Approach to Identification and Treatment of Alcoholic & Non- Alcoholic Fatty Liver Disease

Transcription

1 Approach to Identification and Treatment of Alcoholic & Non- Alcoholic Fatty Liver Disease Kimberly A. Forde, MD Assistant Professor of Medicine Division of Gastroenterology and Hepatology University of Pennsylvania October 11, 2012

2 Non-Alcoholic Fatty Liver Disease (NAFLD) Definition Disease Spectrum Epidemiology Risk Factors Pathogenesis Natural History Diagnosis Treatment

3 NAFLD: Defined Clinicopathologic syndrome Histologic or radiographic presence of excess hepatic fat in the absence of excessive alcohol use (>20 g/d) or other causes of secondary hepatic fat accumulation Spectrum from bland steatosis to non-alcoholic steatohepatitis (NASH) Macrovesicular steatosis Lobular inflammation Ballooning degeneration of hepatocytes

4 NAFLD: Primary/ Secondary Causes Dyslipidemia Primary Acquired Insulin Resistance/ Diabetes Mellitus Secondary Metabolic Medications Surgery Glycogen Storage Diseases Amiodarone, Aspirin, Corticosteroids, Diltiazem, HAART, Methotrexate, Tamoxifen, Total Parenteral Nutrition, Valproic Acid Jejunoileal Bypass, Biliopancreatic Diversion Viral HIV, Hepatitis C (genotype 3a) Other Obesity Acute Fatty Liver of Pregnancy, Organic Solvents, Mushroom Toxin, Reye s Syndrome, Wilson s Disease

5 NAFLD: Disease Spectrum Bland Steatosis Steatohepatitis Steatohepatitis with Fibrosis NAFLD Cirrhosis 20%

6 NAFLD: Epidemiology Estimates differ based on populations studied and modalities used for diagnosis Adams et al. Ann Epidemiol 2007;17:

7 NAFLD: Epidemiology NAFLD differentially affects ethnic groups, sexes and age groups Browning et al. Hepatology 2004;40:

8 NAFLD: Epidemiology Prospective prevalence study Ages Brook Army Medical Center Steatosis determined by US Liver biopsies performed Prevalence (%) NAFLD and NASH Prevalence Williams et al. Gastroenterol 2011;140:

9 Obesity 1 NALFD: Risk Factors 16.4% BMI < 25 kg/m % BMI > 30kg/m 2 Relative Risk 4.6 (95% CI ) Insulin Resistance 2 27% fasting glucose levels < 110 mg/dl 43% with fasting glucose mg/dl 62% with fasting glucose > 126 mg/dl Ethnicity 3 Hispanics > Caucasians> Asians/ African Americans Asian-Americans may be at risk for advanced NAFLD 4 Trend towards severe steatosis Increase in severe inflammation 1. Bellentani et al. Ann Intern Med 2000;132: Jimba et al. Diabet Med 2005;22: Browning et al. Hepatology 2004;40: Tabibian et. al. J Gastroenterol Hepatol 2011;26:

10 NAFLD: Risk Factors Genetic associations PNPLA3 (Adiponutrin) Patatin-like phospholipase domain containing protein 3 rs738409[g] encodes for I148M Associated with increased hepatic fat levels (P = ) Associated with hepatic inflammation (P = ) Associations remained significant after adjustment for obesity, diabetes mellitus, alcohol and ancestry rs [t], encoding S453I, is associated with lower hepatic fat 2 PNPLA3 variants account for 72% of ethnically related variation Romeo et al. Nat Genet 2008;40:

11 NAFLD: Risk Factors Genetic associations Single Nucleotide Polymorphism (SNP) Odds of Histologic Steatosis PNPLA3 (rs738409) OR 3.26, p = 3.6 x NCAN (rs ) OR 1.65, p = 5.29 x 10-5 PPP1R3B (rs ) OR 0.93, p = 0.29 GCKR (rs780094) OR 1.45, p = 2.59 x 10-8 LγPLAL1 (rs ) OR 1.37, p = 4.12 x 10-5 Speliotes et al. PLoS Genet 2011;7:1-14

12 NAFLD: Risk Factors Speliotes et al. PLoS Genet 2011;7:1-14

13 NAFLD: Pathogenesis Obesity Insulin Resistanc e Hebbard et al. Nat. Rev. Gastroenterol. Hepatol. 2010;8:35-44.

14 NAFLD: Natural History Histologic course 37% progress 34% remain stable 29% regress No subjects with bland steatosis progressed Factors for histologic progression Age Diabetes mellitus Higher BMI (>30 kg/m 2 ) Adams et al. J Hepatol 2004;42: Angulo et al. Hepatology 1999;30:

15 NAFLD: Natural History Morbidity and Mortality SMR 1.34 ( ) Liver related death 3 rd leading cause of death malignancy and ischemic heart disease surpass liver related death NASH liver related mortality is higher than that of bland steatosis Adams et al. Gastro 2008;129; Rafiq et al. Clin Gastroenterol Hepatol 2009;7:

16 NAFLD: Natural History Cirrhosis is an established risk factor for HCC 5 year cumulative risk 5-30% 1 Modified by etiology, region and stage of liver disease Incidence of HCC in NAFLD unclear 30%-40% of those with HCC have no classic risk factors Obesity increases risk of HCC 1.90 fold in men BMI , 4.5 fold BMI fold in women BMI , 1.68 fold BMI Diabetes increases risk of HCC 1.73 fold increase in risk Metformin decreased risk of HCC by 51% Thiazolidinediones decreased risk of HCC by 44% 1. Fattovich et al. Gastroenterology 2004;127:S35-S50 2. Calle et al. N Engl J Med 2003;348: Lai et al. Am J Gastroenterol 2012;107:46-52

17 NAFLD: Diagnosis Histologic diagnosis is gold standard (NASH) Limitations Impractical for surveillance and follow up Subject to sampling variability Interpretation is somewhat dependent on quantification Consider if autoantibodies, ferritin/ TS sat elevated and HHC genotype positive, or etiology unclear Autoantibodies found in 21-23% 1,2 Stratification for biopsy based on risks factors for NASH/ fibrosis Vuppalanchi et al. Hepatol Int 2012;6: Adams et al. Am J Gastro 2004;99;

18 NAFLD: Diagnosis Non-invasive markers of fibrosis Non-Invasive Panel Components AUC 95% CI FIB4 Age, AST, Platelets NAFLD Fibrosis Score Age, BMI, IFG, AST, ALT, Platelets, Albumin AST to ALT Ratio AST, ALT AST to Platelet Ratio Index AST, Platelets AST to Platelet Ratio AST, Platelets Bard Score AST, ALT, BMI, DM Shah et al. Clin Gastroenterol Hepatol 2009;7:

19 NAFLD: Diagnosis Imaging Valuable for estimation of steatosis Not well validated for assessment of hepatic fibrosis Modality Degree Steatosis Detected Steatosis Quantification Sensitivity Specificity Ultrasound Moderate-Severe No 60-94% 88-95% CT Moderate-Severe No 50-90% 80-95% MRI Mild Yes 80% 71%

20 Goal of therapy NAFLD: Treatment Prevent the principal causes of death in patients with NASH Liver Prevent cirrhosis by reversing NASH and fibrosis or slowing disease progression Target those patients with an increased risk of fibrosis Active NASH Age > 50 years Metabolic Syndrome Cardiovascular Control of metabolic risk factors Satapathy et al. Trends Endocrinol Metab 2010;21:

21 NAFLD: Treatment Diet and lifestyle modification RCT of lifestyle intervention using a combination of diet, exercise, and behavioral modification on clinical parameters of NASH Promrat et al. Hepatology 2011;51:

22 NAFLD: Treatment Medication induced weight loss Orlistat An inhibitor of fat absorption Calorie restriction and vitamin E with or without Orlistat compared No increase in weight loss or improvement in liver enzymes, insulin resistance or histopathology Weight loss of 5% body weight resulted in improved insulin resistance and steatosis Weight loss of 9% resulted in changes in histopathology Harrison et al. Hepatology 2009;49:80-85

23 NAFLD: Treatment Surgical weight loss Indicated for BMI > 40 kg/m2 Indicated for BMI > 35 kg/m2 with comorbidities Restrictive Procedures Laparoscopic adjustable gastric band Decreased weight Improved insulin resistance, NASH activity, and fibrosis Sleeve gastrectomy Malabsorptive Procedures Roux-en-Y gastric bypass Unclear safety profile? Cirrhosis,? Portal hypertension

24 NAFLD: Treatment Vitamin E Fat soluble vitamin with anti-oxidant properties Reduces levels of TGF-βresulting in attenuation of hepatic fibrosis and necrosis in animal models Pivens Trial 247 subjects randomized to Vitamin E (800 IU/day) versus pioglitazone (30 mg/ day) versus placebo Vitamin E resulted in an improvement in AST, ALT, hepatic steatosis, and lobular inflammation Cirrhotics and diabetics were not included in the study Cardiovascular benefit versus risk unclear Sanyal et al. N Engl J Med 2010; 6:

25 NAFLD: Treatment Sanyal et al. N Engl J Med 2010; 6:

26 NAFLD: Treatment Biguanides Metformin Improves hepatic insulin resistance No difference in sustained reductions in ALT No significant change in histologic endpoints Thiazolidinediones (PPARγ agonists) Pioglitazone Improves insulin resistance, hepatic steatosis and inflammation Redistributes body fat stores from ectopic to adipose tissue No significant improvement in fibrosis Risks include weight gain, fracture, increase in cardiovascular events Rakoski et al. Aliment Pharmacol Ther 2010; 32:

27 NAFLD: Treatment Rakoski et al. Aliment Pharmacol Ther 2010; 32:

28 NAFLD: Treatment Silymarin Silybum marianum extract Anti-oxidant and hepatoprotective properties Multicenter study on-going Betaine Ursodeoxycholic acid Pentoxifylline ACE-inhibitors and receptor blockers

29 NAFLD: Conclusions NAFLD is a spectrum of disease including bland steatosis and NASH, the latter resulting in significant morbidity and mortality Insulin resistance and oxidative stress are the key pathogenic mechanisms Sustained gradual weight loss and exercise are effective therapies for NASH Vitamin E is effective in a select population

30 NAFLD: Board Question 1 A 56 year old female with a history of obesity, hypertension, and hyperlipidemia is seeing you in consultation for evaluation of elevated liver associated enzymes. She reports that her liver enzymes were noted to be elevated once a statin was started for management of her lipids. Her current liver enzymes are as follows: AST 30, ALT 63, and Alkaline Phosphatase 105. Her prior work up was negative for other serologic markers of chronic liver disease. Additionally, hepatic imaging is notable for steatosis.

31 NAFLD: Board Question 1 On physical examination, she has a BMI of 35, her BP is 125/70 and she has no signs of chronic liver disease. The most appropriate set of recommendations are the following: A. Weight loss and discontinuation of statin therapy B. Weight loss and continuation of statin therapy C. Continuation of statin therapy D. Discontinuation of statin therapy

32 NAFLD: Board Question 1 On physical examination, she has a BMI of 35, her BP is 125/70 and she has no signs of chronic liver disease. The most appropriate set of recommendations are the following: A. Weight loss and discontinuation of statin therapy B. Weight loss and continuation of statin therapy C. Continuation of statin therapy D. Discontinuation of statin therapy

33 NAFLD: Board Question 2 The patient from question 1 returns to your office in 6 months time. She has been unsuccessful with weight loss and her liver associated enzymes remain elevated, albeit to the same degree of prior measurements. What is the most appropriate recommendation for her? A. Continued attention to weight loss B. Consultation for gastric bypass C. Discontinuation of statin therapy D. Liver Biopsy

34 NAFLD: Board Question 2 The patient from question 1 returns to your office in 6 months time. She has been unsuccessful with weight loss and her liver associated enzymes remain elevated, albeit to the same degree of prior measurements. What is the most appropriate recommendation for her? A. Continued attention to weight loss B. Consultation for gastric bypass C. Discontinuation of statin therapy D. Liver Biopsy

35 NAFLD: Board Question 3 In the office, you are asked to see a 50 year old obese gentleman for concern of alcoholic liver disease. On history, he admits to alcohol use, consuming 4 drinks daily. On review of his past medical history, he has no history of hypertension, diabetes mellitus or hyperlipidemia. On physical examination, he has a BMI of 32 but no other findings. On review of laboratory data, his AST is 82, ALT 41, Alkaline Phosphatase 200, and GGT 515. Additionally, he had a liver biopsy prior to consultation which revealed evidence of steatohepatitis.

36 NAFLD: Board Question 3 What information is most helpful in suggesting that the etiology of his liver disease is that of alcohol? A. History and Laboratory Data B. History and Physical examination C. Laboratory data D. Liver Biopsy

37 NAFLD: Board Question 3 What information is most helpful in suggesting that the etiology of his liver disease is that of alcohol? A. History and Laboratory Data B. History and Physical examination C. Laboratory data D. Liver Biopsy