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.

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Faculty Disclosures Quentin M. Anstee, BSc, MB BS, PhD, MRCP(UK), FRCP, has disclosed that he has received consulting fees paid to his institution from Acuitas Medical, Eli Lilly, Genfit, Intercept, Inventiva, Janssen, NewGene, Pfizer, Raptor Pharmaceuticals, and Tobira and funds for research support paid to his institution from AbbVie and GlaxoSmithKline. Stephen A. Harrison, MD, COL (Ret.), FAASLD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, the Chronic Liver Disease Foundation, FibroGen, Genfit, Intercept, Medivation, Merck, NGM Biopharmaceuticals, and Pfizer; speaker fees from AbbVie, Alexion, Gilead Sciences, and Merck; and funds for research support paid to his institution from Bristol-Myers Squibb, Conatus, Galectin, Galmed, Gilead Sciences, Immuron, Intercept, Madrigal, Merck, NGM Biopharmaceuticals, and Tobira. Mary E. Rinella, MD, has disclosed that she has received consulting fees from Amarin, BioPharma, Echosens, Enanta, Immuron, Intercept, NGM Biopharmaceuticals, and NuSirt. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Change in Etiology From 2002-2014 (%) NASH and Cryptogenic Cirrhosis 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 Etiology Among Pts Listed for Liver Transplant NASH and cryptogenic cirrhosis P < .0001 HCV infection 150 194 200 124 100 160 148 50 120 25 Pts Aged 35-49 Yrs Change in Etiology From 2002-2014 (%) 80 HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis. -25 40 -50 -100 NASH and Cryptogenic Cirrhosis HCV Infection -78 -150 Slide credit: clinicaloptions.com Banini BA, et al. ACG 2016. Abstract 46.

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 Father: alcohol-related cirrhosis 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 ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure, PCP, primary care provider; T2DM, type 2 diabetes mellitus. Slide credit: clinicaloptions.com

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

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

Rule Out Other Causes of Hepatic Steatosis Examples of other causes of fatty liver Excessive alcohol consumption Malnutrition Examples of other liver diseases that can present with steatosis Hepatitis C, acute hepatitis D Wilson disease Hemachromatosis Medications Parenteral nutrition Lipodystrophy Lysosomal acid lipase deficiency Angulo P, et al. Hepatology. 2007;45:846-854. Brunt EM, et al. Nat Rev Dis Primers. 2015;1:15080. Slide credit: clinicaloptions.com

Patient Case: Ultrasound Findings Bright liver Echotexture increased vs kidney Vascular blurring Slide credit: clinicaloptions.com

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 NAFLD, nonalcoholic fatty liver disease. Hernaez R, et al. Hepatology. 2011;54:1082-1090. Dasarathy S, et al. J Hepatol. 2009;51:1061-1067. Hannah WN Jr, Harrison SA. Hepatology. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

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 100 General population Patients with NAFLD 80 P = .03 60 Top 3 Causes of Death in NAFLD, % Patients (n = 53) Malignancy 28 Ischemic heart disease 25 Liver disease 13 Survival (%) 40 Survival at 10 Yrs General population: 87% Patients with NAFLD: 77% Log-rank P < .005 NAFLD, nonalcoholic fatty liver disease. 20 2 4 6 8 10 12 14 16 Yrs Slide credit: clinicaloptions.com Adams LA, et al. Gastroenterology. 2005;129:113-121.

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 100 100 80 80 60 60 General population Patients with nonalcoholic steatosis ± unspecific inflammation P = NS Survival (%) General population Patients with NASH P = .01 Survival (%) 40 NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NS, not significant; SD, standard deviation. 40 20 20 5 10 15 20 5 10 15 20 Yrs Yrs Slide credit: clinicaloptions.com Ekstedt M, et al. Hepatology. 2006;44:865-873.

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

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 High prevalence of diabetes[4] 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] NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. References 1. Kasturiratne A, et al. J Gastroenterol Hepatol. 2013;28:142-147. 2. Shibata M, et al. Diabetes Care. 2007;30:2940-2944. 3. Sung KC, et al. Diabetes Care. 2012;35:717-722. 4. Ortiz-Lopez C, et al. Diabetes Care. 2012;35:873-878. 5. Loomba R, et al. Hepatology. 2012;56:943-951. 6. de Marco R, et al. Diabetes Care. 1999;22:756-761. 7. Campbell PT, et al. Diabetes Care. 2012;35:1835-1844. 8. Zoppini G, et al. Am J Gastroenterol. 2014;109:1020-1025. 9. El-Serag HB, et al. Gastroenterology. 2004;126:460-468. Slide credit: clinicaloptions.com References in slidenotes.

Clinical Predictors of NASH in Patients With NAFLD Characteristic Outcome Advanced age[1] Greater duration of disease Sex[2] Postmenopausal women experience accelerated disease Race[3] ↑ Prevalence, severity in Hispanic, Asian patients; ↓ Prevalence, severity in black patients HTN, central obesity, dyslipidemia (↑ TG, ↓ HDL), insulin resistance/diabetes[4] Risk increases with metabolic syndrome,* 66% prevalence of bridging fibrosis if older than 50 yrs of age and obese or diabetic[5,6] AST/ALT ratio > 1,[7] low platelets[8] Indicators of NASH cirrhosis Persistently elevated ALT[9] Can be associated with greater risk of disease progression ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATP, Adult Treatment Panel; HDL, high density lipoprotein; HTN, hypertension; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TG, triglycerides. References 1. McPherson S, et al. Am J Gastroenterol. 2016;[Epub ahead of print]. 2. Yang JD, et al. Hepatology. 2014;59:1406-1414. 3. Pan JJ, Fallon MB. World J Hepatol. 2014;6:274-283. 4. Younossi, Z M, et al. Hepatology. 2016;64:73–84. 5. Ratziu V, et al. Gastroenterology. 2000;118:1117-1123. 6. Angulo P, et al. Hepatology. 1999;30:1356-1362. 7. Neuschwander-Tetri BA, et al. Hepatology. 2010;52:913-924. 8. McPherson S, et al. Gut. 2010;59:1265-1269 9. Ekstedt M, et al. Hepatology. 2006;44:865-873. *Based on ATP III criteria. Slide credit: clinicaloptions.com References in slidenotes.

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

Histological Subtypes[1,2] NAFLD Disease Progression Histological Subtypes[1,2] Change in Fibrosis*[3,4] NAFLD 70% to 75% 25% to 30% Regression: 18%-22% Stable: 40%-43% Progression: 34-42% Isolated steatosis Steatosis with mild inflammation NASH Cirrhosis Fibrosis NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. *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):434-438. 2. Kleiner DE, et al. Hepatology. 2005;41(6):1313-1321. 3. McPherson S, et al. J Hepatol. 2015;62:1148-1155. 4. Singh S, et al. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54 Slide credit: clinicaloptions.com

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] ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. 1. Ekstedt M, et al. Hepatology. 2006;44:865-873. 2. Maximos M, et al. Hepatology. 2015;61:153-160. 3. Mofrad P, et al. Hepatology. 2003;37:1286-1292. 4. Amarapurkar DN, Patel ND. Trop Gastroenterol. 2004;25:130-134. 5. Dyson JK, et al. Frontline Gastroenterol. 2014;5:211-218. 6. Verma S, et al. Liver Int. 2013;33:1398-1405. Slide credit: clinicaloptions.com

Tools for Diagnosis of NAFLD 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% 85% 61% 100% 79% 86% 64% 90-96% 92-100% 94% 90% 97% 83% 96% 87-100% 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 Liver biopsy Gold standard, but invasive and subject to sampling error CT, computed tomography; GGT, gamma-glutamyl transferase; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; PDFF, proton density fat fraction. References 1. Alam S, et al. BSMMU J. 2015;8:61-67. 2. Hernaez R, et al. Hepatology. 2011;54:1082-1090. 3. Dasarathy S, et al. J Hepatol. 2009;51:1061-1067. 4. Rogier J, et al. Liver Transpl. 2015;21:690-695. 5. Tang A, et al. Radiology. 2015;274:416-425. 6. McPherson S, et al. J Hepatol. 2009;51:389-397. Slide credit: clinicaloptions.com References in slidenotes.

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% 85% 61% 100% 79% 86% 64% 90-96% 92-100% 94% 90% 97% 83% 96% 87-100% 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 Liver biopsy Gold standard, but invasive and subject to sampling error Liver enzymes and standard imaging modalities cannot distinguish NASH from non-NASH NAFLD CT, computed tomography; GGT, gamma-glutamyl transferase; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PDFF, proton density fat fraction. References 1. Alam S, et al. BSMMU J. 2015;8:61-67. 2. Hernaez R, et al. Hepatology. 2011;54:1082-1090. 3. Dasarathy S, et al. J Hepatol. 2009;51:1061-1067. 4. Rogier J, et al. Liver Transpl. 2015;21:690-695. 5. Tang A, et al. Radiology. 2015;274:416-425. 6. McPherson S, et al. J Hepatol. 2009;51:389-397. Slide credit: clinicaloptions.com References in slidenotes.

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 > 2 93 32 25 95 Transient elastography > 7 kPa 69 80 48 91 MR elastography > 3 kPa 33 98 83 85 LIF, Liver Inflammation and Fibrosis; MR, magnetic resonance; NASH, nonalcoholic steatohepatitis; NPV, negative predictive values; PPV, positive predictive values. Slide credit: clinicaloptions.com Roberts KK, et al. AASLD 2016. Abstract 42.

How Reliable Is Noninvasive Assessment of Liver Fibrosis in NAFLD? NAFLD, nonalcoholic fatty liver disease.

Fibrosis Staging in NASH F1: Perisinusoidal F2: Perisinusoidal + Portal F3: Bridging Fibrosis F4: Cirrhosis NASH, nonalcoholic steatohepatitis. Slide credit: clinicaloptions.com

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 AST, aspartate aminotransferase; ARFI, acoustic radiation force impulse; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4 score; MR, magnetic resonance; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; VCTE, vibration-controlled transient elastography; BARD: body mass index, AST/ALT ratio, diabetes. Slide credit: clinicaloptions.com

Back to Our Case . . . NAFLD Fibrosis Score Parameter Our Patient Age, yrs AST ALT Platelet count, cells x 109 BMI Albumin, g/L Impaired fasting glucose/diabetes? FIB-4 score: NAFLD Fibrosis Score: NAFLD Cutoff Value[1] Stage < -1.455 F0-F2 -1.455 to 0.676 Indeterminate > 0.676 F3-F4 ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; FIB-4, fibrosis-4 score; NAFLD, nonalcoholic fatty liver disease. FIB-4 Cutoff Value[2] Stage < 1.45 F0-F2 1.45 to 3.25 Indeterminate > 3.25 F3-F4 1. Angulo P, et al. Hepatology. 2007;45:846-854. 2. Sterling RK, et al. Hepatology. 2006;43:1317-1325.  Slide credit: clinicaloptions.com

Back to Our Case . . . NAFLD Fibrosis Score Parameter Our Patient Age, yrs 25 AST 63 ALT 70 Platelet count, cells x 109 200 BMI 32 Albumin, g/L 4.0 Impaired fasting glucose/diabetes? Yes FIB-4 score: 0.94 NAFLD Fibrosis Score: -0.96 NAFLD Cutoff Value[1] Stage < -1.455 F0-F2 -1.455 to 0.676 Indeterminate > 0.676 F3-F4 ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; FIB-4, fibrosis-4 score; NAFLD, nonalcoholic fatty liver disease. FIB-4 Cutoff Value[2] Stage < 1.45 F0-F2 1.45 to 3.25 Indeterminate > 3.25 F3-F4 Cutoffs differ at age > 65 years[3] 1. Angulo P, et al. Hepatology. 2007;45:846-854. 2. Sterling RK, et al. Hepatology. 2006;43:1317-1325.  3. McPherson S, et al. Am J Gastroenterol. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

Negative Predictive Value for F3-F4 (%)[1] Can Noninvasive Clinical or Lab Tests Distinguish NASH Stages 0-2 vs 3-4? 100 80 Negative Predictive Value for F3-F4 (%)[1] FIB4 score AST/ALT BARD APRI NAFLD 95 93 84 92 60 Sensitivity (%) 40 20 20 40 60 80 100 ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4 score; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; BARD: body mass index, AST/ALT ratio, diabetes. 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;59:1265-1269. McPherson S, et al. Am J Gastroenterol. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

How Reliable Is Noninvasive Imaging Assessment of Liver Fibrosis in NAFLD? MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty liver disease; SWE, shear wave elastography; US, ultrasound. Reprinted by permission from Macmillan Publishers Ltd: Brunt EM, et al. Nat Rev Dis Primers. 2015;1:15080, copyright (2015). Slide credit: clinicaloptions.com

Diagnostic Performance of Supersonic Shear Imaging, FibroScan, and ARFI Fibrosis Stage AUROC (95% CI) Best Accuracy, % (n/N) Supersonic shear imaging ≥ F2 ≥ F3 F4 0.86 (0.79-0.90) 0.89 (0.83-0.92) 0.88 (0.82-0.92) 80 (185/232) 85 (196/232) 87 (202/232) FibroScan (M probe only) 0.82 (0.76-0.87) 0.86 (0.80-0.90) 0.87 (0.79-0.92) 77 (172/223) 79 (175/223) 89 (198/223) ARFI 0.77 (0.70-0.83) 0.84 (0.78-0.89) 74 (175/236) 79 (186/236) 84 (199/236) ARFI, acoustic radiation force impulse; AUROC, area under receiver operating characteristic. Slide credit: clinicaloptions.com Cassinotto C, et al. Hepatology. 2016;63:1817-1827.

Vibration-Controlled Transient Elastography: Cutoffs for Fibrosis 9.9 F0-F2 10 8.75 8.7 F2-F4 < 7.9 8 F3-F4 7.25 7.0 6 Cutoff, kPa 4 2 US[1] Europe[2] France and Hong Kong[3] 1. Tapper EB, et al. Am J Gastroenterol. 2016;111:677-684. 2. Petta S, et al. Aliment Pharmacol Ther. 2011;33:1350-1360. 3. Wong VW, et al. Hepatology. 2010;51:454-462.  Slide credit: clinicaloptions.com

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

Magnetic Resonance Elastography Stiffness[1] High Low CPR, clinical prediction rule; NAFLD, nonalcoholic fatty liver disease. References 1. Chen J, et al. Radiology. 2011;259:749-756. 2. Imajo K, et al. Gastroenterology. 2016;150:626-637. 3. Cui J, et al. Aliment Pharmacol Ther. 2015;41:1271-1280. 4. Loomba R, et al. Hepatology. 2014;60:1920-1928. 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;259:749-756. ©RSNA. References in slidenotes. Slide credit: clinicaloptions.com

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 NASH, nonalcoholic steatohepatitis. Slide credit: clinicaloptions.com

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

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 < -1.455 FibroScan < 5 kPa Intermediate-risk profile BMI > 29.9* Age > 40 yrs Multiple features of the metabolic syndrome* Noninvasive fibrosis estimation: FIB-4 1.30-2.67 APRI 0.5-1.5 NFS -1.455-0.675 FibroScan 6-11 kPa High-risk profile AST level > AST level Platelets < 150,000 Noninvasive fibrosis estimation: FIB-4 > 2.67 APRI > 1.5 NFS > 0.675 FibroScan > 11 kPa ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; BMI, body mass index; FIB-4, fibrosis-4 score; MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NFS, nonalcoholic fatty liver disease fibrosis score. MR, magnetic resonance; VCTE, vibration-controlled transient elastography. Consider liver biopsy or confirmatory testing for cirrhosis (eg, MRE) Follow and reassess as risk factors evolve Consider liver biopsy *Risk factors in our patient. Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016;13:196-205. Reprinted by permission from Macmillan Publishers Ltd. Slide credit: clinicaloptions.com

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]) DILI, drug-induced liver injury; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. 1. Rinella ME, et al. Gastroenterol Hepatol (NY). 2014 ;10:219-227. 2. Camaschella C, Poggiali E. Haematologica. 2009;94:307-309. Slide credit: clinicaloptions.com

Noninvasive Assessment of Liver Fibrosis to Guide Treatment, Monitor Progression British study comparing identification of advanced fibrosis in patients with NAFLD (N = 145) No data using elastography to assess response to intervention AUROC FIB-4: 0.86 AST/ALT ratio: 0.83 NAFLD fibrosis score: 0.81 BARD: 0.77 APRI: 0.67 NPV, % FIB-4: 95 BARD: 95 AST/ALT ratio: 93 NAFLD fibrosis score: 92 APRI: 84 PPV, % NAFLD fibrosis score: 79 FIB-4: 75 AST/ALT ratio: 55 APRI: 37 BARD: 27 ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4 score; NAFLD, nonalcoholic fatty liver disease; NPV, negative predictive value; PPV, positive predictive value; BARD: body mass index, AST/ALT ratio, diabetes. Slide credit: clinicaloptions.com McPherson S, et al. Gut. 2010;59:1265-1269.

Clinical Take-Home Points Is this NAFLD or something else? It’s NAFLD, likely NASH (exclude other diseases) How to differentiate NAFLD from NASH? Use clinical predictors and noninvasive tests to guide decisions Reliability of noninvasive assessment of liver fibrosis in NAFLD? Reliable for exclusion, very good for identification; can’t differentiate NASH vs NAFLD ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. Is a liver biopsy necessary? Yes: risk factors for NASH and progression; persistently elevated ALT Slide credit: clinicaloptions.com

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