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

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1 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 educational grant from Intercept Pharmaceuticals, Inc.

2 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 Pts Aged Yrs NASH and Cryptogenic Cirrhosis Etiology Among Pts Listed for Liver Transplant NASH and cryptogenic cirrhosis P <.0001 HCV infection HCV Infection Change in Etiology From (%) Banini BA, et al. ACG Abstract 46.

3 Patient Case: 25-Yr-Old Hispanic Male With Obesity, T2DM, and ALT Elevation Referred by PCP for mild ALT/AST elevation (70/63) Other liver chemistries normal over past yr Ferritin 500 ng/ml No current meds Past medical history: dyslipidemia, type 2 diabetes Family history: Mother: diabetes, hypothyroid Physical exam BP 130/85 BMI 32, central obesity Acanthosis nigricans No stigmata of cirrhosis, liver 3 cm below costal margin Normal cardiopulmonary exam No splenomegaly Normal skin and nails Father: alcohol-related cirrhosis

4 Goals Exclude other etiologies Identify risk factors for NASH Assess and quantify fibrosis Serum and imaging biomarkers Role of liver biopsy

5 What Diseases Need to Be Excluded in This Patient? Alcoholism Autoimmune liver disease Wilson disease Viral hepatitis, hemochromatosis Common, father with alcoholism Mother with hypothyroidism Age, devastating if not treated Risk factors, can t miss this

6 Rule Out Other Causes of Hepatic Steatosis Examples of other causes of fatty liver Excessive alcohol consumption Malnutrition Medications Parenteral nutrition Examples of other liver diseases that can present with steatosis Hepatitis C, acute hepatitis D Wilson disease Hemachromatosis Lipodystrophy Lysosomal acid lipase deficiency Angulo P, et al. Hepatology. 2007;45: Brunt EM, et al. Nat Rev Dis Primers. 2015;1:15080.

7 Patient Case: Ultrasound Findings Bright liver Echotexture increased vs kidney Vascular blurring

8 How Reliable Is Ultrasound in Diagnosis of NAFLD? Considerations: Changes consistent with NAFLD may not be detected if < 20% to 30% of liver contains fat Ultrasound findings for fatty liver cannot be distinguished from those of early cirrhosis Hernaez R, et al. Hepatology. 2011;54: Dasarathy S, et al. J Hepatol. 2009;51: Hannah WN Jr, Harrison SA. Hepatology. 2016;[Epub ahead of print].

9 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 < Yrs Adams LA, et al. Gastroenterology. 2005;129: Top 3 Causes of Patients Death in NAFLD, % (n = 53) Malignancy 28 Ischemic heart disease 25 Liver disease 13

10 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) Nonalcoholic Liver Steatosis ± Nonspecific Inflammation NASH Survival (%) General population Patients with nonalcoholic steatosis ± unspecific inflammation Survival (%) General population Patients with NASH 20 P = NS 20 P = Yrs Ekstedt M, et al. Hepatology. 2006;44: Yrs

11 Goals. Exclude other etiologies Identify risk factors for NASH Assess and quantify fibrosis Serum and imaging biomarkers Role of liver biopsy

12 Association Between NAFLD/NASH and Diabetes Mellitus Is Bidirectional Patients with NAFLD/NASH have: Increased risk of developing diabetes [1,2] Synergistic increase in risk of diabetes when combined with obesity or insulin resistance [3] Patients with obesity, NAFLD, or insulin resistance each have 2-4 x the risk of diabetes, but patients with all 3 have 14 x risk of diabetes Patients with diabetes have: Increased risk of NASH with family history of diabetes [5] Increased risk of dying from cirrhosis [6,7] Up to 3-fold increased risk of dying from chronic liver disease, mostly attributable to NAFLD [8] Increased risk of chronic liver disease [9] High prevalence of diabetes [4] References in slidenotes.

13 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. 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, * 66% prevalence of bridging fibrosis 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 References in slidenotes.

14 Goals Exclude other etiologies Identify risk factors for NASH Assess and quantify fibrosis Serum and imaging biomarkers Role of liver biopsy

15 NAFLD Disease Pro rogression Histological Subtypes [1,2] Change in Fibrosis* [3,4] 70% to 75% NAFLD 25% to 30% 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. Ludwig J, et al. Mayo Clin Proc. 1980;55(7): Kleiner DE, et al. Hepatology. 2005;41(6): McPherson S, et al. J Hepatol. 2015;62: Singh S, et al. Clin Gastroenterol Hepatol Apr;13(4):643-54

16 Normal ALT Does Not Rule Out Progressive Disease in NAFLD or NASH Persistently elevated ALT can be associated with disease progression [1] Patients with normal ALT levels can also develop progressive disease [2-4] Up to 80% of NAFLD patients can have normal ALT [5] No designated ALT cutoff for prediction of NASH or advanced fibrosis in NAFLD pts [6] 1. Ekstedt M, et al. Hepatology. 2006;44: Maximos M, et al. Hepatology. 2015;61: Mofrad P, et al. Hepatology. 2003;37: Amarapurkar DN, Patel ND. Trop Gastroenterol. 2004;25: Dyson JK, et al. Frontline Gastroenterol. 2014;5: Verma S, et al. Liver Int. 2013;33:

17 Tools for Diagnosis of NAFLD Method Sensitivity Specificity Comments Liver enzymes GGT [1] 63% 65% Not reliable for diagnosis Ultrasound [2] 85% 94% Inexpensive and accessible, Any degree [3] 61% 100% but cannot distinguish Cutoff 20% [3] 100% 90% fibrosis/steatosis CT without contrast [4] Better in morbid obesity, but Cutoff > 30% 79% 97% affected by iron, fibrosis, and less accurate with less steatosis MRI [5] Detects mild steatosis, Cutoff PDFF 6.4%, gr 1 86% 83% quantifies hepatic fat most Cutoff PDFF 17.4%, gr 2 64% 96% accurately MRS [6] Cutoff 5% 90-96% % Cutoff > 33% % 92-97% Liver biopsy Gold standard, but invasive and subject to sampling error References in slidenotes.

18 Limitations of Noninvasive Tests Method Sensitivity Specificity Comments Liver enzymes GGT [1] 63% 65% Not reliable for diagnosis Ultrasound [2] Any degree [3] Cutoff 20% [3] CT without contrast [4] Cutoff > 30% MRI [5] Cutoff PDFF 6.4%, gr 1 Cutoff PDFF 17.4%, gr 2 MRS [6] Cutoff 5% Cutoff > 33% Liver biopsy 85% 61% 100% 79% 86% 64% 90-96% % 94% 100% 90% Liver enzymes and 97% 83% 96% % 92-97% Inexpensive and accessible, but cannot distinguish fibrosis/steatosis Better in morbid obesity, but affected by iron, fibrosis, and less accurate with less steatosis Detects mild steatosis, quantifies hepatic fat most accurately standard imaging modalities cannot distinguish NASH from non-nash NAFLD Gold standard, but invasive and subject to sampling error References in slidenotes.

19 Imaging for Diagnosis of NASH Prospective analysis of adults without liver disease or substantial alcohol use (N = 270 with results at interim analysis) Cutoff for Detecting NASH, % Sensitivity Specificity PPV NPV LIF score > Transient elastography > 7 kpa MR elastography > 3 kpa Roberts KK, et al. AASLD Abstract 42.

20 How Reliable Is Noninvasive Assessment of Liver Fibrosis in NAFLD?

21 Fibrosis Staging in NASH F1: Perisinusoidal F2: Perisinusoidal + Portal F3: Bridging Fibrosis F4: Cirrhosis

22 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

23 Back to Our Case... NAFLD Fibrosis Score NAFLD Fibrosis Score: Parameter Age, yrs AST ALT Platelet count, cells x 10 9 BMI Albumin, g/l Impaired fasting glucose/diabetes? Our Patient FIB-4 score: NAFLD Cutoff Value [1] Stage < F0-F to Indeterminate > F3-F4 FIB-4 Cutoff Value [2] Stage < 1.45 F0-F to 3.25 Indeterminate > 3.25 F3-F4 1. Angulo P, et al. Hepatology. 2007;45: Sterling RK, et al. Hepatology. 2006;43:

24 Back to Our Case.... NAFLD Fibrosis Score Parameter Our Patient NAFLD Fibrosis Score: Age, yrs 25 AST 63 ALT 70 Platelet count, cells x BMI 32 Albumin, g/l 4.0 FIB-4 score: 0.94 Impaired fasting glucose/diabetes? Yes NAFLD Cutoff Value [1] Stage FIB-4 Cutoff Value [2] Stage < F0-F to Indeterminate < 1.45 F0-F to 3.25 Indeterminate > F3-F4 > 3.25 F3-F4 Cutoffs differ at age > 65 years [3] 1. Angulo P, et al. Hepatology. 2007;45: Sterling RK, et al. Hepatology. 2006;43: McPherson S, et al. Am J Gastroenterol. 2016;[Epub ahead of print].

25 Can Noninvasive Clinical or Lab Tests Distinguish NASH Stages 0-2 vs 3-4? 100 Sensitivity (%) Negative Predictive Value for F3-F4 (%) [1] 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 McPherson S, et al. Gut. 2010;59: McPherson S, et al. Am J Gastroenterol. 2016;[Epub ahead of print].

26 How Reliable Is Noninvasive Imaging Assessment of Liver Fibrosis in NAFLD? Reprinted by permission from Macmillan Publishers Ltd: Brunt EM, et al. Nat Rev Dis Primers. 2015;1:15080, copyright (2015).

27 Diagnostic Performance of Supersonic Shear Imaging, FibroScan, and ARFI Fibrosis Stage AUROC (95% CI) Best Accuracy, % (n/n) Supersonic shear imaging F2 F3 F4 FibroScan (M probe only) F2 F3 F4 ARFI F2 F3 F ( ) 0.89 ( ) 0.88 ( ) 0.82 ( ) 0.86 ( ) 0.87 ( ) 0.77 ( ) 0.84 ( ) 0.84 ( ) 80 (185/232) 85 (196/232) 87 (202/232) 77 (172/223) 79 (175/223) 89 (198/223) 74 (175/236) 79 (186/236) 84 (199/236) Cassinotto C, et al. Hepatology. 2016;63:

28 Vibration-Controlled Transient Elastography: Cutoffs for Fibrosis 10 8 < F0-F2 F2-F4 F3-F4 Cutoff, kpa US [1] Europe [2] France and Hong Kong [3] 1. Tapper EB, et al. Am J Gastroenterol. 2016;111: Petta S, et al. Aliment Pharmacol Ther. 2011;33: Wong VW, et al. Hepatology. 2010;51:

29 Vibration-Controlled Transient Elastography: Known Confounders Inflammation Obesity Nonfasting Cholestasis Alcohol use Congestion Operator inexperience Tapper EB, et al. Clin Gastroenterol Hepatol. 2015;13:27-36.

30 Magnetic Resonance Elastography Stiffness [1] Low High Simple Steatosis Inflammation, But No Fibrosis Fibrosis In NAFLD, higher diagnostic accuracy for fibrosis vs transient elastography and CPRs, [2,3] can accurately predict advanced fibrosis [4] Inflammation can increase stiffness values in the absence of fibrosis [1] Reprinted, with permission, from Radiology 2011;259: RSNA. References in slidenotes.

31 Management Strategies Identification of the risk of NASH and disease progression is guided by: Clinical risk factors (eg, metabolic, family history) Noninvasive markers Fairly accurate to diagnose advanced fibrosis Know the confounders Lesser cutoffs on imaging in combination with other factors can predict NASH with modest accuracy Can reliably exclude advanced fibrosis but not NASH

32 .Goals Exclude other etiologies Identify risk factors for NASH Assess and quantify fibrosis Serum and imaging biomarkers Role of liver biopsy

33 Risk Stratification in Pts With Suspected NAFLD Hepatic steatosis on imaging ± elevated serum ALT levels Evaluate alcohol consumption Confirm NAFLD Exclude alternate causes of ALT levels Low-risk profile BMI < 29.9 Age < 40 yrs No T2DM or metabolic syndrome features Noninvasive fibrosis estimation: FIB-4 < 1.30 APRI < 0.5 NFS < FibroScan < 5 kpa Follow and reassess as risk factors evolve Intermediate-risk profile BMI > 29.9* Age > 40 yrs Multiple features of the metabolic syndrome* Noninvasive fibrosis estimation: FIB APRI NFS FibroScan 6-11 kpa Consider liver biopsy High-risk profile AST level > AST level Platelets < 150,000 Noninvasive fibrosis estimation: FIB-4 > 2.67 APRI > 1.5 NFS > FibroScan > 11 kpa Consider liver biopsy or confirmatory testing for cirrhosis (eg, MRE) *Risk factors in our patient. Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016;13: Reprinted by permission from Macmillan Publishers Ltd.

34 The Role of Liver Biopsy Isolated Steatosis Steatohepatitis/NASH Make diagnosis of NASH (surrogates insufficient) [1] Initiate drug therapy Assess prognosis: liver, cardiovascular, etc Stage fibrosis (if imaging or tests are indeterminate) [1] Rule out concomitant liver disease [1] Autoimmune, Wilson disease, DILI, iron overload (ferritin can be high in NAFLD in absence of iron overload [2] ) 1. Rinella ME, et al. Gastroenterol Hepatol (NY) ;10: Camaschella C, Poggiali E. Haematologica. 2009;94:

35 Noninvasive Assessment of Liver Fibrosis Clinical Take-Home Points to Guide Treatment, Monitor Progression British Is this study NAFLD or comparing identification of advanced fibrosis in patients with NAFLD (N = 145) something else? It s NAFLD, likely NASH (exclude other diseases) AUROC NPV, % PPV, % Use clinical predictors and FIB-4: How to 0.86 differentiate FIB-4: 95 noninvasive NAFLD tests fibrosis to NAFLD from NASH? AST/ALT ratio: 0.83 BARD: 95 guide score: decisions 79 NAFLD fibrosis AST/ALT ratio: 93 FIB-4: 75 Reliability score: 0.81 of noninvasive NAFLD fibrosis Reliable AST/ALT for exclusion, ratio: 55 assessment of liver fibrosis very good for identification; BARD: 0.77 score: 92 APRI: 37 in NAFLD? can t differentiate NASH vs NAFLD APRI: 0.67 APRI: 84 BARD: 27 Yes: risk factors for NASH No Is data a liver using biopsy elastography to assess and response progression; to necessary? intervention persistently elevated ALT McPherson S, et al. Gut. 2010;59:

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