Hirschsprung’s Disease

Introduction

Hirschsprung’s disease is a congenital intestinal motility disorder affecting 1 in 5000 newborns.

It is characterised by aganglionosis of the distal large intestine. The absence of enteric ganglion cells is commonly limited to the rectosigmoid segment but may extend proximally beyond the sigmoid colon.

Subsequently, the denervated length of the colon fails to undergo peristalsis and functional colonic obstruction occurs.¹

Aetiology

In Hirschsprung’s disease, aganglionosis occurs due to disrupted craniocaudal migration of neural crest cells (NCCs) during the first trimester of pregnancy. As a result, these cells fail to reach the distal gut and subsequently differentiate into enteric ganglion cells.²

Genetic studies have discovered at least 24 genes, whose mutations could lead to defective migration and differentiation of NCCs. The gene commonly implicated is the receptor tyrosine kinase (RET) gene, mutations of which have been noted in up to 35% of sporadic cases and 50% of familial cases.^2,3

Pathophysiology and subtypes

The lack of enteric innervation l­eads to tonic contraction of the aganglionic segment. This leads to a lack of effective peristalsis and failure of the internal anal sphincter to relax.

These events result in functional colonic obstruction. Intestinal contents such as faeces accumulate and subsequently secondary dilation of the more proximal healthy innervated colonic tissue occurs.^3,4

Due to the variable nature of the length of aganglionosis, there are three main anatomical subtypes of Hirschsprung’s disease:^2,3

• Short segment: commonest subtype, seen in ~80% of patients where aganglionosis involves only the rectosigmoid segment
• Long segment: the aganglionosis extends proximally beyond the sigmoid colon, typically to the splenic flexure/transverse colon and occurs in ~ 15-20% of patients
• Total colonic aganglionosis: seen in ~5% of patients, where the entire colon is involved

Risk factors

 The following risk factors are associated with an increased likelihood of developing the condition:^4,5

1. Male sex: males have a four-fold higher risk than females of developing Hirschsprung’s disease. However, where the entire colon is involved the sex ratio nears 1:1.
2. Family history: 10% of patients have a positive family history, although most cases are sporadic.
3. Chromosomal associations: found in up to 32% of patients, with the commonest association being Down’s syndrome. Other rarer associations include Waardenburg syndrome and multiple endocrine neoplasia type 2a (MEN2a).

Clinical features

The majority (75%) of cases present during the neonatal period. The severity of symptoms may vary depending on the length of the aganglionic segment.²

History

During the neonatal period, the typical triad of symptoms of Hirschsprung’s disease is:⁴

• Failure to pass meconium within the first 24-48 hours of life, in a term infant
• Abdominal distension
• Bilious vomiting

In practice, however, only 26% of patients present with all three features.⁴ Other symptoms include irritability, “spitty’’ after feeds and feeding intolerance.

For patients who present later in life, clinical features include:^1,4

• History of chronic constipation since birth, which may be associated with overflow diarrhoea
• Faltering growth
• Malnutrition
• Lethargy
• Feeding difficulties

Furthermore, for all age groups, a thorough systems review is required as associated congenital anomalies in other body systems (e.g. ophthalmological, neurological, and cardiac) have been noted in up to 60% of patients.³

Clinical examination

For patients who present early before the onset of HAEC, typical clinical findings include:^2,3

• Abdominal examination: grossly distended abdomen, faecal mass in the left lower quadrant, tympanic percussion note (due to intestinal distension), increased bowel sounds (a sign of early obstruction) which may progressively decrease in frequency
• Digital rectal examination: normally placed patent anus (allowing passage of finger), increased anal sphincter tone, empty rectal vault, withdrawal of the examining finger leads to a gush of liquid stool and flatus known as the “blast sign” due to dramatic rectal decompression.

If the patient presents with HAEC, it is important to look for clinical manifestations of underlying hemodynamic instability such as hypovolemia, hypotension or sepsis.

Differential diagnoses

Due to the non-specific symptoms of Hirschsprung’s disease, there are several differential diagnoses to consider. They can be divided into two categories based on the age of presentation.^2,4

Table 1. Differential diagnoses to consider in the context of Hirschprung’s disease.

Investigations

Rectal biopsy

If there is no evidence of HAEC, the diagnosis of Hirschsprung’s disease can be confirmed by performing a rectal biopsy with acetylcholinesterase (AChE) staining.

The diagnosis requires the histopathological demonstration of:^2,5

• Absence of colonic ganglion cells
• Presence of hypertrophic (> 40 micrometres) AChE-positive nerve fibres in the distal rectum (Figure 1).

A suction rectal biopsy (which can be performed in the outpatient setting), is usually adequate for diagnosis. An alternative method is a full-thickness biopsy performed under general anaesthesia.

Laboratory investigations

If the clinical presentation is ambiguous for Hirschsprung’s disease or the patient presents critically unwell or with clinical features of HAEC, additional relevant laboratory investigations include:

• Full blood count: leukocytosis should raise suspicion for Hirschsprung’s associated enterocolitis or sepsis
• Sepsis investigations: blood cultures, serum lactate test, CRP, urinalysis and culture if the clinical suspicion for sepsis is high
• Arterial blood gas: if indicated (e.g. low SpO2) to assess the degree of hypoxia
• Serum electrolytes: to rule out electrolyte imbalances such as hypercalcemia and hypokalemia which can cause constipation or aggravate it
• Thyroid function tests: to exclude hypothyroidism

Imaging

Relevant imaging investigations include:

• Abdominal X-ray: can reveal features indicative of distal intestinal obstruction (Figure 2). These include air-fluid levels, distended proximal bowel loops (predominantly colonic) and absence of rectal gas.²
• Barium studies: performed after the abdominal X-ray, for identification of the transition zone between the contracted distal bowel and dilated proximal bowel, and the classical “saw-tooth” appearance of the aganglionic segment (Figure 3). Useful in approximating the length of the aganglionic segment for the surgeon.^1,3

Other investigations

Other relevant investigations include:

• Anorectal manometry: the inability to elicit relaxation of the internal anal sphincter in response to distension of the rectum with the balloon is typically seen in Hirschsprung’s disease.²

Management

Initial management

The initial management of Hirschsprung’s disease depends on haemodynamic status, hydration status and any evidence of underlying HAEC.

If the patient is unwell, treatment should focus on stabilising the child first. This would involve measures such as intravenous fluid resuscitation.

Should the child present with features of HAEC, then prompt recognition is vital to prevent disease progression to toxic megacolon, bowel rupture and bacterial sepsis.

Treatment of HEC involves intravenous broad-spectrum antibiotics (e.g. metronidazole), fluid resuscitation, routine colonic irrigation, nasogastric/orogastric bowel decompression and making the patient nil-by-mouth for complete bowel rest.

In addition, the sepsis six care bundle should be initiated within an hour after presentation should sepsis have already developed secondary to HAEC.^2,6

Definitive management

The definitive management of Hirschsprung’s disease is the surgical removal of the aganglionic segment, followed by a pull-through of the proximal healthy bowel down to the anal canal with preservation of sphincter function.

Routine colonic irrigation is performed daily following diagnosis to bridge the gap to surgery. Typically, patients receive one to three daily irrigations using 10-20mL of normal saline solution to wash out the intestinal contents.² Irrigation is vital in preventing enterocolitis due to bacterial overgrowth resulting from faecal stasis.⁵

Three types of pull-through surgical techniques exist:⁴

• Swenson
• Duhamel
• Soave

Consultation with the paediatric surgical team is essential to decide the type of pull-through method and the timing of surgery for the child.²

Complications

General complications of Hirschsprung’s disease include:

• Hirschsprung associated enterocolitis (HAEC)
• Bowel perforation

Post-operative complications can be divided into early and late complications.^5,8

Table 2. Post-operative complications related to Hirschprung’s disease

Key points

• Hirschsprung’s disease is the congenital absence of ganglion cells in the enteric nervous system of a variable length of the large intestine beginning from the terminal rectum.
• The cause of aganglionosis is commonly linked with the mutation of genes in the RET pathway leading to disrupted migration of neural crest cells in utero.
• Clinical presentation typically involves failure to pass meconium within 24-48 hours of life and features of intestinal obstruction such as abdominal distension and bilious vomiting.
• An abdominal X-ray may show features of bowel obstruction such as dilated bowel loops and air-fluid levels. These findings, however, are non-specific.
• Diagnosis is confirmed by rectal biopsy to confirm the absence of ganglion cells.
• Treatment involves supportive care, colonic irrigation and surgical resection of the pathological segment with anastomosis.
• Post-operative complications include enterocolitis, faecal and urinary continence and complications associated with colorectal surgeries such as wound infections and anastomotic leaks.

Reviewer

Dr Khor Shed Peng

Senior Lecturer, Paediatrician, Monash University Malaysia

Editor

Dr Chris Jefferies

References

Text references

1. Lissauer T, and Carroll W. Illustrated textbook of paediatrics. 6th Edition.2022. Elsevier Science. Chapter 14 (p 257-258).
2. BMJ Best Practice. Hirschsprung’s disease. Available from: [LINK]
3. Thakkar H, Curry J. Hirschsprung’s disease. Paediatrics and Child Health. 2020;30(10): 341-344. 
4. Kliegman R, St. Geme J, Blum N, Schor N, Behrman R, and Nelson W. Nelson textbook of pediatrics. 21st Edition. 2020. Elsevier. Chapter 358.
5. Lotfollahzadeh S, Taherian M, Anand S.Hirschsprung Disease.Statpearls [Internet]. Treasure Land (FL): Statpearls Publishing; 2022 Jan. Available from: [LINK]
6. Lewit RA, Kuruvilla KP, Fu M, Gosain A. Current understanding of Hirschsprung-associated enterocolitis: Pathogenesis, diagnosis and treatment. Semin Pediatr Surg. 2022;31(2):151162.
7. NICE. Constipation in children and young people: diagnosis and management.2010. Available from: [LINK]
8. Hagens J, Reinshagen K, Tomuschat C. Prevalence of Hirschsprung-associated enterocolitis in patients with Hirschsprung disease. Pediatr Surg Int. 2022;38:3-24.

Image references

• Figure 1. Marvin 101. Histopatholgy of Hirschsprung’s disease. Licence: [CC BY-SA 3.0]
• ­­­Figure 2. Dr Hani Makky Al Salam. From the case rID: 7570. License: [CC BY-NC-SA]
• ­­­Figure 3. Dr Hani Makky Al Salam. From the case rID: 7570. License: [CC BY-NC-SA]