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 Secretory diarrhea is usually associated with large volumes of watery stools and persists when oral food is withdrawn.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 in those ≥5 yr. The disease is the same with a slightly different age presentation, in that abdominal pain is more common and clearly associated with the diarrhea in older children. The hallmark of the syndrome is diarrhea associated with normal weight growth in well-appearing subjects. In younger children diarrhea is often watery, at times containing undigested food particles. It is usually more severe in the morning. If the child’s fluid intake is >150 mL/kg/24 hr, fluid intake should be reduced to no more than 90 mL/kg/24 hr. The child is often irritable in the first 2 days after the fluid restriction; however, persistence with this approach for several more days results in a decrease in the stool frequency and volume. If the dietary history suggests that the child is ingesting significant amounts of fruit juices, then the offending juices should be decreased. Sorbitol, which is a nonabsorbable sugar, is found in apple, pear, and prune juices and it can cause diarrhea in toddlers. Apple and pear juices contain higher amounts of fructose than glucose, a feature postulated to cause diarrhea in toddlers. In older children, irritable bowel syndrome is often associated with abdominal pain and may be related to anxiety, depression, and other psychologic disturbances.

The most severe etiology includes a number of heterogeneous conditions leading to the intractable diarrhea syndrome, which is often the result of a permanent defect in the structure or function of intestine, leading to progressive, often irreversible intestinal failure, requiring parenteral nutrition for survival. The main etiologies of intractable diarrhea include structural enterocyte defects, disorders of intestinal motility, immune-based disorders, short gut, and multiple food intolerance. The genetic and molecular bases of many etiologies of intractable diarrhea have been recently identified (Table 333-2).

Structural enterocyte defects are due to specific molecular defects responsible for early-onset severe diarrhea. In microvillus inclusion disease, microvilli are sequestered in vacuoles as a consequence of autophagocytosis due to a mutation in myosin that impairs apical protein trafficking leading to aberrant brush border development (Fig. 333-3). Intestinal epithelial dysplasia (or tufting enteropathy) is characterized by disorganization of surface enterocytes with focal crowding and formation of tufts. Abnormal deposition of laminin and heparan sulfate proteoglycan on the basement membrane has been detected in intestinal epithelia. An abnormal intestinal distribution of α₂β₁ and α₆β₄ integrins has been implicated in tufting enteropathy. These ubiquitous proteins are involved in cell-cell and cell-matrix interactions, and they play a crucial role in cell development and differentiation.

Figure 333-3 Microvillus inclusion disease. A, From top to bottom: microvillus inclusion (a), a granule with few microvilli (b), and a lysosome (c) detected in the same enterocyte. Inset: higher magnification of b and c ×11,000, inset ×21,500. B, PAS staining highlights abundant PAS-positive material (arrows) in the apical part of the enterocyte cytoplasm. C, The villous enterocyte lack brush-border microvilli, whereas their apical cytoplasm contains a microvillus inclusion (MI) and numerous lysosomes (L) ×5,500.

(A From Morroni M, Cangiotti AM, Guarino A, et al: Unusual ultrastructural features in microvillous inclusion disease: a report of two cases, Virchows Archiv 448:805–810, 2006.)

Electrolyte transport defects are a subgroup of structural enterocyte defects that include congenital chloride diarrhea, in which a mutation in the solute carrier family 26 member 3 gene (SLC26A3) leads to severe intestinal Cl⁻ malabsorption due to a defect or absence of the Cl⁻/HCO₃⁻ exchanger. The consequent defect in bicarbonate secretion leads to metabolic alkalosis and acidification of the intestinal content, with further inhibition of Na⁺/H⁺ exchanger–dependent Na⁺ absorption. Patients with congenital sodium diarrhea show similar clinical features because of a defective Na⁺/H⁺ exchanger in the small and large intestine, leading to massive Na⁺ fecal loss and severe acidosis.

Multiple food protein hypersensitivity is regarded as a cause of intractable diarrhea syndrome. However, this is usually a diagnosis of exclusion and is based on a relationship between any ingested food and diarrhea. In most cases, multiple food intolerance is not ultimately confirmed by oral challenge, and most children are eventually able to return to a free diet.

Autoimmune processes can target the intestinal epithelium, alone or in association with extraintestinal symptoms. Autoimmune enteropathy is characterized by the production of anti-enterocyte and anti-goblet cell antibodies, primarily IgG, directed against components of the enterocyte brush border or cytoplasm and by a cell-mediated autoimmune response with mucosal T-cell activation. An X-linked immune dysregulation, polyendocrinopathy and enteropathy (IPEX) syndrome is associated with variable phenotypes of chronic diarrhea.

Abnormal immune function, as seen in patients with agammaglobulinemia, isolated immunoglobulin A deficiency, and combined immunodeficiency disorders, can result in persistent infectious diarrhea.

Phenotypic diarrhea, also defined as syndromic diarrhea or tricho-hepato-enteric syndrome, is a rare disease presenting with facial dysmorphism, woolly hair, severe diarrhea, and malabsorption (Fig. 333-4). Half of the patients have liver disease.

Figure 333-4 A child with phenotypic diarrhea showing facial dysmorphism, hypertelorism, and woolly hair. Etiology is unknown, but the presence of affected siblings suggests an autosomal recessive transmission.

Disorders of intestinal motility include derangements of development and function of the enteric nervous system, such as in Hirschsprung disease and chronic idiopathic intestinal pseudo-obstruction (which encompass both the neurogenic and the myogenic forms). Other motility disorders may be secondary to extraintestinal disorders, such as in hyperthyroidism and scleroderma. Motility disorders are associated with either constipation or diarrhea or both, with the former usually dominating the clinical picture.

Short bowel syndrome (Chapter 330.7) is the single most common etiology of diarrhea and intestinal failure. Many intestinal abnormalities such as stenosis, segmental atresia, and malrotation can require surgical resection. In these conditions the residual intestine may be insufficient to carry on its digestive-absorptive functions. Alternatively, small bowel bacterial overgrowth can cause diarrhea, such as in the blind loop syndrome.

In rare cases of severe chronic diarrhea, the gastrointestinal symptoms may be the initial manifestation of a mitochondrial disease or another metabolic disorder, namely carbohydrate-deficient glycoproteins. Finally, when the cause of the diarrhea is undetermined and the clinical course is inconsistent with organic disorders, factitious disorder by proxy (formerly Munchausen syndrome by proxy) should be considered.

The natural history of intractable diarrhea is related to the primary intestinal disease. Food intolerances generally resolve in a few weeks or months, as does autoimmune enteropathy when appropriate immune suppression is started. Children with motility disorders have long-lasting stable symptoms that are rarely fatal, whereas those with structural enterocyte defects never recover, undergoing a more-severe course and often becoming candidates for intestinal transplantation.

Evaluation of Patients

Because of the wide spectrum of the etiologies, the medical approach should be based on diagnostic algorithms that begin with the age of the child, evaluate the weight pattern, and then consider clinical and epidemiologic factors, always taking into account the results of microbiologic investigations. The etiology of chronic diarrhea shows an age-related pattern, and an early onset might suggest a congenital and severe condition. In later infancy and up to 2 yr of age, infections and allergies are more common, whereas inflammatory diseases are more common in older children and adolescents. Celiac disease on the one hand, and chronic nonspecific diarrhea on the other, should always be considered independent of age owing to their relatively high frequency (Table 333-3).

Table 333-3 MAIN CAUSES OF CHRONIC DIARRHEA ACCORDING TO THE AGE OF ONSET*

* In addition to all the diseases listed in Table 333-2.

^† Age range 0-4 years.

^‡ Age range 5-18 years.

Specific clues in the family and personal history may provide useful indications, suggesting a congenital, allergic or inflammatory etiology. A previous episode of acute gastroenteritis suggests postenteritis syndrome, whereas the association of diarrhea with specific foods can indicate a food allergy. A history of polyhydramnios is consistent with congenital chloride or sodium diarrhea or, conversely, cystic fibrosis. The presence of eczema or asthma is associated with an allergic disorder, whereas specific extraintestinal manifestations (e.g., arthritis, diabetes, thrombocytopenia) might suggest an autoimmune disease. Specific skin lesions can suggest acrodermatitis enteropathica. Typical facial abnormalities and woolly hair are associated with phenotypic diarrhea (see Fig. 333-4).

Anthropometric evaluation is an essential step to evaluate “if, since when, and how much” diarrhea has affected body weight. The combined evaluation of the duration and amount of weight loss provides an estimate of the severity of diarrhea.

Initial clinical examination should include evaluating general and nutritional status. Dehydration, marasmus, or kwashiorkor requires prompt supportive interventions to stabilize the patient. Nutritional evaluation is crucial to establish the need for rapid intervention. It should start with the evaluation of the weight and height curves and of the weight for height index to determine the impact of diarrhea on growth. Weight is generally impaired before height, but with time linear growth also becomes affected, and both parameters may be equally abnormal in the long term. Assessment of nutritional status includes the dietary history and biochemical and nutritional investigations. Caloric intake should be quantitatively determined and the relationship between weight modifications and energy intake should be carefully considered.

Biochemical markers assist in grading malnutrition (Table 333-4). The half -life of serum proteins can differentiate between short-term and long-term malnutrition. Assessment of body composition may be performed by measuring mid-arm circumference and triceps skinfold thickness or, more accurately, by bioelectrical impedance analysis or dual emission x-ray absorptiometry (DEXA) scans.

Diagnosis of functional diarrhea is based on pure clinical grounds using established age-related criteria (see Table 333-3). Conversely, a child with persistent diarrhea and suspected malabsorption might be inappropriately “treated” with a diluted hypocaloric diet in an effort to reduce the diarrhea, and persistent diarrhea may be an indirect consequence of ongoing malnutrition. One such example of this vicious cycle is exocrine pancreatic insufficiency due to protein calorie malnutrition.

The search for etiology may be based on the pathophysiology of the diarrhea. Fecal electrolyte concentrations discriminate between secretory and osmotic diarrhea, and the results can guide the subsequent diagnostic approach. Microbiologic investigation of stool samples should include a thorough list of bacterial, viral, and protozoan agents. Proximal intestinal bacterial overgrowth may be sought using the hydrogen breath test after an oral glucose load.

Noninvasive assessment of digestive-absorptive functions and of intestinal inflammation plays a key role in the diagnostic work-up (Table 333-5).

Diagnostic work-up of chronic diarrhea usually requires endoscopy and histology. Small intestinal biopsy can detect a primary intestinal etiology in the majority of cases of chronic diarrhea and malabsorption. Colonoscopy should be performed in all cases of chronic diarrhea in which gross blood or leukocytes are detected in the stools or when an increased frequency of mucoid stools and abdominal pain suggest colonic involvement. Abnormalities in the digestive-absorptive function tests suggest small bowel involvement, whereas intestinal inflammation, as demonstrated by increased calprotectin and rectal nitric oxide, supports a distal intestinal localization. Capsule endoscopy allows exploration of the entire intestine looking for morphologic abnormalities, inflammation, and bleeding.

Biopsies should be performed at multiple sites, even in a normal-appearing intestine, because abnormalities can have a patchy distribution. Histology is important to establish the degree of mucosal involvement through grading of intestinal damage and the evaluation of associated abnormalities, such as inflammatory infiltration of the lamina propria. Morphometry provides additional quantitative information of epithelial changes. In selected cases, light microscopy can help to identify specific intracellular agents, such as cytomegalovirus, based on the presence of parasites or of large inclusion bodies in infected cells. Electron microscopy is essential to detect cellular structural abnormalities such as microvillous inclusion disease. Immunohistochemistry allows the study of mucosal immune activation as well as of other cell types (smooth muscle cells and enteric neuronal cells), and the components of the basal membrane.

Imaging has a major role in the diagnostic approach. A preliminary plain abdominal x-ray is useful for detecting gaseous distention that suggests intestinal obstruction. Intramural or portal gas may be seen in necrotizing enterocolitis or intussusception. Structural abnormalities such as diverticula, malrotation, stenosis, blind loop, and inflammatory bowel disease, as well as motility disorders, may be appreciated after a barium meal and an entire bowel follow-through examination. The latter also provides information on transit time. Abdominal ultrasound can help detect liver and pancreatic abnormalities or an increase in intestinal wall thickness that suggests an inflammatory bowel disease.

Specific investigations should be carried out for specific diagnostic dilemmas. Prick and patch test can support a diagnosis of food allergy, although definitive diagnosis requires oral challenge. Bile malabsorption may be explored by the retention of the bile acid analog ⁷⁵Se–homocholic acid–taurine (⁷⁵SeHCAT) in the enterohepatic circulation. A scintigraphic examination, with radio-labeled octreotide is indicated in suspected APUD (amine precursor uptake and decarboxylation) cell neoplastic proliferation. In other diseases, specific imaging techniques such as CT or nuclear MRI can have important diagnostic value.

Once infectious agents have been excluded and nutritional assessment performed, a stepwise approach to the child with chronic diarrhea may be applied. The main etiologies of chronic diarrhea should be investigated based on the features of diarrhea and their predominant or selective intestinal dysfunction. A step-by-step diagnostic approach is important to minimize the unnecessary use of invasive procedures and overall costs, while optimizing the yield of the diagnostic work-up (Table 333-6, Fig. 333-5).

Figure 333-5 General therapeutic approaches to management of chronic diarrhea. HT, height.

Treatment

Chronic diarrhea associated with impaired nutritional status should always be considered a serious disease, and therapy should be started promptly. Treatment includes general supportive measures, nutritional rehabilitation, elimination diet, and drugs. Drug treatment includes therapies for specific etiologies as well as interventions aimed at counteracting fluid secretion and/or promoting restoration of disrupted intestinal epithelium. Because death in most instances is caused by dehydration, replacement of fluid and electrolyte losses is the most important early intervention.

Nutritional rehabilitation is often essential and is based on clinical and biochemical assessment. In moderate to severe malnutrition, caloric intake may be progressively increased to 50% or more above the recommended dietary allowances. The intestinal absorptive capacity should be monitored by digestive function tests. In children with steatorrhea, medium chain triglycerides may be the main source of lipids. A lactose-free diet should be started in all children with chronic diarrhea, as is recommended by the World Health Organization (WHO). Lactose is generally replaced by maltodextrin or a combination of complex carbohydrates. A sucrose-free formula is indicated in sucrase-isomaltase deficiency. Semi-elemental or elemental diets have the double purpose of overcoming food intolerance, which may be the primary cause of chronic diarrhea, and facilitating nutrient absorption. The sequence of elimination should be graded from less to more restricted diets, such as cow’s milk protein hydrolysate to amino-acid–based formula, depending on the child’s situation. In severely compromised infants it may be convenient to start with amino-acid–based feeding.

Clinical nutrition includes enteral or parenteral nutrition. Enteral nutrition may be delivered via nasogastric or gastrostomy tube and is indicated in a child who cannot be fed through the oral route, either because of primary intestinal diseases or because of extreme weakness. Continuous enteral nutrition is effective in children with a reduced absorptive function, such as short bowel syndrome, because it extends the time of nutrient absorption through the still-functioning surface area. In extreme wasting, enteral nutrition might not be sufficient, and parenteral nutrition is required.

Micronutrient and vitamin supplementation are part of nutritional rehabilitation and prevent further problems, especially in malnourished children from developing countries. Zinc supplementation is an important factor in both prevention and therapy of chronic diarrhea, because it promotes ion absorption, restores epithelial proliferation, and stimulates immune response. Nutritional rehabilitation has a general beneficial effect on the patient’s overall condition, intestinal function, and immune response and can break the vicious circle shown in Figure 333-2.

Drug therapy includes anti-infectious drugs, immune suppression, and drugs that can inhibit fluid loss and promote cell growth. If a bacterial agent is detected, specific antibiotics should be prescribed. Empirical antibiotic therapy may be used in children with small bowel bacterial overgrowth or with suspected bacterial diarrhea. Trimethoprim-sulfamethoxazole, metronidazole or albendazole, and nitazoxanide have a broad pattern of targets, including parasites. In Rotavirus-induced severe and protracted diarrhea, oral administration of human immunoglobulins (300 mg/kg) should be considered.

Immune suppression should be considered in selected conditions such as autoimmune enteropathy. In selected cases, biologic immune suppression may be considered.

Treatment may be also directed at modifying specific pathophysiologic processes. Severe ion secretion may be reduced by pro-absorptive agents, such as the enkephalinase inhibitor racecadotril. In diarrhea due to neuroendocrine tumors, microvillus inclusion disease, and enterotoxin-induced severe diarrhea, a trial with the somatostatin analog octreotide may be considered. Zinc or growth hormone promote enterocyte growth and ion absorption and may be effective when intestinal atrophy and ion secretion are associated.

When other attempts have failed, the only option may be parenteral nutrition or intestinal transplantation.