Updates in Fatty Liver Disease

Updates in Fatty Liver Disease Blaire E Burman, MD Virginia Mason Gastroenterology & Hepatology

Talk Outline Definitions Burden of obesity and NAFLD Complications and natural history Diagnosis Blood work and imaging Biopsy & pathology Non-invasive alternatives Management Lifestyle modifications, weight loss procedures Pharmaceuticals 2014 Virginia Mason

Fatty Liver Disease Then and Now 2014 Virginia Mason

Definitions NAFLD: Non-alcoholic fatty liver disease, includes: NAFL: Non-alcoholic fatty liver = benign or simple steatosis NASH: Non-alcoholic steatohepatitis = clinically significant hepatocellular inflammation and injury with varying degrees of fibrosis OR NAFL and NASH are clinically different entities

The Obesity Epidemic Worldwide prevalence of obesity has nearly doubled over the past 3 decades 2 billion adults worldwide are overweight or obese Obesity prevalence gap between rich and poor nations is narrowing US still accounts for 15% of the worlds obesity

Trends in Obesity: US Overweight Obesity Extreme obesity By 2010, the percentage of adults considered overweight, obese, or extremely obese had climbed to 70% 2 of 3 adults are considered overweight or obese 1 of 3 children and adolescents (aged 6-19) are considered overweight or obese 1 in 5 deaths is attributable to obesity CDC, NHANES, NHIS

A true epidemic Left unchecked, obesity will make the current generation of children the first in human history to have a life span shorter than that of their parents... --David Satcher, MD, PhD, former US Surgeon General As the epidemic of obesity fuels metabolic conditions, the clinical and economic burden of NAFLD will become enormous --Zobair M. Younossi, MD, MPH

Burden of Fatty Liver Disease Obesity remains the most important and well-described risk factor for NAFLD NAFLD is the #1 cause of elevated liver enzymes in both developed and developing countries NAFLD is now the #1 cause of chronic liver disease in the US 1 billion individuals have NAFLD worldwide 80-100 million individuals have NAFLD in the US (at least 10x more than HCV) Accurate epidemiologic data are limited because of lack of population-based studies and reliable non-invasive screening tool

Prevalence Estimates Wide range of estimates depending on: A) population studied B) diagnostic modality NAFLD overlaps with other chronic liver disease 70% of pts with cryptogenic cirrhosis have risk factors for NASH

NAFLD Prevalence Global Data A recent meta-analysis including >8.5 million individuals estimated a 25% global prevalence of NAFLD And 1.5 6.5% prevalence of NASH (10-25% of NAFLD cases) US Data 30% of general population have NAFLD 3-5% will have NASH 80% of those with BMI>30, 70% of those with DMII, and 90% of those presenting for bariatric surgery have NAFLD Bottom Line: NAFLD and NASH are VERY common!

NASH and Ethnicity Hispanics have the highest and non-hispanic blacks have the lowest prevalence of NAFLD In a recent study, NASH was independently associated with being Hispanic [OR 1.72] and inversely associated with being African-American [OR 0.52] Asians tend to develop NAFLD at lower body weight Ethnic disparities in central adiposity and visceral fat distribution? BMI cutoffs should differ by ethnicity Using genome-wide association study, several SNPs have been identified to be associated with NAFLD/NASH However these genetic variants only account for a small amount of variation and likely serve as modifiers of the natural history of NAFLD PNPLA3 gene is associated with hepatic fat content even after adjustment for BMI, diabetes status, alcohol use 11

NAFLD and NASH: Clinical Implications

Pathophysiology: Why does FAT cause FIBROSIS? Fatty acid-lipotoxic liver injury model: Hepatocellular fatty acids (FAs) are supplied from adipose tissue and de novo lipolysis in the liver Oversupply if either: a) too much lipolysis in adipose tissue sending FAs to the liver, or b) excessive supply of carbs promoting formation of new FAs in liver Two major routes of disposal are: 1) oxidation (mostly in mitochondria) and 2) formation of triglyceride (secreted into blood as VLDL) VLDL accumulates as temporary triglyceride droplets (steatosis)

Pathophysiology: Why does FAT cause FIBROSIS? If supply of FAs exceeds the liver's disposal capacity, they may spill over into other pathways that generate lipotoxic lipids Accumulation of excess reactive oxidation species (ROS) and subsequent oxidative stress steatohepatitis NASH leads to hepatocellular injury and the repair response that manifests as liver fibrosis

Metabolic Syndrome Clinically we see linked and overlapping syndromes that all predispose to lipotoxicity in the liver 15

NAFLD Risk Factors & Co-Morbidities Abdominal obesity Risk is proportional to degree of obesity 90% of bariatric surgery pts have NAFLD; >30% have NASH Visceral fat distribution differs by ethnicity Small % of pts will have normal BMI Diabetes & insulin resistance Hypertension Dyslipidemia Obstructive sleep apnea Hypoxia exacerbates liver injury PCOS, hypothyroidism

NAFLD vs NASH Knowledge of whether a patient has simple steatosis or NASH is nafld important to prognosis Is this a spectrum or two different clinical entities? Majority of patients with NAFLD have benign steatosis and are at low risk for liver disease progression Patients with NASH and any amount of fibrosis are at highest risk of progression Singh et al, Gastro, 2015 2014 Virginia Mason

Complications of NAFLD vs NASH Compared to the general population, those with NAFL or NASH have significantly higher overall mortality Patients with NASH have higher liver-related mortality Presence of NASH and hepatic fibrosis is the strongest predictor of (10 year) disease-related complications Risk of cirrhosis development sig higher with NASH vs NAFLD (10.8 vs 0.7%, p<0.001) Risk of liver-related mortality (7.3 vs 0.9%, p<0.001) Risk of overall mortality does not differ as much for NASH vs NAFLD (40.5 vs 33.5%, non-significant) Angulo, Hepatology 2010

NASH: Clinical Implications 25-40% of patients with NASH develop progressive liver fibrosis; 20-30% will eventually develop cirrhosis NASH cirrhosis has a poor long-term prognosis Up to 50% of those with compensated NASH cirrhosis will experience decompensation over 10 years High hospitalization rates, high mortality Is transplant appropriate? 2.5-3% annual risk of liver cancer (HCC) Worse prognosis once HCC occurs

NAFLD and Mortality NASH is now the 2 nd leading etiology of liver disease among patients awaiting liver transplant in the US and is predicted to become the leading indication for transplant in the next decade Yet most patients with NAFLD/NASH will outlive their liver disease and die from fatal complications of CVD Cause of death in NASH: 1) CVD, 2) Cancer, 3) Liver dz Wong RJ et al, Gastro 2015; Armstrong, Hep 2014

Part 1 Summary Prevalence of obesity has increased substantially NAFLD is a major consequence of the obesity epidemic Estimating the true prevalence of NAFLD is challenging NASH is the clinically significant manifestation of fatty liver disease Higher overall and liver-related mortality With rising rates of cirrhosis, ESLD, and HCC, hepatologists will not be out of business anytime soon

NAFLD: Diagnosis

Lab Tests Elevated liver enzymes What is the true upper limit of normal? What is the duration of elevated enzymes? 30-60% of patients with biopsy-proven NASH have normal ALT Levels tend to fall with more advanced NASH Normal ALT does NOT indicate absence of steatohepatitis and/or advanced fibrosis ALT levels do NOT correlate with histologic findings and are NOT helpful in determining disease severity ALT/AST ratio ALT levels are typically 1.5-3.0 x AST levels with NAFLD AST is typically higher than ALT with advanced NASH fibrosis

Lab Tests Exclude other causes of liver disease, and cofactors Autoantibodies are frequently detected at low titer ANA or ASMA < 1:160, IgG normal Elevated ESR, CRP, and even leukocytosis can be seen Systemic inflammatory state in NASH Elevated ferritin is common and usually reflects underlying inflammatory activity or insulin resistance Transferrin saturation < 45% excludes hemochromatosis 24

Lab Tests: Steatosis vs Fibrosis NAFLD fibrosis score: age, BMI, IFG or DM, AST:ALT ratio, platelets, albumin Score < 1.455 excludes advanced fibrosis APRI, FIB-4 Commercially available serologic panels: FibroSure, FibroSpect Biomarkers: cytokeratin-18 25

Imaging Incidental steatosis is a common finding on both US and CT/MRI Should NOT be considered normal and should prompt evaluation At least 30% steatosis necessary Imaging is unreliable for milder degrees of steatosis Imaging can be used to detect NAFLD but, unfortunately, cannot detect the cellular injury and inflammation that characterize NASH Also, negative imaging does not rule out NASH So now we have a patient with a fatty liver on ultrasound and elevated ALT 26

Histology Liver biopsy is the only current way to assess NAFLD severity and prognosis, and is underperformed Consider biopsy in patients at greatest risk for NASH: BMI > 30 Age > 50 Diabetes Hypertension Hispanic AST/ALT > 1 Rising AST

NAFLD Activity Score (NAS, 0-8): 5 consistent with NASH 3-4 considered borderline not diagnostic of NASH 28

Histology Currently the best method to differentiate NAFL from NASH Clear limitations: Invasive, painful, potential complications Sampling error Inter-observer variability Histologically, can only diagnose steatohepatitis, not NASH, and it is up to clinician to assess for significant alcohol 29

NAFLD vs AFLD CHARACTERISTICS NAFLD Alcoholic liver Disease Alcohol History < 21 drinks/week for men < 14 drinks/week for women Increased BMI Increased Variable Diabetes Usually present Variable AST : ALT ratio < 1.0 > 1.5 GGT Increased or normal Significant increased Triglycerides Increased Variable, maybe increased HDL Low Increased MCV Normal Increased Alcoholic and metabolic related liver disease can co-exist Need to rule out other causes of liver steatosis: HCV, medications, starvation/tpn 2014 Virginia Mason

Non-Invasive Diagnostics Vibration-controlled transient elastography (FibroScan) Limited by inflammation, visceral obesity, XL probe Controlled attenuation parameter (CAP) Magnetic resonance elastography (MRE) Superior to FibroScan and lower failure rate Can obtain fat fraction and fibrosis score Coming to VM in June!

Algorithm for Evaluating NAFLD Suspected Fatty Liver (Abn imaging or LFTs) Risk factors for NASH Yes No Non-invasive tests: MRE, Fibroscan, NAFLD fibrosis score Concerning for cirrhosis No Trial of diet and exercise LFT s if initially abnormal Normalized? Yes Reassess And follow as needed Every 6-12 months Yes No Screen for HCC and portal HTN Liver Biopsy 2014 Virginia Mason

NAFLD: Management

Lifestyle Interventions Weight loss and lifestyle modifications are very effective at reducing histopathologic features of NAFD/NASH Unfortunately, majority of patients unable to achieve this Large retrospective study of 900 NAFLD patients: <20% of cohort were able to achieve 5% weight loss over 1-2 years Interestingly, number of clinic visits was an independent predictor or success

Lifestyle interventions for the treatment of NAFLD Lifestyle Modification Weight loss Diet Fructose Polyunsaturated fatty acids Coffee Alcohol Exercise Diet and exercise Recommendation Loss of 3% 5% of body weight to improve hepatic steatosis Loss of 7% to improve NAFLD activity score Loss of 10% to promote regression of fibrosis Calorie restriction with 30% energy reduction; no less than 900 cal/day No specific diet is best sustainability is the key Restriction of foods and beverages high in fructose may be beneficial Insufficient evidence to support routine dietary supplementation Some data to suggest reduction anti-inflammatory effect Synergistic with steatosis; low risk use or avoidance Physical activity to improve hepatic steatosis and CV risk reduction Insufficient evidence for specific activities, duration, frequency, intensity Combined diet and exercise programs produce greater long-term weight loss in general public

NASH Pharmacotherapy Vitamin E PIVENS, a multicenter randomized controlled trial, demonstrated that 800 IU of vitamin E daily for 96 weeks improved NASH in about half of patients treated Improved inflammation and steatohepatitis (43% vs 19%) NO improvement in fibrosis Secondary analysis - combination of weight loss + vitamin E was additive, and weight gain reduced benefit of vitamin E Both studies conducted in patients w/o diabetes or cirrhosis, so the relevance of the findings for such patients remains uncertain Ideal candidate for vitamin E - nondiabetic with aggressive NASH and a relatively low risk for CVD

NASH Pharmacotherapy Insulin sensitizing agents Pioglitazone also studied in PIVENS trial and performed less well than Vitamin E Led to weight gain and CHF risk Not currently recommended Metformin no data for improvement in NASH Recommended as adjunct therapy in patients with diabetes who would otherwise benefit

NASH Future Therapies Obeticholic acid farnesoid X nuclear receptor ligand FLINT trial was stopped early due to efficacy 45% of patients met primary endpoint of 2 pt improvement in NAS score with no worsening of fibrosis (vs 21% placebo) 22% resolved NASH vs 13% placebo Concern over inc LDL and dec HDL and? CVD risk Severe pruritis in 25%, correlated with efficacy Larger Phase III trials ongoing Recently approved for PBC refractory to ursodiol

NASH Future Therapies GLP-1 analogues - Liraglutide FDA approved in 2010 for diabetic control in overweight pts Reduce hepatic steatosis and improve insulin resistance Recent phase II trial randomized 52 patients with NASH to daily liraglutide 1.8 mg SQ or placebo for 48 weeks Higher resolution of NASH (39% vs. 9%) and less worsening of fibrosis (9% vs. 36%) vs placebo Mean change in fibrosis score and % with fibrosis improvement was not significantly different between groups Excellent safety profile Larger trials with longer duration of treatment are needed to determine long-term efficacy of liraglutide in NASH Armstrong et al, Lancet 2016

NASH Future Therapies PPAR-alpha Agonists - Elafibranor Improves insulin sensitivity, glucose homeostasis, lipid metabolism, and reduces inflammation Recent phase II trial data suggests NASH patients treated with elafibranor 120mg/day for 1 year found to resolve NASH without worsening fibrosis overall (19% vs 12% for placebo), and 20% vs 11% for those with higher NAS scores Also improves CV profile Good safety data other than mild increase in creatinine Ratziu et al, Gastro 2016

Quick note about STATINS NAFLD is an independent CVD risk factor Several studies show that NAFLD/NASH patients are not at increased risk of liver injury over general population Some data that statins can improve steatosis, decrease ALT, and maybe even slow progression to steatohepatitis Bottom Line: Statins CAN and often SHOULD be used in patients with NAFLD/NASH despite occasional mild increase in LFTs Athyros et al, Lancet 2010

Risk vs Weight Loss

Fatty Liver Management Bariatric Surgery Consider for morbidly obese individuals (BMI >35) who are unable to sustain weight loss Results in reduced CV death and overall mortality Lasting improvements in metabolic syndrome, diabetic control, and NAFLD disease activity In one prospective study, NASH disappeared in 85%, NAS score decreased from 5 to 1 on average Data to support increased quality of life Safe in cirrhosis? 43

Bariatric Surgery in NASH Cirrhosis 28 morbidly obese, compensated cirrhotics (Child A) underwent roux-en-y gastric bypass Clinical, biochemical, and histologic parameters at baseline and 1 year post-op Complications and 5 year survival compared to 500 non-cirrhotic controls Baseline 1-Year BMI 49.8 39.1 AST 47.5 26 GGT 97.5 52 HgbA1C 7.9% 5.6% Steatosis 50% 10% NAS score 4.0 1.5 Concluded: Bariatric surgery in highly selected compensated cirrhotics has acceptable outcomes Lassailly G et al. AASLD 2015 Abstract 2222

Endoscopic Procedures Orbera balloon» FDA approved in 2015» Spherical silicone balloon filled w/ 450-700cc saline» Used for 6 months» Placed and removed endoscopically» Mean 25% excess weight loss (vs 8%)» Emerging data to support improvement of NAFLD Proportional to degree of weight loss 45

Summary Points Fatty liver disease is an epidemic NASH is underdiagnosed and associated with high morbidity and mortality Cirrhosis, ESLD, liver cancer Death from cardiovascular disease > liver disease Suspect NAFLD with steatosis on imaging +/- elevated LFTs in at-risk individuals Consider biopsy in patients high risk for NASH Non-invasive diagnostics coming soon Weight loss +/- Vitamin E current standard of care Novel therapies emerging

THANK YOU! Questions? 47