CHAPTER 123

Diarrhea

George Gershman, MD

The word “diarrhea” is derived from Greek and means “to flow through.” Diarrhea is associated with increased volume of stool caused by loose consistency and increased frequency of bowel movements. However, frequency of bowel movement and consistency of stool varies significantly from person to person and according to type of diet. For example, some healthy breastfed infants have a bowel movement once a week, whereas others may pass stool 7 to 10 times a day. The stool of breastfed infants is usually looser than that of formula-fed infants.

Diarrhea is a manifestation of various disorders, such as acute and chronic infections, chronic inflammatory bowel disease, food allergy or sensitivity, enzymes deficiency, hormonal imbalance, adverse effects of medications, mucosal atrophy, and short bowel syndrome, that affect either absorption of nutrients and water from the small and large intestines or secretion of fluids toward the intestinal lumen.

Epidemiology

Diarrhea is extremely common worldwide. In the United States, acute gastroenteritis is second in frequency only to upper respiratory tract infections. According to the World Health Organization, 2.5 million children in Latin America, Asia, and Africa die annually of dehydration secondary to diarrhea. In contrast, approximately 400 children die of this condition in the United States each year. These children often come from families of lower socioeconomic status.

In the United States, each child experiences an average of 0.9 episodes of diarrhea per year unless enrolled in a child care facility. In that case, the number increases to up to 3.2 episodes per year, a figure similar to that experienced by children in developing countries. In developing countries, the reported episodes of acute diarrhea vary from 3 to 6 to 8 in certain areas per year in children younger than 5 years. The severity of the infection is influenced by the underlying state of nutrition. An episode of acute gastroenteritis can be devastating for a child who has malnourishment. The fecal-oral route is the major path for the spread of infectious diarrhea. In developing countries, poor sanitation and contaminated drinking water perpetuate the problem. In the past 2 decades, the childhood mortality rate associated with diarrhea declined slowly but steadily primarily because of improved access to oral rehydration solution.

Many pathogens can be responsible for infectious diarrhea. The prevalence of individual pathogens varies widely between geographic areas and among different age groups. For instance, bacterial infections are more common in the first few months after birth and then again in school-age children. Rotavirus, the single most ubiquitous cause of infectious diarrhea worldwide, peaks between 6 and 24 months of age. In recent years, because of the widespread use of rotavirus vaccine in US children, norovirus has become the leading cause of medically attended acute gastroenteritis in the United States and is not only responsible for at least 50% of all outbreaks but the major cause of foodborne illness. On the contrary, Escherichia coli occurs frequently as a sporadic bacterial cause of diarrhea in the United States.

Definitions

Diarrhea is defined as stool mass more than 10 g/kg in infants and more than 200 g in older children. In clinical practice, and in accordance to the World Health Organization, it is acceptable to define diarrhea as “the passage of 3 or more loose or liquid stools per day, or more frequently than is normal for the individual.”

Acute diarrhea is characterized by sudden onset and resolution of diarrhea within 2 weeks. Persistent diarrhea implies an acute onset of diarrhea that lasts at least 14 but less than 30 days. The definition is based on acute-onset diarrhea that continues beyond the expected duration of an infectious etiology. Chronic diarrhea is defined as diarrhea lasting 30 days or more and associated with specific causes (eg, celiac disease, inflammatory bowel disease).

Clinical Presentation

The manifesting symptoms of diarrhea include frequent, watery stools, which may contain blood or mucus. Affected children may experience fever, vomiting, bloating, and abdominal pain. Signs and symptoms of dehydration such as decreased skin turgor, dry mucous membranes, depressed fontanelle, diminished tearing, and tachycardia may be present. Persistent diarrhea may be associated with weight loss and inability to gain weight at an appropriate rate (Box 123.1).

Pathophysiology

Regardless of etiology, diarrhea by definition results from an imbalance in intestinal handling of water and electrolytes. Water transport through the wall of the intestine is always a passive process linked to the active absorption of sodium and chloride. Regulatory mechanisms of water and electrolyte transport across the intestine require integration of the enteric nervous system, cells in the lamina propria mucosae, and epithelial cells. This complex system works through the generation of hormone peptides, active amines, arachidonic acid metabolites, and nitric oxide. The bulk of absorbed water crosses the intestinal epithelium between the cells (tight junctions) following generation of the osmotic gradient by the transport of nutrients and electrolytes. The normal flow of water across the intestine can be disrupted, leading to diarrhea, by 2 processes: (1) excessive osmolality within the intestine caused by either consumption of large amounts of nonabsorbable sugars, such as lactulose, or maldigestion or malabsorption of 1 or more nutrients (eg, monosaccharides or disaccharides) and (2) active secretion of water by enterocytes affected by viral or bacterial infection, toxins, and other substances.

Osmotic diarrhea occurs whenever digestion or absorption is impaired. In general, it is relatively small-volume diarrhea, which is dependent on oral intake and abolished with fasting. The most common causes of osmotic diarrhea are

1. Malabsorption of carbohydrates caused by either excessive consumption (eg, concentrated formulas or carbonated beverages) or decreased production of brush-border enzymes or the presence of nonabsorbable substances such as lactulose, sorbitol, or magnesium salts in the intestinal lumen.

2. Decreased absorptive capacity of the intestine caused by acute or chronic inflammation of the small-bowel mucosa (eg, acute viral gastroenteritis, cow’s milk protein allergy, bacterial overgrowth, giardiasis, celiac disease).

3. Lack of pancreatic enzymes or bile acid.

4. Decreased absorptive capacity of the small intestine secondary to congenital or acquired short bowel syndrome. Recent data suggest that improper differentiation of intestinal enteroendocrine cells has profound effects on the nutrient absorption by the small intestine.

In general, unabsorbed nutrients create an osmotic load that stimulates water leakage into the intestinal lumen across the tight junction. In addition, unabsorbed nutrients, such as carbohydrates, are the substrate for fermentation by colonic bacteria with liberation of short-chain organic acids, which create a secondary osmotic load in the large intestine and exacerbation of osmotic diarrhea.

Secretory diarrhea can be induced by any process, which creates a state of active intestinal secretion. In general, secretory diarrhea is associated with intestinal loss of large volumes of fluids, which continues despite cessation of eating. In the case of isolated small-bowel involvement, the large intestine will partially compensate losses of water and electrolytes. The most common cause of secretory diarrhea is bacterial infection. The other triggers of secretary diarrhea could be viruses (eg, rotavirus, HIV) or protozoan enterotoxins (eg, Cryptosporidium parvum in compromised immune systems). Secretory diarrhea is also seen in patients with neuroendocrine tumors, such as carcinoid tumors, gastrinomas, ganglioneuroblastomas, and congenital disorders of fluid and electrolyte metabolism, such as congenital chloridorrhea. The classic example of secretary diarrhea is infection with enterotoxigenic E coli, and Vibrio cholerae. Both bacteria produce toxins that bind to specific enterocyte membrane receptors and activate adenyl cyclase and production of cyclic adenosine monophosphate (by cholera toxin and heat-labile toxin from enterotoxigenic E coli) or cyclic guanosine monophosphate (by heat-stable toxin produced by E coli). The ultimate pathway involves the opening of chloride channels and massive water loss. Secretory diarrhea is particularly common in the developing countries, where it is related to infection with organisms such as enterotoxigenic E coli, and V cholerae. In the United States, the most common cause of secretory diarrhea is rotavirus infection. Vasoactive intestinal peptidesecreting tumors such as ganglioneuroma and neuroblastoma must be considered in children with persistent secretory diarrhea.

Both osmotic components and secretory components are present in many cases of diarrhea.

Motility disorders such as pseudo-obstruction syndrome or colonic inertia can be associated with persistent nonspecific diarrhea.

Inflammatory diarrhea can be acute, self-limiting (caused by intestinal infections) or chronic (eg, caused by inflammatory bowel disease or a few bacterial pathogens, such as Yersinia enterocolitica, or tuberculosis).

Steatorrhea is defined as presence of excessive amount of fat in the stools. Normally, at least 95% of fat is absorbed. In infants younger than 12 months, 10% of ingested fat may appear in the stool. Steatorrhea can result from fat malabsorption in children with mucosal atrophy (eg, celiac disease) or maldigestion secondary to chronic liver and pancreatic disorders (eg, biliary atresia, cystic fibrosis). Steatorrhea may also be seen in patients who have giardiasis.

Differential Diagnosis

Acute Diarrhea

The major cause of diarrhea in children and infants is acute viral gastroenteritis. The most common virus causing it is rotavirus, which usually spreads during the winter months, hence the term “winter vomiting disease.” Infants present with a history of antecedent mild upper respiratory tract symptoms, followed by fever and vomiting. Watery diarrhea, which is usually free of blood or mucus, then occurs. About 10% of children who have rotavirus infection have signs of otitis media. Dehydration may also occur. Patients typically exhibit mild hypernatremia, with serum sodium values reaching 150 mEq/L. The incidence of rotavirus infection is markedly reduced following the universal administration of rotavirus vaccine. Enteric adenovirus infection is the second most common cause of acute diarrhea.

The most common bacterial agents associated with gastroenteritis in the United States are Shigella, Salmonella, and Campylobacter. Aeromonas, a common pathogen in developing countries, is recovered in less than 1% of cases of diarrhea in the United States.

Campylobacter produces signs of colitis, with blood and mucus in the stools. Patients are usually febrile and experience abdominal cramps. As a rule, children infected with Shigella have more systemic symptoms (eg, higher grade fever, marked leukocytosis). In addition, infants and toddlers are particularly prone to seizures. Tenesmus and blood in stool are common. Infection with Salmonella may also be associated with high fever. Stools may be watery or mushy and often contain a large amount of mucus. Parasitic infections, particularly with Giardia lamblia, Entamoeba histolytica, and C parvum, may be associated with diarrhea and may follow a more protracted course. Infestation with these organisms does not usually result in fever.

Otitis media and urinary tract infection may also be accompanied by diarrhea. Sixty percent of children with hepatitis A develop diarrhea in the first week of illness. Other conditions may also result in diarrhea. In newborns, infection with E coli may produce epidemic outbreaks of large, explosive green stools without blood. Such outbreaks could result in closure of newborn nurseries. Changes in stool consistency in conjunction with feeding intolerance and abdominal distention could be related to necrotizing enterocolitis, especially in preterm infants. Although the exact etiology of necrotizing enterocolitis remains unknown, it is believed that intestinal immaturity leads to a compromised intestinal epithelial barrier, an underdeveloped immune defense, and altered vascular development and tone. The compromised epithelial barrier and underdeveloped immune system, when exposed to luminal microbiota that have been shaped by formula feedings, antibiotic exposure, and cesarean section, can lead to intestinal inflammation and sepsis. Feeding intolerance, bloody stools, pneumatosis intestinalis, and air in the portal vein are the hallmarks of the disorder. Enterocolitis may also occur in infants with Hirschsprung disease (ie, congenital megacolon). Adrenal insufficiency, as well as certain inborn errors of metabolism (eg, galactosemia), may lead to diarrhea. In general, other symptoms such as vomiting occur. Infants may present in shock because of hypovolemia related to dehydration.

Food intolerance may result in diarrhea in infants as well as in older children. Overfeeding or the ingestion of large quantities of fruit juices, dried fruits, or sorbitol-containing products can produce osmotic diarrhea. Food allergies may also be associated with malabsorption. Infants with cow’s milk protein allergy can experience diarrhea, growth impairment, anemia, hypoproteinemia, edema, respiratory symptoms, and eczema. Eosinophilia and elevated levels of immunoglobulin E are uncommon in infants with cow’s milk protein allergy. High cross reactivity between cow’s milk protein and soybean protein in up to 50% of children with cow’s milk protein allergy explains a lack of clinical response after substitution for soy protein-based formula. However, soy-containing formulas are very effective in infants with lactase deficiency. Congenital lactose intolerance is an extremely rare disorder. Acquired lactase deficiency is fairly common, especially in certain racial groups; it is reported in 10% of white patients, 70% to 80% of black patients, and 90% of Asian patients. The disorder is associated with diarrhea, cramping, and bloating after consumption of lactose. The stool has an acid pH, floats because it contains air, and is positive for reducing substances. Lactase deficiency may occur following an episode of acute gastroenteritis, when the brush border of the small intestine has been disrupted.

Persistent Diarrhea

Infants and children may have a protracted course of loose stools following an episode of acute gastroenteritis. Risk factors for persistent diarrhea are caloric and protein malnutrition, vitamin A and zinc deficiency, prior infection (eg, measles), male biological sex and young age (6–24 months), and young maternal age.

In most cases, no cause for persistent diarrhea can be detected, but infestation with Shigella species or enterotoxigenic E coli may be a contributing factor. The possibility of infection with HIV should be considered in infants and children with protracted diarrhea, especially in geographic areas in which disease prevalence is high. Certain children with acute diarrhea have such a modified diet (eg, clear fluids) that they develop starvation stools. These slimy, dark green or golden stools represent succus entericus, the secretion of the small intestine. Starvation stools do not have a fecal odor. Insufficient fat in the diet may contribute to starvation-associated diarrhea.

Chronic Diarrhea

Inflammatory bowel disease, which occurs more commonly in older children and adolescents, is associated with chronic diarrhea. Ulcerative colitis manifests with infiltration of the lamina propria mucosae with inflammatory cells, distortion of the glands, and crypt abscesses. Fever, weight loss, and anorexia are often present. Diarrhea is the hallmark of the disease, and patients experience tenesmus as well as mucus-laden and bloody stools. Inflammation always affects the rectum. It can be localized in the descending colon (left-side colitis) or spread out through the entire large intestine (pancolitis).

Crohn disease may also lead to chronic diarrhea, although lower abdominal pain aggravated by defecation may be a more prominent part of the medical history. Affected individuals frequently experience extraintestinal manifestations of the disease, such as fever, anorexia, weight loss or growth impairment, recurrent stomatitis, uveitis, arthralgia and arthritis, and clubbing. Perianal disease, such as fistulas, may be noted in 30% of patients.

Irritable bowel syndrome (IBS) may lead to chronic diarrhea in infants and children. Affected children do not experience diarrhea at night, which is the sign of infectious or secretory diarrhea. Partially formed or liquid-first stool in the morning and increased frequency during the day are characteristic of IBS. Bowel movement tends to occur after each meal, suggesting a prominent gastrocolic reflex. Children have 3 to 10 mucus-containing stools per day. Alternating periods of constipation may occur. Affected children appear well throughout this illness, without weight loss, growth impairment, fever, leukocytosis, steatorrhea, or protein malabsorption. Their appetite remains good. The first line of treatment of children with IBS-predominant diarrhea is a high-residue diet. Different probiotics have been used recently for treatment of IBS in children with various success rates.

Other frequent causes of chronic diarrhea are consumption of a large amount of fruit juice or carbonated beverages and adverse effects of medications such as antibiotics or nonsteroidal anti-inflammatory drugs.

Many rare conditions can lead to chronic diarrhea: autoimmune enteropathy, microvillus inclusion disease, and intestinal polyposis. Chronic diarrhea may also be associated with maldigestion, as with cystic fibrosis, or malabsorption, such as with celiac disease, or gluten sensitive enteropathy.

Newborns with cystic fibrosis may present with meconium ileus or, rarely, with acute appendicitis. Failure to thrive is common among patients with cystic fibrosis even though many of them have voracious appetites. Stools are large, bulky, and foul smelling secondary to the steatorrhea. Isolated gastrointestinal (GI) concerns are reported in 15% to 20% of patients with cystic fibrosis. Rectal prolapse is not uncommon. Most affected children also experience recurrent pneumonia and chronic pulmonary disease.

Celiac disease is an immune-mediated disorder related to gliadin, a portion of gluten, a protein found in wheat, barley, rye, and oat. Characteristically, a various degree of villous atrophy is apparent on tissue from a small intestinal biopsy. This flattening restricts the absorptive capacity of the intestine and leads to malabsorption. Children with the classic form of celiac disease have short stature, pale skin, sparse hair, protuberant abdomen, and wasted buttocks. In recent reports, subtle signs of celiac disease have been recognized and usually reflect the growth impairment, anemia, iron and folate deficiency, short stature, abnormal liver enzyme levels, dental enamel defects, osteoporosis, delayed puberty, and neurological abnormalities. Symptoms appear a few months after grains are introduced into the diet, usually between the ages of 9 and 12 months. Stools are mushy, bulky, and foul smelling. Fat content in the stool may be 2 to 3 times the normal level.

Evaluation

History

A comprehensive history derived from proper structured and targeted questions is the key for correct approach to the accurate diagnosis of diarrhea (Box 123.2).

Physical Examination

Children should be assessed for the presence of dehydration: altered vital signs, delayed capillary refill, decreased skin turgor, a sunken fontanel, dry mucous membranes, and reduced tearing. Detailed physical examination may reveal signs suggestive of specific diagnosis. For example, persistent severe skin changes in the perianal area or the perianal fistula should trigger a further workup to rule out acrodermatitis enteropathica and Crohn disease, respectfully. Evidence of growth impairment should be determined by assessing the growth parameters. Inability to gain weight over a period of months should initiate the workup of GI disorders such as chronic inflammatory bowel disease, celiac disease, or cystic fibrosis.

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