NASH: What is It? Categories of NAFLD. Welcome to NASHville. 1 st described 1980 by Ludwig, et al. Part of Nonalcoholic Fatty Liver Disease (NAFLD)

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1 Welcome to NASHville Vicki Wettig, M.S.N., CRNP Lancaster Gastroenterology, Inc. NASH: What is It? 1 st described 1980 by Ludwig, et al. Part of Nonalcoholic Fatty Liver Disease (NAFLD) spectrum of fatty liver changes that range from simple steatosis to cirrhosis Most common cause of cryptogenic cirrhosis Hepatic component of the metabolic syndrome Ludwig et al. Mayo Clinic Proceedings1980;55: Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, Categories of NAFLD Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: Human data. Clinics in Liver Dis. 2007; Feb;11(1):

2 NASH: What is It? Nonalcoholic steatohepatitis: liver biopsy findings indistinguishable from alcoholic steatohepatitis No consistent agreement on alcohol amount Some accept g/day in men and 20 g/day in women Some use cutoff of 10 g/day Two studies suggest limited alcohol protective in NASH *Carbohydrate Deficient Transferrin should be negative Most widely used and most specific Ratio of desialylated transferrin to total transferrin 81% sensitivity and 98% specificity *Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 2009;49: Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD single topic conference. Hepatology 2003;22: Desialylated or Carbohydrate Deficient Transferrin Half-life of 14 days Evaluates ratio of desialylated transferrin to total transferrin *Can elevate in sepsis, anorexia nervosa, and airway disease. Ordered through EPIC as Unidentified Lab with identity code # Processed through Quest Preferred fasting Above from a telephone conversation with LGH labs 1/24/2012 Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 2009;49: Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011 *Sauk, J., et al. Clinical manifestations and diagnosis of alcoholic liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Table Pathogenesis of NAFLD Causes of nonalcoholic fatty liver disease (NAFLD) Primary Obesity, glucose intolerance, type 2 diabetes, hypertriglyceridemia, low HDL (high-density lipoprotein) cholesterol, hypertension Nutritional Protein-calorie malnutrition, rapid weight loss, gastrointestinal bypass surgery, total parenteral nutrition Drugs Glucocorticoids, estrogens, tamoxifen, amiodarone, methotrexate, diltiazem, zidovudine, valproate, aspirin, tetracycline, cocaine Metabolic Lipodystrophy, hypopituitarism, dysbetalipoproteinemia, Weber Christian disease Toxins Amanita phalloides mushroom, phosphorus poisoning, petrochemicals, Bacillus cereus toxin Infections Human immunodeficiency virus, hepatitis C, small bowel diverticulosis with bacterial overgrowth Alimentary Pharmacology & Therapeutics Volume 25, Issue 8, pages , 30 MAR 2007 DOI: /j x

3 Pathogenesis of NAFLD Not well elucidated-2 Hit Theory 1 st hit steatosis 2 nd hit oxidative stress Insulin Resistance key to development of NAFLD and perhaps, NASH Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, Insulin Resistance Insulin Resistance a universal phenomenon in NAFLD Increased fat volume leads to: Less sensitivity to insulin resulting in greater breakdown of TG Overabundant circulating FFA contribute to IR Added substrate availability Modify downstream signaling Dysregulated adipokine production increases IR Leptin Deficiency/resistance promotes hepatic, muscle, and pancreatic TG increased IR M. S. Mirza, Obesity, Visceral Fat, and NAFLD: Querying the Role of Adipokines in the Progression of Nonalcoholic Fatty Liver Disease, ISRN Gastroenterology, vol. 2011, Article ID , 11 pages, doi: /2011/ Fat metabolism and energy production in hepatocytes in normal weight persons Pessayre D et al. Am J Physiol Gastrointestinal Liver Physiol 2002;282:G193-G by American Physiological Society

4 Modifications of fat and glucose metabolism in obese persons. Pessayre D et al. Am J Physiol Gastrointestinal Liver Physiol 2002;282:G193-G by American Physiological Society Triglycerides Accumulation of triglycerides in liver Excessive importation of FFA from adipose tissue Decreased hepatic transport FFA (decreased synthesis or secretion of VLDL) Impaired beta-oxidation of FFA Major source TG come from adipose tissue and fatty acid made in liver through de novo lipogenesis Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, Non-Alcoholic Fatty Liver Disease Spectrum (NAFLD) Normal liver Fatty liver (Steatosis) Cirrhosis Steatohepatitis (NASH) Lall C G et al. AJR 2008;190:

5 nonalcoholic steatohepatitis in 62-year-old woman. Lall C G et al. AJR 2008;190: Alcoholic Steatohepatitis Sauk, J., et al. Clinical manifestations and diagnosis of alcoholic liver disease. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, NASH Biopsy with Pericellular Fibrosis Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011.

6 Not All Fat is Created Equally Body Fat Distribution Remarks Subcutaneous About 80% of all body fat. Can functionally be divided into abdominal and gluteofemoral Visceral Drained by the portal vein. Anatomically divided into omental, mesenteric, and retroperitoneal fat 20% of total fat in men and 5-8% in women. Other Peritoneal and orbital M.S. Mizra. Obesity, Visceral Fat, and NAFLD: Querying the Role of Adipokines in the Progression of Nonalcoholic Fatty Liver Disease, ISRN Gastroenterology, vol. 2011, Article ID , 11 pages, doi: /2011/ Not All Fat is Created Equally Regional Differences in Lipolysis Hormone Action on lipolysis Regional differences Catecholamines Stimulating Insulin Inhibiting SCF > VF Prostaglandins Inhibiting SCF > VF Adenosine Inhibiting SCF > VF VF > SCF abd > SCF glf VF: visceral fat; SCF: subcutaneous fat; abd: abdominal; glf: gluteofemoral. M. S. Mirza, Obesity, Visceral Fat, and NAFLD: Querying the Role of Adipokines in the Progression of Nonalcoholic Fatty Liver Disease, ISRN Gastroenterology, vol. 2011, Article ID , 11 pages, doi: /2011/ Progression to NASH Second hit theory First Hit is the deposition of fatty acid in hepatocytes Down-regulates flexibility toward other stressors Second Hit is the concomitant liver damage induced by oxidative stress and lipid peroxidation. Jin X, et al. Increased intestinal permeability in pathogenesis and progress of nonalcoholic steatohepatitis in rats. World J Gastroenterol 2007 March 21;13(11):

7 Oxidative Stress Lipid peroxidation and free oxygen radicals can deplete antioxidant enzymes i.e., glutathione, vitamin E & C, beta carotene Higher levels of xanthine oxidase in NASH with lower levels of antioxidant enzymes heme oxygenase-1, an antioxidant defense enzyme, interrupted the progression of steatohepatitis by inducing an antioxidant pathway and suppressing proinflammatory cytokines Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Role of Hepatic Iron IR associated with increased hepatic iron *Higher prevalence of HFE C282Y heterozygous mutation in NASH Increased parenchymal hepatic iron correlates with severity of fibrosis *Nelson JE, et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology 2007:46(3); Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Acute Phase Response Pathogenesis of NASH Regulation of Blood Vessels Energy Homeostasis A1 acid Glycoprotein SAA3 PTX p3 VEGF Monobutyrin Adiponectin Leptin Resistin TNFα IL-6 Adipocyte LPL Type VI Collagen Lipoprotein Metabolism Innate Immune System Extracellular Matrix Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: Human data. Clinics in Liver Dis. 2007; Feb;11(1):75-104

8 Role of Leptin Produced in adipose tissue, gut, placenta Acts as a negative feedback in normal weight subjects Chronically elevated central leptin: Inability of leptin to reach the hypothalamus Decreased hypothalamic leptin receptors Impaired leptin signal transduction Associated with fibrosis in leptin-deficient mice Leclercq IA, et al. Leptin is essential for fibrogenic response to chronic liver injury. Journal of Hepatology; 37(2): Zhang Y, Scarpace PJ. The role of leptin in leptin resistance and obesity. Physiology and Behavior; 88: (2006) Bray G. Physiology of leptin. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Role of Adiponectin Secreted exclusively by adipocytes Exerts beneficial effect on lipid metabolism High levels associated with favorable CV risk Suppresses hepatic TNFα Downregulated in obesity Lower levels associated with IR and hyperinsulinemia McCulloch DK, et al. Pathogenesis of type 2 diabetes mellitus. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011 Role of Resistin Proinflammatory Increased in NAFLD Higher levels linked to NASH *Associated with IR *Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Pagano C., et al. Increased Serum Resistin in Nonalcoholic Fatty Liver Disease Is Related to Liver Disease Severity and Not to Insulin Resistance. The Journal of Clinical Endocrinology & Metabolism March 1, 2006 vol. 91 no

9 Role of Intestinal Bacteria Able to produce large amounts of ethanol and acetaldehyde Able to oxidize low levels of ETOH to high levels of acetaldehyde Endotoxin production Increased intestinal permeability and portal endotoxemia in obese mice Increased prevalence of SBBO in humans with NAFLD Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Role of Intestinal Bacteria Metabolic Endotoxemia Low-grade inflammation Insulin resistance Increased cardiovascular risk Lipopolysaccharides bind with TLR4 proinflammatory response in target cells TLR4 located on Kupffer cells Manco M, et al. Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocrine Reviews;31(6): Gram-negative-derived LPSs, embedded in freshly synthesized chylomicrons, pass across the intestinal barriers into the lymphatic system and then into the bloodstream. Manco M et al. Endocrine Reviews 2010;31: by Endocrine Society

10 Evidence emerging from the experiments of Cani et al. Manco M et al. Endocrine Reviews 2010;31: by Endocrine Society Hepatocellular Injury FFA induce hepatic IR Saturated FA induce hepatocyte apoptosis FFA induce cytochrome p-450 microsomal lipoxygenases hepato-toxic free radicals With preexisting defects in mitochondrial oxidative phosphorylation, FFA beta oxidation may increase free radical formation, hepatocellular injury, and fibrosis significant mitochondrial structural abnormalities were present in patients with NASH, but not simple hepatic steatosis Hypothesized that in the absence of mitochondrial abnormalities, IR leads to steatosis only Tendler, D. Pathogenesis of nonalcoholic fatty liver disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012 Hepatocellular Injury Support for mitochondrial abnormality theory several genes important for mitochondrial function were significantly underexpressed in NASH patients, suggesting that there is a transcriptional or pretranscriptional basis for impaired mitochondrial function Sreekumar R., et al. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology. 2003;38(1):244.

11 Prevalence and Natural History Liver related 30-40% death over 10 yrs. Cirrhosis *Diabetes Obesity 15-25% NASH *Obesity 6-17% *Increased risk NAFLD *Hispanic, Diabetics 46% McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J. Clin Gastroenterol 2006; 40(S1):S17-S29. Williams CD, et al. Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle- Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study. Gastroenterology 2011; 140(1): Prevalence of NAFLD Prevalence of NASH incompletely understood Most common liver disorder NAFLD affects 20% to 40% of general population in Developed Nations Most common cause of liver disease in preadolescent and adolescent groups Prospective study of 400 subjects (mean age 55), prevalence of NAFLD by ultrasound was 46% More common in men because of greater incidence Metabolic Syndrome More common in Hispanics (58.3%) than Caucasians (44.4%), than African-Americans (35.1%) Of 54 pts with DM, 74% had NAFLD and 22% had NASH. Williams, CD, et al Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle- Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective study. Gastroenterology. 2011;140(1): Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD single topic conference. Hepatology 2003; 37(5): Prevalence of NAFLD Dallas Heart Study of 2200 adults 31% participants had fatty liver (by proton magnetic resonance spectroscopy [MRS] measuring hepatic triglyceride content) Highest prevalence among Hispanics (45%), followed by 33% in Caucasians, and 24% in African Americans. African-Americans and Hispanics have similar obesity rates (48%) and DM rates (21%) African-Americans less likely to have high TG and visceral fat Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed.

12 Prevalence of NAFLD May be increased in women with PCOS In one study, 30% of women with PCOS had elevated ALT (n=70) Other sources for hepatitis excluded In contrast, a population based study of over 18,000 adults found elevated ALT in 2% of all women, 5% of women with DMT2, and 7% of obese women Barbieri, RL, et al. Clinical manifestations of polycystic ovary syndrome in adults. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, Prevalence of NAFLD in Children Autopsy study of children and adolescents found NAFLD in 9.6% overall compared to 38% in obese children NHANES 111, 10% adolescents with a BMI >95 th percentile, had elevated ALT (>30 IU/ml) 52% of adolescents with BMI >95 th percentile who reported consuming 4 drinks per month, had elevated ALT Klish, WJ. Comorbidities and complications of obesity in children and adolescents. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, Prevalence of NAFLD in Children 36 children ages 4 to 16 years diagnosed with NASH. Median 12 years 83% (n=30) were obese 2 had DM, and 2 more developed it. 15 with hepatomegaly and one with splenomegaly None with physical signs of chronic liver disease 7 with hypercholesterolemia, 11 with hypertriglyceridemia 24 had steatosis on ultrasound 24 underwent percutaneous liver biopsy with finding inflammation on 88% and fibrosis-cirrhosis in 75% One 10 year-old boy had established cirrhosis Rashid, M, Roberts, EA. Nonalcoholic steatohepatitis in children. J Pediatric Gastroenterology Nutrition Jan;30(1):48-53.

13 Risk Factors Associated with Progression Better prognosis than ASH/HCV in liver-related complications but not overall mortality Review of 10 studies (n=221) inflammation on initial liver biopsy and older age independent factors DM and elevated amino transferase levels (n=432) Ballooning degeneration & mallory hyaline, or fibrosis (n=132) High Visceral Adiposity Score (VAI) Certain gene polymorphisms linked to prognosis, but clinical utility not established Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011 Pharmacological Treatment of NASH Insulin Sensitizers Weight Loss Agents Glitazones Metformin CB1R blockers Bariatric Surgery Improvement of insulin resistance? *also have insulin sensitizing properties Hepatoprotectants Ursodeoxycholic acid Sartans* Statins Anti-oxidants Cytoprotective agents Anti-apoptotics Anti-inflammatory agents PUFAs* Improvement of liver injury Lam BP, Younossi ZM. Treatment regimens for non-alcoholic fatty liver disease. Annals of Hepatology 2009; 8(1):Supplement:S51-S59.? Treatment-Insulin Sensitizers Weight Loss-1 st line treatment Improves liver enzymes, histology, insulin levels and quality of life Results also seen after Bariatric Surgery Should be gradual Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011 Harrison SA, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clinics in Liver Disease (4);

14 Treatment-Insulin Sensitizing Orlistat Reversibly inhibits gastric and pancreatic lipase Prevents absorption of 30% dietary TG Randomized trial showed mean 8.3% weight loss with orlistat compared to 6% diet alone. 5% loss of body weight associated with improved: IR (p=0.001) and steatosis (p= % loss of body weight associated with improved: IR (p<0.001), adiponectin (p=0.03), steatosis (p=0.005), ballooning (p=0.04), inflammation (p=0.045), HAI (p=0.009) Harrison SA, et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology 2009, 49(1); Treatment-Insulin Sensitizers Glitazones Agonists of peroxisome proliferator-activated receptor gamma (PPARɣ) Promote differentiation of large IR adipocyte to small, metabolically active adipocyte Reduces FFA, TNF-α, and resistin Increases Adiponectin Results in increased FA storage in muscle, decreased hepatic glucose, increased uptake of glucose in the muscle Treatment-Insulin Sensitizers Glitazones Reduced transaminase levels by 30% to 60% ALT normalized in 38% to 100% Reduced steatosis >placebo 47% to 65% Reduced ballooning degeneration in 32% to 54%* 3 studies showed improvement in fibrosis**

15 Treatment-Insulin Sensitizers Glitazones-the rest of the story Weight gain, fluid retention Increased risk for fractures in women Potential for worsening heart failure Black box warning of potential increased risk for MI with rosiglitazone Beneficial effects reverse Steatosis, lobular inflammation, ballooning degeneration statistically worsened in 1 year Treatment-Insulin Sensitizers Metformin-mechanism unclear Decreases hepatic glucose Mouse model, decreases steatosis, transaminases, hepatic TNF-α Improved insulin sensitivity Open-label trial and 2 randomized trials showed improved transaminase in NAFLD Break though of ALT after 6 months Promotes weight loss Lower risk for hypoglycemia Treatment-Insulin Sensitizers Metformin-mechanism unclear Data on histology are conflicting Weak antisteatogenic effect as measured by proton spectroscopy Does not increase circulating adiponectin Black box warning for potential lactic acidosis

16 Treatment-Insulin Sensitizers CB1R Blockers Cannabinoid receptor antagonists Animals with genetic deletion of CB1R have resistance to diet-induced obesity and dyslipidemia All trials halted because of significant neuropsychiatric illness including suicide Explore developing the drug class to act peripherally instead of centrally Jones D. End of the line for cannabinoid receptor 1 as an anti-obesity target? Nature Reviews Drug Discovery 7, (December 2008) doi: /nrd2775 Bray GA. Drug therapy of obesity. In: UpToDate, Pi-Sunyer FX(Ed), UpToDate, Waltham, MA, Treatment-Insulin Sensitizers Surgery Biliopancreatic diversion (BPD) Decreased fibrosis in 11/14 pts with cirrhosis Severe fibrosis decreased in 28 Mild fibrosis appeared in 42->low alb, uncontrolled diarrhea, low intake of alcohol, and menopausal status Lam BP, Younossi ZM. Treatment regimens for non-alcoholic fatty liver disease. Annals of Hepatology 2009; 8(1):Supplement:S51-S59 Kral JG, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery 2004; 135(1):48-58 Treatment-Insulin Sensitizers Surgery Roux-en-Y gastric bypass (RYGB) 108 patients with paired liver biopsy pre and post surgery. No worsening of liver disease All 5 studies showed varying results Overall, NASH resolved in 89% of patients Lam BP, Younossi ZM. Treatment regimens for non-alcoholic fatty liver disease. Annals of Hepatology 2009; 8(1):Supplement:S51-S59

17 Treatment-Insulin Sensitizers Surgery Laparoscopic adjustable gastric banding (LAGB) Limited reports available for paired liver biopsy One report showed improvement in steatosis Fibrosis improved in most patients 19/23 patients with NASH had resolution on subsequent biopsy 24/30 patients with NASH had resolution Occasional reports of regressed cirrhosis Lam BP, Younossi ZM. Treatment regimens for non-alcoholic fatty liver disease. Annals of Hepatology 2009; 8(1):Supplement:S51-S59 Treatment-Hepatoprotectants Ursodeoxycholic Acid (UDCA) Binds to hepatocyte membrane cytoprotective Reduces inflammation and fibrogenesis Studies conflict-no consistent improvement Recent French Multicenter study UDCA dose at 28 to 35 mg/kg for one year versus placebo ALT and GGT significantly reduced in UDCA arm Reduction in serum fibrosis markers as measured on FibroTest Rockey DC. Current and future anti-fibrotic therapies for chronic liver disease. Clinics in Liver Disease 2008; 12(4); Treatment-Hepatoprotectants Sartans Renin-angiotensin involved in NASH transgenic mice with over-expression of renin associated with steatosis->steatohepatitis->fibrosis Livers show increased TNF-α, reactive oxygen species, and apoptosis Valsartan significantly reduced steatosis Angiotensin 2 activates stellate cells

18 Treatment-Hepatoprotectants Sartans PPARɣagonists improve glucose and lipid metabolism Head to head trial of telmisartan (T) and valsartan (V) Paired liver bx within 3 wks prior to and within 2 wks post treatment (20 weeks) Primary endpoint: IR, biochemical improvement, improvement of NASH Georgescu EF, et al. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterology 2009; 15(8): ISSN Treatment-Hepatoprotectants Sartans Head to head trial of telmisartan and valsartan Telmisartan is a more potent agonist of PPARɣ Both groups had lower ALT with T>V BMI did not change HOMA-IR improved within 1 wk (p=0.0001) TG improved (p=0.0013) T>V Total Cholesterol improved (p=0.003) in T NASH activity score improved in both groups (p=0.01) Only ballooning and steatosis significantly in T (p=0.004) Lobular inflammation remained the same Fibrosis score improved (p=0.0001) in T c/t V Georgescu EF, et al. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterology 2009; 15(8): ISSN Treatment-Hepatoprotectants Antihyperlipidemic Agents Fibrates alter lipoprotein through PPARα Improvement in liver enzymes Histology was not measured Bezafibrate showed benefit in tamoxifenassociated steatohepatitis Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD single topic conference. Hepatology 2003; 37(5):

19 Treatment-Hepatoprotectants Statins In mice with chemically induced liver fibrosis Treated for 2 months with either fluvastatin or simvastatin Simvastatin 10/kg significantly decreased fibrosis In mice with bile duct ligation Atorvastatin 15mg/kg/d either prophylactically or therapeutically Immediate/early therapy significantly attenuated fibrosis and HSC activation Later therapy led to more quiescent HSC without effecting inflammation Tribecka J, et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. Journal of Hepatology 2010; 53(4): Lukivskaya O. Comparison of two statins efficacy on a reversibility of experimental rat liver fibrosis. Journal of Hepatology 2007; 46(1): S83. Treatment-Hepatoprotectants Statin safety <3% transaminase elevation in 1 st 3 months Dose dependent 112,000 pt.-year exposure to pravastatin no difference in enzymes elevation c/t placebo Meta-analysis found excess risk (4.2 cases/1000 patients) Cohort study found higher risk of hepatic dysfunction with fluvastatin? Pharmacodynamic effect of lipid lowering Chalasani N. Statins and hepatotoxicity: Focus on patients with fatty liver. Hepatology 2005; 41(4): Rosenson RS. Statins: Actions, side effects, and administration. In: UpToDate. UpToDate, Freeman MW(Ed), UpToDate, Waltham, MA, Treatment-Hepatoprotectants Antioxidants Vitamin E free radical scavenger Protects polyunsaturated fats from peroxidation Improved inflammation & fibrosis in 5/9 patients on Vit E 300 IU/day for 6 months 49 pts randomized for 6 months tx with Vit E 1000 IU & Vit C 1000 mg daily vs. placebo Vitamin group had significant improvement in fibrosis Diabetics had greatest improvement No reduction in inflammation Pazirandeh S, Burns DL. Overview of vitamin E. In: UpToDate. UpToDate, Lipman TO, Motil KJ(Ed), UpToDate, Waltham, MA, Harrison SA, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clinics in Liver Disease (4);

20 Treatment-Hepatoprotectants Vitamin E 247 subjects randomized to receive Vit E 800u v. pioglitazone 30mg v. placebo Vit E & pioglitazone both showed significant reduction in steatosis, lobular inflammation, NAFLD activity score Vit E significantly (P=0.01) improved ballooning degeneration Fibrosis scores not significantly improved in either arm Steatohepatitis resolved in both treatment arms Statistically significant only in pioglitazone (0.001) Sanyal AJ, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis n engl j med; 362(18): Treatment-Hepatoprotectants Caffeine Blocks adenosine, which is shown to limit fibrosis Adenosine acting on A2 receptors stimulates stellate cell-mediated fibrosis (increases collagen 1 & 111) Antioxidant by inhibiting oxidative DNA breakage and generation of hydroxyl radicals Molloy et al.-indirect relationship between coffee caffeine consumption and fibrosis Cronstein BN. Adenosine receptors and fibrosis: a translational review. F1000 Biol Reports2011, 3:21 (doi: /B3-21) Azam S, et al. Antioxidant and prooxidant properties of caffeine, theobromine and xanthine. Medical Science Monitor, 2003;9(9):BR Molloy JW, et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology, 55(2): Treatment-Hepatoprotectants Cytoprotective Agents Pentoxifylline inhibits TNF-α 2 pilot studies showed reduction of transaminases Reduced necroinflammation in 5 pts and reduced fibrosis in 4/6 Probucol is a lipid lowering agent Promotes endogenous antioxidants and is free radical scavenger Reduced liver enzymes consistently among trials Improved steatosis and necroinflammation but not fibrosis Betaine increases S-adenosylmethionine(SAM) Decreases hepatic fat

21 Treatment-Hepatoprotectants Omega 3 PUFA Anti-inflammatory Natural ligands for PPARα In animals, fish oils decrease hepatic TG storage 42 patients showed significant reduction in AST/ALT/GGT and reduced hepatic steatosis 23 patients had ALT improvement, and decreased hepatic steatosis, fibrosis, ballooning, and lobular inflammation. Treatment-Hepatoprotectants Anti-Apoptotics Phase 2 trial of GS-9450, caspase inhibitor 4 weeks of daily dosing resulted in significant, dose-dependent reduction of ALT No serious adverse events reported Ratziu V, et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 2012; 55(2): Liver Transplant 8 female patients with NASH features Within 15 months, 6 developed steatosis 3 had NASH 2 pts went from simple steatosis to NASH/fibrosis over a 1 to 2 year period *71 pts with NASH/CC c/t 83 ETOH pts Infection most common cause of death Cardiovascular in NASH/CC group Malignancies in ETOH Sheth, SG, et al. Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis. In: UpToDate. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011 *Bhagat V, et al. Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease. Liver Transplantation 2009; 15(12):

22 Liver Transplant 1810 patients who underwent LT for NASH, had a survival rate superior to those who underwent LT for HCC, HCV, ETOH, Acute Hepatic Necrosis, Hemochromatosis, or CC Inferior survival to pts who had LT for PBC, PSC, AIH, or HBV Afzali A, et al. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the united states. Liver Transplantation 2012; 18(1): Future Change name? Increase awareness Multidisciplinary Collaborative Networks Simple, sensitive, specific marker of liver injury Long list of multiple mechanisms makes this less likely Liver biopsies with normal transaminases? Transition to NASH or separate entity? Pascale A, et al. An overview of nonalcoholic steatohepatitis: Past, present and future directions. J Gastrointestin Liver Dis 2010; 19(4): 415=423