Diabetes Mellitus and NonAlcoholic Fatty Liver Diseas
Case study
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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 40
hepatomegaly
• Labs:
WBC 4000
HB 12 g/dl
plat 122,000
INR 1
Iron Sat 40%
ALT 76 iu/L (N < 60)
AST 120 iu/L (N<40)
ALP 70 iu/L (N)
Albumin 39 g/L
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 disease
Alcoholic liver disease
Spectrum of Liver Disease in
Diabetics
Chronic viral hepatitis
especially HCV Autoimmune
hepatitis
Wilson’s disease
Spectrum of Liver Disease in
Diabetics
Hemochromatosis
Secondary 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)
Low Risk of progression to
cirrhosis
Increased CDV mortality
Non Alcoholic
Steatohepatitis NASH
Increased risk of progression to cirrhosis
Increased 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)
PATHOGENESIS
THE 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
100
90
80
70
60
50
40
30
20
10
0
non obese
Obese
T2DM
undergoing
bariatric surgery
Chalasani N et al. Hepatology 2012;55:2005-23
NAFLD—Histological Spectrum and
Natural History
Time Progression
10-20yrs
HCC
2-5 %
Cirrhosis
20-25 %
Lobular Inflammation NASH
5%
Non Alcoholoc fatty liver NAFL
Risk Factors For Progression To
Cirrhosis
• Risk factors for progression:
-Diabetes
-BMI > 30
≥ 2 factors consider liver biopsy to
- AST> ALT
assess stage of disease
-Age > 50
-Hispanic
- Ferritin > 1.5 X nml
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. The
echogenicity of the liver is equal to or slightly
Greater than that of the renal cortex (rc).
Normal Liver
Fatty liver
Fibroscan
NAFLD fibrosis score
Age
BMI
Hyperglycemia
Platelet count
Albumin
AST
ALT
http://nafldscore.com
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
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
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
Metformin
Pioglitazone
Hepatoprotectants
Ursodeoxycholic acid
Vitamin E
Omega-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
effect
•
Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement;
, no 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
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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