6/28/2017. Update in NAFLD. Key Points. NAFLD: Epidemiology. US Population: million. NALFD Prevalence 25% 80 million

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1 Update in NAFLD PHILLIP K HENDERSON, DO ASSISTANT PROFESSOR OF MEDICINE UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE INSTRUCTOR OF SURGERY, DIVISION OF TRANSPLANT SURGERY UNIVERSITY OF ALABAMA AT BIRMINGHAM Key Points NAFLD is an emerging worldwide health crisis Estimating fibrosis is crucial Prognosis is directly related to severity of fibrosis NAFLD without fibrosis CAN progress Follow up important NAFLD: Epidemiology US Population: million NALFD Prevalence 25% 80 million 10% Advanced liver disease 4 8 million 1

2 Perspective: HCV Prevalence 3,000,000 50% 1,750, million TOTAL HCV in US 9% 325,000 Infected Diagnosed a Cured Advanced liver disease NASH in US 4 8 million Cirrhosis = abnormal liver tests + APRI >2 NASH Cirrhosis Prevalence is Increasing in the US NHANES US data, mean age years Estimated 420,000 adults with NAFLD associated cirrhosis in 2010 Trends in the prevalence of NAFLD with advanced fibrosis using noninvasive tests Estimated 4.1 million adults with NAFLD associated advanced fibrosis in 2010 Kabbany MN, et al. Am J Gastroenterol 2017;112; NAFLD: Overview 1. Patient assessment Exclude other common liver diseases Cardiovascular risk stratification 2. Fibrosis Assessment Noninvasive Invasive 3. Therapy* Current available therapies Selected medications in development *None FDA Approved 2

3 NAFLD: Individualized Approach Therapy Patient Fibrosis NAFLD: Individualized Approach Patient Therapy Fibrosis Case Presentation 57 year old white man, BMI 34 History of hypertension, type 2 diabetes and dyslipidemia Enalapril, atorvastatin, metformin at stable doses for the last 4.5 years ROS vague intermittent RUQ discomfort, no exacerbating or alleviating factors, present for 1 2 years Preliminary evaluation ALT 63 IU, AST 48 IU, Alkaline Phosphatase 89 IU, Total bilirubin 0.5 mg/dl, albumin 4.5g/dL RUQ US 6 months ago: mild hepatomegaly and echogenic liver parenchyma compatible with fatty liver 3

4 Nonalcoholic Fatty Liver Disease (NAFLD) Spectrum of liver disease Fatty liver NASH cirrhosis hepatocellular carcinoma The most common cause of elevated liver enzymes in Western countries Globally: 1 billion affected US: million with NAFLD, of which 25% have NASH 2 nd leading indication for liver transplantation Ahmed A, et al. Clin Gastroenterol Hepatol 2015;13: What is abnormal? Alanine aminotransferase (AST) Men IU/L Women IU/L Total bilirubin mg/dl Alkaline phosphatase u/l DO NOT GO BY NORMAL LAB VALUES FOR AST Kwo, et al. ACG Practice Guidelines: Abnormal Liver Chemistries What to Order? Two Schools of Thought Directed Testing (i.e. minimalist approach) HepBSAg Hep C Ab Alcohol Screen Liver ultrasound Non directed testing ( Shotgun approach ) All testing from directed plus Hemochromatosis screening Wilson s disease screening Alpha 1 antitrypsin screening Primary biliary cholangitis screening Which is best? 4

5 Decision analytical microsimulation Evaluation of Asymptomatic Elevated Liver Tests Diagnostic yield 53% Less false positives More biopsies Cost depends on disease prevalence Diagnostic yield 54% Lowest cost Less visits More false positives Directed testing strategy more cost effective when prevalence of NAFLD exceeds 51% Prevalence of NAFLD in the US is estimated at 30% Tapper EB, et al. J Hepatol 2017;66: NAFLD: Recognize Confounding Variables Our Patient ANA: Positive, 1:160 ASMA: Negative Serum Ferritin: 780 Transferrin Saturation: 21% ANA positive in up to 30% 1 Titers >1:320 relatively rare Other autoimmune markers negative No significant elevation of ALT/AST (>5x ULN) Normal gamma globulins and IgG Ferritin is elevated in many patients with fatty liver 2 DIOS dysmetabolic iron overload syndrome ~30% 3 Associated with insulin resistance Normal transferrin saturation Role of phlebotomy controversial 1. Cotler SJ, et al. J Clin Gastroenterol 2004;38: Fargion S, et al. Am J Gastroenterol 2001;96: Dongiovanni P, et al. J Hepatol 2011;55: Does This Patient have NAFLD? Sure! The ultrasound said so. Ultrasound may lead to incorrect diagnosis in 10 to 30% of cases False Negative: Need >30% fat for a positive ultrasound False Positive: An echogenic liver may indicate fibrosis, not fat Subjective: Meta analysis specificity 26% to 100% Interpret the ultrasound findings in the context of the clinical presentation Vuppalanchi R, Chalasani N. Hepatology 2009;49: Hernaez R, et al. Hepatology 2011;54:

6 Our Patient: Waist: 44 inches Hypertensive Triglycerides 195mg/dL HDL 42 Diabetic NAFLD is the Hepatic Manifestation of the Metabolic Syndrome Metabolic syndrome: 3 or more of the following Abdominal obesity [ >40 inches males, >35 inches females) Hypertension (>130/>85 mmhg) Elevated triglycerides >150 mg/dl Low HDL (<40 males, <50 females) Fasting BS >100 mg/dl or a diagnosis of diabetes, or evidence of insulin resistance Our Patient 1. Metabolic syndrome 2. Fatty liver by ultrasound 3. Mild elevations in liver enzymes MUST BE FATTY LIVER! Should you worry about something else? When to Question the NAFLD Diagnosis Profoundly elevated liver tests >5x upper limits of normal Negative preliminary evaluation Echogenic liver on ultrasound DOES NOT meet metabolic syndrome criteria NO diabetes or insulin resistance Low threshold for liver biopsy to confirm diagnosis Feldman A, et al. Am J Gastroenterol 2017;112: Kim D, Kim R. Clin Gastroenterol Hepatol 2017;15:

7 Common Causes of Secondary Hepatic Steatosis Alcohol Hepatitis C infection, genotype 3 Wilson s disease Lipodystrophy Starvation Medications Amiodarone, methotrexate, tamoxifen, corticosteroids, HAART Our Patient Mild elevations in liver enzymes Negative evaluation for other causes of liver disease Metabolic syndrome Abnormal hepatic ultrasound compatible with fatty liver NAFLD diagnosis is the most likely etiology What do You do Now??? THE DIAGNOSIS OF NAFLD REQUIRES CAREFUL EVALUATION FOR CARDIAC DISEASE RISKS & AGGRESSIVE MANAGEMENT OF RISK FACTORS 7

8 NAFLD is a Systemic Disease 3 major causes of mortality in NAFLD Cardiovascular disease (13% 30%) All cause malignancy (6% 28% Liver related death (2.8% 19%) NAFL patients have increased overall mortality Cardiovascular disease is most common cause NASH + fibrosis patients Cardiovascular disease is main cause of death Increased liver related mortality Pagadala MR, et al. Clin Liver Dis 2012;16: Chalasani N, et al. Hepatology 2012;55: Most Common Causes of Death in NAFLD Patients Ekstedt M, et al. Hepatology 2015;61: Key Point WHEN NAFLD/NASH DIAGNOSED MUST CONSIDER CARDIOVASCULAR HEALTH!!! something 8

9 NAFLD: Individualized Approach Therapy Patient Fibrosis Key Point Stage of fibrosis and not the presence of NASH is the main determinant of prognosis in NAFLD Fibrosis stage and clinical risk dictate therapy!!! Angulo P, et al. Gastroenterology 2015;149: Ekstedt M, et al. Hepatology 2015;61: NAFLD Natural History million Americans Steatosis ~28% over 11 years NASH ~23% over 8 10 years Cirrhosis ~30% over 8 10 years Decompensation ~7% over 6 7 years HCC Angulo, P. N Engl J Med 2002;346: Aijaz A, et al. Clin Gastroenterol Hepatol 2015;13: Matteoni CA, et al. Gastroenterology 199;116: Pagadala MR, et al. Clin Liver Dis 2012;16:

10 Assessing Prognosis in Fatty Liver Disease Fatty liver NASH Cirrhosis HCC Mild NASH, Mild Fibrosis Severe NASH, Mild Fibrosis Control Group Control Group Mild Fibrosis (stage <2) Advanced Fibrosis (stage 3 4) Ekstedt M, et al. Hepatology 2015;61: Fibrosis Determines Prognosis in Fatty Liver NASH, no fibrosis NASH, with fibrosis Angulo P, et al. Gastroenterology 2015;149: NASH: Diagnostic Difficulties Histologic diagnosis Lack of non invasive markers Subjective diagnosis Requires the presence of: Fat Hepatocyte ballooning Inflammation Often over diagnosed by community pathologists Missed by suboptimal biopsy samples 29% samples <10mm 65% samples >25mm Vuppalanchi R, et al. Clin Gastroenterol Hepatol 2009;7:

11 Advanced Fibrosis Determines Prognosis Non invasive markers available! Histologic diagnosis less subjective than NASH Fibrosis starts in zone 3 Pericellular in pattern Evolves into cirrhosis Chicken wire fibrosis High Risk Clinical Profile for Fibrosis 3 or more of the following Age >50 Obesity (BMI >30) AST/ALT ratio >1 Diabetes or HOMA score >2 Multiple metabolic syndrome criteria Consider liver biopsy to assess degree of fibrosis McCullough AJ. Clin Liv Dis 2004;8: Banini B. Am J Gastroenterol 2017;112: Non Invasive Markers of Fibrosis NAFLD fibrosis score (NFS) Age, BMI, diabetes, AST, ALT, platelets, albumin FIB 4 score calculators/fib 4 Age, AST, Platelets, ALT APRI (AST, platelets) Elastography Routine labs Platelets <150,000 AST:ALT ratio >0.8 Elevated direct bilirubin High level of insulin resistance Angulo P, et al. Hepatology 2007;45: McPherson S, et al. Gut 2010:59; Mazhar SM, et al. Clin Gastroenterol Hepatol 2009; Park CC, et al. Gastroenterology 2017;152: Sumida Y, eta l. BMC Gastroenterol 2012;12:2 11

12 Imaging Assessment of Fibrosis Elastography Reading >8 kpa suggests significant fibrosis Samples a small portion of the liver Available in Alabama MRI elastography Samples the entire liver Not readily available Pooled Results for 9 studies of elastography for detection of cirrhosis in NAFLD: Sensitivity 0.90 (CI ) Specificity 0.87 (CI ) Park CC, et al. Gastroenterology 2017;152: Festi D, et al. Aliment Phamacol Ther 2013;37: Interpreting Non Invasive Markers Highly accurate if no advanced fibrosis predicted Must have >2 non invasive tests in agreement Correlate with clinical picture Detection of advanced fibrosis is sensitive but not specific Test results of advanced fibrosis may be false positive Should confirm with liver biopsy unless clinical picture consistent with advanced fibrosis Ahmed A, et al. Clin Gastroenterol Hepatol 2015;13: Clinical Approach Suspected NAFLD based on imaging & elevated LAE Common liver diseases excluded? Yes Absent Liver biopsy Minimal fibrosis Lifestyle modifications, clinical monitoring Assess for metabolic syndrome Present Non invasive assessment of fibrosis Liver biopsy ANY Suggests significant fibrosis >2Markers Concordant APRI/FIB 4 NAFLD Fibrosis Score Fibroscan 12

13 Our Patient Met the high risk clinical profile Obese Over age 50 Diabetic NAFLD fibrosis score was indeterminate APRI score 1.2 (>1 suggests significant fibrosis) Elastography 8.9 kpa (>8 suggests significant fibrosis) A liver biopsy was performed Liver Biopsy NAFLD: Individualized Approach Patient Therapy Fibrosis 13

14 Staging of Fatty Liver Defines therapy Risk Category Clinical Characteristics Non invasive Markers Low Risk Overweight No Metabolic syndrome/t2dm Age<40 APRI<0.5 NFS< Fibroscan < 5kpa Intermediate risk High Risk Multiple metabolic syndrome features Age>40 Multiple metabolic syndrome features AST>ALT Platelets<150,000 APRI NFS Fibroscan 6 11kpa APRI >1.5 NFS >0.675 Fibroscan >11kpa Low Risk Patient Therapy Liver specific therapy NOT warranted Diet/Exercise encouraged Ensure that cardiovascular disease is optimized!! Follow every 1 2 years High Risk Patient Therapy Liver specific therapy NOT fully studied, consider clinical trials Diet/Exercise encouraged Screening for HCC/Varices Ensure that cardiovascular disease is optimized!! Follow every 3 6 months 14

15 Intermediate Risk Patient Therapy Liver specific therapy SHOULD be considered Diet/Exercise encouraged Ensure that cardiovascular disease is optimized!! Follow every 6 months 1 year Management of Liver Disease in NAFLD NO FDA APPROVED MEDICATIONS TO TREAT NAFLD 15

16 We are Interfering With The Survival of the Human Species! Ability to store excess energy as fat was a desirable trait 16

17 Weight Loss, Exercise and Diet Works, but very few follow it long term Recommend weight loss of 7% 10% of body weight Low glycemic food with increased mono and polyunsaturated fat Avoid high fructose containing foods Bariatric surgery Significant improvement in liver histology No studies done specifically to assess effect on NAFLD Resolution of steatosis ~90% Resolution of NASH ~80% Improvement in fibrosis ~70% Cirrhosis not a contraindication if compensated & no clinical signs of portal hypertension Vuppalanchi R, et al. Hepatology 2009;49: Huang MA, et al. Am J Gastroenterol 2005;100: Mummadi R, et al. Clin Gastroenterol Hepatol 2008;6: Coffee Intake Coffee consumption associated with decreased fibrosis in HCV infection Similar findings in NAFLD Caffeine (mg/d) 122 Fibrosis Stage Stage 1 Stage 2 Stage 3 Molloy JW, et al. Hepatology 2012;55: Animal Study Coffee Effects Reduction in: Fat accumulation Oxidative stress (polyphenols) Inflammation Vitaglione P, et al. Hepatology 2010;52:

18 AST ALT Pioglitazone for NASH Impaired glucose tolerance or type II DM (n=55) Biopsy confirmed NASH All patients placed on weight reduction program Pioglitazone 45mg/d x 6 m vs. placebo Liver Fat Content Plasma Adiponectin Belfort R et al. NEJM 2006;355: Pioglitazone for the Treatment of NAFLD 101 Biopsy proven NASH + prediabetes or T2DM Pioglitazone 45mg/d or placebo Randomized double blind, placebo controlled trial Liver biopsy at baseline and at end of study 18 month study 18 months open label phase Both groups counselled on a hypocaloric diet Cusi K, et al. Ann Intern Med 2016;165:

19 Effect of 18 months of Pioglitazone on Liver Histology 100% 90% 80% 70% 60% 50% 40% 58% 51% 30% 20% 10% 0% 17% 1ry Outcome 19% 2ry Outcome Placebo Pioglitazone Primary outcome: >2 point reduction in NASH score (in 2 categories) Secondary outcome: Resolution of NASH Cusi K, et al. Ann Intern Med 2016;165: Metabolic Changes Cusi K, et al. Ann Intern Med 2016;165: Liver Enzyme Changes P = Cusi K, et al. Ann Intern Med 2016;165:

20 Adiponectin Levels p <0.001 compared to end of placebo p <0.001 Cusi K, et al. Ann Intern Med 2016;165: Tolerability and Side Effects First report with long term (36 months) experience No SAE related to pioglitazone No pioglitazone discontinuation due to AE Weight gain was modest Pioglitazone group: 2.5kg over 18 months Placebo group: 3.1 kg over 36 months No cases of bladder cancer No changes in bone density Cusi K, et al. Ann Intern Med 2016;165: Meta analysis Thiazolidinediones Improvement in Histologic Endpoints All Patients with NASH NASH + Advanced Fibrosis Rosiglitazone Rosiglitazone Pioglitazone Pioglitazone Musso G et al. JAMA Intern Med 2017, Feb 27 [e pub] 20

21 Implications for Practice Pioglitazone better tolerated than expected after up to 3 years of therapy 1 Weight gain is less metabolically active Non abdominal fat 2,3 Recent data suggest no bladder cancer risk 4 Effect on bone density long term needs monitoring Added bonus: Reduced CV events in diabetics 5 Caveat Avoid in diastolic dysfunction risk of CHF 5 1. Cusi K, et al. Ann Intern Med 2016;165: Hirose H, et al. Metabolism 2000;51: Shadid S, et al. Diabetes Care 2003;26: Levin D, et al. Diabetologia 2015;58: Yau H, et al. Curr Diab Rep 2013;13: Metformin Improved liver enzyme levels No demonstrable sustained improvement in liver histology 1,2,3 Associated weight loss may be beneficial Safe even in patients with cirrhosis 4 May reduce risk of HCC in diabetics 5 1. Nair S, et al. Aliment Pharmacol Ther 2004;20: Musso G, et al. Hepatology 2010;52: Alkhouri N, et al. Hepatology 2012;55: Zhang X, et al. Hepatology 2014;60: Zhang H, et al. Scand J Gastroenterol 2013;48:

22 Obeticholic Acid Farsenoid X nuclear reception ligand Suppresses lipogenesis and glycogenesis Improves insulin resistance Reduces hepatic inflammation 141 patients, obeticholic acid vs. placebo 72 weeks Improved liver histology at 72 weeks 45% on OA 21% on placebo Neuschwander-Tetri BA et al. Lancet 2015;385: Obeticholic Acid vs. Placebo ALT AP GGT WEIGHT Always Bad News Elevations in alkaline phosphatase Concerns for hyperlipidemia Cardiovascular risk Pruritus (6%) Liver histology improved but did not return to normal Neuschwander-Tetri BA et al. Lancet 2015;385: Gastroenterology 2015;148:

23 ALT AST Vitamin E for NASH Non diabetics with NASH (n=247) Pioglitazone 30mg/d or Vitamin E as d tocopherol 800 IU/d for 2 years Insulin Resistance Weight Histologic improvement : vitamin E 43% pioglitazone 19% Sanyal A, et al. NEJM 2010;362: Vitamin E Concerns High dose (>1,100 IU/d) may inhibit platelet aggregation Caution in uncontrolled hypertension At least one trial noted increase in heart failure May blunt HDL2 increase in response to lipid lowering drugs 23

24 Small intestine L cells Glucagon Like Peptide 1 Receptor Agonists (GLP 1RAs) 52 NASH patients randomized to liraglutide (1.8mg s/c daily) vs placebo for 48 weeks (~32% had diabetes) Placebo controlled, double blind, randomized 4 sites in the UK 35% had diabetes Metformin, sulfonylurea BMI 34 Endpoint: Resolution of NASH with no worsening in fibrosis Armstrong MJ, et al. Lancet 2016;387: Liraglutide for NASH Change in Weight Change in ALT Armstrong MJ, et al. Lancet 2016;387:

25 Liraglutide for NASH Histology Patients Reaching Primary Outcome 100% 90% 80% 70% 60% 50% 39% 40% 30% 20% 9% 10% 0% Liraglutide Placebo Primary Outcome: Resolution of NASH with no worsening in fibrosis Armstrong MJ, et al. Lancet 2016;387: NAFLD Therapeutic Pipeline Pioglitazone FXR agonist Vitamin E Liraglutide GS 9674 PF VLX 103 CVC Saroglitazar EDP 305 PXS 4728A Elafibranor NGM 282 GR MD 024 LJN 452 IVA 337 Nor UDCA Cenicriviroc Aramchol Emricasan GS 4997 Simtuzumab Perazzo H, et al. Liv Int 2017;37: Management of NASH Recommendations If diabetes or pre diabetes present Favor pioglitazone or GLP 1RA s Pro: reduces intrahepatic insulin resistance, clinical data shows benefit Con: weight gain, cardiac toxicity if diastolic dysfunction Consider metformin Pro: Weight loss, may lower liver cancer risk Con: No change in intrahepatic insulin resistance, clinical studies show limited to no benefit in NASH histology For non diabetics: Consider d tocopherol 800 IU/d All patients Weight loss counseling 25

26 Treat the Patient! Prescribe statins liberally as needed Control hypertension Assess cardiac risk and institute appropriate interventions Bariatric surgery not contraindicated in the absence of clinically significant portal hypertension Evidenced Based Recommendations Our Patient Diabetes Metformin BMI 34 Optimize diabetes management; add Pioglitazone 45mg/d OR Liraglutide 3.0mg sc injection daily Maximize therapy for dyslipidemia and hypertension Reduce cardiovascular risk Encourage low glycemic weight loss diet Encourage exercise Resistance and aerobic training equally effective Consume 2 4 cups of regular coffee/day Bacchi E, et al. Hepatology 2013;58: Ryan MC, J Hepatol 2013;59: Kwon OW, Aliment Pharmacol Ther 2012;35: Molloy JW, et al. Hepatology 2012;55: Take Home Points Fatty Liver Disease The most common cause of abnormal liver tests May progress to cirrhosis and liver cancer in some Fibrosis at diagnosis is the best predictor of prognosis Exclude common causes of liver disease Perform non invasive evaluation for fibrosis Refer for liver biopsy if fibrosis suspected Manage comorbidities, minimize cardiovascular risk Recommend weight loss and exercise Pharmacotherapy for NAFLD is in its infancy 26