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Hirschsprung’s Disease

  • Prem PuriEmail author
  • Christian Tomuschat
  • Hiroki Nakamura
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Abstract

Hirschsprung’s disease (HSCR) is a relatively common cause of intestinal obstruction in the newborn. It is characterized by the absence of ganglion cells in the distal bowel beginning at the internal sphincter and extending proximally for varying distances. The absence of ganglion cells in HSCR has been attributed to a failure of migration of neural crest-derived cells. The earlier the arrest of migration, the longer the aganglionic segment of bowel. 80–90% of patients with HSCR produce clinical symptoms and are diagnosed in the neonatal period. Delayed passage of meconium is the cardinal symptom in over 90% of affected neonates. About one-third of babies with HSCR present with enterocolitis which remains the most common cause of morbidity and mortality in the disease. This chapter describes in-depth the etiopathogenesis, pathophysiology, diagnosis, and management of Hirschsprung’s disease. The progress in understanding of normal gut development and motility has led to an expanding field of research into developing novel therapies for HSCR. During the last decade, there has been an increasing focus on the development of novel stem cell-based therapies for the treatment of HSCR. Research is ongoing to determine the optimal source of stem cells to generate a new enteric nervous system in the aganglionic bowel and also to determine the best way to deliver stem cells to the affected bowel.

Keywords

Hirschsprung’s disease Aganglionosis Enterocolitis Children Constipation Hypoganglionosis Rectal biopsy 

Introduction

Hirschsprung’s disease (HSCR) is characterized by an absence of ganglion cells in the distal bowel and extending proximally for varying distances (Heanue and Pachnis 2007). In over 80% of the patients the aganglionosis is confined to the rectosigmoid. In the remaining patients, the aganglionosis extends beyond the rectosigmoid, involving descending colon, transverse colon or the entire colon with a short segment of terminal ileum. Total intestinal aganglionosis with the absence of ganglionic cells from the rectum to the duodenum is the rarest form of HSCR and is associated with high morbidity and mortality (Nemeth et al. 2001; Ruttenstock and Puri 2009; Senyuz et al. 1989; Ziegler et al. 1987).

Historical Overview

The condition of “congenital megacolon” has been recognized for centuries. The first known description of this condition was by the ancient Indian surgeon Sushruta in 600 BC and later by Fredericus Ruysch, a Dutch anatomist in 1691 (Fiori 1998; Raveenthiran 2011). The most in-depth description of congenital megacolon was reported by Harald Hirschsprung, a pediatrician from Copenhagen, when he presented two infants with this condition to the society of Pediatrics in Berlin in 1886 (Skaba 2007). His treatise was entitled “Constipation in newborns due to dilatation and hypertrophy of the colon”. During the next 60 years, several cases of congenital megacolon were reported and most of these children died. It was not until Keenohan in 1948 and Bodian et al. in 1949 confirmed the diagnosis of Hirschsprung’s disease by recognizing the presence of the contracted and spastic rectosigmoid and absence of ganglion cells in the spastic distal segment. In 1948, Swenson and Bill published their classic paper recommending resection of the contracted and spastic rectosigmoid with the preservation of the sphincter as the treatment for Hirschsprung’s disease (Skaba 2007; Swenson 1999). Although improvements in operative techniques and earlier diagnosis have resulted in a significantly improved morbidity and mortality in patients with HSCR, the dogma stated by Swenson that patients can only be cured by removal of the contracted aganglionic segment of bowel tissue, is still valid (Swenson 1996).

Incidence

The incidence of HSCR is estimated to be one in 5000 live births (Orr and Scobie 1983; Passarge 1967, 2002; Spouge and Baird 1985; Wales 1984). Significant interracial differences in the incidence of HSCR have been reported: 1:10,000 births in Hispanics, 1 in 6667 white subjects, 1 in 4761 in black subjects, and 1 in 3571 Asian subjects (Kenny et al. 2010). The disease is more common in boys, with a male-to-female ratio of 4:1 (Orr and Scobie 1983). The male preponderance is less evident in long-segment HSCR, where the male-to-female ratio is 1.5–2.1 (Heanue and Pachnis 2007; Kenny et al. 2010; Orr and Scobie 1983; Passarge 1967; Puri 2009, 2011; Spouge and Baird 1985).

Etiopathogenesis

The most striking pathological feature in HSCR is dilation and hypertrophy of the proximal colon with abrupt or gradual transition to narrow distal bowel (Fig. 1). Although the degree of dilation and hypertrophy increases with age, the cone-shaped transitional zone from dilated to narrow bowel is usually evident in the newborn.
Fig. 1

Typical gross pathology in Hirschsprung’s disease, with transitional zone at rectosigmoid level

Histologically, HSCR is characterized by the absence of ganglionic cells in the myenteric and submucous plexuses and the presence of hypertrophied non-myelinated nerve trunks in the space normally occupied by the ganglion cells (Fig. 2). The aganglionic segment of bowel is followed proximally by a hypoganglionic segment of varying length. This hypoganglionic zone is characterized by a reduced number of ganglion cells and nerve fibers in myenteric and submucous plexuses as well as a disorganized and reduced numbers of interstitial cells of Cajal (ICCs) (Nemeth et al. 2000; Puri 2009, 2011; Rolle et al. 2002b; Vanderwinden et al. 1996).
Fig. 2

(a) Auerbach’s plexus, containing ganglion cells. (b) Hypertrophied nerve trunks in rectal biopsy from a patient with Hirschsprung’s disease

The enteric ganglion cells are derived primarily from the vagal neural crest cells (Gershon 2008). During normal development, neuroblasts migrate from the vagal neural crest along the bowel wall in a craniocaudal direction from the esophagus to the anus. In the human fetus, neural crest-derived neuroblasts first appear in the developing esophagus at 5 weeks and then migrating down to the anal canal in a craniocaudal direction during the 5th–12th weeks of gestation. The neural crest cells first form the myenteric plexus just outside the circular muscle layer. The mesenchymal-derived longitudinal muscle layer then forms, sandwiching the myenteric plexus after it has been formed in the 12th week of gestation. In addition, after the craniocaudal migration has ended, the submucous plexus is formed by the neuroblasts, which migrate from the myenteric plexus across the circular muscle layer and into the submucosal; this progresses in a craniocaudal direction during the 12th–16th weeks of gestation (Burns et al. 2009). The absence of ganglion cells in HSCR has been attributed to a failure of migration of neural crest cells. The earlier the arrest of migration, the longer the aganglionic segment (Passarge 1967; Puri 2009, 2011).

Pathophysiology

The pathophysiology of HSCR is poorly understood. It has been long recognized that the obstructive symptoms in HSCR are secondary to the abnormal motility of the narrow distal segment, but there is still no clear explanation for the occurrence of the spastic or tonically contracted segment of bowel. Normal intestinal motility requires coordinated interaction of the enteric nervous system (ENS), smooth muscle cells (SMCs), ICCs and platelet-derived growth factor receptor α+-cells (PDGFRα+) (SIP-syncytium). Several abnormalities have been described to explain the basis for motility dysfunction in the contracted bowel in HSCR (Puri 2009, 2011).

Cholinergic Hyperinnervation

In association with aganglionosis, there is a marked increase in cholinergic nerve fibers in the intermuscular zone and submucosa of the aganglionic segment. These fibers appear as thick nerve trunks and correspond to extrinsic preganglionic parasympathetic nerves (Kakita et al. 2000). The continuous acetylcholine release from the axons of these parasympathetic nerves results in an excessive accumulation of the enzyme acetylcholinesterase that is typically found in the lamina propria mucosae, muscularis mucosae, and circular muscle with histochemical staining technique (Tang et al. 2011). Both the thick nerve trunks and the increased acetylcholinesterase activity are most pronounced in the most distal aganglionic rectum and progressively diminish proximally as normal bowel is approached (Weinberg 1975). The cholinergic nerve hyperplasia has been proposed as the main cause of spasticity of the aganglionic segment since acetylcholine is the main excitatory neurotransmitter (Puri 2009, 2011).

Adrenergic Innervation

Adrenergic nerves are increased in number in the aganglionic colon of HSCR and have a chaotic distribution. They are present in the circular and longitudinal muscle layers as well as in the mucosa whereas they are almost absent in normal ganglionic colon (Nirasawa et al. 1986). Because adrenergic nerves normally act to relax the bowel, it is unlikely that adrenergic hyperactivity is responsible for increased tone in the aganglionic colon (Puri 1997, 2009, 2011).

Nitrergic Innervation

Nitric oxide (NO) is considered to be one of the most important neurotransmitters involved in the relaxation of the smooth muscle of the gut (Rivera et al. 2011). It is synthesized in a reaction catalyzed by nitric oxide synthase (NOS). There are three NOS isoforms described: nNOS or neuronal NOS produces NO in nervous tissue, iNOS an inducible NOS isoform is expressed in a variety of activated tissues and produces large amounts of NO or stimulation, and eNOS or endothelial NOS generates NO in blood vessels and is involved in regulating vascular function. Several investigators have studied NOS distribution in the ganglionic and aganglionic bowel in patients with HSCR. In normal and ganglionic colon from patients with HSCR, there is strong NOS staining of the submucous and myenteric plexuses, and there are a large number of NOS positive nerve fibers in the circular and longitudinal muscle as well as in the muscularis mucosae (Rolle et al. 2002a). In the aganglionic segment of HSCR patients, there are no ganglia, and there is an absence or marked reduction of NOS positive nerve fibers in both muscle layers and the muscularis mucosae. The typical hypertrophied nerve trunks in the submucosa and between the circular and longitudinal muscle layers appear weakly stained. The expression of neural NOS mRNA in the aganglionic segment is decreased to 1/50–1/100 of the level expressed in ganglionic bowel (Kusafuka and Puri 1997). Furthermore, recent findings of the upregulation of nitric oxide synthase-interacting protein (NOSIP) in the aganglionic and ganglionic bowel suggest an impairment of local NO production (Tomuschat et al. 2017), which in consequence may prevent smooth muscle relaxation and contribute to motility dysfunction. These results suggest that the defective distribution of nerves containing NOS as well as impaired local NO production may be involved in the pathogenesis of HSCR (Bealer et al. 1994; Puri 2009, 2011).

Interstitial Cells of Cajal

Abnormalities of interstitial cells of Cajal (ICC) have been described in several disorders of human intestinal motility including HSCR. ICCs are scarce, and their network appeared disrupted in aganglionic segments of HSCR (Vanderwinden et al. 1996). ICCs are also reduced in the muscle layers of patients with HSCR, and only a few ICCs can be found around the thick nerve bundles in the space between the two muscle layers in the aganglionic bowel (Yamataka et al. 1997). A disorganized and impaired function of ICCs in the ganglionic bowel proximal to the transitional zone of patients with HSCR has been suggested to contribute to the persistent dysmotility problems observed after properly performed pull-through operation (Puri 2009, 2011; Rolle et al. 2002b).

Platelet-Derived Growth Factor Receptor α+-Cells (PDGFRα+)

Platelet-derived growth factor receptor α+-cells (PDGFRα+) have recently been documented in the human colon (Kurahashi et al. 2012).These cells are found to be distributed in a similar pattern as ICCs and are found alongside neurons and SMCs. PDGFRα+ cells have a role in neurotransmission and the modulation of smooth muscle contraction. Recently a decreased expression of PDGFRα+ in HSCR colon has been described, suggesting a role of these cells in the pathophysiology of this condition (O’Donnell et al. 2016; Puri 2009, 2011).

Smooth Muscle Cells

Smooth muscle cells (SMC) are the effector cells of the bowel, and as a result of communication from the ENS, ICCs, and PDGFRα+, govern intestinal peristalsis. The SMC cytoskeleton consists of proteins whose primary function is to serve as a structural framework that surrounds and support the contractile apparatus of actin and myosin filaments in the body of the SMC. The expression of cytoskeletal proteins in the smooth muscle of HSCR has been reported to be either absent or weak in the aganglionic bowel, whereas it is moderate to strong in the smooth muscle of normal bowel and ganglionic bowel from patients with HSCR (Nemeth et al. 2002). Studies on surface glycoproteins revealed an altered expression, indicating disturbed cell-cell interactions between SMC in patients with HSCR (Covault and Sanes 1986; Moore and Walsh 1985; Puri 2009, 2011; Thiery et al. 1982).

Extracellular Matrix

Extracellular matrix (EM) abnormalities have been described in HSCR. The lethal spotted mouse model which develops aganglionosis is characterized by an abnormal distribution of EM components including laminin, collagen type IV, glycosaminoglycans, and proteoglycans (Tennyson et al. 1990). The laminin concentration in aganglionic bowel has been reported to be twice as high as in the normoganglionic bowel of HSCR and three times greater than an age-matched control. Also, excess collagen VI in a rodent model developed HSCR-like disease due to decreased enteric neural crest-derived cell (ENCDC) migration (Soret et al. 2015). The inhibitory effect of collagen VI on ENCDC migration may partially explain why children with Down syndrome have an increased risk of HSCR since collagen VI genes are on chromosome 21 (Puri 2009, 2011; Soret et al. 2015).

Genetics Factors

HSCR is known to occur in families. The reported overall incidence of familial cases is 7.6%, with a higher incidence of 15–21% in total colonic aganglionosis and 50% in the rare total intestinal aganglionosis (Angrist et al. 1995; Attie et al. 1995).

During the past 20 years, several genes have been identified that control morphogenesis and differentiation of the enteric nervous system. These genes, when mutated or deleted, interfere with the enteric nervous system development. So far, 22 genes are known to be involved in the development of HSCR (Table 1). The rearranged during transfection (RET) gene, encoding a tyrosine kinase receptor, is the major gene causing HSCR (Edery et al. 1994; Tomuschat and Puri 2015). Mutations in the coding region of RET are responsible for 50% of familial HSCR cases and 15% of sporadic ones. The other major gene which plays a dominant role in HSCR is the endothelin B receptor (EDNRB) gene, associated with Waardenburg syndrome (Moore 2017). However, the RET proto-oncogene remains the most consistent with allelic loss being found in more than 80% of all cases. Known interactions between RET and other genes are common and additive/synergistic effects from another genetic variant is the most likely explanation in the pathogenesis of HSCR (Moore 2017). However, all the genes which have been implicated in the development of HSCR together account for only 20% of all cases of HSCR, suggesting potential other genes involved in the pathogenesis of HSCR (Moore 2015; Tam 2016).
Table 1

Genes involved in the morphogenesis and differentiation of the ENS

Gene

Phenotype

Inheritance

Effects on intestinal innervation

RET

HSCR/HSCR-MEN2/FMTC

Dominant, incomplete penetrance

Absence of neuronal plexus in the small and large bowel

TIA, renal agenesis

GDNF

HSCR

Dominant, low penetrance

Absence of neuronal plexus in the small and large bowel

TIA, renal agenesis

EDNRB

WS4/HSCR

Recessive/dominant

Aganglionosis of the distal colon, coat spotting

SOX10

WS4/HSCR

Dominant

Aganglionosis, coat spotting

PHOX2B

CCHS/neuroblastoma + HSCR

Dominant

TIA, no autonomic nervous system, ventilatory anomalies

NRTN

HSCR

Dominant, low penetrance

Moderate deficit of enteric neurons

PSPN

HSCR

Dominant, low penetrance

GFRA1

HSCR

Dominant, low penetrance

TIA, renal agenesis

EDN3

WS4/HSCR

Recessive/dominant

Aganglionosis, coat spotting

ECE1

HSCR with cardiac defects, craniofacial anomalies and autonomic dysfunction

Dominant

Aganglionosis, coat spotting, craniofacial defects

NTF3

HSCR

Dominant, low penetrance

Reduced enteric neurons

NTRK3

HSCR

Dominant, low penetrance

Reduced enteric neurons

PROKR1

HSCR

Dominant, low penetrance

PROKR2

HSCR

Dominant, low penetrance

Hypoplasia of the olfactory bulb and reproductive system

PROK1

HSCR

Dominant, low penetrance

 

SEMA3A

HSCR

Dominant, low penetrance

Deficit of cardiac sympathetic innervation and stellate ganglia malformation

SEMA3D

HSCR

Dominant, low penetrance

NRG1

HSCR

Dominant, low penetrance

Lethal from cardiac defect

NRG3

HSCR

Dominant, low penetrance

ZFHX1B

MWS

Dominant

Lethal at gastrulation

KIAA1279

GSS

Recessive

L1CAM

HSAS/MASA spectrum + HSCR

X-linked

Hydrocephalus

The relationship with Down syndrome further underlines the genetic component in the etiology of HSCR. Down syndrome is the most common chromosomal abnormality associated with aganglionosis and had been reported to occur in 4.5–16% of all cases of HSCR (Friedmacher and Puri 2013). Other chromosomal abnormalities that have been described in association with HSCR include interstitial deletion of distal 13q, partial deletion of 2p and reciprocal translocation, and trisomy 18 mosaic (Table 2).
Table 2

Syndromes commonly associated with Hirschsprung’s disease

Down syndrome (trisomy 21)

Neurocristopathy syndromes

1. Waardenburg-Shah syndrome

2. Yemenite deaf–blind hypopigmentation

3. Piebaldism

4. Goldberg–Shprintzen syndrome

5. Smith–Lemli–Opitz syndrome

6. Multiple endocrine neoplasia 2

7. Congenital central hypoventilation syndrome (Ondine’s curse)

8. Mowat–Wilson syndrome

Recurrence risk to siblings is dependent upon the sex of the person affected and the extent of aganglionosis. Furthermore, the recurrence risk to siblings increases as the aganglionosis extends and brothers of patients with rectosigmoid HSCR have a higher risk (4%) than sisters (1%). Much higher risks are observed in cases of long segment HSCR. The brothers and sons of affected females have a 24% and 29% risk of being affected, respectively (Badner et al. 1990; Bergeron et al. 2013). The risk of familial recurrence of HSCR should be discussed with families of diagnosed patients. Genetic counseling should be offered in these families and in particular for those patients with long segment and total colonic aganglionosis (Mc Laughlin and Puri 2015).

Associated Anomalies

As the cardiac development depends on neural crest cell proliferation and is closely related to the formation of the enteric nervous system, HSCR associated with congenital heart disease (CHD) has been reported in 5–8% of cases, with septation defects being the most frequently recorded abnormalities. The overall reported prevalence of HSCR associated with CHD in infants without chromosomal disorders was 3%. In infants with syndromic disorders, the overall prevalence of HSCR associated with CHD ranged from 20% to 80% (overall prevalence 51%). Septation defects were recorded in 57% (atrial septal defects in 29%, ventricular septal defects in 32%), a patent ductus arteriosus in 39%, vascular abnormalities in 16%, valvular heart defects in 4%, and tetralogy of Fallot in 7%. The prevalence of HSCR associated with CHD is much higher in infants with chromosomal disorders compared to infants without associated syndromes. A routine echocardiogram should be performed in all infants with syndromic HSCR to exclude cardiac abnormalities (Duess and Puri 2015).

The association of urogenital anomalies and HSCR based on the common genetic background of enteric nervous system and human urinary tract development has been well described in the literature. A prevalence of 14.3% associated urological and urogenital anomalies has been reported in HSCR and warrants a thorough urological investigation, especially in syndromic HSCR cases (Hofmann et al. 2014).

Diagnosis

The diagnosis of HSCR is usually based on clinical history, imaging, and rectal biopsy and confirmed by histological examination of rectal biopsy (Jakobson-Setton et al. 2015). The vast majority of patients (80–90%) are diagnosed during the neonatal period. The hallmark symptom in neonates is delayed passage of meconium. Over 90% of affected patients fail to pass meconium in the first 24 h of life. Usually patients present with constipation, increasing abdominal distension (Fig. 3) and vomiting on the first day of life. Some patients present later in childhood, or even during adulthood, with chronic constipation, failure to thrive, and abdominal distension (Puri 2009, 2011). Although, the typical patient is a full-term male infant, HSCR can also occur in premature infants. Prematurity was recorded in 257 cases out of a total number of 4147 infants, giving a prevalence rate of 6% of preterm infants diagnosed with HSCR. Interestingly, in recent years, a higher prevalence of HSCR has been reported in premature infants compared to previous years. Although rare, HSCR should be considered in preterm infants presenting with features of intestinal obstruction (Duess et al. 2014).
Fig. 3

A 2-day-old infant with marked abdominal distention and failure to pass meconium. Suction rectal biopsy confirmed Hirschsprung’s disease

Up to one-third of babies present with fever, bilious vomiting, abdominal distension, and diarrhea due to Hirschsprung-associated enterocolitis (HAEC). HAEC is a life-threatening condition and remains the commonest cause of death. Rectal examination or introduction of a rectal tube results in explosive evacuation of gas and foul-smelling liquid stools.

Imaging

Plain abdominal films in a neonate with HSCR will show signs of distal obstruction with dilated loops of bowel, fluid levels, and airless pelvis. Occasionally, one may be able to see a small amount of air in the undistended rectum and dilated colon above raising the suspicion of HSCR (Fig. 4a). Plain abdominal radiographs obtained from patients with total colonic aganglionosis (TCA) may show characteristics signs of ileal obstruction with air fluid levels or simple gaseous distension of small loops. In patients with enterocolitis, plain abdominal radiography may show thickening of the bowel wall with mucosal irregularity or a grossly dilated colon loop, indicating toxic megacolon. Pneumoperitoneum may be found in those with perforation. Spontaneous perforation of the intestinal tract has been reported in 3% of patients with HSCR (Elhalaby et al. 1995; Puri 2009, 2011).
Fig. 4

Hirschsprung’s disease. (a) Abdominal radiograph in a 4-day-old infant showing marked dilation of large and small bowel loops. Note gas in undilated rectum. (b) Barium enema in this patient reveals transitional zone at sigmoid level

Barium enema performed by an experienced radiologist should achieve a high degree of reliability in diagnosing HSCR in the newborn. It is important that the infant should not have rectal washouts or even digital examinations before barium enema, as such interference may distort the transitional zone appearance and give a false-negative diagnosis. A soft rubber catheter is inserted into the lower rectum and held in position with firm strapping across the buttocks. A balloon catheter should not be used due to the risk of perforation and the possibility of distorting a transitional zone by distension. The barium should be injected slowly in small amounts under fluoroscopic control with the baby in the lateral position. A typical case of HSCR will demonstrate flow of barium from the undilated rectum through a cone-shaped transitional zone into dilated colon (Fig. 4b). Some cases may show an abrupt transition between the dilated proximal colon and the distal aganglionic segment, leaving the diagnosis in little doubt.

In some cases, the findings on the barium enema are uncertain and a delayed film at 24 h may confirm the diagnosis by demonstrating the retained barium and often accentuating the appearance of the transitional zone (Fig. 5). In the presence of enterocolitis complicating HSCR, a plain film will show dilated loops of bowel with fluid levels and a barium enema can demonstrate spasm, mucosal edema, and ulceration (Fig. 6) (Puri 2009, 2011).
Fig. 5

Delayed 24-h film in lateral position showing barium retention with accentuated transition zone at the rectosigmoid

Fig. 6

Enterocolitis complicating Hirschsprung’s disease. Note the fluid levels

In total colonic aganglionosis (TCA), the contrast enema is not pathognomonic and may not provide a definitive diagnosis. The colon in TCA is of normal caliber in 25–77% of cases (Menezes et al. 2008).

Anorectal Manometry

The recto-anal inhibitory reflex (RAIR) is defined as a reflex relaxation of the internal anal sphincter in response to rectal distension and is present in normal children.

In patients with HSCR, the rectum often shows spontaneous waves of varying amplitude and frequency in the resting phase and the internal sphincter rhythmic activity is more pronounced. On rectal distension, with an increment of air, there is complete absence of internal sphincter relaxation. Both term infants and premature babies have been shown to exhibit a well-developed recto-anal inhibitory reflex (RAIR) and anorectal pressures (Fig. 7). In the presence of an RAIR in children of under 1 year of age, HSCR is very unlikely. However, the specificity and positive predictive value of anorectal manometry (ARM) for the diagnosis of HSCR are inferior to those of rectal suction biopsy. Failure to detect the rectosphincteric reflex in premature and term infants is believed to be due to technical difficulties and not to immaturity of ganglion cells. Light sedation, particularly in babies and small children, may overcome technical challenges encountered in this age group (Puri 2009, 2011).
Fig. 7

Anorectal manometry

Rectal Biopsy

The gold standard in diagnosis of HSCR is the examination of rectal biopsy specimens. A suction rectal biopsy should involve sampling a segment of rectal wall 2 cm proximal to the dentate line along the posterior wall of the rectum. A biopsy taken too distally may obtain a specimen from the physiologically aganglionic region erroneously suggesting the presence of HSCR, whereas a biopsy taken too proximally (i.e., 5+ cm) may miss very short segment HSCR (Muise et al. 2016). It is also important to bear in mind that recent enemas causing mucosal edema may influence the quality of the specimens and also a poor technique such as incorrect placement of the biopsy system and low pressure, all contribute to inadequate biopsy specimens (Puri 2009, 2011).

The introduction of immunohistochemical staining (IHC) techniques for the detection of acetylcholinesterase (AChE) activity in the rectal suction biopsy (SRB) has resulted in a reliable and simple method for the diagnosis of HSCR (de Arruda Lourencao et al. 2013). Full-thickness rectal biopsy is rarely indicated for the diagnosis of HSCR except in total colonic aganglionosis. In normal persons, barely detectable acetylcholinesterase activity is observed within the lamina propria and muscularis mucosa, and submucosal ganglion cells stain strongly for acetylcholinesterase. In HSCR, there is a marked increase in acetylcholinesterase activity in lamina propria and muscularis which is evident as coarse, discrete cholinergic nerve fibers stained brown to black (Fig. 8) (Puri 2009, 2011). In total colonic aganglionosis, AChE activity in rectal suction biopsies presents an atypical pattern, different from the classic one. Positive AChE fibers can be found in the lamina propria as well as the muscularis mucosae. However, cholinergic fibers present a lower density than in classical HSCR.
Fig. 8

Acetylcholinesterase staining of suction rectal biopsy. (a) Normal rectum showing minimal acetylcholinesterase staining in mucosa, lamina propria and muscularis mucosae. (b) Hirschsprung’s characterized by marked staining of cholinesterase-positive nerves in the lamina propria and muscularis mucosae

Recently, calretinin, a calcium-binding protein that functions as a calcium sensor/modulator and expressed in submucosal and myenteric ganglion cells and mucosal nerve fibers has been described as an adjunctive or primary diagnostic test in HSCR. Aganglionic segments completely lack calretinin immunoreactivity in enteric nerves (Kapur et al. 2009). The sensitivity and specificity of calretinin IHC are equivalent to rapid AChE and that calretinin IHC may be informative when inadequate tissue is available to establish an H&E diagnosis (Fig. 9). A recent study reported that the definite diagnosis or exclusion of HSCR by calretinin IHC alone was more accurate than rapid AChE alone, with no major errors and fewer equivocal readings (Baker and Kozielski 2014). Moreover, calretinin staining decreased the rate of inconclusive results and increased the likelihood of a confirmed diagnosis. These results are in agreement with previous studies and argue for the addition of calretinin to the usual repertoire of stains used to diagnosis HSCR (Baker and Kozielski 2014).
Fig. 9

Calretinin staining of suction rectal biopsy

Differential Diagnosis

The most common condition that must be differentiated from HSCR is the meconium plug syndrome. Meconium plugs obstructing the colon can present as HSCR with strongly suggestive history and plain films. In meconium ileus, the typical mottled thick meconium may be seen. Also, clear, sharp, fluid levels are not a feature in erect or lateral decubitus views. However, HSCR can sometimes simulate meconium ileus in plain films and may give equivocal findings on Gastrografin or barium enema.

Other causes of intestinal obstruction in newborns such as intestinal atresia, left colon syndrome, and imperforate anus are also common differential diagnoses. Rare differentials such as colonic atresias give similar plain film findings to HSCR. However, it is readily excluded with barium enema showing complete mechanical obstruction. Distal small bowel atresia shows gross distension of the bowel loop immediately proximal to the obstruction with the widest fluid level in it.

Small left colon syndrome is associated with maternal diabetes and presents with marked distension proximal to narrowed descending colon and simulates HSCR at the left colonic flexure. This conditions usually resolve with Gastrografin enema.

Management

Once the diagnosis of HSCR has been confirmed by rectal biopsy examination, the infant should be prepared for surgery. If the newborn has enterocolitis complicating HSCR, correction of dehydration and electrolyte imbalance by infusion of appropriate fluids will be required as well as antibiotic coverage. It is essential to decompress the bowel as early as possible in these babies. Deflation of the intestine may be carried out by rectal irrigations with saline at a volume of 20 mL/kg three times daily via a large catheter located high in the rectum or descending colon. Some babies may require “leveling” colostomy. The level at which the colostomy is placed is determined by rapid frozen sections of seromuscular biopsies obtained from the colon during the operation. One must be assured that there are normal ganglion cells at the site of the proposed colostomy. Children with associated anomalies such as cardiac disease or congenital central hypoventilation syndrome must be investigated and managed before definitive surgical repair (Puri 2009, 2011).

In recent years, the vast majority of cases of HSCR are diagnosed in the neonatal period. Many centers are now performing one-stage pull-through operations in the newborn with minimal morbidity rates and encouraging results. The advantages of operating on the newborn are that the colonic dilation can be quickly controlled by washouts and at operation the caliber of the pull-through bowel is near normal, allowing for an accurate anastomosis that minimizes leakage and cuff infection. A number of different operations have been described for the treatment of HSCR. The four most commonly used operations are the rectosigmoidectomy developed by Swenson and Bill, the retrorectal approach developed by Duhamel, the endorectal procedure developed by Soave and deep anterior colorectal anastomosis developed by Rehbein (Puri 2006). The basic principle in all these procedures is to resect the aganglionic bowel and to bring the ganglionic bowel down to the anus by preserving an intact sphincter mechanism. The long-term results of any of these operations are satisfactory if they are performed correctly. Recently, several investigators have described and advocated a variety of one-stage pull-through procedures in the newborn using minimally invasive laparoscopic techniques. Many pediatric surgeons in recent years perform a transanal endorectal pull-through operation performed without opening the abdomen and have reported excellent results in rectosigmoid HSCR (Puri 2009, 2011).

Role of Colostomy

It is important to recognize a stoma may still be indicated for children with severe enterocolitis, perforation, malnutrition, or massively dilated proximally bowel, as well as in situations where there is inadequate pathology support to identify the transition zone on frozen sections. Many surgeons prefer right transverse colostomy; others advocate performing colostomy just above the transition to the ganglionic bowel. Ileostomy is indicated in patients who have total colonic aganglionosis (Puri 2009, 2011).

Transanal One-Stage Endorectal Pull-Through Operation

Over 80% of patients with HSCR have rectosigmoid aganglionosis. A one-stage pull-through operation can be successfully performed in these patients using a transanal endorectal approach without opening the abdomen. This procedure is associated with excellent clinical results and permits early postoperative feeding, early hospital discharge, no visible scars, and low incidence of enterocolitis (Kim et al. 2010).

A good barium enema study is essential for the transanal one-stage pull-through operation. A typical study of rectosigmoid HSCR will show flow of barium from undilated rectum through a cone-shaped transition zone into a dilated sigmoid colon (Puri 2009, 2011).

Operative Technique

The patient is positioned on the operating table in the lithotomy position. The legs are strapped over sandbags. A Foley catheter is inserted into the bladder. A Denis-Browne retractor or anal retractor is placed to retract perianal skin. The rectal mucosa is circumferentially incised using the cautery with a fine-tipped needle, approximately 5 mm from the dentate line, and the submucosal plane is developed. The proximal cut edge of the mucosal cuff is held with multiple fine silk sutures, which are used for traction (Fig. 10). The endorectal dissection is then carried proximally, staying in the submucosal plane.
Fig. 10

Transanal endorectal pull-through. (a) Rectal mucosa is circumferentially incised using the needle-tip cautery approximately 5 mm above the dentate line and submucosa plane is developed. (b) When the submucosal dissection is extended proximally for about 3 cm the muscle is divided circumferentially, and the full thickness of the rectum and sigmoid colon is mobilized out through the anus. (c) On reaching the transition zone, full-thickness rectal biopsies are taken for frozen section to confirm ganglion cells. (d) Colon is divided several centimeters above the most proximal biopsy site. (e) A standard Soave–Boley anastomosis is performed

When the submucosal dissection has extended for about 3 cm, the rectal muscle is divided circumferentially, and the full thickness of the rectum and sigmoid colon is mobilized out through the anus. This requires division of rectal and sigmoid vessels, which can be done under direct vision using cautery.

When the transition zone is encountered, full-thickness biopsy sections are taken, and frozen section confirmation of ganglion cells is obtained. The rectal muscular cuff is split longitudinally either anteriorly or posteriorly. The colon is then divided several centimeters above the most proximal normal biopsy site (Fig. 10), and a standard Soave–Boley anastomosis is performed (Fig. 10). No drains are placed. The patient is started on oral feeds after 24 h and discharged home on the third postoperative day. Digital rectal examination is performed 2 weeks after the operation. Routine rectal dilatation is not performed unless there is evidence of a stricture (Puri 2009, 2011).

Laparoscopic-Assisted Pull-Through

Despite the fact that many of the benefits of the pull-through procedure can be attained by transanal pull-through alone, significant advantages are realized by performing the laparoscopic dissection (Georgeson and Robertson 2004). Prior to the irreversible step of endorectal dissection, laparoscopy allows verifying the presence of ganglion cells in the proximal colon pedicle by seromuscular biopsy. In cases of total colon aganglionosis, a different type of pull-through operation or ostomy may be considered. Also, laparoscopic mobilization of the intra-abdominal segment increases the mobility of the rectum and makes the endpoint of the endorectal dissection more definitive (Georgeson et al. 1995).

Initially, three ports (Fig. 11) are placed to visualize the transition zone and to perform biopsies for histologic leveling. A window is then made between the colon and superior rectal vessels, and distal dissection of the aganglionic colon is then performed circumferentially, keeping close to the colon wall, carefully preserving the mesenteric blood supply to the rectum. Blunt and sharp dissection of avascular plane posterior to the rectum follows. Anteriorly, the rectum is dissected for about 1–2 cm below the peritoneal reflection. It is important to avoid too extensive lateral dissection, where damage to the nervi erigentes can result. Proximal mesenteric dissection of the colon pedicle with careful preservation of the marginal artery depends on the extent of the aganglionic segments; some patients require sigmoid colon mobilization or division of the lateral colonic fusion fascia up to the splenic flexure. After the endoscopic dissection of the colon and rectum has been completed, the pneumoperitoneum is released and the instruments are removed, and the procedure is completed with an endorectal transanal pull-through.
Fig. 11

Position of trocar sites for laparoscopic pull-through

Once, the anastomosis of the proximal ganglionated colon with the anorectal cuff is completed, reinsufflation for pneumoperitoneum can be performed to inspect the colon pedicle for twisting or potential internal herniation (Georgeson et al. 1995; Puri 2009, 2011).

Postoperative Care

Most infants undergoing pull-through for HSCR can be fed next day. The anastomosis should be calibrated with an appropriately sized dilator 2 weeks after the procedure.

Complications

Early postoperative complications which can occur after any pull-through operation include wound infections, anastomotic leak, anastomotic stricture, retraction or necrosis of the neorectum, intestinal adhesions, and ileus. Late complications include constipation, enterocolitis, incontinence, anastomotic problems, adhesive bowel obstruction and urogenital complications (Puri 2009, 2011).

Anastomotic Leak

The most dangerous early postoperative complication following the definitive abdominoperineal pull-through procedure is leakage at the anastomotic suture line. Factors which are responsible for anastomotic leak include ischemia of the distal end of the colonic pull-through segment, tension on the anastomosis, incomplete anastomotic suture lines, and inadvertent rectal manipulation. If a leak is recognized in a patient without a colostomy, it is imperative to perform a diverting colostomy promptly, to administer intravenous antibiotics and to irrigate the rectum with antibiotic solution a few times daily. Delay in establishing fecal diversion is likely to result in a large pelvic abscess which may require laparotomy and transabdominal drainage (Puri 2009, 2011).

Retraction of Pull-Through

Retraction of a portion or all of the colonic segment from the anastomosis can occur and is usually seen within 3 weeks of the operation. Evaluation under general anesthesia is generally necessary. In occasional patients, resuturing the anastomosis may be feasible transanally. For those with separation of less than 50% of the anastomosis but with adequate vascularity of the colon, a diverting colostomy for approximately 3 months is necessary. For patients with wide separation at the anastomosis, early transabdominal reconstruction of the pull-through is recommended (Puri 2009, 2011).

Perianal Excoriation

Perianal excoriation occurs in nearly half of the patients undergoing pull-through procedure but generally resolves within 3 months with local therapy and resolution of diarrhea. It is helpful to begin placing a barrier cream on the perianal skin promptly after the operation and to continue after each movement for the first few weeks. Resolution of diarrhea will often hasten the clearance of perianal skin irritation.

Enterocolitis

Hirschsprung’s associated enterocolitis (HAEC) is a significant complication of HSCR both in the pre-and postoperative periods. HAEC can occur at any time during the neonatal period onwards to adulthood and can be independent of the medical management and surgical procedure performed. The incidence of enterocolitis ranges from 20% to 58% (Menezes and Puri 2006). Fortunately, the mortality rate has declined over the last 30 years from 30% to 1%. This decrease in mortality is related to earlier diagnosis of HSCR and enterocolitis, rectal decompression, appropriate vigorous resuscitation, and antibiotic therapy. It has been reported that routine postoperative rectal washouts decrease both the incidence and the severity of the episodes of enterocolitis following definitive surgery. In episodes of chronic enterocolitis, which can develop in up to 56% of patients, anal dilatations and metronidazole have been recommended. However, before commencing a treatment regime, a contrast enema should be performed to rule out a mechanical obstruction. Patients with a normal rectal biopsy and recurrent episodes of enterocolitis may require a sphincterotomy (Puri 2009, 2011).

Constipation

Constipation is common after definitive repair of HSCR and can be due to residual aganglionosis and high anal tone. Repeated and forceful anal dilations and intrasphincteric botulin toxin injection under general anesthesia may resolve the problem. In some patients, internal sphincter myectomy may be needed. In patients with scarring, stricture, or intestinal neuronal dysplasia proximal to aganglionic segment, treatment consists treating the underlying cause (Puri 2009, 2011).

Soiling

Soiling is fairly common after all types of pull-through operations; its precise incidence primarily depends on how assiduously the investigator looks for it. The reported incidence of soiling ranges from 10% to 30% (Ruttenstock and Puri 2010). The attainment of normal postoperative defecation is clearly dependent on intensity of bowel training, social background, and respective intelligence of the patients. Mental handicap, including Down syndrome, is invariably associated with long-term incontinence. Those patients with preoperative enterocolitis would also appear to have a marginally higher long-term risk of incontinence. In some patients in whom soiling is intractable and a social problem, a Malone antegrade continence enema procedure may be needed to stay clean (Puri 2009, 2011).

Long-Term Outcome

The vast majority of patients treated with any one of the standard pull-through procedures achieve satisfactory continence and function with time (Menezes et al. 2006). The attainment of normal continence is dependent on the intensity of bowel training, social background, and respective intelligence of patients. Mental handicap, including Down syndrome, is invariably associated with long-term incontinence (Granstrom et al. 2015; Menezes and Puri 2005).

Conclusion and Future Directions

The progress in understanding normal gut development and motility has led to an expanding field of research into developing novel therapies for HSCR. During the last decade, there has been increasing focus on the development of novel stem cell-based therapies for the treatment of HSCR. Stem cell transplantation using laboratory cultured neural stem cells (NSCs) to colonize aganglionic intestine and restore intestinal motility has been proposed as a treatment for HSCR. Transplanted NSCs may contribute to functional improvement directly by repopulating the aganglionic gut with implanted neurons and restoration of neural circuits, and may also release trophic factors or neurotransmitters which can improve intestinal contractile function and finally could open a new field in the treatment of HSCR. However, the optimal source of stem cells to generate a “new” enteric nervous system in the aganglionic bowel in HSCR has yet to be established. Further research is needed to determine the optimal source of stem cells to replace ENS in HSCR and determine the best way to deliver stem cells to the bowel.

Cross-References

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Prem Puri
    • 1
    • 2
    Email author
  • Christian Tomuschat
    • 1
  • Hiroki Nakamura
    • 1
  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublinIreland
  2. 2.School of Medicine and Medical Science and Conway Institute of Biomedical ResearchUniversity College DublinDublinIreland

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