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Fatty Liver Disease

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  1. Fatty Liver Disease Jamie Blazek, MPH, APRN, FNP-C Liver Transplant Department Ochsner Health Systems New Orleans, La

  2. Disclosures None

  3. Objectives • Identify risk factors for fatty liver disease • Order appropriate screening tests • Diagnose and treat fatty liver disease • Initiate appropriate referrals

  4. Terminology • ALD: Alcoholic Liver Disease Significant alcohol consumption* > 21 drinks/week for males > 14 drinks/weeks for females • NAFLD: Non-Alcoholic Fatty Liver Disease steatosis without hepatocyte injury • NASH: Non-Alcoholic Steatohepatitis steatosis with inflammation, hepatocyte injury with or without fibrosis *Sanyal, et al Hepatology 2011

  5. Fatty liver Normal liver

  6. Statistics • Alcoholic liver disease • 15 million people abuse/overuse ETOH in USA • 90% of those will develop fatty livers • Moderate use with another risk factor • Non-alcoholic liver disease • Most common chronic liver disease in USA • 4th most common reason for liver transplant • Projected to be the most common in 10-20yrs • Up to 20-40% adults • 6 million children

  7. By 2020

  8. Natural History of FLDfatty liver steatohepatitis steatohepatitis + fibrosis steatohepatitis + cirrhosiscryptogenic cirrhosis

  9. Mortality risk: Cirrhotics with NAFLD vs hepatitis C • Sanyal,et al Hepatology 2006: • NAFLD had lower rate of mortality • Yatsuji, et al Gastroenterology and Hepatology 2009: • No difference • Both showed pts with NAFLD at lower risk for HCC than Hepatitis C pts.

  10. Middle age Female gender Over-weight or obese Viral hepatitis Iron overload Medications Rapid weight loss Starvation/refeeding syndrome Reye’s syndrome Auto-immune disease Malnutrition Abetalipoproteinemia Overgrowth of bacteria in small intestines TPN Acute fatty liver of pregnancy HELLP syndrome Hispanic ethnicity Hereditary NAFLD: risk factors

  11. Risk factors: Established association • Obesity • Type 2 DM: insulin resistance (IR) • Dyslipidemia • Metabolic syndrome (MS)

  12. Risk factors: Emerging association • Polycystic ovary syndrome • Hypothyroidism • Obstructive sleep apnea • Hypopituitarism • Hypogonadism • Pancreatic-duodenal resection

  13. Risk factor: Medications • Amiodarone • Methotrexate • Tamoxifen • Corticosteroids • Diltiazem • Valproic acid • Highly active antiretroviral therapy

  14. Risk factor: Bacteria overgrowth • Grieco, et al. Hepatology 2009 • 35 pts with NAFLD bx confirmed • 27 pts with celiac disease • 24 healthy individuals • Those with FLD had increased intestinal permeability and increased small bowel bacterial overgrowth • Compare, et al Nutrition Metabolism & Cardiovascular Disease Feb 2012 • Liver is 1st line of defense against gut-derived antigens • Levels of bacterial lipopolysaccharide (component of GN bacteria) are increased in the circulation in several types of chronic liver disease • Can modulation of gut microbia represent a new way to treat/prevent NAFLD????

  15. Screening ConsiderationsAASLD rec’s • Liver biochemistries can be normal • Ultrasounds are expensive • General population screening not recommended • Undergoing surgical procedure? • Planned pregnancy with obese mother? • Systematic screening of family members: not recommended at this time

  16. Further work-up indicated • Incidental finding on imaging for some other reason • Abnormal liver enzymes • Symptoms of liver disease • Rule out other causes: alcohol, medications, hepatitis, etc.

  17. Albumin AST ALT NAFLD fibrosis score http://nafldscore.com Age BMI Hyperglycemia Platelet count

  18. NAFLD fibrosis score • < -1.455: predictor of absence of significant fibrosis (F0-F2 fibrosis) • ≤ -1.455 to ≤ 0.675: indeterminate score • > 0.675: predictor of presence of significant fibrosis (F3-F4 fibrosis)

  19. Algorithm for evaluating NAFLD**taken from AGA position paper 2002 Accidental discovery Screen those with risk factors AST or AST Symptomatic liver disease elevated normal r/o other causes of liver disease monitor ongoing alcohol yes no Abstain Imaging study Echogenic US or fat on CT May need biopsy

  20. Liver biopsyAASLD rec’s • Incidental finding on imagery with normal enzymes: no biopsy indicated, monitor. • Presence of metabolic syndrome and persistently elevated biochemistries may benefit from liver biopsy • Patients with biopsy proven NASH cirrhosis should be screened routinely for esophageal varices and HCC

  21. Assessment • Symptoms • Malaise, fatigue, RUQ discomfort • Snores, disturbed sleep, wakes up tired • Chronic pain disorders, achy muscles • Physical exam • Abdominal obesity • Enlarged liver • RUQ tenderness on palpation • Labs • Consistent with metabolic syndrome • Elevated bilirubin, AST, ALT, AP, GGT

  22. Management: Lifestyle Interventions

  23. Weight loss by lower caloric intake and increased physical exercise * led to improvement in biopsy. 9.3% weight loss: improvement in steatosis, necrosis, and inflammation; not fibrosis 3-5% weight loss improves steatosis but more is needed to improve inflammation Alcohol consumption: heavy intake should be avoided light intake (<1/day) may have benefits**, may not*** * Promrat, et al. Hepatology 2010 ** Dunn, et al. Hepatology 2008 ** Gunji. et al. Am J Gastro 2009 ** Moriya, et al. Alim Pharm Ther 2011 ***Ruhl , et al. Clin Gastro Hepatol 2005 Lifestyle Interventions

  24. ManagementMedications

  25. Insulin sensitizing agents • Metformin * • reduction in IR and enzymes, • no improvement in histology • Thiazolidinediones • Rosiglitazone**: improved enzymes and steatosis, but not inflammation • Pioglitazone:***+weight gain, but improvement in hepatocellular injury *Uygun, et alAliment Pharm Ther 2004 *Nair, et alAliment Pharm Ther 2004 **Ratziu, et alGastroenterology 2008 ***Sanyal, et alNE J Med 2010

  26. PIVENS Study • Pioglitazone , Vitamin E, placebo • 96 weeks • Adults • with NASH • without DM, cirrhosis, Hep C, heart failure • limited alcohol intake over previous 5 years • Randomized trial • Pio group: 80 • Vit E group: 84 • Placebo: 83 Sanyal et al,New England J of Medicine 2010

  27. Primary outcome Vitamin E vs placebo 43% improvement vs 19%: significant (Steatosis, lobular inflammation, hepatocellular ballooning and fibrosis) Pio vs placebo 34% improvement vs 19%: not significant Sanyal et al,New England J of Medicine 2010

  28. Secondary outcome • Vitamin E vs placebo • Also reduction in SGOT/SGPT • Pio vs placebo • Reduction in SGOT/SGPT • Reduction in steatosis, lobular inflammation • Improvement in IR • Increase in weight that did not resolve after discontinuance of Pio Sanyal et al,New EngJ of Med 2010

  29. PIVEN Conclusions • Vitamin E was superior to placebo in adults with NASH and without DM • Pioglitazone may have a role in treating patients with biopsy-proven NASH, however long term safety and efficacy has not been established Sanyal et al,New EnglJ of Med 2010

  30. AASLD recommendations: • Pio can be used to treat certain patients with biopsy-proven NASH who do not have DM but long term safety and efficacy has not been established • Vitamin E 800 IU/day improves liver histology in NASH pts • Not recommended to treat NASH in those with other chronic liver diseases, diabetics, those with NASH cirrhosis or cryptogenic cirrhosis, NAFLD without biopsy

  31. Vitamin E: other concerns • Meta-analysis* including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortality • Vitamin E** > 400 IU/day increases risk of prostate cancer in relatively healthy men *Miller et al Annals of Internal Medicine 2005 ** Klein, et al, JAMA 2011

  32. Other meds for NASH • Ursodeoxycholic acid* • no histologic benefit • Omega-3 fatty acids** • Effective in treating hypertriglyceridemia in pts with NAFLD • Evidence for treatment of NASH inconclusive to date • Large multi-center trial on-going now *Lindor, et al. Hepatology 2004 **Capanni, et al. Alimen Pharm Ther 2006

  33. Statins • CVD common cause of death for NAFLD and NASH • Stratify risks and treat accordingly • Several studies show NAFLD and NASH pts are not at increased risk of liver injury over general population* • No RCTs with histological end points using statins to treat NASH *Chalasani, et al. Am J Gastro 2012

  34. GREACE study* Concluded statins significantly improve liver biochemistries and CV outcomes in pts with elevated enzymes likely due to NASH • Athyros et al Lancet 2010

  35. AASLD Recommendation on Statins “Given lack of evidence that patients with NAFLD and NASH are at increased risk for serious drug-induced liver injury from statins, they can be used to treat dyslipidemia in patients with NAFLD and NASH.”

  36. Bariatric surgery • No RCTs • Cochrane review 2010: lack of RCTs prevents definitive assessment of risks/benefits • Prospective study* • 381 adults with severe obesity, fibrosis score<3 • Clinical, metabolic, liver biopsy comparisons at 1 year and 5 years • Significant improvement in steatosis, ballooning, resolution of probable/definite NASH at 1 and 5 years • Small but significant increase of fibrosis score at 5 years (96% had improvement) *Mathurin et al Gastroenterology 2009

  37. AASLD Recommendation on Bariatric Surgery • Premature to consider foregut surgery as an option to specifically treat NASH • Foregut surgery is not contra-indicated in otherwise eligible pts with NASH or NAFLD WITHOUT cirrhosis • For those with cirrhosis: type, safety and efficacy of foregut surgery is not established

  38. Transplant Considerations

  39. MS & Immunosuppression • Steroids • BP induce IR • lipid metabolism weight gain • gluconeogenesis peripheral glucose utilization • CNIs : pancreatic beta cell toxicity • Nephrotoxicity • TAC - glucose intolerance and de novo DM • CSA - HTN and hyperlipdemia • mTOR inhibitors • hyperlipidemia

  40. Metabolic Syndrome in Kidney Transplant* • Metabolic syndrome (MS) may play a role in allograft loss and poor function • Pathophysiology of MS is altered by immunosuppression * Hricik, Clin J of ASN 2011

  41. Metabolic Syndrome in Kidney Transplant • Prevalence of MS post KTx • 22.6% at 1 year* • 37.7% at 18 months* • 63% at a median of 6 years** * Porrini et al, Amer J of Kid Dis 2006 ** de Vries et al, Amer J of Trans 2004

  42. Metabolic Syndrome in Kidney Transplant • MS lowered creatinine clearance by 5mL/min after 7 years • Systolic BP and hypertriglyceridemia had most negative impact *de Vries et al, Amer J of Trans 2004

  43. Metabolic Syndrome in Kidney Transplant: Blood Pressure Choice of antihypertensive post KTx: Cochrane Group Review http://summaries.cochrane.org/CD003598/ blood-pressure-medication-for-kidney- transplant-recipients

  44. Metabolic Syndrome in Kidney Transplant: Hyperlipdemia • ALERT trial* • Randomized, double blind, placebo control (N=1100) • Fluvastatin was superior to placebo in significantly lowering total and LDL cholesterol in renal transplant pts and in lowering rates of cardiac death and MI • Hypertriglyceridemia: anecdotal use of fenofibric acid, fish oils, ezetimibe *Fellstrom et al Kid Internat 2004

  45. Risk factors for NASH after liver transplant* • Post transplant obesity • TAC based regimen • DM • Hyperglycemia • HTN • ETOH as primary cause for transplant • Pre-transplant allograft biopsy showing steatosis *Dumortier, et al Am J of Gastro March 2010

  46. MS Post Liver Transplant • 44-58% of pts > 6months post OLT • BMI increase of 10% increases risk of post OLT NAFLD • Associated with increased cardiovascular and cerebrovascular events • CVD causes 19-42% non-liver related deaths • Diabetes, HTN, IR add 2-fold increased mortality risk Watt & Charlton J Hepatology 2010

  47. MS Post Liver Transplant • Obesity • Between 1990 and 2002 the % of obese OLT recipients increased from 15% to 25% and average increase of 1kg/year* • Orlistat (tetrahydrolipstatin)** Limited efficacy • May interfere with drug absorption • Post transplant bariatric surgery: few reported cases*** • May interfere with drug absorption * Everhart et al, Liver Transpl Surg 1998 * Richards et al, Transpl Int 2005 ** Cassiman et al, Transpl Int 2006 ***Takata et al, Surg Obes Relat Dis 2008 *** Butte et al, Obes Surg 2007 *** Campsen et al, Obes Surg 2008

  48. MS Post Liver Transplant* • Diabetes post OLT • 5 year occurrence of advanced fibrosis is increased in patients treated for DM (49%) when compared to those with normal insulin sensitivity (20%) • Treatment goals same as general population * Watt & Charlton J Hepatology 2010

  49. MS Post Liver Transplant* • Dyslipidemia post OLT: 45-69% • Changing immunosuppression: CsA to TAC, Rapa to TAC, steroid free • High cholesterol: Statins: • pravastatin most studied; does not require P450 enzyme system • With other statins: reduction in TAC/CsA dose??? • Mediterranean diet • High Triglycerides: • fish oils • Fenofibric acids derivatives: reduction in TAC/CsA dose??? • ezetimide * Watt & Charlton J Hepatology 2010

  50. MS and Heart Transplant* 48% of heart transplant recipients Long term survival better without MS • Differences observed in MS group • Median age older • Pre-tx creatinine higher • Pre-tx HTN higher • BMI higher • Dyslipidemia higher rate • No difference MS vs nonMS • Gender • Underlying etiology • Smoking • DM history pre-tx • Immunosuppression *Sanchez-Lazaro et al Transplantation Proc 2011