Pathogenesis of persistent diarrhea

Although a close relationship between diarrheal disease and malnutrition has long been recog-nized,12 this has been challenged.13 The relationship of persistent diarrhea to malnutrition is less controversial, as the disorder is commonly seen in association with significant malnutrition. In a verbal autopsy study of diarrheal deaths in Bangladesh, Fauveau et al14 found that almost half the deaths were in malnourished children with persistent diarrhea, and the relative risk of dying with persistent diarrhea and severe malnutrition was 17-fold higher than in children with lower degrees of malnutrition.

There are several reasons for malnutrition both to predispose to persistent diarrhea and to follow it.

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Peru (1989) Bangladesh (1982) India (1989) Bangladesh (1992) Pakistan (1 993)

Peru (1989) Bangladesh (1982) India (1989) Bangladesh (1992) Pakistan (1 993)

1-7 days 8-14 days 15-21 days

1-7 days 8-14 days 15-21 days

Figure 12.1 Distribution of diarrheal episodes in community-based studies. From references 7 and 9-11.

These range from achlorhydria with increased risk of small-bowel contamination, systemic immune deficiency, intestinal and pancreatic enzyme deficiency and altered intestinal mucosal repair mechanisms following an infectious insult. An independent relationship has also been demonstrated between cutaneous anergy and the subsequent risk of development of persistent diarrhea.15 There has been much interest in the possibility that such transient immune deficiency may also be a marker of concomitant micronutrient deficiency.16-18 The most striking example of the critical role that the immune system plays in the pathogenesis of persistent diarrhea is the relationship between HIV/AIDS and persistent diarrhea. This is exemplified by the host of studies linking persistent diarrhea with cryptosporidiosis19 and other parasitic infections20,21 in Africa and Asia.

mucosa in persistent diarrhea have revealed patchy villous atrophy and intraepithelial lymphocytic infiltration23 as well as severe mucosal damage and villous atrophy.24

Poor intestinal repair is regarded as a key component of the abnormal mucosal morphology. However, the exact factors underlying this ineffective repair process and continuing injury are poorly understood (Figure 12.2). The end result of this mucosal derangement is poor absorption of luminal nutrients, as well as increased permeability of the bowel to abnormal dietary or microbial antigens.25-27 Alterations of intestinal permeability in early childhood may reflect changes in intestinal mucosal maturation28 and may be affected by concomitant enteric infections.29

A clear understanding of alterations in intestinal morphology and physiology is crucial towards the development of interventional strategies, but there has been little progress in our understanding of this problem in developing countries. This has been largely due to a paucity of studies formally evaluating intestinal biopsy findings in representative populations. A wide variety of pathological changes have been described after persistent diarrhea, ranging from near-normal appearance to mucosal flattening, crypt hypertrophy and lymphocytic infiltration of the mucosa.22 Recent electron microscopic studies of the intestinal

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