Disclosures Dr. Feld Research : Abbott, Abbvie, Gilead, Janssen, Merck Fatty Liver Disease Consulting : Abbvie, Gilead, Merck Speaking : None Dr Shah Jordan Feld MD MPH Relationships with commercial interests: None Toronto Western Hospital Liver Centre Speakers Bureau/Honoraria : None McLaughlin-Rotman Centre for Global Health Consulting Fees: Abbvie, Gilead, Merck, Intercept, Lupin Other: None Learning Objectives Obesity Epidemic 1. Understand the burden of disease caused by fatty liver disease 2. Recognize the difference between simple steatosis and steatohepatitis 3. Develop an approach to management including pharmacological interventions Epidemiology We ’ re not much better… General population studies Canadian Community Health Survey; Stats Canada Ultrasound ~22% Lean 16% Obese 76% Liver tests NHANES III 3-23% 31 34 25 19 28 26 11% liver tests >1.5 x ULN 23 29 22 25 NAFLD 46% in pop ’ n study in US! NAFLD is the commonest cause of elevated ALT in N. America Farrell, Hepatology 2006, Williams Gastroenterology 2011 1
Summary of NAFLD Prevalence What about high risk groups? AASLD estimates: NAFLD DM 62% NAFLD by US 87% confirmed by bx Global prevalence 6.3-33% Hyperlipidemia clinic Median 20% NAFLD 50% Bariatric surgery NASH Up to 90% NAFLD 3-5% 5% unsuspected cirrhosis! NASH Cirrhosis Unknown Chalasani et al Gastro 2012 Clinical Features Diagnosis of Exclusion Labs • Mainly asymptomatic • Hepatomegaly (75%) ALT>AST (usually AST:ALT<1, never>2) (48-100%) • Splenomegaly May have GGT elevation, ALP elevation 1/3 • Uncommonly: Ferritin often high – (50-62%) – more suggestive of (if cirrhosis) NASH RUQ discomfort • • Uncommonly: Fatigue • Palmar erythema • Exclude: Viral hepatitis (HBV/HCV) Malaise • Spider naevi • Autoimmune hepatitis (IgG, ANA, SMA) Ascites • Wilson ’ s** - (ceruloplasmin, Ur Cu) Drug Spectrum of NAFLD Associated Conditions Obesity Alcoholic Liver Disease Metabolic HTN Syndrome DM Hyperlipidemia Steatosis Steatohepatitis + Steatosis Cirrhosis (NASH) Weight gain or LOSS Inflammation Common with anorexia! TPN NonAlcoholic Fatty Liver Disease Macrovesicular Hepatic Steatosis 2
Are there alternatives to Diagnosis biopsy? US, CT, MRI can detect steatosis NAFLD Fibrosis Score Age US is cheaper but less sensitive BMI Liver biopsy is gold standard Hyperglycemia If diagnostic uncertainty Platelet count R/O advanced fibrosis Albumin Fibroscan / Fibrotest AST/ALT ratio Must exclude ETOH (>20 g/day) http://nafldscore.com Without biopsy – CANNOT distinguish Steatosis from NASH Angulo Hepatology 2007 Performance Histology – More than Fat Fat=Steatosis Inflammation=Hepatitis Meta-analysis of 13 studies, 3,064 patients Mallory Hyaline Exclude advanced fibrosis -1.455 Sens 90% Spec 60% Neutrophils Fibrosis Cirrhosis 0.676 Detect advanced fibrosis Sens 67% Spec 97% Gambino Annals of Med 2011 Angulo Hepatology 2007 The Hallmark of NASH NASH vs Steatosis… Does it matter? Ballooning Hepatocytes – necessary to dx NASH 3
Natural History – it ’ s not all Natural History liver! Ten year follow up of 132 patients with biopsy proven NAFLD by type. NAFLD vs Gen pop ’ n Matteoni et al. Gastroenterology 1999 Causes of death Type 1 Fat alone P<0.001 Liver - 3rd vs 13th Type 2 Fat + Inflammation Over 7 years Type 3 Fat + ballooning degeneration 5% cirrhosis Type 4 Fat + fibrosis 2% liver-related and/or Mallory bodies mortality 1 2 3 4 1 required LT 2 HCC Patients with NASH have a significantly higher liver related mortality than patients with simple steatosis. Adams, Gastroenterology 2005 NAFLD = hepatic NAFLD & Mortality manifestation of the metabolic syndrome Individuals with NAFLD increased mortality vs. 1. general population Most common cause of death with NAFL or Obesity 2. NASH is CARDIAC DM & obesity risk factors for progressive fibrosis Patients with NASH, but not NAFL, have 3. increased liver-related mortality DM is a risk factor for death NAFLD 74% NAFLD Syndrome X 22% NASH Diabetes HTN Chalasani et al Gastro 2012 Harrison Gastro 2011 What does NAFLD really mean? So what can we You will get do? diabetes!! Start with lifestyle 4
Principles of Lifestyle Can we make this happen? Management Weight loss Diet and exercise Control of metabolic risk factors DM BP Cholesterol Limit alcohol How much weight do they Weight Loss Approaches need to lose? Any diet that achieves weight loss is effective Options: Low carbohydrate (less injera!) Low fat (replace saturated with unsaturated), <30% total Low caloric Mediterranean Others… Add exercise Aim 20 minutes of aerobic exercise 3 x per week Simple things like walking… 5-10% weight loss adequate to improve ALT and histology Attending internal medicine rounds on the 8 th floor! Harrison Hepatology 2009 Promrat Hepatology 2010 How strict do we have to Some alcohol may actually be? be helpful… • Multiple studies showing that 1-2 drinks per day may reduce progression of NASH • If significant fibrosis complete abstinence 5
Lipid Lowering Agents What about drugs? • Statins are SAFE in NAFLD • Association with ALT/AST elevation but not fibrosis • Hyperlipidemia is a bigger issue • May even improve NASH Adams & Angulo, Postgrad Med J 2006 Chalasani Gastro 2012 Therapies Study Design – PIVENS trial 247 non-DM patients with biopsy proven NASH Randomized – placebo Vitamin E – 800 IU/day Pioglitazone 30 mg od 2 years of treatment – f/u liver biopsy Primary endpoint: Improved histology – decreased ballooning score, with no worsening of fibrosis, NASH score down Sanyal et al NEJM 2010 ALT improved Pioglitazone worked… Sanyal et al NEJM 2010 Sanyal et al NEJM 2010 6
Histology Weight Gain???? * * * * * * * * * * p<0.05 vs plac Sanyal et al NEJM 2010 Sanyal et al NEJM 2010 Is vitamin E safe? But before we put Vit E in the drinking water… Other therapies? My Practice Exclude other causes If BMI>35 + end-organ damage Non-invasive assessment of fibrosis (labs, or BMI>40 consider surgery fibrotest/NAFLD Fibrosis score, Fibroscan) Seems to benefit NASH If suggestive of fibrosis or other etiology – consider biopsy If not – lifestyle changes x 6-12 mo Reduced inflammation & No improvement biopsy! fibrosis at 1 & 5 yrs post surgery Benefits beyond NASH Improved mortality! Mathurin Gastro 2009 7
Action based on biopsy Summary Biopsy with steatosis only – no action NAFLD is increasing everywhere Monitor for metabolic complications Feature of the metabolic syndrome Reassess in 3-5 years Spectrum from steatosis to NASH Steatosis very good prognosis – worry about the Biopsy with NASH heart, not the liver No fibrosis – lifestyle changes follow NASH – worry about the liver too! Fibrosis – if lean, pioglitazone Lifestyle first – 5-10% weight loss with diet/exercise - if obese, vit E – 400 or 800 IU/d Modest alcohol probably okay, coffee helpful Treatment options: Vitamin E, pioglitazone, surgery 8
Recommend
More recommend
