NAFLD: ACG Southern Regional Course Nashville, TN. Speaking - None

Transcription

1 NAFLD: 2015 Naga Chalasani, MD, FACG David W. Crabb Professor of Medicine Director, Division of GI and Hepatology Indiana University School of Medicine ACG Southern Regional Course Nashville, TN Disclosures Consulting - Abbvie - Lilly - Tobira - Nusirt - DS Biopharma Research support - Gilead - Galectin - Intercept Speaking - None Copyright 2015 American College of Gastroenterology 1

2 Outline Background and Definitions Risk Factors Diagnosis Natural History Treatment Cardiovascular Risk Rob, a 42-year-old overweight male Caucasian, BMI 29 Kg/m2 Drinks socially Found to have fasting LDL 160 mg/dl and fasting glucose 113 mg/dl ALT level is 90 IU/L Viral hepatitis screen is negative Serum ferritin is mildly elevated Copyright 2015 American College of Gastroenterology 2

3 Questions pertinent to Rob: Does he have NAFLD? Should he be concerned? How should he be worked up? Should he stop drinking alcohol completely? Does he need a referral to GI? Does he need a liver biopsy? Is it safe to consider statins to lower his LDL? Background NAFLD is present in 30% US adults and 10-15% children By MRI in general population 35% - far higher in select population such as type2 diabetics By CT and US about 15-17% By AST/ALT 7% Most common cause of elevated liver enzymes in both adults and children Up to 5% U.S. adults may have NASH Copyright 2015 American College of Gastroenterology 3

4 Spectrum of NAFLD The spectrum of NAFLD consisting of simple steatosis to steatohepatitis, and cirrhosis. Simple fatty liver is histologically characterized by macrovesicular steatosis with no additional pathology. Fatty liver is generally considered benign. NASH is histologically i ll advanced d fatty liver. It is characterized by steatosis, inflammation, ballooning, Mallory s hyaline, fibrosis. It can lead to cirrhosis and liver failure. Risk Factors for NAFLD Major Co-morbidities Type2 Diabetes Dyslipidemia Obesity Metabolic Syndrome Emerging Associations Hypothyroidism Sleep Apnea Hypopituitarism Hypogonadism Polycystic Ovary Syndrome Pancreatic resection Lonardo A, et al. J Hepatol 2006; 44: Vuppalanchi R, Chalasani N. Hepatology 2009;49: Copyright 2015 American College of Gastroenterology 4

5 Hepatic Outcomes of NAFLD Simple steatosis is largely benign with minimal risk ikof cirrhosis i NASH is progressive with 20% risk of cirrhosis over a 10-yr time horizon NASH cirrhosis is at moderate risk for liver cancer (2-4% per year) Cryptogenic cirrhosis is likely a burnt-out form of NASH in up to 80% of patients Outcomes in NAFLD Surrogates # Studies OR [95% CI] Overall NAFLD vs. General 8studies 1.57 [ ] Mortality Population Incident CVD ALT as a surrogate GGT as a surrogate Imaging as a surrogate 6 studies 10 studies 7 studies 1.10 [ ] 1.57 [ ] 2.05 [ ] Incident ALT as a surrogate 17 studies 1.97 [ ] type2 DM GGT as a surrogate Imaging as a surrogate 12 studies 3 studies 2.74 [ ] 3.51 [ ] Musso G et al. Annals of Medicine 2011 Copyright 2015 American College of Gastroenterology 5

6 Work up of patients with NAFLD Imaging to establish the presence of steatosis Meticulous alcohol and medication history Exclusion of co-existing or competing etiologies Auto-antibodies and hyperferritinemia are common Fasting lipid profile and measures of insulin resistance Liver enzymes can be normal!! Liver biopsy to establish the presence of NASH Surrogate Markers/Predictive Models Predict NASH Metabolic Syndrome CK-18 fragments CK-18 + sfas Oxidized Fatty acids NASH test NASH Predictive Index Obesity NAFLD score NASH Clinical Score NAFIC (ferritin, insulin, collagen) Predict advanced fibrosis Fibrotest NAFLD Fibrosis Score BARD score ELF Fibrometer OWL Genomics IU panel Transient elastography MR elastography Musso G et al. Annals of Medicine 2011 Copyright 2015 American College of Gastroenterology 6

7 CK-18 fragments Circulating CK-18 fragment levels are elevated in NASH patients 10 studies (adult and pediatric studies) Various cut-off values, range U/L Summary estimates: AUC [95% CI]: 0.82 [ ] 0.88] Median Sensitivity: 78% Median Specificity: 87% Musso G et al. Annals of Medicine 2011 NAFLD Fibrosis Score (NFS) Risk score: * age (years) * BMI (kg/m 2 ) * IFG/diabetes (yes=1, no=0) * AST/ALT ratio * platelet (x10 9 /l) * albumin (g/dl) Independent predictor of advanced (bridging or cirrhosis) fibrosis. Based on six variable: Age, BMI, AST/ALT ratio, Hyperglycemia/diabetes, Platelet count and Albumin NAFLD Fibrosis Score predicts long term outcomes in individuals with NAFLD Angulo P et al. Hepatology 45: 2007; ; Kim D, et al. Hepatology 2013:57: ; Angulo P et al: Gastroenterology 2013 Copyright 2015 American College of Gastroenterology 7

8 Controlled Attenuation Parameter (CAP) CAP: Quantification of ultrasonic signal attenuation in the liver Attenuation: The energy loss of an ultrasonic beam as it passes through a material Skin 25 mm 65 mm Explored Tissue 1 cm 3 cm 3 4cm 16 Clinically significant NAFLD LSM by transient elastography was significantly better than NAFLD Fibrosis and FIB4 score for detection of clinically significant fibrosis Cut-off: 10.3kPa Sensitivity: 81% Specificity: 77% Positive predictive value: 92% Negative predictive value: 56% Area under the ROC: Copyright 2015 American College of Gastroenterology 8

9 When to biopsy? 1. Liver biopsy should be considered in patients with NAFLD who are at increased risk to have steatohepatitis and advanced fibrosis. (Strength th 1Eid 1, Evidence - B) 2. 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) 3. Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies i for hepatic steatosis t and coexisting chronic liver diseases cannot be excluded without a liver biopsy. (Strength 1, Evidence - B) Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Gastroenterology, Hepatology, AJG June 2012 Therapeutic approaches Risk factor NASH pathophysiology Anti-fibrotic Obesity - RYGB / Intragastric balloon - Orlistat Diabetes/Insulin resistance - PPAR-ɣɣ ligands - Exenatide / Liraglutide - Sitagliptin Anti-oxidant - Vitamin E / SAMe / L-Carnitine Lipotoxicity - Fish oil/ EPA-E/lovaza E/l - DHA/EPA / PUFA / Aramchol Anti-Lysyl oxidase-like-2 (LOXL2) - Simtuzumab (GS-6624) Galectin binding molecules - GR-MD-02 Dyslipidemia - Statins (atorvastatin) - Ezetimibe Hypertension - ARBs (Losartan) Gut microbiome - Probiotics / Prebiotics - Rifaximin Endotoxemia - Bovine colostrum TNF alpha - Pentoxiphylline Nuclear receptor modulation - Dual PPAR α/δ agonist - Dual PPAR α/γ agonist - FXR ligand (FLINT trial) -OCA Leptin deficiency - Metreleptin Anti-apoptosis - Pancaspase inhibitor (Emricasan) Innate immunity (Anti-CD3 19 mab) PDE-4 inhibition (roflumilast) FXR agonist - Obeticholic acid (OCA) Copyright 2015 American College of Gastroenterology 9

10 Weight loss as a treatment for NAFLD Reduced calorie intake, lifestyle modification, exercise, pharmacological, and surgical options have been explored Difficult to achieve and sustain without an intensive program or surgical intervention Consistent biochemical and histological benefits if weight loss > 7-10% body weight No data available for fad diets (Atkins, South beach, etc.) Weight loss through lifestyle modification and impact on NASH A prospective study of 292 patients with biopsy proven NASH underwent lifestyle modification over 52 weeks. 261 patients had follow-up liver biopsy. At 52 weeks, weight loss >5% was achieved by 30% subjects. The magnitude of weight loss was independently associated with improvement in all histological parameters Vilar-Gomez E, et al. Gastroenterology 2015 (In press) Copyright 2015 American College of Gastroenterology 10

11 Improvement of histological outcomes across different categories of weight loss at the end of treatment Variables WL < 5 (n=205) WL = (n=34) WL = (n=25) WL 10 (n=29) Weight loss (%) 1.78 ± ± ± ± P value Resolution of steatohepatitis* 21 (10) 9 (26) 16 (64) 26 (90) <0.01 NAS improvement 66 (32) 21 (62) 22 (88) 29 (100) <0.001 Steatosis improvement 72 (35) 22 (65) 19 (76) 29 (100) <0.001 Lob. Inflammation improvement 72 (35) 24 (71) 22 (88) 29 (100) <0.001 Ballooning improvement 54 (26) 14 (41) 21 (84) 26 (90) <0.001 Fibrosis status <0.01 Regression 33 (16) 6 (18) 4 (16) 13 (45) Stabilized 129 (63) 25 (74) 21 (84) 16 (55) Weight loss: Bariatric surgery Bariatric surgery improves steatosis and may improve necroinflammation i (and possibly fibrosis) in carefully selected patients Meta-analysis analysis by Mummadi et al. showed that steatosis, steatohepatitis, and fibrosis improve following bariatric surgery However, Cochrane review highlights lack of well designed studies Mummadi RR et al. Clinical Gastro Hepatol 2008 Chavez-Tapia NC, et al. Cochrane Database of Systematic Reviews 2010 Copyright 2015 American College of Gastroenterology 11

12 Naga P. Chalasani, MD, FACG Significant Improvement in histology following bariatric surgery 1st biopsy 2nd biopsy at 8.5 months Mattar SG et al. Annals of Surgery 2005; 242: Significant Improvement in histology following bariatric surgery 1st biopsy 2nd biopsy at 13 months Mattar SG et al. Annals of Surgery 2005; 242: Copyright 2015 American College of Gastroenterology 12

13 Significant Improvement in Fibrosis Insulin sensitizers for NASH Metformin 7 trials including TONIC Meta-analysis analysis showed no significant effect on liver histology - Steatosis OR 1.30 (95% ) 4.08) - Inflammation OR 1.08 (95% ) -Fibrosis OR 0.93 (95% CI: ) Musso G et al. Hepatology 2010; 52: Copyright 2015 American College of Gastroenterology 13

14 n TZDs for NASH Agent Dose Tetri 30 Rosi 8 mg Sanyal 21 Pio 30 mg Belfort 55 Pio 45 mg Duration Enzymes Histology 48 weeks Improved Improved steatosis, Inflammation, and fibrosis 6 months N/A Improved steatosis, Inflammation 6 months Improved Improved steatosis, Inflammation Ratziu 63 Rosi (8 mg) 12 months Improved Improved steatosis Aithal 74 Pio 30 mg 12 months Improved Improved steatosis, inflammation, and fibrosis PIVENS 247 Pio 30 mg 24 months Improved Improved steatosis, inflammation, and ballooning TZDs for NASH: Meta-analysisanalysis Consistently positive effect on liver histology - Steatosis OR405(95% ) - Inflammation OR 3.53 (95% CI ) - Fibrosis OR 1.40 (95% CI: ) Weight gain 2-5 kg (~ 60-70% patients)? Pio better than rosi Responders ~ 45% Histological benefits are lost upon d/c Musso G et al. Hepatology 2010; 52: Copyright 2015 American College of Gastroenterology 14

15 PIVENS Multicenter, double-blind, blind, RCT 247 Non-diabetic adults 96 weeks of treatment Histology at baseline and at conclusion Pioglitazone 30 mg once daily or Vitamin E 800 IU once daily (RRR-α-tocopherol, natural form) or Placebo N Engl J Med 2010; 362: PIVENS Primary end point is histological improvement on central review Improvement in NAS 2 and at least 1 point improvement in either ballooning or fibrosis AND no worsening in fibrosis Intention to treat analysis Pio vs Placebo; Vit E vs. Placebo P <0.025 was significant Copyright 2015 American College of Gastroenterology 15

16 Primary Outcome Vitamin E alone met the pre-specified primary endpoint Proport ion of subjects (% ) /84, p=0.001 NNT=4.4 16/83 26/80, p=0.04 NNT= 6.6 Vit E placebo Pio treatment groups Both vitamin E and pioglitazone increased the proportion of subjects with resolution of NASH propor rtion of subjects (% %) P< P< /84 40/80 23/83 Vitamin E placebo pioglitazone study groups Copyright 2015 American College of Gastroenterology 16

17 Published Online November 7, Partial funding for the trial, obeticholic acid, and placebo were provided by Intercept Pharmaceuticals under a Collaborative Research and Development Agreement with the NIDDK. The FLINT trial Obeticholic acid (OCA), 25 mg orally daily vs placebo Inclusion: adults with NASH on biopsy, NAS 4; Exclusion: cirrhosis N = 283 patients randomized at 8 clinical centers 72 weeks of treatment Biopsy 3 mo. before treatment and after 72 weeks Primary endpoint Improvement in NAFLD activity score 2 pts with no worsening of fibrosis Neuschwander-Tetri et al, The Lancet, Copyright 2015 American College of Gastroenterology 17

18 FLINT key baseline characteristics Obeticholic acid (n = 141) Placebo (n = 142) Age (years) 52 ± ± 12 % Female 69% 63% % Hispanic 16% 15% BMI (kg/m 2 ) 35 ± 7 34 ± 6 Diabetes 53% 52% Hypertension 62% 60% Hyperlipidemia 62% 61% Vitamin E use 21% 23% ALT (U/L) 83 ± ± 51 NAFLD activity score 5.3 ± ± 1.3 Fibrosis stage 1.9 ± ± 1.0 Neuschwander-Tetri et al, The Lancet, FLINT primary endpoint Improvement in NAFLD activity score* (NAS) 2 pts * NAS = steatosis grade (0-3) + inflammation grade (0-3) + ballooning grade (0-2) No worsening of fibrosis Results: Percent of subjects 50% 40% 30% 20% 10% 0% 21% (23/109) Placebo p = % (50/110) OCA 25 mg/day Neuschwander-Tetri et al, The Lancet, Copyright 2015 American College of Gastroenterology 18

19 Improvement in NAS components Steatosis Inflammation Ballooning s Percent of subjects improved 60% 50% 40% 30% 20% 10% 0% p = p = p = % 60% 50% 50% 40% 40% 30% 30% 38% 61% 20% 35% 53% 20% 31% 46% 10% 10% 0% 0% Placebo OCA Placebo OCA Placebo OCA e Change in score p = p = p = Placebo OCA Placebo OCA Placebo OCA Neuschwander-Tetri et al, The Lancet, Improvement in fibrosis and NASH resolution Fibrosis NASH resolution p = p = 0.08 (NS) s Percent of subjects improved 60% 50% 40% 30% 20% 10% 0% 19% Placebo 35% OCA 60% 50% 40% 30% 20% 10% 0% 13% 22% Placebo OCA e Change in score p = Placebo OCA Neuschwander-Tetri et al, The Lancet, Copyright 2015 American College of Gastroenterology 19

20 ALT Enzymes and body weight Alk Phos Off Off GGT Body weight Off Off (EOT) (EOT) Neuschwander-Tetri et al, The Lancet, Serum lipids Neuschwander-Tetri et al, The Lancet, Copyright 2015 American College of Gastroenterology 20

21 Adverse events 6 severe adverse events in obeticholic acid group 4 severe pruritus (1 stopped treatment) 1 hypoglycemia 1 possible cerebral ischemia (dysarthria and dizziness) Moderate e or severe e pruritus P < % in obeticholic acid 6% in placebo Percent of patients Placebo OCA Mild Mod Severe Neuschwander-Tetri et al, The Lancet, FLINT summary Obeticholic acid improved histological features of fnashi including fibrosis i Obeticholic acid treatment was associated with pruritus that was severe in 3% Elevated total and LDL cholesterol and decreased HDL cholesterol warrant further scrutiny in future trials Copyright 2015 American College of Gastroenterology 21

22 Alcohol use in individuals with NAFLD and NASH While heavy drinking is certainly deleterious, there are evolving data to suggest non-heavy drinking may have hepatic and metabolic benefits (Liangpunsakul & Chalasani, Am J Gastro 2012) Practice Guideline Recommendation Patients with NAFLD should not consume heavy amounts of alcohol (Strength -1, Quality B) No recommendation can be made with regards to non-heavy consumption of alcohol by individuals with NAFLD. (Strength 1, Quality B) Cardiovascular disease in NAFLD Heavily enriched with cardiovascular risk factors Increased prevalence of surrogate markers of coronary artery disease Many studies have shown cardiovascular disease as the single most common cause of death in patients with NAFLD Targher G, Day CP, Bonora E. N Engl J Med 2010;363: Chalasani N, et al. Hepatology 2012; 55: Copyright 2015 American College of Gastroenterology 22

23 General guidelines for managing cardiovascular risk in NAFLD A diet low in sodium and simple sugars, with substitution btitti of unsaturated tdftf fat for saturated tdand trans-fats, and increased consumption of fruits and vegetables. Consumption of food products enriched omega3 fatty acids Caloric restriction to achieve and maintain ideal body weight. Moderate to vigorous exercise for 30 min to 60 minutes per day most days of the week Smoking cessation & avoidance of alcohol Statins can be used safely in patients with fatty liver Patients with NAFLD are important targets for statins Risk of serious hepatotoxicity from statins is very rare Patients with underlying liver disease are not at higher risk for statin hepatotoxicity Case series have shown histological improvement in NASH Fish oil is probably the first choice to treat hypertriglyceridemia Chalasani N. Hepatology 2005; 41: ; Hepatology. 2007;46: Copyright 2015 American College of Gastroenterology 23

24 Take Home Messages Exclude competing etiologies and look for coexisting liver diseases Steatosis t is hepatically benign but NASH is progressive and can lead to cirrhosis Patients with NAFLD are at higher risk for incident type2 diabetes and cardiovascular disease Liver biopsy can establish the diagnosis of NASH Management of NAFLD include managing underlying metabolic and cardiovascular risks as well as managing the liver disease Copyright 2015 American College of Gastroenterology 24