Beruflich Dokumente
Kultur Dokumente
DOI 10.1007/s00383-013-3353-1
REVIEW ARTICLE
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Pediatr Surg Int
34, 43]. In a retrospective review by Haricharan and Seo clinical entity of HAEC likely represents a common result
[17], of 52 children who underwent pull-through surgery, of various dysfunctions of intestinal homeostasis.
HAEC admissions decreased by 30 % with each doubling An understanding of the histopathologic changes asso-
of age at diagnosis and increased ninefold when postop- ciated with HAEC may provide insight into its patho-
erative stricture was present. Whether this older age at physiology. Similar to other inflammatory processes of the
diagnosis means a different type of HD or lesser length of colon, HAEC is histologically characterized by cryptitis,
aganglionosis is uncertain; however, this finding is in the appearance of neutrophils in intestinal crypts [6]. This
contradistinction to others who have found that a delay in is associated with crypt dilation and retained mucus. Such
diagnosing HD beyond the first month of life actually mucin retention is unique to only two diseases, Hirsch-
predisposes children to a higher incidence of HAEC [43]. sprung and cystic fibrosis. This progresses to the devel-
This may be due to the fact that the incidence of HAEC has opment of crypt abscesses, mucosal ulceration, and
varied considerably between different surgical groups, fibrinopurulent debris. In severe cases, ischemia, transmu-
most likely secondary to lack of a standard definition of ral necrosis, and perforation may occur, leading to shock
HAEC. Pastor, et al. developed a scoring system for and systemic hypoperfusion. A histological grading system
diagnosis of HAEC through a consensus approach using is shown in Fig. 3, and represents a progression of patho-
the Delphi method by identifying clinical diagnostic cri- logic changes with increasing severity [11]. Interestingly,
teria for HAEC from a larger pool of potential items [32]. these pathologic findings have been found in aganglionic as
Eighteen items were included in the score with the fol- well as ganglionic segments, suggesting a mechanism
lowing criteria receiving the highest scores: diarrhea, beyond the simple absence of ganglia [31].
explosive stools, abdominal distension, and radiologic Another proposed mechanism of HAEC is partial
evidence of bowel obstruction or mucosal edema (Table 1). obstruction, which may lead to stasis, bacterial overgrowth
The frequencies of major presenting features of HAEC are and translocation [7]. The finding of an anastomotic stric-
listed in Fig. 1. Plain abdominal radiographs will likely ture or narrowing has been consistently observed by a
demonstrate colonic dilation (90 % sensitivity), but this is number of investigators as a risk factor for developing
nonspecific (24 % specificity). Gaseous intestinal disten- HAEC, and this may well relate to its pathogenesis [15].
sion with abrupt cutoff at the level of the pelvic brimthe The successful treatment of patients with recurrent HAEC
intestinal cutoff sign (Fig. 2)is both sensitive (74 %) with internal sphincterotomy [33], or a posterior myotomy,
and specific (86 %) for HAEC [10]. Chronic HAEC lends support to functional obstruction as an etiology in
symptoms typically include persistent diarrhea, soiling, some patients. As HAEC also occurs in infants without
intermittent abdominal distension and failure to thrive. In evidence of obstruction, including patients with diverting
patients that present repeatedly with these symptoms, stomas, other factors must play a role.
mechanical obstruction from aganglionosis should be ruled The increased risk of HAEC in patients with Trisomy 21
out in the neo-rectum or a residual proximal segment. The potentially suggests a genetic role in the etiology of HAEC
role of rectal biopsy in the diagnosis of HAEC is contro- [43]. No genetic abnormality has been shown to cause
versial and not recommended during the acute phase given HAEC, however, some genetic variations do correlate with
the high risk of perforation. However, as will be discussed more severe disease. For example, intestinal autonomic
below, a strong consideration for retained or recurrent dysfunction has been associated with mutation in the RET
aganglionosis must be pursued in a child with recurrent proto-oncogene [38], which is known to be associated with
HAEC. HD. In addition, variations in the ITGB2 immunomodu-
latory gene (CD18) have been found in 66 % of patients
with HD, with 59 % of these patients developing HAEC
Pathogenesis [30]. More than one variation in the ITGB2 gene was
associated with more severe HAEC. Continued work on the
Despite being the leading cause of morbidity and mortality role of genetic variation in HAEC may shed more light on
in HD, the pathophysiology of HAEC remains poorly its pathogenesis.
understood. Historically, Fisher and Swenson in 1956 [14] As the primary defect in HD is the congenital lack of
first postulated that this disorder was caused by a defect in intestinal ganglia, an abnormal enteric nervous system
water and electrolyte metabolism. Later theories included (ENS) remains a culprit in the pathogenesis of HAEC. The
partial mechanical obstruction leading to colitis [40]. ENS has a role in intestinal homeostasis, including motil-
Subsequent experience with the disorder has implicated a ity, epithelial barrier function (EBF), mucosal immunity,
variety of causes, including mucosal immunity defects, epithelial transport, and regulation of the gut microbiome.
disordered motility, abnormal mucin production, and Dysfunction of the ENS may lead to the initiation or
infection [3]. As no single etiology has been identified, the propagation of the inflammatory cycle of HAEC. Miyahara
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90
junctions and the ENS. Dysfunctional EBF may result in
83
adherence of pathologic organisms to enterocytes (i.e.
80
69 enteroadhesion), a phenomenon demonstrated with the
70
adherence of C. difficile, Cryptosporidium, and E. coli in
Frequency (%)
60
51 up to 39 % of patients with HAEC in some reports [6].
50
Abnormalities in the amount and composition of mucin,
40 34 a key component of the mucosal barrier, may contribute
27
30 to this dysfunction. HAEC intestinal specimens demon-
20 strate an increase in neutral mucins and a decrease in
10 5 acidic sulfomucins [2]. The production of MUC-2, the
0 predominant mucin expressed in humans, is markedly
Abdominal Explosive Vomiting Fever Lethargy Rectal
Distension Diarrhea Bleeding
depressed in patients with HD and undetectable in those
who develop HAEC [25]. In addition, reduced total
Major Presenting Clinical Feature
colonic mucin turnover correlates with an increased risk
Fig. 1 Frequency of the major presenting clinical features among of HAEC development [1]. These changes may be sec-
patients with HAEC (Adapted from [10]) ondary to abnormalities in the ENS described above, as
the goblet cells that secret mucus are regulated by sub-
and Kato [28] demonstrated markers of neuronal immatu- mucosal neuroendocrine cells, which are reduced in
rity in the proximal, normoganglionic bowel of Hirsch- patients with HAEC [37]. Other regulators of intestinal
sprung patients; and this suggests dysfunction of the ENS EBF, such as mast cells and enteric glial cells, are
beyond the aganglionic segment. Such an abnormal ENS abnormal in HD, but have yet to be fully investigated in
may create an abnormal intestinal equilibrium, where HAEC [3].
perturbations such as partial obstruction or bacterial over- As deficiencies in EBF lead to loss of mucosal integrity,
growth may lead to enterocolitis. the mucosa of patients with HAEC may exhibit diminished
A fundamental component of intestinal homeostasis is recovery. Reduced expression of caudal type homeobox
EBF, a composite function of factors including mucin (CDX) gene-1 and -2 has been found in the mucosa of
production, intraluminal immunoglobulins, epithelial tight patients with HAEC [22]. As these genes are involved in
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Fig. 3 Histopathologic findings of HAEC. a Grade 0, normal III, multiple crypt abscesses per HPF. e Grade IV, intraluminal
mucosa. b Grade I, crypt dilation and retained mucin. c Grade II, fibrinopurulent debris or mucosal ulcerations. Grade V (not shown),
cryptitis or B2 crypt abscesses per high-power field (HPF). d Grade transmural necrosis or perforation [11]
mucosal proliferation and differentiation, this suggests a buccal mucosa. For those with HAEC, however, secretory
deficiency in mucosal healing, which may contribute to IgA was absent from the buccal mucosa altogether. Simi-
prolonged mucosal damage and subsequent enterocolitis. larly, colonic resection specimens studied by Imamura and
Another component of intestinal epithelial defense that Puri [19] showed elevated IgA, IgM and IgG chain plasma
has been implicated in HAEC is the mucosal immune cells in the lamina propria of bowel from patients with
system. Secretory IgA, the predominant immunoglobulin in HAEC, with decreased luminal IgA in the aganglionic
the intestinal tract, plays a role in preventing bacterial segment of these same patients. Similar findings have been
translocation in healthy intestine. Wilson-Storey and Sco- seen in a mouse model of HAEC using Piebald Lethal
bie [51] demonstrated that, in patients with HD, secretory mice, whereby an initial elevation of immunoglobulins was
IgA was undetectable in saliva, while it was increased in measured earlier in the life followed by a precipitous fall
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near the death of these animals [42]. Other immune finding of altered microbial equilibrium is supported by a
changes noted in patients with HAEC included increased recent study evaluating the stool microflora of a child with
distribution of CD57? natural killer cells, CD68? mono- HD during HAEC episodes and during remission, finding a
cytes/macrophages, and CD45RO? leukocytes in the clustering of microbial diversity with HAEC episodes [8].
bowel of patients with HAEC [19]. To determine whether These studies suggest that disequilibrium in the gut mi-
these changes are primary defects predisposing to HAEC, crobiome may result in dominance of a predisposing bac-
or whether they are secondary to enterocolitis, Turnock terial community for HAEC development, though further
et al. [48] evaluated suction rectal biopsies of infants with investigation must be done to establish the specific
HD and found similar levels of mucosal immunoglobulins organisms involved.
regardless of the presence of HAEC. This suggests that in While the elements contributing to HAEC are increas-
patients with HAEC, mucosal IgA production is intact but ingly well described, much work remains in elucidating its
intraluminal transfer is deficient, limiting the role of IgA in pathophysiology. There is increasing evidence that several
mucosal defense [31]. These findings implicate an intrinsic factors, including a dysfunctional ENS, abnormal mucin
immune deficiency in the development of HAEC, which production, insufficient immunoglobulin secretion, and
may explain the increased risk in patients with Trisomy 21, unbalanced intestinal microflora contribute to the devel-
who are known to have abnormal cytotoxic T cell and opment of the common clinical entity of HAEC. A sum-
humoral function. mary of the potential pathophysiologic mechanisms
The factors described above may create a dysfunctional contributing to HAEC is shown in Fig. 4.
environment in which the gut microbiome is susceptible to
a pathologic change in composition leading to HAEC. A
microbial etiology of HAEC has been investigated since Treatment
the first reports of high C. difficile toxin titers in patients
with HAEC as compared to those with HD only and normal The treatment of children presenting with suspected HAEC
controls [47]. These findings were not substantiated in later is resuscitation, decompression of the gastrointestinal tract,
studies, which found variable C. difficile carriage rates [16, and antibiotics. The severity of the episode dictates anti-
52]. While not currently thought to be causative, C. difficile biotic choice; mild episodes of HAEC can be treated with
may flourish in the setting of HAEC, with an associated oral metronidazole alone, while more severe episodes
mortality rate of 50 % if pseudomembranous colitis should be treated with intravenous, broad-spectrum therapy
develops [4]. Changes in the composition of the gut mi- including ampicillin, gentamicin, and metronidazole.
crobiome were evaluated by Shen and Shi [36], who found Unfortunately, there are few studies comparing antimi-
decreased colonization of bifidobacteria and lactobacilli, crobials for the treatment of HAEC. Classically, the colon
probiotic organisms, in patients with HD versus controls, is under considerable pressure, potentially a strong causa-
and even lower colonization in those with HAEC. This tive factor for the HAEC episode. Decompression of the
Fig. 4 Schematic
representation of the potential
pathophysiologic mechanisms Unbalanced
contributing to HAEC microflora
Abnormal mucin
production
Dysfunctional enteric
nervous system
Insufficient
immunoglobulin
secretion
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Pediatr Surg Int
colon is essential and can generally be done with rectal with decrease in number of bowel movements and
washouts. Rectal washouts with saline (1020 mL/kg) abdominal distention. Unfortunately, there have been no
using a large bore soft tube should be initiated immediately follow-up studies to verify these results.
and repeated anywhere from two to four times per day until Surgical or interventional approaches for treatment of
proper decompression as determined by clinical examina- HAEC include botulinum toxin injections, sphincterotomy,
tion. In the case of fulminant disease, washouts should be and posterior myotomy/myectomy (POMM) (Fig. 5). With
avoided due to risk of perforation, but gentle passage of a the observation that post pull-through patients often have
rectal tube to decompress the bowel is critical. Bowel rest tight rectal sphincters, Swenson and coworkers initially
is indicated with parenteral nutrition in cases of prolonged proposed that sphincterotomy prevents enterocolitis.
disease [21, 49]. Inability to adequately decompress the However, a follow-up evaluation did not show significant
bowel or cases of sepsis with HAEC may be an indication improvement with such procedures [41].
for diversion with a leveling colostomy just proximal to the In children with recurrent HAEC, over 12 years fol-
transition zone. Use of intraoperative frozen section his- lowing their pull-through, use of a POMM should be
tology is essential in cases where a child initially present- considered [7]. Use of this approach has been tempered by
ing with HD has HAEC, to level the colon at a site with some series showing poor functional outcomes. A study
ganglion cells. using the transanal POMM approach showed adulthood
Current surgical treatments for HD, including one stage incontinence in four out of fourteen patients who under-
endorectal pull-through (ERPT), have become standard of went POMM procedures as children [18]. Small reports
care. Although pull-through operations relieve the from various groups have shown mixed results [23, 24, 33].
obstructive symptoms of HD, there is a persistent risk of It is possible that the etiology of incontinence in these
the development of enterocolitis, occurring in up to 42 % patients is the transection of part or all of the internal anal
of patients [15, 45, 49]. As compared to patients under- sphincter. If the performance of a POMM is started above
going a two-stage approach, recent data shows a trend the level of the dentate line, damage to the internal anal
toward a higher incidence of enterocolitis in the primary sphincter can be avoided. Wildhaber et al. [50] reported
ERPT group as compared with those with a two-stage excellent continence rates with this approach for recurrent
approach (42.0 vs. 22.0 %). Although this is thought to be HAEC. An additional advantage to the use of a POMM is
primarily due a lower threshold in diagnosing HAEC in that a redo pull-through operation can still be performed in
more recent years, it is possible that a tighter anastomosis case myectomy is not successful.
in these younger infants undergoing a primary pull-through
may be a contributing factor. Risk factors for post pull-
through enterocolitis include anastomotic leak or stricture
and postoperative intestinal obstruction due to adhesions;
such factors increase the relative risk of subsequent
enterocolitis by approximately three-fold [15, 45]. Ruling
out a mechanical cause of partial bowel obstruction should
be undertaken in infants that present with repeated episodes
of enterocolitis following a pull-through procedure. If a
contrast enema is normal, full thickness rectal biopsy is
warranted to rule out aganglionosis in the pull-through
segment [21, 29]. While a rare cause of HAEC, in cases of
retained or secondary aganglionosis, patients will need a
redo pull-through [20]. In cases of anastomotic strictures, a
trial of dilation is recommended with the possibility of a
redo pull-through being reserved if dilations are
unsuccessful.
Medical approaches for treatment of HAEC include
antibiotics and sodium cromoglycate. Although there is no
data to support prophylactic antibiotic therapy post pull-
through, the authors have recommended its use with the Fig. 5 Operative approach to a posterior myectomy (POMM). Note a
first signs and symptoms of HAEC. Sodium cromoglycate, flap of mucosa and submucosa are raised posteriorly about 0.5 to
1 cm above the dentate line. The muscularis is incised and a one-half
a mast cell stabilizer, is not absorbed in the gastrointestinal
centimeter wide segment is carried as far cephalad as possible. It is
tract. A non-randomized study by Rintala and Lindahl [35] critical to keep the segments oriented for pathologic review (repro-
showed a favorable response in three out of five patients duced with permission from [44])
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Pediatr Surg Int
The use of botulinum injections for treatment of recur- HAEC. Unfortunately, use of a high dose of orally deliv-
rent HAEC post pull-through has shown promise in recent ered probiotics failed to offer any prophylactic benefit to
studies [27] with improvement in symptoms and number of this group of patients. Multivariate analysis, adjusting for
hospitalizations; however, long-term results have been length of aganglionosis and age of child, also failed to
mixed with difficulty predicting response in patients. demonstrate any benefit of probiotics to a subgroup of HD
Finally, in rare cases of recalcitrant HAEC not responsive children. This certainly emphasizes the multi-faceted
to medical and surgical intervention, end ileostomy or aspect of the etiology and the complexity of this disorder.
colostomy is a last resort [13].
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Pediatr Surg Int
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