Hirschsprung disease (HD) is a congenital disorder defined by the absence of ganglion cells (GC) at the Meissner's plexus of the submucosa and Auerbach's plexus of the muscularis in the terminal rectum that extends in a variable distance proximally. Its prevalence varies from 1 to 1.63 per 10,000 births.
Once considered deadly, surgical treatment has reduced the disease mortality to 3% in the developed countries. HD most often affects the newborn. It is responsible for non-specific symptomatology, including chronic constipation and neonatal obstruction. Its diagnosis relies upon the histopathological examination of rectal biopsies.
In Hirschsprung disease, there is a disruption of the migration process and differentiation of neural crest cells at the level of the enteric nervous system, which is under the control of the RET gene and its ligands. This disturbance causes a total absence of GC in the nerve plexuses. It leads to the overactivity of the intestine with the persistent release of acetylcholine. Subsequently, there is a continuous contraction of the narrowed (affected) colonic segment and progressive secondary dilatation of the healthy proximal colon.
HD transmission is complex involving multigenic inheritance. Its penetrance is weak, variable, and sex-dependent. The main gene involved is the proto-oncogene RET found in about 35% of sporadic cases and 49% of familial cases. RET mutations may occur in any of the 21 exons of the gene. More than 100 different mutations have been identified. These include nonsense, missense, deletions, and insertions. The other genes involved in the etiopathogenesis of HD are implicated in only 5 to 10% of cases. It includes the ligands of the RET receptor: glial cell-derived neurotrophic factor (GDNF), endothelin-3, endothelin receptor B (EDNRB), SOX10 transcription factor, and the PHOX2B gene.
HD occurs in 1/5000 live births and has an overall 4:1 male predominance. Sex ratio inversion in total or extensive colonic form is observed in the literature. HD is a congenital disorder, presenting mainly in the neonatal period. The diagnosis is made in 65% of the cases before the age of 1 month and in 95% of the cases before the age of one year. It is rarely diagnosed during adulthood, although the eldest age at presentation reported in the literature is seventy-four years.
Disturbed rostrocaudal migration of the neural crest cells (NCC) along a variable length of the intestine is responsible for HD. GC first migrate to the myenteric plexus and then to the submucosal plexus. Animal models have also highlighted an arrest or delay in the migration of NCCs as the factor behind the pathogenesis of HD.
The diagnosis of HD is based on a combination of clinical features, radiological findings, and histopathological evaluation of the biopsied sample. Indeed, the histopathologic examination of the rectal biopsy confirms the diagnosis of the disease by highlighting the association of absence of GC in submucosal and myenteric plexus with hypertrophy of nerve fibers in the aganglionic segment. GC are polygonal cells with abundant fibrillar eosinophilic cytoplasm, eccentric nucleus, and a large nucleolus. To reduce the rate of inconclusive results related to inadequate biopsies, the International Gastroenterology Committee of 2009 defined criteria for performing preoperative biopsies, necessary to ensure a good interpretation.
At least two biopsies should be required, with a minimum diameter of 3mm. The biopsy should have as much mucosa as submucosa. It should be well oriented, included in the correct axis, to avoid tissue loss between the different cutting levels. Preoperative biopsies should be performed at least 2 cm above the dentine line. This area is physiologically devoid of GC and shows physiological hyperplasia of the nerve fibers. Conventional histopathology with hematoxylin-eosin (H and E) stain is commonly used in the diagnosis of HD.
Acetylcholinesterase (AChE) staining is an ancillary method to identify the increased activity of parasympathetic nerve fibers in the lamina propria and the muscularis mucosa and thus, help in making the diagnosis, especially in difficult cases. Normally innervated intestine does not stain with AChE. However, AChE staining is a laborious technique, time-consuming, and needs experienced technicians and pathologists. Immunohistochemistry (IHC) using the calretinin antibody has emerged as a useful technique to confirm or rule out the diagnosis of HD. Calretinin is a vitamin D-dependent protein that binds and buffers calcium in nerve fibers. Its absence causes the accumulation of intra-cytoplasmic calcium with consequent hyperexcitability and cell degeneration. It is expressed physiologically in several cells of human tissue, particularly the central and peripheral nervous systems.
In 2004, Barschak et al. have associated the loss of calretinin expression with the absence of GC, characteristic of HD. Immunolabeling with anti-calretinin antibody results in GC positivity and interstitial nerve fibers of the lamina propria, muscularis mucosa, and submucosa. In the latest recommendations published in 2009, the International Gastroenterology Committee introduced the loss of calretinin expression as one of the diagnostic criteria for HD. Frozen section examination is essential in the management of HD. It can be achieved in two circumstances: to establish the diagnosis of HD and to identify the ganglionic zone during endo-anal resection. This diagnosis is made on biopsies, including only the muscularis of all the colonic walls. It is increasingly recommended to perform circumferential biopsies to make a definitive diagnosis.
Several points in the history and physical examination of HD as one of the differential diagnosis of neonatal bowel obstruction include (1) abnormal maternal amniotic fluid indexes including polyhydramnios, (2) vomiting and specifically bilious emesis, (3) obstipation, which might present with failure to pass meconium in the first 48 hours of life and (4) abdominal distention. History of the colonic obstruction, which might occur during the early neonatal period till adulthood, along with failure to pass meconium during the first 48 hours of the life, which presents in up to 90% of the affected patients, is highly compatible with the impression of HD. However, a history of delayed passage of meconium might be present in up to 40% of the healthy individuals.
Further important pointers in the history of patients with suspected HD include clinical features of Hirschsprung's associated enterocolitis (HAEC), multiple episodes of overflow constipation, and soft distended abdomen. Rare associations with genetic abnormalities, including trisomy 21 and neurocristopathies like Waardenburg syndrome, have also been reported.
Establishing the diagnosis of HD is generally based on the pathological documentation compatible with the absence of the ganglion cells. However, several obstacles have been well-defined in the process of obtaining a definitive pathological diagnosis. These include lack of pathologists' expertise due to the rare exposure to the samples, inadequate and unacceptable quality, disorientation of the submitted tissue to the pathology ward, and normal immature ganglion cells in newborns.
A paramount component of the evaluation process in HD consists of the assessment of the obtained rectal tissue via specific staining methods, including acetylcholinesterase (AChE). However, the crucial role of routine staining methods, including H and E, should not be underestimated. Fresh frozen section tissues might be assessed with ACE staining. Anorectal manometry and contrast enema are other investigations for diagnosing Hirschsprung disease. Anorectal manometry is based on the principle that the recto-anal inhibitory reflex (RAIR) is uniformly present in all healthy newborns. The absence of RAIR on manometry is diagnostic for HD.
The presence of the transition zone, a reversal of recto-sigmoid ratio, mucosal irregularity, irregular contraction, and persistent contrast retention (more than 24 hours) are features of HD on a contrast enema.
The diagnosis of Hirschsprung disease (HD) almost exclusively demands surgical intervention. Pediatric health care providers should possess a comprehensive understanding of the most popular surgical procedures to assist the bridging referral phase between the surgeon and the patient's family. Rectal irrigation before the surgery and in the management of HAEC is highly recommended. It might have a couple of crucial advantages, including colon size decompression and preventing the most devastating complication, enterocolitis. Surgical planning is profoundly affected by the presence of comorbidities, while short-segment HD without any comorbidities can be subjected to a single-stage pull-through procedure. In contrast, in the presence of HAEC or a remarkably dilated colon, a staged reconstruction, starting with a temporary decompressive colostomy, should be preferred.
The recommended timing for a definite pull-through procedure varies from four to six months following colostomy placement. A variety of pull-through surgeries have been identified. The traditional Swenson's technique involves proctectomy, pulling the healthy ganglionated colon through, and anastomosing it to the anus. Novel surgical procedures (e.g., Duhamel's, and Soave's procedure) have the advantage of preserving the intricate innervation to the rectum and bladder. The early postoperative period following the Soave's procedure is critical. Frequent regular sessions of mechanical anastomotic dilations, which might be done at home, are highly recommended. All of these procedures have high success rates, and morbidity is minimal.
An alternative approach is to perform a single-stage transanal Soave's procedure early in the neonatal period, which might obviate the need for an abdominal incision and colostomy. However, the complication rates are quite similar to the more invasive procedures.
Hirschprung disease has been classified as an intestinal dysganglionosis and should be differentiated from intestinal neuronal dysplasia (IND) and isolated hypoganglionosis (IH). The diagnostic criteria for IND have evolved since 1992, and the following diagnostic indexes by Borchard et al. are widely accepted: (1) abnormally hyperplastic submucous plexus, and (2) enhanced peri-vascular acetylcholine esterase (AChE) activity in the submucosal layer. Several additional criteria might be utilized to confirm the IND, including heterotopic ganglion cells, abnormally enhanced acetylcholinesterase activity in the lamina propria, and the circular muscular layer.
Moreover, HD should be differentiated from the wide spectrum of Hirschprung disease variants, which clinically mimic the HD signs and symptoms. It not only includes IND but other disorders with the presence of ganglion cells in rectal biopsies, including intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia (ISA), and megacystis-microcolon intestinal hypoperistalsis syndrome (MMIHS). Internal anal sphincter achalasia might be easily distinguished from the others with the only pathologic finding on the anorectal manometry suggestive of the absence of rectosphincteric reflex, while the intestinal neuronal dysplasia type B (the most common type) might be diagnosed based on the following criteria: submucosal hyperganglionosis with giant ganglia, ectopic ganglion cells, and enhanced acetylcholine esterase activity. Utilizing specific staining on the rectal biopsy specimen might be essential to differentiate the remaining pathologies on the spectrum. Intestinal ganglioneuromatosis, which is mainly confined to the colorectal area and might spare the small bowel, would be differentiated based on the extraordinary proliferation of both the submucosal and myenteric plexuses comprising of thick nerve trunks and accompanied by scattered mature neurons, giant ganglia, and enhanced AChE activity.
Isolated hypoganglionosis, as one of the rarest differential diagnosis in this era, might be suggested based on the immunohistochemical staining. Immature ganglia is a physiologic and age-dependent spectrum presenting with chronic constipation. The normal aging course might reverse the small ganglion cells, which are more evident in nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and neural cell adhesion molecule (NCAM) staining in comparison with routine AChE chemistry.
The absence of the argyrophilic plexus, an infrequent differential diagnosis of HD, might be caused by the disturbed differentiation of the argyrophilic cells. Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is categorized as one of the least common disorders in this spectrum. It might cause the most severe clinical presentations of neonatal functional obstruction syndromes. Several hypotheses have been proposed to identify the exact mechanistic responsible pathways. Although the definitive description has not been well established yet, mutations in the nicotinic acetylcholine receptor (nAChR) and a lack of expression of the alpha3, beta2, and beta4 subunits of nAChR in small bowel tissue might have the similar clinical manifestations.
The quality of life in patients with HD depends on the degree of fecal continence. There is still a dearth of literature highlighting the quality of life in long-standing HD. In one of the unique, comprehensive surveys by a nationwide French study, approximately 3000 patients of the adult population with Hirschprung disease were evaluated utilizing a modified questionnaire. The original questionnaire was described by a Dutch team in 2001 and was pointing not only to HD but also the wide spectrum of anorectal malformations.
One of the most common and devastating Hirschsprung disease-related complications is Hirschsprung-associated enterocolitis (HAEC), which is defined as an inflammatory disorder of the bowel. In order to obtain the diagnosis of HAEC, which is most challenging, a combination of clinical signs and symptoms should be considered. It will result in an inevitably over and under-treatment of patients. The underlying causality of HAEC is still ill-defined. Several hypotheses, including dysbiosis of the intestinal microbiome, impaired mucosal barrier function, altered innate immune responses, and bacterial translocation have been proposed.
The severity of clinical manifestations in HAEC might vary, and several scoring systems have been designed in an attempt to classify the gastrointestinal and systemic presentations, including a Delphi method to make a consensus among a panel of pediatric gastroenterologists and surgeons, and a clinical grading system based on a prospective trial. The former one utilized 16 items, while the latter one is based on three main components of diarrhea, abdominal distention, and systemic manifestations to define the grading of HAEC.
The preferred management of each patient affected with HAEC is based on the corresponding clinical-grade. In the grade I or possible HAEC, outpatient management with oral metronidazole accompanied by fluid and electrolyte might be considered. The more severe cases, including definite and severe HAEC, should be admitted to the hospital and treated with intravenous fluid resuscitation and broad-spectrum antibiotics. Rectal irrigation to remove the retained stool and decrease the bacterial load might be considered in those with abdominal distention irrespective of the HAEC grade. Surgical intervention with a proximal colostomy might be considered in those children with severe HAEC who fail to respond to primary medical management with bowel rest, intravenous fluid resuscitation, rectal irrigations, and broad-spectrum antibiotics.
Several other less frequent post-operative complications in Hirschsprung disease might occur, including an anastomotic leak in up to 1.5% of the patients, anastomotic stricture, wound infections, bleeding, and perianal excoriations. Several abnormal variations in bowel habits, including constipation and fecal incontinence, might occur following the variety of well-defined surgical procedures for HD. The former one might be attributed to high anal resting pressure and weak rectal peristalsis, while the latter one is the result of poor surgical technique.
Although the most worrisome consequence of Hirschsprung disease might not continue until later in adulthood, a significant rate of affected patients who have undergone definite surgery during infancy might experience a change in bowel habit problems during school age. The mentioned complication might result in significant psychological morbidities, considerable alteration in the quality of life, and parental issues, including work leave. Therefore, utilizing an interprofessional team approach to ultimately toilet train the child is crucial, which demands a couple of essential steps, including training optimal defecation skills and toilet behavior.
Parents should be aware of any suspicious symptoms suggestive of HD, including delay in the passage of meconium for more than 48 hours during the neonatal period. Moreover, non-specific symptoms, including constipation, abdominal distention, reflux, nausea, vomiting, and diarrhea, should also raise suspicion.
An interprofessional team approach to treatment based on a bio-psychosocial view can significantly reduce the postoperative chronic bowel problems of the majority of children with operated HD. The central aim is learning self-control: the more the child can evacuate adequate amounts of feces regularly and voluntarily, the less medication he will need, and the more independent he is of the clinician and his parents. Solving defecation issues at an early age prevents invasive procedures from the start of treatment, which is of importance considering the harmfulness of such procedures in a sensitive region, especially in the child's early development.
Depending on the length of the intestine needed to be removed, children with HD may have varying levels of long-term care needs. Temporary or intermittent problems may include frequent and loose stools, difficulty sensing the need to have a bowel movement, problems with peristalsis because the anal opening is tight. From a nutrition perspective, removing a large length of the intestine might prevent a child from getting adequate nutrients and fluids.
Children might suffer from improper digestion, slow growth, and infection. Nutritionists will work to achieve nutrition goals and offer suggestions on how to achieve nutrition requirements to ensure the child grows and develops normally. While the pediatric surgeon is almost always involved in the management of patients with HD, it is important to approach with an interprofessional team of sub-specialists that includes a pediatric gastroenterologist, pediatric radiologists, and a specialist in bowel management protocols. Experienced nurses are also crucial members of the group as they will not only monitor the patient's vital signs and danger signs of possible devastating complications, including HAEC but also assist in educating the patient and family. In the postoperative period, the pharmacist will ensure that the patient is on the correct analgesics, antiemetics, and appropriate antibiotics. [Level 1]
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