The Spectrum of NAFLD. Hepatology Update: The Year in Review Fatty Liver Disease. Hepatology Update: The Year in Review Fatty Liver Disease

Transcription

1 Ludwig 1980, Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Younossi 1997, Matteoni/Younossi 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos 2001, Ong/Younossi 2001, Bugianesi 2002, Ratziu 2002, Saddeh/Younossi 2002, Harrisson 2003, Marchesini 2003, Younossi 2004, Gramlich/Younossi 2004, Fassio 2004, Sanyal 2004, Ong/Younossi 2005, Adams 2005, Ong/Younossi 2008, Mishra/Younossi 2008, Rafiq/Younossi 2010, Hossain/Younossi 2009, Kim/Younossi 2010, Stepanova/Younossi 2010, Hossain/Younossi 2010, Stepnaova, Younossi 2012, Younossi 2012, Chalasani, Younossi 2012 Hilden 77, Ground 82, Hultcrantz 86, Nomura 88, Nonomura 92, El-Hassan 92, Propst 95, Lonardo 97, Bellentani 2000, Clark 2001, Ruhl 2004, Browning 2004, Angelico 2005, Hamagushi 2005, Jimba 2005, Lin 2005, Fan 2005, Zelber 2006, Zhou 2007, Fan 2007, Targher 2007, Lazo 2008, Younossi 2011, Chalasani 2012 The Spectrum of NAFLD Epidemiology Zobair Younossi MD, MPH, FACG, AGAF, FAASLD Chairman, Department of Medicine, Inova Fairfax Hospital Vice President for Research, Inova Health System Professor of Medicine, VCU-Inova Campus Affiliate Professor of Biomedical Sciences, George Mason University Falls Church, Virginia NAFLD Spectrum Normal NASH requires specific pathologic criteria Exclusion of liver diseases Important for prognosis AASLD Guideline: NAFLD: 6-33% NASH: 3-5% Obese: 75% NAFLD and 19% NASH Morbidly Obese: NAFLD: 93% NASH: 26-49% Diabetes: % 23.4% 4.7% to 38.5% 30-46% % 15.8% 17.1% 9.3% to 29% Prevalence of pediatric NAFLD is % Autopsy study from UCSD (N=742) Prevalence: 9.6%, rates increasing with age More common in boys Highest rate in Hispanics Schwimmer JB 2006, Argo C 2009 Although Most Cases are in Obese/Overweight, Lean Individuals Can Also Have NAFLD 11,613 NHANES-III participants NAFLD was defined as fat by ultrasound, absence of excessive alcohol use and other chronic liver diseases Prevalence of NAFLD in obese and overweight: 17.7% (N=2,061) Prevalence of NAFLD in lean individuals (BMI<25): 3.7% (N=431) Lean NAFLD (N=431) Overweight/ Obese NAFLD (N=2061) White, % ± ± AA, % ± ± Hispanic, % 6.97 ± ± Other ethnicity, % ± ± Male, % ± ± IR, % ± ± 1.77 <0.001 Diabetes, % 6.72 ± ± 1.06 <0.001 High chol,% ± ± 1.53 <0.001 Hypertension, % ± ± 1.91 <0.001 Age, yrs ± ± 0.61 <0.001 Body Mass Index ± ± 0.24 <0.001 HOMA 2.77 ± ± 0.30 <0.001 ALT: SI (U/L) ± ± 0.80 <0.001 AST: SI (U/L) ± ± p What is new in 2015 regarding the clinical impact of NAFLD? Younossi Z et al. Medicine

2 NAFLD in Clinical Practice Houston VA patients ( ) with elevated ALT and no liver diseases (n = 19,692) Random sample (n = 450) Structured chart review to confirm the criteria for NAFLD and metabolic syndrome (n=358) NAFLD Case Definition (n = 251) Persistently increased ALT NAFLD Care defined as: 39% - Recognition of ALT increase 22% - Diagnosis of NAFLD/NASH 15% - Recommend lifestyle changes 10% - Referal specialist evaluation 61% No NAFLD Care Natural History of NAFLD No viral hepatitis No excessive alcohol (2 yr prior) In 2015, Despite Being A Common Cause of CLD, NAFLD Metabolic syndrome, BMI 30 Remains Under-recognized in the Clinical Practice Blais P, et al. Am J Gastroenterol. 2015;110: Only the magnitude and proportion of ALT elevation predictive of receiving NAFLD care Which Type of NAFLD Progresses? What Are the Clinical Predictors of Advanced Fibrosis In NAFLD? NAFLD with liver biopsy (N=432) In multivariate analysis, elevated AST and ALT, presence of diabetes mellitus, male gender and Caucasian ethnicity were associated with moderate to severe fibrosis (p<0.0001) Factors Advanced Fibrosis OR (95% CI) P value Hypertension 1.61 ( ) Diabetes 1.64 ( ) HTN and DM 1.69 ( ) HTN+DM+VO 1.72 ( ) Ludwig 1980, Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Matteoni 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos 2001, Ong 2001,, Bugianesi 2002, Ratziu 2002, Harrisson 2003, Marchesini 2003, Younossi 2004, Fassio 2004, Sanyal 2004, Ong 2005, Adams 2005, Ong 2006, Rafiq 2008, Stepanova 2010, Younossi 2012 Hossain N, et al Gastro and Hepatology

3 What Are the Clinical Predictors of Mortality In NAFLD? What Are the Clinical Predictors of Mortality In NAFLD? Histologic NAFLD (N=289) Clinico-demographic data from the time of biopsy NASH (59.2%), non-nash (40.8%) NASH patients were predominantly female, had higher AST, ALT and higher fasting serum glucose Mortality: During median followup of 150 months NASH patients had higher risk of liver-related mortality than non- NASH NAFLD (p-value = ). Overall mortality Liver-related mortality Risk factor ahr ahr (95% CI) (95% CI) NASH 1.13 ( ) 9.16 ( ) Age 1.07 ( ) 1.06 ( ) Male gender 0.95 ( ) 1.44 ( ) Caucasian race 1.67 ( ) 1.85 ( ) Obesity 0.91 ( ) 0.88 ( ) Type II diabetes 2.09 ( ) 2.19 ( ) Hyperlipidemia 1.01 ( ) 0.48 ( ) Stepanova M, et al. Dig Dis Sci 2013 Stepanova M, et al. Dig Dis Sci 2013 What Are the Histologic Predictors of Mortality In NAFLD? NAFLD liver biopsy and mortality data (N=209) Biopsies were read centrally During follow-up (146 months), 31% of patients died with 9% dying of LRM Despite the pathologic protocol, NASH had higher LRM than non-nash NAFLD 13.0% vs. 1.3%, p = Univariate survival analyses [HR (95% CI), p-value] Portal inflam (grade 2) [6.68 ( ), p<0.001] Ballooning (grade 2) [5.32 ( ), p=0.001] MD bodies (grade 2) [4.21 ( ), p=0.002] Portal fib (grade>2) [14.1 ( ), p<0.001] Pericellular fib (grade>2) [4.86 ( ), p=0.003] On multivariate analysis, only significant fibrosis (grade > 2) was an independent predictor of LRM What is new in 2015 about progressiveness of NAFLD? Younossi Z et al Hepatology

4 Prognostic Relevance of Liver Histology in Nonalcoholic : The PRELHIN study International study of NAFLD (N=619) diagnosed Multivariate Analysis between Fibrosis Hazard Ratio (95% CI) P value All liver biopsies centrally Stage ready Median follow-up 12.6 yrs 0 1 (ref) (0.63, 8.91) who died or had OLT (2.26, 24.94) (4.35, 43.65) < (38.3%) of CV disease < (11.94, ) 36 (18.7%) of non-liver CA 18 (9.3%) of liver In 2015, complication we know that NASH (especially with DM) is associated with LRM and stage of fibrosis>2 is predictive Angulo P et of al LRM AASLD 2014 NAFLD and HCC NAFLD and HCC Several case reports and case series of well documented HCC in patients with NAFLD/NASH Two population-based cohort studies of NAFLD One study suggested 0.3% over 6 years Three clinic based cohort studies of NAFLD or NASH (not restricted to cirrhosis) Up to 6% absolute risk of HCC in approximately 20 year follow up Lower relative risk compared to alcohol or HCV What is new in 2015 regarding association of NAFLD with HCC? White D, Kanwal F, El-Serag H. Clin Gastro Hepatol

5 Cases of HCC in the United States: Data from surveillance, epidemiology and end results (SEER)-medicare registries ( ) SEER represents 28% of U.S. population: Cohort included 5,748 cases of HCC and 17,244 non-hcc matched controls (3:1) Number of HCC cases increased between Cause of chronic liver disease in HCC NAFLD and HCC Independent factors associated with HCC OR (95% CI) Male 4.62 (4.17, 5.11) Non white, non black race 1.74 (1.54, 1.97) (Asians and Hispanics) Presence of any liver diseases HCV (60.30, 79.62) HBV (36.73, 61.01) NAFLD (12.16, 15.29) Lower Charlson Comorbidity 0.17 (0.15, 0.19) Index: Healthier scores Younossi Z, et al. EASL 2015, Vienna. #O041 Fewer HCV/HBV pts died within 1-year of dx vs NAFLD (50% vs 62%, p<0.05) Factors independently associated with one-year mortality (HCC cohort) HR (95% CI) Older age 1.02 (1.01, 1.02) Lowerincome 1.33 (1.20, 1.48) Un staged tumor 1.24 (1.12, 1.37) Medicare eligibility, disabled/esrd 1.39 (1.22, 1.58) NAFLD 1.21 (1.01, 1.45) Factors protective against 1-year mortality HR (95% CI) Liver transplant recipients 0.13 (0.09, 0.17) Having localized tumor stage 0.51 (0.47, 0.55) Younossi Z, et al. EASL 2015, Vienna. #O041 NAFLD and HCC Cox proportional hazard model Adjusted survival curve by liver disease HCV HBV NAFLD month of follow-up after HCC diagnosis *Adjusted for age at HCC diagnosis & tumour stage In 2015, we are increasingly recognizing that NAFLD is an important cause of HCC with higher mortality Liver Biopsy & Pathologic Protocols Clinical and Routine Labs -Not very Helpful Routine Radiologic Test (US, CT, MRI) - Only able to detect fat - Not Fibrosis or NASH New Pathogenic Biomarkers Fibrosis: Fibrotest, ELF, Fibrometer NASH: CK-18, NAFLD Diagnostic Panel Diagnostic & Prognostic Biomarkers for NASH Clinical Predictive Panels - Based on routine tests Fibrosis: - APRI, Fib-4, Simple, BARD, BAAT, Fibrotest, NAFLD Fibrosis Score NASH: - Hair, NASH test, NPI New Modalities - Fibroscan: Central Obesity - MR Elastography better What is new in 2015 about non-invasive tests for NAFLD? 5

6 Magnetic Resonance Elastography vs. Clinical Prediction Models for Advanced Fibrosis in NAFLD Magnetic Resonance Elastography vs. Clinical Prediction Models for Advanced Fibrosis in NAFLD Cross-sectional analysis of 102 patients with biopsy-proven NAFLD Fibrosis stage Total = Advanced fibrosis: 19/102 (18.6%) Number of patients Primary analysis: ROC curves of 8 CPRs CPRs ranking by AUROC FIB-4 CPR AUROC 95% CI AUROC Primary outcome: 2D-MRE vs FIB p= ROC curve of 2D-MRE AUROC: p<0.001 AST to ALT ratio APRI BARD FIB-4 NAFLD Fibrosis Score Bonacini CDS Lok Index NASH CRN Model 1) FIB ( ) 2) Lok Index ( ) 3) Bonacini Cirrhosis Discriminant Score ( ) 4) AST to ALT Ratio ( ) 5) NAFLD Fibrosis Score ( ) 6) BARD ( ) 7) APRI ( ) 8) NASH CRN Model ( ) 0.7 2D-MRE FIB-4 p-value: AUROC of 2D-MRE vs FIB-4 DeLong Test In 2015, FIB-4 or NFS can be used to determine candidates for MRE to avoid a liver biopsy for detection of advanced fibrosis Cui JY, et al. EASL 2015, Vienna. #O020 Cui JY, et al. EASL 2015, Vienna. #O020 Obesity Targets Used for Treatment of Non-alcoholic Pro-inflammatory Adipocytokines (Lept, Resistin, IL- 6, TNF-α) Anti-inflammatory Adipocytokines (Adiponectin) 1st hit Insulin Resistance (Adipose, liver and muscle) Hepatic Steatosis Free Fatty Acids Lipoxicity Apoptotic Pathway ER Stress 2 nd hit NASH 2 nd hit Peroxisomal Fatty Acid Genes That Oxidative Influence these Lipid Peroxidation Oxidation Stress Pathways and the Environment Gut Microbiom And Increased Endotoxin No Progression Impaired Progression Level Mitochondrial Function FIBROSIS Modified from Mishra P, Rafiq N, Younossi Z. Practical Management of Liver Disease 2008 Mazzella N et al. CLD

7 Treatment of NAFLD: Weight Loss Pharmacologic Treatment of NAFLD Metabolic Treatment Target: Insulin Resistance Study N Drug Duration (months) Design ALT Histology Marchesini 14 Metformin 4 Open label + N/A Nair 15 Metformin 12 Open label + N/A Bugianesi 55 Metformin 6 RCT + + Uygun 17 Metformin 6 RCT + - Duseja 7 Metformin 6 Open label + N/A Schwimmer 10 Metformin 6 Open label + N/A Morita 5 Nateglinide 5 Open Yes Yes Pharmacologic Treatment of NAFLD Metabolic Treatment Target: Insulin Resistance Author N Drug Time DM? Cirrhosis ALT Fat Bal Infl Fibrosis Caldwell 2001 Promrat 2004 Aithal 2008 Belfort 2006 Ratziu 2008 Sanyal 2010 Mahady 2011* 10 Troglit 400 mg 18 Pio 30 mg Pio mg Pio 45 mg Rosi 8 mg Pio 30 mg 3-6 months 12 1/10 Yes Yes? No?Yes No No No Yes Yes Yes Yes Yes 12 mo No Yes Yes Yes Yes Yes Yes 6 mo Yes No Yes Yes Yes Yes mo Yes No Yes Yes wk No No Yes Yes --- Yes --- n/a n/a n/a n/a Yes Metabolic Treatment Target: Insulin Resistance PIVENS: RCT NASH without DM (N=247) Pioglitazone 30 mg/d (N=80) for 96 weeks Vit E 800 IU/d (N=84) for 96 weeks Placebo (N=83) for 96 weeks Pre- and Post Liver Biopsy Primary endpoint: NAS score decrease of 2 (no higher fib) Secondary endpoints (Path features, enzymes, etc.) Met primary endpoint: Pi 34%, VE 43% & P 19% Histologic secondary endpoints were seen for both Pio and Vit E but no improvement in fibrosis scores Conclusions: Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH. (Strength 1, - Vit E superior to placebo Evidence - A) - Pio did not meet pre-specified primary endpoint Pioglitazone can be (?) used to treat steatohepatitis in patients with biopsy- -proven Other NASH. issues However, include weight it should gain be during noted treatment that majority and that of the improvement patients who of participated liver enzymes in clinical not sustained trials that investigated pioglitazone for NASH were nondiabetic and that long term safety and efficacy of pioglitazone in patients with NASH is not established. Sanyal (Strength A et al N 1, Engl Evidence- J Med. B) 362(18), (2010) 7

8 Pharmacologic Treatment of NAFLD Treatment Target: Oxidative Stress Treatment: Lipid Lowering Agents Authors N Dose Comparators Outcomes Arendt IU/d Placebo Sanyal IU/d Lavine IU/d Pioglitazone, placebo Metformin, placebo Improved steatosis (assessed by CT scan) vs placebo Improved steatosis, inflammation, and ballooning vs placebo Improved steatohepatitis and ballooning vs placebo Harrison Vitamin 45 E (a-tocopherol) 1000 IU/d administered Placeboat daily Improved dose of 800 fibrosis IU/day vs improves baseline liver histology in non-diabetic adults with biopsy-proven NASH and therefore Vitamin E + Sanyal it should 20 be considered 400 IU/das a first-line pharmacotherapy Improved steatosis for this patient vs baseline population. (Strength -1, Quality pioglitazone - B) Until further data supporting its UDCA effectiveness + become Improved available, steatosis, vitamin E is Dufour not recommended to IU/d treat NASH placebo, in diabetic patients, inflammation, NAFLD and without ballooning liver vs biopsy, NASH cirrhosis, or cryptogenic placebo cirrhosis (Strength baseline - 1, Quality - C) Study Design (mts) Meds N ALT Hist Laurin Open label (12) Clofibrate Fernández- Open label (12) Fenofibrate /- Miranda C Basaranoglu RCT (1) Gemfibrozil 46 + NA Horlander Open label (12) Atrovastatin Kiyici Open label (6) Atrovastatin 27 + NA Hatzitolios Open label (6) Atrovastatin + NA Gomez- Open label (12) Atrovastatin 25 + NA Dominguez Given the lack of evidence to show that patients with NAFLD and NASH are Rallidis at increased Open risk for label serious (7) drug-induced Pravastatin liver injury from 5 statins, + statins +/- Ekstedt can be used Retrospect to treat dyslipidemia ( in yrs) patients Statins with NAFLD 68 and NASH + + Merat (Strength RCT 1, Quality (6) B) Probucol 30 + NA Nelson Until RCTs RCT with histological (12) endpoints Simvastatin prove their efficacy, 14 statins + should - Park not be used Open to specifically label (24) treat NASH Ezetimibe (Strength 1, Quality 45 B) + +/- Other Treatment Regimens for NAFLD with Limited Data Antioxidants Betaine N-Acetyl-cysteine Lecithin Silymarin Beta-carotene Anti-TNF agents (Pentoxifylline) Probiotics (VSL#3) ACE inhibitors/arbs Caspase inhibitors Cytoprotective agents/bile Acids - Ursodeoxycholic acid (UDCA) What is new in 2015 about treatment of NAFLD? 8

9 New Targets For Treatment of NASH Obeticholic Acid (OCA) Class Farnesoid X receptor (FXR) agonist Anti-lysyl oxidase-like 2 monoclonal antibody Fatty acid/bile acid conjugate Dual inhibitor of CCR2 and CCR5 Dual peroxisome proliferator-activated receptor alpha/delta agonist Drug Obeticholic acid Simtuzumab Aramchol Cenicriviroc GFT505 Semisynthetic bile acid analog (6α-ethyl-chenodeoxycholic acid) 100 times more potent than chenodeoxycholic acid in binding farnesoid X receptor Treatment with OCA has been associated with Improved insulin sensitivity Reductions in markers of liver inflammation and fibrosis Reductions in triglyceride levels Dose-related weight loss OCA was generally well tolerated; adverse effects were similar across treatment groups Increases in LDL and reductions in HDL Mudaliar S, et al. Gastroenterology. 2013;145: FLINT Phase 2 Trial Design The Farnesoid X Receptor Ligand Obeticholic Acid (OCA) in NASH Treatment FLINT Study: Improved Liver Histology after 72 Weeks of Treatment Interim Analysis when 50% of patients completed treatment and had an end-of-treatment liver biopsy N=283 Patients w/ Histological Evidence of NASH Placebo QD OCA 25 mg QD Follow up Follow up Screening (Biopsy) 72 week Treatment Period 24 week off-drug Primary endpoint: Histological improvement defined as: No worsening in fibrosis; and Decrease in NAS of 2 points Brent A Neuschwander-Tetri et al Lancet 2014 Subgroup with T2DM (OCA: 53% vs placebo 19%, p<0.05) Modest improvement in IR Lipid changes in OCA vs. placebo (HDL, LDL ) Decision: Stop treatment phase of trial as it met efficacy endpoint and no further biopsies Planned phase III RCT Brent A Neuschwander-Tetri et al Lancet

10 Secondary Histologic Endpoints Changes in Lipid Profile Endpoint OCA 25 mg Placebo P-value Fibrosis Improvement (%) 35% 19% 0.01 Hepatocellular Ballooning (%) 46% 31% 0.03 Steatosis (%) 61% 38% Lobular Inflammation (%) 53% 35% Lipid Parameters Measured Total cholesterol LDL HDL Triglycerides OCA Pla OCA Pla OCA Pla OCA Pla Baseline Baseline - 72 wks (n=257) +6* -7* +9* -8* -1* +1* Baseline - 96 wks (n=240) NASH Resolution (%) 22% 13% 0.08 * P 0<0.01 for OCA vs. placebo Neuschwander-Tetri et al. Lancet 2014 Neuschwander-Tetri et al. Lancet 2014 FLINT: Safety and Tolerability Aramchol Mechanism of Action Pruritus higher in OCA group (23% vs 6%) and of higher grade (predominantly moderate pruritus) 1 discontinuation of OCA due to pruritus Other AEs were similar to placebo No differences in severe AEs and most events judged to be unrelated to therapy A large Phase III double-blind, placebo-controlled trial to assess Neuschwander-Tetri et al. Lancet 2014 the safety and efficacy of OCA in adult patients with NASH Synthetic molecule: Conjugated bile acid + saturated fatty acid 1 Reduces hepatic fat via 2 pathways: Inhibits stearoyl coenzyme A desaturase 1 (SCD1) activity, a key enzyme of fatty acid metabolism 1,2 Activates cholesterol efflux by stimulating ATP-binding cassette transporter A1 (ABCA1), a pan-cellular cholesterol pump 1,3 1. Safadi R, et al. Clin Gastroenterol Hepatol. 2014;12: Leikin-Frenkel A, et al. Arch Med Res. 2010;41: Goldiner I, et al. Biochem J. 2006;396:

11 Aramchol 3-Month Phase IIa Trial Liver Fat Content Change from Baseline Safadi R, et al. Clin Gastroenterol Hepatol. 2014;12: Placebo (n = 19) Aramchol 100 mg (n = 18) Aramchol 300 mg (n = 20) P =.02 for aramchol 300 mg vs placebo Phase IIb, 1-year, multicentre, randomised, double-blind, placebocontrolled, international trial to assess the safety and efficacy of 2 aramchol doses (400 mg or 600 mg) vs placebo in noncirrhotic adult Frequency of adverse effects were similar between groups; all adverse effects were mild/moderate patients with NASH GFT505 Mechanism of Action Dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist 1 Improves lipid and glucose metabolism in prediabetics 2 Improves hepatic and peripheral insulin sensitivity in obese patients 3 Improves steatohepatitis and fibrosis in mouse models 1 Antifibrotic and anti-inflammatory effect 1 PPAR-α PPAR-δ Expression Hepatocytes Ubiquitous Action Lipid and lipoprotein metabolism Anti-inflammatory Mitochondrial function, fatty acid oxidation & IS Anti-inflammatory Phase IIb, 1-year, international, multicentre, randomised, double-blind, placebo-controlled 1. Staels B, et al. Hepatology. trial 2013;58: to assess the safety and efficacy of GFT505 (80 2. Cariou B, et al. Diabetes Care. 2011;34: mg 3. or Cariou 120 B, mg et al. Diabetes vs. placebo Care. 2013;36: in noncirrhotic adult patients with NASH Simtuzumab Mechanism of Action Humanised monoclonal antibody 1 Inhibits cross-linking of collagen in pathologic stroma 1,2 Lysyl oxidase-like 2 (LOXL2) levels may correlate with extent of fibrosis and clinically relevant endpoints for idiopathic pulmonary fibrosis (IPF) 2 Very limited data from early human trials Phase IIb, 240-week dose-ranging (200 mg or 700 mg IV q2 weeks, randomised, double-blind trial to assess the efficacy and safety of simtuzumab in adult cirrhotic patients with NASH; followed by optional open-label phase 1. Ratziu V. Nat Rev Gastroenterol Hepatol. 2013;10; Barry-Hamilton V, et al. Nat Med. 2010;16: NASH Treatment Summary 2015 Since the original description of NASH over 30 years ago, despite dozens of clinical trials of different agents, we have failed to identify a single effective treatment for most patients with NASH Research design flaws and Little attention to the complex pathogenic There some promising new treatment protocols Given the heterogeneity of NASH phenotype, targeted treatment using a personalized medicine approach based on pathogenic pathways, clinical and prognostic biomarkers may be required Younossi Z et al APT

12 How Do We Manage our NAFLD Patients in 2015? How Do We Manage our NAFLD Patients in 2015? Elevated aminotransferases Fatty Liver by imaging Exclude other causes of CLD Confirm lack of excessive ETOH Assess risk factors Consider Assessment for IR Histologic NASH Liver biopsy Simple Steatosis No evidence of other CLD Young age No evidence of adv LD Suspicion for other CLD Dx of NAFLD uncertain Continue life style and modifications If non-diabetic: VIT E If diabetic: Pioglitazone? Refer to primary for management of MS and risk of CVD Self directed life style modifications Professionally directed life style modification Repeat lab in 6 months Unsuccessful Goals achieved Risks (DM, IR) Monitor q 6-12 m Liver enzymes elevated High NAFLD Fibrosis score Liver biopsy Medical treatment unsuccessful Consider RCT of new agents Consider Bariatric surgery for those who meet criteria (Summary for 2015) NAFLD is common but is under-recognized in clinical practice NASH patients have higher LRM Stage 2 or greater in NASH is predictive of LRM Liver biopsy remains the gold standard for diagnosis of NASH MRE is the most promising non-invasive test for NASH Clinical predictive tests for fibrosis (NFS and Fib-4) and MRE may be useful clinically to avoid liver biopsy Current treatment considerations for patients with NASH: Life style modifications for all Vitamin E for non-dm NASH??Pio for DM with NASH but be aware of safety concerns Consider bariatric surgery for morbidly obese+/-dm with NASH Future treatment considerations: Clinical trials of new agents are underway 12