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 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 Ferritin 600 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
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. Pathogenesis The two (or three) hit hypothesis

16. HSC: hepatic stellate cells
Possible role of adipose tissue insulin resistance and lipotoxicity in the progression from NAFLD and NASH. (1) In the setting of obesity or T2DM, increased rates of lipolysis and plasma FFA, combined with hyperinsulinemia and hyperglycemia, stimulate excessive hepatic TG synthesis. (2) Steatosis in turn may (i) exacerbate hepatic insulin resistance, (ii) stimulate VLDL secretion, and (iii) increase mitochondrial beta-oxidation. If a new steadystate is achieved, only benign steatosis takes place. (3) If mitochondrial function cannot adapt to the increased FFA flux and respiratory oxidation collapses, lipid-derived toxic metabolites activate inflammatory pathways and hepatocyte lipotoxicity leading to.
Endoplasmic reticulum stress and the unfolded protein response also participate in the pathogenesis of NASH. (4) The cross-talk between hepatocytes, macrophages, and hepatic stellate cells (HSC) determines the degree of the fibrogenic response and potential progression to cirrhosis. (From Cusi K. Non-alcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2009;16:141–9; with permission.
Bacterial overgrowth
HSC: hepatic stellate cells

17. epidemiology

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

19. Prevalence of NAFLD in Select Populations By Ultrasound
Chalasani N et al. Hepatology 2012;55:

20. NAFLD—Histological Spectrum and Natural History
HCC
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
-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
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. NAFLD fibrosis score http://nafldscore.com Age BMI Hyperglycemia
Platelet count
Albumin
AST
ALT

28. NAFLD fibrosis score
< : predictor of absence of significant fibrosis (F0-F2 fibrosis)
≤ 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 activity1 2 3 4 5
1.Lazo M et al. Diabetes Care Kantarzis K et al. Gut Promrat K et al. Hepatology St George A et al. J Gastro Hepatol Hallsworth K et al. Gut 2009

31. Lifestyle Interventions
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 ( min/wk)alone can reduce steatosis but may not affect necroinflammation
2-3 Cups of filtered coffee may prevent fibrosis ???
Weight loss 1-2 pounds per week
* 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

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

33. Summary of trials involving Pioglitazone therapy 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 Metformin therapy 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
Cardiovascular outcomes study
Athyros et 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 hepatocellular ca than the general population
Viral, autoimmune and metabolic liver 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