Definition and Epidemiology

Diarrhea is a symptom, and not a disease per se, of gastrointestinal tract illness, which can occur as a result of a variety of pathologic or non-pathologic conditions. In general, when consuming a typical Western diet, infants pass around 10 mL/kg/day and adults up to 200 g/day of stool. It is not easy to define a normal stool pattern in an individual because the frequency and consistency of stools can vary according to dietary intake and other factors. Frequency of stools in breast-fed infants can range from multiple stools daily to one bowel movement in a week and still be considered within normal range. An operative definition of diarrhea is passing more than three liquid stools per day.

In general, pediatricians, family practice physicians, and pediatric nurse practitioners deal with the majority of cases of pediatric diarrhea. Pediatric gastroenterologists usually see only referred cases in which diarrhea is per­sisting; symptoms involve other organ systems; or there are constitutional symptoms such as fever, weight loss, and arthritis, and if blood is passed. It is important to establish from the start whether the child is indeed having diarrhea. If a stool sample is available for observation it can be of great help. The emphasis in the present chapter is on pathophysiology, differential diagnosis, and approach to diarrhea in the pediatric age group. The management of specific diarrheal etiologies and persistent diarrhea is discussed in other chapters.

Diarrheal diseases are the second leading cause of mortality worldwide in children younger than 5 years of age (760,000 deaths/year) (WHO media news April 2013). In the United States alone, children younger than 5 years of age have more than 20 million episodes of diarrhea each year leading to 200,000 hospitalizations. The death toll in developed countries is much less than that in developing countries (400 deaths each year in the United States), mostly due to better management of diarrheal episodes (Centers for Disease Control and Prevention. The management of acute diarrhea in children: oral rehy­dration, maintenance, and nutritional therapy. MMWR 1992;41(No. RR-16). It is difficult to estimate the prevalence of chronic diarrhea in children given the persistent nature and underreporting of the illness.

Pathophysiology of Stool Formation

The human intestine handles an enormous amount of fluid on a daily basis including secretions by its own cells and external fluid intake. Of this large amount of fluid, only small volumes reach the colon, where the fluid is largely absorbed and a minimal amount is excreted in the feces. Water and solutes are absorbed in the intestine through three independent pathways. First is the sodium-coupled solute transport. This pathway provides absorption of glucose, galactose, amino acids, and oligopeptides across the intestinal mucosa against concentration gradients. Because of increased salt gradients in the enterocyte compared to the lumen, water is then passively moved from the lumen into the enterocyte. The second mechanism is through Na ⁺ /H ⁺ exchangers, which help in absorption of electrolytes without any association with other solutes. The third pathway is paracellular transport. This is an energy-independent, passive pathway allowing large amounts of solute transport across enterocyte membranes. The functioning of this pathway depends on how well the intercellular tight junctions are maintained. In acute diarrhea, Na ⁺ /H ⁺ exchangers and paracellular transport can be affected. However, the sodium-coupled solute transport remains intact, even with viral enteritis associated with epithelial damage. The preservation of this cotransport of glucose and sodium is the basis for oral rehydration therapy (ORT).

The secretory functions of the small intestine are mainly dependent on chloride secretion. Chloride channels at the enterocyte membrane can be activated by various enterotoxins and enteric neurotransmitters. The excessively negative charged Cl ^– in the intestinal lumen causes net passive transfer of Na ⁺ and water to the lumen and hence increased fluid and ion loss. Intestinal absorption occurs mainly at the villi, whereas secretion occurs at crypts, due to differential locations of Na ⁺ channels at villi and Cl ^– channels at crypts. In the colon, net excretion of H ⁺ and HCO ₃ ^– and net absorption of Na ⁺ occurs through Cl ^– /HCO ₃ ^– and Na ⁺ /H ⁺ exchangers. Some HCO ₃ ^– secretion in the colon is also linked to short-chain fatty acid (SCFA) absorption, which is an energy source for colonocytes. On a given day, an adult intestine handles around 8 L of fluid. Around 1 to 2 L is from oral intake and the rest is secreted in the lumen as saliva; gastric, intestinal, and pancreatic secretions; and bile. The small intestine absorbs most of this huge amount of fluid and leaves only 1.2 L for the colon to handle. The colon is able to absorb most of it, and around 200 mL is lost as water in feces. The back and forth movement of water and electrolytes between enterocytes and intestinal lumen in the proximal intestine makes the meal isotonic with plasma as it reaches the proximal jejunum.

In general, the amount, consistency, frequency, and components of stool are an indirect parameter of intestinal health. The journey of food from mouth to anus involves many complex steps, reflecting the integrated functions of different organs. From the normal level of digestive juices—including mucus, electrolytes, and water from enterocytes, exocrine pancreatic function, bile from gallbladder, and intact function of enteroendocrine cells—to normal migrating motor complexes (MMCs) and normal postprandial interruption of MMC, all are important in maintaining normal stool pattern. Any internal or external factor affecting the above-mentioned organs and processes can alter stool consistency or frequency and cause diarrhea.

Classification of Diarrhea

Diarrhea in children can be differentiated into acute and chronic, according to duration. Diarrheal episodes lasting less than 2 weeks are classified as acute and lasting more than 2 weeks as chronic. Different common causes of acute and chronic diarrhea are discussed separately in Boxes 9-1 and 9-2 . Diarrhea can also be differentiated based on pathophysiologic causes into secretory, osmotic, inflammatory, and fatty diarrhea. It is important to note that the distinction of diarrhea into these subcategories is artificial and devised only for ease of understanding. At a subcellular level in intestine, multiple factors play a role simultaneously to cause diarrhea. In a patient with severe inflammatory bowel disease (IBD), the secretory, osmotic, and inflammatory components can all work at the same time to cause diarrhea. In this section, we discuss the pathophysiology of diarrhea under headings of secretory, osmotic, and inflammatory diarrheas.

Pathophysiology of Secretory Diarrhea

Diarrhea is caused mainly by abnormal fluid and electrolyte transport, by decreased absorption, or increased secretion. After the initial discovery that bacterial enterotoxins stimulate chloride and water secretion, it was later found that more than 50% of intestinal secretion is controlled by enterochromaffin cells (ECCs) releasing serotonin (5-hydroxytryptamine; 5-HT). 5-HT activates the enteric nervous system, secondarily enhancing enterocyte chloride secretion. In addition, inflammatory mediators (histamine, serotonin, and prostaglandins) produced by immune cells, intestinal mast cells, eosinophils, macrophages, neutrophils, and mesenchymal cells in the lamina propria and submucosa can initiate and enhance intestinal secretion. These mediators may stimulate enterocytes directly and activate the enteric nervous system. Moreover, this process of electrogenic chloride and bicarbonate secretion inhibits electrically neutral sodium chloride absorption in the small intestine and the colon through intercellular messengers. Because of the net fluid movement into the lumen, this is a combined cause of malabsorption of water and electrolytes and enhanced secretion, seen as diarrhea. Profound fluid and electrolyte losses are common in secretory diarrhea. Infectious causes are most common but note should also be made of tumors producing intestinal secretagogues.

Pathophysiology of Osmotic Diarrhea

In osmotic diarrhea, a meal has the same, normal dilution in the duodenum, but thereafter water content of the intestinal lumen will increase. For instance, lactase-deficient individuals are unable to reabsorb adequate fluid because lactose is not metabolized to galactose and glucose, which act to help transport water and electrolytes. Osmotic diarrhea can be induced to alleviate constipation. Healthy normal adults receiving increasing doses of polyethylene glycol 3350 (PEG 3350) or lactulose have been studied. PEG 3350 (lower molecular weights do not bind water as well) is poorly absorbed, is not digested by human or bacterial enzymes, carries no electrical charge, and causes pure osmotic diarrhea. With daily doses of 50 to 250 g/day, stool weight increases gradually from 364 to 1539 g/day. Stool water content does not rise above 80% because of high fecal concentration of PEG. PEG attracts water: stool weight, water output, and fecal PEG output correlate in a linear fashion.

With lactulose doses increasing from 45 to 125 g/day, stool weight increases from 254 to 1307 g/day. Water content percentage increases from 79% to 90%. With increasing lactulose doses, fecal organic acid content decreases while carbohydrate content increases. This means that with lower dosages up to 95 g/day, organic acids are absorbed and water absorption is cotransported. Only in higher dosages is lactulose no longer fermented so that it contributes directly to diarrhea. Of interest, electrolyte concentrations in diarrheal stools are higher with lactulose than with PEG, and a linear correlation between organic acid output and electrolyte output is obvious. However, conservation of electrolytes is excellent, even with water output greater than 1200 g/day. Diarrhea at lower dosages is caused mainly by unabsorbed organic acids, and with higher dosages by a combination of organic acids and undigested carbohydrate. Because there is no correlation between organic acid concentration and rate of individual bowel movements, the argument of rapid colonic emptying or effects on colonic motility is probably not justified.

Patients with short bowel syndrome showed lower fecal carbohydrate and organic acid excretion as compared to volunteers when both groups were fed 60 g/day of lactulose for 2 weeks. This experiment demonstrates a spontaneous adaptation of the gut flora in short bowel syndrome patients with intact colon. The contribution of fat to osmotic diarrhea is still under debate. Triglycerides do not contribute directly to diarrhea, but their fatty acids might. Medium-chain fatty acids are absorbed in the colon like short-chain fatty acids, or are lost in the feces like long-chain fatty acids. In carbohydrate malabsorption, sodium and water remain in the lumen until the colon is reached, where up to 90 g sugars can be metabolized daily by intestinal microbiota. A considerable amount of SCFAs contributes substantially to energy absorption as well as coabsorption of sodium and water.

Pathophysiology of Inflammatory Diarrhea

Inflammatory diarrhea can be caused by infection, allergy, Crohn’s disease, ulcerative colitis, or other causes. Multiple pathways may be involved in producing diarrhea. After the initial adherence or invasion of infectious agents, various immune cells release inflammatory mediators. Cytokines (such as interleukin 1 [IL-1] and tumor necrosis factor α [TNF-α]), chemokines (such as IL-8, which attracts eosinophils), and prostaglandins induce intestinal secretion by enterocytes and activate enteric nerves. Secondly, subepithelial myofibroblasts destroy the basement membrane by metalloproteinases, damaged enterocytes are extruded, and villous atrophy develops followed by regenerative crypt hyperplasia in the small intestine and colon. These surfaces are covered with immature enterocytes, with insufficient disaccharidases and peptide hydrolase activity. Na ⁺ -coupled glucose, NaCl, and amino acid transporters are reduced, but these crypt cells maintain their Cl ⁻ secretory abilities. In this damage and repair phase, capillaries may leak substantial amounts of protein and calcium, magnesium, and phosphate. For instance, in inflammatory bowel disease, malabsorption occurs only after extended resections, but these protein and mineral losses are frequently encountered and contribute to bone demineralization.

In IBD with colitis, the main electrolyte transport abnormalities are decreased Na ⁺ and Cl ⁻ absorption, lead­ing to impaired water absorption and excessive secretion. The inflamed colonic mucosa loses its transepithelial resistance with subsequent increased electrical conductance and enhanced permeability. The transmucosal potential difference is decreased or lost, and electrogenic Na ⁺ transport is impossible. In addition, Na, ⁺ K ⁺ -ATPase activity is decreased and passive Cl ^– absorption and electroneutral Na ⁺ and Cl ^– absorption are decreased. Thus, the major pathogenic factor in the diarrhea of colitis is this impaired NaCl and water absorption rather than the increased Cl ^– secretion. In microscopic colitis with minimal inflammation, electroneutral NaCl absorption is decreased while a normal potential difference is maintained, as is electrogenic Na ⁺ absorption. Corticosteroids stimulate the transmucosal potential difference and stimulate electrogenic Na ⁺ absorption, and hence Cl ⁻ and water absorption in addition to a general antiinflammatory effect. This explains the immediate beneficial effects of corticosteroids in IBD prior to mucosal healing.

Minor intestinal damage is caused by enterotoxin producing–bacteria such as Vibrio cholerae , enterotoxigenic Escherichia coli , Campylobacter , Yersinia , Salmonella , and Shigella . Small bowel morphology remains unaltered in many bacterial diarrheas. Diarrhea is caused by two mechanisms: enterotoxins and a rise in cyclic AMP (cAMP) in villus and crypt cells. cAMP blocks NaCl uptake in villus cells, causing NaCl malabsorption and diarrhea. Heat-stable toxin has similar effects by elevating cGMP in villus cells. Bacterial toxins induce 5-HT release by ECCs and stimulate the enteric nervous system both locally and distally. An increased calcium concentration in the crypt cells enhances Cl ⁻ secretion to a variable degree. The wide range of water excretion in cholera, between 1 and 10 L of diarrhea per day, is believed related to this nervous stimulatory effect. The secretory effect on cAMP is less pronounced. This mineral malabsorptive secretory diarrhea is related to risks of dehydration. As the bacteria arrive at the distal ileum and colon, they penetrate the mucosa and cause inflammation. This produces bloody diarrhea with tenesmus. The secretory phase has then diminished.

Minor inflammation is noticed with parasites ( Giardia , cryptosporidiosis), bacteria (enteroadherent or enteropathogenic E. coli ), viruses (rotavirus, astrovirus, and Norwalk agent), and idiopathic lymphocytic colitis. The pathogenesis of rotavirus diarrhea is complex. The small bowel distal to the duodenum is affected over a variable length. Mature villous enterocytes are infected, and the virus replicates, shuts down cell function (production of disaccharidases), and induces cell lysis and villous atrophy after 2 to 3 days. Rotavirus causes short-term malabsorption with steatorrhea. The increased mitotic index and migration of crypt enterocytes generates imma­ture cells with limited glucose–Na transport, neutral NaCl transport, low disaccharidase activity, and increased Cl ⁻ secretion. However, the life-threatening dehydrating diarrhea is not easily explained by this mechanism, also because of its patchy distribution. An explanation may be the substantial production of nonstructural protein 4 (NSP4) by rotavirus. It is secreted into the intestine and reabsorbed by other enterocytes that carry specific surface receptors. NSP4 has been shown to be an enterotoxin that enhances Cl ⁻ secretion through elevated intracellular calcium. This mechanism can augment secretion by the enteric nervous system locally and more distally.

In the proximal small intestine, Salmonella , Shigella , Campylobacter jejuni , Yersinia enterocolitica , and enteroinvasive E. coli do not damage enterocytes, but they cause diarrhea through enterotoxins. In the terminal ileum and the large intestine, enterocytes are destroyed and the submucosa invaded, causing inflammation. In ulcerative colitis and Crohn’s disease, the inflammation is moderate to severe. In celiac disease, the degree of inflammation is usually severe. In food allergy, the inflammation might be minor in the small intestine to severe in the large bowel in infants with cow’s milk, soy, or chicken hypersensitivity. The severity of diarrhea is not related directly to the severity of intestinal inflammation because the effect by the immune system and secretion-inducing mediators is variable.

Differential Diagnosis

Malabsorptive Diarrheas