Levin, David N.*; Marcon, Margaret A.†; Rintala, Risto J.‡; Jacobson, Dustin*; Langer, Jacob C.*
*Division of General and Thoracic Surgery
†Division of Gastroenterology, Hospital for Sick Children, Toronto, Canada
‡Department of Paediatric Surgery, Hospital for Children and Adolescents, University of Helskinki, Helsinki, Finland.
Address correspondence and reprint requests to Jacob C. Langer, MD, Robert M. Filler Chair, Paediatric General and Thoracic Surgery, Rm 1526, Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8 Canada (e-mail: firstname.lastname@example.org).
Received 16 February, 2011
Accepted 29 September, 2011
D.L. was supported in part by a Comprehensive Research Experience for Medical Students bursary, University of Toronto, and in part by the Robert M. Filler Chair in Pediatric General and Thoracic Surgery, Hospital for Sick Children, Toronto.
The authors report no conflicts of interest.
Following surgical correction of Hirschsprung disease, many patients develop Hirschsprung-associated enterocolitis (HAEC) a condition that is characterized by intestinal inflammation resulting in abdominal distension, fever, diarrhea, and sepsis (1), which in most cases resolves by early childhood (2). The term “inflammatory bowel disease” (IBD) is usually used to describe Crohn disease and ulcerative colitis, which cause symptoms that include diarrhea, pain, obstruction, weight loss, bloody stool, and fistula formation (3). We have treated a number of children who developed a clinical picture with characteristics of both HEAC and IBD following surgical repair of Hirschsprung disease. These cases raise the possibility that the 2 conditions may have similar etiologies and may represent a spectrum of intestinal inflammatory disease in children.
Retrospective review of 8 patients treated for IBD following surgical management for Hirschsprung disease at 2 tertiary pediatric hospitals (Hospital for Sick Children, Toronto, Canada, and Hospital for Children and Adolescents, Helsinki, Finland).
This boy with trisomy 21 diagnosed with Hirschsprung disease at 2 months of age had a transition zone at the rectosigmoid junction. A Duhamel procedure was performed. Postoperatively the patient experienced recurrent bouts of enterocolitis that responded to sodium cromoglycate.
At age 17, he presented with diarrhea and hematochezia. Colonoscopy identified distal colitis extending to the hepatic flexure. Gastroscopy showed duodenal aftae. Biopsies of colonic and duodenal segments revealed granulomata. Laboratory tests revealed an elevated erythrocyte sedimentation rate (ESR). A diagnosis of Crohn disease was made, and he was managed effectively with mesalazine and oral budenoside.
This boy with trisomy 21 was diagnosed with Hirschsprung disease at 1 month of age with a transition zone in the descending colon. An endorectal pull-through was performed. Postoperatively the patient experienced recurrent bouts of enterocolitis that did not respond to metronidazole or sodium cromoglycate.
At age 12, he presented with diarrhea and hematochezia. Colonoscopy identified distal colitis with stricture. Colonic biopsies showed chronic inflammation with granulomata. Laboratory tests revealed elevated ESR and fecal calprotectin. A diagnosis of Crohn disease was made, and he was managed with mesalazine, azathioprine, and a low-residue and lactose-free diet. Despite therapy, the patient continued to experience moderate recurring symptoms.
This boy with trisomy 21 was diagnosed with Hirschsprung disease at 9 months of age with a transition zone in the rectum. An endorectal pull-through procedure was performed. Postoperatively the patient experienced recurrent bouts of enterocolitis that did not respond to metronidazole or sodium cromoglycate.
At age 9 he presented with chronic diarrhea. Colonoscopy identified moderate pancolitis. Colonic biopsies showed moderate chronic inflammation, with no specific features of Crohn disease or ulcerative colitis and no granulomata. Laboratory tests revealed a mildly elevated ESR, mild anemia and mildly elevated fecal calprotectin. A diagnosis of indeterminate colitis was made. He was managed with mesalazine and a low-residue lactose-free diet, with improvement but incomplete resolution of symptoms.
This girl presented with total colonic Hirschsprung disease. She had a family history significant for irritable bowel syndrome and diverticulitis. She had a loop ileostomy as a newborn and subsequently underwent a modified Martin procedure involving a long side-to-side anastomosis of the ileum with the entire colon. During the next 2 years she required several operations for intestinal obstruction and perianal abscess formation, culminating in the creation of a stoma consisting of the proximal ileocolon. Between ages 4 and 12, she experienced persistent anemia associated with hematochezia and fevers. Serial ileoscopy showed multiple areas of mucosal erosion and fissure formation at the stoma. There was a dilated segment of bowel presumed to be the source of bacterial overgrowth. She underwent resection of this segment. Stoma prolapse, obstruction, abscesses, and dysfunction were treated with multiple stoma revisions. She was treated with metronidazole over this period.
At age 20 her stoma was taken down. The entire ileocolon remaining from her first pull-through was resected, leaving her with relatively foreshortened (220 cm) small bowel, and an ileal Duhamel pull-through was done. The resected ileocolon revealed marked congestion, dense adhesions and abundant omental fat in the serosa with marked flattening and petechial hemorrhage in the mucosa. Microscopically there was diffuse chronic inflammation with focal eosinophilia.
At age 21 she presented with tenesmus, perirectal pain, increased stool frequency, and rectal bleeding. Sigmoidoscopy revealed Crohn-like ulcerations in the distal 40 cm and a small bowel to small bowel fistula at that level. She was treated with ciprofloxacin and metronidazole, with improvement of her symptoms. At last follow-up, she was on mesalazine and ciprofloxacin, having 4 to 6 bowel movements per day.
This girl had a laparoscopic Swenson pull-through at 18 months of age for short segment Hirschsprung disease. She had a brother with long-segment Hirschsprung disease and mother with short segment Hirschsprung disease. Postoperatively she developed a rectovaginal fistula for which she had a defunctioning colostomy that was repaired after healing of the fistula 2 months later.
At age 7 years she presented with chronic diarrhea, fecal urgency, and urinary tract infections. Colonoscopy and biopsy revealed mild nonspecific colitis throughout her entire colon. She was treated with mesalazine, with symptomatic improvement.
On repeat colonoscopy at age 10, again she was found to have mild microscopic colitis with eosinophilic infiltrates. At the time of her last follow-up at age 11, she was doing well on maintenance therapy with mesalazine.
This boy had total colonic Hirschsprung disease for which he underwent a leveling ileostomy at 2 days of life, followed by an ileal Duhamel procedure at 5 months of age. His father had ulcerative colitis and a second-degree relative had Crohn disease on the maternal side.
From age 4 to 14 he presented colicky abdominal pain, explosive foul-smelling bowel movements, hematochezia, nocturnal incontinence, anemia, low serum albumin, and weight loss. Serial sigmoidoscopy revealed nonspecific inflammation with focal ulceration and pseudopolyps in the pouch and distal ileum (Fig. 1A and B). There was a stricture at the site of the Duhamel anastomosis. Biopsies showed acute and chronic pouchitis and granulation tissue (Fig. 1C and D). Serologic testing was negative for Crohn disease. Over this course, treatments included metronidazole, iron supplementation, prednisone, rectal dilatations, and mesalazine. At age 16, mesalazine was switched to azathioprine with good response. He became fully continent without accidents and his anemia resolved. He continued to manage well with just azathioprine.
This boy was diagnosed as having short-segment Hirschsprung disease at 3 months of age with a transition zone in the mid-sigmoid colon, and underwent a Duhamel procedure. Postoperatively he experienced significant diarrhea, which was occasionally bloody, but this resolved during the next 8 months. Both his mother and grandmother had Hashimoto thyroiditis, a maternal great aunt had lupus, and a maternal uncle had Crohn disease.
At age 4 he presented with cyclical episodes of colicky, left-sided abdominal pain associated with increased stooling occurring every 2 to 3 weeks. Investigations revealed a sizable anterior pouch with a spur and a tight posterior anastomosis for which he underwent laparoscopic revision. Biopsies from the upper gastrointestinal tract and colon showed increased eosinophils. Courses of sulfasalazine, mesalazine, and ketotifen were ineffective due to poor compliance. At the time of last follow-up at age 13 he continued to have debilitating abdominal symptoms with blood and mucous in his stools.
This boy was diagnosed as having Hirschsprung disease as a neonate with a mid-sigmoid transition zone, and underwent a Swenson procedure. Postoperative complications included a leak with fistula formation at the leak site. He underwent a repeat Swenson pull-through due to anastomotic stricture and perianal fistulae formation.
At age 4 he presented with severe horseshoe perirectal fistulae (Fig. 2A) and rectal stricture, which was managed with a defunctioning loop colostomy. Subsequent colonoscopy identified severe colitis (Fig. 2B) with lymphoplasmacytic inflammatory infiltrate, fibropurulent exudate and granulomata (Fig. 2C and D). The stoma was converted to an end colostomy to provide complete diversion of stool, and setons were placed (Fig. 2E). The fistulae have persisted despite defunctioning and treatment with ciprofloxacin and metronidazole. Table 1 contains a chart summarizing the salient features of each case, including details about diagnostic tests.
TABLE 1-b Summary of...Image Tools
We have described a group of patients with Hirschsprung disease who have developed a range of symptoms that challenge our conceptualization of what we call HAEC and IBD. We estimate that approximately 700 patients were treated for Hirschsprung disease at these 2 institutions in the last 20 years, indicating that this symptomatology is rare. A potential association between Hirschsprung disease and IBD has been described by 3 authors who reported a total of 4 patients (4–6). It remains unclear whether these cases represent chronic or unusual forms of HAEC, are true examples of IBD, or represent a different unique disease entity.
Six of 8 patients in this series were given a diagnosis of HAEC, and these patients did not improve until it was recognized that they had persistent, unregulated bowel inflammation, and appropriate therapy was initiated. There are several clinical symptoms shared between the classical descriptions of HAEC and IBD; these include pain, fever, diarrhea, and increased stooling frequency (7,8). Although all of the patients in this series had some or all of the aforementioned symptoms, many had findings more typical of IBD (8). In our series, 3 patients had increased ESR, 3 had anemia, and 1 patient had both. One patient had a severe perirectal abscess, 1 had a rectovaginal fistula postrepair, and 1 had recurrent peristomal fistulae as well as a small bowel to small bowel fistula. Other features more typical of IBD were the development of late inflammatory strictures and the presence of granulomata on intestinal biopsies.
Both Hirschsprung disease and IBD have multifactorial etiologies that are not yet fully understood. Three of the patients in this series had trisomy 21. Although there is a well-known incidence of Hirschsprung disease in children with trisomy 21 (9), there has not been an increased risk of IBD reported in this patient group (10). Patients with trisomy 21 tend to have increased morbidity following surgical correction of Hirschsprung disease, including higher incidence of enterocolitis (11) and fecal incontinence (12). Failure to thrive and abnormal stooling may be attributed to mental retardation or concomitant cardiac defects, postponing thorough gastrointestinal investigation—opening the possibility that IBD is underrecognized in this population. How this chromosomal abnormality influences this disease remains to be explored.
In our series, 2 patients had a family history of IBD and 1 had a family history of Hirschsprung disease. No patient had a positive family history of both Hirschsprung disease and IBD. Unfortunately, genetic testing was not performed for any of the patients, and selected serologic studies were only performed for 4 patients—none showing any abnormalities. Future studies including genetic and serologic markers will provide a better understanding of these patients and would add to our insight into these disease processes.
There are genetic mutations recognized to predispose patients to IBD (13) and increasing numbers associated with Hirschsprung disease (14); however, there are no mutations identified as common to both conditions. In IBD, host genetic susceptibility, in the form of a defective mucosal barrier function, can lead to enhanced exposure to luminal bacteria (15). Similarly, there are known abnormalities in mucosal immunity and mucin production in children with Hirschsprung disease who tend to develop enterocolitis (16,17). A study hypothesizing that the defective mucosal barrier seen in both IBD and Hirschsprung disease may have a similar genetic etiology found no increase in the NOD2 susceptibility gene for Crohn disease in patients with HAEC (18). It is possible that previously unrecognized abnormalities in mucosal immunity may play a role in the development of IBD following surgical repair of Hirschsprung disease.
Long-segment aganglionosis has been felt by some authors to leave patients at a higher risk of enterocolitis, especially when reconstructed with a colon pouch procedure (19). The 2 oldest patients in our series at diagnosis of IBD were 17 and 21 years, and both had colon pouch procedures. Because host-gut microbiome interactions likely play a role in the development of IBD, it may be that mechanical factors that affect gut microbiome and allow overgrowth or alterations in colonization predisposes patients to chronic inflammatory changes. Poor emptying and stasis are potentially important etiologic factors.
We have described a series of patients with Hirschsprung disease who subsequently developed a variety of conditions resembling IBD. Understanding and recognizing the clinical presentation, disease course, and treatment of these patients will help to inform diagnosis and management of future patients with this rare association. As more cases are recognized and trends emerge, we may gain insights into the unique nature of IBD in patients with Hirschsprung disease.
The authors thank Robin Vaughan for assistance with this project.
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