Variation of Gut Mucosal Microbiome With Anti-Saccharomyces cerevisiae Antibody Status in Pediatric Crohn Disease.

OBJECTIVES: Crohn disease (CD) is a chronic relapsing condition possibly caused by a dysbiotic microbiome. Approximately 30% to 60% of patients with CD have anti-Saccharomyces cerevisiae antibody (ASCA), but any association with gut microbiota is unexplored. We hypothesized that ASCA positivity would predict a signature microbial status and clinical phenotype. METHODS: Ileocolonic mucosal biopsies were obtained from children with CD (n = 135), and controls without inflammatory bowel disease (n = 45). Comparison was made between ASCA status, microbial diversity, and clinical characteristics. RESULTS: ASCA was highly specific but poorly sensitive for the diagnosis of CD. In patients with CD, ASCA positivity was associated with older age (≥10 years), ileocolonic disease, and long-term risk of surgery. Microbial alpha and beta diversity were similar in patients with CD with or without ASCA, but significantly less when compared to noninflammatory bowel disease controls. Microbial richness was similar across all 3 groups. Fourteen bacterial species were associated with ASCA-positive patients with CD and 14 species with ASCA-negative patients (P < 0.05). After using a false discovery rate correction Ruminococcus torques and bacterium Yersinia enterocolitica 61 remained significantly associated with CD ASCA positivity (P = 0.0178), whereas Enterobacter cloacae and Faecalibacterium prausnitzii were significantly associated with CD ASCA negativity (P = 0.0178 and 0.0342). CONCLUSION: ASCA-positive and ASCA-negative patients with CD have significant differences in gut microbiome composition, which could possibly be influencing the phenotype of the disease.

Can celiac serology alone be used as a marker of duodenal mucosal recovery in children with celiac disease on a gluten-free diet?

OBJECTIVES: Assessment of treatment response in children with celiac disease (CD) after commencing a strict gluten-free diet (GFD) is generally based on the resolution of clinical features and normalization of serology. Recent adult studies have shown that serologic markers do not correlate with mucosal recovery. We aimed (i) to determine whether anti-tissue transglutaminase immunoglobulin (Ig)A (tTG) and anti-deamidated gliadin peptide IgG (DGP) antibodies are sensitive and specific markers of mucosal recovery in children with CD on a GFD for at least 12 months, and (ii) to determine whether a validated dietary questionnaire of compliance can identify patients with mucosal recovery. METHODS: A total of 150 children with biopsy-proven CD were prospectively evaluated with duodenal biopsies at ≥12 months on GFD, paired with repeat tTG and DGP serology. The biopsies were reviewed in a blinded manner by two histopathologists and graded by Marsh criteria. A validated questionnaire of dietary compliance was also administered. RESULTS: Of 150 children recruited, 27 (18%) had positive serology, 97 (65%) had negative serology, and 26 (17%) had equivocal serology. Of the 97 children with negative serology, none had Marsh type 3 enteropathy. Of the 27 patients with positive serology, only 6 had Marsh type 3 changes. The sensitivity and specificity of serology as a marker of significant mucosal pathology was 75 and 85%, respectively, with a positive predictive value of 22% but a negative predictive value of 98%. Of the 129 (86%) questionnaires completed, 88% reported good or excellent compliance with a GFD (negative predictive value 97%). CONCLUSIONS: This study suggests that follow-up using two serological tests in children with CD on a GFD may obviate the need for repeat mucosal biopsy in the majority of patients. A standardized dietary questionnaire may be useful in identifying patients who require further evaluation.

Clinical patterns and outcome of early-onset inflammatory bowel disease.

We sought to determine whether extremely-early-onset childhood inflammatory bowel disease (age <6 years; 20 ulcerative colitis [UC], 8 Crohn disease [CD], 2 indeterminate, sequentially diagnosed) was clinically more severe than in older children (6-17 years; 19 UC, 39 CD, 2 indeterminate). Early-onset UC was marked by less abdominal pain at presentation, but an aggressive course with a significant reduction in weight-for-age, increased use of immunosuppressants, and more surgery. Children with early-onset CD were more likely to have bloody stools at presentation and an isolated colitis. This study supports the suggestion that inflammatory bowel disease phenotype differs in early-onset disease.

Arterial structure and function in children with inflammatory bowel disease.

Background and Aim: People with inflammatory bowel disease (IBD) have an increased risk of cardiovascular disease, including in younger adulthood. This may arise in part from chronic, systemic low-grade inflammation. The process of atherosclerosis may begin in childhood. We sought to determine whether pediatric IBD is associated with adverse changes in arterial structure and function as a marker of early increased cardiovascular risk. Methods: We performed a case-control study comparing children with IBD for a median disease duration of 2.49 (interquartile range 1.23, 4.38) years with healthy children. In a single visit, we collected baseline clinical and anthropometric data, and measured blood pressure, pulse wave velocity, carotid artery distensibility, and aortic and carotid intima-media thickness. High-sensitivity C-reactive protein and fasting lipids were measured. Results: We enrolled 81 children with IBD (40 with Crohn's disease, 40 with ulcerative colitis, and 1 with unspecified IBD) and 82 control participants. After adjusting for age, sex, body mass index z-score, blood pressure, and low-density lipoprotein cholesterol, there was no difference in measures of arterial structure and function in children with IBD compared with controls, nor between those with Crohn's disease or ulcerative colitis. Conclusion: We did not show any differences in arterial structure and function in children with a history of IBD for less than 5 years compared with healthy controls. IBD diagnosed in childhood may provide a window of opportunity to actively reduce standard cardiovascular risk factors and improve future cardiovascular outcomes.

TLR4, IL10RA, and NOD2 mutation in paediatric Crohn's disease patients: an association with Mycobacterium avium subspecies paratuberculosis and TLR4 and IL10RA expression.

Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated in the pathogenesis of Crohn's disease (CD). The role of CD susceptibility genes in association with these microbes is not known. Sixty-two early onset paediatric CD patients and 46 controls with known MAP status were analysed for an association with 34 single nucleotide polymorphisms (SNPs) from 18 CD susceptibility genes. Functional studies on peripheral blood mononuclear cells (PBMCs) were conducted on 17 CD patients with known CD mutations to assess IL-6, IL-10, and TNF-α expression upon stimulation with MAP precipitated protein derivative (PPD) and lipopolysaccharide (LPS). In addition, surface expression of IL10R and TLR4 on resting B cells, NK cells, T cells, and monocytes was assessed. A mutation in TLR4 (rs4986790) and IL10RA (rs22291130) was significantly associated with MAP-positive CD patients compared to MAP-negative CD patients (27.6 vs. 6.1 %, p = 0.021, and 62.1 vs. 33.3 %, p = 0.024, respectively). PPD and LPS significantly increased IL-6, IL-10, and TNF-α production in PBMCs. IL-10 and TNF-α production were significantly lower in a subgroup of CD patients (5/12) with a known NOD2 mutation. Receptor for IL-10 was significantly higher expressed on NK cells (CD56low) and on NK T cells harbouring a NOD2 mutations compared to wildtype cells (p = 0.031 and 0.005, respectively). TLR4 was significantly higher expressed on NK cells (CD56high) harbouring a NOD2 mutations compared to wildtype cells (p = 0.038).

Yellow is pale: the complications and challenges of late diagnosis of extrahepatic biliary atresia.

Extrahepatic biliary atresia classically presents in the neonatal period with jaundice and pale stools. The lack of bile pigment in stool can be unrecognised, delaying diagnosis and surgical treatment. Vitamin K is given at birth to reduce the risk of haemorrhagic disease of the newborn, but this may be inadequate to prevent the development of coagulopathy secondary to fat soluble vitamin malabsorption. We present the case of a 3 month old infant who presented with an intracerebral haemorrhage and coagulopathy thought to be secondary to fat malabsorption resulting from delayed diagnosis of extrahepatic biliary atresia. This was despite the perinatal administration of intramuscular vitamin K. His parents did not recognise the stool pallor as being abnormal. This case illustrates the importance of educating parents on the significance of pale stools, and also the risk of coagulopathy in extrahepatic biliary atresia despite perinatal intramuscular vitamin K.

The use of biologic agents in pediatric inflammatory bowel disease.

PURPOSE OF REVIEW: Therapeutic options and approaches in inflammatory bowel disease (IBD) continue to evolve. This review will summarize the recent studies of treatment strategies, efficacy, safety and outcome of biological agents in the treatment of children with Crohn's disease and ulcerative colitis. RECENT FINDINGS: Although there has been little recent change in the number of biologicals easily available for the treatment of children, usage has broadened in pediatric IBD and new treatment strategies have emerged. The use of biologicals in refractory pediatric ulcerative colitis is now accepted, with evidence supporting their potential for maintenance therapy. In pediatric Crohn's disease, scheduled treatment regimens have shown superiority to episodic treatment. Although the 'top-down' approach with early use of biologicals produces superior remission rates in adults, there is still little evidence in children. Concomitant immunosuppression appears to reduce immunogenicity and improve therapeutic control, but there are added risks for infection and malignancy. SUMMARY: Biologicals now form an integral part of the treatment algorithm in childhood IBD and their use is likely to increase. Treatment regimens, particularly those involving concomitant immunosuppressants, need to take account of the perceptions of risk.

Expression profile of genes involved in pathogenesis of pediatric Crohn's disease.

BACKGROUND AND AIM: Expression profiling of genes specific to pediatric Crohn's Disease (CD) patients was performed to elucidate the molecular mechanisms underlying disease cause and pathogenesis at disease onset. METHODS: We used suppressive subtractive hybridization (SSH) and differential screening analysis to profile the mRNA expression patterns of children with CD and age- and sex-matched controls without inflammatory bowel disease (IBD). RESULTS: Sequence analysis of 1000 clones enriched by SSH identified 75 functionally annotated human genes, represented by 430 clones. The 75 genes have potential involvement in gene networks, such as antigen presentation, inflammation, infection mechanism, connective tissue development, cell cycle and cancer. Twenty-eight genes were previously described in association with CD, while 47 were new genes not previously reported in the context of IBD. Additionally, 29 of the 75 genes have been previously implicated in bacterial and viral infections. Quantitative real-time reverse transcription polymerase chain reaction performed on ileal-derived RNA from 13 CD and nine non-IBD patients confirmed the upregulation of extracellular matrix gene MMP2 (P = 0.001), and cell proliferation gene REG1A (P = 0.063) in our pediatric CD cohort. CONCLUSION: The retrieval of 28 genes previously reported in association with adult CD emphasizes the importance of these genes in the pediatric setting. The observed upregulation of REG1A and MMP2, and their known impact on cell proliferation and extracellular matrix remodeling, agrees with the clinical behavior of the disease. Moreover, the expressions of bacterial- and virus-related genes in our CD-patient tissues support the concept that microbial agents are important in the etiopathogenesis of CD.

Clinical outcome after percutaneous endoscopic gastrostomy in children with malignancies.

Percutaneous endoscopic gastrostomies (PEG) are little-used in pediatric oncology. We evaluated complications and efficacy of PEGs in children with malignancies in a retrospective case series. Outcome measures were infection and weight gain. Sixteen PEGs were inserted in 14 patients (mean age 10.3 years; SD 5.6). Sixteen wound infections occurred in nine children (3.7 episodes/1,000 days). Mean weight-for-age z-score fell from diagnosis to PEG placement (-0.68 (SD 1.2) to -1.32 (SD 1.26); P < 0.001) but stabilized afterward. Two (12%) were removed early. PEG placement reversed early weight loss and infectious complications did not usually lead to early PEG removal.

An Australian audit of vaccination status in children and adolescents with inflammatory bowel disease.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are at increased risk of vaccine preventable diseases (VPD). This includes invasive pneumococcal disease and influenza. The primary aim of this study was to describe compliance with current Australian guidelines for vaccination of children and adolescents diagnosed with IBD. A secondary aim was to review the serological screening for VPD. METHODS: A random sample of patients (0-18 years at diagnosis), were selected from the Victoria Australia state based Pediatric Inflammatory Bowel Disease Register. A multi-faceted retrospective review of immunization status was undertaken, with hospital records audited, a telephone interview survey conducted with consenting parents and the vaccination history was checked against the primary care physician and Australian Childhood Immunization Register (ACIR) records. The routine primary childhood vaccinations and administration of the recommended additional influenza and pneumococcal vaccines was clarified. RESULTS: This 2007 audit reviewed the immunization status of 101 individuals on the Victorian Pediatric IBD database. Median age at diagnosis was 12.1 years, 50% were on active immunosuppressive therapy. 90% (38/42) [95% confidence intervals (CI) 77%; 97%] with complete immunization information were up-to-date with routine primary immunizations. Only 5% (5/101) [95% CI 2%; 11%] received a recommended pneumococcal vaccine booster and 10% (10/101) [95% CI 5%; 17%] had evidence of having ever received a seasonal influenza vaccine. Those living in rural Victoria (p = 0.005) and younger at the age of diagnosis (p = 0.002) were more likely to have ever received an influenza vaccine Serological testing, reviewing historical protection from VPD, identified 18% (17/94) with evidence of at least one serology sample. CONCLUSION: This study highlights poor compliance in IBD patients for additional recommended vaccines. A multi-faceted approach is required to maximize protection from VPD in this vulnerable special risk population.

Slow-transit constipation with concurrent upper gastrointestinal dysmotility and its response to transcutaneous electrical stimulation.

PURPOSE: Transcutaneous electrical stimulation (TES) speeds up colonic transit in children with slow-transit constipation (STC). This study examined if concurrent upper gastrointestinal dysmotility (UGD) affected response to TES. METHODS: Radio-nuclear transit studies (NTS) were performed before and after TES treatment of STC as part of a larger randomised controlled trial. UGD was defined as delayed gastric emptying and/or slow small bowel transit. Improvement was defined as increase of ≥1 Geometric Centre (median radiotracer position at each time [small bowel = 1, toilet = 6]). RESULTS: Forty-six subjects completed the trial, 34 had NTS after stimulation (21 M, 8-17 years, mean 11.3 years; symptoms >9 years). Active stimulation increased transit in >50% versus only 25% with sham (p = 0.04). Seventeen children also had UGD. In children with STC and either normal upper GI motility (NUGM) and UGD, NTS improved slightly after 1 month (57 vs. 60%; p = 0.9) and more after 2 months (88 vs. 40%; p = 0.07). However, mean transit rate significantly increased with NUGM, but not UGD (5.0 ± 0.2: 3.6 ± 0.6, p < 0.01). CONCLUSION: Transcutaneous electrical stimulation was beneficial for STC, with response weakly associated with UGD. As measured by NTS, STC children with NUGM responded slightly more, but with significantly greater increased transit compared to those with UGD. Higher numbers are needed to determine if the difference is important.

Trunk strength and mobility changes in children with slow transit constipation.

BACKGROUND AND AIM: It appears that there are no published reports on childhood slow transit constipation (STC) that have considered the state of the musculoskeletal components of the trunk in these children. The present study aimed to determine whether children with STC have different trunk musculoskeletal characteristics that might be related to their defecation difficulties, compared to controls. METHODS: With the aid of computer-analyzed photographs and clinical testing, 41 children with STC and 41 age-matched controls were examined for Marfanoid features, sitting posture, spinal joint mobility and trunk muscle strength. The latter was assessed by measuring maximum voluntary abdominal bulging and retraction in sitting, and active trunk extension in prone-lying. Levels of general exercise and sedentary activities were evaluated by questionnaire. RESULTS: STC subjects were more slumped in relaxed sitting (P < or = 0.001), less able to bulge (P < or = 0.03) and less able to actively extend the trunk (P = 0.02) compared to controls. All subjects sat more erect during abdominal bulging (P < or = 0.03). CONCLUSION: The results show that STC children have reduced trunk control and posture, which indicates that clinicians should include training of trunk muscles and correction of sitting posture. There was no evidence that children with STC exercised less than the controls.

Standard medical therapies do not alter colonic transit time in children with treatment-resistant slow-transit constipation.

BACKGROUND: Slow transit constipation (STC) is a form of chronic constipation characterised by prolonged passage of faecal matter through the colon. It is diagnosed by demonstrating delayed colonic transit on gastrointestinal transit studies. Traditionally, radio-opaque marker studies are performed. Recently, radioisotope nuclear transit studies (NTS) have been used in our centre to assess gastrointestinal transit time. This study aimed to evaluate if there are changes in colonic transit in STC children resistant to standard medical treatment over a prolonged period. METHODS: Children with STC resistant to standard medical therapy for > or =2 years who had undergone two separate NTS to assess their colonic transit (where the first study had identified slow colonic transit without anorectal retention) were identified after ethical approval. The geometric centre (GC) of radioisotope activity at 6, 24, 30 and 48 h was compared in the two transit studies to determine if changes occurred. RESULTS: Seven children (4 males) with proven STC resistant to standard medical therapy and two transit studies performed at different times were identified. Mean age was 7.0 years (5.4-10.8 years) at first study, and 11.4 years (9.7-14.2 years) at second study, with a mean of 4.4 years (1-8.5 years) between studies. There was no significant difference in colonic transit at any timepoint in the two tests (paired t test). CONCLUSIONS: We conclude that nuclear transit studies are reproducible in assessing slow colonic transit in children with treatment-resistant STC and demonstrate that conventional medical treatment over many years has no effect on underlying colonic motility.

Slow-transit constipation in children: our experience.

Constipation is a common problem in children, with childhood prevalence estimated at between 1 and 30%. It accounts for a significant percentage of referrals to paediatricians and paediatric gastroenterologists. It commonly runs in families, suggesting either an underlying genetic predisposition or common environmental factors, such as dietary exposure. The peak age for presentation of constipation is shortly after toilet training, when passage of hard stools can cause pain on defecation, which then triggers holding-on behaviour in the child. At the time of the next call to stool the toddler may try to prevent defecation by contraction of the pelvic floor muscles and anal sphincter. Unless the holding-on behaviour is quickly corrected by interventions to soften faeces and prevent further pain, the constipation can very rapidly become severe and chronic. Until recently, this mechanism was thought to be the only significant primary cause of constipation in childhood. In this review, we will summarise recent evidence to suggest that severe chronic constipation in children may also be due to slowed colonic transit.

The Microbiome in Paediatric Crohn's Disease-A Longitudinal, Prospective, Single-Centre Study.

BACKGROUND AND AIMS: The gut mucosa is the principal site where Crohn's disease [CD] inflammation occurs. Limited information is available about the gut mucosal microbiome during CD relapse and remission. The aim of our study was to characterize specific changes in the gut microbiome during relapse and remission in a large single-centre paediatric CD cohort. METHODS: We analysed the microbiome of 345 biopsies from 204 patients, including 88 CD first diagnosis [CDFD] patients, 38 relapse [CDRL] patients, 12 remission [CDRM] patients, and 66 controls. Species identification was conducted using oligotyping in combination with ARB/SILVA taxonomic annotation. RESULTS: We observed 45 bacteria to differ between CDFD samples and controls with statistical significance, with Fusobacterium being the most implicated species in CDFD patients. We also identified gender-specific differences in CD. Five species showed a strong association with CDRL patients and 10 species with CDRM patients. Three taxa showed a positive co-occurrence across the two groups. Hespellia porcina [closest taxonomic neighbour to Clostridium oroticum] was the most strongly associated with CDRL samples. Interestingly, Fusobacterium was not part of the CDRL-associated taxa group. Faecalibacterium prausnitzii was equally present in CDFD and control samples. CONCLUSION: This is the first study that has investigated the gut mucosal microbiome in a paediatric CD cohort with longitudinal sampling. Importantly, the microbiome of patients in CDRM did not return to a healthy control state. Neither did the microbiome of patients with CDRL return to the profile seen at CDFD.

24-Hour colonic manometry in pediatric slow transit constipation shows significant reductions in antegrade propagation.

BACKGROUND: The physiological basis of slow transit constipation (STC) in children remains poorly understood. We wished to examine pan-colonic motility in a group of children with severe chronic constipation refractory to conservative therapy. METHODS: We performed 24 h pan-colonic manometry in 18 children (13 boys, 11.6 +/- 0.9 yr, range 6.6-18.7 yr) with scintigraphically proven STC. A water-perfused, balloon tipped, 8-channel, silicone catheter with a 7.5 cm intersidehole distance was introduced through a previously formed appendicostomy. Comparison data were obtained from nasocolonic motility studies in 16 healthy young adult controls and per-appendicostomy motility studies in eight constipated children with anorectal retention and/or normal transit on scintigraphy (non-STC). RESULTS: Antegrade propagating sequences (PS) were significantly less frequent (P < 0.01) in subjects with STC (29 +/- 4 per 24 h) compared to adult (53 +/- 4 per 24 h) and non-STC (70 +/- 14 per 24 h) subjects. High amplitude propagating sequences (HAPS) were of a normal frequency in STC subjects. Retrograde propagating sequences were significantly more frequent (P < 0.05) in non-STC subjects compared to STC and adult subjects. High amplitude retrograde propagating sequences were only identified in the STC and non-STC pediatric groups. The normal increase in motility index associated with waking and ingestion of a meal was absent in STC subjects. CONCLUSIONS: Prolonged pancolonic manometry in children with STC showed significant impairment in antegrade propagating motor activity and failure to respond to normal physiological stimuli. Despite this, HAPS occurred with normal frequency. These findings suggest significant clinical differences between STC in children and adults.

Oesophagitis in children: reflux or allergy?

The prevalence of eosinophilic oesophagitis appears to be increasing in many countries, sometimes rapidly, although this may be partly due to increased disease recognition. Histological methods of assessment and diagnostic criteria vary considerably between major clinical centres. Oesophagitis with over 20 intraepithelial eosinophils per high power field is more likely to be due to allergy than gastro-oesophageal reflux induced acid-peptic mucosal injury. Typical eosinophilic oesophagitis shows involvement of the entire oesophagus, with basal cell proliferation occupying more than 50% of the thickness of the surface epithelium, and high numbers of intraepithelial eosinophils, sometimes concentrated on the surface or as contiguous clusters. Ulceration and prominent neutrophils are atypical and should suggest an alternative or co-existent disease. On endoscopy, the oesophagus may display the typical 'corrugated' mucosal appearance. Clinically, dysphagia or food impaction are the most characteristic symptoms. There is a strong association with other atopic diseases, especially asthma and eczema. To date no evidence has emerged of an increased malignancy risk. Patients with eosinophilic oesophagitis typically fail to respond to acid suppressive medications but respond well to either elemental/elimination diets or aerosolised swallowed corticosteroids. Long-term uncontrolled oesophageal eosinophilic inflammation may lead to progressive subepithelial fibrosis, potentially resulting in strictures or oesophageal narrowing.

Impact of day-case gastroscopy on children and their families.

BACKGROUND AND AIM: Increasing numbers of endoscopies are being carried out in children. The purpose of our study was to evaluate the provision of information about the admission and procedure and the functional and economic impact of day-case gastroscopy on children and their families. METHODS: We administered a structured questionnaire to families of children undergoing elective gastroscopy, with daily follow up by telephone over the next 3 days. RESULTS: One-hundred-and-three children were recruited. All had seen a consultant gastroenterologist (usually the proceduralist) prior to the endoscopy, who had obtained signed consent; 89% of families remembered receiving an explanation from the doctor carrying out the procedure. Nearly all (94%) described the information they received as adequate. However, only one-third of families recalled receiving an explanatory brochure and very few had toured the Day Surgical Unit or seen the complimentary video. Thirty percent were unhappy with the time spent at the Day Surgical Unit and an apparent failure to warn of possible delays, 8% felt that they were not given adequate information prior to discharge, and 39% of children failed to attend school the day after the procedure. Although tiredness or sleepiness was common, no correlation was found between the presence of symptoms and school absence. Complaints about the admission included overcrowding, lack of privacy, excessive noise, and failure to cater for adolescents. Fifty percent of parents took leave from work, but most manipulated work rosters and holidays so that costs to them and to the workplace were minimal. CONCLUSION: Information provision about the procedure and admission appears to be adequate in most families of children undergoing day-case gastroscopy, but may be improved in some areas. Failure to remember elements of the consent and explanatory process is common. Minor morbidity is also common after the procedure.

Crypt fission peaks early during infancy and crypt hyperplasia broadly peaks during infancy and childhood in the small intestine of humans.

BACKGROUND: Postnatal growth of the small intestine occurs by crypt hyperplasia and by the less recognised mechanism of crypt fission. How the small intestine grows is largely extrapolated from animals and is poorly described in humans. AIM: To investigate crypt fission and crypt hyperplasia as mechanisms of intestinal growth in humans. PATIENTS AND METHODS: Proximal intestinal samples were taken from 3 neonates at surgical anastomosis, and duodenal biopsies were taken at endoscopy from 16 infants (mean age 0.7, range 0.3-1.7 years), 14 children (mean age 7.9, range 2.4-16.2 years), and 39 adults. Morphometric measures of villous area, crypt length (measure of crypt hyperplasia), and percentage of bifid crypts (measure of crypt fission) were assessed by a microdissection technique. RESULTS: Mean crypt fission rates in neonates, infants, children, and adults were 7.8%, 15%, 4.9%, and 1.7%, respectively. In particular, crypt fission peaked at 18% in 5 infants from 6 to 12 months of age. Mean crypt length was 123 microm in neonates, 287 microm in infants, 277 microm in children, and 209 microm in adults. Thus, crypt hyperplasia had a broad peak during infancy and childhood. CONCLUSIONS: We conclude that crypt fission was present predominantly during infancy, and crypt hyperplasia occurred during both infancy and childhood.