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NAFLD E SINDROME METABOLICA

Raffaele IORIO

Settore di Epatologia

Dipartimento di Pediatria

Università di Napoli Federico II

Sovrappeso e obesità per regione, bambini 8-9 anni della 3a primaria. Italia, 2010

OKkio alla SALUTE 2010

La diagnosi di obesità e fegato grasso dipende dal pediatra che

ti visita?

SOVRAPPESO

OBESITA’

0

10

20

30

40

50

60

Pediatra

generalista

BMI>85°<90°

BMI>90°<95°

BMI>95°

% Pe

rcent

uale d

i visite

con

diagn

osi co

rrett

a d

i

sov

rapp

eso

-ob

esità

J Pediatr 2005;147:839-42

0

10

20

30

40

50

60

Pediatra

generalista

Pediatra

endocrinologo

BMI>85°<90°

BMI>90°<95°

BMI>95°

% Pe

rcent

uale d

i visite

con

diagn

osi co

rrett

a d

i

sov

rapp

eso

-ob

esità

J Pediatr 2005;147:839-42

0

10

20

30

40

50

60

Pediatra

generalista

Pediatra

endocrinologo

Pediatra

gastroenterologo

BMI>85°<90°

BMI>90°<95°

BMI>95°

% Pe

rcent

uale d

i visite

con

diagn

osi co

rrett

a d

i

sov

rapp

eso

-ob

esità

J Pediatr 2005;147:839-42

Diagnosis and interventions during visits by children with BMI% >85% by clinic type. *P < .01, Pediatric Gastroenterology versus General Pediatrics. †P < .01, Pediatric Endocrinology versus General Pediatrics. ‡P < .05, Pediatric Endocrinology versus General Pediatrics.

J Pediatr 2005;147:839-42

Nat Clin Pract Endocrinol Metab. 2007 Jun;3:458-69

“NAFLD can be considered a liver manifestation of the metabolic syndrome”

NAFLD

DEFINIZIONE DI NAFLD

assunzione di alcool o farmaci

infezioni virali

NPT

errori congeniti del metabolismo

(m.Wilson,emocromatosi,fruttosemia,glicogenosi, etc…)

epatite autoimmune

fibrosi cistica

celiachia

Evidenza istologica di

steatosi macrovescicolare

con o senza infiammazione e

fibrosi in assenza di:

Kleiner DE et al, Hepatology 2005; 41:1313-21

• elevated ALT >6 months AND • abnormal US AND • at least 1 of 3 risk factors, including obesity, diabetes mellitus, hypertriglyceridemia

NAFLD PROBABILE

L’ ”ipocrisia” della definizione

• L’istologia non sempre è disponibile

• I criteri istologici per la definizione della NAFLD hanno subito molteplici revisioni negli ultimi anni

• La lista delle cause da escludere è lunga e complessa

De Bruyne RM et al, Hepatol Int 2010; 4:375-385

PREVALENZA DELLA NAFLD

in pediatria

Studio retrospettivo dei reperti autoptici di 742 bambini (2-19 anni) deceduti per diverse cause (prevalentemente trauma/omicidio) tra il 1993 ed il 2003

Schwimmer JB et al, Pediatrics 2006; 118:1388-1393

Schwimmer JB et al Hepatology 2005; 42:641-648

38% obesi 3%

di 742

NAFLD Spectrum

La storia naturale della

NAFLD?

Priess et al, Clinical Science 2008; 115:141-150

Fassio et al, Hepatology 2004; 40:820-826

Day et al, Gastroenterology 2005; 129:375-378

ADULTI

Quanti casi di cirrosi descritti

in età pediatrica?

Gut 2009; 58:1538-1544


in età pediatrica?

1/43 steatosi: cirrosi

1

1/299 obesi: cirrosi

Am J Gastroenterol 2002; 97:2460-2462

21

2 casi

22

20

J Gastroenterol Hepatol. 2005 Feb;20(2):327-9.

66 children (<21y), followed up to 20 years

• 11 years old: grade 3 varices

• recurrent variceal bleeding

• 20 years old: liver trasplantation

• recurrent NASH after 9 months LT

• 19 years old: cirrhotic-stage NASH

• 25 years: hepatopulmunary

syndrome requiring LT

• recurrent NASH after 6 weeks LT

HISPANIC FEMALE

11 years old

WHITE FEMALE

19 years old

RECURRENCE OF NASH AFTER LT IN CHILDREN

Liv Transpl 2005; 11:108-110

Pediatr Transplant 2007; 11:796-99

Hepatology 2004;39:909-914


in età pediatrica?

Gut 2009; 58:1538-1544

Gut 2004; 53:750-755

WOMEN

MEN

ADULTI

Gastroenterology 2005; 129:113-121

435 PZ

Circulation 2008; 118:277-283

Quanti sono i casi di NAFLD che

richiedono l’epatotrapianto ?

Liver Transpl. 2001 ;7:608-14

ADULTI

The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009

Gastroenterology 2011;141(4):1249-1253

Pediatric Trasplantation 2007;11:755-763

NAFLD???

NAFLD???

Pediatr Transplant. 2004;8:284-94

TERAPIA della NAFLD?

Pediatric Diabetes 2009;10:1-4

Hepatology 2006;2:456-60

68%

Hepatology 2006;2:456-60

Quando il gatto non c’è….

COSA SUCCEDE NEL TEMPO?

Gut 2009; 58:1538-1544

The TONIC Trial

Lavine et al. Contempory Clin Trials 2010;31:62-70 for trial design

Lavine et al. Final results to be presented at AASLD November 2010

173 children (8-17 y) NASH (biopsy)

VIT E:

400 U/die

Metformin: 500 mg x

2 v/die

Placebo

LIFESTYLE

Hepatology, 2010; 52:1274-1281

Sinusoidal Endothelial Dysfunction PrecedesInflammation and Fibrosis in a Model of NAFLD

Marcos Pasarın, Vincenzo La Mura, Jorge Gracia-Sancho, Hector Garcıa-Caldero, Aina Rodrıguez-

Vilarrupla, Juan Carlos Garcıa-Pagan, Jaime Bosch, Juan G. Abraldes*

Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clınic-IDIBAPS, CIBERrehd, University of Barcelona, Barcelona, Spain

Abst ract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associatedwith the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenicfactor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. Theaims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolicsyndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet(CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolicsyndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosiswithout inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liverperfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependentvasodilation. This was associated with a decreased Akt-dependent eNOSphosphorylation and NOSactivity. In summary, wedemonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunctionoccurs before the development of fibrosis or inflammation.

Citat ion: Pasarın M, La Mura V, Gracia-Sancho J, Garcıa-Caldero H, Rodrıguez-Vilarrupla A, et al. (2012) Sinusoidal Endothelial Dysfunction Precedes Inflammationand Fibrosis in a Model of NAFLD. PLoS ONE 7(4): e32785. doi:10.1371/journal.pone.0032785

Editor: Massimo Federici, University of Tor Vergata, Italy

Received June 28, 2011; Accepted February 3, 2012; Published April 3, 2012

Copyright : ß 2012 Pasarın et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by grants from the Instituto de Salud Carlos III (FIS05/0519 and FIS08/0193 to Dr. Abraldes and Dr. Pasarın 09/01261 to Dr.Bosch), and co-financed by FEDER funds (EU, ‘‘Una manera de hacer Europa‘‘). Part of this work was carried out at the Esther Koplowitz Centre, Barcelona.Ciberehd is funded by Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of themanuscript.

Compet ing Interests: The authors have declared that no competing interests exist.

* E-mail: [email protected]

Int roduct ion

The metabolic syndrome is defined as a combination of

abnormalities including central obesity, hypertriglyceridemia,

low levels of HDL cholesterol, hypertension and hyperglycemia

[1]. Insulin resistance (IR) is thought to be the pathophysiological

hallmark of the syndrome [2,3]. Non-alcoholic fatty liver disease

(NAFLD) is the hepatic expression of the metabolic syndrome and

has an increasing prevalence in the western population [4]. The

spectrum of NAFLD lesions is wide, and goes from simple

steatosis, non-alcoholic steatotohepatitis (inflammation, features of

hepatocyte injury with or without fibrosis), to overt cirrhosis [5].

The mechanisms that account for disease progression in NAFLD

are still poorly understood.

Most complications leading to morbidity in patients with the

metabolic syndrome are of vascular origin [6]. One of the factors

contributing to vascular disease in this setting is the presence of

endothelial dysfunction, with decreased nitric oxide (NO)

production [7], which has been consistently observed before

cardiovascular events occur, and even before any pathological

abnormalities in the vascular tree can be demonstrated [8]. This

suggests that endothelial dysfunction is an early pathogenic event

in the course of the vascular complications that occur in these

patients. In keeping with this concept, correction of endothelial

dysfunction is associated with an improvement in the rates of

vascular eventsand, therefore, it isconsidered a useful therapeutic

target in thissyndrome [9,10]. Interestingly, patientswith NAFLD

exhibit systemic endothelial dysfunction and a increased cardio-

vascular risk [11].

The liver sinusoidal endothelium is a very specialized and

phenotypically differentiated endothelium, being its major speci-

ficities the presence of fenestrae and the absence of basal

membrane [12]. Among other functions, an adequately function-

ing sinusoidal endothelium maintains an anti-inflammatory, anti-

thrombotic and anti-fibrotic milieu within the liver parenchyma

[13–15].

Some recent data have shown the presence of microvascular

abnormalities in models of fatty liver, characterized by the

presence of reduced sinusoidal perfusion [16] and structurally

abnormal sinusoidsdue to lipid accumulation in parenchymal cells

and to collagen deposition in thespace of Disse [17]. However, the

presence of liver endothelial dysfunction has not been specifically

investigated. In addition, whether endothelial dysfunction might

occur earlier than other featuresof advanced NAFLD (as it occurs

in the peripheral circulation where endothelial dysfunction

precedes the development of arteriosclerosis) is largely unknown.

The aims of this study were to characterize the changes in liver

histology and liver microcirculatory function in a model of diet-

induced obesity that expresses most features of the metabolic

syndrome.

PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e32785





Abstract

Non-alcoholic fatty liver disease (NAFLD) isthe hepatic manifestation of the metabolic syndrome. Most morbidity associatedwith the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenicfactor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. Theaims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolicsyndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet(CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolicsyndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosiswithout inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liverperfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependentvasodilation. This wasassociated with a decreased Akt-dependent eNOSphosphorylation and NOSactivity. In summary, wedemonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunctionoccurs before the development of fibrosis or inflammation.

Citation: Pasarın M, La Mura V, Gracia-Sancho J,Garcıa-Caldero H,Rodrıguez-Vilarrupla A, et al. (2012) Sinusoidal Endothelial Dysfunction Precedes Inflammationand Fibrosis in a Model of NAFLD. PLoSONE 7(4): e32785. doi:10.1371/journal.pone.0032785



Copyright: ß 2012 Pasarın et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Compet ing Interests: The authors have declared that no competing interests exist.


Introduct ion






(NAFLD) isthe hepatic expression of the metabolic syndrome and



steatosis, non-alcoholic steatotohepatitis (inflammation, features of


















vascular risk [11].







[13–15].




abnormal sinusoidsdueto lipid accumulation in parenchymal cells

and to collagen deposition in thespaceof Disse [17]. However, the



occur earlier than other featuresof advanced NAFLD (asit occurs



The aimsof thisstudy were to characterize the changes in liver



syndrome.

PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e32785





Abst ract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associatedwith the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenicfactor. However, whether NAFLD isassociated with endothelial dysfunction within the hepatic vasculature is unknown. Theaims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolicsyndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet(CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolicsyndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosiswithout inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liverperfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependentvasodilation. This was associated with a decreased Akt-dependent eNOSphosphorylation and NOSactivity. In summary, wedemonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunctionoccurs before the development of fibrosis or inflammation.

Citation: Pasarın M, La Mura V, Gracia-Sancho J,Garcıa-Caldero H,Rodrıguez-Vilarrupla A, et al. (2012) Sinusoidal Endothelial Dysfunction Precedes Inflammationand Fibrosis in a Model of NAFLD. PLoSONE 7(4): e32785. doi:10.1371/journal.pone.0032785



Copyright: ß 2012 Pasarın et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Competing Interests: The authors have declared that no competing interests exist.


Introduct ion






(NAFLD) isthe hepatic expression of the metabolic syndrome and



steatosis, non-alcoholic steatotohepatitis (inflammation, featuresof


















vascular risk [11].







[13–15].




abnormal sinusoidsdueto lipid accumulation in parenchymal cells

and to collagen deposition in thespaceof Disse [17]. However, the



occur earlier than other featuresof advanced NAFLD (asit occurs



The aimsof thisstudy were to characterize the changes in liver



syndrome.

PLoSONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e32785

Journal of Nutritional Biochemistry 2011; in press

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