Hirschsprung Disease — Current Diagnosis and Management
Hirschsprung disease is a common cause of neonatal and infantile large gut obstruction. It is characterised by varying extent of contiguous aganglionosis extending from the anorectum proximally. Since its recognition, the diagnosis and management has continuously evolved with advances in histological evaluation and surgical techniques. This article summarizes the current modalities of investigation and optimal surgical management of Hirschsprung disease and concludes with a reference to the Indian scenario.
KeywordsHirschsprung disease Current diagnosis Management Indian
Hirschsprung disease (HD) is the commonest cause of functional large gut obstruction in children. It is characterized by contiguous bowel aganglionosis extending proximally from the anus to varying extents, with a ganglionic to aganglionic histologic ‘transition’ zone occurring before a normally innervated zone. The Rectosigmoid form (RsHD) is the classic, common variety (75–80%); Long segment colonic Hirschsprung disease (LScHD; 10–15%) or Total colonic aganglionosis with ileal involvement upto 50 cm proximal to the ileocecal junction (TCA; 5–7%) are uncommon [1, 2, 3]. A related entity, Internal anal sphincter achalasia (IASA), earlier termed ultra short segment HD is touched upon.
With better awareness and easier reach of tertiary health care, now an increasing number present in the neonatal period or infancy. Unless the distal-most ganglionic segment is too dilated, a single stage surgical management is feasible. This article deals with the current modalities of diagnosis and algorithm of management in Hirschsprung disease with particular reference to the Indian context.
Diagnosis of Hirschsprung Disease
Radiographic studies – Plain abdominopelvic X-rays, contrast enema
Biopsy – Rectal biopsy, levelling biopsies
Unlike several anatomic bowel malformations, HD rarely lends itself to an antenatal diagnosis. Occasionally, long segment (colonic / total colonic aganglionosis) disease may be suspected with a past history of sibling affliction or stigmata of an associated neurocristopathy or echogenic bowel on antenatal ultrasonography or MRI . Most are however, diagnosed postnatally.
A clinical presentation of large bowel obstruction presenting at any time from the postnatal period to adulthood but dating back to infancy/ early childhood is typical. Failure to pass meconium within 24–48 h of birth is the cardinal clinical feature in 80–90% infants with HD but also in 30–40% children without HD and in 30–35% of healthy preemies. Abdominal distension, non bilious vomiting and constipation dating back to early infancy is characteristic . Other presentations include an acute ‘toxic’ enterocolitis at any age, infantile constipation that often manifests at weaning and a recurrent symptom complex of constipation with intervening spurious diarrhea; these may culminate in failure to thrive. Associated dysmorphology, trisomy 21 and signs of neurocristopathy (e.g., white forelock of Wardenberg syndrome, multiple cutaneous nevii) are rare. Hirschsprung associated enterocolitis is a fulminant sepsis  with bowel distension and may present as perforation of the cecum or appendix.
Medical conditions like hypothyroidism and sepsis may mimic HD. TCA must be differentiated from meconium plug syndrome, small left colon syndrome (diabetic mother), distal small bowel /colonic atresia and meconium ileus – cystic fibrosis complex. Clinical observation of the nasogastric aspirates, serial abdominal girth, systemic review and response to rectal stimulation often clarify the suspicion.
In an older child, habitual constipation must be ruled out. A normal meconium history, recent onset of constipation, poor dietary fiber, associated voiding disturbances and psychological overlay is frequent. There is a conspicuous lack of abdominal distension and the rectum is filled with feces till the anal verge and soils the perineum.
Unlike generally believed, TCA may present beyond infancy with chronic features. IASA may be asymptomatic or manifests with subtle to frank obstructive symptoms indistinguishable from classical HD.
Usually, screening investigations (imaging, anorectal manometry) precede histological confirmation. The choice of screening investigation depends on the availability and expertise of the centre. In India, imaging, rather than manometry, is widely available and employed for the provisional diagnosis.
Anorectal Manometry (ARM)
In HD as well as IASA, the normal Rectoanal inhibitory reflex (RAIR) or inhibition of the resting rhythmic activity of the internal anal sphincter with rectal distension, is lost . It is preserved in habitual constipation. ARM is minimally invasive but demands technical expertise and laboratory standardization. Unlike neonates and infants, it is more easily performed in an older cooperative child and has a variable (75–95%) accuracy. The reflex is established by 26 wk of gestation and is elicited even under sedation /anesthesia; thus allowing for evaluation in preemies, neonates, infants and uncooperative patients .
False positives and false negatives are largely technical (suboptimal rectal distension, air leak, erroneous transducer site, probe displacement, relaxation of external anal sphincter etc.) and may be seen in up to 25%. The sensitivity and specificity of ARM is excellent (90–94%) but a histopathological confirmation is mandatory prior to surgical intervention . Recent procedural modifications include sleeve micromanometry assembly and transperineal ultrasonographic assessment of the RAIR.
Imaging - Plain Radiographs and Contrast Studies
In LScHD, the transition zone features are correspondingly proximal, while in TCA the ‘microcolon’ has a foreshortened splenic flexure and sigmoid loop and assumes a question mark configuration. In both, the rectosigmoid ratio may still be preserved and the rTZ may be long [14, 15]. Despite precautionary measures, including slow instillation of contrast, real time fluoroscopic evaluation and guarded interpretation, false positive (43%) and false negative rates (20%) are recognized in all forms and ages. False negatives are frequent in neonates and in long segment disease. Besides, in 10% of cases, radiologists do not concur on the site and length of the radiologic TZ in LScHD and TCA .
Overall, the contrast enema is a good screening investigation to select cases for a final histopathological confirmation .
Histopathological confirmation is the gold standard for diagnosis with 93–98% sensitivity and specificity . It is a two step investigation (i) Rectal biopsy to establish aganglionosis in all forms of the disease (ii) proximal bowel biopsies or ‘leveling’. The site of ‘leveling’ biopsies is based on the clinicoradiological suspicion of the extent of involvement; it is aimed at mapping the ganglionic-aganglionic transition and the distal most level of normal innervation (Fig. 1).
Routine staining technique: Hematoxylin & Eosin (H & E)
Special staining techniques: AChE (Acetylcholinesterase) enzyme histochemistry, Calretinin immunohistochemistry. AChE stain highlights the abnormal parasympathetic nerve fibers arborising from the submucosal nerve trunks centrifugally through the lamina propria and between the mucosal glands towards the epithelial surface. Calretinin is a vitamin D-dependent calcium-binding protein with expression in ganglion cells and intrinsic nerves normally present in the bowel wall.
The rectal biopsy is the primary sample to establish the diagnosis of HD. It may be partial (mucosubmucosal) or full thickness and is obtained from atleast 2 cm above the dentate line to avoid the physiological hypoganglionic zone. A suction rectal biopsy is a simple, efficient, reliable and quick outpatient procedure. However, the sample is ‘adequate’ for comment on enzyme histochemistry only with enough submucosal tissue. In contrast to conventional H & E staining of paraffin sections where 60–80 serial sections are carefully examined to exclude a diagnosis of HD, AChE staining on fresh muco-submucosal tissue sections or Calretinin staining on formalin fixed tissue sections offers a conclusive diagnosis with a couple of sections. Frozen H & E with concurrent AChE staining on fresh tissue clinches the diagnosis in 30–45 min [18, 19, 20].
Once rectal aganglionosis is established, serial seromuscular point biopsies are evaluated proximally . The gross and radiological transition zone guide the siting of these biopsies. The length of the radiologic transition zone (rTZ) and histologic transition zone (hTZ) may not correlate in LScHD and TCA. The hTZ extends more proximally with discrepancies in circumferential innervation [22, 23]. In TCA, the evaluation extends into the ileum; the earlier reliance on appendicular histology is challenging and not advisable . At the distal-most normal point biopsy, a ‘doughnut’ of the bowel is carefully scrutinized before normal circumferential innervation (NI) is pronounced . Thus a stringent intraoperative evaluation of bowel innervation is central to ‘leveling’ (Fig. 1).
The histological features in the aganglionic (absence of ganglion cells in the plexii, hypertrophic nerve bundles in submucosa and myenteric plexus), ganglionic (regularly distributed normal morphology ganglion cells along the circumference, normal nerve fiber distribution) and intervening transition segment (a variable mix of both features) are well documented. In TCA, the colonic biopsies are typically ‘bland’ and show neither ganglion cells nor hypertrophic nerve bundles till the small bowel transition is reached.
IASA has normal distribution of ganglion cells in the rectal biopsy, but recent observations have shown a definite AChE positive nerve fibers pattern [18, 26]. Here, rectal biopsies are taken either as a longitudinal strip of muco-submucosa / multiple small bits at 0.5 cm distance from just above the dentate line cranially for a 2–4 cm. The latter combines an internal anal sphincter myotomy which is therapeutic.
Proper biopsy technique, coordination between the surgeon and the pathologist and experience of the two are crucial factors in this diagnostic exercise.
Most cases of HD are sporadic. Yet, the disease seems to be a sex modified, multifactorial state with a heterogeneous inheritance involving dominant/ recessive and polygenic forms in multiple pathways . More than a dozen gene loci related to early embryonic development, including RET, EDNRB, GDNF, NTN,, EDN3, ECE1, SOX10 and SIP1 are involved. The two major gene loci of diagnostic importance are the long arm Ch 10 (RET proto oncogene, in 7–41% of HD, mendelian inheritance, incomplete penetrance, sex dependent, poor geno-phenotypic correlation, correlates with AChE positive features) and the 13q22-EDNRB gene coding for nitric oxide synthetase. Genetic correlates are sometimes found in long segment disease and familial occurrences. However, since multiple pathways are involved and the gene expression is complex, inheritance patterns and pedigree analysis are difficult and genetic counseling is not the norm .
Treatment of Hirschsprung Disease
The logistics of rectal biopsy (outpatient basis/ intraoperative evaluation under anesthesia, punch /suction biopsy, partial /full thickness) and leveling biopsies (laparotomy/ laparoscopic/ endorectal) described earlier is closely linked to the available expertise and protocol of management at a centre. The principles of treatment include complete excision of the meticulously mapped aganglionic and transition zones and surgical apposition of the distal-most normally innervated bowel within 1–2 cm of the dentate line. The caudal limit of anastomosis aims at dividing the cranial half of the spastic internal anal sphincter while preserving the external anal sphincter in entirety.
During emergency situations (enterocolitis, bowel perforation, acute intestinal obstruction, unprepared bowel) where intraoperative ‘leveling’ is not feasible, a ‘blind’ proximal stoma at the distal most dilated bowel is performed and multiple seromuscular biopsies are obtained for mapping the zones. Elective surgery is always scheduled after suitable bowel preparation and may be staged (initial stoma, later pull though) or single staged depending on the intraoperative leveling and dilatation at the pull through level. Traditionally, the standard definitive pull through procedures for colonic HD are Swenson, Duhamel and Soave. Though technically different, they produce comparable results with minor differences . Today, the two common procedures preferred worldwide are ‘single’ staged – Duhamel and Transanal endorectal pull through (TAERPT) . TAERPT is generally reserved for RsHD and avoids a laparotomy; however in LScHD, additional laparotomy / laparoscopic assistance for colonic mobilisation is necessary.
In TCA, where the pull through level extends into the distal or mid ileum, surgical modifications have included retaining a patch of left/right colon on the pull through ileum for enhancing water absorption and minimizing fecal fluid loss . Recently TCA is being managed with a preliminary leveled ileostomy and a conventional Duhamel procedure with comparable outcome. During the intervening period, the distal ileum adapts to takeover the absorptive bowel function to a considerable extent. As stated earlier, IASA responds well to internal anal sphincter myotomy or myectomy; the alternative therapy with intrasphincteric injection of botulinum toxin is temporary .
The Indian Scenario
Clinical diagnosis and imaging (plain, contrast enema) form the mainstay of diagnosis across the country. Histological confirmation and leveling with routine Hematoxylin & Eosin staining on paraffin sections guides the surgical management in most tertiary centres; frozen section guidance is offered in a few. A handful employ AChE or Calretinin staining as an adjunct modality routinely; of late the latter is being adopted more frequently. Intraoperative leveling and single stage pull through is feasible in a select few only. However, since the surgeon - pathologist coordination and expertise is not as optimal in many practising centres across the country - teaching/non teaching, government/private/corporate, several stomas and pull throughs continue to be ‘blind’ or not ‘leveled’. This compromises the outcome significantly. These problems are peculiar to our country and have to be addressed with continuing education and training of all medical personnels involved in health care of children.
Though literature is divided on this issue, the long term outcome of the principled management of HD is generally excellent in the largest segment of HD - RsHD. In LScHD, the quality of life approaches that of RsHD with a slightly increased frequency of bowel movement. However in TCA, the outcome is more guarded with modest somatic growth and a propensity for diarrheic episodes. IASA is eminently managed with internal sphincter disruption or paralysis.
In conclusion, a strong clinical suspicion of HD and allied disorders may be reasonably bolstered by findings on imaging or anorectal manometry. Confirmation of diagnosis and leveling is currently achieved by combination of histopathological - histochemical modalities in an individualised fashion. The surgical management is tailored to effect a lasting cure with specific surgical intervention. Genetic assays are still experimental but may offer more practical means of diagnosis in the future.
The authors acknowledge the contribution of several faculty members from the Departments of Pediatric Surgery and Pathology**, St. John’s Medical College Hospital, Bangalore who have been part of the ‘Hirschsprung Team’ at the Academy from 1998 to 2017: Ashley D’Cruz, Usha Kini**, M K Babu**, Anand Alladi, Sanjay Rao, Antony Robert Charles, Mainak Deb, Shubha AM, Divya P**, Nandeesh BN**, Saleem KM, Prasanna Kumar AR, Kiran M, Lokendra Yadav**, Maria Bukelo** & Amanda Pinto**.
KD and SM have jointly prepared the manuscript and are responsible for the intellectual content. KD will act as guarantor for the paper.
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