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Hirschsprung Disease

First submitted by:
Stefan Scholz
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Author: Stephanie H Chen, MS3 University of Pittsburgh Medical School

Editor: Stefan Scholz, M.D.

Introduction

Hirschsprung disease (congenital aganglionic megacolon) is a developmental disorder of the enteric nervous system, characterized by the absence of ganglion cells in the distal colon resulting in functional obstruction.[1]

History

The condition of “congenital megacolon” was first described in the 17th century by Frederick Ruysch, who described a 5-year-old child dying from an intestinal obstruction, and later in 1887 by Harald Hirschsprung, a pathologist at Queen Louise Children’s Hospital in Copenhagen, who described two cases of the condition that ultimately bears his name.[2] Until the twentieth century, the underlying pathologic abnormality was unknown and thus, surgeons usually resected the dilated proximal bowel with or without primary anastomosis.[3] As a result, most children with congenital megacolon died, presumably from malnutrition and enterocolitis. Whitehouse and Kernohan finally described the pathophysiology in the mid 20th century in a case series of their own which documented the aganglionosis within the distal colon or rectum as the cause of the functional obstruction.[4]  In 1949, Swenson described the first definitive procedure for Hirschsprung disease, a rectosigmoidectomy with preservation of the sphincters.[5] Technical difficulties in small infants, and the debilitated and malnourished state in which most children presented, caused most surgeons to adopt a multi-staged approach with colostomy as the initial step,[6] an approach that became the standard of care for decades. In recent years, improvements in surgical technique, and earlier suspicion and diagnosis of the disease, have resulted in an increasing amount of single-stage and minimally invasive procedures. These advances have resulted in significantly improved morbidity and mortality in infants with Hirschsprung disease.

Pathophysiology

Hirschsprung disease is characterized by congenital aganglionosis of the distal bowel. The aganglionosis always involves the anus and extends proximally for a variable distance. Both the myenteric (Auerbach) plexus and submucosal (Meissner) plexus are absent, resulting in poor bowel motility and function.

Enteric ganglion cells are derived from the neural crest. By 13 weeks post-conception the neural crest cells have migrated through the gastrointestinal tract from proximal to distal end, after which they differentiate into mature ganglion cells.[7] In infants with Hirschsprung disease migration and subsequent differentiation is interrupted or incomplete due to an unclear mechanism. The most prevalent theory is that the neural crest cells never reach the distal intestine because they either mature or differentiate earlier than they should.[8-10] Alternatively, another possible etiology is that normal migration occurs, but the neural crest cells in the distal intestine fail to survive, differentiate, or proliferate.[11, 12] In reality, it is most likely a combination of mechanisms with multiple genetic causes.

Epidemiology

Hirschsprung disease occurs at an approximate rate of 1 case per 5400-7200 newborns in the United States. International studies have reported rates ranging from approximately 1 case per 1500 newborns to 1 case per 7000 newborns.[13,14] The median age of diagnosis is 2-6 months with 90% of patients diagnosed within the newborn period.[15] Hirschsprung disease is uncommon in premature infants. There is a male predominance with a male-to-female ratio of approximately 4:1. However, with long-segment disease, the incidence increases in females. There is no association with race.

Approximately 20% of infants will have one or more associated abnormality involving the neurological, cardiovascular, urological, or gastrointestinal system.[16] Associated syndromes and disorders include: Down Syndrome, Neurocristopathy syndromes, Waardenburg-Shah Syndrome, Yemenite deaf-blind syndrome, Piebaldism, Goldberg-shprintzen syndrome, Multiple Endocrine nepolasia type II, and congenital central hypoventilation syndrome.

Untreated Hirschsprung disease in infancy has a mortality rate of up to 80% reported. Operative mortality rates for any of the interventional procedures are very low. However, in cases of treated Hirschsprung disease, the mortality rate may be as high as 30% secondary to enterocolitis. Surgical complications include anastomotic leak (5%), anastomotic stricture (5-10%), intestinal obstruction (5%), pelvic abscess (5%), and wound infection (10%). Long-term complications include ongoing obstruction, incontinence, chronic constipation, enterocolitis, and late mortality. Although many patients will suffer post-operative complications, long term studies have reported greater than 90% of children experience significant improvement and will do relatively well.[17] Patients with associated syndromes and long-segment disease have poorer outcomes.[18-20]

Clinical Presentation

Hirschsprung disease should be considered in any newborn presenting during the neonatal period with delayed passage of meconium beyond the first 24 hours of life (90% patients), abdominal distention, bilious vomiting, and feeding intolerance suggestive of distal intestinal obstruction. Some patients present with cecal or appendiceal perforation as the initial events.[21] Patients may also present later in childhood, or even during adulthood with chronic constipation.  This is more common among breastfed infants who usually develop constipation around the time of weaning. Clinical features that may help distinguish Hirschsprung disease from more common causes of childhood constipation include failure to pass meconium in the first 48 hours of life, failure to thrive, poor feeding, gross abdominal distention, and dependence on enemas without significant encopresis.[22]

Approximately 10% of children present with diarrhea, fever, and abdominal distention due to Hirschsprung-associated enterocolitis (HAEC). While the etiology remains controversial, it is thought to be associated with stasis caused by the functional obstruction, resulting in bacterial overgrowth with secondary infection.  There is also some evidence of alterations in intestinal mucin and immunoglobulin production that may decrease intestinal defense against bacterial invasion.[23, 24] HAEC may be chronic, severe, and even life-threatening if the colon perforates.

Differential Diagnosis

Intestinal atresia, meconium ileus, meconium plug syndrome, constipation, hypothyroidism, intestinal motility disorders, intestinal pseudoobstruction, IBS, acute/chronic/toxic megacolon.

Work-Up

Imaging

If there is clinical suspicion for Hirschsprung disease based on history or plain radiographs with dilated loops of bowel, the first step is water-soluble contrast (barium) enema (take radiographs immediately after hand injection of contrast and again 24 hours later). Pathognomonic finding on contrast enema is a transition zone between normal and aganglionic bowel, where the distal colon is narrowed in relation to a dilated proximal colon. However, approximately 10%-25% of neonates with Hirschsprung disease may not demonstrate a transition zone.[25] A reversed recto-sigmoid index and retention of contrast in the colon on a 24 hour post-evacuation film is also suggestive of Hirschsprung disease.

Anorectal manometry

Anorectal manometry uses an inflatable balloon to measure the relaxation reflex of the internal anal sphincter after rectal distention.[26] However, this test is not widely available for neonates and results are often operator dependent. Additionally, false-positive results may occur due to artifact from contraction of the external sphincter, movement, or crying. Anorectal manometry is generally not used in the US, however it can be useful for ruling out Hirschsprung disease if the test is normal, avoiding the need for rectal biopsy.[27]

Rectal biopsy

The gold standard for definitive diagnosis of Hirschsprung disease is histologic evaluation of rectal biopsy, where the absence of ganglion cells in the submucosal and myenteric plexuses is the definitive finding. The biopsy should be taken at least 1-1.5 cm above the dentate line because there is a normal paucity of ganglion cells below this level.

Most surgeons use a simple suction biopsy technique where the rectal mucosa and submucosa are sucked into a suction device and the self-contained cylindrical knife cuts off the tissue. The advantage of this technique is there is a low risk of perforation or bleeding and can be performed at the bedside. In cases where the suction biopsy yields an inadequate specimen, punch biopsies and full-thickness biopsies provide deeper tissues and should be used. Disadvantages of a full thickness rectal biopsy include potential bleeding, scarring, and need for general anesthesia.

The specimen is usually stained with hematoxylin and eosin as well as acetylcholinesterase. The acetylcholinesterase intensely stains the hypertrophied nerve trunks throughout the lamina propia and muscularis propia creating a characteristic pattern in Hirschsprung disease.[28] Recently, immunochemical identification with calcitonin is also being used to diagnose Hirschsprung disease.[29]

In general, rectal biopsy is not recommended in premature infants as ganglion cells may be difficult to recognize and the procedure confers higher risks in a small premature infant. Recommendations include decompressing the rectum using stimulation and/or irrigations and waiting until the child is closer to term before doing rectal biopsy.

Surgical Management

Pull-through Procedure

Surgical management of Hirschsprung disease consists of removal of the aganglionic bowel and reconstruction of the intestinal tract by reanastomosis of the normally innervated bowel to the anus with preservation of normal sphincter function. The pull-through procedures most commonly performed are the Swenson, Duhamel, and Soave procedures. Historically, treatment included creating a diverting colostomy given high rates of stricture and leak with the single stage procedure.[30] However, given recent improvements in surgical technique, anesthesia, hemodynamic morning as well as earlier diagnosis, a primary pull-through procedure is usually offered to patients who do not present late.[31-33] With the advent of laparoscopic surgery, minimally invasive techniques are today the standard of care.

Swenson Procedure

Orvar Swenson, who just recently died in April 2012, described the first surgical approach to Hirschsprung disease in 1940s. The pull-through procedure involves removal of the entire aganglionic colon, with an end-to-end anastomosis of the normal colon to the low rectum. This operation is done through a laparotomy with a deep a pelvic dissection and the anastomosis performed from a perineal approach after eversion of the aganglionic rectum.[34]

Soave Procedure

The Soave procedure was introduced in the 1960s as a way to avoid the risks of injury to pelvic structures inherent in the Swenson procedure. The Soave procedure consists of removing the mucosa and submucosa of the rectum and placing the pull-through bowel within a “cuff” of aganglionic muscle. The original description of the procedure left the pull-through colon hanging out through the anus with a subsequent operation several weeks later creating the final anastomosis. Boley later modified this procedure, performing a single stage operation with primary anastomosis at the anus.[35]

Duhamel procedure

First described in 1956, the Duhamel procedure entails bringing the normal colon down retro-rectal, through the bloodless plane between the rectum and sacrum. The aganglionic colon is resected to the rectum and the normal proximal colon and rectum are brought together in an end-to-side anastomosis. By joining the two walls in this manner, a new lumen is created which is aganglionic anteriorly and normally innervated posteriorly.  The advantage of this procedure is the large anastomosis decreasing the risk for stricture, less pelvic dissection, and the presence of a “reservoir” which is helpful for children with longer aganglionic segments.

Laparoscopic pull-through

The first laparoscopic approach to pull-through surgery for Hirschsprung disease was described in 1995 by Georgeson.[36] A laparoscopic biopsy is performed to identify the transition zone, followed by laparoscopic mobilization of the rectum below the peritoneal reflection and endoscopic dissection of the colon and rectum. A short mucosal dissection starting at the dentate line, similar to the Soave procedure, is also performed and the rectum is then prolapsed through the anus with the anastomosis done transanally.

This procedure has been associated with shorter hospital and similar early outcomes to the open procedures.[37] Additionally, laparoscopic approaches to the Duhamel and Swenson operations have also been described with excellent short-term results.[38, 39]

Transanal (perineal) pull-through

This pull-through approach is completely transanal without any intra-abdominal dissection or laparoscopic mobilization.  A circumferential mucosal incision is made 0.5 to 1 cm above the dentate line (depending on the size of the child), and a submucosal dissection is performed proximally. The rectal muscle is incised circumferentially and the dissection continued on the outer rectal wall, creating a rectal cuff with a division to prevent narrowing. The entire rectum and part of the sigmoid colon are then delivered through the anus. The bowel is divided above the transitional zone and anastomosed into the cuff from below. In patients with a more proximal transitional zone, laparoscopy or a small umbilical incision can be used to mobilize the left colon and/or splenic flexure to achieve adequate length.

The transanal approach has a low complication rate, requires minimal analgesia, and is associated with shorter hospital stays and early feeding.[40-43] Outcomes were reported to be as effective as open techniques with decreased postoperative incontinence and constipation, however, further randomized controlled trials are necessary to verify the benefit.[44] Additionally, opinions vary regarding the need for a preliminary biopsy to identify the pathologic transition zone[45], prone versus supine position[46], and the rectal cuff length.[47]

Long-Segment Hirschsprung Disease

Long-segment Hirschsprung disease is defined as a transition zone that is proximal to the midtransverse colon. Total colonic aganglionosis, usually involving some distal ileum, is the most common. Rarely, the entire small bowel is also aganglionic, or near-total aganglionosis with only 10-40 cm of normally innervated jejunum. Patients with long-segment disease are more likely to have a positive family history[48] and contrast enema usually shows a shortened, relatively narrow colon (“question mark colon”).[49] Sequential colonic biopsies are taken to look for ganglion cells on frozen sections  and identify the level of aganglionosis. Most surgeons create a stoma and do a definitive reconstruction procedure later.

The reconstructive procedures for long-segment Hirschsprung disease include: straight pull-through, colon patch, and J-pouch construction. Pull-through procedures using any one of the standard techniques (Swenson, Duhamel, Soave) bring the normally innervated ileum to just above the anal sphincter. A colon-patch is a side-to-side anastomosis between normally innervated ileum and aganglionic colon, thus using the small bowel for motility and colon as a reservoir for storage of stool and absorption of water. A J-pouch procedure involves an ileum to anal anastomosis with connected loops of folded ileum that form an internal reservoir.[50]
The surgical options for children with near-total aganglionosis include bowel-lengthening procedures such as the Binachi[51] or serial transverse enteroplasty procedure[52] or intestinal transplant followed by pull-through surgery.[53]

Postoperative Care

Most children undergoing a laparoscopic or transanal pull-through for standard Hirschsprung disease may be fed immediately post-operatively and can be discharged within 24-48 hours on no medications. One to two weeks after the procedure the anastomosis should be calibrated with a dilator or finger. Parents should dilate the anastomosis anywhere from daily to weekly for 4-6 total weeks. Additionally, parents should apply barrier creams to the buttocks as many children will have frequent stools and perineal skin breakdown post-operatively.

Follow up

Post-operative problems include wound infection, intra-abdominal bleeding, intestinal perforation, bowel obstruction, rectovesical or rectovaginal fistulas, and enterocolitis.[54] Long-term problems in children surgically treated for Hirschprung disease including ongoing obstructive symptoms, soiling, and enterocolitis.[55] Children should follow up with the surgeon, at least until they are beyond the toilet training process in order to identify and provide early treatment for these problems. However, in general, most of these problems resolve after the first 5 years of life, and the majority of Hirschsprung patients report satisfactory outcomes.[56, 57] Children with long-segment disease, down syndrome, and comorbidities tend to have worse clinical outcomes.[58, 59]

Obstructive symptoms including: abdominal distention, bloating, vomiting, or ongoing severe constipation can present any time post-operatively. There are five major reasons for persistent obstructive symptoms following a pull-through procedure[60]:

  1. Mechanical obstruction is most commonly caused by a stricture after a pull-through, and less commonly by an aganglionic spur (Duhamel procedure), twist in the pulled through bowel, or narrowing due to a long muscular cuff (Soave procedure).  Diagnosis of mechanical obstruction is made through digital rectal examination and barium enema. Serial dilation or pull-through revision may be required to relieve the obstruction.[61-63]
  2. Persistent aganglionosis is a rare outcome that may be due to pathologist error,[64] insufficient resection,[65] or ganglion cell loss after the pull-through.[66] Revision of the pull-through may be necessary if repeat rectal biopsy above the previous anastomosis fails to show normal ganglion cells.[63]
  3. GI Motility disorders associated with Hirschsprung disease include gastroesophageal reflux, delayed gastric emptying, small bowel dysmotility, disordered colonic motility.[67] Investigations for motility disorders may include radiologic shape study, radionuclide colon transit study[68], colonic manometry[68], and laparoscopic biopsies evaluating for intestinal neuronal dysplasia.[70] Focal abnormalities may be treated with resection and repeat pull-through using normal bowel. Patients with more diffuse abnormalities may  benefit from prokinetic agents or even cecostomy placement for antegrade colonic enemas.[71]
  4. Internal sphincter achalasia may cause obstructive symptoms due to nonrelaxation. Most cases will resolve spontaneously by the age of 5 years, however in the meantime intrasphincteric botulinum injection,[72-74] nitroglyceride paste, or topical nifedipine may be used for symptom management. Internal sphincterotomy or myectomy can be also used, but may increase risk of future soiling problems.[75, 76]
  5. Functional megacolon is a common cause of constipation in children that results from stool-holding behavior.[77] Treatment is bowel management regimens consisting of laxatives, enemas, and behavior modification. Cecostomy and antegrade enemas or proximal stoma are sometimes used in severe cases of obstructive symptoms and may be reversed later on.

Fecal Soiling may occur after a pull-through procedure as a result of abnormal sphincter function, abnormal sensation, overflow incontinence associated with constipation, or hyperperistalsis of the pulled-through bowel.[78]

  1. Abnormal sphincter function may be due to sphincter injury during pull-through or previous myectomy or sphincterotomy. Evaluate with anal manometry.
  2. Abnormal sensation may involve an inability to feel rectal distention or inability to detect the difference between gas and stool due to a loss of transitional epithelium. Diagnosis can be made by physical examination and anal manometry.
  3. Patients with severe obstipation may leak small amounts of stool around their fecal mass and develop a massively distended rectum which can be seen on abdominal radiograph or barium enema.[79]
  4. Hyperperistalsis of the pulled-through bowel results in an inability of the anal sphincter to achieve control despite normal sphincter function.[69] Anal or colonic manometry may be useful for diagnosis.

Patients without constipation who demonstrate abnormal sphincter function, sensation, and hyperperistalsis should be given a constipating diet and medications such as loperamide. Children with constipation or stool-holding behavior will benefit from high-fiber diet and passive laxative therapy.

Hirschsprung associated enterocolitis (HAEC) describes an inflammatory condition of the bowel mucosa that can result in life-threatening intestine perforation both before and after surgery. HAEC affects 10-30% of Hirschsprung patients and represents the most common cause of mortality in children with Hirschsprung disease. Patients typically present with fever, abdominal distention, diarrhea, elevated white blood cell count, and evidence of intestinal edema on abdominal radiograph.[80] Treatment of HAEC includes broad-spectrum antibiotics, IV fluids, nasogastric drainage, and decompression of the rectum and colon.

 

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