Year : 1995 | Volume
: 1 | Issue : 3 | Page : 152--156
Intractable diarrhea of infancy
From the Academic Department of Pediatric Gastroenterology, Queen Elizabeth Hospital for Children, London, United Kingdom
J A Walker-Smith
Academic Department of Pediatric Gastroenterology, Queen Elizabeth Hospital for Children, London E28PS
The current concept of intractable diarrhea of infancy is that of a heterogeneous syndrome with diverse etiologies. The purpose of this review is to provide an update on this group of diseases. As modern diagnostic techniques become available, new disorders will continue to be recognized.
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Walker-Smith J A. Intractable diarrhea of infancy.Saudi J Gastroenterol 1995;1:152-156
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Walker-Smith J A. Intractable diarrhea of infancy. Saudi J Gastroenterol [serial online] 1995 [cited 2022 Dec 2 ];1:152-156
Available from: https://www.saudijgastro.com/text.asp?1995/1/3/152/34052
In 1968, Avery, Villavicencio and Lilly  first described a severe syndrome of chronic diarrhea as infantile intractable diarrhea. The phrase they used to describe the diarrhea was "prolonged and intractable despite extensive hospital therapy."
The syndrome had the following features:
- Diarrhea of more than two weeks duration
- Age, less than three months
- Three or more stool cultures negative for bacterial pathogens
- All were managed with intravenous fluids
- Despite hospital management, diarrhea was persistent and intractable
- There was a high mortality
In current practice the term "intractable diarrhea" has come to be extended beyond the age of three months - and to describe children with chronic diarrhea - which is severe and prolonged and associated with poor nutrition. These are children with chronic diarrhea which is not easily resolved.
Three clinical variants of the syndrome may be recognized:
Chronic diarrhea persisting despite intravenous fluid and nil by mouth. This is very likely to be secretory diarrhea, e.g., pancreatic cholera or Verner-Morrison syndrome.Chronic diarrhea that disappears on intravenous fluids and nil by mouth, only to recur whenever oral feeding is resumed. This is likely to be osmotic diarrhea, and associated with small intestinal enteropathy. Although in some patients, it is clear that both secretory and osmotic diarrhea are present.Chronic diarrhea that has been managed by a variety of elimination diets but still persists; again. this is likely to be associated with small intestinal enteropathy.
Thus the intractable diarrhea syndrome of infancy embracing these three groups is a heterogeneous syndrome with diverse etiologies.
Intractable diarrhea of infancy may be defined as a syndrome of severe chronic diarrhea associated with malnutrition which is not easily resolved by conventional management. It is a heterogeneous syndrome with a number of causes.
This heterogenicity is clear from Avery's original report. Eight children, six of whom died, had idiopathic conditions which Avery et al termed "nonspecific enterocolitis" as both small and large intestinal abnormalities were found; four of these cases were diagnosed on admission as gastroenteritis. However, although the authors listed small intestinal biopsy as a diagnostic test, it was just recommended as a means to confirm or exclude celiac disease. It was only autopsy material which was available for study of small intestinal mucosal morphology.
Shwachman, Filler and Khaw  were the first to perform small intestinal mucosal biopsies on five such patients, which they later extended to eleven cases .
They performed light microscopy and assayed disaccharidase levels and found a moderatelysevere to mild lesion in nine cases. Their studies were only possible because the children had been kept alive by parenteral nutrition.
It is this development of parental nutrition as a practical option for infants in the early 1970's that transformed the scene and enabled infants who otherwise would have died, to survive. As a result, it became possible to perform investigations to determine the cause of their intractable diarrhea.
A full diagnostic work-up of these children requires morphological and functional assessment of both the small and large intestinal mucosa, including small intestinal biopsy and colonoscopy with multiple colonic biopsies.
It is now clear that not only is proximal small intestinal biopsy important, but that the development of safe and effective total colonoscopy in infancy over the past 15-20 years, has been another major advance which has led to increased understanding of the intractable diarrhea syndrome.
Functional assessment is more difficult. Testing of stools for excess stool-reducing substances is a practical and simple test for diagnosis of sugar intolerance. However, serial estimation of intestinal permeability is a practical opinion. The pioneering work of Muller et al  using lactulose as a marker of intestinal mucosal damage led on to the work of Menzies  who developed a practical test of intestinal permeability based on differential absorption of two inert sugars. Lactulose and rhamnose may be useful examples of this approach . However, the importance of small intestinal biopsy in the children remains as true as ever and will be emphasized in this paper.
This extensive diagnostic approach for children with intractable diarrhea has led to the recognition of specific disease entities and at times, specific therapy resulting in effective treatment and so, elimination of the intractable diarrhea as a symptom complex in many cases.
It thus, must be remembered that failure to make a specific diagnosis in children may be due to diagnostic inadequacy, which in turn may be due to lack of the existence of a clinical entity or lack of availability of particular diagnostic techniques. For example, undiagnosed celiac disease can go on to intractable diarrhea. This has clearly been shown in India where only in recent years, has it been appreciated that celiac disease in Northern India is an important cause of intractable diarrhea .
Within the broader syndrome of intractable diarrhea, is the syndrome known as malnutrition in chronic diet-associated infantile diarrhea (McDAID) . The features of this syndrome include: diarrhea of more than two weeks duration, malabsorption and intestinal malfunction, which is further aggravated when food and/or specific dietary products are fed. Fasting usually brings about improvement in the diarrhea, but may lead to considerable nutrition deterioration. These diet-associated problems have dramatically decreased in the developed world. This relates to a decline in gastroenteritis and the recognition of temporary cow's milk protein intolerance occurring as a sequel. Thus, in the past, undiagnosed lactose intolerance and cow's milk sensitive enteropathy were important causes of intractable diarrhea . In Europe we are now usually left with non diet-associated intractable diarrhea. Unfortunately in the developing world, especially
Africa, AIDS is increasing as an important cause of intractable diarrhea.
In summary, many of the infants who present with intractable diarrhea, in fact, eventually prove to have a diagnosable condition, i.e., have a specific diagnosis sometimes with specific therapy, sometimes without. However, there does remain an important group in whom no primary cause can be determined.
As an example of the clinical spectrum of intractable diarrhea, in Europe, Phillips , during a survey of small intestinal biopsies in 589 children, between 1976 and 1986 at Queen Elizabeth Hospital for Children, described twenty children (3.4% eleven male, nine female; median age 5.5 months, range 2-21 months) who had intractable diarrhea. They had undergone a total of forty-seven biopsies during the study period. Four of these children on investigation proved to have microvillous atrophy; two children had glucose-galactose malabsorption (diagnosis had been missed by initial clinician) and six had autoantibodies against gut epithelium detected in their serum and were diagnosed as autoimmune enteropathy. One child, referred from Bangladesh, had several infective organisms detected in stool and mucosa, although immune deficiency was not established. This could be a variant of postenteritis enteropathy. Definite diagnoses were not established for the small intestinal enteropathies found in the remaining case. Seven of the children in this group died, four with microvillous atrophy, two with autoimmune enteropathy and one with idiopathic intractable diarrhea.
This summary is typical of the type of children now presenting in Europe with the intractable diarrhea syndrome. However, it does exclude children with enterocolitis.
Categories of Intractable Diarrhea
It is now possible after extensive diagnosis, to divide intractable diarrhea syndrome into four categories:
Failure to make a diagnosis of any kindSpecific diagnosis but no therapySpecific diagnosis but therapy of variable efficacyNo specific or only partial diagnosis
There are now fewer and fewer patients who fit into category 1 and this will not be discussed here.
Specific Diagnosis But No Therapy
Two examples of this are microvillous atrophy and congenital enterocyte heparan sulphate deficiency.
Davidson et al  in Canada, described five infants with severe diarrhea and failure to thrive from birth, leading to death in four cases. All infants had small intestinal villous atrophy, without crypt hypertrophy, i.e., hypoplastic villous atrophy. There was a familial history in four cases and the term familial enteropathy was used to describe this syndrome. Electron microscopy of three of the children showed striking ultrastructural changes in one. Involutions of the apical membrane of some surface epithelial cells were seen containing microvilli, and secretory granules accumulated in upper crypt cells. Schmitz et al  and Goutet et al , both in France, reported three similar children with these ultrastructural abnormalities. Schmitz called this syndrome congenital microvillous atrophy. A case has since, been described where the child was well for the first weeks of life . The specific diagnostic features of microvillous atrophy have been reviewed . A detailed review has now 1been published of children with this disorder .
Congenital Enterocyte Heparan Sulphate Deficiency
A new cause of intractable diarrhea syndrome of infancy, associated with histologically-normal small intestinal mucosa by conventional assessment, has been described by Murch et al 1995 . This syndrome begins in the first days of life and is characterized by chronic diarrhea associated with profound hypoproteinemia. The diarrhea is secretory in character and there is severe protein-losing enteropathy. The small intestinal mucosa is normal on light microscopy, although there is some minor thickening of the subepithelial basement membrane with increased fibrillar collagen on electron microscopy. However, there is almost complete absence of epithelial glycosaminoglycans. There is in particular, a gross reduction of sulphated glycosaminoglycans (heparan sulphate) in the basolateral membrane, lining the lateral intercellular spaces. As glycosaminoglycans play a major role in retaining circulating proteins within the vasculature, it has been proposed that this loss is responsible for the severe enteric protein loss and secretory diarrhea in these infants. These infants have been thus described as suffering from "minimal-change" enteropathy, analogous to lesions in the glomerulus of the kidney in patients with nephrotic syndrome. So far there is no effective therapy.
Specific Diagnosis But Therapy of Variable Efficacy
The best example of this is autoimmane enteropathy. This syndrome describes children with intractable diarrhea and small intestinal enteropathy who possess an antibody against their intestinal epithelium and thus, appear to have an autoimmune enteropathy . Further research is required to elucidate whether this is a primary event or a secondary one. Whether or not this is so, these children represent a very difficult management problem with a high mortality . They have a characteristic clinical syndrome which may be associated with other autoimmune phenomena, e.g., diabetes mellitus associated with islet cell antibody. This syndrome has now been seen in a number of countries. However, its relative frequency is not yet clear. In a highlyselected group of twenty-five infants with intractable diarrhea, fourteen in fact had evidence of this syndrome. This may exaggerate its true importance as these were all selected cases . Cyclosporin can be effective in the management of such children .
Another example is congenital secretory diarrhea due to defective jejunal brush-border Na+/H+ exchange .
No Specific or Only Partial Diagnosis
The best examples here are small intestinal enteropathy of unknown origin and intractable enterocolitis of infancy .
Small Intestinal Enteropathy of Unknown Origin
Small intestinal enteropathy of unknown origin can be a very severe disorder. It is possible that it is a variant of autoimmune enteropathy. These children with intractable diarrhea with an enteropathy of unknown origin may have an immunological pathogenesis, as there are increased numbers of inflammatory cells in the lamina propria. They need to be distinguished from children with autoimmune enteropathy. In an ESPGAN study group of 13 non-autoimmune and 18 autoimmune children with small intestinal enteropathy, these two groups were compared in relation to age and onset of diarrhea. They were all 12 months or under. There was a higher mortality in the autoimmune group. Such children may be totally dependent on home parenteral nutrition and they provide a very great challenge at present for both diagnosis and management.
Intractable enterocolitis of infancy is a disorder of unknown origin which can resemble Bechet's colitis (23). This disorder is now often reported in communities with a high degree of consanguinity. It typically presents in infancy. It may sometimes resemble Crohn's disease. The children often require sub-total colectomy for severe colitis. The long-term progress may be quite good.
As more causes of intractable diarrhea are recognized with better diagnostic techniques, the residuum of cases where the diagnosis is incomplete and therapy unsatisfactory, continues to decline. These cases however, remain as one of the most difficult problems faced by pediatric gastroenterologists for whom they provide a continuing challenge.
However, the diagnostic advances over the past twenty-five years whereby it has become safe and effective to biopsy both the small and large intestine of infants, has led to the notable advances in our ability both to make a diagnosis and also to understand pathogenesis. These advances too, have in part only been possible because highlyeffective parenteral nutrition is now able to keep these babies alive. In previous years they would have died.
New disorders continue to be recognized  as modern diagnostic techniques are applied to the intestinal mucosa. This is an exciting area for further development.
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