Diabetologie. Nash Sinaia

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NON-ALCOHOLIC FATTY LIVER NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN METABOLIC DISEASE (NAFLD) IN METABOLIC SYNDROME&TYPE 2 D.M. SYNDROME&TYPE 2 D.M. M.D., Ph.D., Prof.Dr.Amorin-Remus Popa, M.D., Ph.D., Prof.Dr.Amorin-Remus Popa, University of Oradea, University of Oradea, Emergency clinical hospital Emergency clinical hospital

Transcript of Diabetologie. Nash Sinaia

Page 1: Diabetologie. Nash Sinaia

NON-ALCOHOLIC FATTY LIVER NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN METABOLIC DISEASE (NAFLD) IN METABOLIC

SYNDROME&TYPE 2 D.M.SYNDROME&TYPE 2 D.M.

M.D., Ph.D., Prof.Dr.Amorin-Remus Popa,M.D., Ph.D., Prof.Dr.Amorin-Remus Popa,

University of Oradea,University of Oradea,

Emergency clinical hospitalEmergency clinical hospital

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-Novel diseases, firstly recognized at the beginning of the second millenium

-Hepatic expression of the “so-called” metabolic syndrome

-Because of epidemic burden of O. , D.M. and metabolic diseases, NFALD and NASH -> probably the most common hepatic disease worldwide

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Epidemiology and natural history of primary NAFLD

Current definition of non-alcoholic steatohepatitis

-histological leasons of steatohepatitis-risk factors of complications of I.R.-* a semiology cause of I.R.

(Prof.Vlad Ratziu, NASH, the liver and I.R. – 2009)

NAFLD-histological spectrum of liver damage-from simple steatosis -to advanced fibrosis and cirrhosis-individuals without a relevant alcohol

comsumption (<20g/day)

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NAFLD – does not progress to end-stage liver dissease

NASH -is ↗ for hepatic fibrosis-20-30% of cases have histological signs of

fibrosis, inflammation and necrosis↓

high risk for -cirrhosis-terminal liver failure-hepatocellular carcinoma

Paloma Almeda-Valdes, Daniel Cuevas-Ramos, Carlos Alberto Aquilar-Salinas – Metabolic syndrome and non-acoholic fatty liver disease –

Annals of Hepatology 2009,8(1): Supplement: S18-S24

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NAFLD – def. – condition of fat accumulation in the liver in the absence of excessive alcohol consumption (less than 20g/day)

-any other specific causes of hepatic steatosisa.Primary origin – aetiology not yet completely understood

• Related strictly to the presence of IR• Occurs as the initial part of the M.S.• Accompany O., D.M. type 2, DLP

b.Secondary • Nutritional - malnutrition, rapid weight loss• Metabolic - abetalipoproteinemia, lipodystrophy• Drug-induced-glucocorticoids, methotrexate,

chemotherapics, tamoxifene• Other conditions-jejunal diverticulitis with bacterial

overgrowth, inflammatory bowel disease, occupational exposure

(Bellentani S, Marino M. Epidemiology and Natural history of non-alcoholic fatty liver disease (NAFLD). Annals of Hepatology 2009)

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Nonalcoholic

Fatty Liver

Disease

2. Etape diagnostique : distinction stéatose vs stéatohépatite

Excessive liver fatExcessive liver fat

SteatohepatitisBland steatosis

Diagnostic distinction based on hepatocyte cell injury(ballooning, necrosis /inflammation, Mallory bodies)

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Steatosis without other histological signs Steatosis without other histological signs

Bland steatosisBland steatosis

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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SteatosisSteatosis

SteatohepatitisSteatohepatitis

Hepatocyte cell injuryHepatocyte cell injuryBallooning, lobular Ballooning, lobular inflammation/necrosis,inflammation/necrosis,Mallory bodies, PMNMallory bodies, PMN

ballooningballooning

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 10: Diabetologie. Nash Sinaia

3. Etape pronostique : Évaluer le stade de fibrose

F0 (/F1 ?)F0

F4

Perisinusoïdal FibrosisPortal FibrosisPrognostic value

Nonalcoholic

Fatty Liver

Disease

Excessive liver fatExcessive liver fat

SteatohepatitisBland steatosis

Diagnostic distinction based on hepatocyte cell injury(ballooning, necrosis /inflammation, Mallory bodies)

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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• Pourquoi la stéatose ?Pourquoi la stéatose ?

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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NAFLD : a Model of Insulin NAFLD : a Model of Insulin Resistance-Induced Liver InjuryResistance-Induced Liver Injury

Normal liverNormal liver

STEATOSISSTEATOSIS

STEATOHEPATITISSTEATOHEPATITIS

CIRRHOSISCIRRHOSIS

??

HEMORRAGEHEMORRAGELIVERLIVER

FAILUREFAILURE CANCERCANCER

????

??

INSULININSULINSENSITIVITYSENSITIVITY

Insulin Insulin ResistanceResistance

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Physiologie de la répartition des substrats énergétiques :Physiologie de la répartition des substrats énergétiques :à distance des repas, le foie produit du glucose (PHG) et le tissu adipeux à distance des repas, le foie produit du glucose (PHG) et le tissu adipeux

produit les acides gras nécessaires au muscle et au foie (voies inhibées par produit les acides gras nécessaires au muscle et au foie (voies inhibées par l’insuline)l’insuline)

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Dpr.-ussualy-U.S.(ultrasonography)-moderate and severe steatosis

-only when fat on liver biopsy exceeds 33%-more sensitive techniques

-MR imaging and spectroscopy -expense and lack of feasibility in large

population

AASLD – diagnosis of NAFLD at fat accumulation in the liver of at least 5 to 10% by weight

→LIVER BIOPSY = gold standardDallas Heart Study / 30% of adult Americans \- NAFLDDionysos Study \ 25% of adult Italians /-

79% and 55% patients with NAFLD – normal aminotransferase levels – liver enzymes highly underestimate the prelevance of NAFLD

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Prévalence de la stéatose Prévalence de la stéatose échographiqueéchographique

SujetNormal

Obésité DiabèteType 2

Sd métabolique

%

22

7470

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Prévalence de la stéatopathie Prévalence de la stéatopathie métabolique chez les patients avec métabolique chez les patients avec augmentation des transaminasesaugmentation des transaminases

AutresAutres

NormalNormal

StéatopathiesStéatopathiesmétabolqiuesmétabolqiues

StéatoseStéatose

26%26%

32%32%SteatohépatiteSteatohépatite

23%23%

19%19%

58 %58 %

Evaluation prospective multicentrique française (21 Evaluation prospective multicentrique française (21 centres) des 274 sujets avec augmentation inexpliquée centres) des 274 sujets avec augmentation inexpliquée des transaminasesdes transaminases

De Ledinghen, Ratziu, J Hepatol 2006De Ledinghen, Ratziu, J Hepatol 2006Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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TAKE HOME MESSAGESTAKE HOME MESSAGES

• Liver injury needs to be assessed in Liver injury needs to be assessed in patients with insulin resistancepatients with insulin resistance

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Steatosis Independently Induces Steatosis Independently Induces Hepatic IRHepatic IR

3 day high fat diet3 day high fat diet

STEATOSISSTEATOSIS

No increase visceral fatNo increase visceral fat

No increased portal FFANo increased portal FFA

No muscle adipose IRNo muscle adipose IR

MUSCLE:MUSCLE: normal normalglucose uptakeglucose uptake

ADIPOSE T :ADIPOSE T : normal normalinhibition of FFA inhibition of FFA release by insulinrelease by insulin

insulin suppressioninsulin suppressionof hepatic glucose of hepatic glucose

productionproduction

HEPATIC INSULIN RESISTANCEHEPATIC INSULIN RESISTANCE

Samuel, Shulman, JBC 2004Samuel, Shulman, JBC 2004

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Liver Fat is Associated with Liver Fat is Associated with Defects in Insulin Action Defects in Insulin Action

Independent of Obesity in Normal Independent of Obesity in Normal MenMen

30 Healthy controls differing in the 30 Healthy controls differing in the amount of liver fatamount of liver fat

Individuals with high liver fat content had :Individuals with high liver fat content had : Higher fasting hyperinsulinemia (7.3 vs 5.3)Higher fasting hyperinsulinemia (7.3 vs 5.3) Higher TG levels (1.4 vs 0.9)Higher TG levels (1.4 vs 0.9) Lower HDLc (1.4 vs 1.6)Lower HDLc (1.4 vs 1.6) Higher blood pressure (130 vs 122)Higher blood pressure (130 vs 122) Impaired insulin suppression of glucose and Impaired insulin suppression of glucose and

FFAFFASeppala-Lindroos, JCEM 2002Seppala-Lindroos, JCEM 2002

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Liver Fat Content : a Major Liver Fat Content : a Major Determinant of Insulin Determinant of Insulin

Requirements in DiabetesRequirements in Diabetes

60% of the variation of the daily insulin requirements was 60% of the variation of the daily insulin requirements was attributable to the variation of hepatic fat contentattributable to the variation of hepatic fat content

% fat liver was most closely correlated with reduced % fat liver was most closely correlated with reduced suppression of hepatic glucose production by insulinsuppression of hepatic glucose production by insulin

N=20 stable Type 2, Insulin treated diabetic Pts N=20 stable Type 2, Insulin treated diabetic Pts

Ryysy, Diabetes 2000Ryysy, Diabetes 2000Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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NAFLD patients present increased subclinical atherosclerosis compared to non-steatosis individuals

-CVD is the second most common cause of death in NAFLD

-hepatic steatosis alone -> triad: steatosis, hepatocellular necrosis, inflammation

-I.R. -> obesity, D.M. type 2, DLP

-NAFLD – component of M.S -> increase risk of coronary heart disease and C.V. complications

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Competitive Risks : Heart vs LiverCompetitive Risks : Heart vs Liver

Early endothelial dysfunction in NAFLDEarly endothelial dysfunction in NAFLD• Independent of BMI, HOMA ?Independent of BMI, HOMA ?

Villanova, Hepatology 2005Villanova, Hepatology 2005ControlsControls

NAFLDNAFLD

Median 1.2%Median 1.2%

Median 3.7%Median 3.7%

*Framingham 10-year risk*Framingham 10-year risk

Ioannou, Gastroenterology 2006Ioannou, Gastroenterology 2006

Higher CV risk profile* in NAFLDHigher CV risk profile* in NAFLD

controlscontrols steatosissteatosis NASHNASH

Villanova, Hepatology 2005Villanova, Hepatology 2005

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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N=4222N=4222

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

00<50<50 50-5950-59 60-6960-69 70-7970-79

% p

atie

nts

wit

h p

laq

ue

% p

atie

nts

wit

h p

laq

ue

**

Age (yr)Age (yr)

No steatosisNo steatosis

****

SteatosisSteatosis

* p < 0.05* p < 0.05

Higher prevalence of carotid plaques in NAFLDHigher prevalence of carotid plaques in NAFLD• Independent of BMI, diabetes, smoking, lipid profileIndependent of BMI, diabetes, smoking, lipid profile

Higher carotid intima media thickness in NAFLDHigher carotid intima media thickness in NAFLD

• Mediated through visceral fat and serum TGMediated through visceral fat and serum TG

Volzke, W J Gastro 2005Volzke, W J Gastro 2005

Targher, Diabetes Care 2004Targher, Diabetes Care 2004

Competitive Risks : Heart vs LiverCompetitive Risks : Heart vs Liver

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 24: Diabetologie. Nash Sinaia

FFAs - increase in O. patient, D.M. type 2, H.S., C.V.D.

- myocardial dysfunction, proarrhythmic

M.S. -liver release pro-atherogenic factors–CRP,

fibrinogen, PAI-1, other inflammatory cytokines

I.R., DLP => CVD progression (Abdeen et al)

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Liver Fat : Center Stage for Liver Fat : Center Stage for Metabolic Syndrome ?Metabolic Syndrome ?

STEATOSISSTEATOSIS

HypertensionHypertension

DiabetesDiabetes

AtherosclerosisAtherosclerosis

ALTALT

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 26: Diabetologie. Nash Sinaia

TAKE HOME MESSAGESTAKE HOME MESSAGES

• Liver injury needs to be assessed in Liver injury needs to be assessed in patients with insulin resistancepatients with insulin resistance

• Steatohepatitis worsens phenotypical Steatohepatitis worsens phenotypical complications of insulin resistance complications of insulin resistance

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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LIVER FATLIVER FAT

Chronic Chronic inflammatoryinflammatory

statestateHepatic IRHepatic IR

Systemic IRSystemic IR

Liver InjuryLiver Injury

• VulnerabilityVulnerability

•NASH/Cirrhosis/liver cancerNASH/Cirrhosis/liver cancer

• NecrosisNecrosis• Innate immune systemInnate immune system• ApoptosisApoptosis

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 28: Diabetologie. Nash Sinaia

Marqueurs sériques non-Marqueurs sériques non-invasifs disponiblesinvasifs disponibles

FibroTestFibroTest ELF PanelELF Panel AnguloAngulo Fibromètre Fibromètre Ac Hyaluronique Ac Hyaluronique Score de LainéScore de Lainé

FIBROSE

SteatoTesSteatoTestt

STEATOSE

NASHTestNASHTest CK 18 ?CK 18 ?

STEATOHEPATITE

Wieckowska, Hepatology 2006Wieckowska, Hepatology 2006

Cales, Hepatology 2005Cales, Hepatology 2005

Angulo, Hepatology 2007Angulo, Hepatology 2007

Guha, Hepatology 2008 Guha, Hepatology 2008

Ratziu, BioMedCentral Gastro 2006Ratziu, BioMedCentral Gastro 2006

Poynard, BMC Gastro 2006Poynard, BMC Gastro 2006

Rosenberg, Gastroenterology 2004 Rosenberg, Gastroenterology 2004

Poynard, Comp Hepatol 2005 Poynard, Comp Hepatol 2005

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 29: Diabetologie. Nash Sinaia

TAKE HOME MESSAGESTAKE HOME MESSAGES

• Liver injury needs to be assessed in Liver injury needs to be assessed in patients with insulin resistancepatients with insulin resistance

• Steatohepatitis worsens phenotypical Steatohepatitis worsens phenotypical complications of insulin resistancecomplications of insulin resistance

• Steatohepatitis increases liver-Steatohepatitis increases liver-related morbidity/mortality (cirrhosis related morbidity/mortality (cirrhosis and hepatocellular cancer) and hepatocellular cancer)

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 30: Diabetologie. Nash Sinaia

No changeNo changeMuscle fatMuscle fat

Improvement Improvement in hepatic IRin hepatic IR

Liver fatLiver fat Body fatBody fat

ModestModestWeight lossWeight loss

Petersen, Diabetes 2005Petersen, Diabetes 2005

Tiikkainen, Diabetes 2003Tiikkainen, Diabetes 2003

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy

Cytokines play a pivotal role in pathogenesis and severity of NAFLD.-adipose tissue - endocrine organ - key role in energy homeostasis

- its metabolic products – adipokines- local- peripheral- central effects

Hypertrophied adipocytes -> release chemokines -> recruit macrophages -> releaseinflammatory cytokines

- stimulate inflammatory- suppress anti-inflammatory adipokines

Liver injury -> most adipokines are also produced and secreted by hepatocytes.I. Adipokines - leptin

- adiponectin- resistin- TNF-α - IL-6

new - visfatin - retinol-binding protein 4 (RBP4)

(Emmanuel A. Tsochatzis, George V. Papatheodoridis, and Athanasios J. Archimandritis: Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy, Mediators of

Inflammation, vol. 2009, pag. 831670, 8 pages)

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The primary insult in NASH -> accumulation of triglycerides in the liver(as a result of IR)HyperIns. - ↗ glucose uptake \

- ↗ lipogenesis - inhibits lipolysis in the adipose tissue 1. ↗ synthesis of fatty acids in the liver -> lipid accumulation in the hepatocytes 2. ↗ oxidative stress within the hepatocytesII. Leptin - ↗ R.I. -> ↗ steatosis

- proinflammatory role -> mediator of liver fibrosisIII. Adiponectin - secreted by adipocytes = anti-inflammatory adipokine

- ↘ body fat- improves hepatic and peripheral insulin sensitivity- inversely associated with BMI and IR

Adiponectin induction -> protective action of saturated fat in liverIV. TNF-α - associated with obesity and IR

- TNF-α profibrotic action is mediated - Kupffer cells activationV. Resistin - recently discovered adipokine

- secreted by adipose tissue and macrophages- proinflammatory action- stimulates TNF-α and IL-12- regulates the secretion of IL-6 and IL-1BETA

(Emmanuel A. Tsochatzis, George V. Papatheodoridis, and Athanasios J. Archimandritis: Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy, Mediators of

Inflammation, vol.2009, pag. 831670, 8 pages)

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VI. IL-6 – hepatoprotective action -> ↘ oxidative stress->preventing mitochondrial dysfunction

short-term action long-term action -> sensitize the liver to injury and apoptotic cell death

VII. Other Cytokines - RBP4 - secreted - adipose tissue ↗ I.R. state- Visfatin -> insulin-mimicking effects, by activating the insulin

receptor

Therapeutic Implications!!! Adipokines are key players in the pathogenesis and progression of NAFLDThe use of drugs directly targeting adipokines.a.Pentoxifylline - nonspecific TNF-α inhibitor - 1200 mg/day - ↘ of serum transaminases after 12 monthsb.Infliximab – selectively blocker of TNF-αc.Pioglitazone - improves NASH lesions - ↗ adiponectin levels – hepatoprotective action d.Tocilizumab - IL-6 receptor antibody

(Emmanuel A. Tsochatzis, George V. Papatheodoridis, and Athanasios J. Archimandritis: Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy, Mediators of

Inflammation, vol. 2009, pag. 831670, 8 pages)

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Fatty liver (by US) -> predict the development

- IFG- T2DM

Irrespective of BMI

(T.Yamada, M.Fukatsu, S.Suzuki, T.Wada, T.Yoshida – Fatty liver predicts impaired fasting glucose and type 2 DM in Japanese Undergoing a healts

checkup, J.G.H.F, 25, 2010, 352-356)

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Increased risk of liver cancer in Increased risk of liver cancer in diabetic personsdiabetic persons

Japan, General population, 40-69 yrsJapan, General population, 40-69 yrs

97,771 subjects 6,462 incident cancer cases

10.7 yrs mean f/u

MEN (n=3907, DM 366) WOMEN (n=2555, DM 104)

All cancers 1.27 (1.14-1.42) 1.21 (0.99-1.47)

Liver cancer 2.24 (1.64-3.04) 1.94 (1-3.73)Inoue, Arch Intern Med 2006Inoue, Arch Intern Med 2006

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

Page 36: Diabetologie. Nash Sinaia

Liver disorders in the elderlyThe prevalence of steatosis in the general population evaluated with ultrasound is approximately : 20 – 30 %.Its prevalence is increasing with advancing age ranging a peak of 62.8% in females and 59.5% in males between 46 - 75 years in a general population from Central Italy.Over 75 years: the prevalence of fatty liver ↘

=> effect of mortality due to M.S.10-15% patients -> advanced fibrosis, cirrhosis, HCCCohort study : Olmsted county (Minnesota)

NAFLD: - significantly higher mortality than expected- mortality was independently associated with:

- age- diabetes- cirrhosis

- increased risk for NAFLD- higher intake of soft drinks&meat- high fat / high calories diet

NAFLD treatment: as prevention rather than cure.prevention - children in primary school

- gradual weight loss – also to elderly(Annarosa Floreani: Liver disorders in the elderly, Best Practice & Research Clinical Gastroenterology, 2009)

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Identification and treatment of metabolic complications in pediatric obesity

Pediatric population -> O. -> I.R., Type 2 D.M., Hyperlipidemia, HTA, PCOS, NASH.

-Pediatric obesity : tripled over the past 25 years- 16% girls- 18% boys

+ overweight: - 32% girls- 35% boys

-up 90% of children NAFLD are O.W. or O.- I.R. ↗- ↗ T.G., atherogenic lipid profile- HTA

Direct corelations - number of components of M.S.- higher transaminase levels with more fibrosis on biopsy.

(Ode KL, Frohnert BI, Nathan BM: Identification and treatment of metabolic complications in pediatric obesity, Rev. Endocr. Metab. Disord., 2009, 10: 167-188)

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-> obese chinese school children with ↗ ALT & steatosis by liver u.s. – group control

↘ BMI, AST, ALT, I.R. -> - summer camp- vit. E

Dietary modifications may not equate to weight loss => ↘ BMI => ↘ NAFLD

Antioxidants : -> vit. E (α – tocopherol)study : NO. s.s. diference between vit.E, vit.C, placebo

- diet + 2 fold ↗ vit. E => ↘ ALT => larger scale studyInsulin sensitizers : - Pioglitazone

- MetforminOnly Metformin -> appropriate for use in children

Schwimmer et al. – 10 obese children with NAFLD by biopsy -> Met. 500mg x 2 -. S.s. ↘AST, ALT, liver fat, IRNobili et al. – 28 children NAFLD -> Met. 1,5g/day+lifestyle intervention lifestyle intervention

Both groups -> significantly↘ weight, improve ALT, AST, liver fatOther therapies : ursodeoxycolic acid – ineficient in monotherapy

- Pentoxyfilline – down regulates TNF-α production - promising

(Ode KL, Frohnert BI, Nathan BM: Identification and treatment of metabolic complications in pediatric obesity, Rev. Endocr. Metab. Disord., 2009, 10: 167 - 188)

Page 39: Diabetologie. Nash Sinaia

NAFLD in pediatric O.Now: NAFLD – the most common cause of liver disease in childhood.

NHANES - 1999 – 2004 – 8% US children ages 12 – 19- ↗ liver enzymes in the absence of other causes- predilection - Mexican-American children

- male gender- 9,6% - 2 – 19 ages – autopsy

Obese youth – 14 – 24%Treatment – no conclusively proven effective for NAFLD

-Lifestyle interventions – weight loss, key components -> the greater the weight loss, the greater reductions in ALT levels

-Antioxidants vit.E) Metformin -> mixed results

Conclusions : weight reductions through lifestyle intervention.No extrem and rapid weight loss => worsening fibrosis

(Ode KL, Frohnert BI, Nathan BM: Identification and treatment of metabolic complications in pediatric obesity, Rev. Endocr. Metab. Disord., 2009, 10: 167 - 188)

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Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis.

Aging -> strongest risk factor for A.D.T2DM, dyslipidemic conditions – cofactors for A.D.

- mild cognitive impairment (MCI)- dementia

- chronic hyperglicemia- IR- oxidative stress- accumulation of A.G.E.P.- ↗ proinflammatory cytokines- microvascular disease

Same insult : -> liver -> NASH, M.S.-> brain -> MCI, AD – type neurodegeneration

Peripheral I.R. Brain I.R. = link <= mediated by a liver-brain axis of neurodegenaration <= excessive neurotoxic lipids <= ceramides across blood-brain barrier(BBB)

(Warren Alpert Medical School of Brown University, Providence, RI 02912, USA: Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis., Current Opinion

in Investigational Drugs, 2009, 10 (10), 1049 - 1060)

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Ceramides - I.R.- inflammatory- o. stress- cell death

S.H. (irrespective of etiology) -> ↗ hepatic& visceral ceramide production -> cognitive impairment and neurodegeneration

S.H. + peripheral I.R.-> liver brain axis of neuroinflammation&neurodegeneration by ceramides which can cross the BBB.

Insulin – senziting agents – dietary measures -> ↘ MCI, AD

(Warren Alpert Medical School of Brown University, Providence, RI 02912, USA: Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis., Current Opinion

in Investigational Drugs, 2009, 10 (10), 1049 - 1060)

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Is exercise an effective treatment for NASH?

- weight loss is known to be effective as evident in several controlled trials and, in the extreme, with bariatric surgery.Today : skeletal muscle physiology is closely integrated with overall energy homeostasis => increased physical conditioning appears to be closely linked to improved hepatic metabolism !!! independent of changes in body weight

? effects of exercise on liver fat metabolism? how best to measure the degree of physical conditioning

The migratory palmipedes : (migratory geese and ducks)- don’t develop histological NASH- seasonal or pre-migratory steatosis -> carbohydrate loading ->foie gras farming.

Similar seasonal variation in liver fat -> non-hibernating animals.Causes : - changes in thyroid metabolism - altered lipoprotein metabolism

- skeletal muscle energy utilization - in animal : adaptative process preceding increased activity

(Caldwell S, Lazo M : Is exercise an effective treatment for NASH? Knowns and unknowns, Annals of Hepatology, 2009, 8(1). Suppl. – S60 – S66)

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Little trials :Rector et al : simple addition of an exercise to an animal model of IR -> profound effects on the development of fatty liverYamauchi et al : Sumo wrestler of Japan

- BMI don’t accurately reflect the percentage of body fat - is due to increased muscle mass.- D.and other metabolic disorders are increased -> exercise training without

weight loss have significant limitations 3 months or less periods of exercise favorably change a number of parameters, without weight loss

- improvement of NASH ? -> more extended periods?Bonekamp et al. : 6-month intervention of 45 minutes exercise + weight lifting - 3 times per week, significant reduction of liver fat in the absence of significant weight loss.- visceral adiposity and steatosis -> correlate inversely with the degree of cardiorespiratory fitnessConclusions : NASH - diet

- exercise induced weight lossEvidence supports the role exercise, independent of weight loss:

- longer duration of physical activity- optimal intensity and amount - unknown- best method to measure?- basal health of the liver

(Caldwell S, Lazo M : Is exercise an effective treatment for NASH? Knowns and unknowns, 2009)

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Protective Role of Coffee in NAFLDCofee drinking: - inverse & graded association with the risk of liver cancer

- greater comsumption -> ↘ risk of hepatocarcinomaex.: 2 cups of coffe per day -> ↘ 43% specific risk

Hypothesis: some ingredient in cofee could protect against cirrhosis & alcoholic cirrhosiscoffee, not other beverages with caffeine – inhibits the onset of alcoholic& non-alcoholic liver cirrhosis

↗ body weight -> ↗ γ-GTcoffee drinks ↘ the risk of ↗ γ-GTcoffee drinks ↘ R.I., ↘ risk of elevated ALT

Coffee drink in NAFLD is inversely associated with the degree of bright liver involvement and with overweightness.

Conclusion: a posible, favorable and/or preventive role of coffee use in the natural history of NAFLD, similar to that reported in hepatocarcinoma, cirrhosis and not mediated by I.R., is envisage.

(Daniela Catalano, Giuseppe Fabio Martines, Antonia Tonzuso, Clara Pirri, Francesca M. Trovato and Guglielmo M. Trovato, Protective Role of Coffee in NAFLD, Dig. Dis. Sci. ,2009)

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Pharmacological Pharmacological treatmenttreatmentof NASHof NASH

Improve Improve Insulin Insulin

sensitivitysensitivity

Hepato-Hepato-protectantsprotectants

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Treatments:

10 – 15% NASH -> C.H. (cc)

Hussein&all.: 14 pac. = L.B. before and after treatment with 6 month of orlistat 120 mg tid

Results: 70% - reduced fatty infiltration22% - improve inflammation by two

grades50% - improve inflammation by one

gradeimprove in transaminases level, total

cholesterol, triglycerides, LDL, IR index

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Weight loss by surgical measures

-bariatric surgery-Roux-en-Y gastric bypas, gastroplasty,

laparoscopic adjustable gastric banding

Review of 19 study of histological effects of gastric bypass of NAFLD. Verna and Berk: bariatric surgery

- usually improves steatosis- occasional reports of regressed cirrhosis

Some authors: the risk of liver disease progression due to rapid weight loss within the first few postoperative month – bariatric surgery in NAFLD and NASH.

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Weight loss induced by bariatric procedures could be beneficial for NASH treatment.

The lack of randomised clinical trials to demonstrate the beneficial or harmful effects of bariatric surgery procedures for treatment of NASH could not enable us to reach any scientifically sustained conclusion.

(Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database of

Systematic Reviews 2010, The Cochrane Library)

Bariatric surgery for non-alcoholic steatohepatitis in obese patients

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Insulin sensitizing agentsTZD: pioglitazone&rosiglitazone

- increase fatty acid oxidation- decrease fatty acid production within

the liver- improve R.I. - peripherall

- within the liver(Menon KVN, Angulo P, Lindor KD. Severe cjolestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus. Am J Gastroenterol 2001)

- improve transaminases&steatosis(Aithal GP, Thomas JA,Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, Freeman JG, Morgan L, Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008)

- improve in hepatocellular injury, mallory body and fibrosis(Ratziu V, Charlotte F, Jacqueminet S, et al. One year randomized placebo-controlled double-blind trial of rosiglitazone in nonalcoholic steatohepatitis: results of the Pilot trial. Hepatol 2006)

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Side effects: - mild weight gain- lower extremity edema

Controversy over the increase cardiac risk of rosiglitazone

Metformin: significant decreases in steatosis,

necroinflammation and steatosislack of placebo controlled trials

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Lipid lowering agents

Statins - concerns for hepatotoxicity-rare-use of statin in the setting of

compensated liver disease is safe.(Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatol 2006)(Gomez-Dominguez E, Gispert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemidic, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006)(Lewis JH, Mortensen ME, Zweig S. Efficacy and safety of highdose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatol 2006)

Fibrates: pio., a PPAR-γ agonist with peak PPAR-α activity, has shown some benefit in NAFLD-> it is possible fenofibrate may have some benefit as well

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Antioxidants

Oxidative stress – “second hit” in the pathogenesis of NAFLDStudies: vitamin E, alpha-tocopherol

Cytoprotective agents

UDCA = used in primary biliary cirrhosisprimary sclerosing cholangitis

Some conditions: UDCA & dietary restriction were not superior to

dietary restriction alone

Benefits: UDCA + vitamin E

Others: lecithin, silymarin, beta-carotene, metadoxine – might be

examined

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Anti-TNF agents

Agents improving necrosis, inflammation and fibrogenesis caused by pro-inflammatory adipocytokines (TNF-α)

Pentoxifylline - xanthine derivative that affects blood viscosity

- treatment of claudication- inhibit TNF-α- improvements in transaminases

(Satapathy SK, Garg S., Chauhan R, et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004)(Adam LA, Zein CO, Angulo P, et al. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004)

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Novel treatments

ARB(losartan) - telmisartan \ -> stimulator PPAR-γ

- irbesartan / ↓insulin sensitizing

(Yokohama S, Yoneda M, Haneda M et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatol 2004)

Incretin analogues (exenatide and sitagliptin)(Ding X, Saxena NK, Lin S. Exendin-4, a glucagon-like protein 1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatol 2006)(Tushuizen ME, Brunck MC, Pouwels PJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006)

Sulfonylureas second generation – repaglinide, nateglinide

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Essais thérapeutiques en Essais thérapeutiques en courscours

Acide ursodesoxycholique forte dose, Acide ursodesoxycholique forte dose, multicentrique national , n=126multicentrique national , n=126

Trophos : essai pilote 30 pts en coursTrophos : essai pilote 30 pts en cours CB1 R blockers 2 essais interrompus CB1 R blockers 2 essais interrompus

(Sanofi, Pfizer)(Sanofi, Pfizer) Hépatoprotecteur (inhibiteur PDE4), Hépatoprotecteur (inhibiteur PDE4),

Astellas en coursAstellas en cours Antiapoptotique (anticaspase 3), Gilead en Antiapoptotique (anticaspase 3), Gilead en

courscours

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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Conclusions: some certines- bariatric surgery- TZD- vitamin E

Focus on treating the comorbid conditions associated with metabolic syndrome.Life-style : diet + exercise

?? of physical activity is required to produce significant changes in hepatic fat(Kwon do Y, Jung YS, Kim SJ, Park HK, Kim YC. Impaired sulfur-amino acid metabolism and oxidative stress in nonalcoholic fatty liver are alleviated by betaine supplemention in rats. J. Nutr 2009)(Nugent C, Younossi ZM. Evaluation and management of obesity-related non-alcoholic fatty liver disease. Nature Clinical Practice Gastroenterology & Hepatology 2007)

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TAKE HOME MESSAGESTAKE HOME MESSAGES

• Liver injury needs to be assessed in patients Liver injury needs to be assessed in patients with insulin resistancewith insulin resistance

• Steatohepatitis worsens phenotypical Steatohepatitis worsens phenotypical complications of insulin resistancecomplications of insulin resistance

• Steatohepatitis increases liver-related Steatohepatitis increases liver-related morbidity/mortality (cirrhosis and hepatocellular morbidity/mortality (cirrhosis and hepatocellular cancer) cancer)

• Set up collaborative networks with Set up collaborative networks with endocrinologistsendocrinologists

• The era of targeted therapies in NASH is starting The era of targeted therapies in NASH is starting and therefore therapeutic trials are essentialand therefore therapeutic trials are essential

Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance

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