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Nonalcoholic Fatty Liver Disease

Nonalcoholic Fatty Liver Disease. Stephanie H. Abrams, MD, MS Assistant Professor of Pediatrics Baylor College of Medicine Medical Director-Kamp K’aana shabrams@bcm.edu. NASH: a typical case. 57 year old white female with elevated LFTs in 2008

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Nonalcoholic Fatty Liver Disease

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  1. Nonalcoholic Fatty Liver Disease Stephanie H. Abrams, MD, MS Assistant Professor of Pediatrics Baylor College of Medicine Medical Director-Kamp K’aana shabrams@bcm.edu

  2. NASH: a typical case • 57 year old white female with elevated LFTs in 2008 • No symptoms; history of obesity, type 2 diabetes, hypertension, hyperlipidemia, depression/anxiety • Meds: metformin, olmesartan/HCTZ, thyroxine, alprazolam, metoprolol, sertraline, clonidine, vitamins • SH: Occasional alcohol; nonsmoker • PE: BMI 41 kg/m2 • Lab: ALT 77, AST 81, AP 179, T bili 0.3, gluc 199, plts 168, INR 1.1

  3. NASH: a typical case • Liver biopsy: NASH, NAS 4, stage 2 with extensive periportal fibrosis • Plan: weight loss, exercise • Follow up at 6 months: "No symptoms"; "working on wt loss" • PE: weight down 3 lbs/6 months

  4. NASH: a typical case • Admitted after no follow up x 2 years • Increased abdominal girth, dyspnea, leg edema • Wt up 60 lbs in 6 weeks • Minor MVA with confusion • Interim diagnosis: obstructive sleep apnea • PE: Ascites, 3+ leg edema, alert/oriented • Lab: ALT 55, AST 102, Alb 2.6, INR 1.7, MELD 15, plts 149 • CT: nodular liver, splenomegaly, perisplenic varices, moderate ascites

  5. NASH: a typical case • Abdominal CT:

  6. NASH: a typical case • Summary: • Progression of NASH to cirrhosis in setting of obesity, DM2, HTN • Near normal liver enzymes

  7. Prevalence of NAFLD in Adults • NAFLD was present in 46% of all subjects by ultrasound (n=400) • 74% of diabetics • Prevalence higher in men (58.9%) • Most common in Hispanics (58.3%), Caucasians (44.4%), African Americans (35.1%) • NAFLD patients: • Were more likely to have HTN, higher BMI, & DM • Ate more fast food & exercised less • NASH present in 12.2% of all adults • Present in 22.2% of diabetics • Advanced fibrosis in 22.5% • 30% of all of those with NAFLD NASH: 12% Williams CD, et al. Gastroenterology 2011; 140: 124-131

  8. Prevalence of NAFLD in Children • Fatty liver was present in 13% of all subjects • Prevalence higher in boys (11.1%) compared with girls (7.9%) • Prevalence increases with age • 17.3% for ages 15-19 years • NASH present in 3% of all children Schwimmer, et al. Pediatrics 2006

  9. Using a logistic regression model, the odds ratio for the presence of fatty liver in Hispanics was 5.0 Schwimmer, et al. Pediatrics 2006

  10. NASH as an indication for transplant * *PN = Probable NASH based on risk factors Brandman et al, AASLD 2011

  11. NASH Accounted for 10.3% of all Liver Transplantation at the Cleveland Clinic in 2006 33.1% 12.8% 10.3% www.clevelandclinic.org

  12. Pathogenesis: new ideas • “Two hit” vs lipotoxicity

  13. Liver fat metabolism: Insulin resistance Diet, uncontrolled diabetes Excess peripheral lipolysis Excess carbohydrates Increased circulating fatty acids De novo lipogenesis Hepatocellular free fatty acids Triglyceride VLDL (secreted) B Tetri

  14. “Two-hit” hypothesis: Insulin resistance Diet, uncontrolled diabetes Excess peripheral lipolysis Excess carbohydrates Increased circulating fatty acids De novo lipogenesis SER (P450) ω-oxidation 2 Hepatocellular free fatty acids Peroxisomal β-oxidation ROS Mitochondrial β-oxidation Triglyceride 1 Lipid droplets (steatosis) NASH VLDL (secreted) ROS = reactive oxygen species B Tetri

  15. Insulin resistance Diet, uncontrolled diabetes Lipotoxicity hypothesis: Excess peripheral lipolysis Excess carbohydrates Increased circulating fatty acids De novo lipogenesis SER (P450) ω-oxidation Hepatocellular free fatty acids Peroxisomal β-oxidation Lipotoxic metabolites Mitochondrial β-oxidation • ER stress • Inflammation • Apoptosis • Necrosis Triglyceride Lipid droplets (steatosis) NASH VLDL (secreted) B Tetri Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010

  16. Lipotoxicity hypothesis: Insulin resistance Diet, uncontrolled diabetes Excess peripheral lipolysis Excess carbohydrates • Ceramides • Diacylglycerols • Lysophosphatidyl choline • Others Increased circulating fatty acids De novo lipogenesis SER (P450) ω-oxidation Hepatocellular free fatty acids Peroxisomal β-oxidation Lipotoxic metabolites Mitochondrial β-oxidation • ER stress • Inflammation • Apoptosis • Necrosis Triglyceride Lipid droplets (steatosis) NASH VLDL (secreted) B Tetri Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010

  17. Treatment of NASH Insulin resistance Diet, uncontrolled diabetes • Weight loss • Exercise • TZDs? • Cut the carbs! Excess peripheral lipolysis Excess carbohydrates • Divert to muscle • Exercise Increased circulating fatty acids • Divert to muscle • Exercise De novo lipogenesis SER (P450) ω-oxidation Hepatocellular free fatty acids Peroxisomal β-oxidation Lipotoxic metabolites • Diminish toxicity • Vitamin E? • Fish oil? • Ursodiol? Mitochondrial β-oxidation • ER stress • Inflammation • Apoptosis • Necrosis Triglyceride • Facilitate storage/secretion • Betaine? Lipid droplets (steatosis) NASH VLDL (secreted) B Tetri Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010

  18. NASH and the Metabolic Syndrome Bad diet + Obesity + Sedentary + Genetic predisposition Increased liver triglyceride Steatosis Excess circulating NEFA IR β-oxidation Lipotoxic intermediates in the liver NASH NEFA: nonesterified fatty acids, ie, free fatty acids IR: insulin resistance PCOS: polycystic ovary syndrome

  19. NASH and the Metabolic Syndrome Cancer Hypertriglyceridemia Hypercholesterolemia β-cell loss PCOS Hyperinsulinemia Diabetes Bad diet + Obesity + Sedentary + Genetic predisposition Increased liver triglyceride Steatosis Excess circulating NEFA IR β-oxidation Lipotoxic intermediates in the liver NASH Renin- angiotensin activation Vascular disease Sleep apnea CAD/PVD HTN NEFA: nonesterified fatty acids, ie, free fatty acids IR: insulin resistance PCOS: polycystic ovary syndrome

  20. Treatment of NASH • Lifestyle modification remains the primary treatment recommendation • Neuschwander-Tetri, B. A. Lifestyle modification as the primary treatment of NASH. Clinics in Liver Disease (2009) 13: 649-665 • Harrison, S. A. and Day, C. P. Benefits of lifestyle modification in NAFLD. Gut (2007) 56: 1760-1769. • Sullivan, S. Implications of diet on nonalcoholic fatty liver disease. CurrOpinGastroenterol (2010) 26: 160-164. • Bariatric surgery • Pillai, A. A. and Rinella, M. E. Non-alcoholic fatty liver disease: is bariatric surgery the answer? Clinics in Liver Disease (2009) 13: 689-710. • Drugs • Ratziu, V. and Zelber-Sagi, S. Pharmacologic therapy of non-alcoholic steatohepatitis. Clinics in Liver Disease (2009) 13: 667-688. • Trial results

  21. NASH CRN PIVENS trial • Pioglitazone vs Vitamin E vs Placebo in adults • Excluded diabetics, cirrhotics

  22. Vitamin E (rrr α-tocopherol) 800 IU/day placebo Pioglitazone (30 mg/day) PIVENS Study Design Randomization Eligibility assessed by local pathologist (1:1:1) Wk 0 End of treatment Liver Biopsy Wk 96 Week 120 end of study Month -6 Liver biopsy N Engl J Med (2010) 362: 1675-1685

  23. PIVENS • Primary endpoint: • Decrease in NAS by 2 or more points, with • at least a 1 point drop in ballooning, and • no worsening of fibrosis • 2 Primary comparisons: • Vitamin E vs placebo • Pioglitazone vs placebo • Significance set at p< 0.025 • Secondary endpoints: • changes in individual histologic features • resolution of steatohepatitis • changes in anthropometrics, insulin resistance, quality of life • adverse events N Engl J Med (2010) 362: 1675-1685

  24. Vitamin E alone met the pre-specified primary endpoint P< 0.001 P< 0.04 36/84 NNT=4.4 26/80 NNT= 6.6 16/83

  25. Both vitamin E and pioglitazone increased the proportion of subjects with resolution of NASH P< 0.0008 P< 0.01 44/84 40/80 23/83 N Engl J Med (2010) 362: 1675-1685

  26. Liver enzymes N Engl J Med (2010) 362: 1675-1685

  27. Change in body weight N Engl J Med (2010) 362: 1675-1685

  28. Who should we treat with vitamin E? Should we look for low vitamin E levels? Does reduction in the ALT mean the patient is responding?

  29. Who should we treat with vitamin E? • Responders didn’t have low initial vitamin E levels • The increase in vitamin E did not correlate with response • Non-compliance did not explain non-response Vit E treated Loomba et al, AASLD 2010

  30. Who should we treat with vitamin E? • Responders didn’t have low initial vitamin E levels • The increase in vitamin E did not correlate with response • Non-compliance did not explain non-response Vit E treated Placebo Loomba et al, AASLD 2010

  31. Who should we treat with vitamin E? • ALT dropped a bit more in responders than placebo • ALT dropped in both responders and non-responders Non-responders P = 0.005 Responders Loomba et al, AASLD 2010

  32. PIVENS trial summary • Vitamin E helped in about half the patients • Non-cirrhotic, non-diabetic • Natural vitamin E, 800 IU/day • We don’t know why it works • We can’t predict who will respond or who is responding • Pioglitazone helped a bit less that half the patients • Non-cirrhotic, non-diabetic • Weight gain is a problem • Long-term safety is still an issue

  33. NASH CRN TONIC trial • Treatment of NAFLD in Children = TONIC • NASH Clinical Research Network study • Hypothesis: metformin and vitamin E are superior to placebo for the treatment of NAFLD Lavine et al, JAMA (2011) 305: 1659-1668

  34. TONIC trial • Multicenter, double masked, double placebo, randomized Metformin 500 mg bid + vitamin E placebo or Vitamin E (natural form) 400 IU bid + metformin placebo or Both placebos bid • Treatment duration: 2 years • A priori endpoint: change in ALT • Secondary endpoint: histology Lavine et al, JAMA (2011) 305: 1659-1668

  35. TONIC: changes in primary endpoint (ALT) Metformin Placebo ALT Vitamin E Lavine et al, JAMA (2011) 305: 1659-1668

  36. TONIC: changes in primary endpoint (ALT) Metformin No significant differences Placebo ALT Vitamin E Lavine et al, JAMA (2011) 305: 1659-1668

  37. TONIC results: Liver biopsy changes Vitamin E increased resolution of NASH(from initial definite or borderline NASH) P = 0.006 N.S. % with resolution of NASH Lavine et al, JAMA (2011) 305: 1659-1668

  38. TONIC trial summary • Vitamin E helped about half the children • Primary endpoint of ALT change not met (placebo improved) • Biopsies did improve • 800 IU of natural vitamin E daily • Metformin did not help Lavine et al, JAMA (2011) 305: 1659-1668

  39. Treatment of NASH 2011 • Focus on preventing adipose IR and associated systemic lipotoxicity • Doing this treats NASH and comorbidities • Lifestyle modification • Exercise: Goal of 30-45 minutes aerobic daily • Weight loss • gradual and sustained • bariatric surgery an option • Healthy eating • portion control • avoid sugar sweetened beverages • no trans-fats

  40. Treatment of NASH 2011 • Drugs • Vitamin E? • Thiazolidinediones? (pioglitazone, rosiglitazone) • Statins? • Metformin-no benefit of improving hepatic insulin sensitivity • Not effective: ursodiol, betaine • Benefit of controlling co-morbidities on NASH? • Recognize and treat obstructive sleep apnea • Treating hyperlipidemia, improving glycemic control: no effect on liver

  41. Future directions • Incretin mimetics? • Naturally occurring: GIP, GLP-1 • Made by enteroendocrine L-cells • Responsible for 70% of post-prandial insulin secretion • Delays gastric emptying, increases satiety • Peripheral effects? • Analogue: exenetide • Inhibit breakdown by inhibiting DPP-4: gliptins (sitagliptin, saxagliptin) • FXR ligands? • Farnesoid X receptor = nuclear receptor activated by bile acids

  42. FXR agonist for NASH • FXR = “Farnesoid X receptor” = ligand activated nuclear receptor • Bile acids are the major natural ligands • Increased bile acids  decreased synthesis, increased export

  43. FXR agonist for NASH Cholesterol BA Gut BA BA = Bile acids BA

  44. FXR agonist for NASH Cholesterol BA Exporters (MDRs, BSEP) Gut TGR5 Bile acid receptor BA + FXR BA Hepatic and peripheral effects FGF19 synthesis by enterocytes BA = Bile acids FGF=Fibroblast growth factor FXR = Farnesoid X receptor FXR BA

  45. Regulation of gene expression by FXR Neuschwander-Tetri, B. A. Curr Gastroenterol Rep (2012) 14: 55-62

  46. FXR agonist for NASH High affinity FXR ligand

  47. Research options at SLU • NASH Clinical Research Network studies • NASH CRN treatment trials • FLINT (FXR Ligand in the Treatment of NASH) • Enrolling now! • “Database” observational study, seeking: • Ideally patients suspected of having NAFLD but not yet biopsied • Can enroll with a biopsy < 3 months old • Annual visits with free lab tests until 2014 tetriba@slu.edu

  48. OBESITY FAT STORAGE 2nd Hit 1st Hit FIBROSIS Inflammation Necrosis Apoptosis FFAs Lipid Peroxidation ROS Scavengers HSCs activation Pathogenesis of NASH: A Two “Hit” Hypothesis FFAs Hyperinsulinemia Insulin sensitivity Leptin sensitivity Adiponectin effect Dyslipidemia Type 2 Diabetes TNFa ATP IKKb NF-kb Endotoxin IL-6 Leptin LPO end products TNFa Festi, et al. Ob Rev. 2004; 5: 27- 42

  49. Normal Environment Steatosis Steatosis genes Steatohepatitis Oxidative Stress, cytokine, & endotoxin related genes Fibrosis & cirrhosis Genes Fibrosis genes Day CP. Liver International 2006

  50. Alcohol intake Low is protective Dietary factors Low antioxidant vitamins  saturated fat Obesity * Food intake Lack of exercise Type II DM* Small bowel bacterial overgrowth Sleep apnea syndrome Environmental Factors *Have a genetic component Wilfred de Alwis, NM & CP Day Seminars Liv ds. 2007

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