Abstract
Aim of the study
Total intestinal aganglionosis (TIA) occurs in less than 1% of patients with Hirschsprung disease (HD), and TIA is the most severe form of HD. Survival has improved with the advent of parenteral nutrition and intestinal transplantation (ITx). The field of ITx has rapidly progressed in the last two decades and has now become an established treatment for patients with intestinal failure. The purpose of this meta-analysis was to determine the clinical outcome of ITx in patients with TIA.
Methods
A systematic literature search for relevant articles was performed in four databases using the combinations of the following terms: “total intestinal aganglionosis”, “intestinal transplantation”, and “Hirschsprung disease/Hirschsprung’s disease” for studies published between 2003 and 2016. The relevant cohorts of ITx in patients with TIA were systematically searched for clinical outcomes.
Main results
Thirteen studies met defined inclusion criteria, reporting a total of 63 patients who underwent ITx for TIA. Majority of patients were males (71.0%), and median age of ITx was 4.3 (range 0.25–17.6) years. Isolated ITx was performed in 37% patients and multivisceral ITx in 63%. Mean follow-up period was 40 months (range 1–154). Overall survival rate was 66%; the longest survivor was 12.8-year-old after ITx.
Conclusion
ITx appears promising in the management of TIA. ITx can be considered a feasible treatment option for patients with TIA who suffer from life-threatening complications of intestinal failure.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Total intestinal aganglionosis (TIA) occurs in less than 1% of patients with Hirschsprung disease (HD), and TIA is the most severe form of HD [1,2,3,4,5,6,7]. Survival has improved with the advent of total parenteral nutrition (TPN) and intestinal transplantation (ITx) [8,9,10,11]. TPN and central catheter placement has made it possible to maintain children with TIA in a stable nutrition state for many years [12]. However, the long-term use of TPN is associated with serious complications such as recurrent episodes of central venous catheter sepsis and end-stage liver disease [13,14,15,16].
Various surgical procedures have been proposed for the treatment of TIA, but these procedures have not provided a sufficient improvement to allow patients to be weaned from TPN [17,18,19,20,21]. In 1987, extended myectomy–myotomy procedure was described for the management of TIA [22]. However, there are a few long-term survivors reported in TIA following myectomy–myotomy procedure and therefore most surgeons have abandoned this procedure for the better option of ITx.
The field of ITx has rapidly progressed in the last two decades and has now become an established treatment for patients with intestinal failure [8,9,10,11]. The purpose of this meta-analysis was to determine the clinical outcome of ITx in patients with TIA.
Materials and methods
A systematic review and meta-analysis were conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of the literature was performed in the PubMed, Embase, Medline and Cochrane Library electronic database for the keywords “total intestinal aganglionosis”, “intestinal transplantation”, and “Hirschsprung disease/Hirschsprung’s disease” for studies published between 2003 and 2016. There was no restriction regarding the language of the publications. Reference lists of relevant articles were manually searched for further cohorts. Duplicates were deleted. Resulting publications were reviewed in detail for epidemiology, operative treatment, morbidity, and clinical outcome. The relevant articles were reviewed by title, keywords, and abstract by the authors (H.N. and P.P.), and a full-text assessment of selected articles was performed.
Results
The initial search yielded a total of 332 publications, of which 318 were identified by electronic database searching and 14 from cross-referencing (Fig. 1). After removal of 190 duplicate listed articles, 142 titles, keywords, and abstracts were screened. Of these, 62 nonrelevant studies were excluded. The remaining 80 publications were assessed in full-text for eligibility, and 67 articles were excluded because they did not address any of the selection criteria. In total, data from 13 studies [8, 23,24,25,26,27,28,29,30,31,32,33] (published between 2003 and 2016) met defined inclusion criteria and were included in the cumulative analysis.
Sixty-three patients who underwent ITx for TIA were included in this study. Table 1 summarizes the characteristics of the included studies. Majority of patients were males (71.0%), and median age of ITx was 4.3 (range 0.25–17.6) years. Isolated ITx was performed in 37% patients and multivisceral ITx in 63%. Mean follow-up period was 40 months (range 1–154). Overall survival rate was 66%; the longest survivor was 12.8-year-old after ITx.
The main complications were infectious (bacterial, CMV, EBV, HSV, mucormycosis, fungal), immunological (cellular ± humoral rejection, autoimmune hemolytic anemia), tumoral (EBV-related lymphoproliferative disorders), toxic (hypertension, impairment of renal function), dermatologic (severe generalized dermatosis, probably multifactorial: GVH, HSV6, medication toxicity), and encephalopathy.
Some authors prescribed anti-infective prophylaxis. Sauvat et al. used 1 month of total gut decontamination and acyclovir or ganciclovir during the first three postoperative months. Pakarinen et al. used rotating enteral antimicrobial therapy for bacterial overgrowth, including different combinations of metronidazole, ciprofloxacin, amoxicillin, and fluconazole.
Four studies reported immunosuppressive medication. IL-2 antibody, thymoglobulin, steroids, tacrolimus, sirolimus, daclizumab, basiliximab, and a combination of basiliximab and rabbit antithymocyte globulin or alemtuzumab were used.
Discussion
The total intestinal aganglionosis (TIA) with an absence of ganglion cells from the duodenum or upper jejunum to the rectum is the most rarest form of HD and is associated with high morbidity and mortality [34]. Various surgical procedures such as myectomy–myotomy have proved fruitless in achieving stable enteral autonomy. Permanent dependency on parenteral nutrition was the only available therapy for patients with TIA until intestinal transplantation (ITx) became an acceptable form of replacement therapy for intestinal failure. During the last two decades, ITx has rapidly progressed and has now become an established treatment for patients with intestinal failure. Our meta-analysis revealed 63 patients with TIA who underwent ITx.
Difficulty to arrive at a definite diagnosis was a common finding in all the cases of TIA. There were no absolute clinical criteria for TIA that were reproducible except the presence of nonspecific signs of intestinal obstruction [17]. In a previous report [34], in only 5.9% cases, meconium passage within the first 2 days was documented. Most of the patients presented with abdominal distention and bile-stained vomiting shortly after birth. Diarrhea, fever, and abdominal distention in HD are always symptoms of enterocolitis, and this remains the most serious complication of TIA [35]. Plain abdominal radiographs showing dilated or normal caliber intestinal loops are not always helpful. The findings on the barium enema are uncertain, and a delayed film at 24 h may confirm the diagnosis by demonstrating the retained barium. The only positive means of identifying the extent of aganglionosis was by rectal biopsy or operative biopsy. However, the extent of aganglionosis was often not accomplished at an initial laparotomy and most cases required multiple laparotomies to confirm the extent of aganglionosis. TIA most often lead to the placement of an end-jejunostomy, short bowel syndrome, and associated parenteral nutrition dependence, which predisposes patients to further complications [12, 34]. Development of intestinal failure-associated liver failure, loss of venous access sites, or frequent septic catheter infections were indications for ITx in the majority of patients [8, 36]. Intestinal failure-associated liver failure is the most life-threatening complication [37, 38]. Recent data have confirmed the role of small intestinal bacterial overgrowth in the onset of intestinal failure-associated liver failure especially in the patients with short bowel syndrome [39,40,41].
The main complications of ITx were infectious, immunological, toxic, dermatologic, and encephalopathy. Nearly 80% of the immune cells of the human body reside in the gut. After the ITx, the graft is repopulated with recipient cells; this is the main reason for the complexity of the immunological management of the intestinal graft compared to other organs. The immunotherapy must be targeted to each patient [42,43,44].
Data from the International Transplant Registry have proved the importance of using induction therapies that include monoclonal or polyclonal antibodies against leukocytes [45, 46]. Not only has the use of tacrolimus allowed better survival, but also the implementation of different immunosuppressive agents, such as sirolimus, has had a positive impact on survival [45, 47]. The improvements in immunosuppressive regimens and graft monitoring have increased the 5-year survival to greater than 55%, and 10-year survival to greater than 30% [45]. A previous review [34] showed that overall survival rate was 34% after ITx; however, in the present review, the overall survival rate was 66%; the longest survivor was 12.8-year-old after ITx.
In conclusion, these results suggest that ITx has become the standard of care for patients with irreversible intestinal failure due to markedly improve outcomes. ITx can be considered a definitive treatment option for patients with TIA who are suffering from life-threatening complications of intestinal failure.
References
Caniano DA, Ormsbee HS 3rd, Polito W, Sun CC, Barone FC, Hill JL (1985) Total intestinal aganglionosis. J Pediatr Surg 20(4):456–460
MacKinnon AE, Cohen SJ (1977) Total intestinal aganglionosis. An autosomal recessive condition? Arch Dis Child 52(11):898–899
Talwalker VC (1976) Aganglionosis of the entire bowel. J Pediatr Surg 11(2):213–216
Coran AG, Teitelbaum DH (2000) Recent advances in the management of Hirschsprung’s disease. Am J Surg 180(5):382–387
Solari V, Ennis S, Yoneda A, Wong L, Messineo A, Hollwarth ME, Green A, Puri P (2003) Mutation analysis of the RET gene in total intestinal aganglionosis by wave DNA fragment analysis system. J Pediatr Surg 38(3):497–501. doi:10.1053/jpsu.2003.50087
Rudin C, Jenny PM, Fliegel CP, Ohnacker H, Heitz PU (1986) Zuelzer–Wilson’s syndrome and absence of the enteric nervous system. Two rare forms of anomalies of the enteric nervous system with identical clinical symptoms. Z Kinderchir 41(5):287–292. doi:10.1055/s-2008-1043361
Rudin C, Jenny P, Ohnacker H, Heitz PU (1986) Absence of the enteric nervous system in the newborn: presentation of three patients and review of the literature. J Pediatr Surg 21(4):313–318
Sauvat F, Grimaldi C, Lacaille F, Ruemmele F, Dupic L, Bourdaud N, Fusaro F, Colomb V, Jan D, Cezard JP, Aigrain Y, Revillon Y, Goulet O (2008) Intestinal transplantation for total intestinal aganglionosis: a series of 12 consecutive children. J Pediatr Surg 43(10):1833–1838. doi:10.1016/j.jpedsurg.2008.03.028
Sigurdsson L, Reyes J, Kocoshis SA, Mazariegos G, Abu-Elmagd KM, Bueno J, Di Lorenzo C (1999) Intestinal transplantation in children with chronic intestinal pseudo-obstruction. Gut 45(4):570–574
Rovera GM, Schoen RE, Goldbach B, Janson D, Bond G, Rakela J, Graham TO, O’Keefe S, Abu-Elmagd K (2003) Intestinal and multivisceral transplantation: dynamics of nutritional management and functional autonomy. JPEN J Parenter Enter Nutr 27(4):252–259. doi:10.1177/0148607103027004252
Bond GJ, Reyes JD (2004) Intestinal transplantation for total/near-total aganglionosis and intestinal pseudo-obstruction. Semin Pediatr Surg 13(4):286–292
Fouquet V, De Lagausie P, Faure C, Bloch J, Malbezin S, Ferkhadji L, Bauman C, Aigrain Y (2002) Do prognostic factors exist for total colonic aganglionosis with ileal involvement? J Pediatr Surg 37(1):71–75
Kleinhaus S, Boley SJ, Sheran M, Sieber WK (1979) Hirschsprung’s disease—a survey of the members of the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg 14(5):588–597
Ikeda K, Goto S (1984) Diagnosis and treatment of Hirschsprung’s disease in Japan. An analysis of 1628 patients. Ann Surg 199(4):400–405
Tatekawa Y, Muraji T, Takamizawa S (2007) A case report of a patient with near total intestinal aganglionosis followed by the role of extended myectomy and synbiotics therapy. J Pediatr Surg 42(4):E9–12. doi:10.1016/j.jpedsurg.2007.01.058
Goulet O, Ruemmele F (2006) Causes and management of intestinal failure in children. Gastroenterology 130(2 Suppl 1):S16–S28. doi:10.1053/j.gastro.2005.12.002
Fortuna RS, Weber TR, Tracy TF Jr, Silen ML, Cradock TV (1996) Critical analysis of the operative treatment of Hirschsprung’s disease. Arch Surg 131(5):520–524 (discussion -524–525)
Marty TL, Seo T, Matlak ME, Sullivan JJ, Black RE, Johnson DG (1995) Gastrointestinal function after surgical correction of Hirschsprung’s disease: long-term follow-up in 135 patients. J Pediatr Surg 30(5):655–658
Ziegler MM, Royal RE, Brandt J, Drasnin J, Martin LW (1993) Extended myectomy–myotomy. A therapeutic alternative for total intestinal aganglionosis. Ann Surg 218(4):504–509 (discussion 509–511)
Saxton ML, Ein SH, Hoehner J, Kim PC (2000) Near-total intestinal aganglionosis: long-term follow-up of a morbid condition. J Pediatr Surg 35(5):669–672. doi:10.1053/jpsu.2000.5939
Shimotake T, Go S, Tomiyama H, Aoi S, Iwai N (2002) Proximal jejunostomy with or without myectomy–myotomy modification in five infants with total intestinal aganglionosis: an experience with surgical treatments in a single institution. J Pediatr Surg 37(6):835–839
Ziegler MM, Ross AJ 3rd, Bishop HC (1987) Total intestinal aganglionosis: a new technique for prolonged survival. J Pediatr Surg 22(1):82–83
Nwoye UO, Chaudhry QL, Mercer DF, Wendy GJ, Botha J, Langnas AN (2010) Experience of intestinal transplantation for total intestinal aganglionosis in children. Am J Transplant 4:379
Mannan AASR, Ko HM, Harpaz N (2016) Tu1865 post-transplant lymphoproliferative disorder in small bowel transplant recipients: a single center experience. Gastroenterology 150(4):S963. doi:10.1016/s0016-5085(16)33259-0
Chardot C, Irtan S, Dupic L, Telion C, Moulin F, Zahar J, Canioni D, Lambot K, Charbit M, Boutemy A, Talbotec C, Colomb V, Goulet O, Aigrain Y, Revillon Y, Lacaille F (2011) Evolution of intestinal transplantation–multivisceral transplantation. JPGN 52:1
Sharif K, Beath SV, Kelly DA, McKiernan P, van Mourik I, Mirza D, Mayer AD, Buckels JA, de Ville de Goyet J (2003) New perspective for the management of near-total or total intestinal aganglionosis in infants. J Pediatr Surg 38(1):25–28. doi:10.1053/jpsu.2003.50004 (discussion 25–28)
Pakarinen MP, Kurvinen A, Koivusalo AI, Ruuska T, Makisalo H, Jalanko H, Rintala RJ (2013) Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition. J Pediatr Surg 48(2):333–338. doi:10.1016/j.jpedsurg.2012.11.010
Varkey J, Simren M, Jalanko H, Oltean M, Saalman R, Gudjonsdottir A, Gabel M, Borg H, Edenholm M, Bentdal O, Husby S, Staun M, Makisalo H, Bosaeus I, Olausson M, Pakarinen M, Herlenius G (2015) Fifteen years’ experience of intestinal and multivisceral transplantation in the Nordic countries. Scand J Gastroenterol 50(3):278–290. doi:10.3109/00365521.2014.999255
Chang HK, Kim SY, Kim JI, Kim SI, Whang JK, Choi JY, Park JM, Jung ES, Rha SE, Kim DG, Moon IS, Lee MD (2016) Ten-year experience with bowel transplantation at Seoul St. Mary’s Hospital. Transplant Proc 48(2):473–478. doi:10.1016/j.transproceed.2015.12.065
Ganousse-Mazeron S, Lacaille F, Colomb-Jung V, Talbotec C, Ruemmele F, Sauvat F, Chardot C, Canioni D, Jan D, Revillon Y, Goulet O (2015) Assessment and outcome of children with intestinal failure referred for intestinal transplantation. Clin Nutr 34(3):428–435. doi:10.1016/j.clnu.2014.04.015
Hukkinen M, Koivusalo A, Merras-Salmio L, Rintala RJ, Pakarinen MP (2015) Postoperative outcome and survival in relation to small intestinal involvement of total colonic aganglionosis. J Pediatr Surg 50(11):1859–1864. doi:10.1016/j.jpedsurg.2015.05.017
Neuvonen MI, Kyrklund K, Lindahl HG, Koivusalo AI, Rintala RJ, Pakarinen MP (2015) A population-based, complete follow-up of 146 consecutive patients after transanal mucosectomy for Hirschsprung disease. J Pediatr Surg 50(10):1653–1658. doi:10.1016/j.jpedsurg.2015.02.006
Ramisch D, Rumbo C, Echevarria C, Moulin L, Niveyro S, Orce G, Crivelli A, Martinez MI, Chavez L, Paez MA, Trentadue J, Klein F, Fernandez A, Solar H, Gondolesi GE (2016) Long-term outcomes of intestinal and multivisceral transplantation at a single center in Argentina. Transplant Proc 48(2):457–462. doi:10.1016/j.transproceed.2015.12.066
Ruttenstock E, Puri P (2009) A meta-analysis of clinical outcome in patients with total intestinal aganglionosis. Pediatr Surg Int 25(10):833–839. doi:10.1007/s00383-009-2439-2
Puri P (2011) Hirschsprung’s disease. In: Puri P (ed) Newborn surgery, 3rd edn. Hodder Arnold, London, pp 554–565
Avitzur Y, Grant D (2010) Intestine transplantation in children: update 2010. Pediatr Clin North Am 57(2):415–431. doi:10.1016/j.pcl.2010.01.019 (table of contents)
Guarino A, De Marco G, Italian National Network for Pediatric Intestinal F (2003) Natural history of intestinal failure, investigated through a national network-based approach. J Pediatr Gastroenterol Nutr 37(2):136–141
Gupte GL, Beath SV, Protheroe S, Murphy MS, Davies P, Sharif K, McKiernan PJ, de Ville de Goyet J, Booth IW, Kelly DA (2007) Improved outcome of referrals for intestinal transplantation in the UK. Arch Dis Child 92(2):147–152. doi:10.1136/adc.2005.090068
Mencin A, Kluwe J, Schwabe RF (2009) Toll-like receptors as targets in chronic liver diseases. Gut 58(5):704–720. doi:10.1136/gut.2008.156307
Yang L, Seki E (2012) Toll-like receptors in liver fibrosis: cellular crosstalk and mechanisms. Front Physiol 3:138. doi:10.3389/fphys.2012.00138
El Kasmi KC, Anderson AL, Devereaux MW, Fillon SA, Harris JK, Lovell MA, Finegold MJ, Sokol RJ (2012) Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology 55(5):1518–1528. doi:10.1002/hep.25500
Kaufman SS (2001) Small bowel transplantation: selection criteria, operative techniques, advances in specific immunosuppression, prognosis. Curr Opin Pediatr 13(5):425–428
Fishbein TM, Florman S, Gondolesi G, Schiano T, LeLeiko N, Tschernia A, Kaufman S (2002) Intestinal transplantation before and after the introduction of sirolimus. Transplantation 73(10):1538–1542
Pearce RJ, Pota H, Evehe MS, el Ba H, Mombo-Ngoma G, Malisa AL, Ord R, Inojosa W, Matondo A, Diallo DA, Mbacham W, van den Broek IV, Swarthout TD, Getachew A, Dejene S, Grobusch MP, Njie F, Dunyo S, Kweku M, Owusu-Agyei S, Chandramohan D, Bonnet M, Guthmann JP, Clarke S, Barnes KI, Streat E, Katokele ST, Uusiku P, Agboghoroma CO, Elegba OY, Cisse B, Ie AE, Giha HA, Kachur SP, Lynch C, Rwakimari JB, Chanda P, Hawela M, Sharp B, Naidoo I, Roper C (2009) Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med 6(4):e1000055. doi:10.1371/journal.pmed.1000055
Smith JM, Skeans MA, Horslen SP, Edwards EB, Harper AM, Snyder JJ, Israni AK, Kasiske BL (2017) OPTN/SRTR 2015 annual data report: intestine. Am J Transplant 17(Suppl 1):252–285. doi:10.1111/ajt.14127
Abu-Elmagd KM, Costa G, Bond GJ, Soltys K, Sindhi R, Wu T, Koritsky DA, Schuster B, Martin L, Cruz RJ, Murase N, Zeevi A, Irish W, Ayyash MO, Matarese L, Humar A, Mazariegos G (2009) Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges. Ann Surg 250(4):567–581. doi:10.1097/SLA.0b013e3181b67725
Abu-Elmagd KM, Costa G, Bond GJ, Wu T, Murase N, Zeevi A, Simmons R, Soltys K, Sindhi R, Stein W, Demetris A, Mazariegos G (2009) Evolution of the immunosuppressive strategies for the intestinal and multivisceral recipients with special reference to allograft immunity and achievement of partial tolerance. Transpl Int 22(1):96–109. doi:10.1111/j.1432-2277.2008.00785.x
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Nakamura, H., Henderson, D. & Puri, P. A meta-analysis of clinical outcome of intestinal transplantation in patients with total intestinal aganglionosis. Pediatr Surg Int 33, 837–841 (2017). https://doi.org/10.1007/s00383-017-4107-2
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00383-017-4107-2