Saudi Journal of Gastroenterology
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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

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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.

How to cite this article:
Walker-Smith J A. Intractable diarrhea of infancy. Saudi J Gastroenterol 1995;1:152-6

How to cite this URL:
Walker-Smith J A. Intractable diarrhea of infancy. Saudi J Gastroenterol [serial online] 1995 [cited 2022 Dec 9];1:152-6. Available from:

   Terminology Top

In 1968, Avery, Villavicencio and Lilly [1] 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:

  1. 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.
  2. 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.
  3. 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.

   Definition Top

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.

   Early Descriptions Top

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 [2] were the first to perform small intestinal mucosal biopsies on five such patients, which they later extended to eleven cases [3].

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.

   Diagnosis Top

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 [4] using lactulose as a marker of intestinal mucosal damage led on to the work of Menzies [5] 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 [6]. 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 [7].

Within the broader syndrome of intractable diarrhea, is the syndrome known as malnutrition in chronic diet-associated infantile diarrhea (McDAID) [8]. 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 [9]. 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.

   Clinical spectrum Top

As an example of the clinical spectrum of intrac­table diarrhea, in Europe, Phillips [10], 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 Top

It is now possible after extensive diagnosis, to divide intractable diarrhea syndrome into four categories:

  1. Failure to make a diagnosis of any kind
  2. Specific diagnosis but no therapy
  3. Specific diagnosis but therapy of variable efficacy
  4. No 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 Top

Two examples of this are microvillous atrophy and congenital enterocyte heparan sulphate defi­ciency.

Microvillous Atrophy

Davidson et al [11] 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 [12] and Goutet et al [13], 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 [14]. The specific diag­nostic features of microvillous atrophy have been reviewed [15]. A detailed review has now 1been published of children with this disorder [16].

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 [17]. 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 Top

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 [18]. 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 [19]. 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 [20]. Cyclos­porin can be effective in the management of such children [21].

Another example is congenital secretory diarrhea due to defective jejunal brush-border Na+/H+ exchange [22].

   No Specific or Only Partial Diagnosis Top

The best examples here are small intestinal enteropathy of unknown origin and intractable enterocolitis of infancy [23].

   Small Intestinal Enteropathy of Unknown Origin Top

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 Top

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.

   Conclusion Top

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 [17] as modern diagnostic techniques are applied to the intestinal mucosa. This is an exciting area for further development.

   References Top

1.Avery GB, Villavicencio O and Lilly JR. Intractable diarrhea in early infancy. Pediatr 1969;41:712.  Back to cited text no. 1    
2.Shwachman H, Filler RM and Khaw KT. A new method of treating malnourished infants with severe chronic diarrhea. Acta Pediatr Scand 1970;59:446-7.  Back to cited text no. 2    
3.Shwachman H, Lloyd-Still JD, Khaw KT, Antonowicz I. Protracted diarrhea of infancy treated by intravenous alimentation. II Studies of small intestinal biopsy results. Am J Dis Child 1973;125:365-8.  Back to cited text no. 3    
4.Muller M, Walker-Smith JA, Shmerling DH, Curtius HCH, Prader A. Lactulose: a gas liquid chromatography method of determination and evaluation of its use to assess intestinal mucosal damage. Clin Chim Acta 1969;24:45-9.  Back to cited text no. 4    
5.Menzies IS. Quantitative estimation of sugars in blood and urine by paper chromatography using direct densitometry. J Chromatography 1973;81:109-11.  Back to cited text no. 5    
6.Ford RPK, Menzies IS, Phillips AD, Walker-Smith JA Turner MW. Intestinal sugar permeability: relationship to diarrheal disease and small bowel morphology. J Pediatr Gastroenterol and Nutr 1985;4:345-8.  Back to cited text no. 6    
7.Khoshoo V, Bhan MK, Jain R, Phillips AD, Walker­Smith JA, Unsworth DJ, Stintzing G. Celiac disease as cause of protracted diarrhea in Indian children. Lancet 1988;i: 126-7.  Back to cited text no. 7    
8.Lifshitz F, Bowie MD, Klish WJ, Savilahti E, Walker­Smith JA. Terminology and classification of patients with malnutrition in chronic diet-associated infantile diarrhea: McDAID. In: Chronic Diet-Associated Infan­tile Diarrhea Diagnosis and Management. CH Lifschitz and B Nicholas, Editors Academic San Diego Press 1990:436-9.  Back to cited text no. 8    
9.Walker-Smith JA. Cow's milk intolerance as a cause of postenteritis diarrhea. J Pediatr Gastroenterol and Nutr 1982;1:163-75.  Back to cited text no. 9    
10.Philips AD. Microscopic studies of chronic diarrhea in early childhood (PhD thesis) 1990.  Back to cited text no. 10    
11.Davidson GP, Cutz E, Hamilton JR, Gall DG. Familial enteropathy: a syndrome of proctracted diarrhea from birth, failure to thrive and hypoplastic villous atrophy. Gastroenterol 1978;75:783-90.  Back to cited text no. 11    
12.Schmitz J, Ginies JL, Arnaud-Battandier F et al. Con­genital microvillous atrophy, a rare cause of neonatal intractable diarrhea. Pediatr Research 1982;16;1014.  Back to cited text no. 12    
13.Goutet JM, Boccon-Gibod L, Chatelet F et al. Familial proctracted diarrhea with hypoplastic villous atrophy: report of two cases. Pediatr Research 1982;16:1045.  Back to cited text no. 13    
14.Carruthers L, Dourmashkin R, Phillips AD. Disorders of the cytoskeleton of the enterocyte. Clin Gastroenterol 1986;5:105-21.  Back to cited text no. 14    
15.Phillips AD, Jenkins P, Raafat F, Walker-Smith JA Con­genital microvillous atrophy specific diagnostic features. Arch Dis Child 1985;60:730-5.  Back to cited text no. 15    
16.Phillips AD, Schmitz J. Familial microvillous atrophy: a clinicopathological survey of 23 cases. J Pediatr Gas­troenterol and Nutr 1992;14:380-96.  Back to cited text no. 16    
17.Murch SH, Klein NJ, Levin M, Phillips AD, Walker­Smith JA. Do sulphated glycosaminoglycans limit intesti­nal albumin loss? J Ped Gastro Nutrit 1993;17:472.  Back to cited text no. 17    
18.Unsworth J, Hutchins P, Mitchell J et al. Flat, small intestinal mucosa and autoantibodies against the gut epithelium. J Pediatr Gastroenterol and Nutr 1982;1:503-15.  Back to cited text no. 18    
19.Mitton SG, Mirakian R, Larcher VF, Dillon MJ, Walker-Smith JA. Enteropathy and renal involvement in an infant with evidence of widespread autoimmune dis­turbance. J Pediatr Gastroenterol and Nutr 1989;8:397­401.  Back to cited text no. 19    
20.Mirakian R, Hills S, Richardson A, Milla PJ, Walker­smith JA and Bottazzo GF. HLA product expression and lymphocyte subpopulations in jejunum biopsies of chil­dren with idiopathic protracted diarrhea and enterocyte antibodies. J Autoimmunity 1988;1:263-77.  Back to cited text no. 20    
21.Sanderson IR, Phillips AD, Spencer J, Walker-Smith JA. Response of autoimmune enteropathy to Cyclospo­rin A therapy. Gut 1991;32:1421-6.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Booth IW, Stange G, Murer H, Fenton TR, Milla PJ. Defective jejunal brush-border Na+/H+ exchange: a cause of congenital secretory diarrhea. Lancet 1985;i:1066-9.  Back to cited text no. 22    
23.Sanderson IR, Risdon RA, Walker-Smith JA. Intracta­ble ulcerating enterocolitis of infancy. Arch Dis Child 1991;66:295-300.  Back to cited text no. 23  [PUBMED]  

Correspondence Address:
J A Walker-Smith
Academic Department of Pediatric Gastroenterology, Queen Elizabeth Hospital for Children, London E28PS
United Kingdom
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Source of Support: None, Conflict of Interest: None

PMID: 19864847

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