Chapter 85 Gastrointestinal Structure and Function
Abnormalities in gastrointestinal (GI) and hepatobiliary function occur frequently in the pediatric intensive care unit (PICU) from primary GI disease, following surgery, or from complications of systemic disease. The pediatric intensivist is called on for expertise in the preoperative and postoperative management of numerous GI tract and hepatobiliary diseases, as well as secondary dysfunction that may complicate diseases involving other organ systems. The GI tract subserves a wide range of functions beyond simple digestion that have an impact on systemic immunological, endocrinological, and microbiological functions.1 Intact gut function beyond digestive function is of vital importance for the maintenance of health. Recent attention to alterations in GI function, interactions between liver and lung and between liver and kidneys have led to the view that the gut plays a role as an “engine” of multiple organ dysfunction.2 Thus a practical working knowledge of the GI system and its integrated function is essential for the management of critically ill patients.
Intestinal Structure, Digestion, and Absorption of Nutrients, Water, and Electrolytes
The functional absorptive unit of the intestines consists of villi and crypts. The cells of the small intestine are separated from one another by specialized junctions that serve as gaskets to prevent back diffusion of material into the intestinal lumen. A mucus layer secreted by goblet cells in crypts separates enterocytes from direct contact with the luminal contents (Table 85-1).
Table 85–1 Functional Units of the Intestine
| Structure | Function |
|---|---|
| Enterocyte | Formed in crypts; migrate to villus over 2–3 days; lifespan of 6 days |
| Villi | Absorption |
| Crypts | Secretion |
| Microvilli | Amplify surface area; contain enzymes and transport systems |
Stem cells in crypts produce enterocytes and other specialized epithelial cells that migrate up the villous axis as they become differentiated. This migratory process takes 48 to 72 hours. Mature villous cells live 6 days. They have microvilli making up the brush border that contain digestive enzymes and membrane bound transport systems for nutrient and electrolytes. Small bowel enterocyte microvilli are estimated to increase the luminal surface area of the cell 14- to 40-fold.3 The cells at the villous tip have a predominantly absorptive function, while crypt cells are primarily secretory. Rotavirus infections cause villous loss resulting in small intestinal mucosa composed largely of crypts and immature villi. This causes a net secretory state leading to malabsorption and osmotic diarrhea. Malabsorption of nutrients is another manifestation of villous injury.
Water and Solute Transport Across the Intestinal Epithelium
Surface area and integrity of intercellular junctions are the major determinants of water and solute flux across epithelium. The transport of solute and water across epithelium occurs either by active or passive transport or by facilitated diffusion (Table 85-2). The gut conserves large volumes of endogenously secreted material associated with digestion. The average luminal fluid input of the gut is about 9 L/day and composed of oral intake and endogenous secretions. Approximately 8.8 L is absorbed, about 7 L in the small intestine and 1.8 L in the colon. Less than 0.2 L is excreted as a component of the normal stool output. When rapid changes in dietary intake or endogenous secretions occur, the intestinal mucosa can adapt transport functions in order to compensate for the changes. The loss of mucosal surface area through disease or surgical resection alters net flux of solute and water in GI tract. Furthermore, loss of specialized absorptive function may occur following loss of specific areas of gut. An example of this occurs in the setting of short bowel syndrome from resection of terminal ileum, with loss of ability to absorb bile acids and intrinsic factor.3 Malfunction of absorptive mechanisms may lead to life threatening loss of fluid and electrolytes.
Table 85–2 Intestinal Transport Mechanisms
| Active | Passive | Facilitated Diffusion |
|---|---|---|
| Against electrochemical gradient | Ionic specificity | Saturable kinetics |
| Saturable kinetics | May be associated with transport of a nonelectrolyte | Substrate specific |
| Requires ATP | Proceeds down electrochemical gradient | Depends on carrier molecules (glucose, amino acid) |
| Steady state based on concentration differences | ||
| Displays first-order kinetics | ||
| May occur by convection via osmotic or hydrostatic gradient |
In contrast, critical illness alters energy requirements. In general, the prolonged physiological stress during critical illness causes an increased metabolic rate as well as gluconeogenesis in excess of that needed to maintain serum glucose. Proteolysis and peripheral oxidation of amino acids with increased ureagenesis is also observed. This state leads rapidly to malnutrition as a result of so-called autocannibalism, characterized by levels of glucagon higher than insulin levels and by elevated catecholamines and cortisol that drive the relentless breakdown of peripheral tissues. These hormonal changes result in catabolism of endogenous stores of protein, carbohydrates and fat to provide metabolic substrate necessary to support the metabolic stress response.4 Children with burn injury demonstrate extreme hypermetabolism in the initial phases of illness.5 Children on dialysis have a negative nitrogen balance and loss of folate and selenium.6 Use of catecholamines or neuromuscular blocking agents represent risk factors for undernutrition in critically ill children on dialysis.7 During high physiologic stress, nutrition delivered to patients must be changed to allow for decreased reliance on fat and carbohydrate for energy production. Proteins are increasingly relied on and must be replaced with additional amino acids to support ongoing synthesis of protein including immunoglobulins by the liver and immune system. Protein requirements for various age groups are as follows: 0 to 2 years, 2 to 3 g/kg/day; 2 to 13 years, 1.5 to 2 g/kg/day; and 13 to 18 years, 1.5 g/kg/day.8 Depressed levels of specific amino acids have been found in critically ill children.9
Enteral nutrition is the preferred method of feeding for critically ill children. Restriction of fluid intake seems to be the main barrier to the delivery of adequate nutrition, particularly in infants undergoing cardiac surgery.10 Early transpyloric enteral nutrition is well tolerated in critically ill children and is not associated with an increase in incidence of complications.11 Small-bowel feeds allow a greater amount of nutrition to be successfully delivered to critically ill children compared with gastric feeds. However, small-bowel feeds do not prevent aspiration of gastric contents.12 The institution of a feeding protocol has been found to achieve goal feedings quickly and also improve tolerance of enteral feedings in patients admitted to the pediatric intensive care unit.13 Enteral nutrition may also have some anti-inflammatory effects by lowering expression of specific cytokines.14 The use of specialized formulas is not currently recommended in critically ill children. No effect from adequacy of feeding has been seen on hormone levels such as insulinlike growth factor-1 (IGF-1) and thyroid hormones.15
Digestion of Carbohydrates
Dietary carbohydrates may be classified in several ways (Box 85-1). Monosaccharides, such as glucose and fructose, are present in fruits, sweet corn, corn syrup, and honey. Disaccharides are simple sugars, such as sucrose (glucose + fructose), maltose (glucose + glucose), and lactose (glucose + galactose), the principal mammalian sugar. Polysaccharides, such as starch, are polymers of glucose and are abundantly present in wheat, grains, potatoes, peas, beans, and vegetables. Fiber consists of nondigestible complex polysaccharides of plant origin. This includes both water insoluble and water soluble fiber. The average American diet is 3:1 soluble to insoluble fiber. Some studies have shown that a water-soluble fiber, partially hydrolyzed guar gum can be used to decrease stool output in cholera.16 Insoluble fibers affect fecal bulk, whereas soluble fibers have viscous effects in the upper GI tract including delayed gastric emptying, decreased postprandial glycemic response, and a constipating effect.
Carbohydrates are a major source of calories in healthy children. Carbohydrates are generally broken down by means of glycolysis and the Krebs cycle pathway (see Chapter 74). Carbohydrates may be stored as glycogen and lipids when ingested beyond momentary energy needs or converted to structural materials. A person’s requirement for energy is highly dependent on activity level or, in hospitalized patients, the degree of hypermetabolism accompanying illness. The maximal ability to utilize carbohydrates may be limited during periods of high physiological stress as a result of the complex effects of hormonal mediators of the stress response.
Digestion of carbohydrates begins with the process of chewing that decreases the size of food particles, thereby increasing the total surface area for subsequent action by digestive juices. Salivary secretions are necessary for lubrication and also contain salivary amylase, an endoenzyme that cleaves oligosaccharides. Salivary amylase is rapidly inactivated by gastric acid, leaving the majority of starch digestion to occur in the duodenum under the action of pancreatic amylase and the intestinal brush border disaccharidase enzymes. Amylase contained in human milk facilitates starch digestion in breast-fed infants because of their low levels of endogenous salivary and pancreatic amylase.17 Pancreatic amylase is the major enzyme of starch digestion resulting in short oligosaccharides, maltotriose, maltose, and α-limit dextrins. The amylase concentration becomes limiting in cases of pancreatic insufficiency when amylase levels become less than 10% of normal.18
The enterocyte is incapable of absorbing carbohydrates larger than monosaccharides. Therefore, further hydrolysis to monosaccharides is performed by intestinal brush-border disaccharidases of which the clinically important ones are lactase, which breaks down lactose, and sucrase, which breaks down sucrose. These enzymes are synthesized in the enterocyte and are subsequently inserted into the apical brush border membrane. With the exception of lactase and occasionally sucrase, the disaccharidases are rarely rate-limiting for complete carbohydrate digestion. Deficiencies of any of the disaccharidase enzymes, either acquired or hereditary, may result in carbohydrate malabsorption. This is characterized by osmotic diarrhea with elevated fecal reducing sugars, abdominal distension and flatulence secondary to fermentation of undigested oligosaccharides by colonic bacteria. An example of this is congenital sucrase isomaltase deficiency, an autosomal recessive disorder that is associated with absence of sucrase and maltase.19,20
Absorption of carbohydrates occurs in several ways. During periods of high luminal carbohydrate concentration, simple diffusion of monosaccharides may occur. Additionally, two transport mechanisms exist in the brush border for the absorption of monosaccharides.21 First, glucose, galactose and xylitol are transported with sodium by the Na+/glucose cotransporter. A low intracellular sodium concentration is created by the sodium-potassium-adenosine triphosphatase (Na+-K+ adenosine triphosphatase [ATPase]) pump located on the basolateral membrane. The resulting concentration gradient leads to movement of luminal sodium across the apical membrane, bringing with it glucose or galactose in a one-to-one molar ratio. Glucose-galactose malabsorption is a deficiency of this transport mechanism leading to neonatal onset of severe diarrhea.22 The second mechanism is a non‑energy-dependent facilitated transport system for fructose. The intestinal transport mechanisms are summarized in Table 85-2. The capacity to absorb fructose is limited, and excess ingestion has been found to cause symptoms of carbohydrate malabsorption.23
Clinical conditions that cause loss of the epithelium and brush border system may lead to symptoms of carbohydrate malabsorption. These conditions include: rotoviral gastroenteritis, inflammatory bowel disease, celiac disease, sprue, ischemia/hypoxia, bacterial overgrowth of the proximal gut as a result of either stasis or use of antacids, and malnutrition. Severe mucosal damage requires 7 to 10 days for recovery of brush border function. Several infant and enteral formulas rely on starch as a carbohydrate source to minimize reliance on lactase. Recent studies have observed that lactose digestive capability with lactase can be maintained despite small bowel mucosal damage.24 Lactose absorption is primarily related to lactase activity as opposed to mucosal growth.25
Digestion of Proteins
The GI tract has developed efficient mechanisms for processing exogenous peptides and complex proteins (Box 85-2). It is also very efficient at recycling endogenous proteins such as digestive enzymes, mucus, sloughed cells, and plasma proteins that leak into the alimentary tract.26 The recommended dietary protein intakes in healthy children range from 2.5 to 3.5 g/kg/day in early infancy to 1.2 g/kg/day during childhood, and 0.8 to 0.9 g/kg/day in adolescence.8 The enteral processing of proteins may be divided into digestive and transport phases.
In the digestive phase, gastric acid secretion initiates denaturation of complex proteins making them more susceptible to the actions of proteolytic enzymes. The chief cells of the stomach release pepsinogens that are converted to active pepsins under the influence of gastric acid. The pepsins are endopeptidases that release relatively large peptides and are inactivated when the pH rises above 4 as the food enters the duodenum. The completeness of gastric proteolysis depends in part on the rate of gastric emptying, the pH of intragastric contents, and the types of protein ingested.26 It is noteworthy that patients with achlorhydria or those receiving antacids, H2 blockers, or both agents have no evidence of impaired protein digestion ability. In addition to initiating protein digestion in the mature subject, pepsins act as milk clotting factors, which are important in the neonate for curd formation and provide bulk to the infant’s stools.
Luminal digestion proceeds in the small intestine mediated by five pancreatic peptidases that are secreted by the pancreatic acinar cells as proenzymes and activated by enterokinase and trypsin. Each peptidase possesses proteolytic activity at specific internal or external peptide bonds. Proteins are degraded typically into mixtures of one-third free amino acids and two-thirds peptides containing two to six amino acid residues,27 which are suitable substrates for the brush border peptidases. The brush border peptidases convert the oligopeptides into monopeptides, dipeptides, and tripeptides suitable for transport into the enterocyte.
In the transport phase, specific membrane-associated transport mechanisms exist for the uptake of amino acids and dipeptides.28 They involve simple diffusion, facilitated transport, and carrier-mediated active transport (Table 85-3). Na+-coupled active transport is an energy-dependent process associated with the uptake of luminal Na+ and an amino acid (or glucose) and exchange of the sodium and associated molecule for K+ through the basolateral membrane on the serosal side.29 Peptide transport may also occur using an H+/peptide transport protein which moves according to an H+ gradient in the acidic pH microclimate of the intestinal brush border. This microclimate is maintained by Na+-H+ exchange in the brush border and Na+-K+-ATPase in the basolateral membrane.30 An important characteristic of these transporters is that many amino acids are absorbed more rapidly as dipeptides than as free amino acids. This fact has been capitalized on in the development of enteral nutritional formulas because oligopeptide mixtures have a lower osmolarity and are more efficiently absorbed than single amino acid solutions of equal nitrogen content. Because of the efficient gastrointestinal absorption of dipeptides, patients with specific amino acid transport defects (e.g. Hartnup disease [defective tryptophan transport] and lysinuric protein intolerance [defect in dibasic amino acid transport: lysine, arginine]) infrequently have GI symptoms related to dietary protein malabsorption and instead more commonly manifest with non-GI symptoms such as aminoaciduria.
Once inside the enterocyte, peptides are quickly degraded into their constituent amino acids by cytoplasmic peptidases that complement the activity of the brush border peptidases. Only minute quantities of intact peptide and protein gain access to the systemic circulation. The cytoplasmic amino acids derived from digested proteins are a major source of free amino acids used directly by the enterocyte. When absorbed beyond cellular needs, the free amino acids are released to the portal venous circulation for hepatic and systemic use. Only 23% of absorbed amino acid nitrogen passes to the periphery without modification.31 Of the remaining nitrogen, 57% is converted to urea with the carbon skeleton salvaged for synthesizing other substances and 20% of the total ingested amino acids are used directly for hepatic protein synthesis.
During periods of fasting, the enterocyte derives the majority of its nourishment from the mesenteric arterial vascular supply, whereas during digestion, the enterocyte derives a significant part of its nutrient requirements from the luminal contents. Experience with mucosal recovery and adaptation after injury reveals that an enteral route of nutrition permits optimal recovery. In the premature infant and neonate, the small intestine is capable of absorbing intact milk proteins by pinocytosis. These proteins may include secretory immunoglobulins from breast milk as well as food antigens.32 Peptidase inhibitors have been demonstrated in colostrum and breast milk, partially explaining the failure of normal digestive mechanisms to degrade some of these complex dietary proteins. Both antibodies and antigens ingested with maternal milk create an important part of the immune repertory developed during early infancy.33 Although the exact time of “closure” of the intestinal mucosa to the uptake of macromolecules has not been defined in human infants, other mammals demonstrate marked intestinal impermeability to foreign proteins by the time of weaning34 from breastfeeding.
Digestion of Lipids
Dietary fat accounts for approximately 50% to 70% of the nonprotein calories consumed by infants and approximately 30% of nonprotein calories consumed after age 2 years (Box 85-3).35 Dietary fat is ingested principally in the form of triglycerides containing the fatty acids palmitate and oleate (C16:0 and C18:1, respectively). Dietary triglycerides of animal origin predominantly contain long-chain (i.e., longer than C14 chain length) saturated fatty acids. Polyunsaturated fatty acids are mostly of vegetable origin and include linoleic and linolenic acid, also referred to as essential fatty acids because of absent de novo synthesis in humans. Other dietary lipids include fat-soluble vitamins, cholesterol, prostaglandins, waxes, and phospholipids.
In healthy adults, digestion and absorption of fat is complete with only 5% to 7% of ingested fat escaping absorption. Under normal physiological conditions healthy infants up to age 9 to 12 months fail to absorb 15% to 35% of dietary fat. Digestion and absorption of dietary fat is generally completed by the middle third of jejunum; however, the presence of dietary fiber may reduce the rate and extent of absorption. Loss of dietary fat places children at significant risk for calorie and fat-soluble vitamin malnutrition.
Digestion of Fat
Fat digestion begins with formation of emulsions, which increase the surface area for enzyme interaction. Emulsification begins with release of fat by mastication and gastric “milling” of chyme. Bile salts and coating by phospholipid derived from the diet results in a stable emulsion droplet with a hydrophobic center consisting of triglyceride, cholesterol esters and diglyceride in a hydrophilic envelope. Mammary, lingual, and gastric lipases play an important role in direct lipolysis of long- and medium-chain triglycerides that are present in maternal milk.36 Lingual and gastric lipases are active at pH <5 and begin digestion of fat in the stomach; however, overall only play a limited role in the digestion of lipids. Intragastric lipolysis is consistent across all age groups.37
Most of the enzymatic degradation of dietary lipids to fatty acids and monoglyceride is by the action of pancreatic lipase and co-lipase, and requires an alkaline environment (pH 6 to 8). This underscores the importance of secretion of bicarbonate by the pancreas and biliary tree in order to neutralize gastric acid. Co-lipase is an essential cofactor for lipase action. Co-lipase’s role is to displace the bile salt-triglyceride interaction in emulsion droplets and micelles to facilitate lipase hydrolysis of the triglyceride. Triglyceride hydrolysis occurs at the interface between the emulsion droplet and aqueous phase within the lumen. This is a two-step process. The first step is the enzymatic hydrolysis of long-chain triglycerides and liberation of fatty acids from the glycerol backbone. The second step is formation of fatty acid micelles, that is most efficiently accomplished with the aid of bile salts38 to traffic the fatty acids across the unstirred water layer to the mucosa for absorption.
Transit through the unstirred water layer adjacent to the epithelial surface is considered the rate-limiting step in lipid absorption. Intrinsic gut brush border lipase enzymes are involved as well. The milieu of the unstirred water layer is acidic (pH 5 to 6) owing to the activity of the brush border membrane sodium-hydrogen (Na+/H+) exchanger. The acid environment facilitates dissociation of fatty acids from micelles resulting in a high concentration of fatty acids necessary for diffusion across the mucosal membrane.39,40
Once inside the enterocyte, long-chain fatty acids and monoglycerides are resynthesized into triglycerides and packaged as chylomicrons. Lipoproteins (e.g., apo-A, apo-B) and cholesterol are attached to the intestinal chylomicrons and confer important properties for the subsequent systemic uptake and metabolism of the chylomicrons. This process appears to be defective in cystic fibrosis and may account for some of the fat malabsorption seen in this disease.41 Chylomicrons are exported into the intercellular space and transported through the intestinal lacteals to become part of the intestinal lymph. On entering the bloodstream through the thoracic duct, the chylomicrons are associated with other apolipoproteins that allow them to be recognized by specific peripheral tissues.42
Regulation of Electrolyte and Water Movement
Movement of water is closely linked to the movement of solute in the form of electrolytes and nutrients. Water transport is a largely passive process that occurs through paracellular routes in the intestine coupled with solute movement. Expression of transporters involved in intestinal water and electrolyte transport is regionally specific. Electrolytes are taken up by enterocytes at the apical membrane and extruded through the basolateral membrane into the paracellular space. The relatively hypertonic paracellular fluid pulls water into this space, increasing the hydrostatic pressure locally. Because the tight junction between enterocytes is more impermeable to fluid flux than the capillary membranes, fluid and electrolytes are preferentially driven in the direction of the vascular space.1,43,44 Tight junctions are selective and dynamic in function and are regulated by a number of signaling pathways and cellular processes that can determine the size, selectivity, and flow of molecules across this barrier.3
The gut responds to both systemic and local stimuli to regulate motility, transport, and digestive functions. Secretion and motility are mediated through typical agonist membrane receptor mechanisms, by local autocrine and paracrine action, or through remote endocrine and neurocrine actions. Regulation of intestinal motility is crucial for keeping the chyme in contact with the epithelial surface long enough for efficient absorption of nutrients while permitting removal of unusable material and bacteria from the alimentary tract on a regular basis. GI smooth muscle demonstrates phasic and tonic patterns of contraction. Numerous factors affecting the frequency of contractions include changes in autonomic tone, stimulation of the gut by neurohormonal peptides or pharmacologic agents, and noxious stimuli associated with infectious or inflammatory processes. Hypoxia and ischemia decrease motility, frequently leading to paralytic ileus. Neural regulation of the GI tract integrates the processes of intestinal water and electrolyte transport, motility and blood flow. The augmentation of water and electrolyte absorption after a meal in the jejunum is neurally mediated.45 The enteric nervous system is capable of functioning independently but also may be modified by autonomic nervous system.3
Many other factors alter the functions of the gut. The terminal ileum and colon are particularly important in this respect. The presence of an ileostomy increases the risk of excessive sodium losses, dehydration, and electrolyte abnormalities. Terminal ileal resection or other diseases of the terminal ileum such as Crohn disease or radiation enteritis may result in bile acid malabsorption. In patients with bile acid malabsorption, bile acids reach the colon, which stimulates electrolyte and chloride secretion. Patients with mild to moderate malabsorption present with watery diarrhea and may respond to a bile acid binder such as cholestyramine.46 Impairment of water and ion absorption in inflammatory bowel disease may occur because of numerous mechanisms including alteration of epithelial integrity, augmented secretion, and reduced absorption. In addition, intestinal inflammation is associated with defects in epithelial barrier function. It is not known what effect inflammation may have on ionic function.47 Hyperosmolality of the ileal and colonic contents leads to an osmotic diarrhea. This state is seen when unabsorbed nutrients enter the distal alimentary tract and are broken down by enteric bacteria, resulting in increased luminal osmotic activity and osmotic diarrhea.
Electrolyte Transport
Several basic mechanisms exist for the transport of electrolytes by the epithelia. Na+ may be transported by numerous mechanisms. The regulation of Na+ absorption is closely regulated such that anion secretion is closely aligned with Na+ absorption.48 A Na+-H+ exchange-mechanism present throughout the intestine results in a 1:1 exchange of luminal sodium for protons. Coupled Na-Cl absorption, Na-Cl co-transport, Na-K-Cl co-transport, and movement of Na+ down its electrochemical gradient as in Na-Glucose co-transport are other mechanisms by which Na+ moves across the intestinal epithelium. The Na+-H+ exchanger plays a role in regulation of intracellular pH, regulation of cell volume, initiation of cell growth in response to various trophic factors, and metabolic response to insulin. To maintain electrical neutrality, the epithelium simultaneously exchanges Na+ for H+ and Cl− for HCO3. The presence of glucose in the lumen of the small intestine stimulates increased sodium absorption through coupled transport. Uptake of glucose is carrier mediated although the coupled transport of glucose with sodium is electrogenically driven by the Na+ gradient across the cell membrane.49 Absorption of glucose by Na-Glucose transport results in activation of myosin light chain kinase to regulate tight junction-permeability.50 Backflow of sodium into the lumen is a passive process since a major task for the GI tract is sodium conservation. Systemic acidosis increases Na+ and Cl− absorption in the ileum and colon, whereas alkalosis has the opposite effect. As seen in other epithelial tissues, aldosterone increases ileal and colonic absorption of Na+ and can increase absorption of water in colon three- to fourfold.51 Spironolactone blocks this effect. Glutamine has been shown to stimulate water and electrolyte absorption in the jejunum.52 Glucocorticoids increase sodium and water absorption in the distal colon. Opiate receptor stimulation increases active sodium and chloride absorption in the ileum, and opiate antagonists decrease basal absorption of water and electrolytes. The primary antidiarrheal effect of opiates, however, is mediated through a slowing of transit time.1
In the colon, active absorption and secretion of K+ occurs in a manner consistent with K+-H+ exchange, is electroneutral and independent of Na+-Cl− exchange. After the ions have entered the enterocyte at the luminal surface, extrusion occurs through the basolateral membrane into the paracellular spaces. The process of sodium extrusion depends on Na+-K+-ATPase pumping function located at the basolateral membranes. Oxidative stress inhibits water and electrolyte absorption in the jejunum through inhibition of Na-K ATPase on the basolateral membrane.53
Extrusion of Cl− occurs along an electrochemical potential difference.54 The intraluminal secretion of water and other electrolytes appears to follow active secretion of Cl− from the crypt cells of the jejunum, ileum, and colon. This is a common physiological pattern in the liver, pancreas, and kidney. Numerous substances such as muscarinic receptor agonists, serotonin, and substance P likely work through second messengers and signaling cascades to induce active chloride secretion. Vasoactive intestinal peptide mediates increased secretion of electrolytes and water by increased cyclic adenosine monophosphate production that stimulates active chloride secretion and inhibits sodium-chloride absorption. Certain arachidonic acid metabolites, especially prostaglandins (e.g., prostaglandin E1), have been shown to increase active chloride secretion leading to increased loss of electrolytes and fluid. Many laxatives and antacids may affect fluid and electrolyte balance by stimulating active electrolyte and fluid secretion in the terminal ileum. In addition, these agents may increase mucosal permeability and stimulate motility.1
Disruption of normal Na+-K+-ATPase activity results in the net secretion of fluid and electrolytes. This mechanism is the final common pathway in a number of secretory diarrheal states such as cholera, enterotoxigenic Escherichia coli, Salmonella spp., Campylobacter jejuni, and Clostridium perfringens that appear to act via second messenger pathways via their toxins.55 Rotavirus appears to have several mechanisms of causing diarrhea. The first appears to be a mechanism of increasing chloride secretion with a resulting secretory diarrhea mediated by Ca++, a different mechanism than most bacterial mediated diarrheal diseases. The second is an osmotic diarrhea caused by villus destruction and resultant malabsorption.56 In addition, the effects of various paracrine and endocrine mediators alter intestinal adenyl cyclase activity and lead to changes in electrolyte and water balance.54
