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Hirschsprung's Disease

Eleanor J. Rutherford, MD

 

Hirschsprung's disease (congenital megacolon) is caused by failure of migration of enteric ganglia derived from the neural crest cells. This migration occurs from cranial to caudal and explains why the anus (just above the dentate line) is always involved in Hirschsprung's disease. As the lack of nerve connections moves proximally, progressively more colon is involved. In 75% of cases, the rectosigmoid area is involved, 15% to 20% extends variably to the rest of the colon, and in the most severe cases the entire colon (5%-10%) or the entire intestinal tract (<1%) can be affected. This progressive failure of migration of neural crest-derived connections explains why no skip areas are found in patients with Hirschsprung's disease and why once the transition zone is accurately identified (by biopsy), the definitive resection and surgical reconstruction of the gastrointestinal (GI) tract can be performed.

The incidence of Hirschsprung's disease is 1 in 5000 live births and has a male-to-female predominance of 4:1; however, in long-segment Hirschsprung's disease (total colon) this is not the case with a male-to-female ratio approaching 1:1. No racial predilection exists for this disease, and affected infants are usually term babies of good size. The genetic predisposition of Hirschsprung's disease is well described, with a familial component responsible for 10% of cases. In addition, genetic involvement of the RET proto-oncogene has been implicated in 50% of familial cases and 15% of sporadic cases. Other associations are reported with trisomy 21, MEN 2A and the endothelin 3 genes (in connection with Waardenburg's syndrome). In countries with increased levels of consanguinity (i.e., Oman and Saudi Arabia), the reported incidence of Hirschsprung's disease increases to 1 in 1800, with an 11% incidence of Down syndrome.

Clinical Findings at Presentation

History

With an increasing number of cases diagnosed in the newborn period, failure to pass meconium in the first 24 to 48 hours of life is the most consistent finding (95%). These babies can appear well, and with early discharge postdelivery, the diagnosis can be missed in the newborn nursery. In other newborns, the symptoms progress more quickly, and low intestinal obstruction is manifested by a history of abdominal distention, vomiting (which may become bilious or feculent), and obstipation. The most severely affected infants can present with a history of lethargy, fever, obtundation, and even profound shock. These infants (suffering from Hirschsprung's enterocolitis) can be confused with many other disorders causing neonatal sepsis with ileus in the newborn period and can be a diagnostic dilemma. In the cases not appreciated at birth, most are diagnosed before 2 years of age. These patients present with refractory constipation treated with multiple dietary manipulations, cathartics, and enemas. A history of stools being produced only with stimulation and rarely occurring spontaneously is common. In addition, the quality of the stools is either occasional and massive or more frequent and pelletlike. Rarely, parents describe stools as normal in caliber and consistency; the stools have a characteristic pungent odor. Surgical consultation is sought often after lengthy attempts at medical management have failed. In summary, the key historical findings in patients with Hirschsprung's disease are failure to pass meconium, abdominal distention, onstipation/obstipation, vomiting, lethargy, enterocolitis, and perforation.

Of note, even in older patients, when reviewing the birth history, failure to pass meconium during the first day of life is frequently elicited.

Physical Examination

The physical findings present are determined by the age at presentation and the severity of the illness. In the newborn period, well, but constipated, infants have distended, soft abdomens with normal or hyperactive bowel sounds. Rectal examination is often very helpful. The examiner will sense slightly increased pressure on the examining finger but no stenosis or obstruction. The ampulla is frequently empty; however, when the examining finger is removed, an explosive evacuation of stool and gas often follows, which to the uninitiated can be quite surprising.

More ill newborns are more distended with tense abdomens but without peritoneal signs unless perforation has occurred. These infants often react minimally to the examiner and can be quite lethargic. Fever; tachycardia; and, most ominously hypotension can be present.

Older infants and children have chronically distended, nontender abdomens with large fecal masses, usually on the left side. Rectal examinations can be unremarkable, the ampulla may be empty, and anal tone appears normal. Infrequently, explosive stools are produced after the examination as in newborns.

Diagnostic Studies

The critical diagnostic tests are anorectal manometry and histologic examination of the rectal biopsy segment.

Anorectal manometry measures the reaction of the internal anal sphincter, the most distal smooth muscle segment of the GI tract (aganglionic in all cases of Hirschsprung's disease), to balloon distention of the rectum. The normal reaction to this filling of the rectum is internal anal sphincter relaxation. In patients with Hirschsprung's disease, either failure of relaxation or paradoxic increase in internal anal sphincter pressure with rectal distention is present. Early work suggested that manometry was not accurate in the newborn period; however, with improved equipment and study techniques, this is no longer the case. The positive predictive value is more than 90% (failure of relaxation), and false-negatives are virtually nil (normal response with relaxation). Therefore, this is a very important and reliable screening test for Hirschsprung's disease because it may be performed at the bedside, is noninvasive, and is without complications.

The required diagnostic test to diagnose Hirschsprung's disease is a rectal biopsy revealing the absence of ganglion cells. This can be accomplished by rectal suction biopsy, rectal punch biopsy, or operative full-thickness biopsy. The technical improvements in rectal suction biopsy make this the preferred method at most centers. Specimens should be taken at three locations for quality control, and improved diagnostic accuracy (usually 2, 4, and 6 cm above the dentate line). This procedure is done at the bedside and rarely causes perforation (< 1%). The only caveat of this technique is the difficulty pathologists experience in determining whether sufficient submucosa is present in the specimen to reliably diagnose Hirschsprung's disease on hematoxylin and eosin staining; however, newer histochemical techniques have ameliorated this concern and made the diagnostic reliability of this procedure much more certain. Acetylcholinesterase staining is the most widely used technique and in combination with hematoxylin and eosin staining is the current standard. The pathologic findings of absent ganglion cells, hypertrophied nerve, and adequate submucosa are diagnostic for Hirschsprung's disease. Newer techniques include nitric oxide synthase markers, neural cell adhesion molecules, and NADPH diaphorase histochemistry (which can be done intraoperatively). Recent work shows that rectal biopsy specimens held at 4C can be stored for as many as 14 days and still reliably have acetylcholinesterase staining techniques. This allows smaller centers to transfer specimens and gain the reliability of using this technology.

Rectal punch biopsies, first described in 1972, are safe, reliable, and also virtually complication free while providing a deeper specimen. The specimen is obtained in the newborn nursery using a rectal speculum and tonsil biopsy forceps. One deep specimen is obtained posteriorly, 2 cm above the dentate line, and is sent for quick section. A rectal pack, expelled spontaneously in several hours, is all that is needed. Rarely, postprocedure bleeding is problematic (< 1%). With the two techniques described, operative biopsy is only required in emergency cases performed for perforation, obstruction, or sepsis before diagnosis and for leveling biopsies performed at the time of definitive surgery.

In virtually all cases of suspected Hirschsprung's disease, a plain abdominal radiograph is obtained. In neonates, this frequently reveals distended bowel loops with an abrupt cut-off below the pelvic brim. A lateral film can be helpful in this regard, revealing a relatively airless rectum. Rectal examinations before this study can distort the result. Later in the course, increased signs of obstruction with air-fluid levels occur. In seriously ill infants with enterocolitis, grossly distended bowel loops with bowel wall thickening suggestive of edema are noted. Those most seriously affected may have perforation with obvious free air in the abdomen. The next test should be expedient laparotomy.

After plain films, most children have dilute barium or water-soluble enema studies. This test should be performed gently and slowly under fluoroscopic control to minimize the chance for perforation. The postevacuation or delayed (24-hour) film frequently reveals the transition zone virtually diagnostic for Hirschsprung's disease. Centers that prefer water-soluble contrast do so to prevent the chance for barium peritonitis if perforation occurs.

Special Diagnostic Concerns

Total colon Hirschsprung's disease and ultrashort-segment Hirschsprung's disease can create diagnostic challenges that should be mentioned. With total colon Hirschsprung's disease, patients may initially present with cecal or ileal perforation as newborns. Therefore, a biopsy for ganglion cells should routinely be performed during the exploratory laparotomy. If Hirschsprung's disease is diagnosed, an ileostomy is indicated. In less severe cases, the barium enema does not reveal a transition zone in the colon, and the caliber of the bowel often appears normal. This can cause a delay in diagnosis. In these cases, manometry or biopsy is indicated even with a normal contrast study. Surprisingly, some children with total colonic disease are not detected during the newborn period and can present with anything from troublesome constipation to profound enterocolitis with septic shock. As with any disease, a careful history should lead the practitioner to consider total colon Hirschsprung's disease in what may otherwise be a confusing picture.

With ultrashort-segment Hirschsprung's disease, children usually have been seen and treated by many practitioners for persistent constipation with a history of normal radiologic evaluation and a noncontributory physical examination. The key here is manometry, which will be abnormal (an absent relaxation reflex), combined with a rectal biopsy that frequently reveals ganglion cells (remember this was taken 2 cm above the dentate line and the affected bowel may be distal to this point). This combination is highly suggestive of ultrashort-segment Hirschsprung's disease.

Differential Diagnosis

Hirschsprung's disease in the newborn period can present similarly to other congenital obstructive GI tract diseases. The differential diagnosis of Hirschsprung's disease includes:

Infants presenting with obstructive symptoms:
Atresia (anal, colonic, jejunoileal)
Cystic masses (ovarian, mesenteric, renal)
Meconium plug syndrome or ileus (cystic fibrosis)
Gastrointestinal tract duplication
Incarcerated hernia (inguinal or internal)
 
Small left colon syndrome
Seriously ill infants with obstruction:
Malrotation with volvulus
 
Necrotizing enterocolitis
 
Meconium peritonitis
Metabolic conditions
 
Hypothyroidism
Electrolyte abnormalities
Maternal cocaine or heroin use
Sepsis with ileus

Many of these diseases, infants are usually well, and symptoms relate to lack of meconium passage. The workup to differentiate these entities from Hirschsprung's disease consists of contrast enema studies and sonography. The contrast studies diagnose (and sometimes cure) meconium ileus and plug syndromes and define GI tract atresias and small left colon syndrome. The abrupt cutoff caused by incarcerated hernias coupled with physical findings in the groin should be unmistakable. Sonography is very helpful in defining cystic masses causing extrinsic obstruction, such as duplications and mesenteric cysts.

In more seriously ill infants, conditions to be considered in the differential diagnosis usually reveal themselves via historical factors (i.e., bilious vomiting in malrotation or maternal history), presentation factors (i.e., pneumatosis intestinalis in necrotizing enterocolitis [NEC] or in utero bowel obstruction in meconium peritonitis), or with appropriate radiologic and laboratory parameters coupled with a thorough physical examination. Because operations for Hirschsprung's disease are principally elective and malrotation with volvulus or NEC can be surgical emergencies, expeditious resuscitation and radiologic contrast studies are required to delineate these issues.

In older children, Hirschsprung's disease is frequently confused with functional constipation; however, findings more frequently seen with constipation (and not seen in Hirschsprung's disease) include: encopresis, nondistended abdomen, rectal vault full of stool, no transition zone on barium enema, and normal manometry.

Treatment

In all cases of Hirschsprung's disease, operative intervention is the definitive treatment. The current debate on therapy deals with one-stage repair in the newborn period (open or laparoscopic) versus the conventional multistage repair requiring colostomy and staged reconstruction. The details of the three major operations (i.e., Swenson, Duhamel, and Soave) are not germane to this text except to note that if individual surgeons' or centers' selection bias is eliminated and comparisons are made of large groups of patients receiving the three operations, the results are virtually identical. In addition, all three procedures can be done in a single stage in the newborn period, open or laparoscopically. Critical review of the literature suggests the following:

One-stage repair is feasible in all patients, including newborns less than 4 kg and less than 30 days of age.
The complications pertaining to colostomy creation and removal are eliminated (upwards of 25% morbidity alone is related to the colostomy).
Overall health care dollars are decreased per patient treated in one-stage repairs.
Outcome studies reveal similar complication rates and functional results comparing one-stage to multistage procedures.
The ability to perform one-stage repairs is dependent not only on surgeons' experience with the procedure but also on the experience of pathologists.

Therefore, the authors' current recommendations on treatment for Hirschsprung's disease in stable, elective patients is one-stage repair in the newborn period without colostomy. Preoperatively, rectal irrigation and anal dilation should be done to clean out the GI tract and prevent enterocolitis. Staged repairs should be reserved for unstable, septic patients requiring urgent fecal diversion or older children with massive GI tract dilation requiring defunctionalization to shrink the GI tract before definitive reconstruction.

The issue of open versus laparoscopic one-stage procedures is not as clear. Although the cosmetic aspects of laparoscopic repairs are somewhat better, with low, transverse, small incisions, there need not be much difference. As with many laparoscopic procedures, operating time is increased, and hospitalization time and time to GI tract function are usually decreased. Long-term follow-up data in large comparative series are needed to assess the real differences long- and short-term with these two modes of surgical therapy. The technical operation received by the patient does not differ irrespective of the method chosen to perform it.

Two areas of special concern are total colon Hirschsprung's disease and ultrashort-segment Hirschsprung's disease. In total colon Hirschsprung's disease, although many different surgical procedures are espoused, a Duhamel procedure with side-to-side stapled ileorectal anastomosis is the authors' preference. It has a low complication rate, is far less technically challenging than some of the more complex procedures, and can be safely performed in a single stage during the newborn period. In ultrashort-segment Hirschsprung's disease, a full-thickness, generous (2-3 cm in length) internal anal sphincter myectomy is both diagnostic (by evaluating the entire removed muscle strip for ganglion cells) and therapeutic. It is technically simple, can be performed on an outpatient basis, and has good to excellent results.

Long-Term Complications, Prognosis, and Follow-Up

As previously described, evaluation of long-term results for all three operations is relatively similar. Approximately 65% to 85% of patients eventually achieve excellent results with normal bowel habits, no soiling, and infrequent constipation. An additional 15% to 20% of patients report troublesome constipation, occasional soiling, and infrequent incontinence. In 5% to 10% of patients, severe constipation or incontinence is a long-term issue. The treatment of constipation in the postoperative period is principally dietary manipulation, stool softeners, laxatives, and occasionally anal dilatation. A few patients require routine enemas or operative internal anal sphincterotomy, which, if indicated, can be curative.

In incontinent patients, manometric evaluation may reveal poor sphincter function (internal, external, or both). If this is the case, purposeful constipation with prograde (via a cecostomy tube or Malone procedure) or retrograde enemas provide for social, but not physiologic, continence.

Approximately 25% of children in most large series receive reoperation for stenosis, prolapse, bowel obstruction, abscess drainage, sphincterotomy, or (rarely) surgical revision. The incidence of reoperation should decrease with the elimination of the routine use of colostomy diversion. In all reports, neurologically impaired children or those with trisomy 21 fare far worse than their normal peers, with a twofold or threefold increase in incontinence or severe constipation. In all long-term reports, over time, continence rates improve progressively. Therefore, long-term detailed follow-up is indicated and required for all patients to achieve the most satisfactory outcomes.

A special caution for those with total colon Hirschsprung's disease is that these children often have some degree of failure to thrive and can develop iron deficiency anemia and decreased B12 levels. Vitamin supplements, monthly B12 injections, and routine laboratory and nutritional assessment are indicated.

Hirschsprung's Enterocolitis

Hirschsprung's enterocolitis can occur preoperatively and postoperatively (either after colostomy or definitive repair). The reported incidence varies from 20% to 60%, and in older reports it was the principal cause of mortality in Hirschsprung's disease. With increased awareness and early recognition, mortality from Hirschsprung's enterocolitis is now uncommon. The clinical triad of explosive watery diarrhea, abdominal distention, and fever should presumptively diagnose Hirschsprung's enterocolitis in patients known to have Hirschsprung's disease. Positive stool and blood cultures are uncommon and do not aid in diagnostic accuracy or treatment. On presentation, these children should have immediate intravenous rehydration; frequent rectal irrigation with warm, normal saline; and intravenous metronidazole. Virtually all patients respond to this therapy.

In the preoperative period, the cause of Hirschsprung's enterocolitis is thought to be increased intraluminal pressure in the colon above the transition zone causing relative ischemia in the distended bowel wall with transmigration of colonic bacteria; however, causative agents, such as Clostridium difficile, Staphylococcus aureus, and rotavirus suggest that other factors may pertain because these are not the principal flora of the colon. Other factors described relate to changes in the mucin production and the intrinsic barrier function of the bowel wall.

A recent report evaluating postoperative factors causing Hirschsprung's enterocolitis revealed patient factors (e.g., sex, age, and weight at surgery) and technical factors (e.g., choice of operation, number of stages and length of involved bowel, presence of preoperative Hirschsprung's enterocolitis) had no effect on the incidence of Hirschsprung's enterocolitis postoperatively; however, mechanical factors (e.g., anastomotic stricture or leak and intestinal obstruction) were predictive of a 2.8- to 3.5-fold increase in Hirschsprung's enterocolitis. Therefore, frequent rectal dilation postoperatively to avoid stricture formation, one-stage repairs (which may decrease the frequency of bowel obstructions), and rectal irrigation for several weeks to months after surgery may aid in decreasing the incidence of Hirschsprung's enterocolitis in the postoperative period.