASH is an often under-recognized cause of cryptogenic cirrhosis NASH-related (cryptogenic) cirrhosis increases the risk of hepatocellular carcinoma (HCC). 15. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) 16. Disease progression from NAFLD to NASH to cirrhosis/liver failure and HCC. 17. Independent predictors for progression of fibrosis: Age > 4550 BMI > 2830 kg/m2 Degree of insulin resistance Diabetes Hypertension The degree of fibrosis on liver biopsy (stage) is predictive of the prognosis 18. FIBROSIS STAGE : INDEPENDENT FACTOR FOR LIVER MORTALITY 19. NASH SURVIVAL RATES IN COMPARISON WITH SIMPLE STEATOSIS AND ALCOHOLIC STEATOHEPATITIS (ASH) 20. Causes of mortality in cirrhotic NASH patients: Liver failure Sepsis Variceal hemorrhage HCC Cardiovascular disease 21. DIAGNOSIS PATIENT HISTORY AND CLINICAL EVALUATION Asymptomatic vague symptoms of fatigue, malaise, and abdominal discomfort. Detailed patient history of alcohol Appropriate specialized questionnaires or scoring systems for the evaluationof alcohol consumption Eg. CAGE questionnaire 22. Abdominal obesity Enlarged liver RUQ tenderness on palpation Central obesity correlates with severity of inflammation on biopsy, and dorsocervical lipohypertrophy (buffalo hump) correlates with hepatocyte injury. In case of progression/advanced liver disease: spider angiomas, ascites, hepatomegaly, splenomegaly, palmar erythema, jaundice, hepatic encephalopathy. Physical exam 23. The presence of any of the following, especially with a history of abnormal AST/ALT, should lead to a work-up for NAFLD/NASH: Presence of obesity, especially morbid obesity (BMI > 35) Diagnosis of type 2 diabetes mellitus Diagnosis of metabolic syndrome History of obstructive sleep apnea Presence of insulin resistance Chronic elevation of AST/ALT, otherwise unexplained 24. CALCULATION OF INSULIN RESISTANCE 25. ROUTINE LABORATORY FINDINGS AND IMAGING TESTS Elevated ALT and AST: In 10% of NASH patients, ALT and AST may be normal, especially with simple steatosis. AST/ALT ratio < 1this ratio is usually > 2 in alcoholic hepatitis. An abnormal ferritin level in the presence of normal transferrin saturation should always suggest a need to rule out NASH. Tests to exclude: secondary causes of hepatic steatosis 26. Imaging - confirming fat accumulation in the liver: The magnetic resonance imaging (MRI) test has a quantitative value, but cannot distinguish between NASH and ASH. Ultrasound is the usual screening test for fatty liver. 27. WHEN TO OBTAIN A LIVER BIOPSY IN PATIENTS WITH NAFLD? Liver biopsy should be considered in patients with NAFLD who are at increased risk to have steatohepatitis and advanced fibrosis. (Strength 1, Evidence - B) The presence of metabolic syndrome and the NAFLD Fibrosis Score may be used for identifying patients who are at risk for steatohepatitis and advanced fibrosis. (Strength 1, Evidence - B) Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies for hepatic steatosis and co-existing chronic liver diseases cannot be excludedwithout a liver biopsy. (Strength 1, Evidence - B) 28. NASH CLINICAL RESEARCH NETWORK HISTOLOGICAL SCORING SYSTEM 29. DIAGNOSTIC TESTS FOR FATTY LIVER 30. A wide variety of attempts have been made to develop scoring systems or imaging techniques that will allow noninvasive diagnosis of NASH and avoid the need for a liver biopsy. Specialized imaging modalities, including FibroScan, using a novel controlled attenuation parameter, and positron emission tomography (PET) scanning suffer from the same limitations of limited availability, high cost, and lack of sufficient controlled data. NON-INVASIVE ASSESSMENT OF STEATOHEPATITIS AND ADVANCED FIBROSIS IN NAFLD 31. NON-INVASIVE ASSESSMENT OF STEATOHEPATITIS AND ADVANCED FIBROSIS IN NAFLD The NAFLD Fibrosis Score Enhanced Liver Fibrosis (ELF) panel Transient Elastography Circulating levels of cytokeratin-18 (CK18) 32. NAFLD FIBROSIS SCORE Age BMI Hyperglycemia Platelet count Albumin AST ALT < -1.455: 90% sensitivity and 60% specificity to exclude advanced fibrosis > 0.675: 67% sensitivity and 97% specificity to identify the presence of advanced fibrosis. 33. DIAGNOSTIC STRATEGY FOR NASH 34. MANAGEMENT Therapeutic rationale Targets for therapy : insulin resistance and oxidative stress Goals of treatment: reduce the histologic features and improve insulin resistance and liver enzyme levels. 35. LIFESTYLE INTERVENTION Weight loss generally reduces hepatic steatosis, achieved either by hypocaloric diet alone or in conjunction with increased physical activity. Loss of at least 35% of body weight appears necessary to improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necroinflammation. Exercise alone in adults with NAFLD may reduce hepatic steatosis but its ability to improve other aspects of liver histology remains unknown. 36. AVOID FRUCTOSE Fructose (+++++ in corn syrup) Soda, canned industrial dishes Experimental Data Mice fed with fructose devaloped more severe inflamatory injuries compare to High fat diet Mice -kholi, Hepatology 2010- Human Data In patients with NASH fructose consumption is associated with liver fibrosis -Abdel malek Hepatology 2010- 37. INSULIN SENSITIZING AGENTS METFORMIN A recent meta analysis concluded that 612 months of metformin plus lifestyle intervention did not improve aminotransferases or liver histology, compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes. June 2012 AGA 1597 Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH. (Strength 1, Evidence - A) 38. INSULIN SENSITIZING AGENTS THIAZOLIDINEDIONES Rosiglitazone**: improved enzymes and steatosis, but not inflammation Pioglitazone:***+weight gain, but significantly improved aminotransferases, steatosis, ballooning, and inflammation *Uygun, et al Aliment Pharm Ther 2004 *Nair, et al Aliment Pharm Ther 2004 **Ratziu, et al Gastroenterology 2008 ***Sanyal, et al NE J Med 2010 39. PIVENS STUDY Pioglitazone , Vitamin E, placebo 96 weeks Adults with NASH without DM, cirrhosis, Hep C, heart failure limited alcohol intake over previous 5 years Randomized trial Pio group: 80 Vit E group: 84 Placebo: 83 Sanyal et al, New England J of Medicine 2010 40. PRIMARY OUTCOME Vitamin E vs placebo 43% improvement vs 19%: significant (Steatosis, lobular inflammation, hepatocellular ballooning and fibrosis) Pio vs placebo 34% improvement vs 19%: not significant Sanyal et al, New England J of Medicine 2010 41. SECONDARY OUTCOME Vitamin E vs placebo Als