Chronic Diarrhea

Definition and Epidemiology

Chronic diarrhea is defined as a diarrheal episode that lasts for ≥14 days. Its epidemiology has 2 distinct patterns. In developing countries, chronic diarrhea is often the result of an intestinal infection that lasts longer than expected. This syndrome is often defined as protracted diarrhea, and there is no clear distinction between protracted and chronic diarrhea. In countries with high socioeconomic conditions, chronic diarrhea is less common and its etiology is more diverse, showing an age-related pattern. The outcome of diarrhea depends on its cause and ranges from benign conditions such as toddler’s diarrhea, to severe congenital diseases such as microvillus inclusion disease that can lead to irreversible intestinal failure and ultimately death.

Pathophysiology

The mechanisms of diarrhea are generally divided into secretory and osmotic, but often diarrhea is the result of both mechanisms. Secretory diarrhea is usually associated with large volumes of watery stools and persists when oral food is withdrawn. Osmotic diarrhea is dependent on oral feeding, and stool volumes are usually not as massive as in secretory diarrhea (Fig. 333-1).

Figure 333-1 Pathways of osmotic and secretory diarrhea. Osmotic diarrhea is due to functional or structural damage of intestinal epithelium. Nonabsorbed osmotically active solutes drive water into the lumen. Stool osmolality and ion gap are generally increased. Diarrhea stops in children when they are not eating. In secretory diarrhea, ions are actively pumped into the intestine by the action of exogenous and endogenous secretagogues. Usually there is no intestinal damage. Osmolality and ion gap are within normal levels. Large volumes of stools are lost independent of food ingestion.

Secretory diarrhea is characterized by active electrolyte and water fluxes toward the intestinal lumen, resulting from either the inhibition of neutral NaCl absorption in villous enterocytes or an increase in electrogenic chloride secretion in secretory crypt cells due to the opening of the cystic fibrosis transmembrane regulator (CFTR) chloride channel. The other components of the enterocyte ion secretory machinery are the Na-K-2Cl cotransporter for the electroneutral chloride entrance into the enterocyte; the Na-K pump, which decreases the intracellular Na⁺ concentration, determining the driving gradient for further Na⁺ influx; and the K⁺ selective channel, which enables K⁺, once it has entered the cell in together with Na⁺, to return to the extracellular fluid.

Electrogenic secretion is induced by an increase of intracellular concentration of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), or calcium in response to microbial enterotoxins or to endogenous endocrine or nonendocrine moieties, including inflammatory cytokines. Another mechanism of secretory diarrhea is the inhibition of the electroneutral NaCl-coupled pathway that involves the Na⁺/H⁺ and the Cl⁻/HCO₃⁻ exchangers. Defects in the genes of the Na⁺/H⁺ and the Cl⁻/HCO₃⁻ exchangers are responsible for congenital Na⁺ and Cl⁻ diarrhea, respectively.

Osmotic diarrhea is caused by nonabsorbed nutrients in the intestinal lumen due to one or more of the following mechanisms: intestinal damage (such as in enteric infection), reduced functional absorptive surface (such as in celiac disease), defective digestive enzyme or nutrient carrier (such as in lactase deficiency), decreased intestinal transit time (such as in functional diarrhea), and nutrient overload exceeding the digestive capacity. Osmotic diarrhea occurs whenever digestion or absorption is impaired. Whatever the mechanism, the osmotic force generated by nonabsorbed solutes drives water into the intestinal lumen. An example of osmotic diarrhea is lactose intolerance. Lactose, if not absorbed in the small intestine, reaches the colon, where it is fermented to short-chain organic acids, generating an osmotic overload that overwhelms the absorptive capacity.

In many children, chronic diarrhea is induced by multiple mechanisms, intersecting each other and often producing a vicious cycle. A paradigm of chronic diarrhea generated by multiple mechanisms is provided by HIV infection, in which immune derangement, enteric infections, nutrient malabsorption, and intestinal damage, together with a direct enteropathogenic role of HIV, trigger and maintain chronic diarrhea (Fig. 333-2).

Figure 333-2 HIV directly induces immune impairment and intestinal dysfunction. Intestinal infections and nutrient malabsorption contribute to malnutrition. The latter in turn contributes to immune impairment and intestinal dysfunction. The vicious cycle is responsible for diarrhea and ultimately results in wasting, the terminal stage of AIDS. HIV can also directly induce diarrhea through its transactivating transfer factor Tat.

(From Berni Canani R, Cirillo P, Mallardo G, et al: Effects of HIV-1 Tat protein on ion secretion and on cell proliferation in human intestinal epithelial cells, Gastroenterology 124:368–376, 2003.)

Etiology

A list of the main causes of chronic diarrhea is shown in Table 333-1.

Enteric infections are by far the most common cause of chronic diarrhea in developing and industrialized countries, and sequential infections with the same or a different pathogen may be responsible for prolonged symptoms. Entero-adherent Escherichia coli and Cryptosporidium parvum have been implicated in chronic diarrhea in developing countries. In developed countries chronic infectious diarrhea usually runs a benign course and the etiology is often viral. Rotavirus and Norovirus are often involved, whereas cytomegalovirus and Clostridium difficile are emerging agents of severe diarrhea in children.

Opportunistic microorganisms induce diarrhea exclusively, or more severely, or for more-prolonged periods, in specific populations, such as immunocompromised children. Enteric cryptosporidiosis is the most common cause of severe and protracted diarrhea in AIDS, but HIV may be directly responsible for diarrhea and for HIV enteropathy.

In small intestinal bacterial overgrowth, diarrhea may be the result of either a direct interaction between the microorganism and the enterocyte or the consequence of the deconjugation and dehydroxylation of bile salts and the hydroxylation of fatty acids due to an abnormal proliferation of bacteria in the proximal intestine (Chapter 330.4).

Postenteritis syndrome is a clinical-pathologic condition in which small intestinal mucosal damage persists after acute gastroenteritis. Sensitization to food antigens, secondary disaccharidase deficiency, or an infection or reinfection with an enteric pathogen is responsible for postenteritis syndrome. A change of the gut microflora due to the infectious agent and/or antibiotic therapy can contribute to postenteritis diarrhea.

A reduction of intestinal absorptive surface is responsible for diarrhea in celiac disease, a permanent gluten intolerance that is sustained by a genetic basis affecting as many as 1/100 normal people, depending on geographic origin. Gliadin induces villous atrophy, leading to a reduction of functional absorptive surface area that is reversible upon implementation of a strict gluten-free diet (Chapter 330.2).

Allergy to cow’s milk protein and other foods can manifest with chronic diarrhea, especially during infancy. Eosinophilic gastroenteritis is characterized by eosinophilic infiltration of the intestinal wall and is strongly associated with atopy.

In older children and adolescents, inflammatory bowel disease including Crohn disease, ulcerative colitis, and indeterminate colitis, are major causes of chronic diarrhea.

Chronic diarrhea may be the manifestation of maldigestion due to exocrine pancreatic disorders (Chapter 343). In most patients with cystic fibrosis, pancreatic insufficiency results in fat and protein malabsorption. In Shwachman-Diamond syndrome, exocrine pancreatic hypoplasia may be associated with neutropenia, bone changes, and intestinal protein loss. Specific isolated pancreatic enzyme defects result in fat and/or protein malabsorption. Familial pancreatitis, associated with a mutation in the trypsinogen gene, may be associated with pancreatic insufficiency and chronic diarrhea.

Liver disorders can lead to a reduction in the bile salts, resulting in fat malabsorption. Bile acid loss may be associated with terminal ileum diseases, such as Crohn disease or disease following ileal resection. In primary bile acid malabsorption neonates and young infants present with chronic diarrhea and fat malabsorption due to mutations of ileal bile transporter.

Carbohydrate malabsorption and lactose intolerance may be due to a molecular deficiency of lactase or sucrase-isomaltase, or to congenital glucose-galactose malabsorption. Lactose intolerance is more commonly a consequence of secondary lactase deficiency due to intestinal mucosal damage. A progressive, age-related loss of lactase activity affects about 80% of the nonwhite population and may be responsible for chronic diarrhea in older children receiving cow’s milk.

The most benign etiology is chronic nonspecific diarrhea that encompasses functional diarrhea (or toddler’s diarrhea) in children <4 yr of age and irritable bowel syndrome