New perspective for the management of near-total or total intestinal aganglionosis in infants

Sharif, K.; Beath, S.V.; Kelly, D.A.; McKiernan, P.; van Mourik, I.; Mirza, D.; Mayer, A.D.; Buckels, J.A.C.; de Ville de Goyet, J.

doi:10.1053/jpsu.2003.50004

« Previous Next »Journal of Pediatric Surgery
Volume 38, Issue 1 , Pages 25-28, January 2003

New perspective for the management of near-total or total intestinal aganglionosis in infants☆

Presented at the 49th Annual Congress of the British Association of Paediatric Surgeons, Cambridge, England, July 23-26, 2002.

Liver Unit at Birmingham Children's Hospital, and Liver Unit at Queen Elizabeth Hospital, Birmingham, England

Abstract

Background Purpose: Extensive intestinal aganglionosis is rare. The diagnosis and treatment are known to be difficult and it had been considered to be fatal. The aim of this study was to review our experience with children with extensive intestinal aganglionosis. Methods: Retrospective analysis was conducted in patients referred to the intestinal transplantation unit since 1993. Presentation and outcome were analysed looking at 2 groups who had either undergone previous subtotal intestinal resection (group I) or no or limited resection (group II). Results. Eight children were selected (3 patients in group I and 5 in group II). Group I was remarkable in that patients all were referred early in age with progressing liver failure. Parents of one patient refused to accept transplantation as treatment, and he died one month later. Two noncirrhotic patients were maintained in the parenteral nutrition programme and currently progress well with enteral feedings. The other 5 patients underwent transplant, and 4 of 5 are alive after transplantation with a mean follow-up of 22.2 months (range 0.4 to 63.6). Conclusions: Subtotal resection of intestine at the time of diagnosis must be avoided. Conservative management with parenteral nutrition may be associated with long-term good outcome. Small bowel transplant may open new perspective in the management of patients with end-stage liver disease. J Pediatr Surg 38:25-28. Copyright 2003, Elsevier Science (USA). All rights reserved.

Keywords: Hirschsprung disease, total intestinal aganglionosis, intestine surgical resection, parenteral nutrition, surgical techniques, intestinal transplantation

Total or near-total intestinal aganglionosis (NTAG; absence of ganglionic innervation throughout the entire or nearly entire gastrointestinal tract) represents the most extreme and rare form of Hirschsprung's disease.¹, ², ³ It is rare, affecting less than 5% of infants with Hirschsprung's disease.⁴ The diagnosis and treatment is known to be difficult,¹ and some consider it to be a fatal condition in infancy², ³, ⁵ because chronic intestinal obstruction and dependence to long-term total parenteral nutrition (TPN) are associated with high morbidity and mortality rates.

Various palliative treatments have been proposed,⁶, ⁷, ⁸ and recently intestinal transplantation has been undertaken.⁹ However, no report has addressed the issues related to modern management, in particular the role of preemptive enterectomy of aganglionic bowel remains controversial. Therefore, we reviewed our experience of NTAG including that of intestinal transplantation in selected cases.

Back to Article Outline

Materials and methods

All patients referred to the Birmingham Children's Hospital's liver and small bowel transplantation unit since 1993 were reviewed retrospectively. Patients with extensive aganglionosis (extending up to jejunum or above) were selected for the study. The following parameters were recorded: length of aganglionosis, associated malformations, family history of Hirschsprung's disease, condition at referral (age, weight, Z score, serum Bilirubin, platelet count, liver histology), management methods, types of grafts used in transplanted patients, and outcome.

Patients were divided into 2 groups with group I comprising patients with the whole of aganglionated intestine previously resected, and group II with no (or limited) resection of the aganglionated intestine. Group I and II patients and their outcome was compared.

Back to Article Outline

Results

Of 110 patients referred between 1993 and 2002, 8 had NTAG (7 boys and 1 girl) with median age of 5.6 months (range, 0.9 to 20.8 months). Patient characteristics are detailed in Table 1.

Table 1. Patients' characteristics with associated anomalies and family history

Case No.	Age at Referral (mo)	Sex	Length of Residual Normal Intestine Distal to DJ Flexure (cm)	Associated Anomalies	Family History	Outcome
Group I
1	9	Girl	35	Absent left kidney	Nil	Alive
2	2	Boy	30	Nil	Brother + father family history	Alive
3	3	Boy	10	Hypothyroid + absent left kidney	Nil	Alive
Group II
4	2	Boy	10	Warrdenburg-Shah syndrome	Two siblings	Died
5	12	Boy	35	Absent right kidney	Nil	Alive
6	8	Boy	50	Hypothyroidism	Father and uncle	Died
7	21	Boy	40	Nil	Nil	Alive
8	1	Boy	30	Nil	Nil	Alive

Abbreviation: DJ, duodeno-jejunal.

The aganglionosis extended to the proximal jejunum in all patients, with a median length of normal innervated intestine (measured from duodeno-jejunal flexure) of 32.5 cm (range, 10 to 50 cm). Four patients were noted to have associated anomalies—single kidney (n = 3) or hypothyroidism (n = 2). Family history of Hirschsprung's disease was present in 4 patients (father or sibling in 2 cases each with one having extensive aganglionosis and Wardenburg syndrome and 3 others having rectosigmoid disease only).

Group I (patients who had preemptive resection of all of aganglionic intestine) consisted of 3 patients (one girl and 2 boys) and group II of 5 patients (all boys). Compared with group II (Table 2), group I was remarkable in that patients were all referred early in age with established cirrhosis, portal hypertension, and progressing liver failure.

Table 2. Comparison between children referred with previous resection of the whole aganglionated intestine (group I) and children with no or limited bowel resection (group II)

Referral Parameters	Group I (n = 3)	Group II (n = 5)
Median age at referral (range)	2.9 (1.8-9.5) mo	8.3 (0.9-20.8) mo
Median bilirubin level at referral (range)	109 (66-265) μmol	40 (11-359) μmol
Platelets at referral (median)	57 (52-81) 10³mL	203 (33-528) 10³ mL
Level of aganglionosis (measured from DJ flexure), mean (range)	26 (10-35) cm	33 (10-40) cm
Median age at assessment for transplant (range)	7.4 (5.5-9.9) mo	12.6 (6.6-24) mo
Median weight at transplant (range)	8.1 kg (7.1-9.3)	15.35 kg (9.7-30.7)
Established cirrhosis	3/3	2/4

Abbreviation: DJ, duodeno-jejunal.

Table 3 details management and outcome in these 8 cases.

Table 3. Management type, types of grafts, and follow-up

Patient No.	Age at Listing (mo)	Weight atListing (kg)	Weight at Transplant (kg)	Donor to Recipient Weight Ratio	Type of Graft	Follow-Up (yr)
Group I*
1	10.2	6.6	8.0	2.7	Reduced liver and small bowel	1.1
2	6.8	7.6	9.0	3.9	Reduced liver and small bowel	3.6
3	7.6	6.0	7.1	2.1	Reduced liver and small bowel	0.4
Group II
4	8.1	Parents declined transplant				Died
5	17.6	9.8	18	1	Isolated small bowel	5.3
6	11.6	9.7	9.7	6.2	Reduced liver and small bowel	Died
7	Managed conservatively with enteral and parenteral feeding					0.7
8	Managed conservatively with parenteral nutrition					5.0
*All patients in group I had previous resection of their whole small and large aganglionated intestine. Group II patients had no or limited bowel resection. All patients had stoma at referral.

Six patients were listed for transplantation (5 for liver and small bowel transplantation because of associated end-stage liver disease, and one for isolated small intestine owing to thrombosis of superior vena cava), 3 in each group. Patients in group I had to be listed for transplantation much earlier than group II cases as expected from their early presentation with established severe liver disease. Accordingly, they were younger and smaller in size at transplant compared with group II patients. More importantly, because of previous resection of their entire intestine, Group I patients presented with greatly reduced space in the abdominal cavity, which was a major technical challenge for transplanting abdominal organs. Expansion of the abdomen cavity was done in one patient before transplantation by insertion of a tissue expander in the abdomen followed by progressive expansion, which facilitated organ implantation later. A similar operation could not be considered for the 2 other cases in group I, because of their extremely poor condition and severe coagulopathy, and organs had to be reduced in size more than usual for successful transplantation. Patients of group II underwent transplant without specific technical problems.

The parents of one patient declined transplantation as treatment, and the patient died one month later. All 5 other patients underwent transplant (4 liver and small bowel and one isolated small intestine) with a median waiting time of 10.2 months (range, 1.2 to 38 months). One of the 5 patients who received transplants died 7 days after transplantation of graft failure and sepsis. Currently, 4 patients are alive and well after transplantation, with a mean follow-up of 32.1 months (range, 4.4 to 63.6 months). The 2 last patients, who were referred before liver disease was established, were treated successfully conservatively and currently are doing well with continuing home parenteral nutrition and progressing with some enteral feeding.

Back to Article Outline

Discussion

Hirschsprung's disease involving the entire colon is seen in only 5% of Hirschsprung's patients,¹, ², ³, ⁴ and NTAG is even less common as reflected in our series with only 8 cases referred from the entire United Kingdom in 10 years.

Until 1987 when Ziegler et al⁸ reported a first long-term survivor of NTAG, extensive aganglionosis was a fatal condition with a high mortality rate during infancy. This situation has improved in recent years with the advent of total parenteral nutrition and innovative surgical techniques,³, ⁶, ⁷, ¹⁰, ¹¹ but the very extensive forms of the disease still carrying poor prognosis as reported by Fouquet et al¹² with longer aganglionic segment cases associated with prolonged total parenteral nutrition (TPN) duration and poorer survival rate.¹², ¹³

In cases of short aganglionic segment, surgical resection of diseased segment and restoration of gut continuity achieve good results and long-term outcome. However, in patients with NTAG, surgical resection does not leave enough normal bowel to support full/enteral feeding, and prolonged parenteral nutrition is necessary. In that context, new surgical options have been considered that retain part of the diseased small bowel, such as right colon patch⁴, ¹¹ or “myectomy-myotomy.”⁸ Results with these techniques still are poor with few reports showing limited success¹⁰ and high rates for postoperative complications.¹, ⁴ Thus overall, most patients with NTAG currently are growing with dependence for TPN and high risk of TPN or disease-related complications in infancy.

In the last decade, intestinal transplantation has emerged as a life-saving procedure for patients with irreversible intestinal failure.¹⁰, ¹⁴ Severe complications such as progressive liver disease or compromised vascular access accentuate the problems facing these patients.¹⁴, ¹⁶ Natural history of parenteral nutrition–induced liver failure in small infants often is that of rapid progression and death as suggested by Beath et al¹⁵ who showed that the main risk factor for death within 6 months in children assessed for intestinal transplant was liver disease especially where cholestasis (bilirubin > 100 μmol/L), presence of splenomegaly and cirrhosis on liver biopsy are present.¹⁵ In this series, of 8 patients, 5 had established cirrhosis at the time of assessment with liver dysfunction and coagulopathy; they thus were proposed for combined liver and bowel transplant. One other noncirrhotic patient received isolated small bowel transplant because he had only one central vein remaining patent. On the contrary, 2 other patients referred early had no cirrhosis and currently are managed by parenteral and enteral nutrition. In both cases, the short segment of normal jejunum allows some enteral feeding which is increased with time as the bowel grows and adapts. Probably they will remain with a stoma for life, but improvement of their condition with age is considered possible.

Three children were referred with previous resection of the whole aganglionated intestine. The rationale for doing this is uncertain and, as far as we know, it has not been proposed for managing NTAG, nor shown to improve outcome. On the contrary, it has been associated, in our experience, with earlier complications, evolution toward liver cirrhosis, and the need to consider transplantation in very young and small infants. The previous resection of the whole bowel resulted in a contracted abdomen, the latter could have reduced their chance of getting a graft in time and did increase technical difficulties for the transplant operation. Group I patients were more technically demanding. Although a high risk of death while waiting for a graft is reported in similar cases,⁹ no infant in this series died before transplant. They benefited from new techniques (pretransplant abdominal expansion and the use of en-bloc combined reduced-liver and bowel grafts¹⁶).

We believe there is no advantage to extensive bowel resection at the time of diagnosing NTAG, and this type of procedure should be avoided. We recommend a simple proximal stoma should be created and attention then be given to (1) use the proximal jejunum optimally, (2) prevention of complications of parenteral nutrition, and (3) protection of central venous access.

Total or near-total aganglionosis is a rare disease. Small bowel transplant has emerged as a possible surgical treatment for this fatal entity, but earlier referral to expert unit should be considered for preserving the option of continuing conservative management and parenteral nutrition.

Resection of the whole of the intestine at the time of diagnosis should be avoided because it seems associated with rapid deterioration of liver function and need for transplantation early in life; also it makes pretransplant management more difficult and transplantation more technically demanding.

Back to Article Outline

Acknowledgements

The authors thank their colleagues Professor Booth, Mr Holmes, Mr Nichols, Dr Al-Jawad, Dr Puntis, Dr Mitton, Dr Datzell, and Dr Sullivan for referring patients and sharing their follow-up information. The authors thank to their data managers C. Lloyd and D. Sandhu for their support in the completion of this manuscript.

Back to Article Outline

Discussion

A. Aigrain (Paris, France): Do you think that one of the prognostic factors in all of these patients is that regardless of whether you succeed to have functioning stoma, even if the duodenum and stomach are not innervated. If not, they quickly become cirrhotic and have to be transplanted quickly. If you have a functioning stoma, it is possible to wait, but it would be advised that these patients should be referred to a specialized unit to consider small intestine and colon transplant. I would agree not to remove the intestine because of the abdominal space problem that you mentioned.

K. Sharif (response): This series is from a centre dealing with transplant only. We do not do the initial and neonatal surgery, but I share your idea that if the stoma is working, then it may give you a better chance of delaying transplant because 2 of our patients currently are treated conservatively with 1- and 5-year follow-up, respectively.

Back to Article Outline

References

Senyuz OF, Buyukunal C, Danismend N, et al. Extensive intestinal aganglionoisis. J Pediatr Surg. 1989;24:453–456

Shim WKT, Derieg M, Powel BR, et al. Near total intestinal aganglionosis in Waardenburg-Shah syndrome. J Pediatr Surg. 1999;34:1853–1855

Finley R, Cohen Z, Mares AJ. Near Total aganglionosis with extreme short bowel syndrome a difficult surgical dilemma. Eur J Pediatr Surg. 1999;9:235–255
- View In Article

Stringel G. Extensive intestinal aganglionosis including the ileum: A new surgical technique. J Pediatr Surg. 1986;21:667–670

Caniano DA, Ormsbee HS, Polito W, et al. Total intestinal aganglionois. J Pediatr Surg. 1985;20:456–460

Martin LW. Surgical Management of Hirschsprung's disease involving the small intestine. Arch Surg. 1968;97:183–189
- View In Article
- MEDLINE

Ikeda K, Goto S. Total colonic aganglionosis with or without small bowel involment: An analysis of 137 Patients. J Pediatr Surg. 1986;21:319–322

Ziegler MM, Ross AJ, Bishop HC. Total intestinal aganglionosis: A new technique for prolonged survival. J Pediatr Surg. 1987;22:82–83

Fecteau A, Atkinson P, Grant D. Early referral is essential for successful pediatric small bowel transplantation: The Canadian experience. J Pediatr Surg. 2001;36:681–684

Saxton ML, Elin SH, Hoehner , et al. Near-total intestinal aganglionosis: Long-term follow-up of a morbid condition. J Pediatr Surg. 2000;35:669–672

Kimura K, Nishijima E, Muraji T, et al. A new surgical approach to extensive aganglionosis. J Pediatr Surg. 1981;16:840–843

Fouquet V, De Lagausie P, Faure C, et al. Do prognostic factors exit for total colonic aganglionosis with ileal involvement?. J Pediatr Surg. 2002;37:71–75

N-Fekete C, Ricour C, Martelli H, et al. Total colonic aganglionosis (with or without ileal involvement): A review of 27 cases. J Pediatr Surg. 1986;21:251–254

Sigurdsson L, Reyes J, Kocoshis SA. Intestinal transplantation in children. Curr Gastroenterol Rep. 1999;1:259

Beath SV, Needham SJ, Kelly DA, et al. Clinical features and prognosis of children assessed for isolated small bowel or combined small bowel and liver transplantation. J Pediatr Surg. 1997;32:459–461

Ville de Goyet J, Mitchell A, Mayor D, et al. En bloc combined reduced-liver and small bowel transplant: From large donors to small children. Transplantation. 2000;69:555–559