Non-Alcoholic Steatohepatitis (NASH): What the Gastroenterologist Should Know

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1 Non-Alcoholic Steatohepatitis (NASH): What the Gastroenterologist Should Know Naga P. Chalasani, MD, FACG Professor of Medicine and Cellular & Integrative Physiology Director, Division of GI and Hepatology Indiana University School of Medicine ACG/FGS Spring Symposium 2013 Potential Conflicts Conflicts related to NAFLD Enterome Conflicts related to DILI Salix, Abbott, Merck, Sanofi, GSK, Lilly, Mochida Research Support Intercept, Lilly, GenFit, Gilead, Enterome, Galectin

2 Outline Background and Definitions Risk Factors Natural History Diagnosis Treatment NAFLD NAFLD is present in 30% U.S. adults and 10-15% children Most common cause of elevated liver enzymes in both adults and children Up to 5% US adults may have NASH It may account for up to 80% of cryptogenic cirrhosis

3 Spectrum of NAFLD: NAFL vs. NASH Simple fatty liver is histologically characterized by macrovesicular steatosis with no additional pathology. Fatty liver is generally considered benign from a hepatic standpoint. NASH is histologically advanced fatty liver. It is characterized by steatosis, inflammation, ballooning, and fibrosis. It can lead to cirrhosis and liver failure. Spectrum of NAFLD Normal Steatosis (NAFL) Steatohepatitis (NASH) Fibrosis/ cirrhosis

4 Risk Factors for NAFLD Major Co-morbidities Type2 Diabetes Dyslipidemia Obesity Metabolic Syndrome Emerging Associations Hypothyroidism Sleep Apnea Hypopituitarism Hypogonadism Polycystic Ovary Syndrome Lonardo A, et al. J Hepatol 2006;44: McCullough A, et al. J Clin Gastroenterol 2002;34: NAFLD: Racial differences Caldwell et al. first noticed that African- Americans are underrepresented among NASH patients (0.6%) Browning et al. estimated that AA have a 3.9 fold lower prevalence of cryptogenic cirrhosis at Parkland Hospital Am J Gastroenterol 2002 Jun;97(6): Am J Gastroenterol 2004 Feb;99(2):292-8

5 NAFLD: Racial differences Prevalence of steatosis ( 1 H-MR Spect) in 2,971 multiethnic adults in Dallas Heart Study All 31% Hispanics 45% Whites 33% Blacks 24% * Blacks had comparable obesity and diabetes but had as much hyper TG and low HDL. Hepatology Dec;40(6): Hepatic Outcomes of NAFLD Simple steatosis is largely benign with minimal risk of cirrhosis NASH is progressive with 20% risk of cirrhosis over a 10-yr time horizon NASH cirrhosis is at moderate risk for HCC (2-4% per year) Cryptogenic cirrhosis is likely a burnt-out form of NASH in up to 80% of patients Post-transplant recurrence may occur

6 Outcomes in NAFLD Surrogates # Studies OR [95% CI] Overall Mortality NAFLD vs. General Population 8 studies 1.57 [ ] Incident CVD ALT as a surrogate GGT as a surrogate Imaging as a surrogate 6 studies 10 studies 7 studies 1.10 [ ] 1.57 [ ] 2.05 [ ] Incident type2 DM ALT as a surrogate GGT as a surrogate Imaging as a surrogate 17 studies 12 studies 3 studies 1.97 [ ] 2.74 [ ] 3.51 [ ] Musso G et al. Annals of Medicine 2011 NASH Vs. Steatosis Outcomes # studies OR [95% CI] Overall Mortality 5 studies 1.81 [ ] Liver-related Mortality 5 studies 5.71 [ ] CVD related Mortality 5 Studies 0.01 [ ] Musso G et al. Annals of Medicine 2011

7 Key Elements in the Diagnosis NAFLD - No significant alcohol consumption - No competing etiologies (e.g., autoimmune, HCV, etc), or medications (e.g., amiodarone, tamoxifen) - Imaging evidence of hepatic steatosis - Aminotransferases may or may not be elevated NASH In addition to above, liver biopsy is needed to establish the presence of NASH Diagnosis of NAFLD/NASH Aminotransferases can be normal in patients with NAFLD and even NASH ALT ULN set at a lower threshold will likely pick up most NAFLD, but aminotransferase levels cannot distinguish NASH from NAFLD Imaging tests currently are not able to establish the presence of NASH Mofrad P, et al. Hepatology 2003;37:

8 Work up of patients with NAFLD Imaging to establish the presence of steatosis Meticulous alcohol and medication history Exclusion of co-existing or competing etiologies Auto-antibodies and hyperferritenemia are common Fasting lipid profile and measures of insulin resistance Liver biopsy to establish the presence of NASH When to biopsy? Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Gastroenterology, Hepatology, AJG 2012

9 Surrogate Markers/Predictive Models Predict NASH Metabolic Syndrome CK-18 fragments CK-18 + sfas Oxidized Fatty acids NASH test NASH Predictive Index Obesity NAFLD score NASH Clinical Score NAFIC (ferritin, insulin, collagen) Predict advanced fibrosis Fibrotest NAFLD Fibrosis Score BARD score ELF Fibrometer OWL Genomics IU panel Transient elastography MR elastography Musso G et al. Annals of Medicine 2011 Non-invasive marker of NASH In Vivo Assessment of Liver Cell Apoptosis as a Novel Biomarker of Disease Severity in NAFLD ELISA Kit to measure: Quantitative measurement of caspase-generated cytokeratin-18 fragments in serum Wieckowska et al Hepatology 2006

10 CK-18 fragment levels are markedly Increased in Patients with NASH Not NASH Normal Steatosis NASH 202 U/L 215 U/L 766 U/L P< fragments (U/L) CK-18 fragments Circulating CK-18 fragment levels are elevated in NASH patients 10 studies (adult and pediatric studies) Various cut-off values, range U/L Summary estimates: AUC [95% CI]: 0.82 [ ] Median Sensitivity: 78% Median Specificity: 87% Musso G et al. Annals of Medicine 2011

11 Selected Fibrosis Models # studies AUC [95% CI] Sens Spec Fibrotest 2 studies F [ ] 76% 74% NAFLD Fibrosis Score 13 studies F [ ] Cut-off 90% 60% % 97% BARD Score 6 studies F [ ] Cut-off 2 72% 64% ELF 1 study Any 0.76 [ ] 61% 80% fibrosis F [ ] 70% 80% F [ ] 80% 90% Fibrotest: α2 macroglobulin, ApoA, haptoglobin, GGT, Total Bilirubin NAFLD Fibrosis Score: Age, BMI, Diabetes, AST/ALT ratio, albumin, Platelets BARD score: BMI > 28, AST/ALT ratio > 0.8, Diabetes ELF: Hyaluronic acid, PIIINP, TIMP NAFLD Fibrosis Score patients, 480 estimation group, 253 validation group [US, UK, and Australia] Independent predictors of advanced (bridging or cirrhosis) fibrosis: Age BMI AST/ALT ratio Hyperglycaemia (FBG >6.1mmol/l or diabetes) Platelet count Albumin Angulo et al Hepatology 2007

12 ROC in model building group 1.0. Sensitivity > < : NPV = 93% 0.676: PPV =90% AUC = 0.88±0.02 Only 24% indeterminate specificity Risk score: * age (years) * BMI (kg/m 2 ) * IFG/diabetes (yes=1, no=0) * AST/ALT ratio * platelet (x10 9 /l) * albumin (g/dl) The ELF score Age, HA, PIIIP, TIMP Derived in400 test cases, validated in 521 Rosenberg, Burt Gastroenterology

13 The future?: Mayo + ELF serum fibrosis markers ROC Curve 1.0 Source of the Curve Simplesevere ELF Combinedsevere Reference Line 0.8 Sensitivity vs any fibrosis Mild vs mod/severe fibrosis Mild/mod vs Severe fibrosis Specificity Mayo / / / Mild/mod vs severe fibrosis ELF / / / Mayo + ELF / / / Guha et al Hepatology 2008 How to treat a patient with NAFLD? If a patient has NASH, then attention should be paid to both metabolic co-morbidities as well as liver disease However, if a patient has steatosis alone, then attention should be paid to metabolic and cardiovascular morbidities.

14 Treatment of liver disease in NAFLD Potential Options Life style modification Insulin sensitizers Vitamin E Bariatric surgery Tested but do not work: UDCA, Metformin Under investigation: Pentoxifylline, Obeticholic acid, Eicosapentanoic acid, and many others Ongoing Phase 3 programs Intercept 747 (Obeticholic acid) FXR agonist Phase 3 study through NASH CRN EDA-E (Ethyl Icosapentate) Phase 3, multicenter study (Medpace/Fulcrum/Mochida) Combined PPARα/δ agonist (GenFit)

15 Lifestyle Modification Weight loss, either by hypocaloric diet alone or in conjunction with exercise, reduces hepatic steatosis Weight loss ~ 5% of body weight is necessary for improving in steatosis Weight loss ~ 7-10% of body weight is necessary for improving in necroinflammation No data available on specific diets Weight loss: Bariatric surgery Bariatric surgery improves steatosis and may improve necroinflammation (and possibly fibrosis) in carefully selected patients Meta-analysis by Mummadi et al. showed that steatosis, steatohepatitis, and fibrosis appear to improve following bariatric surgery However, Cochrane review highlights lack of well designed studies Mummadi RR et al. Clinical Gastro Hepatol 2008 Chavez-Tapia NC, et al. Cochrane Database of Systematic Reviews 2010

16 Naga P. Chalasani, MD, FACG Significant Improvement in histology following bariatric surgery 1st biopsy 2nd biopsy at 13 months Mattar SG et al. Annals of Surgery 2005; 242: Significant Improvement in histology following bariatric surgery 1st biopsy 2nd biopsy at 8.5 months Mattar SG et al. Annals of Surgery 2005; 242:

17 Naga P. Chalasani, MD, FACG Significant Improvement in Fibrosis Bariatric Surgery for NASH Bariatric surgery specifically to treat NASH is premature at this time NASH would greatly respond to foregut bariatric surgery It can be performed even in compensated cirrhotics as long as portal hypertension is absent (no varices and no intra-abdominal collaterals by imaging)

18 Insulin Sensitizers Metformin No role in either adults or children TZDs improve liver histology but weight gain is a problem. Rosiglitazone is essentially unavailable Role of pioglitazone is unclear improves histology in non-diabetics with NASH, but it is not approved in non-diabetics. Accumulating evidence for unfavorable safety profile. n Agent Dose Tetri 30 Rosi 8 mg Sanyal 21 Pio 30 mg Belfort 55 Pio 45 mg TZDs for NASH Duration Enzymes Histology 48 weeks Improved Improved steatosis, Inflammation, and fibrosis 6 months N/A Improved steatosis, Inflammation 6 months Improved Improved steatosis, Inflammation Ratziu 63 Rosi (8 mg) 12 months Improved Improved steatosis Aithal 74 Pio 30 mg 12 months Improved Improved Steatos, inflammation and fibrosis PIVENS 247 Pio 30 mg 24 months Improved Improved steatosis, inflammation and ballooning

19 AASLD/AGA/ACG Practice Guideline Vitamin E: PIVENS trial Multicenter RCT, 247 patients, Placebo vs. vit E (800 iu/d) vs. pioglitazone (30 mg/d), 96 weeks Histology primary end point Compared to placebo (19%), significantly greater proportion of patients in vitamin E group (43%) met the primary end point (p<0.01, NNT:4.4) TONIC trial in children also showed histological improvement with vitamin E Sanyal AJ, et al. N Engl J Med 2010;362: Lavine JE, et al. JAMA 2011

20 AASLD/AGA/ACG Practice Guideline Alcohol use in patients with NAFLD and NASH While heavy drinking is certainly deleterious, there are evolving data to suggest non-heavy drinking may have hepatic and metabolic benefits

21 Cardiovascular disease in NAFLD Heavily enriched with cardiovascular risk factors Increased prevalence of surrogate markers of coronary artery disease Many studies have shown cardiovascular disease as the single most common cause of death in patients with NAFLD General guidelines for managing cardiovascular risk in NAFLD A diet low in sodium and simple sugars, with substitution of unsaturated fat for saturated and trans-fats, and increased consumption of fruits and vegetables. Consumption of food products enriched with omega3 fatty acids Caloric restriction to achieve and maintain ideal body weight. Moderate to vigorous exercise for 30 min to 60 minutes per day most days of the week Smoking cessation & avoidance of alcohol

22 Statins can be used safely in patients with fatty liver Patients with NAFLD are important targets for statins Risk of serious hepatotoxicity from statins is very rare Patients with underlying liver disease are not at higher risk for statin hepatotoxicity Case series have shown histological improvement in NASH Fish oil is probably the first choice to treat hypertriglyceridemia Chalasani N. Hepatology 2005;41: ; Hepatology 2007;46: All patients with NAFLD Patients with NASH COMMENTS Weight Loss Yes Yes 5% Weight loss for improving steatosis & 7-10% weight loss is needed for improving necro-inflammation. Management of Dyslipidemia Insulin resistance and diabetes Bariatric Surgery Yes, as appropriate Yes, as appropriate Yes, as appropriate Yes, as appropriate Fish oil is the first line medication for hypertriglyceridemia & Statins are the treatment of choice for improving LDL-Cholesterol Metformin improves insulin resistance but has no effect on liver histology. Will help steatosis and necroinflammation if performed for other indications. Should not be performed to specifically treat NASH. Should not be performed in those varices. Vitamin E No Yes Recent SELECT study showed increased risk of prostate cancer. Pioglitazone No Yes Weight gain, CHF, bone loss, and bladder cancer (very rarely)

23 Take Home Messages Exclude competing etiologies and look for coexisting liver diseases Steatosis is hepatically benign but NASH is progressive and can lead to cirrhosis Patients with NAFLD are at higher risk for incident type2 diabetes and cardiovascular disease Liver biopsy can establish the diagnosis of NASH Management of NAFLD include managing underlying metabolic and cardiovascular risks as well as managing liver disease