Enterocolitis Associated with Hirschsprung's Disease

Despite major improvements in the understanding of the pathophysiology and genetics of Hirschsprung's disease, little advancement has occurred in either elucidating the etiology of Hirschsprung's-associated enterocolitis (HAEC) or its prevention. Despite the recognition of this process in Harald Hirschsprung's first description of the disease in 1886, little attention was given to this disease process for the next 70 years (1). Swenson and Fisher, in 1956, were the first to recognize the association of enterocolitis and Hirschsprung's disease (2). Over the past four decades, HAEC has been a major cause of morbidity and mortality in infants and children with Hirschsprung's disease. With an increased understanding of the mucosal defense mechanisms, a host of potential causative factors have been advanced to explain this disease process. This review will attempt to sort out what is known clinically about this disorder and will review potential etiologies and therapy of HAEC.

Clinical Presentation and Diagnosis

Bill and Chapman were the first to accurately characterize the clinical aspects of HAEC (3). They speculated that the cause of this disorder was a partial mechanical obstruction similar to the colitis associated with other forms of bowel obstruction. Their description of the natural history of the process helped to alert physicians to the high risk of HAEC in Hirschsprung's disease patients. The classic clinical manifestations that they described in HAEC include abdominal distention, fever and foul smelling stool (3). There is, however, a wide range of clinical presentations of HAEC. A compilation of symptoms from patients with HAEC, treated at our Children's Hospital, noted the following in decreasing frequency: abdominal distension, explosive diarrhea, vomiting, fever, lethargy, rectal bleeding and shock (4). Many cases of diarrhea or abdominal distention may be mistakenly diagnosed as a gastroenteritis or the obstructing sphincter syndrome; however, most of these are cases of mild HAEC. To facilitate the diagnosis of HAEC, Elhalaby, et al developed a clinical grading system (Table 1) based on several clinical criteria (5). An occasional case of HAEC may present as a perforation of the bowel proximal to the aganglionic segment (6, 7).

The diagnosis of HAEC is typically based on the classic presentation of a neonate with a history of constipation starting in the newborn period, followed by abdominal distention and liquid, foul-smelling stool. Examination will show a markedly distended abdomen which is hyperesonant to percussion. Rectal examination often results in an explosive discharge of gas and stool. Post-pullthrough HAEC may present in a very similar fashion and is typically seen within the first two years following the child's pullthrough (8). Abdominal radiographs may be quite helpful. The proximal colon is distended with an almost toxic megacolon appearance (Lellie, 1997 Holschnier). An extremely useful finding is what we term a 'cut-off sign' in the recto-sigmoid region (Figure 1A) with an absence of air distally (4). This sign can be seen in all forms of HAEC and was noted in 74% of patients during an HAEC episode compared to only 14% of the time in-between episodes of HAEC. Other common findings were small bowel dilatation in 74% and multiple air-fluid levels in 79%. Occasionally, pneumatosis intestinalis may be seen (4, 9). Because of the risk of perforation, a contrast enema should not be done in the presence of clinical HAEC. However, it is not uncommon to see findings of subclinical HAEC during such radiologic studies (Figure 1B). Typically, an irregular mucosal lining, with a resultant 'sawtooth' appearance is seen.

The timing of HAEC and the clinical course of Hirschsprung's disease shows that the two times an infant is at highest risk for the development of HAEC is either before the diagnosis of Hirschsprung's disease has been made, or following the definitive pullthrough. Although occasionally described, HAEC is distinctly uncommon in those patients with a decompressing colostomy (10). The diagnosis of Hirschsprung's disease after the first week of life places the neonate at a substantially higher risk for the development of HAEC (11). In this report, the mean age at diagnosis of neonates with Hirschsprung's disease was 16.6 days in those who developed HAEC and 4.6 days in those neonates without HAEC. Post-pullthrough HAEC may be due to associated internal sphincter spasm which is commonly associated with Hirschsprung's disease and may act to functionally obstruct the passage of stool (12). Although the course of enterocolitis is usually most severe in those infants who have not yet had the diagnosis of enterocolitis made, a recent report describes the death of 5 infants due to HAEC anywhere from 3 weeks to 20 months after their pullthrough procedure (13).

Incidence and Associated Risk Factors

The incidence of HAEC varies widely among reported series. Table 3 lists the incidence of HAEC in several large series. The mean incidence was 25%, but the range was quite wide (from 17% to50%) and may represent differences in the manner in which HAEC is diagnosed. This is perhaps most evident by the large variation in mortality rates in two of the largest series of Hirschsprung's disease patients (14, 15). In a review of the Surgical Section of the American Academy of Pediatrics, Kleinhaus reported a low rate of HAEC, but a high mortality rate. Whereas in a review of Japanese cases of Hirschsprung's disease, Ikeda noted a high rate of HAEC, but a low mortality rate (14, 15). Additionally, a clear decline in the incidence has occurred over the past 40 years with improved and more prompt diagnosis of the disease as demonstrated by the 50% incidence of HAEC in Bill and Chapman's series, and the much lower incidence (Table 3) in more recent series (3).

Several factors have been associated with an increased incidence of enterocolitis. As stated above, one fairly well substantiated risk factor is a delay in the diagnosis of Hirschsprung's disease (10, 11). Others have claimed that once an infant develops HAEC, they are at increased risk to develop other enterocolitic episodes in the future (16). Although some have speculated that early development of HAEC may somehow alter the defense mechanisms of the intestine and predispose the patient to recurrent episodes of HAEC, many other investigators have not found such a predisposition (11, 17, 18).

Increased length of the aganglionic segment has also been associated with the development of HAEC (8, 14, 15, 19). Intuitively, if the disease process is complicated by the degree of obstruction, longer lengths of aganglionosis should be associated with a higher incidence of HAEC. However, others have failed to find such an association (10, 11, 17, 18).

Infants with Trisomy 21 appear to be at increased risk of developing HAEC (20). In one series on HAEC, almost 45% of infants with Trisomy 21 and Hirschsprung's disease developed HAEC (11). This association of Trisomy 21 and HAEC has been confirmed in subsequent series (10, 18, 21). More than likely, this association is due to an immune deficiency, both humoral and cellular, which probably predisposes these infants to HAEC (22-24).

Other associated anomalies may place the infant at risk for the development of enterocolitis. Caneiro found that 53% of infants with associated anomalies developed HAEC compared to 26% with Hirschsprung's disease alone (18). Elhalaby noted that 47% of infants with anomalies developed HAEC compared to 29% without (4). It is not clear if this association is due to the large number of patients with Down's Syndrome; and, unfortunately, neither author adequately analyzed this data by separating out patients with Trisomy 21.

Post-Pullthrough Enterocolitis

Rates of post pullthrough enterocolitis vary widely among series (table 4), ranging from 2% to 27%. In the two largest series, a significantly higher incidence of enterocolitis was noted in those patients undergoing the Swenson pull-through. This higher incidence was noted in Swenson's own review from 1975, and this may be due to the inclusion of several patients who underwent this pull-through in the earlier years of the Swenson procedure, prior to it being modified to a more distal anastomosis. Post-operative enterocolitis has been associated with a fairly high rate of mortality in several series. In fact, when examining those deaths due to Hirschsprung's disease, several series noted that approximately 50% of deaths resulted from complications directly related to an enterocolitic episode.

Pathology

The gross pathologic description of HAEC (Figure 2) is probably best given by Harald Hirschsprung's first report of the disease itself (25). The following is a quote from his description of the lesion:

'...in the second case separate larger and deeper ulcerations that penetrate to the serosa, and indications of peritonitis can be seen on the serosal surface. Near the larger ulceration, we find an abscess under the mucosa that measures 2 cm...Mottled spaces can be seen in the submucosa containing pus.'

Like many other inflammatory disease processes of the intestine, HAEC is manifested by the appearance of neutrophils within the crypts of the intestine. A careful analysis of the natural progression of this disease process shows several discrete phases which can be used to grade the pathologic severity of the enterocolitic process. A grading system is shown in table 2. The system goes from a grade 0 with no pathologic abnormality to grade I which shows a marked amount of mucus streaming from the crypts of the intestine (Figure 3A). This mucin retention is a histopathologic process unique to only two diseases, Hirschsprung's and cystic fibrosis. Though not absolute, the diagnosis of Hirschsprung's disease is suggested based on this finding alone from a suction rectal biopsy, even without sufficient submucosa. Subsequent grades of HAEC show a progressive increase in crypt abscesses (Figure 3B), followed by the destruction of the intestinal epithelium and eventual perforation of the bowel. The latter 3 grades may look quite similar to ulcerative colitis. Our own group, and others, have had occasional difficulty in differentiating between HAEC and ulcerative colitis (26, 27). Although there are reports of an ischemic enterocolitis as a complication of Hirschsprung's disease, this finding is unusual (28). In a report by Teich, et al, all four of the cases described involved extremely ill neonates who were in septic shock, and this low perfusion state may have been the actual cause of the ischemic findings. Others have reported the association of necrotizing enterocolitis and HAEC in the same patients based on the radiologic finding of pneumatosis intestinalis (18). This radiologic finding, however, can be non-specific and does not necessarily indicate the child has necrotizing enterocolitis.

Morbidity and Mortality

The morbidity and mortality associated with the development of HAEC is quite high. Hospitalizations for many of these infants can be complicated and lengthy. Caneiro noted that hospitalizations ranged from 6 to 29 days (mean 13 days) (18). The cost of caring for an infant with HAEC is over two and one-half times as high as that for an infant with Hirschsprung's disease and no enterocolitis (11). Certainly in this era of cost containment, the ability to avoid such a complication is particularly critical. In addition to morbidity, mortality may also occur. Although death is generally an uncommon complication of HAEC, many series include reports of infants dying of the disease, and in many they comprise the majority of all deaths due to Hirschsprung's disease (Table 4). Mortality rates range from 0% to 33%; again most likely reflecting differences in the way in which HAEC is diagnosed (Table 3). Mortality rates also appear to be due to associated factors such as Trisomy 21.

Potential Causes

An appreciation of the pathologic changes in HAEC allows for consideration of potential pathophysiologic processes which could cause this disease. Historically, Swenson and Fisher postulated that the disorder was due to a defect in water and electrolyte metabolism (2). Subsequently, Swenson revised this concept and stated that improper fluid absorption was actually the result of chronic constipation (26). Several more recent theories on the etiology of HAEC have since been proposed including: infectious, ischemic, obstructive, as well as hypersentivity reactive causes (29). Below potential contributing factors for the development of HAEC are discussed.

  • Obstruction
    Perhaps one of the earliest proposed etiologies of HAEC was primary obstruction. This concept was originally proposed by Glotzer, et al and was further supported by Bill and Chapman (3). In Glotzer's model, he created an artificial obstruction in a dog's colon (30). Although the pathologic description showed multiple punctate ulcerations and some focal inflammation, the pathologic description of HAEC mentioned above, including the profuse amount of mucus and the large number of crypt abscesses, was not seen. Thus, although obstruction may account for some part of the pathogenesis, the etiology of HAEC is probably more complicated.

  • Infectious
    Infectious etiologies, including bacterial and viral, of HAEC have been proposed by several investigators. Hardy, et al found an increased incidence of Clostridium difficile (C difficile) in their patients with HAEC (31). In their report, they noted that children with Hirschsprung's disease had persistent retention of C difficile beyond 12 months of age, despite the usual loss of this organism in gastrointestinal tracts of normal children. This suggested that patients with Hirschsprung's disease may be more susceptible to infectious agents such as C difficile, and that this may predispose them to a high incidence of infections. This higher incidence of C difficile was also noted in Caneiro's series, and interestingly, both reports were from London, England (18). In other reports on HAEC, C difficile was identified in very fewer infants with HAEC (29, 32), suggesting that the specific type of organism may be less important that the actual predisposition to infections with pathologic organisms. With a lack of normal motility, bacterial overgrowth may occur which could allow such pathogens to grow in larger than normal amounts. The entero-invasive property of an organism, allowing it to penetrate the epithelial barrier, may have greater importance than the specific strain of organism (see below). Wilson-Storey has suggested that HAEC may be associated with a rotavirus infection (33).

  • Mucus
    The profound amount of mucus seen in the early stages of HAEC has prompted investigators to examine alterations in the intestinal mucus of Hirschsprung's disease patients. Mucus is a comprised of both several glycoproteins as well as secretory immunoglobulin A (IgA), and serves to protect the intestine by directly binding and inactivating a number of different organism (34). Akary first noted the abnormal composition of mucins from patients with Hirschsprung's disease (35). In his work, no changes were noted in the secretion of mucus; however, an increase in the sulphated mucins was noted in Hirschsprung's disease patients, particularly those with enterocolitis. These changes were further confirmed by Teitelbaum, et al, who also noted a loss of acidic (sulphated) mucins and an increase in neutral mucins in colonic sections obtained from patients with HAEC (29). More recently, a study of the dynamic turnover of mucins produced by epithelium from patients with Hirschsprung's disease has been done (36). In this report, the investigators studied colonic mucosal cultures and demonstrated a significant decrease in mucin turnover in both aganglionic and ganglionic bowel of patients with Hirschsprung's disease compared to age-matched controls. This correlates well with the observed mucin retention seen in both aganglionic and ganglionic bowel, and suggests that an abnormal mucus defense barrier may contribute to HAEC.

  • Enterocyte Adherence
    Enterocyte adherence appears to be a major way in which organisms can gain access to the epithelial barriers (37). A study of HAEC demonstrated that 39% of patients with clinicial , pre-pullthrough HAEC had enterocyte adherence on histologic examination of tissue specimens. The organisms in this study were either Esherichia coli, Clostridia difficile or Cryptosporidium. This suggests that the adherent nature of the organism may be more important that the actual organism itself.

  • Alteration in Intestinal Immunocytes
    Once an organism adheres to the epithelium of the intestine, it still must get past the complex immunologic system of the intestinal wall. The immunologic defense mechanisms of the intestine comprise both a humoral branch via the production of secretory immunoglobulin A (S-IgA) and a cellular branch with a rich source of T-lymphocytes within the epithelium (intraepithelial lymphocytes), lamina propria, discrete lymphoid follicles (Peyer's Patches) and in mesenteric lymph nodes [Lundqvist, 1996 #838]. Investigation into the alterations noted in these lymphoid populations must be tempered with the fact that changes may be either a primary cause of HAEC or a consequence of its development. Several investigators have examined changes in S-IgA formation and secretion. An analysis of white blood cell (WBC) counts of infants with HAEC has demonstrated lower counts and decreased WBC function compared to other patients (38). This may reflect an overall defect in the immunologic system of patients with HAEC; however, more insight has been found from examination of the intestinal immune system.

    Wilson-Storey and Scobie noted in human patients that S-IgA levels were apparently normal in the intestinal lamina propria, however, it failed to be released into the intestinal lumen (39). Imamura, et al examined IgA, IgM and J chain containing plasma cells in patients with HAEC and noted an increased amount of these immunoglobulins (40). However, lower levels of luminal secretory components were found in the aganglionic colons of HAEC patients, again suggesting that there may be a defect in the release of these immunoglobulins. In another study of lamina propria IgA levels, however, lower levels were noted in Hirschsprung's disease patients and even lower levels were found in those patients with HAEC (41).

    Using a mouse model of Hirschsprung's disease, the piebald lethal strain which generally dies of enterocolitis within the first 90 days of life, has allowed further immunologic investigation of the pathogenesis of HAEC. Compared to heterozygote controls, an initial rise in S-IgA serum levels was seen early in the life of these mice, followed by a decline as HAEC developed (42). Similarly, Fujimoto noted that although immunocytes in the lamina propria that were positive for S-IgA were higher in piebald lethal mice, they were markedly lower during acute illness (43). This suggests that declines in S-IgA levels may be a result of HAEC not a cause.

    An assessment of T-lymphocyte and natural killer immune systems has also been performed (40, 41). In both of these studies, it was noted that increased levels of T-lymphocytes were found in the bowel wall of patients with HAEC compared to other patients with Hirschsprung's disease. Examination of natural killer cells showed a significant increase in these cells in the lamina propria of ganglionic bowel of patients with HAEC compared to patients with Hirschsprung's disease without HAEC patients and control patients (40). Finally, the aganglionic portion of Hirschsprung's disease has a decreased production of nitric oxide, which may also contribute to the production of HAEC. Nitric oxide has several non-specific actions for defense against bacterial, mycobacterial and viral agents (44). Although this has not been investigated, a decline in its production may result in a deficient immunologic barrier.

    Importantly, no study has been done which has examined the gastrointestinal tract in a serial fashion to document whether the observed changes in the intestine occur as a result of HAEC or are the primary cause of HAEC. Figure 5 summarizes the several potential etiologies for the development of HAEC discussed above.

  • Intestinal Neuronal Dysplasia
    The association of Hirschsprung's disease with Intestinal Neuronal Dysplasia (IND)has been described in the literature (45). In a recent report by this same group, several patients with significant stooling problems, including HAEC, after definitive pull-through were shown to have evidence of IND, despite the complete removal of the aganglionic segment (46). In an examination of 10 patients with persistent bowel problems, 5 of whom had enterocolitis, all showed some evidence of IND. It is, however, uncertain what percent of all patients with post-pullthrough HAEC patients may have such abnormalities. Although we have not personally seen IND in association with Hirschsprung's disease in our experience, investigation on the cause of post-pullthrough HAEC should include a rectal biopsy which should be examined for aganglionosis as well as for the presence of IND.

Treatment

In 1964, Swenson suggested that the treatment of HAEC should be rectal tube decompression (2). Rectal washouts should be the initial approach in the care of a child, regardless of age, who presents with HAEC. The technique consists of the use of a soft red rubber catheter (at least 16 Fr) with multiple side holes cut to facilitate drainage. The catheter should be gently advanced (often as saline is flowing) above the aganglionic level. After catheter advancement, gas and stool should be aspirated, followed by repetitive irrigations of 20 to 30 ml of saline, followed by removal of the tube. The procedure should be repeated every 4 to 6 hours until the child is decompressed. Importantly, enemas without a decompressing tube, should be avoided as they may worsen the enterocolitis. Not uncommonly, this treatment alone can often alleviate an even a fairly high grade enterocolitis.

Along with washouts, intravenous antibiotics or, in mild cases, oral metronidazole should also be used. Should the disease process fail to improve or the infant deteriorate, consideration should be given, in a neonate, to the performance of a leveling colostomy. This typically occurs in infants with long segment disease where rectal washouts cannot reach the dilated proximal bowel (47).

Recently, rectal irrigations have been used in a prophylactic fashion after the definitive pullthrough procedure (48). In this report, a significant reduction in the number of patients who developed enterocolitis was noted. It is possible that the washouts served to decompress the intestine for the first few months after the pullthrough procedure or may have served to either prevent colonic distention or washout enteropathogenic organism in the colonic lumen.

If repeated bouts of enterocolitis persist after the definitive pullthrough procedure, then an investigation into a mechanical cause should be undertaken. This should start with a contrast enema to insure that there is no obstruction in the neo-rectum, a potentially correctable cause (11). If this is normal, a suction rectal biopsy should be performed to rule out retention of an excess amount of aganglionic bowel as well as other possible etiologies such as IND (46, 49). Should these biopsies be normal, as is usually the case, consideration should be given to the performance of a posterior anal myotomy or myectomy. Published experience with this technique by several groups has demonstrated it to be safe and have a very low to absent incidence of fecal incontinence (50, 51). This more recent experience, however, is in contrast to a relatively poor experience with the procedure by Swenson who felt it did not benefit many of his patients (8). Polley, et al performed 3 internal sphincterotomies in 8 patients with persistent enterocolitis and Marty, et al performed 8 in 37 patients with post-pullthrough enterocolitis (52, 53). Overall, results of these internal sphincterotomies are quite good; however, both of these authors advocate a significant period of conservative therapy, since most patients with post-pullthrough enterocolitis will improve over time.

Conclusions

The development of enterocolitis in patients with Hirschsprung's disease remains a perplexing problem. Clearly recognition of this problem is essential to either its prevention or to early intervention in its treatment.


Table 1. Clinical grading system for Hirschsprung's-associated enterocolitis.
Grade Clinical symptoms
I Mild explosive diarrhea, mild or moderate abdominal distension, and no systemic manifestations
II Moderate explosive diarrhea, moderate to severe abdominal distention, mild systemic symptoms
III Severe explosive diarrhea, marked abdominal distention, shock or impending shock
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Table 2. Pathologic grading of Hirschsprung's-associated enterocolitis.
Grade Pathologic findings
0 Normal mucosa
I Crypt dilatation, mucin retention
II Cryptitis or < 2 crypt abscesses/HPF
III Multiple crypt abscesses/HPF
IV Fibrinopurulent debris and mucosal ulceration
V Transluminal necrosis or perforation
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Table 3. Incidence of Enterocolitis in several reported series of Hirschsprung's disease (3, 8, 10, 11, 14, 15, 17-19, 54).
Report Overall Trisomy 21 Incidence of Long segment Pre-pullthrough MX*
Kleinhaus 18% ns 25% 15% 30%
Ikeda ns ns 44.3% 29.2%(24.3 to 44.3) 1.8-2.4%
Teitelbaum 24% 46% 29% 16% 16%
Elhalaby 33.9% 37.5% 55% not stated 0%
Rescorla 18% 26% 32% 6% 9%
Caneiro 32% 50% not different 16% 4%
Bill 50% ns 66% 45% 33%
Foster 17% ns 5% 10% 0%
Surana 30% 47% 38% 13% 10%
*Mortality (Mx) due to enterocolitis is based on the total number of infants with enterocolitis.
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Table 4. Enterocolitis (HAEC) post-pullthrough from several large series of Hirschsprung's disease (11, 12, 14, 15, 52, 53, 55-59).
Report Type of Pullthrough Incidence of Enterocolitis HAEC needing Surgery Percent of deaths due to post pullthrough enterocolitis
Kleinhaus Mix1 RPT 2%
Duhamel 6%
Swenson 16%		 none 75%
Rehbein Rehbein 0% none
Holschneider Mix ERPT
Chapter 13.2%
Duhamel 4.7%
Swenson 3.7%
Rehbein 6.3%		 none
Teitelbaum Duhamel 6.3% 60% 0%
Ihezue ERPT2 7.4% none
Swenson Swenson 21% none 46%
Marty Mix 27% 22% 71%
Harrison Mix 12% none 10%
Polley ERPT 16% 38% 0%
Ikeda Mix ERPT 12%
Duhamel 14%
Swenson 34%		 none
Elhallaby ERPT 21.4% 16% 0%
1 - Many different types of pullthroughs
2 - Endorectal pullthrough

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Figure Legend

    Figure 1. Roengenographic evidence of enterocolitis.

  1. Example of a 'cut-off sign' (arrows) on a plain radiograph.
  2. Contrast enema in a child with enterocolitis. Note the irregular mucosal lining (arrows) consistent with edema and ulcerations of the mucosa.

    Figure 2. Gross appearance of the colonic mucosal lining of a patient with severe HAEC.

    Figure 3. Histologic appearance of HAEC

  1. Histologic grade I HAEC, note the mucin retention in the colonic crypts.
  2. Histologic grade III HAEC, note the multiple crypt abscesses.

    Figure 4. Schematic summary of the potential mechanisms involved in the development of HAEC.

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