4 Nutritional management in diarrhoeal disease

4 Nutritional management in diarrhoeal disease STEFANO GUANDALINI

MD

Professorof Pediatrics

AYSE PINAR DINCER MD University Nutrition,

of Chicago, Department 5841 S. Maryland Avenue,

of Pediatrics, Section Chicago, Illinois, USA

of Gastroenterology,

Hepatology

and

Adequate nutritional intervention in diarrhoeal diseasein children is crucial in obtaining optimal control of a disorderthat may becomelife-threatening. During recent years,important advanceshave been made in our understanding of the pathophysiology of diarrhoeal states, in the formulation of oral rehydration solutions and in the role of micro- and macronutrientsin diarrhoeal disorders.This chapter outlines some of the relevant concepts in the pathophysiology of diarrhoeal disease and provides a rationale for nutritional intervention. Guidelinesfor nutritional managementin the settingsof acute-onsetdiarrhoea, post-enteritisprotracted diarrhoea and chronic non-specificdiarrhoea are provided, mostly based on controlled clinical trials and me&analyses of evidence-basedmedicine. Key words: diarrhoea, feeding; children; nutrition; absorption; secretion; malabsorption.

Diarrhoeal diseases, particularly acute-onset forms, continue to constitute a major health problem worldwide. In underdeveloped countries, the 1992 estimate of the impact on morbidity and mortality as a result of diarrhoeal disease in children by the World Health Organisation (WHO) (Bern et al, 1992) reported a global mortality of about 3.3 million deaths per year and an incidence of 2.6 episodes per child per year. In developed countries, as expected, the impact on mortality is definitely lower. The incidence of diarrhoeal disease, however, remains high, as it has been estimated that each child in the first 3 years of life experiences around one episode per year (Guandalini, 1988). It is well known that nutrition plays an important role in diarrhoeal disease. In fact, malnourished children are at a markedly higher risk of developing acute and particularly prolonged diarrhoea (Lima et al, 1992; Baqui et al, 1993); also, an optimal nutritional management of the child with diarrhoea, whether malnourished or not, is obviously crucial for preserving at its best the nutritional status, as well as for influencing the outcome of the illness. We will address some of the most relevant issues in the nutritional handling of diarrhoeal diseases in children, with a particular Bailli&e S Clinical GastroenterologyVol. 12, No. 4, December 1998

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emphasis on children of developed countries, aiming to provide an updated and concise overview of the field and to outline general guidelines. PATHOPHYSIOLOGICAL BASIS OF NUTRITIONAL MANAGEMENT IN DIARRHOEA Nutrient

absorption

We will provide here a brief outline of those aspects of nutrient digestion and absorption that are important for a fuller understanding of the nutritional and feeding issues in diarrhoeal disease. After nutrients have reached the proximal small intestine, the pancreatic enzymes (a-amylase, lipase and proteases) hydrolyse starches, triglycerides and proteins respectively into: maltose, maltotriose and dextrins; fatty acids and monoglycerides; and low molecular weight peptides (2-6 amino acid residues) and free amino acids. The final digestion of carbohydrates then occurs at the intestinal surface: oligosaccharidases (two maltases, a sucrase-isomaltase and a lactase) are components of the enterocyte’s brush border and, at that site, actively hydrolyse their substrates. They thus generate glucose, galactose and fructose. Oligosaccharides (amylose and amylopectin from starches as well as sucrose and lactose) are completely hydrolysed to monosaccharides, and, in normal circumstances, no oligosaccharide enters the enterocyte or crosses the gut barrier. Glucose and galactose traverse the brush border by means of the same carrier (SGLT-I), known to be defective in congenital glucose-galactose malabsorption. SGLT-1 also has a site for sodium; after both glucose and sodium are bound, they are translocated into the cytoplasm by means of the favourable electrochemical gradient for sodium (Wright et al, 1997). The maintenance of this gradient requires the energy-dependent action of Na-K ATPase, an enzyme located in the basolateral membrane. Glucose absorption is a highly efficient process that is able to handle a large monosaccharide load. Fructose absorption, on the other hand, is sodium independent and only proceeds down a favourable concentration gradient thanks to a specific fructose transporter, GLUTS. The small intestinal absorptive capacity for fructose is limited compared with that of glucose (and of sucrose). After monosaccharides enter the enterocyte, a sodium-independent carrier, GLUT2, then facilitates the exit of hexoses across the basolateral membrane. As for protein digestion, a mixture of free amino acids and low molecular weight peptides (with a ratio of 1:2) is the final result of intraluminal digestion. Free amino acids are transported into the enterocyte by separate systems, each recognizing a group, with somewhat overlapping specificities, All these transporters also have an affinity for sodium, with the exception of the carrier system for cationic amino acids, called y’. Dipeptides and tripeptides can be hydrolysed at the brush border and then transported as free amino acids. However, unlike oligosaccharides, they may also be taken up intact by a specific carrier showing broad affinity for

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different peptides but having no affinity for free amino acids. The di- and tripeptide carrier, Pept-1, located in the brush border membrane, appears to be a unique transporter in that it has no aftinity for sodium but instead couples the entry of the di- or tripeptide with that of a proton (II+) (Adibi, 1997). For its action, the presence of an inside-negative membrane potential is required. It is thus apparent that the absorption of the final products of intraluminal protein digestion is a highly organized process, only partially sodium dependent, which maximizes efficiency and avoids competition. In lipid transport, fatty acids, monoglycerides and hydrophobic vitamins combine with bile salts to form micelles, which are hydrophilic and capable of crossing the unstirred water layer; the lipids then penetrate the mucous coat layer and the brush border. In the cytoplasm of the enterocytes, fatty acids and monoglycerides are re-esterified to triglycerides in vacuoles derived from the smooth endoplasmic reticulum that migrate to the Golgi apparatus and then to the basolateral membrane for the final vesicular transport. Water and electrolyte

absorption

The intestine absorbs large quantities of sodium, chloride and bicarbonate. It also secretes II+ ions and, to a lesser extent, bicarbonate as well. In fact, it is important to notice that the intestine is capable of both the absorption and secretion of electrolytes and of water, which passively follows the net solute transport. Thus the net absorption of water, sodium, chloride and potassium is the result of two opposing unidirectional fluxes of ions, one absorptive, the other secretory. The two processes are probably anatomically separated: absorption takes place mainly in the mature epithelial cells whereas secretion seems to occur in the crypts. Most absorbed water crosses the intestinal epithelium between the cells following the osmotic gradient generated by the transcellular transport of nutrients and electrolytes. Electrolytes are transported both paracellularly and transcellularly. The paracellular transport across the tight junctions is always passive (or ‘diffusional’) in response to the electrochemical gradient. In contrast, electrolyte transport through the epithelial cells may be either active or passive. The most important ion in terms of the handling of the net intestinal absorption of water and nutrients is sodium. Three different processes of sodium absorption, all driven by the Na-K ATPase previously mentioned, have been described. ‘Electrogenic’ sodium absorption Sodium enters the cell down its electrochemical gradient, through selective channels, uncoupled to other substrates. This process has been demonstrated both in the small and the large intestine, where it is preponderant. ‘Neutral’ NaCl absorption This transport process operates predominantly in the ileum. The transport is mediated by two coupled anti-ports; one exchanges Na+/H+ (the cation

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exchanger), and the other exchanges Cl-/I-RX- (the anion exchanger). The Na+/H+ anti-port maintains intracellular pH, increasing it in the presence of extracellular sodium. Sodium absorption coupled to the absorption of organic solutes This process operates throughout the small intestine. As already stated, the entry of glucose and most amino acids is coupled to sodium. The existence of sodium-coupled glucose absorption, and its integrity during most diarrhoeal disorders (see below), is considered to be the pathophysiological cornerstone of the evidence for the utilization of solutions to be administered orally in children and adults with diarrhoea. Regulatory mechanisms of electrolyte transport We now know that a variety of factors, mainly hormones and neurotransmitters, predominantly acting either as paracrine agents or at nerve endings, may affect intestinal electrolyte transport in either the absorptive or the secretory direction. Table 1 lists the agents that are the best known modulators of intestinal ion transport. It is apparent that the enteric nervous system has a crucial role in regulating water and electrolyte transport. The intracellular mediators of secretion that are eventually responsible for regulating transepithelial ion transport mechanisms in response to the agents listed in Table 1, as well as to exogenous agents such as bacterial toxins, are cyclic AMP, cyclic GMP and Ca”. They are generated in response to different cascades of metabolic pathways and eventually act on different protein kinases, resulting in changes of functional proteins (such as the Cl- channel CFTR) and ultimately affecting ion transport. Table 1. Regulatory agents of intestinal water and electrolyte transpott. Source Stimulate absorption Stimulate secretion Mucosal epithelial cells Somatostatin Serotonin GasttWcholecystokinin Neurotensin Guanylin Nitric oxide Lamina propria cells ? Arachidonic acid metabolites Nitric oxide Several cytokines Bradykinin Enteric neurones Norepinephrine Acetylcholine Neuropeptide Y Serotonin Vasoactive intestinal peptide Nitric oxide Substance P Purinergic agonists Blood Epinephrine Vasoactive intestinal peptide Corticosteroids Calcitonin Mineralocotticosteroids Prostaglandins Atrial natriumtic peptide

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NUTRIENT ABSORPTION IN DIARRJ3OEAL STATES: THE RATIONALE FOR ORAL REHYDRATION SOLUTIONS In normal circumstances, absorptive processes for water and electrolytes prevail over secretory processes, and, as a net result, water is absorbed. Diarrhoea can thus be viewed as the result of a derangement in the absorptive-secretory processes briefly outlined above. The reversal of the normal net absorptive status to secretion can be the result of either an osmotic force acting in the lumen, driving water movement across the dynamic tight junctions from the serosal to the luminal compartment (osmolar diarrhoea, as typically observed in lactose malabsorption), or an active secretory state induced in the crypt cell compartment (secretory diarrhoea, best exemplified by enterotoxin-induced diarrhoea). In many cases, both mechanisms co-exist. For example, in rotavirus enteritis, a serious disruption of absorptive functions occurs as a result of the selective invasion of the mature enterocytes by the invading organisms. In this circumstance, osmolar diarrhoea ensues. However, the reduction of the number of absorptive cells in the gut lining also unmasks the secretion in the crypts, and a secretory component is superimposed. The secretory nature of rotaviral diarrhoea is probably further augmented by a recently described enterotoxin, the rotavirus non-structural protein NSP4 that acts as a viral enterotoxin to induce diarrhoea and causes Ca++-dependent transepithelial Cl- secretion (Dong et al, 1997). It is now well established that diarrhoeas induced by ‘classical’ enterotoxigenic bacteria such as Vibrio cholerae or enterotoxigenic Escherichia coli (ETEC) leave intact small intestinal mucosal morphology and absorptive functions. Such a demonstration, obtained almost 30 years ago in relation to cholera toxin and cyclic AMP-induced secretion in several in vitro and in vivo systems (Hirschhorn et al, 1968; Cash et al, 1970; Field et al, 1972), was later confirmed in cyclic GMP-induced diarrhoeas (Guandalini et al, 1982) and has been fundamental in providing the pathophysiological basis for the worldwide utilization of oral rehydration solutions (ORSs). In fact, as previously outlined, the coupling between sodium and glucose entry allows for the ongoing absorption of these substances even during active fluid secretion due to states of stimulated Cl- secretion. Thus, as a result, the enhanced fluid absorption allows rehydration to take place in spite of the large fluid loss seen in enterotoxic diarrhoeas. It should be noted that increased intracellular levels of both cyclic AMP and cyclic GMP leave intact the uptake of not only glucose, but also amino acids and low molecular weight peptides, thus providing a basis for the potential use of other nutrients in an effort to produce a more effective fluid-promoting ORS. However, despite several promising laboratory studies favouring the idea of a ‘super’ ORS, solutions based on a mixture of glucose and individual amino acids have never proved superior to ‘traditional’ ORSs in the field. The question of the composition of the ‘ideal’ ORS has been long debated. The ORS originally proposed by the WHO and successfully

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employed over the years in so many thousands of cases in both adults and children still maintains its undisputed role in underdeveloped countries, where cholera infection continues to represent an important morbidity and mortality problem (Seas et al, 1996). In recent years, however, an increasing body of evidence has been generated in favour of newer, hypo-osmolar solutions (for reviews, see Mahalanabis, 1996; Desjeux et al, 1997; Thillainayagam et al, 1998). Such ORSs are made hypo-osmolar by reducing the concentration of glucose and sodium (with glucose concentrations of 75- 100 mmol/l and sodium of 60-75 mmol/l, and an osmolality of 225-250 mosm/l). These solutions were originally proposed by an ad hoc Working Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) which recommended a specific hypo-osmolar glucose-based 60 mmol/l sodium solution as optimal for use in children in Europe in 1992 (Booth et al, 1992). They appear to have the additional advantage of allowing a reduced stool output while being just as effective in obtaining and maintaining rehydration, and can be safely given throughout the duration of diarrhoea (Santosham et al, 1996). Although there is mounting evidence that they can be utilized even in cholera, their primary use should at present be seen in the children of developed countries. Additionally, it has also become clear that several cereals (including staple foods) can be utilized in a balanced electrolyte solution (Molla and Molla, 1997) in order to provide a hypotonic solution more fully exploiting the different absorptive pathways available for nutrients and water, and offering the additional advantage of furnishing a higher caloric intake. Among these ‘improved’ solutions, rice-based ORS (in which cooked rice 50 g/l is used instead of glucose) has been proved, in several investigations carried out mainly in underdeveloped countries, to be consistently safe and effective (Santosham et al, 1990; Pizarro et al, 1991). Studies comparing glucose-based with rice-based ORSs generally show that, although ricebased ORSs tend to result in a somewhat decreased stool output during the first 12-24-hour period, both ORSs are well accepted and basically perform equally well (Faruque et al, 1997; Saniel et al, 1997). Interestingly, it was recently shown that an aqueous extract from boiled rice powder was able to prevent, in a dose-related manner, the shrinkage of small intestinal crypt cells in response to an analogue of cyclic AMP (Macleod et al, 1995), an effect indicating the prevention of ion secretion. The same investigators later showed in vitro that such anti-secretory action is the result of a direct inhibitory effect on the activated CFTR Cl- channel. (Matthews et al, 1998). As the efficacy of some probiotics in decreasing the duration and/or severity of acute diarrheoal diseases, particularly rotavirus enteritides, has been documented in recent years (for a review of this subject see Guandalini, 1998), the Working Group on Acute Diarrhoea of ESPGHAN has recently completed a trial assessing the safety and efficacy of the administration of Luctobucihs GG (ATCC 53103) within the ORS to children ranging from 1 month to 3 years old presenting with acute-onset diarrhoea in 12 European centres (Guandalini and the Working Group on

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Acute Diarrhoea of ESPGHAN, 1998). Data from a total of 287 children were analysed. In the overall group (35% rotaviral, 32.6% bacterial or protozoan, 32.4% undetermined aetiology), there was a statistically significant effect of Latobacillus GG that reduced the duration of diarrhoea (after enrollment) from 72 to 58 hours. Furthermore, restricting the analysis to the 101 patients having rotaviral diarrhoea, the duration of the diarrhoea, the rate of disappearance of watery stools and the duration of hospital stay (the latter being reduced by a mean of 24 hours) were all significantly improved by the probiotic in the ORS. In the group receiving the ORS containing Luctobacillus GG, only 2.8% of all patients (regardless of aetiology) had a diarrhoea lasting more than 7 days, compared with 11.4% of the placebo group (x2= 8.56, P = 0.0034). Whether or not the recommendation of using this or other probiotics as a routine supplementation of ORS, at least in developed countries, will be made in the future is at present still unclear. In conclusion, it should be strongly reinforced that oral rehydration therapy with glucose-based ORSs must be viewed as by far the safest, most effective and most physiological way to provide rehydration, or maintain hydration, in children with acute diarrhoea worldwide, most certainly including developed countries, as recommended not only by the ad hoc Committee of ESPGHAN (Booth et al, 1992), but also by the American Academy of Pediatrics (Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis, 1996). Indeed, it appears that developed countries are still far behind in understanding and implementing such effective means of treatment (Reis et al, 1994). Yet, when critically evaluated in a recent large meta-analysis, oral rehydration therapy was found overall to be able to provide effective treatment without the need to resort to intravenous rehydration in 96.4% of children in the developed countries (Gavin et al, 1996). FEEDING

THE

CHILD

WITH

ACUTE

DIARFUJOEA

The problem of nutritional repair in children with acute-onset diarrhoea and that of the management of feeding during an acute diarrhoeal illness has been debated for a long time. Indeed, there is general agreement that, in breast-fed infants, breast milk should be continued without any need for interruption, as it has been convincingly shown not only that breast-feeding has a well-known protective effect on the development of gastroenteritis (Golding et al, 1997), but also that continued breast-feeding allows faster recovery and provides improved nutrition (Brown, 1992). Furthermore, the withdrawal of breast-feeding during diarrhoea has been shown to have a highly significant deleterious effect on the development of dehydration in infants with acute watery diarrhoea in an underdeveloped country (Bhattacharya et al, 1995). In artificially fed infants, however, the issue is much more controversial. The necessity of a ‘bowel rest’, as well as its duration, and the need for the restriction of specific foodstuffs such as cow’s milk proteins or lactose have been the subject of a long debate. Indeed, until recent years, the vastly prevailing attitude has favoured a

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variable period of fasting followed by a ‘gradual’ reintroduction of solid foods and the use of lactose-free formulas. However, several well-conducted studies in the past few years have seriously questioned the scientific basis of such an approach while providing evidence that, in weaned children not severely dehydrated or acidotic, a rapid return to full feeding after oral rehydration is completed in the first 4-6 hours is not only well tolerated (Isolauri and Vesikari, 1985; Isolauri et al, 1986; Chew et al, 1993), but also actually allows a faster recovery of the increased intestinal permeability found in rotavirus-induced enteritis (Isolauri et al, 1989). Indeed, the evidence so far reported about the absorption of ‘regular food’ in acute diarrhoea would suggest that the absorption of macronutrients should be somewhat depressed in rotaviral diarrhoea but rather well maintained in secretory diarrhoeas due to enterotoxigenic organisms. In a classical study published in 1983, Molla et al addressed this issue by investigating 68 children with acute infectious diarrhoea. After rehydration, all the patients were freely given feeds identical to those administered before the onset of diarrhoea. The results show that the absorption of nutrients is indeed more affected in invasive diarrhoeas (such as those due to rotavirus and Shigella) than in enterotoxic diarrhoeas. The absorption of most nutrients had returned to normal levels 2 weeks after the acute episode. Thus a certain degree of malabsorption, albeit transient, is to be expected in invasive diarrhoeas causing loss of absorptive area, while in enterotoxic diarrhoeas, the intestinal handling of nutrients is only minimally altered. To further investigate the issue, the Working Group on Acute Diarrhoea of ESPGHAN has recently completed a multicentre study evaluating the effect of early versus delayed resumption of full feeding in European children with acute diarrhoea (Sandhu et al, 1997). The design of the study implied conducting oral rehydration therapy with a reduced-osmolality solution formulated according to the previous recommendations (Booth et al, 1992), and then assigning the patients to either the ‘gradual’ or the ‘early’ refeeding group. Two hundred and thirty patients (mean age 14 months) were examined; their profile on entry into the study showed no statistically significant difference between the two branches of the study. After 4 hours of oral rehydration therapy, patients were assigned to the study group: the ‘early’ fed ones immediately resumed their normal diet, including lactose-containing formulae, while the late-feeding group of patients continued to receive only ORS for 24 hours. Results of this study very clearly showed that weight gain was significantly greater in patients re-fed early not only during the first day after oral rehydration, but also throughout hospitalization, and the trend was confirmed as late as day 14 post-enrollment (Figure 1). This better gain was obtained without any ‘toll’, in that no difference was observed in the incidence of vomiting and watery stools (Figures 2 and 3). Also, by day 5, no patient in either group had lactose intolerance. After reaching this conclusion and reviewing previously published evidence (Brown et al, 1988; Nanulescu et al, 1995), including the large meta-analysis by Brown et al (1994), the ESPGHAN Working Group

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200

100 0 During Rehydration

After Rehydration

During Hospitalisation

ByDay

ByDay

Figure 1. Weight gain according to refeeding regimen in patients with acute diarrhoea. Reproduced from Sandhu et al (1997, Journal of Pediatric Gastroenferology and Nufrition 24: 522-527) with permission.

0

1

2

3

4

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14

DAYS

Figure 2. Frequency of vomiting according to refeeding regimen in patients with acute diarrhoea. Reproduced from Sandhu et al (1997, Journal of Pediatric Gastroenterology and Nutrition 24: 522-527) with permission.

recommended (Walker-Smith et al, 1997) that ‘the optimal management of mild-to-moderately dehydrated children in Europe should consist of (a) oral rehydration with ORS over 3-4 hours, and (b) rapid reintroduction of normal feeding thereafter’. The use of lactose-free formulae was also discouraged as it appeared to be unjustified. In fact, lactose intolerance, once thought to be a major problem in children with diarrhoea, is now believed to be uncommon in developed countries (Lancet, 1987). In the

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q loo E 60 (I) P 60 $

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20 0 0

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6

14

DAYS Figure 3. Frequency of watery stools according to refeeding regimen in patients with acute diarrhoea. Reproduced from Sandhu et al (1997, Journal of Pediatric Gastroenterology and Nutrition 24: 522-527) with permission.

ESPGHAN study, only 3% of the children had signs of lactose malabsorption on admission, and none of them had such signs at day 5 postenrollment (Sandhu et al, 1997). However, the occurrence of lactose intolerance should not be completely disregarded. In uncommon circumstances, diarrhoea may worsen on the reintroduction of milk or ‘normal’ formulae; if this event is shown to be accompanied by a decrease in stool pH and the appearance of reducing substances (more than OS%), lactose intolerance should be assumed and a lactose-free formula utilized for some time in order to prevent the development of post-enteritis protracted diarrhoea (Penny et al, 1989; Penny and Brown, 1992). Over the past few years, some interest has been generated on the utilization of soy fibre in treating children with acute or persistent diarrhoea. In fact, Brown et al (1993) have shown a positive effect of soy fibre in reducing the duration of watery stool output resulting from a number of infectious enteritides. Also in the USA, an effect of soy fibre in shortening (by about 15 hours) the median duration of diarrhoea in infants and children above 6 months has been shown (Vanderhoof et al, 1997). However, it should be pointed out that the results of these studies show a reduction not of stool output but of the liquid component of the stool (possibly merely a ‘cosmetic’ effect). Furthermore, some concerns exist on the possible negative effect of fibre on the absorption of micronutrients. Thus, given the overall small effect so far demonstrated, at least in developed countries, and pending further studies, certainly no general recommendation on the addition of soy fibre is at this point warranted. In children in underdeveloped countries, attention has recently been focused on the micronutrient deficiencies that are found in malnourished children with diarrhoea, particularly on the role of zinc deficiency. In fact, zinc is known to be essential for growth, protein synthesis, RNA and DNA synthesis, T-cell function and development of the intestinal mucosa, all biological phenomena involved in intestinal function. Furthermore, it is also known that intestinal losses of zinc are increased during diarrhoea (Castillo-Duran et al, 1988). In 1988, Sachdev et al reported that children receiving a zinc supplement tended to have a decrease in the frequency and

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duration of diarrhoea, the most favourable clinical outcome being shown by those patients who were zinc deficient. Sazawal et al reported in 1995 that zinc supplementation resulted in a decreased duration and severity of acuteonset diarrhoea in malnourished children in India. A subsequent study by the same group (Sazawal et al, 1997), a community-based, double-blind trial on a large number of children, documented that zinc supplementation had a significant effect in reducing the number of diarrhoeal episodes and their duration in children older than 11 months and in those with a low plasma zinc level. In a double-blind, controlled study in Bangladesh, Roy et al (1997) similarly showed that the supplementation of 20 mg per day of elemental zinc to malnourished children with acute diarrhoea resulted in a shorter duration of diarrhoea, a lesser stool output, a better weight gain and an improved zinc serum status. All these changes were again more evident in initially zinc-deficient subjects. Interestingly, two recent observations shed some light on the possible mechanism linking zinc deficiency with diarrhoea. First, it was demonstrated that zinc deficiency induces an increased expression of uroguanylin, a guanylate cyclase-activating peptide (Blanchard and Cousins, 1997); also, an induction of nitric oxide synthase in response to interleukin 1a was obtained in zinc-deficient rats (Cui et al, 1997), and it is known that nitric oxide is an intestinal secretagogue. Whatever the underlying mechanism, it is clear that if the type of clinical finding previously reported were to be confirmed, the supplementation of zinc would probably be recommended for malnourished children with acute diarrhoea, or even more in general to malnourished children living in areas with a high risk of developing diarrhoea. NUTRITIONAL DIARRHOEAL

MANAGEMENT DISORDERS

IN SELECTED

CHRONIC

Chronic diarrhoea with prolonged mucosal injury is often associated with a deterioration in nutritional status and is an important contributory factor in the occurrence of malnutrition. With increasing duration, its consequences are likely to be greater, with a very high case fatality rate. In underdeveloped countries, it is calculated that 40-60% of infant diarrhoeal deaths are due to persistent diarrhoea in combination with malnutrition (Fauveau et al, 1991; Victora et al, 1992). Chronic diarrhoea with malabsorption can be the result of a large number of causes (Table 2), and it is quite obvious that dietetic and nutritional interventions are important in each of these conditions. However, in circumstances in which the disease is well identified, it is clear that the selection of proper feeding management is also well defined. Examples are coeliac disease, sucrase-isomaltase deficiency and short gut syndrome. As the full discussion of each condition is beyond the scope of this chapter, we will instead, in the following paragraphs, limit our attention to two disorders chosen as examples from the two extremes: persistent postinfectious diarrhoea and chronic, non-specific diarrhoea.

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Table 2. Pathophysiological classification of the main malabsorption syndromes. Disorders of entemcyte Disorders of transport digestive/absorptive functions from the enterocyte

Disorders of intraluminal digestion Cystic fibrosis Schwachman syndrome Congenital absence of lipase Enterokinase deficiency Protein-calorie malnutrition Chronic pancreatitis Cholestasis Primary bile acids malabsorption

Persistent

post-enteritis

Glucose-galactose malabsorption Sucrase-isomaltase deficiency Microvillous inclusion disease Congenital chloridorrhea Congenital sodium-losing diarrhoea Short bowel syndrome Acrodermatitis enteropathica Cow’s or soy milk protein intolerance Protracted gastrointestinal infections (viral, bacterial, protozoal) Coeliac disease Autoimmune enteropathy Eosinophilic gastmenteropathy Protein-calorie malnutrition Small bowel bacterial overgrowth Drug-induced enteropathies

diarrhoea

A-P-lipoproteinaemia Lymphangiectasia

(PPD)

The WHO has defined persistent diarrhoea as an episode beginning acutely and lasting for at least 14 days (World Health Organisation, 1985). It has been calculated that between 1% and 20% of acute-onset diarrhoeal episodes run a prolonged course. Table 3 provides a list of the main causes leading to the syndrome of persistent post-enteritis diarrhoea (PPD). Postinfectious PPD is frequently seen in association with malnutrition and, in underdeveloped countries, is the cause of 30-40% of all diarrhoeal deaths (Bhandari et al, 1992, 1994). In this setting, PPD also has an evident effect on nutrition, leading to the well-known vicious circle of diarrhoeamalnutrition-diarrhoea (Bhutta and Hendricks, 1996). As such, it is evident that optimal nutritional repair becomes fundamental to the proper management of this condition. What is known of the pathophysiology of nutrient absorption in protracted diarrhoea? The problem is a complex one, as it is well known that the pathogenesis of the condition is variable. In fact, an episode of acute infectious enteritis might evolve into a prolonged course by a variety of mechanisms (Guandalini, 1997). This translates into a wide range of small intestinal, mucosal, morphological and biochemical abnormalities, from almost normal to villous atrophic mucosa with a continuous or patchy appearance, brush border and/or intraluminal digestive enzyme deficiencies and variable degrees of increased intestinal permeability, to the presence or absence of small bowel bacterial overgrowth. Figure 4 presents a diagrammatic scheme of the pathogenetic changes seen in PPD. Thus feeding choices that would allow both the resolution of the prolonged diarrhoeal episode and the nutritional repletion of the child are far from clear and simple. Yet they must be done in a timely fashion so that the child is investigated as needed, while a full nutritional supplement is provided, pending the risk of developing the dreadful syndrome of

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Table

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3. Main causes of persistent

post-enteritis

diarrhoea. Food allergy-_

Infections lnfestinal (persisting recurrent infection)

or

Enteritis and/or colitis Rotavirus Adenovirus EPEC EAggEC Salmonella Shigella Clostridium diJicile Giardia Cryptosporidium parvum Small bowel bacterial overgrowth

Extra-intestinal

Cow’s milk protein intolerance Soy protein intolerance Multiple food intolerances

Urinary tract infections Respiratory tract infections

1

Small intestinal mucosal

I -

Acute infectious gastroenteritis

-b

Entjt&

Secondary lactase deficiency

fermentation I

release I

4 Lactose intolerance

deconjugation

Sensitization

$ Osmotic diarrhoea

i Enteropathy from food sensitization

9 trient

diarrhoea

f-

malabsorption

1 secretory diarrhoea

Figure 4. Pathogenetic scheme in persistant post-enteritis 1997, Diarrhea1 Disease 38: 153-170) with permission.

secretory effect

* diarrhoea.

Reproduced

from

Guandalini

intractable diarrhoea, an entity still causing a sizeable death toll despite improved knowledge (Guarino et al, 1995). From a clinical point of view, while it should be borne in mind that, in the individual patient, the role played by each of the above-mentioned changes may be different, it is usually the deficiency of proper carbohydrate digestion and absorption that plays the biggest role. The digestion of lactose is most frequently impaired, but the absorption of monosaccharides can also be impaired, most commonly as a result of reduced surface area, but also secondary to the increased concentration of deconjugated bile acids, which have been shown to inhibit active glucose transport (Fasano et al, 1994). An important factor

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leading to PPD is thought to be the development of food protein sensitization, which in infancy is mainly cow’s milk protein (Walker-Smith, 1994). This entity is in fact believed to be, in developed countries, the most common single cause of chronic diarrhoea. As a consequence, the practical nutritional approach that can be employed in infants and children with PPD in developed countries is to remove cow’s milk proteins and lactose from the diet. Although soy ‘milks’ are frequently employed, they should actually be avoided (American Academy of Pediatrics, 1998), as it is now well established that up to 50% of infants who are cow’s milk protein intolerant may become also allergic to soy protein in a short time. Thus protein (casein, a-lactalbumin or soy protein) extensive hydrolysate formulae such as Alimentum, Nutramigen, Pregestimil and Pregomin are adequate as the first choice. In already wasted children with a poor appetite having an inadequate intake, this regimen (see the algorithm reported in Figure 5) is best provided, in amounts progressively increased as tolerated until all caloric requirements are met, via continuous enteral (i.e. nasogastric tube) feeding (Brasseur and Goyens, 1997). Otherwise, if the child shows a good oral intake, fractionated meals of the protein hydrolysate can be offered. A good response to this intervention is indeed very frequent, lending further support to the notion that food allergies do in fact play an important role in this syndrome. However, if diarrhoea and wasting persist, carbohydrate tolerance should be checked as monosaccharide malabsorption can occur and lead to the persistence of diarrhoea through an osmotic mechanism. If this is the case, a carbohydrate-free diet has to be (usually transiently) employed. In this context, the utilization of so-called ‘homemade diets’ is acceptable as long as they are not employed for a prolonged period of time, given the high degree of uncertainty that they present in terms of adequate micronutrient and/or electrolyte content (De Vizia et al, 1995; D’Eufemia et al, 1996). Otherwise, the possibility that some other component of the hydrolysate is not tolerated should be sought. It is indeed known that a very small minority of patients with severe cow’s milk allergy might be unable to tolerate even the extensive hydrolysates. Although the mechanism underlying the intolerance may well be allergic, as it has been well shown to occur particularly in infants with multiple food allergies (Businco and Cantani, 1991; Hill et al, 1995), an extensive mucosal injury and concomitant digestive/absorptive failure may also occur. In all these circumstances, ‘true’ elemental formulae, i.e. formulae whose nitrogen component is based exclusively on a nutritionally complete and balanced solution of free amino acids, and is thus by definition unable to trigger any allergic reaction, is definitely indicated. A recently developed formula possessing also low osmolarity and matching this requirement is Neocate (Sampson et al, 1992; Vanderhoof et al, 1997). Indeed, Vanderhoof et al (1997) demonstrated in their study that most infants with persistent symptoms of formula protein intolerance after treatment with protein hydrolysates respond well to a trial of Neocate, with symptoms resolving rapidly. A majority of these patients experienced an abrupt exacerbation of symptoms in response to protein hydrolysate challenge and continued to use the elemental formula. Isolauri et al (1995)

NUTRITION

IN Malnourkhed,

11 (Extensive

DIARRHOEAL

711

DISEASE

unwilling/unable

to

Not malnourished,

willing and able

1

protein hydrolysates)

1

Success Diarrhoea

Elemental diet (i.e. amino acid-based formula) via NG tube feeding

Elemental diet (i.e. amino acid-based formula) PO

If diarrhoea/ wasting persist

Need for total parenteral Figure 5. Suggested algorithm for the nutritional approach diarrhoea. PO = oral; CHO= carbohydrate; NG = nasogastric.

persists

nutrition to the child

with persistent

post-enteritis

demonstrated the efficacy and nutritional safety of feeding such an amino acid-based formula to infants for more than 9 months. In situations in which extensive hydrolysate and/or amino acid-based formulae cannot be given (because of their high cost or any other considerations), more complex foods can be employed, as there are recent studies suggesting that malnourished patients with chronic diarrhoea are capable of tolerating more complex diets, such as the time-honoured chicken-based diets. In a recent randomized, double blind study (Nurko et al, 1997) comparing a chicken-based diet with elemental and soy protein diets in hospitalized children with persistent diarrhoea and third-degree malnutrition, a significantly better nitrogen balance was found in children fed the chicken diet. Thus this approach may offer the benefits of good tolerance, low cost, availability and more ready cultural acceptance. It is evident that failure to improve after the suggested step-wise approach (Figure 5), with the ongoing lack of any specific diagnosis, would necessitate the utilization of

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S. GUANDALINI

total parenteral nutrition, an intervention that ensures the continuing provision of nutritional needs while all necessary, sophisticated further diagnostic steps can be provided in a tertiary-level centre. Chronic

non-specific

diarrhoea

At the other spectrum of the chronic diarrhoeal disorders stands chronic nonspecific diarrhoea (CNSD) or ‘toddler’s diarrhoea’. This disorder occurs primarily in young children between the ages of 6 months and 4 years and is thought to be, in developed countries, the most common cause of prolonged diarrhoea in this age group. By definition, it is not associated with malabsorption, is benign and is transient. Indeed, children with CNSD do not suffer from their condition, look well and grow and develop normally. Pathogenesis The pathophysiology of CNSD is still unclear. Many factors have been proposed as causing this syndrome. An increase in the adenylate cyclase activity (potentially leading to a secretory condition) in the jejunal biopsies of children with CNSD was reported earlier (Tripp et al, 1980). More recently, a ‘primary glucoamylase deficiency’ was described in a group of children with abdominal distension, flatulence and chronic diarrhoea as a result of starch malabsorption (Lebenthal et al, 1994). The relationship of this entity to CNSD is at present unclear. A subset of children may present with prolonged diarrhoea because of excessive fluid intake often induced by parents because of a fear of dehydration (Greene and Ghishan, 1983). These children will respond favourably to a reduction of their fluid intake. A disorder of small intestinal motility has also been convincingly shown to be present in at least a subset of children with CNSD and possibly to be responsible for its pathogenesis. In healthy children, the motor migrating complex (MMC) typical of the fasting phase of motility is interrupted when food enters the digestive system and is replaced by post-prandial activity. In children suffering from CNSD, Fenton et al (1983) demonstrated that nutrients failed to interrupt the MMC and to induce the normal postprandial motor pattern. It is conceivable that this situation, attributed to a delayed maturational development of gastrointestinal motility, may lead to decreased small bowel transit time, increasing delivery to the colon of bile acids, fluids and incompletely absorbed nutrients (e.g. fatty acids), which may have an additional role in inducing diarrhoea. In recent years, the role of carbohydrates in inducing CNSD has received great attention. In developed countries, particularly it seems in the USA, fluid consumption takes place in the form of carbohydrate-rich beverages (Dennison, 1996). CNSD has been associated with juice consumption, especially juices high in sorbitol and those with a high fructose:glucose ratio. In a group of children with excessive intakes of energy-rich fluids, the excess carbohydrate consumption was found to be responsible for diarrhoea (Hourihane and Rolles, 1995). Apple juice malabsorption has been shown to play a role in CNSD (Kneepkens et al, 1989). As apples,

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pears and their juices have a high content of fructose, the role of fructose malabsorption has been extensively investigated. In fact, as stated above, fructose absorption is not linked to that of sodium, and is limited compared with that of glucose. Indeed, when fructose is consumed as a part of mixed diet, its absorption improves because of the stimulating effect that amino acids and glucose have on fructose absorption (Hoekstra and van den Aker, 1996), thereby increasing intestinal water absorption. However, when presented in high concentration in juices, its absorption is suboptimal. It was indeed shown that children with CNSD are more frequently found to be incomplete fructose absorbers than healthy controls (Hoekstra, 1995; Kneepkens and Hoekstra, 1996). Clinical presentation Infants with this disorder typically start with what appears to be an acuteonset diarrhoea and then progressively go on to have 2-6 loose, foulsmelling, mostly semi-watery stools. A decreased intestinal transit time is evidenced by the appearance of undigested food in the stools, a constant feature of this syndrome. It is in fact well known that parents often consider the presence of food remnants to be proof of malabsorption and food intolerance. It is also important to notice that diarrhoea is often intermittent as these children tend to alternate between normal and loose stools, presenting at times even with constipation. There are usually no bowel movements at night and it is common to have a large semi-formed stool in the morning, progressively followed by a deterioration of stool consistency as the day goes on. Typically, parents tend to over-react to this condition and may get extremely worried and frustrated by the continuing diarrhoea. Differential

diagnosis

Although the physician confronted with a young child with chronic diarrhoea must consider in the differential diagnosis the possibility of a malabsorption syndrome, specific investigations are seldom necessary as the diagnosis is established rather easily by the characteristic symptoms, associated with a normal physical development. However, it is a common experience that tests are often needed in order to provide the parents with firm and convincing evidence that a malabsorption syndrome has indeed been excluded. In this context, a D-xylose blood absorption test accompanied by a stool search for common parasites (Giardia and Cryptosporidium) and, where available, by the semi-quantitative determination of steathorrhea by the steatocrit test (Guarino et al, 1992; Amann et al, 1997; Van den Neucker et al, 1997) is sufficient, if the results are negative. Approach and nutritional

management

In this entity, the role of dietary handling is crucial both to reach the diagnosis and to provide a rational treatment. Thus special attention should be paid to take a detailed dietary history. Dietary measures have often been

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instituted from the beginning of the symptoms to control the diarrhoea, resulting in a high-fluid, high-carbohydrate and low-fat diet. Additionally, because of the presence of food particles in the stool, an assumption of food allergy may be made, and a further reduction of fat and fibre intake may occur. This results in the institution of hypocaloric diets, which on the one hand may be responsible for or contribute to the symptom, and on the other, in IO-20% of cases, end up impairing the child’s growth and weight gain. It is obvious that, when this is the case, the diagnosis itself may become blurred as a malabsorptive state might be unduly suspected. Thus, after establishing the diagnosis, a strong emphasis has to be put on the self-limiting nature of the condition and on its completely benign outcome, while dietetic measures mainly involve removing all previous dietary irregularity: the excessive use of fruit juices and carbohydrate-rich beverages, and any totally unnecessary dietetic restrictions. The child has to be allowed a rich, complete diet. Increasing the intake of fat and of fibre is generally recommended as this is thought to allow more time for water and electrolyte absorption by prolonging the intestinal transit time. REFERENCES Adibi S (1997) The oligopeptide transporter (Pep&l) in human intestine: biology and function. Gastroenterology 113: 332-340. American Academy of Pediatrics Committee on Nutrition (1992) Soy protein-based formulas: recommendations for use in infant feeding. Pediatrics 101: 148-153. Amann ST, Josephson SA, Toskes PP et al (1997) Acid steatocrit: a simple, rapid gravimetric method to determine steatorrhea. American Journal of Gastroenterology 92(12): 2280-2284. Baqui A, Bradley Sack R, Black R et al (1993) Cell-mediated immune deficiency and malnutrition are independent risk factors for persistent diarrhea in Bangladeshi children. American Journal of Clinical

Nutrition

58: 543-548.

Bern C, Martines J, de Zoysa I & Glass RI (1992) The magnitude of the global problem of diarrhoeal disease: a ten year update. Bulletin of the World Health Organization 70(6): 705-714 (review). Bhandari N, Bhan M & Sazawal S (1992) Mortality associated with acute watery diarrhea, dysentery and protracted diarrhea in rural north India. Acta Pediatrica S381: 3-6. Bhandari N, Sazawal S, Clemens JD et al (1994) Association between diarrheal duration and nutritional decline: implications for an empirically validated definition of persistent diarrhea. Indian Journal of Pediatrics 61(S): 559-566. Bhattacharya SK, Bhattacharya MK, Manna B et al (1995) Risk factors for development of dehydration in young children with acute watery diarrhoea: a case control study. Acta Paediatrica 84(2): 160- 164. Bhutta Z & Hendricks K (1996) Nutritional management and persistent diarrhea in childhood: a perspective from the developing world. Journal of Pediatric Gastroenterology and Nutrition 22: 17-37. Blanchard RK & Cousins RJ (1997) Upregulation of rat intestinal uroguanylin mRTNA by dietary zinc restriction. American Journal of Physiology 272: G972-G978. *Booth I, Cunha Ferreira R, Desjeux JF et al (1992) Recommendations for composition of oral rehydration solutions for the children of Europe. Journal of Pediatric Gastroenterology and Nutrition 14: 113-115. Brasscur D & Goyens P (1997) Enteral nutrition for the therapy of chronic diarrhea. Diarrhea1 Disease 38: 289-3 16. Brown KH (1992) The dietary management of acute childhood diarrhea: optimal timing of feeding and appropriate use of local mixed diets. Archives Latinoamericanos de Nutrition 42 (3, supplement): 45Sd7S (review). Brown KH, Perez F, Peerson JM et al (1993) Effect of dietary fiber (soy polysaccharide) on the

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severity, duration, and nutritional outcome of acute, watery diarrhea in children. Pediatrics 92(2): 241-247. *Brown KH, Peerson JM & Fontaine 0 et al (1994) Use of nonhuman milks in the dietary management of young children with acute diarrhea: a meta analysis of clinical trials. Pediatrics 93(l): 17-27. Brown KH, Gastanaduy AS & Saavedra JM (1988) Effect of continued oral feeding on clinical and nutritional outcomes of acute diarrhoea in children. Journal of Pediatrics 112: 191-200. Businco L and Cantani A (1991) Hypersensitivity reaction in an infant fed hydrolysed lactalbumin. Journal of Pediatric Gastraenteralogy and Nutrition 13: 429-43 1. Cash RA, Forrest JN, Nalin DR & Abrutyn E (1970) Rapid correction of acidosis and dehydration of cholera with oral electrolyte and glucose solution. Lancer 2(7672): 549-5.50. Castillo-Duran C, Vial P & Uauy R (1988) Trace mineral balance during acute diarrhoea in infants. Journal of Pediatrics 113: 452-457. Chew F, Penna FJ, Peret Filho LA et al (1993) Is dilution of cows’ milk formula necessary for dietary management of acute diarrhoea in infants aged less than 6 months? Lancet 341(8839): 194-197. Cui L, Takagi Y, Wasa M et al (1997) Induction of nitric oxide synthase in rat intestine by interleukinlalpha may explain diarrhea associated with zinc deficiency. Journal of Nutrition 127(9): 1729-1736. Dennison BA (1996) Fruit juice consumption by infants and children: a review. Journal of the American College of Nutrition 15 (5, supplement): 4S-11% Desjeux JF, Briend A, Butzner JD (1997) Oral rehydration solution in the year 2000: pathophysiology, efficacy and effectiveness. Builliere s Clinical Gastroenterology 11: 509-527. D’Eufemia P, Lucarelli S, Giardini 0 & Cardi E (1996) Metabolic alkalosis. Actu Paediatrica 85: 1518. “Dong Y, Zeng CQ, Ball JM et al (1997) The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5trisphosphate production. Proceedings of the National Academy of Science of the USA 94: 3960-3965. Faruque AS, Hoque SS, Fuchs GJ & Mahalanabis D (1997) Randomized, controlled, clinical trial of rice versus glucose oral rehydration solutions in infants and young children with acute watery diarrhoea. Acta Paediatrica 86(12): 1308- 1311. Fasano A, Verga MC, Raimondi F & Guandalini S (1994) Effects of deconjugated bile acids on electrolyte and nutrient transport in the rabbit small intestine in vitro. Journal of Pediatric Gastroenterology and Nutrition 18: 327-333. Fauveau V, Yunus M, Zaman K et al (1991) Diarrhea mortality in rural Bangladeshi children. Journal af Tropical Pediatrics 37: 3 I- 36. Fenton TR, Harries JT & Milla PJ (1983) Disordered small intestinal motility: a rational basis for toddlers’ diarrhoea. Gut %l(lO): 897-903. Field M, Fromm D, al-Awqati Q & Greenough WB III (1972) Effect of cholera enterotoxin on ion transport across isolated heal mucosa. Journal of Clinicul Investigation 51(4): 796-804. Gavin N, Merrick N & Davidson B (1996) Efficacy of glucose-based oral rehydration therapy. Pediatrics 123: 45-51. *Gelding J, Emmett PM & Rogers IS (1997) Gastroenteritis, diarrhoea and breast feeding. Early Human Development 29(49): S83-S103 (review). Greene HL & Ghishan FK (1983) Excessive fluid intake as a cause of chronic diarrhea in young children. Journal of Pediatrics 102: 836-840. Guandalini S (1997) Prolonged diarrhea: etiology and pathogenesis. Diarrhea1 Disease 38: 153170. Guandalini S (1998) Probiotics in the treatment of diarrheal diseases in children. Gastroenterology International 11 (supplement 1): 87-90. Guandalini S and the ESPGHAN Working Group on Acute Diarrhea (1998) Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. Journal of Pediatric Gastroenterology and Nutrition 26: 547. Guandalini S, Mighavacca M, de Campora E et al (1982) Cyclic GMP effects on nutrient and electrolyte transport in rabbit ileum. Gastroenteralogy 83: 15-2 I. Guarino A, Tarallo L, Greco Let al (1992) Reference values of the steatocrit and its modifications in diarrhea1 diseases. Journal of Pediatric Gastroenterology and Nutrition 14(3): 268-274. Guarino A, Spagnuolo MI, Russo S et al (1995) Etiology and risk factors of severe and protracted diarrhea. Journal ofpediatric Gastroenterology and Nutrition 20(2): 173- 178.

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DJ, Cameron DJ, Francis DE et al (1995) Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. Journal of Allergy and Clinical Immunology 96(3): 386-394. Hirschhom N, Kinzie JL, Sachar DB et al (1968) Decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions. New England Journal of Medicine 279(4): 176-181. Hoekstra J (1995) Fructose breath hydrogen tests in infants with chronic non specific diarrhea. European Journal of Paediatrics 154: 362-364. Hoekstra JH & van den Aker JH (1996) Facilitating effect of amino acids on fructose and sorbitol absorption in children. Journal of Pediatric Gastroenterology and Nutrition 23(2): 118-124. Hourihane JOB & Rolles CJ (1995) Morbidity from excessive intake of high energy fluids: the squash drinking syndrome. Archives of Disease in Childhood 72: 14l- 143. lsolauri E & Vesikari T (1985) Oral rehydration, rapid feeding, and cholestyramine for treatment of acute diarrhea: Journal of Pediatric Gastroenterology and Nutrition 4(3): 366-374. lsolauri E, Vesikari T, Saha P et al (1986) Milk versus no milk in rapid refeeding after acute gastroenteritis. Journal of Pediatric Gastroenterology and Nutrition S(2): 254-261. lsolauri E, Juntunen M, Wiren S et al (1989) Intestinal permeability changes in acute gastroenteritis: effects of clinical factors and nutritional management. Journal of Pediatric Gastroenterology and Nutrition 8(4): 466-473. lsolauri E, Was Y, Makinen-Kiljunen S et al (1995) Efficacy and safety of hydrolysed cow milk and amino acid derived formulas in infants with cow milk allergy. Journa! of Pediatrics 127: 550-557. Kneepkens CM & Hoekstra JH (1996) Chronic nonspecific diarrhea of childhood: pathophysiology and management. Pediatric Clinics of North America 43(2): 375-390. Kneepkens CMF, Douwes A & Jakobs C (1989) Apple juice, fructose and chronic nonspecific diarrhea. European Journal of Pediatrics 148: 571-573. Lancet (1987) What has happened to carbohydrate intolerance following gastroenteritis? Lmcet 1: 23-24, Lebenthal E, Khin-Maung U, Zheng BY et al (1994) Small intestinal glucoamylase deficiency and starch malabsorption: a newly recognized alpha glucosidase deficiency in children. Journul of Pediatrics 124(4): 541-546. Lima AAM, Fang Cl & Schorling JB (1992) Persistent diarrhea in Northeast Brazil: etiologies and interaction with malnutrition. Actu Puediatrica S381: 39-44. Macleod R, Bennett H & Hamilton J (1995) Inhibition of intestinal secretion by rice. Lancer 346: 90-92. Mahalanabis D (1996) Current status of oral rehydration as a strategy for the control of diarrhoeal diseases. Indian Journal of Medical Research 104: 115- 124. Matthews Cl, MacLeod R, Zheng SX et al (1998) Rice may inhibit intestinal secretion by a direct effect on activated cystic fibrosis trammembrane conductance regulator (CFTR) chloride channels. Journal of Pediatric Gastroenterology and Nutrition. *Molla A & Molla A (1997) Cereal-based oral rehydration in the treatment of diarrhea. Diarrhea1 Disease 38: 125-138. Molla A, Molla A, Sarker S & Khatun M (1983) Whole-gut transit time and its relationship to absorption of macronutrients during diarrhoea and after recovery. Scandinavian Journal of Gastroenterology 18: 537-543. Nanulescu M, Condor M, Popa M et al (1995) Early refeeding in the management of acute diarrhoca in infants of 0- 1 year of age [see comments]. Actu Paediutrica 84(9): 1002- 1006. Nurko S, Garcia-Aranda JA, Fishbein E et al (1997) Successful use of a chicken based diet for the treatment of severely malnourished children with persistent diarrhea: a prospective, randomized study. Journal of Pediatrics 131(3): 405-412. Penny ME & Brown KH (1992) Lactose feeding during persistent diarrhcea. Actu Paediatricu Supplement 381: 133-138. Penny ME, Paredes P & Brown KH (1989) Clinical and nutritional consequences of lactose feeding during persistent post-enteritis diarrhoea. Pediatrics 84: 835-844. Pizarro D, Posada G, Sandi L & Moran JR (1991) Rice-based oral electrolyte solutions for the management of infantile diarrhea. New England Journal of Medicine 224: 517-521. *Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis (1996) Practice parameter: the management of acute gastroenteritis in young children. Pediutrics 97: 423436.

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Reis EC, Goepp JG, Katz S & Santosham M (1994) Barriers to use of oral rehydration therapy. Pediatrics 93(5): 708-711. Roy S, Tomkins A, Akramuzzaman S et al (1997) Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea. Archives of Disease in Childhood 77: 196-200. Sachdev H, Mittal N, Mittal S & Yadav H (1988) A controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants. Journal of Pediatric Gastroenterology and Nutrition 7: 877-88 1. Sampson HA, James JM & Bemhisel-Broadbent J (1992) Safety of an amino acid-derived infant formula in children allergic to cow milk. Pediatrics W(3): 463-465. Sandhu BK, Isolauri E, Walker-Smith JA et al (1997) A muhicentre study on behalf of the European Society of Paediatric Gastroenterology and Nutrition Working Group on Acute Diarrhoea. Early feeding in childhood gastroenteritis. Journal of Pediatric Gastroenterology and Nutrition 24: 522-527. Saniel MC, Zimicki S, Carlos CC et aI (1997) Acceptability of rice based and flavoured glucose based oral rehydration solutions: a randomized controlled trial. Journal of Diarrhoeal Disease Research E(2): 47-52. Santosham M, Fayad I, Hashem M et al (1990) A comparison of rice-based oral rehydration solution and ‘early feeding’ for the treatment of acute diarrhea in infants. Journal of Pediatrics 116: 868-875. *Santosham M, Fayad I, Abu Zikri M et al (1996) A double blind clinical trial comparing World Health Organization oral rehydration solution with a reduced osmolarity solution containing equal amounts of sodium and glucose. Journal of Pediatrics 128(l): 45-51. Sazawal S, Black R, Bahn M et al (1995) Zinc supplementation in young children with acute diarrhea in India. New England Journal of Medicine 333: 839-844. Sazawal S, Black R, Bahn MK et al (1997) Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea-a community-based, double blind, controlled trial. American Journal of Clinical Nutrition 66: 413-418. Seas C, DuPont H, Valdez LM & Gotuzzo E (1996) Practical guidelines for the treatment of cholera. Drqs 51: 966-973. Thillainayagam A, Hunt J & Farthing M (1998) Enhancing clinical efficacy of oral rehydration therapy: is low osmolahty the key? Gastroenterology 114: 197-210. Tripp JH, Muller DP & Harries JT (1980) Mucosal (Na+ K+) ATPase and adenylate cyclase activities in children with toddler diarrhea and the postenteritis syndrome. Pediatric Research 14(12): 1382-1386. Van den Neucker A, Pestel N, Tran TM et al (1997) Clinical use of acid steatocrit. Actu Paediatrica 86(5): 466-469. Vanderhoof JA, Murray ND, Kaufman SS et al (1997) Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants [see comments]. Journal of Pediatrics 131(S): 741-744. Vanderhoof JA, Murray ND, Paule C & Ostrom K (1997) Use of soy fiber in acute diarrhea in infants and toddlers. Clinical Pediatrics 36: 135-139. Victora C, Huttly SR, Fuchs SC et al (1992) Deaths due to dysentery, acute and persistent diarrhea among Brazilian infants. Acta Pediatrica S381: 7- 11. De Vizia B, Mansi A, Giangregorio A & Troncone R (1995) Metabolic alkalosis due to the use of an oligoantigenic diet in infancy. Acfa Paediutrica 84: 103-105. Walker-Smith JA (1994) Intractable diarrhoea in infancy: a continuing challenge for the paediatric gastroenterologist. Acta Paediatrica Supplement 83(395): 6-9 (Review). *Walker-Smith JA, Sandhu B, Isolauri E et al (1997) Guidelines prepared by the ESPGAN Working Group on acute diarrhea: recommendations for feeding in childhood gastroenteritis. Journal of Pediatric Gastroenterology and Nutrition 24: 619-620. World Health Organisation (1985) Persistent Diarrhea in Children. DiarrheaI disease control CDDIDDM185.1 Geneva: WHO. Wright E, Hirsch J, Loo DD et al (1997) Regulation of Na+/glucose cotransporters. Journal of Experimental Biology 200: 287-293.