Questioning the Correlation Between Incidence of Hirschsprung Disease and Indications for Rectal Biopsy

Introduction

Chronic constipation is a common and persistent problem in childhood, accounting for approximately 3% of visits to pediatric out-patient clinics and 25% of visits to pediatric gastroenterology clinics.^1,2 Hirschsprung’s disease (HD) is rare but is a valid differential diagnosis for children of any age with severe constipation.^3,4 However, because of the large number of children with symptomatic constipation, it is reasonable to try assisting defecation with laxatives and enemas before resorting to rectal mucosal/submucosal biopsy (RMSBx) required to diagnose HD.

RMSBx is an invasive procedure if performed using general anesthesia for optimum accuracy according to published guidelines, ⁵ and rectal suction biopsy is available as an office/outpatient procedure, but is potentially traumatizing to both patient and caregivers. As a result, the process of diagnosing HD reliably is challenging. The case of an adult with chronic constipation managed effectively without enemas but who was eventually diagnosed with HD prompted review of the indications for RMSBx as enema usage had conventionally been considered an absolute prerequisite for RMSBx.

Methods

The medical records of all the children older than 1-year-old and less than 15 years old who presented or were referred with clinical signs and symptoms of chronic constipation between 2012 and 2022 were reviewed, retrospectively. All cases were followed-up at specialty outpatient clinics staffed by board certified wound, ostomy, and continence nurses who monitored defecation with laxative (L) and enema (E) usage and their effectiveness. From 2012 to 2018, RMSBx was indicated when enemas were required to assist defecation after laxatives alone were ineffective (E+). Because of the case of chronic constipation managed without enemas, the indications for RMSBx were modified in 2019 to include patients requiring laxatives for at least 3 months, irrespective of enema usage (L+). Infants less than 12 months old and children with chromosomal anomalies were excluded (Fig. 1).

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FIG. 1.

Diagnostic diagram for constipation. RMSBx, rectal mucosal/submucosal biopsy; E, enema; L, laxative; HD, Hirschsprung’s disease.

In the present study, the effect of enema usage was assessed by comparing E+ with L+. For thoroughness, L+ was subdivided into subjects who benefitted from enemas (L+E+) and those who did not require enemas (L+E−). Subjects were compared for rates of RMSBx (E+RMSBx versus L+RMSBx and L+E+RMSBx versus L+E−RMSBx) and incidence of HD (E+HD versus L+HD and L+E+HD versus L+E−HD).

RMSBx were performed under general anesthesia according to a standard technique that is described elsewhere. Briefly, a wedge biopsy under direct vision after anal dilatation with the patient in the lithotomy position was performed. All RMSBx specimens were examined by two board certified pathologists with extensive experience of diagnosing HD in pediatric patients.

Subject demographics, surgical results, and postoperative outcomes 1 year after surgery (frequency of spontaneous defecation, percentage of bowel movements requiring assistance with laxatives or enemas) were compared.

Data were analyzed using standard statistical methods. Demographic data and postoperative outcomes were compared using the Student’s t-test. The chi-squared test or Fisher’s exact test were used to analyze correlation between bowel function and the incidence of complications. For all statistical tests, P of .05 was used as the cut-off value for significance. This study was approved by the institutional review board of Juntendo University School of Medicine.

Results

There were 562 children with chronic constipation identified for this study. According to types of assisted defecation, there were E+ (n = 410) and L+ (n = 152). Overall, RMSBx rates were significantly higher in L+ at 42/152 (27.63%) compared with E+ at 36/410 (8.78%) (p < .01). For L+, RMSBx rates were L+E+ (n = 15/42) and L+E− (n = 27/42). Incidence of HD in L+ (L+HD) was 13/42 (30.95%) and in E+ (E+HD) was 8/36 (22.22%); this difference was not statistically significant (P = .38). Incidence of HD in L+E+ (L+E+HD) was 5/15 (33.33%) and in L+E− (L+E−HD) was 8/27 (29.63%); this difference was not statistically significant (P = .80). For HD subjects, no common demographic features were identified; gender ratios (M:F) were E+HD 4:4 versus L+HD 8:5 (P = .60) and L+E+HD 3:2 versus L+E−HD 5:3 (P = .92); differences were not statistically significant. All HD cases were diagnosed with rectosigmoid type HD. Mean ages (range) in years at diagnosis were: E+HD 3.38 (1–5) versus L+HD 3.85 (1–11) (P = .67) and L + E+HD 3.40 (2–6), L+E−HD 4.13 (1–11) (P = .79).

Mean operative times (hours) for laparoscopy-assisted primary Soave pull-through performed for HD diagnosed by RMSBx, were similar in hours E+RMSBx 4.38 ± .60 versus L+RMSBx 4.15 ± .47 (P = .35) and L+E+RMSBx 4.20 ± .57 versus L+E-RMSBx 4.13 ± .44 (P = .39). No intraoperative complications were reported, but there was one intrapelvic abscess in each of E+pull-through for HD and L+pull-through for HD (L+E-pull-through for HD); this difference was not statistically significant (P = .71). There were no reports of postoperative enterocolitis requiring hospitalization recorded.

For postoperative bowel function, at 6 months, frequency of voluntary bowel movements was not statistically different between E+HD (1.75/day) versus L+HD (2.03/day) (P = .59) and L+E+HD (1.60/day) versus L+E−HD (2.31/day) (P = .60); and at 12 months, voluntary bowel movements were confirmed in E+HD for 7/8 (87.5%) versus L+HD for 11/13 (84.6%) (P = .85) and L+E+HD for 4/5 (80%) versus L+E−HD for 7/8 (87.5%) (P = .71); these differences were not statistically significant. Laxatives were required in E+HD for 2/8 (25%) versus L+HD for 3/13 (23.1%) (P = .91) and L+E+HD 1/5 (20%) versus L+E−HD for 2/8 (25%) (P = .83); these differences were not statistically significant.

Discussion

The timing for investigating chronic constipation in infants is controversial because of a spectrum of factors that can influence bowel function. Diagnosing HD is intimately associated with investigating chronic constipation. While Singh et al. ⁶ found that 90% of children with HD were diagnosed in the neonatal period, other papers report less and Rahmen et al. ⁷ found that 53% of positive diagnoses for HD were made in children presenting after the neonatal period. It is unclear why such large discrepancies exist, but the indications for RMSBx and how RMSBx are performed may be implicated.

Defining universally acceptable indications for RMSBx remains challenging. On one hand, there are reports that suggest that stable bowel function is not physiologically possible during the neonatal period, so HD would be unlikely and therefore RMSBx was unnecessary^8,9 while on the other, the United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines published 2010 specify only five indications for RMSBx, including delayed passage of meconium and symptoms since the first few weeks of life, for performing rectal biopsies to rule out HD [National Institute for Health and Clinical Excellence. ¹⁰ As a consequence of this background controversy, infants less than 1-year-old were excluded from the present study to better focus on constipation as a chronic issue and not as a transient allergic/behavioral response. Thus, any child requiring assistance to defecate persisting after an arbitrary age (1-year-old in the case of the present study) requires specific investigation. Interestingly, in the present study, when the past medical history of all HD subjects was reviewed retrospectively, there were only 3 cases in E+HD (n = 8) and 4 cases in L+HD (n = 13) who had symptoms from the neonatal period and only 1 case in E+HD (n = 8) and 1 case in L+HD (n = 13) with delayed meconium excretion, suggesting that the NICE guidelines may not be clinically relevant.

Identifying HD as the cause of chronic constipation requires RMSBx and the effect of broadening the indications for RMSBx was one aim of the present study. This can be problematic, particularly in patients with less severe chronic constipation that can be managed without enemas where treatment becomes habitual over time. ¹¹ The incidence of adult HD is unknown, but has been suggested to be as high as 2% of all HD cases. ¹² It is still unclear whether adult HD, which is arbitrarily defined as HD diagnosed when a patient is over 10 years of age, ¹³ is due to failure of diagnosis during childhood or whether it is in fact due to late onset, but the majority of adult HD patients have symptoms that began in childhood. ¹² Thus, HD should be considered when investigating patients of any age with refractory constipation. Obviously, when constipation can be managed successfully by laxatives and enemas, some patients may reach adulthood without being investigated. ¹⁴ Since Doodnath et al. reported 490 cases of HD in adults between 1950 and 2009 in a meta-analysis, ¹³ the number has exceeded 600 cases, ¹⁵ and the oldest patient in whom a diagnosis of HD was made was in a 74-year-old male. ¹⁶ The diagnosis of HD in adults can be missed very easily as it is commonly considered as a condition affecting early childhood, in particular, neonates, and can present with classic clinical features of abdominal distention, rectal emptiness or, on the contrary, the presence of a hard fecal impaction detect by rectal examination, ¹⁴ which can arise from decompensation of the dilated proximal colonic segment. Although, the negative RMSBx rate seems high (73.1%: 57/78), RMSBx was performed specifically to diagnose HD, so other factors must be involved in causing chronic constipation. Expanding the indications for RMSBx to include L+ allows more patients with chronic constipation to be investigated for HD.

Rectal manometry has been used in the diagnosis of HD with variable success rates, ¹⁷ but it is time-consuming. Even if reliable results are obtained, a definitive diagnosis of HD still requires histologic confirmation of the absence of enteric ganglion cells in the distal rectum. Contrast enemas have been proposed as a potential screening test but there is a high level of associated radiation exposure, a negative contrast enema does not rule out HD, and a positive result does not allow a conclusive diagnosis of HD to be made.^17,18 Information from a contrast enema study should be reserved for surgical planning for patients who have already been diagnosed with HD because of aganglionosis.

The majority of RMSBx would appear to be ganglionic and therefore could be considered unnecessary in hindsight ¹⁹ and they are not without complications; sometimes serious. ²⁰ Suction rectal biopsy, often performed as an office/outpatient clinic procedure has a reported complication rate of .7%, with persistent rectal bleeding requiring transfusion occurring in .5% and bowel perforation in .1%. ²¹ With RMSBx performed as part of the present study, direct tissue sampling is performed using scissors which should have a lower risk for traumatic bleeding compared with suction rectal biopsy. Although general anesthesia is required for RMSBx, there were no procedure-related complications in this series and when taken in consideration with low complication rates reported in the literature,^21,22 RMSBx would probably be safer and more reliable than rectal suction biopsy for obtaining adequate tissue accurately for a definitive diagnosis of HD without the psychosocial and physical stress associated with a rectal suction biopsy, especially if it is unsuccessful, and potential morbidity related to undiagnosed HD. ⁷ An additional factor affecting the preference for RMSBx at the author’s institute is experience of a case of severe bleeding after suction biopsy that required emergency surgery to control.

Although no statistically significant differences were identified, and the number of subjects in the present study is small, the incidence of HD in L+ was higher than in E+, which suggests that broadening the indications for RMSBx could help identify more HD cases as a cause for chronic refractory constipation. Follow-up studies are planned as more patients undergo RMSBx.