Seven children were referred over a 3-year period with intractable diarrhoea of infancy, in whom nonspecific inflammatory bowel disease was subsequently diagnosed; this combination had not been seen by us before 1990. None responded to exclusion of cow's milk or soya, and infection was identified in only one patient (Adenovirus). All required parenteral nutrition, and only one achieved remission with steroids. The response to colectomy was also disappointing.
The prevalence and significance of IBD in children with intractable diarrhoea are unknown, although the case of an infant with congenital diarrhoea and intestinal inflammation had been reported (16). Also increased mucosal T-cell numbers have been identified in a subgroup of seven of 13 children with intractable diarrhoea and villous atrophy (17).
Within our cohort of patients there was considerable difference in the clinical features, distribution, nature, and severity of the histological changes. The onset of IBD also varied as the delay between presentation with intractable diarrhoea and rectal bleeding ranged from 0-26 months. In patient 7 intractable diarrhoea was the main clinical problem, and endoscopy was not contemplated until her younger sister developed a florid colitis shortly after birth.
Where pathological examination of the whole colon was possible after colectomy or at postmortem (cases 1, 2, and 4), severe nonspecific inflammatory bowel disease was found, confirming the biopsy findings. There were insufficient criteria for a firm diagnosis of Crohn's disease to be made, although all three had either previously or subsequently developed small-bowel or upper-gastrointestinal-tract pathology. All seven patients were classified as having chronic nonspecific IBD, and although patient 1 had some features of intractable ulcerating enterocolitis of infancy (14), the ulcers were not large or flask-shaped, as described in this condition. None of the seven infants fulfilled clincal or histological criteria for Behcet's disease (18) or collagenous colitis (19). Microscopic colitis (20) was excluded by the abnormal macroscopic appearances of our patients at endoscopy.
Small-bowel mucosal injury and disaccharidase deficiency are a common accompaniment to intractable diarrhoea of infancy (21). In our series there was an inflammatory response in five and villous atrophy of variable severity in six. Villous atrophy has been described in animals exclusively given total parenteral nutrition; however, all our patients were given some enteral nutrition during these periods of intravenous feeding. Moreover, patients 3 and 5, who had the most severe villous atrophy, were not receiving parenteral nutrition at the time of their small-bowel biopsies. Parenteral nutrition thus does not appear to be the primary cause of the villous atrophy found in these infants with IBD. In addition, there was no evidence to support a diagnosis of autoimmune enteropathy or congenital microvillous atrophy. An eosinophilic infiltration was noted in four of our patients, but the lack of symptom periodicity, peripheral eosinophilia, and prompt response to steroids typically seen in eosinophilic enteropthy (22) made this diagnosis untenable.
Comparing patients 3 and 5 with the other children, it appears that both had total villous atrophy, yet less severe proctocolitis and a better response to steroid therapy. Their outcomes are also superior since the other five have either died or required long-term parenteral nutrition at home. Apart from a later onset, there is little to differentiate them from the others in their clinical features, family history, or early feeding practices. They shared the common endoscopic findings of nonspecific proctocolitis and so may represent the better end of a single disease spectrum. If one is to postulate a single disease process for all these cases, then it must have considerable clinical and pathological heterogeneity. Although they are rare, Crohn's disease and ulcerative colitis can both occur in infancy, but none of our patients had the subacute obstruction that has been described in the infantile form of Crohn's (10). Perhaps given time to evolve, the classic discontinuous panintestinal and transmural inflammatory changes would manifest.
Alternately, there may be more than one disease process. IBD may occur insidiously in a proportion of patients and immediately in others. We speculate that these infants with intractable diarrhoea who are found to have changes reflective of IBD well after the original symptoms began could have developed it as a consequence of nutritional deficiency. Recently, the importance of glutamine and short chain fatty acids (SCFA) has been recognised in small-and large-bowel function, respectively (23). SCFA, predominantly butyrate, has been shown to alter colonic sodium and water absorbtion, mucosal blood flow, and mucin production (24). SCFA deficiency has been proposed as a cause of the colitis and diarrhoea seen in time of famine, and absent luminal SCFA supplies after defunctioning colostomy may lead to diversion colitis. Irrigation of SCFA into the rectal stump of a patient with diversion colitis has reversed the macroscopic and histological evidence of inflammation (25).
All patients, except patients 1 and 3, were given pectin, which is converted to SCFA by bacterial degradation in the colon. However, the age at which this diet was commenced varied from 6 to 24 months, by which time the colitis associated with SCFA deficiency might have already become well established.
In conclusion, seven infants with intractable diarrhoea of infancy had features of chronic nonspecific IBD. All had proctocolitis, and six had small-bowel or upper-gastrointestinal-tract involvement. The heterogeneity in their presentation and histology may indicate more than one disease process. The true prevalence of the condition will be known only if endoscopy is undertaken in cases of intractable diarrhoea. Further work is required to investigate the pathophysiology and possible significance of nutritional deficiencies in this condition.
Acknowledgment: We gratefully acknowledge the help of John Stanton in the nutritional treatment of these patients.
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Keywords:© Lippincott-Raven Publishers
Inflammatory bowel disease; Infancy; Prevalence