Pathophysiology

A total of 8 to 9 L of fluid enters the healthy intestines on a daily basis. Only 1 to 2 L are derived from food and liquid intake; the rest is from salivary, gastric, pancreatic, biliary, and intestinal secretions. Each day, about 90% of this fluid is absorbed in the small intestine, 1 L enters the colon, and about 100 mL is excreted in stool. Normal stool output is approximately 100 to 200 g/d. Diarrhea is defined as stool output greater than 200 g/d in children older than 2 years of age and greater than 10 mL/kg/d in children younger than 2 years of age. It is also described more practically as an increase in liquidity and frequency of bowel movements. Diarrhea can be categorized by duration, as either acute (≤2 weeks) or chronic (>2 weeks), or by mechanism, as osmotic or secretory. It can also be categorized by the presence or absence of malabsorption (Figure 111-1).

Figure 111-1 Diarrhea.

Both secretory and osmotic diarrhea are caused by defective or impaired mucosal absorption. In osmotic diarrhea, excess amounts of nonabsorbed substances, such as lactose, lactulose, fructose, or sorbitol, remain in the intestinal lumen, causing luminal water retention. After these luminal substances enter the colon, they are processed by colonic flora, producing large amounts of organic acids, increased flatulence, and faster transit. The fecal osmolar gap [290 mOsm/L − {2 × (measured stool sodium + measured stool potassium)}] is usually greater than 50 mOsm/L in the setting of osmotic diarrhea. When an abnormal gap is found, reducing substances, stool pH, and fecal fat should be measured. Osmotic diarrhea improves with fasting. Examples of osmotic diarrhea include lactase deficiency, celiac disease, and short bowel syndrome. Secretory diarrhea is the result of abnormal ion transport in epithelial cells, leading to decreased absorption of electrolytes and increased secretion of fluid. The fecal osmolar gap is less than 50 mOsm/L, and the diarrhea persists despite fasting. Examples include congenital chloride and sodium diarrhea, cholera, and neuroendocrine tumors.

Another important underlying mechanism of diarrhea is dysmotility. For example, pseudo-obstruction may result in bacterial stasis, overgrowth and resultant diarrhea, while hyperthyroidism may be associated with diarrhea because of rapid intestinal transit.

The character of the stool can help to determine the origin of diarrhea. Watery, voluminous, nonbloody stool with few or no white blood cells (WBCs) and low pH (<5.5) is likely to emanate from disease of the small intestine. Low-volume, mucusy, often bloody diarrhea with a large number of WBCs and higher pH often originates from the colon. The most common electrolyte abnormalities related to diarrhea include hypokalemic metabolic acidosis caused by bicarbonate and potassium losses in stool.

Bloody diarrhea is a concerning symptom. The most common cause is infection, especially in a setting of fever and acute onset. If bloody diarrhea is progressive and persistent, chronic inflammatory causes should be considered. The age of the patient is also important. In infants, milk protein–induced enterocolitis is a common cause of bloody stools.

Etiology And Pathogenesis

The most common cause of acute diarrhea is infection (see Chapter 96). In young children, this is most often viral, with the most common agents being rotavirus, adenovirus, astrovirus, and norovirus. Norovirus causes 60% to 90% of nonbacterial gastroenteritis in the United States, affecting 23 million Americans each year. Rotavirus is a leading cause of death in children younger than 5 years of age worldwide. In immunocompromised hosts, viruses, including cytomegalovirus, Epstein-Barr virus, and BK virus, should be considered. It is estimated that 70% of infectious diarrhea is foodborne, and thus a detailed history of exposures is very important (Table 111-1). Exposure to untreated water may cause giardiasis. Use of public swimming pools poses a risk of Shigella, Giardia, Cryptosporidium, and Entamoeba infection, with the last three being chlorine resistant. Home pets can transmit infections. For example, turtles carry Salmonella spp. History of foreign travel may narrow exposures based on the specific destination. The most common etiology of traveler’s diarrhea remains enterotoxigenic Escherichia coli. Cryptosporidium and Giardia spp. are responsible for most parasitic infections in developed countries. Cyclospora outbreaks have occurred in the United States. Clostridium difficile infection, previously thought to affect only hospitalized patients or those taking antibiotics, is now responsible for 40% of community-acquired diarrhea. A recent increase in C. difficile infections has been observed, some attributable to the resistant strain, BI/NAP1. An overgrowth of toxin-producing Clostridium organisms causes pseudomembranous colitis, which may be a potentially life-threatening condition. Vibrio cholerae remains a cause of illness and death in war zones and developing countries. The mechanism of infectious diarrhea is primarily secretory. It can quickly lead to electrolyte abnormalities and acidosis. Infection may result in villous atrophy, which can add an osmotic component. Mucosal healing after infection may lead to transient postinfectious diarrhea.

Table 111-1 Foodborne Infectious Agents

Several other causes of acute diarrhea, particularly in afebrile children, may be particularly concerning. Intussusception, a telescoping of two segments of bowel that occurs mostly in children between 6 months and 2 years of age, may present with bloody diarrhea (see Chapter 109). The typical presentation is colicky abdominal pain, vomiting, and an abdominal mass. “Currant jelly” stools do not occur in all patients with intussusception but are pathognomonic for the condition. Hemolytic-uremic syndrome (HUS) is an uncommon but potentially fatal illness that may present with acute bloody diarrhea. HUS begins as a mild gastroenteritis that evolves into hematochezia, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (see Chapter 64). Less commonly, appendicitis may present with abdominal pain and diarrhea as a result of colonic irritation from the inflamed appendix (see Chapter 5).

Other acute causes of diarrhea include inflammatory bowel disease (IBD; see Chapter 110), overfeeding (caused by increased osmotic loads), antibiotic-associated diarrhea (likely caused by changes in bowel flora), extraintestinal infections (otitis media, urinary tract infection, pneumonia), and toxic ingestions.

Clinical Presentation

In any patient presenting with acute diarrhea, a thorough history and physical examination should guide the immediate and subsequent evaluation and therapy. It is important to quantify the duration and frequency of stooling in addition to emesis, liquid intake, and urine output to assess for hydration status. A travel history should be obtained. Recent antibiotic use may suggest pseudomembranous colitis with C. difficile. The presence of abdominal pain may occur in infectious enteritis; however, it may also be indicative of intussusception (colicky, episodic) or appendicitis (periumbilical, right lower quadrant). Bloody diarrhea is usually typical in bacterial enteritis but may be seen in viral illness, HUS, or colitis. Associated vomiting suggests viral gastroenteritis. In infectious diarrhea, there is usually a 1- to 8-day incubation period with a sudden onset of symptoms. There may be associated fever, vomiting, crampy abdominal pain, bloody stools, tenesmus, loss of appetite, and dehydration. The immune state of the child should be determined because an immunocompromised child may present with more unusual organisms.

The physical examination begins with the general appearance of the child—does the child look malnourished or has he or she lost weight? Vital signs then help to guide evaluation and management. Fever usually indicates infection. Pulse and blood pressure changes may indicate dehydration, shock, or sepsis. A careful abdominal examination should look for bowel sounds (to evaluate for obstruction) and masses (to evaluate for intussusception). A stool sample should be guaiac tested for microscopic blood.

Evaluation And Management

Patients should be assessed for hydration status and electrolyte abnormalities, with correction as indicated. Acute viral gastroenteritis often requires aggressive rehydration with intravenous fluids or oral rehydration solutions. Stool should be sent for viral polymerase chain reaction, culture, and C. difficile toxin assay. Most gastrointestinal (GI) infections, except for C. difficile, do not require treatment. Antibiotics tend to prolong diarrhea and result in a carrier state. There are special circumstances, such as Salmonella enteritis in young infants and immunocompromised patients, for which antibiotic therapy is indicated. Most infections resolve in 14 days in healthy children. Antidiarrheal agents are typically not effective and should be avoided in children. Serious complications, such as sepsis, HUS, pancreatitis, urinary tract infection, and perforation, are uncommon.

Etiology And Pathogenesis

Chronic diarrhea manifesting as two to eight large, loose bowel movements per day, occurring during the daytime, in an otherwise healthy and normally growing child is usually attributable to functional diarrhea. Chronic nonspecific diarrhea of childhood (toddler’s diarrhea) most commonly affects young children 6 months to 5 years of age and is typically due to excessive fluid or carbohydrate intake, low fat intake, or rapid transit. Irritable bowel syndrome (IBS) is another cause of functional diarrhea in older children with a prevalence of 11% and is two times more common in girls than boys. Functional diarrhea is mainly caused by osmotic effects of carbohydrates such as sorbitol and fructose or dysmotility with rapid transit.

Figure 111-2 Differential diagnosis of chronic diarrhea.

Congenital diarrheas are rare causes of voluminous, watery stools that present at birth. These disorders include chloride and sodium diarrhea, structural enterocyte abnormalities (e.g., microvillus inclusion disease and intestinal epithelial dysplasia or tufting enteropathy), and disaccharidase malabsorption (e.g., congenital sucrase-isomaltase deficiency and glucose–galactose transporter deficiency). Sodium and chloride diarrhea are autosomal recessive disorders that present at birth with secretory diarrhea in the presence of normal mucosa. In chloride diarrhea, the Cl/HCO₃ exchanger in the brush border membrane is defective, leading to excessive chloride loss in the stool. Sodium diarrhea, which is exceedingly rare, is likely the result of an impaired Na/H exchanger leading to excessive loss of sodium in stool. Microvillous inclusion disease likely involves an intracellular trafficking defect. Congenital disaccharidase deficiencies derive from gene mutations of the involved proteins.

Lactose intolerance (hypolactasia) is an inherited disorder caused by reduced genetic expression of the enzyme lactase-phlorizin hydrolase, which results in carbohydrate malabsorption. It is most common among American Indians and Asians and is least prevalent among Northern Europeans. Congenital hypolactasia is exceedingly rare. Lactase deficiency (a form of disaccharidase deficiency) in enterocytes results in the rapid passage of ingested lactose to the colon, where it is processed by bacterial flora and converted to short-chain fatty acids and hydrogen gas. Lactose malabsorption can also be a secondary process caused by mucosal injury, bacterial overgrowth, or inflammation.

Malabsorption of fat may also result in chronic diarrhea (Figure 111-3). Digestion of protein and fat begins in the oral cavity by salivary amylase and lipase and continues in the duodenum by pancreatic enzymes. Pancreatic enzymes are initially secreted as inactive proenzymes, which are activated by enterokinase, a brush border membrane protease. Enterokinase activates trypsinogen to its active form trypsin, which in turn activates the rest of the digestive enzymes. Lack of enterokinase, colipase, or lipase results in maldigestion of fats, failure to thrive, and steatorrhea. In cystic fibrosis, the secretion of pancreatic enzymes is diminished by hyperviscosity and mucous plugging of ducts. Bile acids participate in fat digestion and absorption by emulsifying long chain fatty acids, allowing them to form chylomicrons, which are then transported to the liver through lymphatics.

Figure 111-3 Malabsorption and celiac disease.

Fat malabsorption can be secondary to bile acid disorders or pancreatic insufficiency. Bile acid disorders include chronic cholestasis, terminal ileum resection, bacterial overgrowth, and primary bile acid malabsorption. Pancreatic insufficiency can result in both fat and protein malabsorption. It can result from cystic fibrosis, recurrent severe inflammation, and syndromes such as Shwachman-Diamond syndrome (short stature, pancreatic insufficiency, neutropenia, skeletal abnormalities). Enterokinase deficiency in the brush border may result in malabsorption caused by impaired activation of pancreatic proenzymes. Abetalipoproteinemia presents shortly after birth with steatorrhea and failure to thrive and if untreated may result in neurologic damage. Diarrhea with protein loss can be caused by a wide spectrum of disorders, including IBD, celiac disease, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, and lymphangiectasia.

Several conditions causing chronic diarrhea are the result of an abnormal immune response to antigens in food or in the GI tract itself. Celiac disease is caused by gluten sensitivity, causing inflammation of the small intestine (see Figure 111-3). In celiac disease, exposure to gluten and its active component gliadin results in an abnormal immune activation. This dietary gluten-triggered immune process leads to villous blunting or flattening, crypt elongation, and lymphocytic infiltration of the lamina propria. This disease affects about 1% of the population and can present any time between infancy and adulthood. It is associated with higher prevalence of HLA DQ2/DQ8; therefore, family history is important. It is also more common in the setting of Down’s syndrome, type 1 diabetes, IgA deficiency, Turner’s syndrome, William’s syndrome, and autoimmune thyroiditis. Chronic IBD, including Crohn’s disease and ulcerative colitis, usually presents with slow-onset, sometimes bloody, diarrhea (see Chapter 110). Allergic colitis, which is often the result of milk or soy allergy, may present as bloody or nonbloody diarrhea in infants. Food allergies resulting in malabsorption may be caused by eosinophilic gastroenteritis (Figure 111-4). This disorder is often associated with multiple food proteins and other atopic conditions, such as asthma, eczema, and allergic rhinitis. Mechanisms of eosinophilic disorders that are associated with eosinophilic infiltration of various parts of the GI tract are poorly understood. They seem to involve an interaction among genetic predisposition, environmental exposures to foods and allergens, immunoglobulin E (IgE)–mediated activation of the immune system, and possible interaction with GI microbiota. Rare immune deficiencies that cause diarrhea include IPEX syndrome, severe combined immune deficiency, and autoimmune enteropathy. IPEX syndrome is caused by a mutation in the FoxP3 gene in T-regulatory cells, resulting in a lack of immune homeostasis. Autoimmune enteropathy, which is associated with antienterocyte antibodies, may occur as part of IPEX but can also be isolated.

Figure 111-4 Eosinophilic gastroenteritis.

Neuroendocrine tumors, such as gastrinoma (Zollinger-Ellison syndrome), carcinoid, and VIPoma (pancreatic cholera), are rare in children and cause secretory diarrhea as a result of overproduction of intestinal hormones. Intestinal anendocrinosis is a rare autosomal recessive disorder that causes severe diarrhea and is associated with type 1 diabetes. In this condition, mutation of neurogenin 3 results in deficient enteroendocrine cells perturbing the balance of fluid secretion and absorption, which in turn results in malabsorptive diarrhea.

Motility disorders are both diagnostically and therapeutically complex. They can be primary or secondary processes. Intestinal motility is controlled by the enteric nervous system which interacts with multiple hormones, neurotransmitters, and extraintestinal stimuli. Hyperthyroidism is a common cause of alterations in intestinal dysmotility leading to mild to moderate diarrhea. Rapid transit time may be the result of increased neuronal stimulation. Lack of proper peristalsis may lead to bacterial overgrowth with associated diarrhea. Hyperthyroidism is associated with rapid transit, hypersecretion, increased adrenergic stimulation, and possibly a small degree of fat malabsorption secondary to rapid transit.

Clinical Presentation And Evaluation

Management