Hirschsprungs Disease

(Also Called 'HD - Hirschsprung's Disease ')

What is Hirschsprung's disease?

Hirschsprung's disease (HD) is a disease of the large intestine (colon). It usually occurs in children and results in a blockage of the intestine so that stool cannot pass through. Some children with HD can't have bowel movements at all, and the stool creates a blockage in the intestine. If HD is not treated, stool can fill up the large intestine, causing serious problems such as infection, bursting of the colon, and even death. HD occurs five times more often in boys than it does in girls. HD occurs in 1 out of every 5,000 births. It is sometimes associated with inherited diseases such as Downs syndrome.

How does HD cause constipation?

Normally, muscles in the large intestine push stool to the anus, where stool leaves the body. The intestines ability to push is enabled by nerve cells in the intestine called ganglion cells. A person with HD does not have these nerve cells in part of the large intestine, creating the problems associated with the disease. Sometimes these nerve cells are missing from only a few centimeters but they can also be missing from long segments of the large intestine.

For people with HD, the healthy muscles of the intestine push the stool until it reaches the part of the intestine without the nerve cells. At this point, the stool stops moving. New stool then begins to collect behind it.

Sometimes the ganglion cells are missing throughout the whole large intestine and even parts of the small intestine. When the diseased section of the intestine reaches 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 causes HD?

HD develops before a child is born. Normally, nerve cells grow in the baby's intestine soon after the baby begins to develop in the womb. These nerve cells grow down from the top of the intestine all the way to the anus. With HD, the nerve cells stop growing before they reach the end.

It is unclear why the nerve cells stop growing; however, there is no evidence that it is caused by the mothers actions or activities while she is pregnant.

What are the symptoms of HD?

Symptoms of HD usually show up in very young children. Sometimes, however, they don't appear until the teenage years or adult life. The most common symptoms include:

Failure to pass meconium (contents of the fetal intestine) shortly after birth Failure to pass first stool within 24 to 48 hours after birth Constipation (possibly worsening over time) Abdominal swelling Vomiting (usually gradual onset) Watery diarrhea (in newborns) Poor weight gain Slow growth (in children under 5 years) Malabsorption Fever/infection Loss of appetite

How is HD diagnosed?
HD is diagnosed after a thorough physical exam and some tests. During the physical exam, the doctor might be able to feel the abdomen and detect the area where the large intestine is obstructed. The abdomen might also be swollen. There are many tests a doctor might used to determine whether a child has HD. These include:

Abdominal X-ray looking for a bowel blockage Rectal exam During this exam, the doctor will check the rectum for a lack of stool, as well as whether the anal canal feels narrowed.

Barium enema X-ray Barium is a liquid that makes the intestine show up better on the X-ray. For this test, barium is inserted into the intestine through the anus and then X-rays are taken. In places where the nerve cells are missing, the intestine looks too narrow. If a narrowed area of the large intestine shows on the X ray, the doctor knows HD might be the problem.

Manometry This test is mostly used in older children. During the test, the doctor inserts a small balloon inside the rectum and then inflates it. Under normal circumstances, the anal muscle will relax. If it doesn't, HD might be the cause.

Biopsy A biopsy is the most accurate test for HD. The doctor removes a tiny piece of the intestine and then looks at it under a microscope. If the nerve cells are missing, HD can be confirmed.

How is HD treated?
Most children will need surgery to correct the condition.

Pull-through surgery
This surgery is performed by taking out the part of the intestine that doesn't work and connecting the remaining healthy part to the anus. After pull-through surgery, the child has a working intestine.

Many times, pull-through surgery can be done right after the diagnosis of HD. However, children who have been very sick might first need surgery called an ostomy. During an ostomy, the doctor takes out the diseased part of the intestine. The doctor then creates a small hole in the child's abdomen, called a stoma, and connects the top part of the intestine to the stoma. This enables stool to leave the body through the stoma while the bottom part of the intestine heals. Stool collects in a bag attached to the skin around the stoma and needs to be emptied several times a day. Some doctors prefer to perform an ostomy on every child before doing the pull-through surgery.

When the doctor is ready to do the pull-through surgery, he or she will disconnect the intestine from the stoma and attach it just above the anus. Since the stoma isn't needed any more, the doctor will either repair it during the pullthrough surgery or will wait about six weeks to make sure that the pull-through surgery was successful.

In some cases, the doctor removes the entire large intestine and connects the small intestine to the stoma. This surgery is called an ileostomy. If the doctor leaves part of the large intestine and connects it to the stoma, the surgery is called a colostomy.

What is the prognosis for HD?

Most babies are more comfortable after having an ostomy performed because they can pass gas more easily are no longer constipated. Older children, too, often feel more comfortable, though they might have trouble adjusting to the ostomy. Your child will be taught how to take care of the stoma and how to change the bag when needed. Most children can lead a normal life after surgery.

After the pull-through surgery, 90 percent of the children pass stool normally. Some might have diarrhea for a while, but eventually the stool will become more solid and the child will need to go to the bathroom less often. Babies might develop a diaper rash from the diarrhea. Toilet training might be delayed since the child learns how to use the bottom muscles only after pull-through surgery. Older children might have accidents for a while after the surgery, but this will improve with time.

When should I call my childs doctor?

Infections can be very dangerous for a child with Hirschsprung's disease, and it is important that parents remain watchful for signs. Infection of the large and small intestines, called enterocolitis, can happen before or after pullthrough or ostomy surgery. If left untreated, this infection can become life-threatening. The most common symptoms of infection include:

Fever Swollen abdomen Vomiting Diarrhea Bleeding from the rectum Excessive fatigue/exhaustion

Another complication of surgery is a puncture that develops in the wall (intestinal perforation) of the intestine. Intestinal perforation has many of the same symptoms as enterocolitis; however, it also causes severe abdominal pain (intensified by any movement) and nausea.

If your child shows any of the symptoms of enterocolitis or intestinal perforation, call your childs doctor immediately. Also call your childs doctor if you child has abdominal pain or develops never symptoms after treatment for HD.

Hirschsprung's disease, or congenital aganglionic megacolon, involves an aganglionic section of bowel[1] (the normal enteric nerves are absent) that starts at the anus and progresses upwards. The length of bowel that is affected varies but seldom stretches for more than about 30 cm. It arises when certain nerve cells in the gut (called ganglion cells) fail to develop and mature correctly.

Contents
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1 History and description 2 Genetic basis 3 Clinical features 4 Diagnosis 5 Treatment 6 See also 7 References

8 External links

[edit] History and description

Reports of the condition date back to 1691.[2] This disease is named after Harald Hirschsprung, the Danish physician who first described the disease in 1888,[3][4] describing two infants who had died with swollen bellies. Hirschsprungs disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent, causing chronic constipation.[5] The lack of ganglion cells is in the myenteric plexus, which is responsible for moving food in the intestine. A barium enema is the mainstay of diagnosis of Hirschsprungs, though a rectal biopsy showing the lack of ganglion cells is the only certain method of diagnosis. The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time, Hirschsprungs was considered a multi-factorial disorder, where a combination of nature and nurture were considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprungs disease could be mapped to a stretch of chromosome 10.[6][7] This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate the single gene that they thought caused Hirschsprungs.

[edit] Genetic basis

Several genes and loci have been shown or suggested to be associated with Hirschsprung's disease: Type HSCR1 HSCR2 HSCR3 HSCR4 HSCR5 HSCR6 HSCR7 HSCR8 HSCR9 OMIM Gene Locus 142623 RET 10q11.2 600155 EDNRB 13q22 600837 GDNF 5p13.1-p12 131242 EDN3 20q13.2-q13.3 600156 ? 21q22 606874 ? 3p21 606875 ? 19q12 608462 ? 16q23 611644 ? 4q31-32 602229 SOX10 22q13 600423 ECE1 1p36.1 602018 NRTN 19p13.3 602595 SIP1 14q13-q21

Hirschsprung's disease can also present as part of a syndrome in Waardenburg-Shah syndrome, Mowat-Wilson syndrome, Goldberg-Shpritzen megacolon syndrome, and congenital central hypoventilation syndrome.[8] In 2002, scientists thought they found the solution. According to this new research, Hirschsprung's is caused by the interaction between two proteins encoded by two variant genes. The RET proto-oncogene on chromosome 10 was identified as one of the genes involved. The protein with which RET has to interact in order for Hirschsprungs disease to develop is termed EDNRB and is encoded by the gene EDNRB located on chromosome 13. RET codes for proteins that assist cells of the neural crest (which later become ganglion cells) in their movement through the digestive tract during the development of the embryo. EDNRB codes for proteins that connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to these two genes mutating so the wrong proteins are produced. Research published in June 2004 suggests that there are several genes associated with Hirschsprungs disease.[9] Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprungs disease than previously thought. RET can mutate in many ways and is associated with Down's syndrome. Since Down Syndrome is comorbid in two percent of Hirschsprungs cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome. RET is also associated with thyroid cancer and neuroblastoma. Both of these disorders have also been observed in Hirschsprungs patients with greater frequency than in the general population. One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. The earlier the mutation of RET occurs in Hirschsprungs disease, the more severe the disorder becomes. Hirschsprung's disease, hypoganglionosis, gut dysmotility, gut transit disorders and intussusception have been recorded with the dominantly inherited neurovisceral porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria). Children may require enzyme or DNA testing for these disorders as they may not produce or excrete porphyrins prepuberty.

[edit] Clinical features

A: Plain abdominal radiograph showing a PARTZ at rectosigmoid, arrow. B: Plain abdominal radiograph showing a PARTZ at midsigmoid, arrow. C: Plain abdominal radiograph showing a

PARTZ at descending colon, arrow. D: Contrast enema showing a CETZ at rectosigmoid, arrow. E: Contrast enema showing a CETZ at midsigmoid, arrow. F: Contrast enema showing a CETZ at descending colon, arrow. With an incidence of 1/5000 births, the most cited feature is absence of ganglion cells: notably in males, 75% have none in the recto-sigmoid, and 8% with none in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally; the absence of ganglion cells results in a persistent over-stimulation of nerves within the affected region, resulting in contraction. 1) Delayed passage of meconium. 2) Abdominal distension. 3) Constipation.

[edit] Diagnosis
Hirschsprung's disease is suspected in a baby who has not passed meconium within 48 hours of delivery. Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours. Definitive diagnosis is made by suction biopsy of the distally narrowed segment.[citation needed] Diagnostic techniques involve anorectal manometry,[10] barium enema, and rectal biopsy. Radiologic findings may also assist with diagnosis.[11]

[edit] Treatment
Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. There used to be two steps typically used to achieve this goal.

The first stage used to be a colostomy. When a colostomy is performed, the large intestine is cut and an opening is made through the abdomen. This allows bowel contents to be discharged into a bag. Later, when the childs weight, age, and condition is right, a pull-through procedure is performed.

Orvar Swenson, the same man who discovered the cause of Hirschsprungs, first performed it in 1948.[12] The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull through procedure is the typical method for treating Hirschsprungs in younger patients. Swenson devised the original procedure, but the pullthrough surgery has been modified many times. The Swenson, Soave, Duhamel, and Boley procedures all vary slightly from each other:

The Swenson procedure leaves a small portion of the diseased bowel. The Soave procedure leaves the outer wall of the colon unaltered. The Boley procedure is just a small modification of the Soave procedure. The term "Soave-Boley" procedure is sometimes used.[13][14] The Duhamel procedure uses a surgical stapler to connect the good and bad bowel.

Of those 15% of children who do not obtain full control, various other treatments are available. If constipation is the problem then usually laxatives or a high fiber diet will overcome the problem. If lack of control is the problem then a stoma may be necessary. The ACE or Malone is also an answer. This is where a tube goes through the abdominal wall to the appendix, or if available, to the colon. Then once a day the bowel is flushed. Children as young as 6 do fine with administering this on their own. If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures, such as the posterior rectal myectomy, can be performed.
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Pathophysiology
Congenital aganglionosis of the distal bowel defines Hirschsprung disease. Aganglionosis begins with the anus, which is always involved, and continues proximally for a variable distance. Both the myenteric (Auerbach) plexus and the submucosal (Meissner) plexus are absent, resulting in reduced bowel peristalsis and function. The precise mechanism underlying the development of Hirschsprung disease is unknown. Enteric ganglion cells are derived from the neural crest. During normal development, neuroblasts will be found in the small intestine by the 7th week of gestation and will reach the colon by the 12th week of gestation.3 One possible etiology for Hirschsprung disease is a defect in the migration of these neuroblasts down their path to the distal intestine. Alternatively, normal migration may occur with a failure of neuroblasts to survive, proliferate, or differentiate in the distal aganglionic segment. Abnormal distribution in affected intestine of components required for neuronal growth and development, such as fibronectin, laminin, neural cell adhesion molecule (NCAM), and neurotrophic factors, may be responsible for this theory.4,5,6 Additionally, the observation that the smooth muscle cells of aganglionic colon are electrically inactive when undergoing electrophysiologic studies also points to a myogenic component in the development of Hirschsprung disease.7 Finally, abnormalities in the interstitial cells of Cajal, pacemaker cells connecting enteric nerves and intestinal smooth muscle, have also been postulated as an important contributing factor.8,9 Three neuronal plexus innervate the intestine: the submucosal (ie, Meissner) plexus, the intermuscular (ie, Auerbach) plexus, and the smaller mucosal plexus. All of these plexus are finely integrated and involved in all aspects of bowel function, including absorption, secretion, motility, and blood flow. Normal motility is primarily under the control of intrinsic neurons. Bowel function is adequate, despite a loss of extrinsic innervation. These ganglia control both contraction and relaxation of smooth muscle, with relaxation

predominating. Extrinsic control is mainly through the cholinergic and adrenergic fibers. The cholinergic fibers cause contraction, and the adrenergic fibers mainly cause inhibition. In patients with Hirschsprung disease, ganglion cells are absent, leading to a marked increase in extrinsic intestinal innervation. The innervation of both the cholinergic system and the adrenergic system is 2-3 times that of normal innervation. The adrenergic (excitatory) system is thought to predominate over the cholinergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric inhibitory nerves, the increased tone is unopposed and leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.