Hepatosteatosis. Prof Samir Helmy Assaad-Khalil Unit of Diabetes & Metabolism Alexandria Faculty of Medicine. 2007. Agenda. Definition Common Causes of Steatosis Prevalence Data Ethnic and gender differences Relationship between fatty liver disease & Met. Syndrome
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Prof Samir Helmy Assaad-Khalil
Unit of Diabetes & Metabolism
Alexandria Faculty of Medicine
*HIV, human immunodeficiency virus.
* Asian versus other groups combined
* Asian versus other groups combined
Yasemin H. et al., Annals of Hepatology 2006; 5(2): April-June: 109-114
Ide T et al., Nat Cell Biol. 2004 Apr;6(4):351-7.
“2 Hit” Paradigm
“First hit” – Excess fat accumulation
a) Formation of lipid hydroperoxides.
b) Induction of certain microsomal enzymes e.g. cytochrome P450 2 El.
a) Mitochondrial damage with inhibition of mitochondrial electron transport chain activity.
b) Release of mitochondrial free radicals.
c) Depletion of mitochondrial glutathione pools.
a) Kupffer’s cell dysfunction
b) Impaired phagocytosis
c) Chronic low grade endotoxemia.
b) IL-6 and IL-8
c) Promote neutrophil chemotaxis & an inflammatory
CVH, chronic viral hepatitis; NASH, nonalcoholic steatohepatitis;
NAFLD,nonalcoholic fatty liver disease
Sotirios K. et alDig DisSci DOI 10.1007/s10620-006-9126-0
Serum leptin levels in patients with a normal liver or stable hepatic
steatosis (group 1) and with increased hepatic steatosis (group 2)
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Serum cytokine values of NAFL and control groups.
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Comparison of BMI of groups with & without
Comparison of cholesterol and triglyceride levels
of groups with & without steatosis (P<0.05).
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The liver metabolizes FFAs (partly mediated by lipase which is inhibited by insulin)
Interruption of insulin signaling in hepatocytes causes fatty liver. Increase hepatic FA content causes hepatic IR
Insulin resistance (IR)
When FFAs accumulate in the liver , they are oxidized by mitochondria .
When FFAs accumulation exceeds oxidation ,the triglycerides and fat accumulate in the liver
- Insulin signaling
- fat in liver
TNF plays an important role in IR evidenced by improvement of insulin sensitivity by genetic disruption of type 1 TNF receptors
Endotoxins from intestinal bacteria escape into the mesenteric blood & trigger a sustained hepatic inflammatory cytokine response (TNF).
NASH patients have higher concentration of total & FFA and total saturated & monounsaturated FAs, mainly due to the increase of: Hexadecanoic acid, Hexadecenoic acid &
Octadecenoic acid. While absolute PUFA was not increased
Chronic oxidative stress with a) Induction
of certain microsomal enzymes
(cytochrom P450 2 El) b) Lipid
peroxidation. c) Mitochondrial damage
with depletion of mitochondrial glutathion
pools and release of mitochondrial free
radicals which induce lipid peroxidation
of hepatocyte membranes; initiate an
inflammatory response with release of
cytokines (TNF , IL-6, IL- 8) and
Reduced antipyrine clearance (Cl-AP (reflects hepatic microsomal oxidative capacity)
Hepatic iron may contribute to the pathogenesis
of NASH by : 1- Induction of lipid peroxidation of
organelle membranes resulting in membrane disruption.
2- Impaired mitochondrial oxidative metabolism. 3-
Hepatocyte injury and death. 4- Lipocyte activation and
stimulation of collagen type I gene activation & fibrosis.
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Examples of non-alcoholic fatty liver disease (NAFLD)
OLT= Organ Liver Transplant
Charlton et al. Liver Transpl, 2001
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Significant improvement of histologic lesions 8 months after gastroplasty. H&E ×250.
Diffuse grade 3 steatosis & steatohepatitis in liver biopsy taken during gastroplasty.
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