The Metabolic Syndrome and the Liver · The Metabolic Syndrome and the Liver September 28, 2007...
Transcript of The Metabolic Syndrome and the Liver · The Metabolic Syndrome and the Liver September 28, 2007...
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SASL « Hot Topics »
The Metabolic Syndrome
and the Liver
September 28, 2007
Antoine HadengueGastroentérologie et Hépatologie
Hôpitaux Universitaires de Genève
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Non-Alcoholic Fatty Liver Diseases
Diagnostic criteria Histology
Natural history S 1% / Yr SH 2% C 3% HCC
(only 3% die of liver)
Non-invasive tests PPV: F0-2 vs F3-4, 70-90%, A ???
Therapy Exercise first !
Perspectives CB-1 agonists
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The Metabolic Syndrome
and the Liver
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Obesity
HypertensionDyslipidemia Diabetes
Athero-sclerosis
The « Metabolic Syndrome »1960’s: clustering of risk factors
? ? ?
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« Free fatty acidsassociated with obesity
cause both the insulin resistance andthe matching hyperinsulinemia of the
prediabetic state. »
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The « Metabolic Syndrome »1994-2003: Lipotoxicity
LiverVasc. Panc. Kidney Muscle Heart Colon...
Fat,FFAs
Insulin resistance
Cell / tissue damage
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P Cani et al. Diabetes 2007
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P Cani et al. Diabetes 2007
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P Cani et al. Diabetes 2007
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CD 14 deleted
P Cani et al. Diabetes 2007
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The « Metabolic Syndrome »2007: The « Gut / LPS connection »
Fat diet
Vasc. Panc. Kidney Liver Muscle Heart Colon...
∼ Gut Flora / Permeability ?
Endotoxins ⇒⇒⇒⇒ CD 14 ⇒⇒⇒⇒ TNF
Obesity, Insulin resistance
Steatosis, tissue damage
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1. Lipotoxicity• Fat building
• Fat oxidants / antioxidants
• Adipokines
• Fat and insulin resistance
Fatty Livers
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Building up Steatosis
Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ⇓⇓⇓⇓(mitochondrial)
Secretion ⇓⇓⇓⇓(MTP → VLDL assembly)
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Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ⇓⇓⇓⇓(mitochondrial)
Secretion ⇓⇓⇓⇓(MTP → VLDL assembly)
Building up Steatosis
HCV
PP
AR
αα αα⇓⇓ ⇓⇓
MTP⇓⇓⇓⇓
SREBP-1⇑⇑⇑⇑
S Clément, J Hepatol 2007
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HCV induces the proteolyticcleavage of SREBPs
Waris G, Felmlee D, Negro F ... J Virol 2007
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HCV induces the proteolyticcleavage of SREBPs
Waris G, Felmlee D, Negro F ... J Virol 2007
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Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ???(mitochondrial)
Secretion ???(MTP → VLDL assembly)
Building up Steatosis
HBV
?
?
SREBP-1⇑⇑⇑⇑
PPAR γγγγ⇑⇑⇑⇑
Kim et al Gastroenterology 2007
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Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ⇓⇓⇓⇓(mitochondrial)
Secretion ⇓⇓⇓⇓(MTP → VLDL assembly)
Building up Steatosis
Alcool
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Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ⇓⇓⇓⇓(mitochondrial)
Secretion ⇓⇓⇓⇓(MTP → VLDL assembly)
Building up Steatosis
Insulin⇑
PP
AR
αα αα⇓⇓ ⇓⇓
MTP⇓⇓⇓⇓
SREBP-1⇑⇑⇑⇑
Glucose⇑
ChREBP⇑⇑⇑⇑
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Building up Steatosis
Several players,
One game?
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Overweight patients have more steatosis thanlean patients irrespective of viral genotype
Fartoux et al Gut, 2005
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Insulin resistance is more marked whensteatosis is due to genotype 1 vs 3
Fartoux et al Gut, 2005
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Building up Steatosis
Many players,
Many games ?
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The oxidant /antioxidant balance
ROS / RNSProduction
Celldamage
ProteinsAminoacids
ThioredoxinMetallothioneinTaurineL-arginine…
Low MWAntiox.
α-lipoic acidGlutathionevitamin Cvitamin E…
Antiox.Enzymes
SODCatalaseGlutathion perox.…
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WAT
« Adipokines »
InflammationIL-1 /IL1RATNFIL-6, 8, 10MCP-1RantesPAI-1
AngiogenesisVEGFMMPs
Energy homeost.LeptinIL-1 /IL1RA, IL-6TNFMCP-1TGFββββ
Insulin Sens.LeptinIL-1 /IL1RA, IL-6TNF / AdiponectinResistinRBP 4
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« Adipokines » and liver cells
Type Hepatocyte Stellate cells
TNF, IL-6 Insulin resistance Pro-fibrogenic
MCP-1 ? PI3K ⇑, migration
VEGF ? Activation
Leptin ⇓ Insulin resistance Profibrogenic
Adiponectin ⇓ Insulin resistance Anti-fibrogenic
Angiotensinogen ? Fibrogenic (via ATII)
PAI-1 ? Fibrogenic
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1. Lipotoxicity• Fat building
• Fat oxidants / antioxidants
• Adipokines
• Fat and insulin resistance
Fatty Livers
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Insulin Resistance More insulin needed to keep glucose homeostasis
⇒ Systemic Hyperinsulinic Clamp⇒ Hepatic 14Glucose uptake⇒ Cellular Altered Phosphorylation
(IRS, Akt... )
⇒ Practical HOMA score
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HOMA =one index of insulin resistance(More insulin needed to keep glucose homeostasis)
Fasting insulin ( µµµµU/mL) X
Fasting glucose (mmol/L) /22.5
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Insulin Resistance “Syndrome” Extends Across Entire Range of Fasting Glucose
PP<0.001 for all trends using linear regression or Mantel<0.001 for all trends using linear regression or Mantel--HaenszelHaenszel cc22
MelgsMelgs JB et al. JB et al. Diabetes.Diabetes. 1998;45(suppl 2):193A.1998;45(suppl 2):193A.
HbA1c (mean %) 5.1 5.2 5.2 5.3 5.4 5.5 7.6
Fasting insulin (mean mU/mL) 25 26 28 30 33 35 58
Obesity (%) 15 20 28 34 36 42 64
Hypertension (%) 12 9 13 10 23 34 49
HDL-C <35 mg/dL (%) 5 9 10 13 17 20 35
Triglycerides 200 mg/dL (%) 10 10 15 15 18 35 49
FGFG11Glucose ToleranceGlucose Tolerance FGFG22 FGFG33 FGFG44 FGFG55 IGTIGT DMDM
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Intracellular insulin signalling
I LECLERCQ et al. J Hepatol 2007
HCV
Hyperinsulinemia
FAs
TNF…
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Fatty livers get insulin resistant…… insulin resistant livers get fat !
resistance
TNF, IL-6…
Lipid. Perox.
⇑⇑⇑⇑
●OH ← H2O2
Fe
CYP2E1
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1. Fat, lipotoxicity, endotoxins
2. Steatosis: a cofactor in
diseases other than NAFLD� Hepatitis C
� Hepatocellular carcinoma
� … Adenomas
� And back to Steatohepatitis
Fatty Livers
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Hep C: Steatosis as a co-factor of liver fibrosis
E Powell et al. Hepatology 2005
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Hep C: Response to Interferon + RibaMultifactorial Analysis
Odds ratio
Caucasian 1.85Low viral load 0.57Fibrose Score 0.90PEG-IFN Dose 1.37HOMA 0.87
Conjeevaram et al. Hepatology 2007
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Hepatocellular CarcinomaIndependent risk factors in 771 pts with cirrhosis
Relative riskBMI > 25 2.0BMI > 30 kg/m2 2.8Diabetes 1.6Age > 60 2.4Age > 70 3.0Male 2.0HCV 1.6Mixed etiology 2.6
N’Kountchou et al. Clin Gastroenterol Hepatol 2006
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Liver adenomas
• Oral contraceptives /androgens• HNF1- α (+/- MODY 3)• Telangiectasic adenomas
– BMI > 25 61 %– Steatosis outside tumor 70 %– Steatotic tumor 53 %– CRP > 5 mg/l 90 %– …HCC foci 3 %
V Paradis et al. Hepatology 2007
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Steatosis altersthe natural history
of
Hepatitis C, H
CC, adenomas,
Drug-induced liver disease,
Hemochromatosis...
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Steatohepatitis
�Alcohol
�Metabolic syndrome
�Pullulations (Diverticules, intestinal surgery, diabetes (!))
�Drugs (Amiodarone, Tamoxifen, NSAIDs, Methotrexate …)
�…
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Methotrexate liver fibrosis : Obesity and Diabetes are Risk factors
(169 liver biopsies from 71 patients)
Rosenberg P. et al. J Hepatol 2007
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Steatohepatitis : towards a unified concept ?
OxidativeOxidative Stress (Stress (IronIron, , SleepSleep apneaapnea...) ...)
AlcoholAlcohol
MetabolicMetabolic SdSd / / InsulinInsulin Resistance Resistance
DrugsDrugs / / toxinstoxins / CYP2E1 / CYP2E1 inductorsinductors
NASH Risk Score ?
+
+
+
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Metabolic Sd and the Liver
�Watch steatosis, a cofactor in mostacute and chronic liver diseases
�Beware insulin resistanceAvoid insulin therapy, iron overload…
�In patients with steatohepatitisLook for / treat cofactors(alcoholic, genetic, toxic, metabolic…)
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