Diabetes Mellitus and Non- Alcoholic Fatty Liver Diseas

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

Case study continued• Physical exam:

BMI 40hepatomegaly

• 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/LIron Sat 40% S Ferritin 600 ug/L(N

<350)

Abdominal Ultrasound

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 ?

Spectrum of Liver Disease in Diabetics

Non Alcoholic Fatty live diseaseAlcoholic liver disease

Spectrum of Liver Disease in Diabetics

Chronic viral hepatitis especially HCV Autoimmune hepatitisWilson’s disease

Spectrum of Liver Disease in Diabetics

HemochromatosisSecondary iron overload

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

Classification of NAFLD

NAFLD

Non Alcoholic fatty liver NAFL (steatosis without inflammation)

Non Alcoholic Steatohepatitis NASH

Low Risk of progression to cirrhosisIncreased CDV mortality

Increased risk of progression to cirrhosisIncreased risk of CDV mortality

Simple Steatosis NAFL

>5%–10% macrosteatotic hepatocytes

NASH (without fibrosis)

Hepatocyte Ballooning and Mallory Bodies

Mallory Body

Cirrhosis (stage 4) Early stage 3

(bridging fibrosis)

PATHOGENESISTHE TWO (OR THREE) HIT HYPOTHESIS

Bacterial overgrowth

HSC: hepatic stellate cells

EPIDEMIOLOGY

Prevalence of NAFLD

Vernon G et al. Aliment Pharmacol Ther. 2011;34:274-85.

Prevalence of NAFLD in Select Populations

By Ultrasound

non obese Obese T2DM undergoing bariatric surgery

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Chalasani N et al. Hepatology 2012;55:2005-23

NAFLD—Histological Spectrum and Natural History

HCC

Non Alcoholoc fatty liver NAFL

Lobular Inflammation NASH

Cirrhosis

Tim

e Pr

ogre

ssio

n 10

-20y

rs

20-25 %

2-5 %

5%

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

Diagnosis

Diagnostic Approach

• Liver enzymes• Viral, autoimmune, and metabolic ( iron

studies and ceruloplasmin)• Lipid profile• TSH• Imaging: US, CT, MRI, Fibroscan • NAFLD score• Liver biopsy

Normal appearance of the liver at US. Theechogenicity of the liver is equal to or slightlyGreater than that of the renal cortex (rc).

Normal Liver

Fatty liver

Fibroscan

NAFLD fibrosis score

http://nafldscore.com

AgeBMIHyperglycemiaPlatelet count

AlbuminASTALT

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)

Treatment

• Life style modification• Pharmacologic therapy• Surgery

Summary of life style intervention studies: Diet and physical activity

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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

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 ( 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. Alim Pharm Ther 2011***Ruhl , et al. Clin Gastro Hepatol 2005

Pharmacotherapy

Insulin Sensitizers

MetforminPioglitazone

Hepatoprotectants

Ursodeoxycholic acidVitamin EOmega-3

Summary of trials involving Pioglitazone therapy for NAFLD

• Abbreviations: RCT, randomized controlled trial; , improvement; , no effect.

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

Summary of trials involving Metformin therapy for NAFLD

Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.

Summary of trials involving Vitamin E therapy for NAFLD

• Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.

effect

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

AASLD Recommendations-Vit E

• “until further data supporting its effictiveness become available, vit E is not recommended to treat NASH in diabetics”

Summary of trials involving UDCA therapy for NAFLD

• Abbreviations: n/a, not available;

AASLD Recommendations

• Metformin and usrodeoxycholic acid do not induce histologic improvement

• Not recommended as specific therapies for NAFLD

Summary of Bariatric surgery trials for NAFLD

• Abbreviations: n/a, not available; , improvement; , no effect

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

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

GREACE Study: Safety of Statins in Patients with Abnormal LFT

• Athyros et al Lancet 2010

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.”

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

Thank You