Diabetes Mellitus and Non- Alcoholic Fatty Liver Diseas

1. Diabetes Mellitus and Non- Alcoholic Fatty Liver Diseas

2. Case study • 56 year old Kuwaiti man • T2DM and hypercholestremia diagnosed 6 years ago • “little” Alcohol intake during weekends • Medications - Metformin - Gliclazide - Atorvastatin - Baby Aspirin

3. Case study continued • Physical exam: BMI 40 hepatomegaly • Labs: WBC 4000 ALT 76 iu/L (N < 60) HB 12 g/dl AST 120 iu/L (N<40) plat 122,000 ALP 70 iu/L (N) INR 1 Albumin 39 g/L Iron Sat 40% S Ferritin600 ug/L(N <350)

4. Abdominal Ultrasound

5. Questions • What is the most likely cause of abnormal LFT in this patient ? • Would you proceed to liver biopsy if viral, autoimmune, and metabolic markers are negative ? • Should you stop statins ? • How would manage this patient ? • Would you recommend bariatric surgery ?

6. Spectrum of Liver Disease in Diabetics Non Alcoholic Fatty live disease Alcoholic liver disease

7. Spectrum of Liver Disease in Diabetics Chronic viral hepatitis especially HCV Autoimmune hepatitis Wilson’s disease

8. Spectrum of Liver Disease in Diabetics Hemochromatosis Secondary iron overload

9. Definition of Non-Alcoholic Fatty Liver Disease (NAFLD) • Evidence of fatty accumulation in the liver by imaging or histology • Alcohol intake less than 21 and 14 drinks per week for men and women respectively • No causes for secondary fat accumulation eg drugs, TPN, starvation, etc

10. Classification of NAFLD NAFLD Non Alcoholic fatty liver NAFL (steatosis without inflammation) Non Alcoholic Steatohepatitis NASH Low Risk of progression to cirrhosis Increased CDV mortality Increased risk of progression to cirrhosis Increased risk of CDV mortality

11. Simple Steatosis NAFL >5%–10% macrosteatotic hepatocytes

12. NASH (without fibrosis)

13. Hepatocyte Ballooning and Mallory Bodies Mallory Body

14. Cirrhosis (stage 4) Early stage 3 (bridging fibrosis)

15. PathogenesisThe two (or three) hit hypothesis

16. Bacterial overgrowth HSC: hepatic stellate cells

17. epidemiology

18. Prevalence of NAFLD Vernon G et al. Aliment PharmacolTher. 2011;34:274-85.

19. Prevalence of NAFLD in Select PopulationsBy Ultrasound Chalasani N et al. Hepatology 2012;55:2005-23

20. HCC NAFLD—Histological Spectrum and Natural History Time Progression 10-20yrs 2-5 % Cirrhosis 20-25 % Lobular Inflammation NASH 5% Non Alcoholoc fatty liver NAFL

21. Risk Factors For Progression To Cirrhosis • Risk factors for progression: -Diabetes -BMI > 30 - AST> ALT -Age > 50 -Hispanic - Ferritin > 1.5 X nml ≥ 2 factors consider liver biopsy to assess stage of disease

22. Diagnosis

23. Diagnostic Approach • Liver enzymes • Viral, autoimmune, and metabolic ( iron studies and ceruloplasmin) • Lipid profile • TSH • Imaging: US, CT, MRI, Fibroscan • NAFLD score • Liver biopsy

24. Normal appearance of the liver at US. The echogenicity of the liver is equal to or slightly Greater than that of the renal cortex (rc).

25. Normal Liver Fatty liver

26. Fibroscan

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

28. 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)

29. Treatment • Life style modification • Pharmacologic therapy • Surgery

30. Summary of life style intervention studies: Diet and physical activity 1 2 3 4 5 1.Lazo M et al. Diabetes Care 2010. 2. Kantarzis K et al. Gut 2008 3. Promrat K et al. Hepatology 2010. 4. St George A et al. J Gastro Hepatol 2009. 5. Hallsworth K et al. Gut 2009

31. Aim Hb A1c < 6.5 Correct dyslipidemia Alcohol consumption should be avoided or limited to one drink a day. 10 % weight loss led to improvement in steatosis, necrosis, and inflammation; not fibrosis. Moderate exercise ( 150-200 min/wk)alone can reduce steatosis but may not affect necroinflammation 2-3 Cups of filtered coffee may prevent fibrosis ??? * Promrat, et al. Hepatology 2010 ** Dunn, et al. Hepatology 2008 ** Gunji. et al. Am J Gastro 2009 ** Moriya, et al. AlimPharmTher 2011 ***Ruhl , et al. Clin Gastro Hepatol 2005 Lifestyle Interventions

32. Pharmacotherapy Insulin Sensitizers Metformin Pioglitazone Hepatoprotectants Ursodeoxycholic acid Vitamin E Omega-3

33. Summary of trials involving Pioglitazonetherapy for NAFLD • Abbreviations: RCT, randomized controlled trial; , improvement; , no effect.

34. AASLD recommendations: • Pioglitazone can be used to treat NASH in patients who have DM but long term safety and efficacy has not been established • Caution in patient with impaired myocardial function

35. Summary of trials involving Metformintherapy for NAFLD Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.

36. Summary of trials involving Vitamin E therapy for NAFLD • Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect. effect

37. Vitamin E: Safety 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

38. AASLD Recommendations-Vit E • “until further data supporting its effictiveness become available, vit E is not recommended to treat NASH in diabetics”

39. Summary of trials involving UDCA therapy for NAFLD • Abbreviations: n/a, not available;

40. AASLD Recommendations • Metformin and usrodeoxycholic acid do not induce histologic improvement • Not recommended as specific therapies for NAFLD

41. Summary of Bariatric surgery trials for NAFLD • Abbreviations: n/a, not available; , improvement; , no effect

42. 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

43. 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

44. GREACE Study: Safety of Statins in Patients with Abnormal LFT • Athyroset al Lancet 2010

45. 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.”

46. Take Home Messages • NAFLD is very common in diabetics who are at higher risk of cirrhosis and hepatocellularcathan the general population • Viral, autoimmune and metabolicliver disease should be ruled out in diabetics with NAFLD • Liver biopsy maybe considered in high risk patients • Lifestyle modification is the cornerstone of treatment • No drugs are currently recommended • Statins and fibrates are safe in NAFLD patients except in those with decompensated cirrhosis

47. Thank You