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Fisiopatologia de la diarrea


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Fisiopatologia de la diarrea

Fisiopatologia de la diarrea

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  • 1. E-mail: Current Paediatrics (2001) 11, 291d295 ^ 2001 Harcourt Publishers Ltd doi:10.1054/cupe.2001.0188, available online at on Understanding diarrhoea W. M. Bisset Consultant Paediatric Gastroenterologist, Royal Aberdeen Children’s Hospital, Cornhill Road, Aberdeen, AB25 2ZG, UK KEYWORDS diarrhoea, paediatric, coeliac disease, food hypersensitivity, short gut syndrome Summary Diarrhoeal diseases are among the most common causes of childhood mortality and morbidity throughout the world. In health, the gut is in a dynamic state with the secretion of intestinal juices being balanced by the absorptive capacity of the intestine. When this equilibrium is disturbed by increased secretion or reduced absorption, diarrhoea will occur. The absorption of sugars and amino acids by the small intestine is facilitated by co-transport with sodium, with water following passively. Most secretory processes are dependent on the active transport of chloride into the lumen of the gut. In infectious diarrhoea, secretion may be stimulated by enterotoxins or by inflammation of the gut. Mucosal damage secondary to allergic processes, coeliac disease or surgical resection will reduce absorption. Armed with an understanding of the pathophysiology of diarrhoea, the clinician is in a better position to diagnose and treat children with such problems. ^ 2001 Harcourt Publishers Ltd PRACTICE POINTS E Water is absorbed passively by the intestine and follows the osmotic gradient created by the active transport of electrolytes and solute E Oral rehydration solution promotes increased in- testinal absorption; they have no effect on secretion E Osmotic diarrhoea ceases when the patient has no oral intake, but secretory diarrhoea continues E The true incidence of coeliac disease of one in 300 is 10 times higher than previously thought (most effected individuals have no symptoms) E One in 20 infants may have a dietary protein intolerance, and cows milk protein is the most frequent cause E After surgical resection, the remaining small intestine grows in length and electrolyte absorption increases INTRODUCTION Millions of children die each year as a consequence of dehydration secondary to diarrhoeal illnesses. In deve- loping countries, infective diarrhoea is one of the major causes of childhood mortality, while in wealthier countries, although few children die as a result of diarrhoeal illness, it remains a very significant cause of infant morbidity. The aim of this review is to describe the normal physiology of the gastrointestinal tract and highlight how derangement of these processes can lead to the development of diarrhoea. Definition Stool consistency or colour can vary greatly, but the total stool volume is probably the best indicator of whether normal intestinal function is deranged. The normal stool output in an infant is between 5 and 10 g/kg/day and diarrhoea is said to occur when this upper limit is exceeded or the total daily output is more than 200 g. NORMAL INTESTINAL FUNCTION Digestion The main function of the small intestine is to allow the normal digestion and absorption of nutrients. Luminal digestion is facilitated by the presence of bile salts which solubilize lipids, and by pancreatic enzymes which are
  • 2. Figure 1 A schematic view of an absorptive villus enterocyte (A) and a secretory crypt enterocyte (B). The mucosal absorption (A) of glucose and amino acids is primarily through co-transport with sodium. Mucosal secretion (B) is driven by the movement of chloride. The sodium/potassium ATPase pump ensures that the inside of the enterocytes have a low sodium concentration and a negative charge relative to the lumen. This electrochemical gradient drives the movement of sodium into absorptive cells, and chloride out of secretory cells. Water moves down the osmotic gradient passively. responsible for the digestion of lipids, protein and carbo- hydrate. Lipids are broken down to free fatty acids, proteins to amino acids, di and tripeptides, and carbohy- drates to monosaccharides, disaccharide and limit dex- trins. Most nutrients have been absorbed by the time luminal contents reach the ileum, although bile salts and vitamin B12 are both absorbed exclusively from the ileum. Fluid and electrolyte transport It is important to realize that the intestine does not actively transport water and that its movement is always secondary to the active transport of some other solute or electrolyte across the intestinal epithelium. These active processes are powered by the sodium potassium ATPase pump which ensures that the inside of enterocytes have a low sodium concentration and a negative charge. The electrical and osmotic gradient created by this pump drives most intestinal transport processes (Fig. 1). Following a meal, sodium absorption is coupled to the transport of monosaccharides and amino acids. Speci- fic membrane proteins co-transport sodium with either glucose or galactose, while a family of proteins is responsible for the transport of neutral, aromatic, imino, dibasic and acidic amino acids with sodium. The sodium and glucose in oral rehydration solutions work through the above mechanism to potentiate water absorption by the small intestine. In glucose-galactose malabsorption, the sodium glucose/galactose transport protein is defective leading to the development of a chronic osmotic diarrhoea from the time of the first feed. Ileal and colonic sodium absorption is predominantly via sodium channels which are under the regulatory influence of glucocorticoid and mineralocorticoids. In the colon, the junction between enterocytes is much less leaky than in the small intestine, allowing sodium to be absorbed even when luminal concentrations are low. This facilitates the conservation of electrolytes, and the formation of a low volume stool. The absorption of sodium in the colon is stimulated by the presence of short-chain fatty acids (the break down products of undigested carbohydrate). Antibiotic therapy is likely to disrupt short-chained fatty acid production with a resultant reduction in colonic absorption and the development of diarrhoea. In the terminal ileum and colon, sodium absorption is also coupled with hydrogen and chloride absorption with bicarbonate. Failure of the latter later mechanism results in the development of congenital chloride losing diarrhoea. Intestinal fluid secretion is driven primarily by the active secretion of chloride. Chloride is transported into the enterocytes coupled with sodium, down the sodium gradient created by the sodium potassium ATPase on the basal lateral membrane. Increases in cyclic AMP, cyclic GMP and ionic calcium result in the opening of chloride channels on the luminal enterocyte membrane, with resultant movement of chloride, down its electro- chemical gradient, into the lumen followed by the secretion of water. This chloride channel is defective in cystic fibrosis MECHANISMS OF DIARRHOEA In an infant, about 280 ml/kg of digestive juices pour into the small intestine each day; more than double that found in an adult. Much of this volume is re-absorbed in the small intestine, but approximately 20% passes into the colon. Further absorption of fluid and electrolyte by the colon results in relatively small volumes of stool being passed, and in both children and adults, less than 2% of all water and electrolytes entering the small intes- tine is passed as stool. An increase in stool volume leading to diarrhoea can occur if: 292 CURRENT PAEDIATRICS
  • 3. Table 1 Common causes of malabsorption in childhood Intraluminal Mucosal Pancreatic: Cystic fibrosis Enteropathies: Post gastroenteritis Food allergic Hepatics: Hepatocellular failure Coeliac disease Cholestasis Inflammatory: Crohn’s disease Infective: Bacterial overgrowth Anatomical: Short gut syndrome Anatomical: Ileal resection Drugs: Chemotherapeutic agents Congenital: Transport defects e rare E the amount of fluid passing into the colon from the small intestine is increased E the absorptive capacity of the colon is reduced E the colon is actively secreting fluid. In older children and adults, increased small intestinal secretion may not necessarily lead to the development of diarrhoea if the colon has enough reserve capacity to cope with the added volume load. In young infants, however, where a relatively larger volume of fluid is passed into the colon, this reserve capacity is already taken up and therefore any pathological process is likely to more readily result in the development of diarrhoea. Where solute is inadequately absorbed, this will inevitably have an osmotic effect, drawing extra fluid into the lumen of the gut with resulting diarrhoea. A characteristic feature of so-called osmotic diarrhoea is that it ceases completely when the oral intake is stopped. This is in contrast to patients with active secretory diarrhoea where the secretion continues irrespective of the oral intake.1 CAUSES OF DIARRHOEA Acute infective diarrhoea By far the most common cause of acute diarrhoea is enteropathogenic infection. The pathogenesis of enteric infection, with the exception of a few organs such as Staphylococcus aureus and Bacillus cereus where toxin ingestion produces symptoms, is dependant on the en- teric pathogens entering and colonizing some part of the intestine.2 The first stage of this process is the attachment of the infective agent to the lining of the gut. Once bound to the cells, diarrhoea may be induced either by the release of enterotoxins which stimulate intestinal secretion or, alternatively, the infective agent might disrupt the structure of the enterocytes either with or without invasion. Infective agents may also induce a local inflammatory response which can lead to further secretion and bleeding into the gut. Infections with some intestinal helminths may also induce an IgE- mediated intestinal anaphylactic reaction. Enteric pathogens induce diarrhoea by increasing se- cretion, decreasing intestinal absorption through mucosal damage, or a combination of the two. Increased intestinal secretion Cholera is the classic example of a secretory diarrhoea. The cholera toxin stimulates an increase in cAMP levels within the enterocytes which leads to massive secretion of chloride and water. The presence of many infective agents initiates a local inflammatory response, and the release of substances such as 5HT and VIP will further stimulate secretion. In cryptosporidia infection, mucosal prostaglandin levels are thought to be a major factor in the secretory process. Decreased intestinal absorption Where the enteric pathogens damage the brush border membrane of the cells or disrupt the villous structure, nutrient absorption will be compromised, resulting in a large osmotic load that will in itself lead to increased diarrhoea. The most common cause of diarrhoea in temperate countries in young children is rotavirus infection. This virus invades the enterocytes and disrupts the micro villus structures, leading to cell death and the development of villus atrophy.3 Intestinal motility is increased with many enteric infections, leading to symptoms of pain and marked intestinal hurry which further compromises the ability of the colon to salvage the increased fluid load within the gut. Malabsorption Malabsorption may result if either the early luminal or later mucosal stages of digestion are disrupted (Table 1). UNDERSTANDING DIARRHOEA 293
  • 4. This will be further compromised by rapid intestinal transit or loss of absorptive surface due to surgical resection. Cystic fibrosis, a genetic defect of the chloride trans- porter found in duct and mucosal membranes, is the most common hereditory cause of luminal malabsorption in developed countries. The production of inspissated secretions in the pancreas leads to pancreatic insufficiency and, in the small intestine, to meconium ileus. Luminal digestion will also be compromised if there is a failure of bile salt secretion in chronic liver disease or premature deconjugation of bile salts due to bacterial overgrowth. Failure of mucosal digestion can occur where brush border enzyme activity is reduced. This most commonly occurs after enteric infections when lactase activity may be temporarily reduced, but less commonly, genetic de- fects of these enzymes may result in conditions such as sucrose-isomaltose deficiency. Structural damage to the small intestinal mucosa will compromise both digestion and absorption. Damage to the villi occurs in some infective diarrhoeas, in food allergic disease or may result from specific sensitization to the dietary protein found in gluten, resulting in coeliac disease. The end result irre- spective of the primary cause is malabsorption with development of an osmotic diarrhoea. Coeliac disease Coeliac disease requires the combination of a genetic predisposition and the presence of gluten in the diet. Contact of gluten with the small intestine of a susceptible individual leads to a marked inflammatory infiltrate within the lamina propria, with the development of a crypt hyperplastic subtotal villus atrophy. In the most severe form, this leads to profound malabsorption with severe diarrhoea.4,5 Over 95% of individuals with coeliac disease have raised circulating antibodies to gliadin, reticulin or endomysium, making it possible to screen for this condition. This has led to the realization that the majority of individuals with coeliac disease probably have few if any symptoms and the suggested incidence of this condition has increased 10-fold in recent years to a present level of one in 300. This lack of symptoms is a reflection of the lower dietary gluten load on young children, and the increasing functional reserve of the intestine in the older child that compensates for the proximal enteropathy. Coeliac disease is much more common in children with Down syndrome and diabetes with an incidence of about one in 20. Food allergy In developed countries, the incidence of food allergy is increasing and it has been suggested that up to one in 20 children under the age of 3 years may have some form of allergy to dietary food protein. When a child ingests a dietary antigen to which he or she is sensitized, this may lead either to a local reaction such as abdominal pain, diarrhoea or vomiting, or more distant reactions such as urticaria or wheeze.6 Where the allergic reaction is acute, dietary antigen stimulates sensitized mast cells with the release of inflammatory mediators, causing intestinal secretion and diarrhoea. Some children, however, have more delayed reactions with tissue damage which in the small intestine causes villus destruction and symptoms of malabsorption, with damage to the colon leading to a colitis with symptoms of blood and diarrhoea. These delayed symptoms may develop days after the ingestion of the offending protein. By far the most common dietary protein that causes allergy is cows milk protein, followed by soya, egg and wheat. Treatment is with antigen avoidance under close dietary supervision. In the majority of children, the problem is self-limiting and improves spontaneously in the second or third year of life. Surgical causes Resection of intestine may be required in babies with necrotizing enterocolitis, in infants with malrotation or in older children with Crohn’s disease. Small resections have very little if any effect on the child but resection of larger lengths of small intestine is compensated by ad- aptation of the remaining segment with villus hypertrophy and gut lengthening. It is known that the ileum adapts better than the jejunum and that where the ileo-caecal valve has been resected, adaptation may be significantly compromised. The major stimulus to this adaptation is the presence of food within the lumen of the gut. The adaptive process after massive small intestinal resections will take many months.7,8 In a child with a terminal ileostomy, the absorption of nutrients is not adversely affected, but because the ab- sorption surface area of the colon is lost, loss of water and electrolytes is greatly increased. Stimulation of ileal sodium pumps by increased mineralocorticoid levels leads in time to a reduction in losses, but such children remain vulnerable to the effects of gastroenteritis and chronic sodium depletion may lead to poor growth. Intractable diarrhoeal processes Most infective diarrhoeas in well-nourished individuals are self limiting. In malnourished children, however, re- peated infection will lead to further malnutrition, which in turn will compromise healing and repair of enteric mucosa.9,10 Repeated infections are also likely to lead to bacterial overgrowth of the small intestine, with resultant bile salt deconjugation and fermentation of 294 CURRENT PAEDIATRICS
  • 5. carbohydrates. Damage to the enteric mucosa will also facilitate the passage of antigen across the mucosa, which in turn may lead to sensitization to dietary proteins. Unless these processes can be interrupted by the institution of adequate nutrition and the prevention of further infections, the child is likely to enter a downward spiral resulting ultimately in death. EVALUATION OF THE PATIENT WITH DIARRHOEA As in most areas of paediatrics, a good history will give clues to the underlying cause of diarrhoea and the exam- ination will ascertain if the child is dehydrated or mal- nourished. With an acute onset of symptoms, and other family members similarly affected, an infective problem is most likely. Symptoms related to the ingestion of specific dietary proteins or diarrhoea developing in a bottle-fed baby in the first few months of life raises the possibility of an allergic aetiology. Where symptoms of diarrhoea are present from birth, one of the rarer congenital causes might also be considered. Serial measurements of height and weight will give valuable information about growth, and will help differentiate the well child with chronic loose stools due to a benign condition, such as toddler diarrhoea, from the patient with coeliac disease or cystic fibrosis who might be failing to thrive. Investigations and treatment Investigations depend on the likely differential diagnosis for the patient. Where the problem is likely to be infective, stool culture, microscopy or immunofluores- cence is most appropriate. Treatment is supportive and aimed at preventing dehydration and further infection. Allergic disease can be diagnosed by the process of withdrawal and challenge, and if coeliac disease is suspected, measurement of circulating antibodies and ultimately a jejunal biopsy is required. Treatment in both these conditions is with dietary exclusion. REFERENCES 1. Castro-Rodriguez J A, Salazar-Lindo E, Leon-Barua R. Differen- tiation of osmotic and secretory diarrhoea by stool carbohydrate and osmolar gap measurements. Arch Dis Childhood 1997; 77: 201d205. 2. Farthing M J G. Acute diarrhoea: pathophysiology. In: Gracy M, Walker-Smith J A, eds. Diarrheal Disease. Philadelphia: Lippinicot- Raven, 1997, pp. 55d74. 3. Belhorn T. Rotavirus diarrhea. Curr Prob Pediatr 1999; 29: 198d207. 4. Murray J A. The widening spectrum of celiac disease. Am J Clin Nutr 1999; 69: 354d365. 5. Catassi C, Fabiani E. The spectrum of coeliac disease in children. Bailliere’s Clin Gastroenterol 1997; 11: 485d507. 6. Vanderhoof J A. Food hypersensitivity in children. Curr Opin Clin Nutr Metabol Care 1998; 1: 419d422. 7. Warner B W, Vanderhoof J A, Reyes J D. What’s new in the management of short gut syndrome in children. J Am Coll Surg 2000; 190: 725d736. 8. Booth I W, Lander A D. Short bowel syndrome. Bailliere’s Clin Gastroenterol 1998; 12: 739d773. 9. Lee W S, Boey C C. Chronic diarrhoea in infants and young children: causes, clinical features and outcome. J Paediatr Child Health 1999; 35: 260d263. 10. Gracy M. Diarrhoea and malnutrition. J Paediatr Gastroenterol Nutr 1996; 22: 6d16. UNDERSTANDING DIARRHOEA 295