Hirschsprung-associated enterocolitis develops independently of NOD2 variants

Backgroud/Purpose

Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC.

Methods

Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease.

Results

Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants.

Conclusion

Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.     

A PLEA FOR INCIDENTAL APPENDECTOMY IN PEDIATRIC PATIENTS WITH MALIGNANCY

The evaluation of right lower quadrant (RLQ) abdominal pain in pediatric patients with malignancy can be difficult. However, since the mortality rate from peritoneal infections in these patients is very high, the differential diagnosis of RLQ peritoneal irritation, mainly of acute appendicitis (AA) versus neutropenic enterocolitis (NE), is crucial. Three cases of pediatric patients with malignancy demonstrating these difficulties are represented to enlighten this problem. The first patient died of multiorgan failure after operation for perforated appendicitis without generalized peritonitis. The second had a severe life-threatening postoperative complication because of delayed diagnosis of acute appendicitis. The third patient with malignant pelvic spread, underwent an unnecessary abdominal exploration for suspected AA. In all these cases and probably in many others, the clinical outcome could have been different if a previous incidental appendectomy had been performed during the primary abdominal operation. Incidental appendectomy in oncologic patients is recommended to facilitate the differential diagnosis of RLQ pain and to exclude the diagnosis of AA.     

表皮生长因子及其受体在新生鼠肠损伤中的动态变化

目的 检测新生鼠肠损伤时回肠组织表皮生长因子(epidermal growth factor,EGF)、转化生长因子α(transforming growth factor-α,TGF-α)及表皮生长因子受体(epithelial growth factor receptor,EGFR)的动态变化,探讨其在新生儿坏死性小肠结肠炎中的作用. 方法 1日龄新生Wistar大鼠随机分为实验组40只和对照组8只.实验组腹腔注射5 mg/kg内毒素(lipopolysaccharide,LPS),对照组注射同等剂量无菌生理盐水.实验组大鼠于注射LPS后1、3、6、12和24 h处死后分离胃肠道,观察回肠组织形态学改变,测定肠组织EGF、EGFR蛋白表达及EGFR mRNA和TGF-αmRNA的动态变化,并与对照组进行比较. 结果 实验组于注射LPS后1、3、6、12和24 h回肠组织损伤评分分别为(1.28±0.62)分,(1.75±0.74)分,(1.98±0.75)分,(2.85±0.41)分和(2.35±0.63)分,均明显高于对照组(0.12±0.17)分(P<0.01);EGF蛋白水平分别为(235.9±44.3)pg/mgprot,(231.8±30.0)pg/mg prot,(223.3±48.1)pg/mg prot,(211.7±47.0)pg/mg prot和(221.4±39.0)pg/mg prot,显著低于对照组[(287.7±42.6)pg/mg prot](P<0.05),EGF浓度与肠损伤程度呈负相关(r=-1.000,P<0.01);注射LPS后EGFR蛋白和mRNA表达增加,但与肠损伤程度无相关性(r=0.800,P>0.05);TGF-α mRNA在注射LPS后1 h和3 h明显上调. 结论 EGF水平降低可能在新生儿坏死性小肠结肠炎发生发展中起关键作用.     

Abnormal expression of blood group-associated antigen (BGA) in colon of Hirschsprung's disease

The entire segment of resected colon obtained from 15 patients with Hirschsprung's disease (HD) was examined with conventional mucin histochemistry (PASAB, HID-AB) to investigate the mucin composition and blood group-associated antigens (BGA) (sialosyl-Le^a, Le^a, Le^y, Le^b) for detecting mucosal cell differentiation. The BGA Le^b were absent in normal distal colon and rectum but present in fetal colon. Immunoreactivity of Le^b, which is a marker of undifferentiated crypt cells, was observed through out the crypts in aganglionic colon. Depletion of sulphated and neutral mucin was also a characteristic finding in the aganglionic mucosa. These findings suggest that the colonic mucosa of aganglionic bowel represents persistence of a fetal stage of development. These cellular abnormalities may be a factor in the pathogenesis of enterocolitis complicating HD.     

Evaluation of risk factors in the development of enterocolitis complicating Hirschsprung's disease

Enterocolitis remains a major cause of morbidity and mortality in patients with Hirschsprung's disease (HD). Forty-one (30%) of 135 patients treated for HD from 1975 to 1992 developed enterocolitis; enterocolitis occured preoperatively in 25. It was a presenting feature in 17 infants, including 11 neonates. The proportion of patients presenting with enterocolitis in the neonatal period increased with advancing age, 6 (11%) out of 56 presenting within the 1st week and 5 (24%) out of 21 after 1 week. Episodes of enterocolitis continued in 7 of these 25 patients after a pull-through procedure. Sixteen patients had a first episode of enterocolitis after surgery: 3 after a colostomy, and 13 after a pull-through procedure. The incidence of enterocolitis was 28% in patients with rectosigmoid involvement and 38% in patients with long-segment or total colonic aganglionosis (P= 0.1). Enterocolitis occured in 8 (47%) of 17 patients with trisomy 21 as compared to 33 of 118 (28%) other patients (P= 0.1). Four of the 41 patients died as a result of enterocolitis, 3 in the neonatal period after a colostomy performed at a mean age of 22 days, although the symptoms suggestive of HD were present since birth. Prompt diagnosis and expeditious management are necessary in patients with HD.     

先天性巨结肠症术后小肠结肠炎发生与合并神经节细胞减少症的相关性分析

目的探讨先天性巨结肠症（HD）合并神经节细胞减少（HYP）与术后肠炎发生的相关性。方法对97例在我院行巨结肠根治术的患儿进行随访，随访时间1．5～8年，平均3．4年。分为两组：A组70例，为HD；B组27例，为HD合并HYP。对其排便功能与术后小肠结肠炎（EC）的发生情况进行分析比较。结果A组术后发生肠炎有8例（11．4%），B组发生肠炎有11例（40．7％），两组相比较差异有统计学意义（P〈0．005）。按照李正的评分系统，A组排便功能评分为优者比率为85．7％，明显高于B组的62．9％（P〈0．05）。A组便秘复发率为2．9％（2／70），B组为14．8％（4／27），但两者之间差异无统计学意义（P〉0．05）。结论HD合并HYP患儿术后较HD更易发生小肠结肠炎，完全切除HYP肠管可降低EC的发生率，减轻肠炎发生的程度。     

Yersinia colitis

A 2-year-old child with a febrile, nonbloody diarrheal illness of acute onset with repeatedly negative stool and blood cultures for pathogenic bacteria is presented. Sigmoidoscopic and roentgenographic studies revealed an inflammatory colitis. Fortunately, diagnostic perserverance and a high index of suspicion resulted in a positive stool culture forYersinia enterocolitica. Serologic study and clinical course provided data consistent with the diagnosis of an infections colitis due toYersinia enterocolitica. This case demonstrates the necessity to considerYersinia enterocolitica in the radiographic differential diagnosis of Crohn's disease of the colon or ulcerative colitis, as well as intractable diarrhea of childhood.     

Observations on the immunocytes and macrophages in megacolon

An immunoperoxidase staining method was used to study specific immunoglobulin-containing cells in the intestinal mucosa of children who presented with features suggestive of Hirschsprung's disease. No evidence was found to substantiate the hypothesis of an immunologic component in the etiology of Hirschsprung's disease. The megacolon in this condition had an increased proportion of IgG-containing cells and a reduced proportion of IgA-containing cells when compared with normal and unobstructed colon; this may be a reflection of an abnormal mucosal immune defense leading to susceptibility to the enterocolitis found in Hirschsprung's disease. Numerous lipofuscin-bearing macrophages were seen in the colonic mucosa of children with anal stenosis who were given anthraquinone laxatives for varying periods. The possibility that this represents an early stage of melanosis coli, as well as the likelihood of anthraquinones contributing to the pathogenesis of acquired megacolon, are considered. S. S. Wijesinha was on study leave from the Department of Health, Republic of Sri Lanka, and was supported by a Scholarship awarded by the Association of Commonwealth Universities.     

伪膜性肠炎的相关危险因素研究

目的探讨伪膜性肠炎发生的相关危险因素,提高对该病的认识以及制定针对性的预防措施。方法回顾性分析了2009年1月—2010年12月我院住院确诊的56例伪膜性肠炎患者的临床资料。选择非伪膜性肠炎患者60例作为对照组。自行设计调查表,从年龄、性别、慢性基础疾病、免疫抑制剂、住院天数、肠道手术史、非肠道手术史、肠内营养、清洁灌肠、泻药、抗生素种类、抗生素应用时间等方面进行调查,采用单变量分析(χ2检验)进行对比,筛选出伪膜性肠炎有关因素,多变量分析(条件Logistic回归)方法筛选出主要危险因素。结果单因素分析显示病例组与对照组之间在年龄、应用免疫抑制剂、住院天数、肠道手术史、应用肠内营养、应用清洁灌肠、应用泻药、应用抗生素种类≥3以及抗生素应用时间≥10 d这9个方面差异有统计学意义(P<0.05);多因素条件Logistic回归显示年龄、应用免疫抑制剂、住院天数、应用清洁灌肠及泻药、应用抗生素种类≥3以及抗生素应用时间≥10 d这7个因素是危险因素,与伪膜性肠炎密切相关。结论伪膜性肠炎与多种因素有关,建议通过合理使用抗生素、加强对老年患者的监测、注意早期肠内营养,减少伪膜性肠炎的发生。