Fatty Liver Disease A growing epidemic

Transcription

1 Fatty Liver Disease A growing epidemic Updates in GIM for Primary Care Don C. Rockey March 9 th, 2018

2 Disclosures 2018 Research Funding (all to MUSC) NIH/NIDDK Actelion Pharmaceuticals Gilead Sciences Galectin Therapeutics Connatus Pharmaceuticals Shire Intercept Pharmaceuticals Cumberland Pharmaceuticals Mallinckrodt Pharmaceuticals Stock, speakers bureau, etc - none

3 What you can expect to learn 1. Identify symptoms and signs that suggest the presence of NAFLD 2. Recognize sequelae of chronic NAFLD 3. Describe the basic foundations of NAFLD treatment

4 Outline Patient presentation Differential diagnosis/definition Burden of disease Non-invasive evaluation Prognosis Treatment Summary

5 Patient Presentation Illustrative Case (NAFLD) 54 year old man with T2DM, hypertension, and hyperlipidemia found to have abnormal liver tests No symptoms FH + mother having some sort of liver disease, but he is not sure what it was PE remarkable for BMI 33, abdominal obesity, otherwise normal Lab data = AST 72, ALT 59 (2x ULN), bili & INR normal

6 Patient Presentation What do you recommend next? Repeat liver tests in 3 months ANA, AMA and ASMA HCV antibody HCV RNA Liver biopsy

7 Differential diagnosis of isolated abnormal aminotransferases Liver Hepatitis C, B (chronic) ETOH NASH Drugs/toxins AIH Passive congestion Α1 anti-trypsin def. Wilson s disease Hemochromatosis Cryptogenic cirrhosis Non-Liver Celiac disease Hemolysis Myopathies/muscle injury Hyperthyroidism Macro-AST

8 Risk Factors for NAFLD Nutritional abnormalities: Obesity, TPN, rapid weight loss Metabolic diseases: Diabetes mellitus, hyperlipidemia, dysbetalipoproteinemia, liposdystrophy Medications: synthetic estrogens (tamoxifen), corticosteroids,diltiazem, nifedipine, methotrexate, perhexiline, amiodarone Surgery: Jejunoileal bypass, gastropexy, extensive small bowel loss, biliopancreatic diversion Occupational exposure: environmental toxins- hydrocarbons, industrial solvents

9 What is NAFLD/NASH? NAFLD = nonalcoholic fatty liver disease simple fatty infiltration of the liver, manifest by hepatocyte fat deposition NASH = nonalcoholic steatohepatitis fat, inflammation, hepatocyte necrosis/injury, fibrosis

10 What is NAFLD/NASH?

11 Pathogenesis/Spectrum of NAFLD Normal Fatty Liver Obesity Metabolic syndrome Insulin resistance Oxidative stress Inflammatory signaling Cytokines Inflammation (NASH) Injury Wounding Cirrhosis

12 Fatty Liver Disease

13 Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010 (*BMI 30, or about 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

14 Approach to low grade elevation in aminotransferases Abnormal AST and/or ALT History / Context Alcohol? Metabolic Syndrome? Repeat liver tests HCV early + HCV Persistent + Risk factors Hepatology HBV serology/autoimmune markers,? Ferritin/Iron Counseling (ETOH / Lifestyle modification Hepatology Schreiner/Rockey COG In Press

15 Outline Patient presentation Differential diagnosis/definition Burden of disease Non-invasive evaluation Prognosis Treatment Summary

16 Burden of Disease 300 Million Normal Fatty Liver 75 Million Inflammation (NASH) 30 Million 5-10 Million Cirrhosis

17 Burden of Disease NASH is the most rapidly growing indication for LT in the US Cholankeril, G. Dig Dis Sciences, 2017

18 Patient Presentation Repeat liver tests are the same. HCV RNA negative. Autoimmune markers negative. Now? Reassure and follow Ultrasound Transient elastography Calculate the APRI Liver biopsy

19 Outline Patient presentation Differential diagnosis/definition Burden of disease Non-invasive evaluation Prognosis Treatment Summary

20 Fibrosis and Outcomes Alaskan cohort - HCV (n = 407) Liver biopsy baseline Ishak Fibrosis Stage 0-1 (mild) Probability 2 (moderate) 3-4 (severe) Bruden, et al. Hepatology 2017, 66(1): (cirrhosis) (ESLD = ascites, esophageal varices, hepatic encephalopathy, or coagulopathy (international normalized ratio > 1.2 or platelet count <130,000)

21 Fibrosis in NAFLD/NASH 209 biopsy proven NAFLD patients Median followup 12.2 years Survival Probability Time, Months Younassi, Hepatology 2011

22 Non-invasive diagnosis - NASH Blood - Fib-4, NFS, APRI Imaging (US, MRI, CT, transient elastography)

23 Non-invasive diagnosis - NASH Imaging (US, CT, MRI) Typically best at detecting simple fat Poor at fibrosis unless advanced with cirrhosis (evidence of portal hypertension)

24 Transient elastography Rockey DC. Gastroenterology 2009.

25 Patient Presentation Repeat liver tests are the same. HCV RNA negative. Autoimmune markers negative. Now? Reassure and follow Ultrasound Transient elastography Calculate the APRI Liver biopsy

26 Patient Presentation Empiric treatment is reasonable in most patients at this stage

27 Patient Presentation Presents 4 years later with persistent elevation of liver tests; BMI 38, platelet count noted to be 140; AST/ALT same Reassure and follow Liver biopsy Obesity surgery Vitamin E

28 Non-invasive diagnosis - NASH Fib-4 For NASH: Fib4 < 1.30 = F0-F1 Fib4 score > 2.67 = F3-F4

29 Non-invasive diagnosis - NASH NFS NAFLD Fibrosis Score

30 Non-invasive assessment of fibrosis - APRI APRI = AST to Platelet Ratio Index AST (U/L) AST ULN (U/L) x 100 Platelet count (10 9 /L) = APRI Value

31 Non-invasive assessment of fibrosis - APRI Illustrative Case AST 72 (ULN, 40 U/L), plts = 1.8 x 100 = 180 =

32 APRI and Fibrosis ( Significant fibrosis - F2-4) Test Threshold No. of Studies (patients) Sensitivity Specificity (3,277) 86% 54% (438) 81% 50% (473) 59% 86% (3,146) 35% 91% (From Shaheen and Meyers, Hepatology 2007)

33 APRI and Fibrosis ( Significant fibrosis - F2-4) Test Threshold No. of Studies (patients) Sensitivity Specificity (3,277) 86% 54% (438) 81% 50% (473) 59% 86% (3,146) 35% 91% (From Shaheen and Meyers, Hepatology 2007)

34 Patient Presentation Picrosirius Red Stage 3 fibrosis Picrosirius Red (Normal)

35 Outline Patient presentation Differential diagnosis/definition Burden of disease Non-invasive evaluation Prognosis Treatment Summary

36 Treatment - NAFLD

37 Treatment - NAFLD Diet and exercise Insulin sensitizers Metformin Thiazolidinediones (rosiglitazone, pioglitazone) Lipid lowering medications Atorvastatin Specific pharmacological Rx: Antioxidants o Vitamin E, pentoxyfilline Ursodeoxycholic acid Others

38 Lifestyle modification - weight loss and exercise Weight loss Small trials as little as 5% weight loss reduces hepatic fat, lowers ALT Reduces NAS score As little as 7% weight loss leads to histological improvement Exercise Exercise alone reduces hepatic fat (even without weight loss) Likely reduces NAS score and fibrosis

39 Lifestyle modification - weight loss and exercise Dietary recommendations Restrict the overall calorie intake to 1,200-1,500 kcal/day for women and 1,500-1,800 kcal/day for men. Restrict certain foods (particularly, high-carbohydrate foods, low-fiber foods, or high-fat foods) in order to create an energy deficit by reduced food intake. Individualize the choice of calorie-restricted diet to the patients preferences and health status. Physical activity recommendations Target physical activity to yield a calorie deficit of at least 400 kcal/day. Add (500) steps at (3-day) intervals up to a target value of 10,000-12,000 steps/day. Jogging, cycling, or swimming (30-60 min/day) may replace walking. Resistance training may be added or be an alternative for certain patients.

40 Obesity Surgery Leads to improvement in steatosis, hepatocyte ballooning and resolution of NASH at 1/5 years Complete resolution of NASH in up to 82% of patients Improves liver function Current AASLD Guidelines: it is premature to consider foregut bariatric surgery as an established option to treat NASH. Dixon JB, et al. Hepatology, 2012 Mathurin P, et al. Gastroenterology, 2009 Alizai PH, et al. Obesity Surgery, 2015 Chalasani N, et al. Hepatology, 2012

41 Pharmacological Rx Best Studied Pioglitazone (PPAR gamma agonist) Vitamin E (antioxidant) Obeticholic acid (FXR agonist)

42 PIVENS trial Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) 96 week study including 247 adults with NASH (no DM) 3 arms Pioglitazone (30 mg daily, 80 subjects) Vitamin E (800 IU daily, 84 subjects) Placebo (83 subjects) Results (biopsy) Improvement in steatohepatitis in 34% pioglitazone, 43% Vit E, and 19% placebo No improvement in fibrosis *Pioglitazone associated with 4.7 Kg weight gain *Vitamin E SE s Sanyal A, et al. NEJM, 2010

43 FLINT trial Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT) Obeticholic acid, 25 mg daily vs. placebo NASH adults, NAS of 4 or higher Cirrhotics excluded N= 283 subjects (NASH CRN) Liver histology baseline and 72 weeks Primary endpoint - improvement in NAFLD activity score of 2 or more and no worsening of fibrosis Tetri BA, et al. Lancet, 2015

44 FLINT trial Stopped early at interim analysis - followup liver biopsies not done in 64 patients Obeticholic acid led to reduced ALT and 50 (45%) of 110 patients in the obeticholic acid group vs. 23 (21%) of 109 in placebo had improved histological features in NASH Pruritus 23% Increase in total and LDL cholesterol, and decrease in HDL cholesterol Tetri BA, et al. Lancet, 2015

45 Drugs in Major Trials Obeticholic acid (FXR, phase 3) Elafibranor (PPAR α/γ, phase 3) Cenicriviroc (CCR2/5 Chemokine antagonists, phase 3) Multiple phase 2

46 Patient Presentation Presented 3 years later with a chief complaint of SOB, mild scleral icterus, + fluid wave, INR 1.7

47 Patient Presentation Illustrative Case Not a transplant candidate TIPS, HVPG 22 mm Hg reduced to 6 mm Hg Progressive liver failure

48 Risk of HCC Number with HCC Dyson J, et al. J Hepatology, 2014

49 NASH Studies at MUSC

50 Take Home NAFLD is common NASH is the complication of greatest concern (especially with fibrosis) Diagnosis is often incidental (abnormal AST/ALT) Therapy weight loss and exercise, bariatric surgery Watch for pharmacological therapies coming soon Remember the risk of cancer

51 Questions