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Intestinal Failure-Associated Liver Disease

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Current Concepts of Intestinal Failure

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Abstract

Intestinal failure (IF)-associated liver disease (IFALD) refers to hepatobiliary dysfunction, which arises during parenteral nutrition (PN) delivered for compromised bowel function and related intestinal failure. Clinical hallmark of IFALD is cholestasis, which may rapidly progress to biliary cirrhosis and liver failure especially in newborns with immature liver function. Initial histological changes are dominated by cholestasis and inflammation, which are largely replaced by fibrosis and steatosis with prolonged duration of PN and increasing age. Abnormal liver fibrosis and steatosis persist after weaning of PN in a significant proportion of patients. Pathogenesis of IFALD is complex and multifactorial including both hepatotoxic effects of PN and disturbed intestinal function. All PN lipids excluding fish oil-derived emulsions contain plant sterols, which in experimental studies activate Kupffer cells through toll-like receptor 4 signaling and attenuate bile transporter expression synergistically with increased lipopolysaccharide permeability in mice. Plant sterols correlate with biochemical and histological signs of liver injury in children with IF, who also display intestinal barrier dysfunction with overabundance of lipopolysaccharide producing Proteobacteria in their intestinal microbiota in association with intestinal inflammation and elevated serum proinflammatory cytokines. Reduction of farnesoid X receptor induction and fibroblast growth factor 19 secretion due to extensive distal resection and altered bile acid metabolism may contribute to maintenance of liver injury also after weaning off PN. No specific therapy for IFALD is currently available. Multidisciplinary preventive measures include limitation of PN lipid load and plant sterol content, while maintaining balanced fatty acid profile and avoidance of systemic bacteremia by dedicated central venous catheter care and surgical treatment of obstructive short bowel pathology predisposing to bacterial overgrowth.

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Abbreviations

FGF 19:

Fibroblast growth factor 19

FXR:

Farnesoid X receptor

ICV:

Ileocecal valve

IF:

Intestinal failure

IFALD:

Intestinal failure-associated liver disease

IL:

Interleukin

LPS:

Lipopolysaccharide

PN:

Parenteral nutrition

SBS:

Short bowel syndrome

TLR4:

Toll-like receptor 4

TNFα:

Tumor necrosis factor α

References

  1. Pironi L, Arends J, Baxter J, Bozzetti F, Peláez RB, Cuerda C, et al. ESPEN endorsed recommendations. Definition and classification on intestinal failure in adults. Clin Nutr. 2015;34:171–80.

    Article  PubMed  Google Scholar 

  2. Squires RH, Duggan C, Teitelbaum DH, Wales PW, Balint J, Venick R, et al. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr. 2012;161:723–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pakarinen MP. Autologous intestinal reconstruction surgery as part of comprehensive management of intestinal failure. Pediatr Surg Int. 2015;31:453–64.

    Article  PubMed  Google Scholar 

  4. Kelly DA. Preventing parenteral nutrition liver disease. Early Hum Dev. 2010;86:683–7.

    Article  CAS  PubMed  Google Scholar 

  5. Lee WS, Sokol RJ. Intestinal microbiota, lipids, and the pathogenesis of intestinal failure-associated liver disease. J Pediatr. 2015;167:519–26.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mutanen A, Lohi J, Heikkilä P, Koivusalo AI, Rintala RJ, Pakarinen MP. Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure. Hepatology. 2013;58:729–38.

    Article  CAS  PubMed  Google Scholar 

  7. Mutanen A, Lohi J, Heikkilä P, Jalanko H, Pakarinen MP. Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure. J Hepatol. 2015;62:1391–7.

    Article  CAS  PubMed  Google Scholar 

  8. Lauriti G, Zani A, Aufieri R, Cananzi M, Chiesa PL, Eaton S, et al. Incidence, prevention, and treatment of parenteral nutrition-associated cholestasis and intestinal failure-associated liver disease in infants and children: a systematic review. J Parenter Enteral Nutr. 2014;38:70–85.

    Article  Google Scholar 

  9. Kurvinen A, Nissinen MJ, Andersson S, Korhonen P, Ruuska T, Taimisto M, et al. Parenteral plant sterols and intestinal failure-associated liver disease in neonates. J Pediatr Gastroenterol Nutr. 2012;54:803–11.

    Article  CAS  PubMed  Google Scholar 

  10. Avitzur Y, Wang JY, de Silva NT, Burghardt KM, DeAngelis M, Grant D, et al. Impact of intestinal rehabilitation program and its innovative therapies on the outcome of intestinal transplant candidates. J Pediatr Gastroenterol Nutr. 2015;61:18–23.

    PubMed  Google Scholar 

  11. Lacaille F, Gupte G, Colomb V, D’Antiga L, Hartman C, Hojsak I, et al. Intestinal failure-associated liver disease: a position paper of the ESPGHAN working group of intestinal failure and intestinal transplantation. J Pediatr Gastroenterol Nutr. 2015;60:272–83.

    Article  CAS  PubMed  Google Scholar 

  12. Wales PW, de Silva N, Kim JH, Lecce L, Sandhu A, Moore AM. Neonatal short bowel syndrome: a cohort study. J Pediatr Surg. 2005;40:755–62.

    Article  PubMed  Google Scholar 

  13. Tillman EM. Review and clinical update on parenteral nutrition-associated liver disease. Nutr Clin Pract. 2013;28:30–9.

    Article  PubMed  Google Scholar 

  14. Kumpf VJ. Parenteral nutrition-associated liver disease in adult and pediatric patients. Nutr Clin Pract. 2006;21:279–90.

    Article  PubMed  Google Scholar 

  15. Beath S, Pironi L, Gabe S, Horslen S, Sudan D, Mazeriegos G, et al. Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplant. Transplantation. 2008;85:1378–84.

    Article  PubMed  Google Scholar 

  16. Mutanen A, Heikkilä P, Lohi J, Raivio T, Jalanko H, Pakarinen MP. Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure. J Hepatol. 2014;60:183–90.

    Article  CAS  PubMed  Google Scholar 

  17. Moss RL, Das JB, Raffensperger JG. Total parenteral nutrition-associated cholestasis: clinical and histopathologic correlation. J Pediatr Surg. 1993;28:1270–5.

    Article  CAS  PubMed  Google Scholar 

  18. Ganousse-Mazeron S, Lacaille F, Colomb-Jung V, Talbotec C, Ruemmele F, Sauvat F, et al. Assessment and outcome of children with intestinal failure referred for intestinal transplantation. Clin Nutr. 2015;34:428–35.

    Article  CAS  PubMed  Google Scholar 

  19. Pichler J, Horn V, Macdonald S, Hill S. Intestinal failure-associated liver disease in hospitalised children. Arch Dis Child. 2012;97:211–4.

    Article  PubMed  Google Scholar 

  20. Duro D, Mitchell PD, Kalish LA, Martin C, McCarthy M, Jaksic T, et al. Risk factors for parenteral nutrition–associated liver disease following surgical therapy for necrotizing enterocolitis: a Glaser Pediatric Research Network Study. J Pediatr Gastroenterol Nutr. 2011;52:595–600.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Beath SV, Davies P, Papadopoulou A, Khan AR, Buick RG, Corkery JJ, et al. Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg. 1996;31:604–6.

    Article  CAS  PubMed  Google Scholar 

  22. Ralls MW, Demehri F, Feng Y, Woods Ignatoski KM, Teitelbaum DH. Enteral nutrient deprivation in patients leads to a loss of intestinal epithelial barrier function. Surgery. 2015;157:732–42.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Goulet O, Olieman J, Ksiazyk J, Spolidoro J, Tibboe D, Köhler H, et al. Neonatal short bowel syndrome as a model of intestinal failure: physiological background for enteral feeding. Clin Nutr. 2013;32:162–71.

    Article  CAS  PubMed  Google Scholar 

  24. Cober MP, Killu G, Brattain A, Welch KB, Kunisaki SM, Teitelbaum DH. Intravenous fat emulsions reduction for patients with parenteral nutrition-associated liver disease. J Pediatr. 2012;160:421–7.

    Article  CAS  PubMed  Google Scholar 

  25. Gabe SM. Lipids and liver dysfunction in patients receiving parenteral nutrition. Curr Opin Clin Nutr Metab Care. 2013;16:150–5.

    Article  CAS  PubMed  Google Scholar 

  26. Xu Z, Harvey KA, Pavlina T, Dutot G, Hise M, Zaloga GP, et al. Steroidal compounds in commercial parenteral lipid emulsions. Nutrients. 2012;4:904–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mutanen A, Nissinen MJ, Lohi J, Heikkilä P, Gylling H, Pakarinen MP. Serum plant sterols, cholestanol, and cholesterol precursors associate with histological liver injury in pediatric onset intestinal failure. Am J Clin Nutr. 2014;100:1085–94.

    Article  CAS  PubMed  Google Scholar 

  28. Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology. 1993;105:1806–13.

    Article  CAS  PubMed  Google Scholar 

  29. Merras-Salmio L, Pakarinen MP. Refined multidisciplinary protocol based approach to short bowel syndrome improves outcomes. J Pediatr Gastroenterol Nutr. 2015;61:24–9.

    PubMed  Google Scholar 

  30. Kosters A, Karpen SJ. The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis. 2010;30:186–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rangel SJ, Calkins CM, Cowles RA, Barnhart DC, Huang EY, Abdullah F, et al. Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg. 2012;47:225–40.

    Article  PubMed  Google Scholar 

  32. Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP. Intestinal microbiota signatures associated with histological liver steatosis in pediatric-onset intestinal failure. JPEN J Parenter Enteral Nutr. 2015. pii: 0148607115584388. [Epub ahead of print].

    Google Scholar 

  33. Spencer AU, Neaga A, West B, Safran J, Brown P, Btaiche I, et al. Pediatric short bowel syndrome: redefining predictors of success. Ann Surg. 2005;242:403–9.

    PubMed  PubMed Central  Google Scholar 

  34. Grijalva J, Vakili K. Neonatal liver physiology. Semin Pediatr Surg. 2013;22:185–9.

    Article  PubMed  Google Scholar 

  35. El Kasmi KC, Anderson AL, Devereaux MW, Fillon SA, Harris JK, Lovell MA, et al. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology. 2012;55:1518–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. El Kasmi KC, Anderson AL, Devereaux MW, Vue PM, Zhang W, Setchell KD, et al. Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med. 2013;5(206):206ra137. doi:10.1126/scitranslmed.3006898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, Von Furstenberg R, Moore DD, et al. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res. 2007;62:301–6.

    Article  CAS  PubMed  Google Scholar 

  38. Vlaardingerbroek H, Ng K, Stoll B, Benight N, Chacko S, Kluijtmans LA, et al. New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs. J Lipid Res. 2014;55:466–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zaloga GP. Phytosterols, lipid administration, and liver disease during parenteral nutrition. J Parenter Enteral Nutr. 2015;39:39S–60.

    Article  Google Scholar 

  40. Iyer KR, Spitz L, Clayton P. New insight into mechanism of parenteral nutrition-associated cholestasis: role of plant sterols. J Pediatr Surg. 1998;33:1–6.

    Article  CAS  PubMed  Google Scholar 

  41. Demehri FR, Barrett M, Ralls MW, Miyasaka EA, Feng Y, Teitelbaum DH. Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation. Front Cell Infect Microbiol. 2013;3:105. doi:10.3389/fcimb.2013.00105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. D’Antiga L, Dhawan A, Davenport M, Mieli-Vergani G, Bjarnason I. Intestinal absorption and permeability in paediatric short-bowel syndrome: a pilot study. J Pediatr Gastroenterol Nutr. 1999;29:588–93.

    Article  PubMed  Google Scholar 

  43. Ziegler T, Luo M, Estívariz C, Moore 3rd D, Sitaraman S, Hao L, et al. Detectable serum flagellin and lipopolysaccharide and upregulated anti-flagellin and lipopolysaccharide immunoglobulins in human short bowel syndrome. Am J Physiol Regul Integr Comp Physiol. 2008;294:R402–10.

    Article  CAS  PubMed  Google Scholar 

  44. Buchman AL, Moukarzel AA, Bhuta S, et al. Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. JPEN J Parenter Enteral Nutr. 1995;19:453–60.

    Article  CAS  PubMed  Google Scholar 

  45. Harris JK, El Kasmi KC, Anderson AL, Devereaux MW, Fillon SA, Robertson CE, et al. Specific microbiome changes in a mouse model of parenteral nutrition associated liver injury and intestinal inflammation. PLoS One. 2014;9(10):e110396. doi:10.1371/journal.pone.0110396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. van Erpecum KJ, Schaap FG. Intestinal failure to produce FGF19: a culprit in intestinal failure-associated liver disease? J Hepatol. 2015;62:1231–3.

    Article  CAS  PubMed  Google Scholar 

  47. Pereira-Fantini P, Lapthorne S, Joyce S, Dellios N, Wilson G, Fouhy F, et al. Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease. J Hepatol. 2014;61:1115–25.

    Article  CAS  PubMed  Google Scholar 

  48. Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013;368:17–29.

    Article  CAS  PubMed  Google Scholar 

  49. Pakarinen MP, Kurvinen A, Gylling H, Miettinen TA, Pesonen M, Kallio M, et al. Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition. Dig Liver Dis. 2010;42:554–9.

    Article  CAS  PubMed  Google Scholar 

  50. Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology. 2012;142:355–65.

    Article  CAS  PubMed  Google Scholar 

  51. Jahn D, Rau M, Hermanns H, Geier A. Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease. Cytokine Growth Factor Rev. 2015. doi:10.1016/j.cytogfr.2015.07.016 [Epub ahead of print].

    PubMed  Google Scholar 

  52. de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab. 2013;17:657–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang XF, Liu GS, Yi B. Correlation between mutation of MDR3 gene exon 6 and parenteral nutrition-associated cholestasis of preterm infants. Exp Ther Med. 2014;8:1655–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Petit LM, Girard D, Ganousse-Mazeron S, Talbotec C, Pigneur B, Elie C, et al. Weaning off prognosis factors of home parenteral nutrition for children with primary digestive disease. J Pediatr Gastroenterol Nutr. 2016;62(3):462–8 [Epub ahead of print].

    Article  CAS  PubMed  Google Scholar 

  55. Hukkinen M, Kivisaari R, Lohi J, Heikkilä P, Mutanen A, Merras-Salmio L, et al. Transient elastography and aspartate aminotransferase to platelet ratio predict liver injury in paediatric intestinal failure. Liver Int. 2015. doi:10.1111/liv.12887 [Epub ahead of print].

    PubMed  Google Scholar 

  56. Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med. 2015;3(1):5. doi:10.3978/j.issn.2305-5839.2014.12.06.

    PubMed  PubMed Central  Google Scholar 

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Financial Support

Mikko Pakarinen was supported by research grants from the Finnish Pediatric Research Foundation, the Sigrid Juselius Foundation, and the Helsinki University Central Hospital research funds.

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Authors and Affiliations

  1. Section of Pediatric Surgery, Pediatric Liver and Gut Research Group Helsinki, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Stenbackinkatu 11, 281, Helsinki, 00029 HUS, Finland

    Mikko P. Pakarinen & Annika Mutanen

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  1. Mikko P. Pakarinen
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  2. Annika Mutanen
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Correspondence to Mikko P. Pakarinen .

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Editors and Affiliations

  1. Children's Hospital, Helsinki University Central Hospital, HUS Helsinki, Finland

    Risto J. Rintala

  2. Children's Hospital, Helsinki University Central Hospital, HUS Helsinki, Finland

    Mikko Pakarinen

  3. Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden

    Tomas Wester

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Pakarinen, M.P., Mutanen, A. (2016). Intestinal Failure-Associated Liver Disease. In: Rintala, R., Pakarinen, M., Wester, T. (eds) Current Concepts of Intestinal Failure. Springer, Cham. https://doi.org/10.1007/978-3-319-42551-1_4

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  • DOI: https://doi.org/10.1007/978-3-319-42551-1_4

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