SINDROME METABOLICA: NUOVI APPROCCI TERAPEUTICI Valerio Nobili, M.D. Responsabile UOC Malattie Epatometaboliche Direttore Lab di Ricerca Malattie Epatiche Ospedale Pediatrico Bambino Gesu’ [email protected]

I do not have any conflict of interest

123.000 contacts

June 2014 in press

Invited Review Non-alcoholic fatty liver and metabolic syndrome in children: a vicious circle Alterio A, Alisi A, and Nobili V

The results show significant differences between the two diagnostic criteria MS was more frequent in obese than in overweight adolescents regardless of criteria.

Now more than ever, a consensual definition of the syndrome is required to better discriminate the associated risks

OSAS

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In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials American Journal of Respiratory and Critical Care Medicine Volume 189 Number 1 January 2014

The study in this issue of the Journal by Nobili and colleagues is the first studies linking OSAS to a serious marker of metabolic end-organ morbidity, namely nonalcoholic fatty liver disease (NAFLD)

MAY 2014 (in press)

Association between Nocturnal Blood Pressure Dipping and Insulin Resistance in Children Affected by NAFLD Ugo GIORDANO, Claudia DELLA CORTE, Giulia CAFIERO, Daniela LICCARDO, Attilio TURCHETTA, Kazem Mohammad HOSHEMAND, Danilo FINTINI, Giorgio BEDOGNI, Maria Chiara MATTEUCCI, and Valerio NOBILI.

RESULTS

The anthropometric and metabolic measurements of the 101 children with NAFLD were as follow. 76 children (75.3%) were systolic non-dippers and 23 of them were also diastolic non-dippers (30.3%). As compared to systolic dippers, systolic nondippers had higher medians of mean nocturnal SBP, OGTT glucose at 0, 60 and 120 min, OGTT insulin at all time points, HOMA and ISI.

23

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MAY 2014

NORMAL BLOOD VESSELS

11 anni

MILD BLOOD VESSELS TORTUOSITY

13 anni

SEVERE BLOOD VESSELS TORTUOSITY

2013

SINDROME METABOLICA

Hepatology. 2014 Mar;59(3):1174-97

Dicembre 2012

Mechanisms of steatosis associated with I148M PNPLA3 Equilibrium: Hepatocellular fat content 6% 

Equilibrium: Hepatocellular fat content 0-5%

Macrovescicular steatosis Lipid droplets ER PA

Tg ER PNPLA3 148Met

PNPLA3 148Ile

Lipogenesis Hydrolysis of triglycerides Lipoprotein export

LPA He, J Biol Chem 2010 Kumari, Cell Metab 2012 Pirazzi, J Hepatol 2012

Zhong Li, J Clin Invest 2012 Hyysalo, Diabetes 2013

J Pediatr Gastroenterol Nutr 2014 May;58(5):632-6

FLT Fatty Liver Test    

PNPLA3 LPIN – 1 KLF – 6 SOD – 2

(Hepatology 2010) (JPGN 2011) (Gastroenterology 2008) (J of Hepatology 2010

2014 May;9(3):392

December 2012

January 2012

Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach Alisi A, Feldstein AE, Villani A, Raponi M, and Nobili V

• Currently,

especially in children, no consensus exists on the therapeutic strategy to be adopted after a diagnosis of NAFLD. • To

date, loss of weight and physical activity represent the first line of treatment against this disease.

Two-year Follow-up in 21,784 Overweight Children and Adolescents With Lifestyle Intervention

129 treatment centers lost of follow-up

SDS BMI reduction 0.5

6

6

6

100 80 60

After 24 months, 90% lost and only 5%reduced BMI

40 20 0

12 24

12 24

12 24

time (months)

Reinehr T, et al Obesity 2009

2013

DOCOSAHEXAENOIC ACID SUPPLEMENTATION DECREASES LIVER FAT CONTENT IN CHILDREN WITH NON-ALCOHOLIC FATTY LIVER DISEASE: LONG-TERM RESULTS OF A RANDOMISED CONTROLLED CLINICAL TRIAL Valerio Nobili, Anna Alisi, Claudia Della Corte, Patrizia Risé, Claudio Galli, Carlo Agostoni and Giorgio Bedogni

Supplementation with long-chain ω3-fatty acids, and in particular docosahexaenoic acid (DHA), has recently gained interest as a potential treatment for liver fat accumulation and of the metabolic and hepatic complications of NAFLD

We showed DHA supplementation increases insulin sensitivity, which is paralleled by a reduction in insulin resistance, and decreases fat liver content, thus restoring part of the normal lipidomic profile. Nobili V et al. NMCD 2013

PLoS One. 2014 Feb 4;9(2):e88005. doi: 10.1371

IL-6 TNF-a

Before DHA

After DHA

Accepted on January 2014

40-45 % of obese children have low vitamin D levels !!!

JULY 2011

“we believe that multitargeted therapy could be the way forward for treating these children. Such therapy consists of combinations of therapeutic approaches directed against various potential targets” .

DHA

Probiotics ? VIT E + Colina

Silybin + Vit D

April 2014

April 2014

*

December 2012

EDITORIAL December 2013 Hepatic Progenitor Cells: Another Piece in the NAFLD Puzzle Dawn M Torres, Stephen A Harrison As showed by Nobili and coworkers, HPCs express adiponectin, resistin, and GLP-1, which become available to resident liver cells and, so doing, it may have important pathophysiological implications in the modulation of hepatic insulin resistance and the progression of liver injury. This study, by Nobili et al., it will open new future therapeutic options……………….

In submission May 2014

Obalon intragastric balloon in the treatment of pediatric obesity: a pilot study Nobili V; Della Corte C; Liccardo D, Mosca A; Caccamo R; Morino GS; Ceriati E; Alisi A; Alterio A; De Peppo F.

Metabolic Syndrome

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Walker’s Pediatric Gastrointestinal Disease, 6th ed., Vol. 2. Edited by R. Kleinman, O. Goulet, G. Mieli-Vergani, et al. (Shelton, CT: People’s Medical Publishing House—USA, July 2014

Giorgio V, Alisi A, Villani A, Nobili V. “Fatty Liver Disease in Children“

Lancet 2013; 381: 73–87

The power of research in children to turn the tide of the growing burden of non-communicable, chronic, adult diseases that have their origins in early life, to benefit the health of an ageing population and future generations, and to reduce health-care costs is inadequately recognised.

Collaborations “Bambino Gesù” Children’s HospitalIRCCS: University of Milan Dr. Anna Alisi Pr. Carlo Agostoni Dr. Melania Manco Dr. Rita Devito Dr. Donatella Comparcola University of Florence: Dr. Maria Rita Sartorelli Pr. Massimo Pinzani Dr. Andrea Pietrobattista Pr. Fabio Marra Dr. Arianna Alterio Dr. Fiorella Piemonte Dr. Andrea Masotti Liver Research Centre,

Basovizza, Trieste Pr. Claudio Tiribelli Dr. Giorgio Bedogni Paediatric Liver Centre, King's College Hospital, London Pr. Giorgina Mieli-Vergani Pr. Anil Dhawan

Washington University School of Medicine, St. Louis: Pr. Elizabeth M. Brunt

“La Sapienza” University: Pr. Silvia Leoni Dr. Giovannella Bruscalupi Dr. Andrea Vania University of Turin: Pr. Maurizio Parola Dr. Elisabetta Bugianesi

Institute of Hepatology, University College London: Pr. William M. Rosenberg

Dept. of Pediatric Gastroenterology, Newcastle University, Cleveland Clinic, Cleveland: Newcastle, United Kingdom: Pr. Ariel E. Feldstein Pr. Christopher P. Day

Mayo Clinic, Rochester: Pr. Paul Angulo

Stop now please !!!!