The Metabolic Syndrome and the Liver...« Free fatty acids associated with obesity cause both the...

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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…)