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Introduction
Background
In 1886, Harold Hirschsprung first described Hirschsprung disease as a cause of
constipation in early infancy. Early recognition and surgical correction of Hirschsprung
disease protects affected infants from enterocolitis and debilitating constipation.

Pathophysiology
Hirschsprung disease results from the absence of enteric neurons within the myenteric
and submucosal plexus of the rectum and/or colon. Enteric neurons are derived from the
neural crest and migrate caudally with the vagal nerve fibers along the intestine. These
ganglion cells arrive in the proximal colon by 8 weeks' gestation and in the rectum by 12
weeks' gestation. Arrest in migration leads to an aganglionic segment. This results in
clinical Hirschsprung disease.

Frequency
United States
Hirschsprung disease occurs in approximately 1 per 5000 live births.
International
Prevalence may vary by region and has been shown to be as high as 1 per 3000 live births
in the Federated States of Micronesia.1

Mortality/Morbidity
The overall mortality of Hirschsprung enterocolitis is 25-30%, which accounts for almost
all of the mortality from Hirschsprung disease.

Sex
Hirschsprung disease is approximately 4 times more common in males than females.

Age
Nearly all children with Hirschsprung disease are diagnosed during the first 2 years of
life. Approximately one half of children affected with this disease are diagnosed before

they are aged 1 year. A small number of children with Hirschsprung disease are not
recognized until much later in childhood or adulthood.

Clinical
History

During the newborn period, infants affected with Hirschsprung disease may
present with abdominal distention, failure of passage of meconium within the first
48 hours of life, and repeated vomiting. A family history of a similar condition is
present in about 30% of cases.
Nearly one half of all infants with Hirschsprung disease have a history of delayed
first passage of meconium (beyond age 36 h), and nearly one half of infants with
delayed first passage of meconium have Hirschsprung disease.
Unlike children experiencing functional constipation, children with Hirschsprung
disease rarely experience soiling and overflow incontinence.
Children with Hirschsprung disease may be malnourished. Poor nutrition results
from the early satiety, abdominal discomfort, and distention associated with
chronic constipation.
Older infants and children typically present with chronic constipation. This
constipation often is refractory to usual treatment protocols and may require daily
enema therapy.
Hirschsprung enterocolitis can be a fatal complication of Hirschsprung disease.
Enterocolitis typically presents with abdominal pain, fever, foul-smelling and/or
bloody diarrhea, as well as vomiting. If not recognized early, enterocolitis may
progress to sepsis, transmural intestinal necrosis, and perforation.

Physical

Examination of infants affected with Hirschsprung disease reveals tympanitic

abdominal distention and symptoms of intestinal obstruction. Individuals in this
age group may also present with acute enterocolitis or with neonatal meconium
plug syndrome.
Children with Hirschsprung disease are usually diagnosed by age 2 years.
o Older infants and children with Hirschsprung disease usually present with
chronic constipation. Upon abdominal examination, these children may
demonstrate marked abdominal distention with palpable dilated loops of
colon. Rectal examination commonly reveals an empty rectal vault and
may result in the forceful expulsion of fecal material upon completion of
examination.
o Less commonly, older children with Hirschsprung disease may be
chronically malnourished and/or present with Hirschsprung enterocolitis.

Causes

Genetic causes
o The disease is generally sporadic, although incidence of familial disease
has been increasing.
o Multiple loci appear to be involved, including chromosomes 13q22,
21q22, and 10q.
o Mutations in the Ret proto-oncogene have been associated with multiple
endocrine neoplasia (MEN) 2A or MEN 2B and familial Hirschsprung
disease.2,3
o Other genes associated with Hirschsprung disease include the glial cellderived neurotrophic factor gene, the endothelin-B receptor gene, and the
endothelin-3 gene.
Associated conditions
o Hirschsprung disease is strongly associated with Down syndrome; 5-15%
of patients with Hirschsprung disease also have trisomy 21.
o Other associations include Waardenburg syndrome, congenital deafness,
malrotation, gastric diverticulum, and intestinal atresia.

Differential Diagnoses
Constipation

Other Problems to Be Considered

Intestinal neuronal dysplasia
Meconium plug syndrome
Neonatal small left colon syndrome
Hypoganglionosis

Workup
Laboratory Studies

CBC count: Order this test if enterocolitis is suspected. Elevation of WBC count
or a bandemia should raise concern for enterocolitis.

Imaging Studies

Plain abdominal radiography: Perform this test with any signs or symptoms of
abdominal obstruction.
Unprepared single-contrast barium enema: If perforation and enterocolitis are not
suspected, an unprepared single-contrast barium enema may help establish the
diagnosis by identifying a transition zone between a narrowed aganglionic
segment and a dilated and normally innervated segment. The study may also
reveal a nondistensible rectum, which is a classic sign of Hirschsprung disease. A
transition zone may not be apparent in neonates, because of insufficient time to

develop colonic dilation, or in infants who have undergone rectal washouts,

examinations, or enemas.

Other Tests

Rectal manometry: In older children who present with chronic constipation and an
atypical history for either Hirschsprung disease or functional constipation,
anorectal manometry can be helpful in making or excluding the diagnosis.4
Children with Hirschsprung disease fail to demonstrate reflex relaxation of the
internal anal sphincter in response to inflation of a rectal balloon.

Procedures

The definitive diagnosis of Hirschsprung disease rests on histological review of

rectal tissue.
o Obtain tissue either by suction rectal biopsy or transanal wedge resection.
If a suction biopsy is performed, take the biopsy 2-2.5 cm above the
dentate line on the posterior wall to minimize the risk of perforation.
o Carefully examine biopsy specimens for the presence or absence of
ganglion cells in the submucous plexus (suction rectal biopsy) or
myenteric plexuses (transanal wedge resection).
In the hands of an experienced pathologist, the resulting biopsy and absence of
ganglion cells confirm the diagnosis and allow the initiation of treatment. Skip
lesions of aganglionosis have been reported in cases of Hirschsprung disease.
Acetylcholinesterase staining of the tissue can be performed to assist with the
pathologic assessment. Acetylcholinesterase staining identifies the hypertrophy of
extrinsic nerves trunks. In short-segment Hirschsprung disease, the diagnosis can
be made with a properly placed rectal suction biopsy alone or in combination with
anorectal manometry.

Histologic Findings

Histologic findings include the absence of ganglion cells in the myenteric plexus
and hypertrophic extrinsic nerve fibers.

Treatment
Medical Care

If a child with Hirschsprung disease has symptoms and signs of a high-grade

intestinal obstruction, initial therapy should include intravenous hydration,
withholding of enteral intake, and intestinal and gastric decompression.
Decompression can be accomplished through placement of a nasogastric tube and
either digital rectal examination or normal saline rectal irrigations 3-4 times daily.
Administer broad-spectrum antibiotics to patients with enterocolitis.

Immediately request surgical consultation for biopsy confirmation and treatment

plan.
While awaiting surgical intervention in the event of a planned single-stage pullthrough procedure, the baby should receive scheduled vaccinations.

Surgical Care

The surgical options vary according to the patient's age, mental status, ability to
perform activities of daily living, length of the aganglionic segment, degree of
colonic dilation, and presence of enterocolitis.
Surgical options include colostomy at the level of normal bowel, rectal irrigations
followed by rectal resection with a pull-through procedure once bowel caliber is
restored to normal, and a staged procedure with placement of a diverting
colostomy followed by a pull-through procedure. The single-stage pull-through
procedure may be performed with laparoscopic, open, or transanal techniques.
This procedure is generally performed after the newborn has had rectal irrigations
at home and has passed the physiologic nadir.
The ability to perform a single-stage pull-through procedure largely depends on
the availability, experience, and capabilities of the staff pathologist because
aganglionic intestine must not be in the pull-through segment.
Recurrent postoperative enterocolitis may require treatment. Current therapeutic
options include rectal dilations, application of topical nitric oxide, posterior
myotomy/myectomy,5 or injection of botulinum toxin.6

Diet

A special diet is not required. However, preoperatively and in the early

postoperative period, infants on a nonconstipated regimen, such as breast milk,
are more easily managed.

Activity

Postoperatively, patients may return to their normal physical activities.

Medication
Drug therapy currently is not a component of the standard of care for this disease itself;
however, some medications may be used to treat complications of Hirschsprung disease.
See Treatment. Medications may include antibiotics for the treatment of enterocolitis or
the use of botulinum toxin injection at the anal sphincter for the treatment of recurrent
enterocolitis due to anal hypertonicity.

Medicinet.co.uk

Hirschsprung Disease
What is Hirschsprung's disease?
Hirschsprung's (HURSH-sprungz) disease, or HD, is a disease of the large intestine.
The large intestine is also sometimes called the colon. The word bowel can refer to the
large and small intestines. Hirschsprung's disease usually occurs in children. It causes
constipation, which means that bowel movements are difficult. Some children with
Hirschsprung's disease can't have bowel movements at all. The stool creates a blockage in
the intestine.
If Hirschsprung's disease is not treated, stool can fill up the large intestine. This can cause
serious problems like infection, bursting of the colon, and even death.
Most parents feel frightened when they learn that their child has a serious disease. This
information will help you understand Hirschsprung's disease and how you and the doctor
can help your child.

Why does Hirschsprung's disease cause constipation?

Normally, muscles in the intestine push stool to the anus, where stool leaves the body.
Special nerve cells in the intestine, called ganglion cells, make the muscles push. A
person with Hirschsprung's disease does not have these nerve cells in the last part of the
large intestine.
Healthy large intestine: Nerve cells are found throughout the intestine.

Hirschsprung's disease large intestine: Nerve cells are missing from the last part of
the intestine.

In a person with Hirschsprung's disease, the healthy muscles of the intestine push the
stool until it reaches the part without the nerve cells. At this point, the stool stops moving.
New stool then begins to stack up behind it.
Sometimes the ganglion cells are missing from the whole large intestine and even parts of
the small intestine before it. When the diseased section reaches to or includes the small
intestine, it is called long-segment disease. When the diseased section includes only part
of the large intestine, it is called short-segment disease.

What is the treatment for Hirschsprung's disease??

Pull-through Surgery
Hirschsprung's disease is treated with surgery. The surgery is called a pull-through
operation. There are three common ways to do a pull-through, and they are called the
Swenson, the Soave, and the Duhamel procedures. Each is done a little differently, but all
involve taking out the part of the intestine that doesn't work and connecting the healthy
part that's left to the anus. After pull-through surgery, the child has a working intestine.
Before surgery: The diseased section is the part of the intestine that doesn't work.

Step 1: The doctor removes the diseased section.

Step 2: The healthy section is attached to the rectum or anus.

Colostomy and Ileostomy

Often, the pull-through can be done right after the diagnosis. However, children who
have been very sick may first need surgery called an ostomy. This surgery helps the child

get healthy before having the pull-through. Some doctors do an ostomy in every child
before doing the pull-through.
In an ostomy, the doctor takes out the diseased part of the intestine. Then the doctor cuts a
small hole in the baby's abdomen. The hole is called a stoma. The doctor connects the top
part of the intestine to the stoma. Stool leaves the body through the stoma while the
bottom part of the intestine heals. Stool goes into a bag attached to the skin around the
stoma. You will need to empty this bag several times a day.
Step 1: The doctor takes out most of the diseased part of the intestine.

Step 2: The doctor attaches the healthy part of the intestine to the stoma (a hole in
the abdomen).

If the doctor removes the entire large intestine and connects the small intestine to the
stoma, the surgery is called an ileostomy. If the doctor leaves part of the large intestine
and connects that to the stoma, the surgery is called a colostomy.
Later, the doctor will do the pull-through. The doctor disconnects the intestine from the
stoma and attaches it just above the anus. The stoma isn't needed any more, so the doctor
either sews it up during surgery or waits about 6 weeks to make sure that the pull-through
worked.

What will my child's life be like after surgery?

Ostomy
Most babies are more comfortable after having an ostomy because they can pass gas
more easily and aren't constipated anymore.
Older children will be more comfortable, too, but they may have some trouble getting
used to an ostomy. They will need to learn how to take care of the stoma and how to
change the bag that collects stool. They may be worried about being different from their
friends. Most children can lead a normal life after surgery.
Nurses at the hospital can teach you and your child how to care for a stoma and can talk
to you about your worries.
Adjusting After Pull-through
After a pull-through, 9 out of 10 children pass stool normally. Some children may have
diarrhea for a while, and babies may develop a nasty diaper rash. Eventually the stool
will become more solid and the child will need to go to the bathroom less often. Toilet
training may be delayed, as the child learns how to use the bottom muscles only after
pull-through surgery. Older children might stain their underwear for a while after the
surgery. It is not their fault. They can't control this problem, but it improves with time.
Some children become constipated because 1 in 10 children with Hirschsprung's disease
has difficulty moving stool through the part of the colon without nerve cells. A mild
laxative may also be helpful. Ask your doctor for suggestions.
Diet and Nutrition
Drinking plenty of liquids is important after surgery for Hirschsprung's disease.
One job of the large intestine is to collect the water and salts the body needs. Since your
child's intestine is shorter now, it absorbs less. Your child will need to drink more to make
sure his body gets enough fluids.
An infant who has long-segment disease requiring an ileostomy may need special tube
feedings. The shortened intestine does not allow the bloodstream enough time to absorb
nutrients from food before it is pushed out of the body as stool. Tube feedings that deliver
nutrients can make up for what is lost.
Eating high-fiber foods like cereal and bran muffins can help reduce constipation and
diarrhea.
Infection

Infections can be very dangerous for a child with Hirschsprung's disease. Infection of the
large and small intestines is called enterocolitis. It can happen before or after surgery to
treat Hirschsprung's disease. Here are some of the signs to look for:

fever

swollen abdomen
vomiting
diarrhea
bleeding from the rectum
sluggishness

Call your doctor immediately if your child shows any of these signs. If the problem is
enterocolitis, your child may be admitted to the hospital. In the hospital, an intravenous
(I.V.) line may be needed to keep body fluids up and to deliver antibiotics to fight the
infection. The large intestine will be rinsed regularly with a mild salt water solution until
all remaining stool has been removed. The rinse may also contain antibiotics to kill
bacteria.
When the child has recovered from the infection, the doctor may advise surgery. If the
child has not had the pull-through surgery yet, the doctor may prepare for it by doing a
colostomy or ileostomy before the child leaves the hospital. If the child has already had a
pull-through operation, the doctor may correct the obstruction with surgery.
Enterocolitis can be life threatening, so watch for the signs and call your doctor
immediately if they occur.
Long-segment Hirschsprung's disease
Sometimes Hirschsprung's disease affects most or all of the large intestine, plus some of
the small intestine. Children with long-segment Hirschsprung's disease can be treated
with pull-through surgery, but there is a risk of complications such as infection, diarrhea,
and diaper rash afterward. Parents need to pay close attention to their child's health. Also,
since some, most, or all of the intestine is removed, drinking a lot of fluid is important.

http://surgery.med.umich.edu/pediatric/clinical/physician_content/a-m/hirschsprung.shtml

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 Tlymphocytes 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 postpullthrough 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

Mild explosive diarrhea, mild or moderate abdominal distension, and

no systemic manifestations

II

Moderate explosive diarrhea, moderate to severe abdominal

distention, mild systemic symptoms

Severe explosive diarrhea, marked abdominal distention, shock or

impending shock
Go Back to Text
III

Table 2. Pathologic grading of Hirschsprung's-associated enterocolitis.

Grade
Pathologic findings
0

Normal mucosa

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

Go Back to Text
Table 3. Incidence of Enterocolitis in several reported series of Hirschsprung's
disease (3, 8, 10, 11, 14, 15, 17-19, 54).
Trisomy Incidence of Long
PreReport Overall
MX*
21
segment
pullthrough
Kleinhaus

18%

ns

25%

15%

30%

ns

ns

44.3%

29.2%(24.3 to
44.3)

1.82.4%

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%

Ikeda
Teitelbaum

Surana
30%
47%
38%
13%
10%
*Mortality (Mx) due to enterocolitis is based on the total number of infants with
enterocolitis.
Go Back to Text
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
Incidence of
HAEC Percent of deaths

Pullthrough

Kleinhaus

Mix1

Rehbein

Rehbein

Enterocolitis
RPT 2%
Duhamel 6%
Swenson 16%

needing
Surgery

due to post
pullthrough
enterocolitis

none

75%

0%

none

Holschneider Mix

ERPT

Chapter

13.2%
Duhamel 4.7%
Swenson 3.7%
Rehbein 6.3%

none

Teitelbaum

Duhamel

6.3%

60%

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%

Elhallaby
ERPT
21.4%
1 - Many different types of pullthroughs
2 - Endorectal pullthrough

0%

none
16%

0%

Hirschsprung's Disease
Although Hirschsprung's disease has been recognized for over 100 years, it is only within
the past 3 decades that improved surgical management has been achieved and only within
the past few years that an appreciation for the origin of this disease has developed. Over
the past few years, significant insight into the etiology of Hirschsprung's disease has
taken place. Recent refinements in the surgical techniques for Hirschsprung's disease
have occurred. Included in these advances is the performance of the endorectal pullthrough in the newborn period. Others advances in our understanding of Hirschsprung's
disease have occurred through detailed studies of patients with Hirschsprung's disease
including those with Trisomy 21 syndrome, persistent stooling abnormalities after the
pull-through and associated neuronal intestinal dysplasia (NID).

Genetic Deletion in Hirschsprung's Disease

Perhaps one of the most exciting developments in Hirschsprung's disease is the recent
attempt at identifying its etiology. Several advances have recently been made in
determining the genes associated with Hirschsprung's disease. It has long been
appreciated that Hirschsprung's disease may affect more than one family member in 4 to
8% of cases [1] . Martucciello, et al found a deletion in the long arm of chromosome 10
that was associated with Hirschsprung's disease [2]. This child had long segment (total
colonic Hirschsprung's disease) and no family history. Last year, further investigation by
this group and others narrowed the location of this mutation between 10q11.2 and q21.2 (
Figure 1) [3, 4] . In the work by Luo, et al the location of the Hirschsrpung's genetic
abnormality overlaped the region of the RET proto-oncogene. The RET proto-oncogene
appears to play a major role in the development of the intestinal nervous system and its
deletion is also found in patients with the multiple endocrine neoplasia type 2A (MEN
2A) [5] . This may explain why a few patients with Hirschsprung's disease also have
MEN 2A [6].

Etiology of Hirschsprung's disease

Several investigators have suggested that the development of Hirschsprung's disease is
due to a lack of migrating nerve cells to develop. One study has recently examined neural
cell adhesion molecules (NCAM) in Hirschsprung's disease. Bowel containing ganglion
cells (both in control patients and in those with Hirschsprung's disease) had a large
amount of NCAM, whereas there was an absence of NCAM in the aganglionic segments
[9]. NCAM is believed to be important in nerve cell migration to specific locations
during embryogenesis [10] . One might speculate that a loss of NCAM may explain the
developmental absence of ganglion cells in Hirschsprung's disease (Figure 2). Another
intense area of investigation is the relation of Hirschsprung's disease to nitric oxide

production. It has been well recognized for several years that the loss of ganglion cells in
Hirschsprung's disease results in a loss of nerves [11].

Surgical Therapy

With increasing awareness of Hirschsprung's disease by the pediatric community and

easier accessibility to obtain a diagnosis with suction rectal biopsy, the diagnosis of
Hirschsprung's disease is being made at a much earlier age [21] . As a result, one of the
most significant changes in the management of Hirschsprung's disease is the performance
of the pull-through procedure in the newborn period. This approach is in contrast to the
previous approach of a colostomy during the newborn period with a subsequent pullthrough at 9-12 months of life once the child had attained a weight of approximately 20
pounds [15] . Initial success with an initial endorectal pull-through was first noted by So,
et al in 1980 [17]. Cilley, et al reported on 15 neonates who underwent a one-stage
endorectal pull-through [18*]. Ages at the time of surgery ranged from 2 to 52 days
(mean 13 days) and no operative complications occurred. The technique is virtually
identical to that performed in older children (Figure 3). All operations were performed
within 24 hours of diagnosis and as early as 48 hours of age.
The Duhamel procedure is another approach now used in the neonatal period [19] . In this
report, a primary Duhamel pull-through was performed in 22 infants whose ages ranged
from 14 to 90 days (mean 44 days). Postoperative complications occurred in 18%,
including 3 cases of enterocolitis and one case of a retained rectal spur. Kckaydin, et al
reported on their experience with the Swenson procedure in 10 neonates [20]. A primary
pull-through was performed in 6 of these 10 infants with no postoperative complications.
Unlike the previous two series, however, these operations included performance of a
colostomy.

Limited surgery for Hirschsprung's disease

Anal myectomy has been performed as definitive surgery for low-segment Hirschsprung's
disease. A fair number of these patients, however, had persistent constipation requiring
enemas and laxatives on a regular basis. Although the authors were satisfied with these

results, most surgeons are reluctant to perform an anal myectomy because of the risk of
leaving a significant amount of abnormal aganglionic bowel.

Stooling abnormalities following surgery

Another difficult area in Hirschsprung's disease is the care of the patient with persistent
stooling abnormalities after a pull-through. Occasionally, the surgeon is faced with a
child with persistent constipation or recurrent enterocolitis after their pull-through
procedure. Because the frequency of these problems is fairly low, little has been written
about the management of these children. Rectal biopsy shall be performed in the
evaluation of the patient with persistent stooling problems after a pull-through. A
diagnostic work-up for such patient is shown above.

Trisomy 21
Another group of patients with Hirschsprung's disease that is particularly challenging to
manage are those with Trisomy 21 (Down's Syndrome). The association of Trisomy 21
and Hirschsprung's disease has only recently been appreciated [27] . In a study by Quinn,
et al, 13% of their patients with Hirschsprung's disease had Trisomy 21 [28] .
Interestingly, the outcome of these patients was quite poor. Although a definitive pullthrough was performed on 13 of these 17 patients, only one of 13 surviving patients had
normal bowel function. Two of the patients had to revert back to a colostomy. These
authors suggest that a definitive pull-through in a child with Trisomy 21 requires careful
consideration. These authors' results are somewhat in conflict with another previously
published series on patients with Trisomy 21 and Hirschsprung's disease [27] . In this
latter series, 6 of 13 patients with Trisomy 21 were deemed to be candidates for a

definitive pull-through. Each of these children had a good result with daytime continence
although nighttime incontinence did occur.

Enterocolitis of Hirschsprung's disease

Another difficult group of patients are those with Hirschsprung's associated enterocolitis
(HEC). This entity can be difficult to differentiate from gastroenteritis or a child with an
excessively spastic internal anal sphincter. An intestinal 'cut-off' sign (loss of rectal air
approximately at the top of the pelvis on X-ray).

Neuronal Intestinal Dysplasia

Neuronal intestinal dysplasia (NID) is an unusual disorder of the gastrointestinal tract that
may be related to Hirschsprung's disease. Three basic forms of the disease are noted.
These are: hyperganglionosis (giant ganglia) in Auerbach's (myenteric muscle) plexus;
abnormal ganglia; or a combination of the two. All three of these forms may be seen with
Hirschsprung's disease; and each of these may be localized or involve all or most of the
intestinal tract. Investigators have noted the occurrence of Hirschsprung's disease in 2075% of NID cases [26- 27,30] . The significance of NID as seen on pathologic
examination As such, some surgeons rely predominately on the clinical presentation of
constipation for planning any subsequent surgical intervention.