Non-Alcoholic Fatty Liver Disease

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1 Non-Alcoholic Fatty Liver Disease Varun Saxena, MD MAS Gastroenterology and Hepatology Kaiser Permanente South San Francisco Assistant Clinical Professor University of California San Francisco January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

2 Grand Rounds: 1/25/2017 Please sign the attendance sheet in the room to claim your credit. Kaiser Permanente South San Francisco has determined that the speakers (Dr. Saxena, Dr. Kao) and the planning committee (Dr. Becker, Dr. Sheikh, Dr. Zheng, Dr. Liu, Dr. Jones, Rebecca Bayrer, Heather Miller) for this activity do not have any relevant financial relationships. Kaiser Permanente South San Francisco takes responsibility for the content, quality, and scientific integrity of this CME Activity. Kaiser Permanente does not endorse any brand-name products. January , Kaiser Foundation Health Plan, Inc For internal use only

3 Objectives Describe the clinical presentation, prevalence, and diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) Evaluate and refer patients who may be higher risk for complications from Non-Alcoholic Fatty Liver Disease (NAFLD) Develop follow-up plan for patients with abnormal liver function tests 3 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

4 Outline U.S. Obesity Epidemic Definitions and Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Fatty Liver (NAFL) and Non-Alcoholic Steatohepatitis (NASH): Case Presentation Diagnosis of NAFLD and NAFL vs. NASH Natural History of NAFL vs. NASH Treatment of NASH 4 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

5 Outline U.S. Obesity Epidemic Definitions and Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Fatty Liver (NAFL) and Non-Alcoholic Steatohepatitis (NASH): Case Presentation Diagnosis of NAFLD and NAFL vs. NASH Natural History of NAFL vs. NASH Treatment of NASH 5 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

6 What U.S. state has the lowest / highest rate of obesity and what are those rates? A. California 20% / Alabama 33% B. Colorado 20% / Mississippi 36% C. California 24% / Alabama 36% D. Colorado 24% / Mississippi 33% 0% 0% 0% 0% 0% 0% Data per the CDC2015 California 20% Colorado 20% Montana 20% California 24% Colorado 24% Montana 24% 6 August 1, Kaiser Foundation Health Plan, Inc. For internal use only.

7 What U.S. state has the lowest / highest rate of obesity and what are that rates? FYI - Data is from the CDC 2015 A. California (20%) / Alabama (33%) B. Colorado (20%) / Mississippi (36%) C. California (24%) / Alabama (36%) D. Colorado (24%) / Mississippi (33%) 7 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

8 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

9 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

10 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

11 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

12 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

13 13 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

14 Outline U.S. Obesity Epidemic Definitions and Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Fatty Liver (NAFL) and Non-Alcoholic Steatohepatitis (NASH): Case Presentation Diagnosis of NAFLD and NAFL vs. NASH Natural History of NAFL vs. NASH Treatment of NASH 14 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

15 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes New Patient to Your Clinic Asymptomatic on today s visit Past medical history: dyslipidemia, type 2 diabetes Family History: Mother: diabetes, hypothyroidism Father: alcohol-related cirrhosis Social History: Works at SFO with luggage Used to drink 1-2 beers per night, quit as New Years resolution No tobacco or illicit normal normal normal Physical exam: BP 130/85 BMI 34, central obesity Acanthosis nigricans No stigmata of cirrhosis, liver 3cm below costal margin Normal cardiopulmonary exam No splenomegaly Normal skin and nails Total Cholesterol: 220 HDL: 33 LDL: 143 Triglycerides: 256 A1c: January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

16 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes New Patient to Your Clinic Besides management of his metabolic risk factors (cholesterol, T2DM and obesity), what do you do next regarding his abnormal liver enzymes? A. Call GI On-Call for Advice B. Send Your Favorite GI at Kaiser SSF a Message on HealthConnect for Advice C. Get an Ultrasound D. Refer to econsult on Abnormal Liver Enzymes and send a bunch of blood tests E. Both C and D F. Repeat liver enzymes in 6 months Call GI On Call for Advice Send Your Favorite GI at... 0% 0% 0% 0% 0% 0% Get an Ultrasound Refer to econsult on Ab... Both C and D Repeat liver enzymes in.. 16 August 1, Kaiser Foundation Health Plan, Inc. For internal use only.

17 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes New Patient to Your Clinic Besides management of his metabolic risk factors (cholesterol, T2DM and obesity), what do you do next regarding his abnormal liver enzymes? A. Call GI On-Call for Advice B. Send Your Favorite GI at Kaiser SSF a Message on HealthConnect for Advice C. Get an Ultrasound D. Refer to econsult on Abnormal Liver Enzymes and send a bunch of blood tests E. Both C and D F. Repeat liver enzymes in 6 months 17 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

18 New Abnormal Liver Enzymes econsult Clinical Decision - Flow Diagram 18 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

19 New Abnormal Liver Enzymes econsult Clinical Decision - Flow Diagram 19 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

20 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes Follow-Up Visit You send your patient to weight loss program and start him on metformin. His BMI is now 33 and you repeat the blood tests: normal normal normal Total Cholesterol: 193 HDL: 33 LDL: 121 Triglycerides: 201 A1c: 6.8 He has not started any new medications or herbal supplements besides what you prescribed and he continues to be abstinent from alcohol. 20 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

21 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes What Liver Diseases Need to Be Excluded in This Patient? Alcoholism Autoimmune liver disease Wilson disease Viral hepatitis, hemochromatosis, alpha-1-antitrypsin def Common, father with alcoholism Mother with hypothyroidism; very specific therapy Age, devastating if not treated; very specific therapy Risk factors, can t miss this; very specific therapies 21 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

22 New Abnormal Liver Enzymes econsult Clinical Decision - Flow Diagram 22 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

23 New Abnormal Liver Enzymes econsult Clinical Decision - Flow Diagram 23 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

24 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes Follow-Up Visit You follow the abnormal liver enzymes econsult recommendations and send additional blood tests and obtain an ultrasound: Hepatitis A Total IgG: Positive Hepatitis B Surface Antigen: Negative Hepatitis B Surface Antibody: Positive Hepatitis B Core Antibody IgG: Negative Hepatitis C Antibody: Negative Ferritin: normal Iron: normal TIBC: normal % Sat: normal He completes his ultrasound which shows fatty infiltration of the liver. Ceruloplasmin: normal Alpha-1-Antitrypsin Level: normal Anti-Nuclear Antibody: negative Anti-Actin Antibody: normal Quantitative IgG: normal 24 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

25 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes New Patient to Your Clinic Which of the following have you officially diagnosed in your patient? A. Non-Alcholic Fatty Liver Disease (NAFLD) B. Non-Alcholic Fatty Liver (NAFL) C. Non-Alcholic Steatohepatitis (NASH) D. None of the above, he just has abnormal liver enzymes Non Alcholic Fatty Liver... 0% 0% 0% 0% Non Alcholic Fatty Liver... Non Alcholic Steatohepat... None of the above, he ju.. 25 August 1, Kaiser Foundation Health Plan, Inc. For internal use only.

26 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes New Patient to Your Clinic Which of the following have you officially diagnosed in your patient? A. Non-Alcoholic Fatty Liver Disease (NAFLD) B. Non-Alcoholic Fatty Liver (NAFL) C. Non-Alcoholic Steatohepatitis (NASH) D. None of the above, he just has abnormal liver enzymes 26 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

27 Non-Alcoholic Fatty Liver Diseasae (NAFLD) Terminology Non-alcoholic fatty liver (NAFLD) definition / diagnosis: Hepatic steatosis on imaging or liver biopsy Ethanol intake <20-30g daily Absence of other causes of liver disease No medications known to cause hepatic steatosis Farrell, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

28 Non-Alcoholic Fatty Liver (NAFL) and Non- Alcoholic Steatohepatitis (NASH) Terminology Non-alcoholic fatty liver (NAFL) definition / diagnosis: Simple fat (steatosis) no inflammation, necrosis or fibrosis Largely benign Non-alcoholic Steatohepatitis (NASH) definition / diagnosis: Steatotis and injury (ballooning, inflammation, fibrosis) A potentially serious liver disease Farrell, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

Non-Alcoholic Fatty Liver Disease (NAFLD) NAFL (NAS)

Fat Inflammatory cells Ballooned Liver cells ±

Risk of Hepatocellular Carcinoma 29 January 25, 2017

29 Non-Alcoholic Fatty Liver Disease (NAFLD) NAFL (NAS) NASH Hepatic Fat Farrell, Hepatology, 2006 Hepatic Fat Inflammatory cells Ballooned Liver cells ± Fibrosis Cirrhosis Inflammation ± Hepatic Fat High Risk of Hepatocellular Carcinoma 29 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

30 Risk Factors for NAFLD Obesity/central adiposity Insulin resistance Hypertriglyceridemia Hypertension Bedogni, Hepatology, 2005 Chalassani, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

31 Risk Factors for NAFLD Obesity/central adiposity Insulin resistance Hypertriglyceridemia Hypertension NAFLD is the hepatic manifestation of the metabolic syndrome Bedogni, Hepatology, 2005 Chalassani, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

32 Risk Factors for NAFLD Obesity/central adiposity Insulin resistance Hypertriglyceridemia Hypertension Hispanic ethnicity Hereditary/genetic PCOS HIV Sleep apena Hypothyroidism Pancreato-duodenal resection Hypogonadism NAFLD is the hepatic manifestation of the metabolic syndrome Bedogni, Hepatology, 2005 Chalassani, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

33 Other Causes of Hepatic Steatosis If have these, then do not have NAFLD Examples of other causes of fatty liver Excessive alcohol consumption Malnutrition Medications (Methotrexate) Parenteral nutrition Examples of other liver disease that can present with steatosis Hepatitis C (genotype 3), acute hepatitis D Lipodystrophy Wilson s disease Lysosomal acid lipase deficiency Hemachromatosis Angulo, Hepatology, 2007 Brunt, Nat Rev Dis Primers, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

34 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes You have diagnosed NAFLD How are we going to figure out if he has NAFL or NASH? Does he need a liver biopsy? If we biopsied every patient like him, IR would only be doing liver biopsies! 34 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

35 Clinical Predictors of NASH in Patients with NAFLD Characteristic Advanced age [1] Sex [2] Race [3] HTN, central obesity, dyslipidemia ( TG, HDL), insulin resistance/diabetes [4] AST/ALT ratio > 1, [7] low platelets [8] Persistently elevated ALT [9] *Based on ATP III criteria. 1. McPherson, Am J Gastroenterol, Yang, Hepatology, Pan, World J Hepatology, 2014 Outcome Greater duration of disease Postmenopausal women experience accelerated disease Prevalence, severity in Hispanic, Asian patients; Prevalence, severity in black patients Risk increases with metabolic syndrome, * particularly if older than 50 yrs of age and obese or diabetic [5,6] Indicators of NASH cirrhosis Can be associated with greater risk of disease progression 4. Younossi, Hepatology Ratziu, Gastroenterology, Angulo, Hepatology, Neuschwander-Tetri, Hepatology, McPherson, Gut, Ekstedt, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

36 NAFL vs. NASH Only NASH causes liver fibrosis We have non-invasive ways of diagnosing liver fibrosis Let s use non-invasive ways of dx ing liver fibrosis to predict NASH 36 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

37 Noninvasive Diagnosis of Liver Fibrosis in NAFLD Clinical or Laboratory Tests Imaging Simple AST/platelet ratio index FIB-4 index NAFLD fibrosis score BARD score Complex NASH FibroSure ELF HepaScore Elastography VCTE FibroScan MR elastography ARFI 37 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

38 Noninvasive Clinical or Lab Tests Distinguish NASH Stages 0-2 vs Sensitivity (%) Negative Predictive Value for F3-F4 (%) FIB4 score 95 AST/ALT 93 BARD 95 APRI 84 NAFLD Specificity (%) Strength of noninvasive fibrosis predictive tests is in their ability to exclude advanced disease (F3-F4) Least accurate in identifying middle ranges of fibrosis 1. McPherson, Gut, McPherson, Am J Gastroenterol, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

39 Noninvasive Diagnosis of Liver Fibrosis in NAFLD Clinical or Laboratory Tests Imaging Simple AST/platelet ratio index FIB-4 index NAFLD fibrosis score BARD score Complex NASH FibroSure ELF HepaScore Elastography VCTE FibroScan MR elastography ARFI 39 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

40 NAFLD Fibrosis Score and FIB-4 Score NAFLD Fibrosis Score: Parameter Age, yrs AST ALT Platelet count, cells x 10 9 BMI Albumin, g/l Impaired fasting glucose/diabetes? FIB-4 score: NAFLD Cutoff Value [1] Stage < F0-F to Indeterminate > F3-F4 1. Angulo, Hepatology, Sterling, Hepatology, 2006 FIB-4 Cutoff Value [2] Stage < 1.45 F0-F to 3.25 Indeterminate > 3.25 F3-F4 40 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

41 New Abnormal Liver Enzymes econsult Clinical Decision - Flow Diagram 41 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

42 New Abnormal Liver Enzymes econsult Clinical Decision - Flow Diagram 42 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

43 New Fatty Liver Disease econsult For Class Clinical Decision - Flow Diagram 43 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

44 New Fatty Liver Disease econsult For Class Clinical Decision - Flow Diagram 44 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

45 New Fatty Liver Disease econsult For Class Clinical Decision - Flow Diagram 45 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

46 New Fatty Liver Disease econsult For Class Clinical Decision - Flow Diagram 46 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

47 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes Calculating NAFLD and FIB-4 NAFLD Fibrosis Score: Parameter Our Patient Age, yrs 39 AST 88 ALT 44 Platelet count, cells x BMI 33 Albumin, g/l 3.9 Impaired fasting glucose/diabetes? YES FIB-4 score: 3.34 NAFLD Cutoff Value [1] Stage < F0-F to Indeterminate > F3-F4 1. Angulo, Hepatology, Sterling, Hepatology, 2006 FIB-4 Cutoff Value [2] Stage < 1.45 F0-F to 3.25 Indeterminate > 3.25 F3-F4 47 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

48 New Fatty Liver Disease econsult For Class Clinical Decision - Flow Diagram 48 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

49 New Fatty Liver Disease econsult For Class Clinical Decision - Flow Diagram 49 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

Patient Case: 39-Yr-Old Hispanic Male with Obesity,

Fatty Liver Disease Class After learning about

NASH, Stage 3 Fibrosis F1: Perisinusoidal F2:

Cirrhosis Farrell, Hepatology, 2006 50 January 25,

50 Patient Case: 39-Yr-Old Hispanic Male with Obesity, T2DM and Abnormal Liver Enzymes He Attends the Fatty Liver Disease Class After learning about fatty liver disease, he opts for a liver biopsy: NASH, Stage 3 Fibrosis F1: Perisinusoidal F2: Perisinusoidal + Portal F3: Bridging Fibrosis F4: Cirrhosis Farrell, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

51 Outline U.S. Obesity Epidemic Definitions and Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Fatty Liver (NAFL) and Non-Alcoholic Steatohepatitis (NASH): Case Presentation Diagnosis of NAFLD and NAFL vs. NASH Natural History of NAFL vs. NASH Treatment of NASH 51 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

52 Progression of NAFL to NASH to Hepatocellular Carcinoma Based on best estimates Farrell, Hepatology, 2006 Younoussi, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

NAFLD Disease Progression Histological Subtypes 1,2

Regression: 18%-22% Isolated steatosis Steatosis with

Fibrosis Progression: 34-42% *N = 108 pts with

6 yrs follow-up (data from serial biopsies). 1.

53 NAFLD Disease Progression Histological Subtypes 1,2 NAFLD 70% to 75% 25% to 30% Change in Fibrosis* 3,4 Regression: 18%-22% Isolated steatosis Steatosis with mild inflammation NASH Stable: 40%-43% Cirrhosis Fibrosis Progression: 34-42% *N = 108 pts with NAFL/NASH and median 6.6 yrs follow-up (data from serial biopsies). 1. Ludwing, Mayo Clin Proc, Kleiner, Hepatology, McPherson, J Hepatol, Singh, Clin Gastroenterol Hepatol, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

54 Mortality in Patients with NAFLD Patients with NAFLD (N = 420) matched by age and sex to general population in Minnesota, followed for 7.6 ± 4.0 yrs General population Patients with NAFLD P =.03 Survival (%) Survival at 10 Yrs General population: 87% Patients with NAFLD: 77% Log-rank P <.005 Top 3 Causes of Death in NAFLD, % Patients (n = 53) Malignancy 28 Ischemic heart disease 25 Liver disease Yrs Adams, Gastroenterology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

55 Mortality Due to NASH Among Patients with NAFLD Patients with NAFLD (N = 129) matched by age and sex within same county in Sweden and followed for 13.7 yrs (SD: 1.3 yrs) 100 Nonalcoholic Liver Steatosis ± Nonspecific Inflammation 100 NASH Survival (%) General population Patients with nonalcoholic steatosis ± unspecific inflammation Survival (%) General population Patients with NASH 20 P = NS 20 P = Yrs Ekstedt, Hepatology, Yrs 55 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

56 Pts Aged Yrs NASH: Number One Indication for Liver Transplant in Pts Aged < 50 Yrs In 2015 registry of pts listed for liver transplant, NASH surpassed HCV infection Banini, ACG, 2016 Abstract 46 Etiology Among Pts Listed for Liver Transplant NASH and cryptogenic cirrhosis P <.0001 HCV infection NASH Cirrhosis HCV Infection 56 January 25, Kaiser Foundation Health Plan, Inc. For internal use only. Change in Etiology From (%)

57 Outline U.S. Obesity Epidemic Definitions and Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Fatty Liver (NAFL) and Non-Alcoholic Steatohepatitis (NASH): Case Presentation Diagnosis of NAFLD and NAFL vs. NASH Natural History of NAFL vs. NASH Treatment of NASH 57 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

58 Percentage of Weight Loss Associated With Histological Improvement in NAFLD Analysis of data from 4 randomized studies Weight loss 10% Weight loss 7% Fibrosis regression (45% of pts) NASH resolution (64% to 90% of pts)* Weight loss 5% Ballooning/inflammation (41% to 100% of pts)* Weight loss 3% Hannah, Clin Liver Dis, 2016 Steatosis (35% to 100% of pts)* *Depending on degree of weight loss. 58 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

59 Pharmacologic Treatment Options Studied in NASH Agent Good Evidence for Use [1] Limited or Insufficient Evidence for Use [1] AASLD NAFLD/NASH Recommendation [2] Vitamin E NASH without diabetes NASH with diabetes or cirrhosis NASH without diabetes Pioglitazone NASH with or without diabetes NASH with cirrhosis Can be used for steatohepatitis Metformin No significant effect on liver histology [2] Not recommended Pentoxifylline Needs further study to determine ideal subpopulation 1. Rinella, Gastroenterol Hepatol, Chalasani, Hepatology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

60 Bariatric Surgery Improves Clinical Parameters Prospective study following bariatric surgery in pts who are severely obese (N = 381) with 1 comorbidity, no excessive drinking < 2 yrs, no chronic liver diseases Liver biopsies assessed by 2 blinded reviewers for fibrosis (F0-4), NAFLD scoring to determine NASH ( 3, probable or definite; 5, definite) Parameter Before Surgery After 5 Yrs P Value Diabetes mellitus, n (%) 94 (24.8) 24 (10.8) Arterial hypertension, n (%) 185 (48.8) 85 (37.0).0005 Serum triglycerides, mean (g/l) Fasting glucose, mean (g/l) Insulin resistance index, mean ALT, mean (IU/L) GGT, mean (IU/L) Mathurin, Gastroenterology, January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

61 Bariatric Surgery Improves Fibrosis in Patients with NASH Prospective study of bariatric surgery in pts who are morbidly obese with biopsy-validated NASH, 1 comorbidity factor for > 5 yrs, no chronic liver disease (N = 109) Pts (%) Lassailly, Gastroenterology, 2015 Distribution of Fibrosis METAVIR Scores Baseline January 25, Kaiser Foundation Health Plan, Inc. For internal use only After 1 Yr Wilcoxon signedrank paired t test P <.003 Fibrosis METAVIR Score F4 F3 F2 F1 F0

62 Emerging Treatments in NASH: Phase III Drug Mechanism of Action Study Population Trial Primary Endpoint(s) Elafibranor PPAR α/δ agonist [1] NASH with fibrosis RESOLVE-IT [2] Resolution of NASH w/o fibrosis worsening Obeticholic acid FXR agonist (bile acid) [3] NASH with fibrosis REGENERATE [4,5] Improvement in fibrosis w/o NASH worsening; improvement in NASH w/o fibrosis worsening 1. Ratziu, Gastroenterology, ClinicalTrials.gov. NCT January 25, Kaiser Foundation Health Plan, Inc. For internal use only. 3. Neuschwander-Tetri, Lancet, ClinicalTrials.gov. NCT Ratziu, EASL 2016, Abstract THU-488

63 Emerging Treatments in NASH: Phase II Drug Cenicriviroc Simtuzumab Mechanism of Action Inhibitor of CCR2/CCR5 Monoclonal antibody to LOXL2 [3] Study Population Trial Primary Endpoint(s) NASH with liver fibrosis Liver fibrosis secondary to NASH CENTAUR [1,2] NCT [4] Improvement in NAS w/o fibrosis worsening Morphometric quantitative collagen change; EFS Fatty acid bile Aramchol acid conjugate [5] NASH Aramchol_005 [6] Change in liver triglycerides by NMRS Liraglutide GLP-1 analogue Overweight NASH LEAN [7,8] Resolution of NASH w/o fibrosis worsening GR-MD-02 Emricasan Galectin-3 inhibitor [9] Caspase inhibitor Liver fibrosis and portal hypertension in NASH cirrhosis NASH with liver fibrosis NASH-CX [10] ENCORE-NF [11] Improvement in HVPG Improvement in fibrosis w/o NASH worsening 1. ClinicalTrials.gov. NCT Friedman, Contemp Clin Trials, Meissner, Liver Int, ClinicalTrials.gov. NCT Safadi, Clin Gastroenterol Hep, ClinicalTrials.gov. NCT Armstrong, Lancet, ClinicalTrials.gov. NCT Harrison, Aliment Pharmacol Ther, ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

64 Emerging Treatments in NASH: Phase II Drug(s) Selonsertib Mechanism(s) of Action ASK1 inhibitor Study Population NASH with F2- F3 liver fibrosis Trial GS-US [1,2] Primary Endpoint(s) Safety and tolerability JKB-121 TLR-4 antagonist NASH Pro [3] change in ALT, hepatic Safety and tolerability; fat; TTP NGM-282 FGF-19 agonist [4] NASH [5] Change in hepatic fat BMS FGF-21 agonist NASH MB [6] Safety and tolerability; change in hepatic fat GS-0976 ACC inhibitor NASH GS-US [7] Safety and tolerability GS-9674, GS-0976 FXR agonist (bile acid) ACC inhibitor NAFLD GS-US [8] Safety and tolerability Volixibat ASBT inhibitor NASH NCT [9] Improvement in NAS w/o fibrosis worsening 1. Loomba, AASLD 2016, Abstract LB-3 2. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT Hegade. Therap Adv Gastroenterol, ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

65 Take Home Points Non-Alcoholic Fatty Liver Disease (NAFLD) is very common and Non-Alcoholic Steatohepatitis (NASH) is a serious liver condition Follow the new econsults for your abnormal liver enzyme and fatty liver disease patients, provide me feedback to improve #1 Treatment for NAFLD, NAFL and NASH is weight loss Pharmacologic treatment options include Vitamin E and pioglitazone with numerous therapies in the pipeline NASH is an indication for bariatric surgery 65 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

66 Any Questions? 66 January 25, Kaiser Foundation Health Plan, Inc. For internal use only.

67 Please sign the attendance sheet in the room to claim your credit. Please complete the Online Survey: This survey will be ed to participants and will close within 10 days of the date the was sent. 67 August 1, Kaiser Foundation Health Plan, Inc. For internal use only.

NAFLD and NASH: The Not-So-New Kids on the Block

NAFLD and NASH: The Not-So-New Kids on the Block Mary E. Rinella, MD Associate Professor of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois This program is supported by an