Hirschsprung's disease associated enterocolitis:A comprehensive review

Hirschsprung’s disease(HSCR)is a congenital disorder characterized by failure of the neural crest cells to migrate and populate the distal bowel during gestation affecting different lengths of intestine leading to a distal functional obstruction.Surgical treatment is needed to correct HSCR once the diagnosis is confirmed by demonstrating the absence of ganglion cells or aganglionosis of the affected bowel segment.Hirschsprung’s disease associated enterocolitis(HAEC)is an inflammatory complication associated with HSCR that can present either in the pre-or postoperative period and associated with increased morbidity and mortality.The pathogenesis of HAEC remains poorly understood,but intestinal dysmotility,dysbiosis and impaired mucosal defense and intestinal barrier function appear to play a significant role.There is no clear definition for HAEC,but the diagnosis is primarily clinical,and treatment is guided based on severity.Here,we aim to provide a comprehensive review of the clinical presentation,etiology,pathophysiology,and current therapeutic options for HAEC.

Robotic-assisted proctosigmoidectomy for Hirschsprung’s disease:A multicenter prospective study

BACKGROUND Robotic surgery is a cutting-edge minimally invasive technique that overcomes many shortcomings of laparoscopic techniques,yet few studies have evaluated the use of robotic surgery to treat Hirschsprung’s disease(HSCR).AIM To analyze the feasibility and medium-term outcomes of robotic-assisted proctosigmoidectomy(RAPS)with sphincter-and nerve-sparing surgery in HSCR patients.METHODS From July 2015 to January 2022,156 rectosigmoid HSCR patients were enrolled in this multicenter prospective study.Their sphincters and nerves were spared by dissecting the rectum completely from the pelvic cavity outside the longitudinal muscle of the rectum and then performing transanal Soave pull-through procedures.Surgical outcomes and continence function were analyzed.RESULTS No conversions or intraoperative complications occurred.The median age at surgery was 9.50 months,and the length of the removed bowel was 15.50±5.23 cm.The total operation time,console time,and anal traction time were 155.22±16.77,58.01±7.71,and 45.28±8.15 min.There were 25 complications within 30 d and 48 post-30-d complications.For children aged≥4 years,the bowel function score(BFS)was 17.32±2.63,and 90.91%of patients showed moderate-to-good bowel function.The postoperative fecal continence(POFC)score was 10.95±1.04 at 4 years of age,11.48±0.72 at 5 years of age,and 11.94±0.81 at 6 years of age,showing a promising annual trend.There were no significant differences in postoperative complications,BFS,and POFC scores related to age at surgery being≤3 mo or>3 mo.CONCLUSION RAPS is a safe and effective alternative for treating HSCR in children of all ages;it offers the advantage of further minimizing damage to sphincters and perirectal nerves and thus providing better continence function.

Decreased expression of hyperpolarisation-activated cyclic nucleotide-gated channel 3 in Hirschsprung's disease

AIM: To determine if hyperpolarisation-activated nucleotide-gated(HCN) channels exist in human colon, and to investigate the expression of HCN channels in Hirschsprung's disease.METHODS:We investigated HCN1,HCN2,HCN3 and HCN4 protein expression in pull-through specimens from patients with Hirschsprung’s disease(HSCR,n=10)using the proximal-most ganglionic segment and distalmost aganglionic segment,as well as in healthy control specimens obtained at the time of sigmoid colostomy closure in children who had undergone anorectoplasty for imperforate anus(n=10).Fluorescent immunohistochemistry was performed to assess protein distribution,which was then visualized using confocal microscopy.RESULTS:No HCN1 channel expression was observed in any of the tissues studied.Both HCN2 and HCN4proteins were found to be equally expressed in the aganglionic and ganglionic bowel in HSCR and controls.HCN3 channel expression was found to be markedly decreased in the aganglionic colon vs ganglionic colon and controls.HCN2-4 channels were seen to be expressed within neurons of the myenteric and submucosal plexus of the ganglionic bowel and normal controls,and also co-localised to interstitial cells of Cajal in all tissues studied.CONCLUSION:We demonstrate HCN channel expression in human colon for the first time.Reduced HCN3expression in aganglionic bowel suggests its potential role in HSCR pathophysiology.

Genetic interactions and modifi er genes in Hirschsprung's disease

Hirschsprung's disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung's disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung's disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung' s disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung's disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modif ier genes.

Megacolon in adulthood after surgical treatment of Hirschsprung's disease in early childhood

Hirschsprung＇s disease （HD） is a disorder associated with congenital malformation of the enteric nervous system with segmental aganglionosis. Prevailing therapy includes a resection of the affected part of the bowel, However, patients often do not obtain complete functional improvement after surgical treatment. We present the case of a 25-year-old woman who had surgical treatment of lid in early childhood. After that procedure she had clinical features of constipation for years in the end, passing of stool once a week, requiring laxatives and enemas. We diagnosed an incomplete resection of the aganglionic bowel via rectal biopsy and resected the remaining aganglionic segment. Two months after surgery the patient＇s bowel function improved to a frequency of 1-4 stools per day. We conclude that regular follow-up is required to identify lid patients with persistent alterations of bowel function after surgery. In patients presenting with constipation, recognition of a remaining aganglionic segment or other alterations of the enteric nervous system should be aimed at in an early stage. 2005 The WJG Press and Elsevier Inc. All rights reserved

Hirschsprung's disease:Is there a relationship between mast cells and nerve fibers?

AIM:To define the topography of mast cells and their numbers in cases of Hirschsprung's disease(HD)and non-HD,assess neural hypertrophy using imaging software and to study the relationship between mast cells and nerve fibers.METHODS:HE stained sections of 32 cases of chronic constipation in the age group of 0-14 years were reviewed for ganglion cells.AChE staining was performed on frozen sections of colonic and rectal biopsies.Based on their findings cases were divided into HD and non-HD and mast cells stained by toluidine blue were evaluated.Image analysis by computerized software was applied to S-100 stained sections for assessment of neural hypertrophy.RESULTS:Difference between number of mast cells in HD group(mean=36.44)and in non-HD group(mean =14.79)was statistically significant.Image analysis morphometry on S-100 stained sections served as a useful adjunct.The difference between number,size,and perimeter of the nerve fibers between HD and non-HD group was statistically significant.CONCLUSION:Mast cells are significantly increased in HD and their base line values are much higher in Indian children than that reported in Western literature.Their role in HD needs further research.Morphometry of S-100 stained nerve fibers is a useful adjunct to conventional methods for diagnosis of HD.

Genetic polymorphism of UL144 open reading frame of human cytomegalovirus DNA detected in colon samples from infants with Hirschsprung's disease

AIM： To explore the genetic diversities of UL144 open reading frame （ORF） of cytomegalovirus DNA detected in colon tissue from infants with Hirschsprung＇s disease （HD） by sequencing UL144 DNA in 23 aganglionic colon tissue and 4 urine samples from 25 HD infants. METHODS： Nest PCR was performed for amplification of the UL144 gene. The UL144 gene was analyzed with soffwares, such as DNAclub, BioEdit, PROSITE database, and DNAstar. RESULTS： The strains from HD patients were distributed among three genotypes of UL144： group 1A （64%）, group 2 （24%）, and group 3 （12%）. The UL144 genotypes between strains from HD and control group were compared by chi square test （x^2 = 1.870, P = 0.393）. Strains from the colon were sporadically distributed in UL144 genotypes. CONCLUSION： There are genetic diversities of UL144 ORF in colon tissue of infants with HD. However, cytomegalovirus UL144 genotypes are not associated with clinical manifestations of HD.

Persistent bowel dysfunction after surgery for Hirschsprung’s disease:A neuropathological perspective

Hirschsprung’s disease(HD)is a congenital disorder,characterized by aganglionosis in the distal part of the gastrointestinal tract.Despite complete surgical resection of the aganglionic segment,both constipation and fecal incontinence persist in a considerable number of patients with limited treatment options.There is growing evidence for structural abnormalities in the ganglionic bowel proximal to the aganglionosis in both humans and animals with HD,which may play a role in persistent bowel dysfunction.These abnormalities include:(1)Histopathological abnormalities of enteric neural cells;(2)Imbalanced expression of neurotransmitters and neuroproteins;(3)Abnormal expression of enteric pacemaker cells;(4)Abnormalities of smooth muscle cells;and(5)Abnormalities within the extracellular matrix.Hence,a better understanding of these previously unrecognized neuropathological abnormalities may improve follow-up and treatment in patients with HD suffering from persistent bowel dysfunction following surgical correction.In the long term,further combination of clinical and neuropathological data will hopefully enable a translational step towards more individual treatment for HD.

Reoperation in an adult female with "right-sided" Hirschsprung's disease complicated by refractory hypertension and cough

Hirschsprung's disease(HD) is an intestinal malformation caused by the innate absence of ganglion cells in the neural plexus of the colorectal wall, and is most common in male infants. It is rare in adult, and is usually left-sided. Herein we reported based on the CARE guidelines a case of a 47-year-old adult female suffering from "right-sided" HD complicated by refractory hypertension and cough. The patient with a history of cesarean section and with digestive unfitness(abdominal pain, distention, and constipation) only since 20 years old had recurrence of HD after initial surgery due to the incomplete removal of the HD-affected bowel based on a diagnosis of "chronic ileus", leading to the relapse of the digestive symptoms and the emergence of some intractable circulatory and respiratory complications which could be hardly controlled by conservative treatment. During the long interval before coming to our department for help, she had been re-hospitalized for several times with various misdiagnoses and supplied merely with symptomatic treatment which could only achieve temporary symptomatic relief. At her admission to our department, the imaging examinations strongly indicated recurrent HD which was further supportedb y p a t h o l o g i c a l e x a m i n a t i o n s, a n d r i g h t h e m i-colectomy was performed to remove the remnant aganglionic intestinal segment. Intraoperative and postoperative pathology supported the completeness of the definitive resection. Post-operation, the patient's bowel motility significantly improved, and interestingly, the complications disappeared. For adult patients with long-term constipation combined with cough and hypertension, rare diseases like HD which requires definite surgery and which could be "right-sided" should not be overlooked. It is vital to diagnose and cure HD patients in childhood. Through the comparison of the two surgeries, it is noteworthy that for diagnosed HD, sufficient removal of the non-functional intestine confirmed by intraoperative pathology is essential.

Literature Review of the Frequency of Reoperations after One Stage Transanal Endorectal Pull-Through Procedure for Hirschsprung’s Disease in Children

Background: Transanal endorectal one-stage pull-through (TERPT) procedure in children with Hirschsprung’s disease (HD) has gained worldwide acceptance. However surgical success is often reported separately, while the necessity for true reoperation is difficult to establish. Aim: To evaluate the incidence of reoperations following TERPT procedure. The findings will be important in counseling and planning childcare for HD patients as well as providing a benchmark for single centers clinical results. Methods: A literature review of reported TERPT operations on children with HD between 1998 through 2011 was performed. Only planned TERPT operation reports were included. Information was collected with particular emphasis on reoperations and their reasons. Results: Out of 26 published articles 23 were included, reporting on 836 children, female/male ratio: 1/3.3, undergoing the TERPT procedure as the only operative intervention with described postoperative courses. The children comprised neonates, 3 years of age (12%). The average follow up was 18.5 (6 - 38) months. The resected bowel length mean was 20.5 cm. Forty-one reoperations were reported (4.9%), including 24 laparotomies, 8 laparoscopies, 6 colostomies and ileostomies in 3 children. Only 2 re-do TERPT were reported (0.2%). Seven patients were considered TERPT failures (0.8%) with 5 requiring diverting colostomies and additional transabdominal pull-through operations. Two myectomies were performed (0.2%). One child with aganglionosis underwent a Duhamel pull through. Two (0.2%) had serious damage to the urinary tract also one child with a vas deferens lesion was reoperated. Two bowel obstructions required adhesiolysis. Eight anastomotic dehiscences (0.9%) required surgery after reparation. One prolapse of the pulled through colon was reported. Six patients (0.7%) suffered anastomotic leaks. Anastomotic strictures rate was 2.8%, all repaired with anal dilatation. Conclusion: The review supports the low incidence of reported reoperations for the TERPT procedure.

Literature Review of the Outcome after One-Stage Transanal Endorectal Pull-Through Procedure for Hirschsprung’s Disease in Children

Background: Transanal endorectal one-stage pull-through (TERPT) procedure in children with Hirschsprung’s disease (HD) is frequently used worldwide. In order to give the families realistic expectations and to plan the medical care for the years after TERPT, the long term outcome is of great importance. Aim: To collect information on the long term outcome reported after one stage TERPT procedure for HD in children 0 - 15 years. Method: A literature review on the outcome of planned TERPT from 2005 through 2012 was carried out. Information was collected on the number of daily stools a few months postoperatively, incontinence and constipation and the measures taken to deal with these. Results: The reports are few and prospective studies were missing. The results show an initial high frequency of daily stools, 12% had later abnormal stool patterns, 21% had fecal incontinence and 10% had problems with constipation. Conclusion: In order to compare the long term outcome, it would be desirable to have uniform regular reports on the daily frequency of passed stools, incontinence and constipation during the first years after TERPT. Such knowledge would be of importance for the information given to the guardians of children with HD preoperatively to TERPT and in the planning of the future care. The findings can, furthermore, provide a benchmark for the outcome from a single centre.

Mutation of RET proto-oncogene in Hirschsprung's disease and intestinal neuronal dysplasia

AIM： To investigate the genetic relationship between Hirschsprung＇s disease （HD） and intestinal neuronal dysplasia （IND） in Chinese population.METHODS： Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control. Genomic DNA was extracted according to standard procedure. Exons 11,13,15,i7 of RET proto-oncogene were amplified by polymerase chain reaction （PCR）. The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism （SSCP） and sequencing of the positive amplified products was performed.RESULTS： Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11 at nucleotide 15165 G→A （G667S）, 2 frameshifc mutations in exon 13 at nucleotide 18974 （18974insG）, 1 missense mutation in exon 13 at nucleotide 18919 A→G （K756E） and 1 silent mutation in exon 15 at nucleotide 20692 G→A（Q916Q） were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13 at nucleotide 18888 T→G （L745L） were detected. No mutation was found in IND patients and controls.CONCLUSION： Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of REr proto-oncogene mutation is quite different between IND and HD in Chinese population, IND is a distinct clinical entity genetically different from HD.

An Updated “Historical” Algorithm for Hirschsprung Pa-tients Who Present Late or Severely Ill

Some children with previously undiagnosed Hirschprung’s disease present severely ill at an advanced age with markedly dilated bowel and enterocolitis. In this manuscript, the authors propose the following treatment algorithm: 1) a diverting transverse loop colostomy, 2) a transanal Soave endorectal pull-through, and 3) colostomy closure. The authors report their experience with five patients.

Adult patients with allied disorders of Hirschsprung’s disease in emergency department:An 11-year retrospective study

BACKGROUND In the past years,only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung’s disease(ADHD),most of which were individual case reports or lacked detailed clinical information.Although many studies have reported patients presenting to the emergency department(ED)with recurrent abdominal symptoms for a number of disorders,there are few data involving ADHD.However,owing to a lack of awareness of the disease,misdiagnoses and mistreatments are common.Severe complications such as perforation,bleeding,malabsorption,and even death in ADHD had been reported by many studies.AIM To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively.METHODS We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital.Their basic information,clinical manifestations,and imaging findings were analyzed.Blood indices were compared between the ADHD and irritable bowel syndrome(IBS)groups.RESULTS Adult patients with ADHD had a mean age of 48.8±14.3 years,and 77.4%had been treated before admission.The transverse colon was the most common dilated part(73.6%),and constipation(67.9%)was the most common symptom.ADHD patients can present with uncommon symptoms and false-negative imaging findings.Logistic regression analysis indicated that body mass index(BMI)[odds ratio(OR)=0.786,P=0.013],cholinesterase(per 1000 units;OR=0.693,P=0.008),and blood chlorine(OR=0.816,P=0.022)were determined to be independent related factors between the ADHD and IBS groups.The area under the receiver operating characteristics curve of these three indices combined was 0.812(P<0.001).CONCLUSION Emergency physicians should be vigilant regarding patients with chronic constipation,abdominal pain,or abdominal distension,and consider the possibility of ADHD despite its rarity.Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD.BMI,cholinesterase,and blood chlorine have good discriminative abilities between ADHD and IBS.The nutritional status of adult patients with ADHD is worthy of further attention.Surgical treatment for adult patients with ADHD is important and inevitable.

Very early onset perinatal constipation:Can it be cow’s milk protein allergy?

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung’s disease(HD),meconium ileus due to Cystic Fibrosis,etc.The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis,such as anorectal manometry or rectal suction biopsy.What if there was another etiology of perinatal constipation,that is far lesser known?Cow’s milk protein allergy(CMPA)is often diagnosed in infants within the first few weeks of life,however,there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero,therefore allowing symptoms to show as early as day one of life.The presentation is more atypical,with perinatal constipation rather than with bloody stools,diarrhea,and vomiting.The diagnosis and management would be avoidance of cow's milk protein within the diet,with results and symptom improvement in patients immediately.Therefore,we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients.This entails first ruling out CMPA with safe,noninvasive techniques with diet modification,and if unsuccessful,then moving forward with further diagnostic modalities.

腹腔镜下改良Swenson法治疗小儿先天性巨结肠症

目的介绍腹腔镜下改良Swenson法治疗先天性巨结肠症的经验和体会.方法应用改良Swenson法治疗先天性巨结肠症100例,短段型21例,常见型72例,长段型7例,年龄8个月～7岁,平均年龄1.5岁.脐部和左右下腹放置内径0.5 cm的0°或30°腹腔镜和操作钳,设定CO2压力8～12 mmHg,取结肠浆肌层组织做病理诊断,紧贴肠管处理需要切除的结肠系膜血管,达齿状线上0.5～1 cm水平后经直肠肛门内翻拖出切除,结肠直肠全层心形斜形吻合.结果手术时间80～170 min,平均110 min.术中出血量不足10 ml.全部病例治愈,无一例死亡,皮下气肿5例,尿潴留6例,全部病例随访6～18个月,术后结肠炎5例,污粪2例,吻合口狭窄1例,迟发吻合口漏1例.结论腹腔镜下改良Swenson法治疗先天性巨结肠症创伤小,方法简单,具有改良Swenson法的优点,是一种值得推广的手术方法.

经肛门改良Soave术Ⅰ期根治小儿先天性巨结肠的近期疗效及影响因素分析

目的：观察经肛门改良Soave 术Ⅰ期根治小儿先天性巨结肠（HD）的近期疗效，并分析其影响因素。方法：132例HD患儿于全身麻醉或骶管阻滞麻醉下施行经肛门改良SoaveⅠ期根治术，术后常规给予抗生素治疗。结果：共切除肠管标本19～56 cm，平均（35．07±3．15） cm；平均手术时间（120．48±18．34） min；术中平均出血（45．74±8．14） mL，所有患儿均于术后24 h 内恢复肠道功能，术后6个月肛门功能总优良率为90．90％。 Cox 模型多因素分析表明，吻合口狭窄、肠炎等并发症是术后6个月肛门功能优良与否的独立影响因素（P ＜0．05）。结论：经肛门改良Soave术Ⅰ期根治小儿HD创伤小，并发症少，术后肠炎及吻合口狭窄是近期疗效的独立影响因素。

先天性巨结肠病变肠段CAD、S-100的检测及意义

目的探讨检测先天性巨结肠(HD)病变肠段组织中组织蛋白酶D(CAD)、S-100的临床意义。方法31例经常规病理检查确诊的HD患儿,均行手术治疗,术后随访,并对其病变肠段组织中的CAD、S-100进行检测。取5例正常结肠组织(C组)作对照。结果 31例患儿手术后21例有肠炎、便秘(A组),10例无症状(B组)。CAD、S-100检测显示,A组肠管扩张段切缘神经节细胞缺如3例、减少5例、未成熟2例、发育不良1例,B组肠管扩张段切缘及C组肠管组织中神经节细胞未见异常。结论对HD病变肠段进行CAD、S-100检测,有助于HD的确诊,对HD病变切除范围的确定有指导作用,有利于减少术后肠炎、便秘等。

腹腔镜下改良Soave术治疗婴幼儿先天性巨结肠20例

目的总结腹腔镜下改良Soave术治疗婴幼儿先天性巨结肠(HD)的手术方法、操作经验和疗效。方法对婴幼儿HD患儿20例(男16例,女4例;年龄3.5个月-4岁)采用气管插管全身麻醉,腹腔镜下应用超声刀切断拖出段结肠系膜,会阴部采用改良Soave术完成手术。结果病例均顺利完成手术,平均手术时间132 min,平均切除结肠肠管长度35 cm,平均术中出血14 mL,均未输血。术后发生小肠结肠炎2例。随访6个月-3年,平均14.5个月,无便秘、污粪、肠梗阻、肛门黏膜外翻、吻合口狭窄等并发症发生,排便控制在1-2次/d。结论腹腔镜下改良Soave术治疗婴幼儿HD具有创伤小、出血少、操作简便、恢复快、并发症少等优点。

快速康复外科在Soave手术行先天性巨结肠根治术中的应用

目的探讨快速康复外科(Fast track surgery,FTS)理念运用于先天性巨结肠手术后对患儿病情恢复和家属心理产生的影响。方法选取自2014年5月-2017年6月在四川省乐山市中医医院行肛门Soave先天性巨结肠根治术的患儿48例,随机分为2组,其中围手术期应用快速康复外科理念的患儿作为试验组(23例),单纯采用经肛门Soave先天性巨结肠根治术的患儿作为对照组(25例)。对2组患儿的术后住院时间、各类插管留置时间、肠道功能恢复时间及患儿家属心理焦虑评分进行对比分析。结果术后住院时间:FTS试验组患儿(5.25±2.08)d,对照组(12.63±4.28)d,2组比较差异有统计学意义(P<0.05)。术后排便时间:FTS试验组(3.1±0.9) d,对照组(5.6±0.8) d,2组比较差异有统计学意义(P<0.05)。术后首次排气时间:FTS试验组(41.58±15.32)h,对照组(25.32±12.63)h,FTS试验组快于对照组,2组差异有统计学意义(P<0.05)。入院后3 d、术后3 d患儿家属的汉密尔顿焦虑量表(Hamilton anxiety scale, HAMA)评分:FTS试验组均低于对照组,差异均有统计学意义(P<0.05);试验组和对照组患者术后相关并发症发生率分别为21.74%(5/23)、36.00%(9/25),2组差异无统计学意义(P>0.05)。结论在先天性巨结肠手术中运用快速康复外科理念,可缩短患者术后住院时间,促进肠道功能恢复,减轻患儿家属的焦虑心理,且未增加手术相关并发症,值得在临床上推广使用。