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Aspetti fisiopatologici del processo di adattamento

intestinaleRuolo della terapia farmacologica

Luca Maggio UCSC - Roma

Adattamento Intestinale Adattamento Intestinale

1.1. Che cosᾼ» ?Che cosᾼ» ?

is the process by which intestinal mass and is the process by which intestinal mass and intestinal surface area increase, intestinal surface area increase,

and absorptive capacity of individual and absorptive capacity of individual enterocytes improves, enterocytes improves,

such that the residual intestine assumes such that the residual intestine assumes functions essential to sustain life without functions essential to sustain life without the need for parenteral nutritionthe need for parenteral nutrition

AdaptationAdaptation

Kocoshis SA. Medical management of pediatric intestinal failure. Semin Pediatr Surg. 2010 Feb;19(1):20-6.


1. Che cosᾼ» ?2.2. Cosa succede ?Cosa succede ?

Fernando Navarro, Wallace A. Gleason, J. Marc Rhoads and Ruben E. Quiros-Tejeira. Short Bowel Syndrome: Epidemiology, Pathophysiology, and Adaptation. NeoReviews 2009;10;e330-e338

1. Iperplasia epiteliale Iperplasia epiteliale 2.2. Allungamento villi Allungamento villi 3.3. Aumento Cripte Aumento Cripte4.4. Ipertrofia Muscolare Ipertrofia Muscolare5.5. Circonferenza Circonferenza6.6. Allungamento & Allungamento &

IspessimentoIspessimento

Adattamento StrutturaleStrutturale

Healey KL, Bines JE, Thomas SL, Wilson G, Taylor RG, Sourial M, Pereira-Fantini PM. Morphological and functional changes in the colon after massive small bowel resection. J Pediatr Surg. 2010 Aug;45(8):1581-90.


1.1. Trasporto NutrientiTrasporto Nutrienti

2.2. Funzioni Funzioni enzimaticheenzimatiche

3.3. Transito IntestinaleTransito Intestinale

Adattamento FunzionaleFunzionale


1. Che cosᾼ» ?2. Cosa succede ?3.3. Quanto dura ?Quanto dura ?

Jeppesen, PB. Clinical significance of GLP-2 in short bowel syndrome. J. Nutr. 2003;133:3721-3724


1. Che cosᾼ» ?2. Cosa succede ?3. Quanto dura ?4.4. Si pu” prevedere ?Si pu” prevedere ?

Ileo Ha maggiori capacit¿ di adattamento rispetto allᾼintestino Ha maggiori capacit¿ di adattamento rispetto allᾼintestino pi⁄ prossimalepi⁄ prossimaleIl chilo si muove pi⁄ lentamente che nel digiuno (maggiore Il chilo si muove pi⁄ lentamente che nel digiuno (maggiore possibilit¿ di assorbimento)possibilit¿ di assorbimento)La resezione ileale accelera i tempi di svuotamento gastrico La resezione ileale accelera i tempi di svuotamento gastrico per la perdita del riflesso (slow down) ileogastricoper la perdita del riflesso (slow down) ileogastrico

ICVRallenta il transito intestinaleRallenta il transito intestinalePreviene il reflusso del contenuto cecale e di batteriPreviene il reflusso del contenuto cecale e di batteri

ColonAssorbimento di acqua ed elettrolitiAssorbimento di acqua ed elettrolitiAssorbimento di Ac.Grassi a catena cortaAssorbimento di Ac.Grassi a catena corta

Goday PS. Short bowel syndrome: how short is too short ? Clin Perinatol. 2009 Mar;36(1):101-10

1.1. the the percentage of residual small bowel length percentage of residual small bowel length for for gestational age; the greater the percentage, the better gestational age; the greater the percentage, the better is the likelihood of adaptation is the likelihood of adaptation

2.2. presence of the presence of the ICV ICV

3.3. presence of an intact presence of an intact coloncolon or most of the colon or most of the colon

4.4. presence of an presence of an ostomyostomy

5.5. the the percentage of enteral calories tolerated percentage of enteral calories tolerated at specific at specific time intervalstime intervals


Predictors of Adaptation

Ivan R. Diamond, Marie-Chantal Struijs, Nicole T. de Silva Paul W. Wales. Does the colon play a role in intestinal adaptation in infants with short bowel syndrome? A multiple variable analysis. Journal of Pediatric Surgery 2010; 45, 975–979


1. Che cosᾼ» ?2. Cosa succede ?3. Quanto dura ?4. Si pu” prevedere ?5.5. Si pu” valutare ?Si pu” valutare ?

CitrullinaCitrullina

1.Prodotta solo da enterociti

2.Scarsa quantit¿ nella dieta3.Non nella miscela NP4.Non incorporata nelle proteine sintetizzate5.Non liberata da proteolisi6.Non metabolizzata dal fegato

7.Convertita in ARG a livello renale, aumenta in corso di isufficienza renale8.Ridotta in corso di gastroenterite

Rhoads JM, Plunkett E, Galanko J, Lichtman S, Taylor L, Maynor A, Weiner T, Freeman K, Guarisco JL, Wu GY. Serum citrulline levels correlate with enteral tolerance and bowel length in infants with short bowel syndrome. J Pediatr. 2005 Apr;146(4):542-7.

Rhoads JM, Plunkett E, Galanko J, Lichtman S, Taylor L, Maynor A, Weiner T, Freeman K, Guarisco JL, Wu GY. Serum citrulline levels correlate with enteral tolerance and bowel length in infants with short bowel syndrome. J Pediatr. 2005 Apr;146(4):542-7.

CIT > 19 mol/L

Sensibilit¿ 94% Specificit¿ 67%

Citrullina e sospensione della NP

Bailly-Botuha C, Colomb V, Thioulouse E, Berthe MC, Garcette K, Dubern B, Goulet O, Couderc R, Girardet JP. Plasma citrulline concentration reflects enterocyte mass in children with short bowel syndrome. Pediatr Res. 2009 May;65(5):559-63.


1. Che cosᾼ» ?2. Cosa succede ?3. Quanto dura ?4. Si pu” prevedere ?5. Si pu” valutare ?6.6. Si pu” promuovere ?Si pu” promuovere ?

Jeppesen, PB. Clinical significance of GLP-2 in short bowel syndrome. J. Nutr. 2003;133:3721-3724

1. Nutrizione a. Parenteraleb. Enterale

Barclay AR, Beattie LM, Weaver LT, Wilson DC. Systematic review: medical and nutritional interventions for the management of intestinal failure and its resultant complications in children. Aliment Pharmacol Ther. 2011 Jan;33(2):175-84


2. Complicanzea. Prevenzioneb. Terapia



2. Complicanzea. Prevenzioneb. Terapia

3. Fattori Trofici


Growth HormoneGrowth Hormone

Wales PW, Nasr A, de Silva N, Yamada J. Human growth hormone and glutamine for patients with short bowel syndrome. Cochrane Database of Systematic Reviews 2010, Issue 6.


mg/kg/day weeks Elleg≈rd 1997 0.024 8Scolapio 1997 0.14 3Szkudlarek 2000 0.14 4Seguy 2003 0.05 2-3Byrne 2005 0.10 4


The benefits of treatment were not sustained after cessation of therapy in all but one study.

It is not known whether efficacy would be improved if HGH was utilized during the early phase of adaptation or in the paediatric population during rapid gut development.

At this time, the available literature does not endorse the routine use of HGH or glutamine in short bowel syndrome


Mean age (yrs) Range

Elleg≈rd 1997 49 30 to 72 Scolapio 1997 12.9 3 to 19 Szkudlarek 2000 32 to 74 Seguy 2003 35 19 to 51Byrne 2005 18 to 75

Nucci AM, Finegold DN, Yaworski JA, Kowalski L, Barksdale EM Jr. Results of growth trophic therapy in children with short bowel syndrome. J Pediatr Surg.2004 Mar;39(3):335-9;

Ladd AP, Grosfeld JL, Pescovitz OH, Johnson NB. The effect of growth hormone supplementation on late nutritional independence in pediatric patients with short bowel syndrome. J Pediatr Surg. 2005 Feb;40(2):442-5.

1. 8 children with neonatal SBS were included. All were dependent on parenteral nutrition (PN) for > 3 years (range, 3.8-11.6 years),

2. The subjects received rhGH 0.13 mg/kg/d subcutaneously over a 12-week period.

3. Between baseline and the end of treatment, significant increases were observed in concentrations of

a. serum insulin-like growth factor 1 (103.1 ë 49.9 ïg/L vs 153.5 ë 82.2 ïg/L)

b. serum insulin-like growth factor-binding protein 3 (1.7 ë 0.6 mg/L vs 2.5 ë 0.9 mg/L)

c. plasma citrulline (16.5 ë 14.8 ïmol/L vs 25.2 ë 18.3 ïmol/L)

4. A median 54% increase in enteral intake (range, 10%-244%) was observed

5. Net energy balance improved significantly

6. Only 2 patients could be definitively weaned from PNGoulet O, Dabbas-Tyan M, Talbotec C, Kapel N, Rosilio M, Souberbielle JC, Corriol O, Ricour C, Colomb V. Effect of recombinant human growth hormone on intestinal absorption and body composition in children with short bowel syndrome. JPEN 2010 Sep-Oct;34(5):513-20.

Epidermal growth Epidermal growth factorfactor

Effetto sulla riparazione tissutale (bassi livelli) e sullᾼaumento delle cripte e della superficie mucosa intestinale (alti livelli) Marti U, Burwen S, Jones A. Biological effects of epidermal growth factor with emphasis on the gastrointestinal tract and liver: an update. Hepatology 1989;9:126 - 38.

Aumenta il trasporto di glucosio e lᾼattivit¿ degli enzimi dellᾼorletto a spazzolaO’Loughlin E, Winter M, Shun A, et al. Structural and functional adaptation following jejunal resection in rabbits: effect of epidermal growth factor. Gastroenterology 1994;107:87 - 93.Hardin J, BuretA,Meddings J, et al. Effect of epidermal growth factor on enterocyte brush border surface area. Am J Physiol 1999;264:G312-18.

Effetto anti-infettivo (batteri patogeni intestinali)Buret A, Olson M, Gall G, et al. Effects of orally administered epidermal growth factor on enteropathogenic E. coli infection in rabbits. Infect Immun 1998;66:4917- 23.

Stabile e biodisponibile se somministrato per via enteraleCalnan DP, Fagbemi A, Berlanga-Acosta J, et al. Potency and stability of C terminal truncated human epidermal growth factor. Gut 2000;47: 622- 7.

Elevati livelli nel Latte materno

Sigalet DL, Martin GR, Butzner JD, Buret A, Meddings JBA pilot study of the use of epidermal growth factor in pediatric short bowel syndrome. J Pediatr Surg. 2005 May;40(5):763-8

100 mcg p.o per 6 sett.

Sigalet DL, Martin GR, Butzner JD, Buret A, Meddings JBA pilot study of the use of epidermal growth factor in pediatric short bowel syndrome. J Pediatr Surg. 2005 May;40(5):763-8

GLP - 2GLP - 2

Riduce I tempi di svuotamento gastricoWojdemann M, Wettergren A, Hartmann B, et al. Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs. Scand J Gastroenterol 1998;33:828–32.

Riduce la secrezione gastrica Wojdemann M, Wettergren A, Hartmann B, et al. Inhibition of sham feedingstimulated human gastric acid secretion by glucagon-like peptide-2. J Clin Endocrinol Metab 1999;84:2513–17.

Aumenta il flusso ematico intestinale Guan X, Stoll B, Lu X, et al. GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets Gastroenterology 2003;125:136–47

Stimola la crescita dellᾼintestino (proliferazione cellule epiteliali e cripte)Drucker DJ, Erlich P, Asa SL, et al. Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A 1996;93:7911–16.

Inibisce lᾼapoptosi degli enterocitiTsai CH, Hill M, Asa SL, et al. Intestinal growth-promoting properties of glucagon-like peptide- 2 in mice. Am J Physiol 1997;273:E77–84.

Sigalet DL, Martin G, Meddings J, Hartman B, Holst JJ. GLP-2 levels in infants with intestinal dysfunction. Pediatr Res. 2004 Sep;56(3):371-6.

Jeppesen PB, Sanguinetti EL, Buchman A, Howard L, Scolapio JS, Ziegler TR, Gregory J, Tappenden KA, Holst J, Mortensen PB. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005 Sep;54(9):1224-31

> 18 aa

Pereira-Fantini PM, Nagy ES, Thomas SL, Taylor RG, Sourial M, Paris MC, Holst JJ, Fuller PJ, Bines JE. GLP-2 administration results in increased proliferation but paradoxically an adverse outcome in a juvenile piglet model of short bowel syndrome. J Pediatr Gastroenterol Nutr. 2008 Jan;46(1):20-8.

InsulinInsulin

Shulman RJ. Effect of enteral administration of insulin on intestinal development and feeding tolerance in preterm infants: a pilot study. Arch Dis Child Fetal Neonatal Ed 2002;86:F131–3.

Sukhotnik I, Shehadeh N, Shamir R, et al. Oral insulin enhances intestinal re-growth following massive small bowel resection in rat. Dig Dis Sci 2005;50:2379–85.

Shamir R, Kolacek S, Koletzko S, Tavori I, Bader D, Litmanovitz I, Flidel-Rimon O, Marks KA, Sukhotnik I, Shehadeh N. Oral insulin supplementation in paediatric short bowel disease: a pilot observational study. J Pediatr Gastroenterol Nutr. 2009 Jul;49(1):108-11.

1 U/kg x 4 p.o.(Actrapid) x 28 gg


45,6% 58,9%

Shamir R, Kolacek S, Koletzko S, Tavori I, Bader D, Litmanovitz I, Flidel-Rimon O, Marks KA, Sukhotnik I, Shehadeh N. Oral insulin supplementation in paediatric short bowel disease: a pilotobservational study. J Pediatr Gastroenterol Nutr. 2009 Jul;49(1):108-11.


The evidence base for medical and nutritional interventions in paediatric IF is limited and of poor quality.

Low patient numbers, high drop-out rates from studies and ethical considerations that limit patient enrolment have undoubtedly hindered the commencement and successful completion of RCTs.

Current guidelines for patient management are extrapolated primarily from adult evidence and expert opinion

Ivan R. Diamond, Marie-Chantal Struijs, Nicole T. de Silva Paul W. Wales. Does the colon play a role in intestinal adaptation in infants with short bowel syndrome? A multiple variable analysis. Journal of Pediatric Surgery 2010; 45, 975–979

Ho cercato di indagare i Ho cercato di indagare i contorni di unṽisola ma ho contorni di unṽisola ma ho trovato i confini di un oceano. trovato i confini di un oceano.

L.L.WittgesteinWittgestein

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