SASL « Hot Topics »
The Metabolic Syndrome
and the Liver
September 28, 2007
Antoine HadengueGastroentérologie et Hépatologie
Hôpitaux Universitaires de Genève
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
The Metabolic Syndrome
and the Liver
Obesity
HypertensionDyslipidemia Diabetes
Athero-sclerosis
The « Metabolic Syndrome »1960’s: clustering of risk factors
? ? ?
« Free fatty acidsassociated with obesity
cause both the insulin resistance andthe matching hyperinsulinemia of the
prediabetic state. »
The « Metabolic Syndrome »1994-2003: Lipotoxicity
LiverVasc. Panc. Kidney Muscle Heart Colon...
Fat,FFAs
Insulin resistance
Cell / tissue damage
P Cani et al. Diabetes 2007
P Cani et al. Diabetes 2007
P Cani et al. Diabetes 2007
CD 14 deleted
P Cani et al. Diabetes 2007
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
1. Lipotoxicity• Fat building
• Fat oxidants / antioxidants
• Adipokines
• Fat and insulin resistance
Fatty Livers
Building up Steatosis
Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ⇓⇓⇓⇓(mitochondrial)
Secretion ⇓⇓⇓⇓(MTP → VLDL assembly)
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
HCV induces the proteolyticcleavage of SREBPs
Waris G, Felmlee D, Negro F ... J Virol 2007
HCV induces the proteolyticcleavage of SREBPs
Waris G, Felmlee D, Negro F ... J Virol 2007
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
Synthesis ⇑⇑⇑⇑(SREBP-1, PPARγ → FAS)
ββββ- Oxidation ⇓⇓⇓⇓(mitochondrial)
Secretion ⇓⇓⇓⇓(MTP → VLDL assembly)
Building up Steatosis
Alcool
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⇑⇑⇑⇑
Building up Steatosis
Several players,
One game?
Overweight patients have more steatosis thanlean patients irrespective of viral genotype
Fartoux et al Gut, 2005
Insulin resistance is more marked whensteatosis is due to genotype 1 vs 3
Fartoux et al Gut, 2005
Building up Steatosis
Many players,
Many games ?
The oxidant /antioxidant balance
ROS / RNSProduction
Celldamage
ProteinsAminoacids
ThioredoxinMetallothioneinTaurineL-arginine…
Low MWAntiox.
α-lipoic acidGlutathionevitamin Cvitamin E…
Antiox.Enzymes
SODCatalaseGlutathion perox.…
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
« 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
1. Lipotoxicity• Fat building
• Fat oxidants / antioxidants
• Adipokines
• Fat and insulin resistance
Fatty Livers
Insulin Resistance More insulin needed to keep glucose homeostasis
⇒ Systemic Hyperinsulinic Clamp⇒ Hepatic 14Glucose uptake⇒ Cellular Altered Phosphorylation
(IRS, Akt... )
⇒ Practical HOMA score
HOMA =one index of insulin resistance(More insulin needed to keep glucose homeostasis)
Fasting insulin ( µµµµU/mL) X
Fasting glucose (mmol/L) /22.5
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
Intracellular insulin signalling
I LECLERCQ et al. J Hepatol 2007
HCV
Hyperinsulinemia
FAs
TNF…
Fatty livers get insulin resistant…… insulin resistant livers get fat !
resistance
TNF, IL-6…
Lipid. Perox.
⇑⇑⇑⇑
●OH ← H2O2
Fe
CYP2E1
1. Fat, lipotoxicity, endotoxins
2. Steatosis: a cofactor in
diseases other than NAFLD� Hepatitis C
� Hepatocellular carcinoma
� … Adenomas
� And back to Steatohepatitis
Fatty Livers
Hep C: Steatosis as a co-factor of liver fibrosis
E Powell et al. Hepatology 2005
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
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
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
Steatosis altersthe natural history
of
Hepatitis C, H
CC, adenomas,
Drug-induced liver disease,
Hemochromatosis...
Steatohepatitis
�Alcohol
�Metabolic syndrome
�Pullulations (Diverticules, intestinal surgery, diabetes (!))
�Drugs (Amiodarone, Tamoxifen, NSAIDs, Methotrexate …)
�…
Methotrexate liver fibrosis : Obesity and Diabetes are Risk factors
(169 liver biopsies from 71 patients)
Rosenberg P. et al. J Hepatol 2007
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 ?
+
+
+
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…)