Chronic Diarrhea

The mechanisms of diarrhea are generally divided into secretory and osmotic, but often diarrhea is a combination of both mechanisms. In addition, inflammation and motility disorders may contribute to diarrhea. Secretory diarrhea is usually associated with large volumes of watery stools and persists when oral feeding is withdrawn. Osmotic diarrhea is dependent on oral feeding, and stool volumes are usually not as massive as in secretory diarrhea (Fig. 341-1).

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 as a result of the opening of the cystic fibrosis transmembrane regulator (CFTR) chloride channel or both. The result is more secretion from the crypts than absorption in the villous that persists during fasting. The other components of the enterocyte ion secretory machinery are (1) the Na-K 2Cl cotransporter for the electroneutral chloride entrance into the enterocyte; (2) the Na-K pump, which decreases the intracellular Na⁺ concentration, determining the driving gradient for further Na⁺ influx; and (3) the K⁺ selective channel, that enables K⁺, once it has entered the cell together with Na⁺, to return to the extracellular fluid.

Electrogenic secretion is induced by an increase of intracellular concentration of cyclic adenosine monophosphate, cyclic guanosine monophosphate, 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 as a result of 1 or more of the following mechanisms: (1) intestinal damage (e.g., enteric infection); (2) reduced absorptive surface area (e.g., active celiac disease); (3) defective digestive enzyme or nutrient carrier (e.g., lactase deficiency); (4) decreased intestinal transit time (e.g., functional diarrhea); and (5) nutrient overload, exceeding the digestive capacity (e.g., overfeeding, sorbitol in fruit juice). Whatever the mechanism, the osmotic force generated by nonabsorbed solutes drives water into the intestinal lumen. A very common 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, releasing hydrogen that is detected in the lactose breath test, and generating an osmotic overload. In many children chronic diarrhea may be caused by multiple mechanisms.

Etiology

Enteric infections are by far the most frequent cause of chronic diarrhea, both in developing and industrialized countries but, outcomes are often very different. In the former, comorbid conditions, such as HIV/AIDS, malaria, or tuberculosis, result in malnutrition that impairs the child's immune response, thereby potentiating the likelihood of prolonging diarrhea or acquiring another enteric infection. In children with HIV/AIDS, the viral infection itself impairs immune function and may trigger a vicious circle with malnutrition. Sequential infections with the same or different pathogens may also be responsible for chronic diarrhea.

In developing countries, enteroadherent Escherichia coli and Giardia lamblia have been implicated in chronic diarrhea, whereas, in developed countries, chronic infectious diarrhea usually runs a more benign course and the etiology is often viral, with a major role of rotavirus and norovirus (Table 341-1). Opportunistic microorganisms induce diarrhea exclusively, more severely or for more prolonged periods, in specific populations, such as immunocompromised children. Specific agents cause chronic diarrhea or exacerbate diarrhea in many chronic diseases. Clostridium difficile or cytomegalovirus act as opportunistic agents in oncologic patients as well as in patients with inflammatory bowel diseases. Cryptosporidium may induce severe and protracted diarrhea in AIDS patients.

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 deconjugation and dehydroxylation of bile salts, and hydroxylation of fatty acids due to an increased proliferation of bacteria in the proximal intestine. Postenteritis diarrhea syndrome is a clinicopathologic condition in which small intestinal mucosal damage persists after acute gastroenteritis. Sensitization to food antigens, secondary disaccharidase deficiency, persistent infections, reinfection with an enteric pathogen, or side effects of medication may be responsible for causing postenteritis diarrhea syndrome, thought to be related to perturbations of the intestinal microbiome. Functional diarrhea which may be related to the pathogenesis of irritable bowel syndrome may be caused by complications of an acute gastroenteritis. Noninfectious chronic diarrhea is the manifestation of a broad number of heterogeneous conditions that vary with the age of the patient (Table 341-2; see also Table 336-5).

A reduction of intestinal absorptive surface is responsible for diarrhea in celiac disease, a genetically determined permanent gluten intolerance that affects as many as 1 in 100 individuals, depending on geographic origin. In the genetically susceptible host, gliadin, the major protein of gluten, reacts with the immune system to cause villous atrophy. The reduction of functional absorptive surface area is reversible upon restriction of gluten from the diet. Celiac disease presents with more severe intestinal symptoms in younger children. Allergy to cow's milk protein and other food proteins also may present during infancy with chronic diarrhea. Eosinophilic gastroenteritis is characterized by eosinophilic infiltration of the intestinal wall and is strongly associated with atopy. However, whereas diarrhea in food allergy responds to withdrawal of the responsible food, this does not always occur in eosinophilic gastroenteritis, in which immune suppression may be needed.

Lactose intolerance or carbohydrate malabsorption may be caused by a brush-border enzyme defect in lactase, sucrase-isomaltase, or to a defect in the sodium/glucose cotransporter protein (SGLT1) that is transcribed from the SLC5A1 gene causing congenital glucose-galactose malabsorption. The result of these genetic mutations is chronic diarrhea. More commonly, lactose intolerance is secondary to lactase deficiency caused by intestinal mucosal damage. Depending on ethnicity, a progressive, age-related, loss of lactase activity may begin around age 7 yr and affects approximately 80% of the nonwhite population, and acquired hypolactasia may be responsible for chronic diarrhea in older children receiving cow's milk (adult-type lactase deficiency).

In older children and adolescents, inflammatory bowel diseases, including Crohn disease, ulcerative colitis, and inflammatory bowel disease–undetermined, cause chronic diarrhea that is often associated with abdominal pain, elevated inflammatory markers, and increased concentrations of fecal calprotectin or lactoferrin (see Chapter 336). The age of onset of inflammatory bowel disease is broad, with rare cases described in the 1st few mo of life, but the peak incidence in childhood occurring in adolescence. The severity of the symptoms is highly variable with a pattern characterised by long periods of well-being followed by exacerbations. Growth retardation and delays in sexual maturation may precede the onset of gastrointestinal symptoms by up to 18 mo.

Chronic diarrhea may be the manifestation of maldigestion caused by exocrine pancreatic disorders. In most patients with cystic fibrosis, exocrine pancreatic insufficiency results in steatorrhea and protein malabsorption. In Shwachman-Diamond syndrome, exocrine pancreatic hypoplasia may be associated with neutropenia, bone changes, and intestinal protein-losing enteropathy. Specific isolated pancreatic enzyme defects, such as lipase deficiency, result in fat and/or protein malabsorption. Familial pancreatitis, associated with a mutation in the trypsinogen gene, may be associated with exocrine pancreatic insufficiency and chronic diarrhea. Mutations in CFTR, CTRC, PRSS1, SPINK 1, and SPINK 5 are all associated with hereditary pancreatitis.

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

The most benign etiology of chronic diarrhea is nonspecific diarrhea that encompasses functional diarrhea (or toddler's diarrhea) in children younger than 4 yr of age and irritable bowel syndrome in those 5 yr of age and older. The diseases fall under the umbrella of functional disorders, in that in older children abdominal pain is often associated with diarrhea alternating with constipation and growth and weight gain are normal.

Diarrhea may be the result from an excessive intake of fluid and carbohydrate. If the child's fluid intake were >150 mL/kg/24 hr, fluid intake should be reduced not to exceed 90 mL/kg/24 hr. The child is often irritable in the 1st days of the fluid restriction; however, persistence results in a decrease in the stool frequency and volume. If the dietary history suggests that the child is ingesting significant amounts of fruit juice, especially apple juice, then the consumption of juice should be decreased. Sorbitol, which is a nonabsorbable sugar, is found in apple, pear, and prune juices, and often causes diarrhea in toddlers. Moreover, 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 of chronic diarrhea includes a number of heterogeneous congenital conditions leading to syndromes related to intractable diarrhea. This is often the result of a permanent defect in the structure or function of the enterocyte, leading to progressive, potentially irreversible intestinal failure. The main etiologies of intractable diarrhea include structural enterocyte defects, disorders of intestinal motility, immune-based disorders, short gut syndrome, and disorders without demonstrable abnormalities.

Structural enterocyte defects are caused by specific molecular defects responsible for early onset, severe diarrhea. In microvillus inclusion disease, microvilli are sequestered in vacuoles as a consequence of autophagocytosis because of a defect in protein trafficking disrupting enterocyte polarity (Fig. 341-2). Intestinal epithelial dysplasia (or tufting enteropathy) is caused by focal crowding of enterocytes that produce epithelial abnormalities resembling tufts (tears). 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 is implicated in tufting enteropathy. These ubiquitous proteins are involved in cell–cell and cell–matrix interactions, and play a crucial role in cell development and differentiation.

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 from a defect in 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. Familial diarrhea syndrome caused by a mutation guanylate cyclase-C is characterized by abdominal pain, dysmotility, and inflammation coupled with mild secretory diarrhea.

Disorders of intestinal motility include abnormal development and function of the enteric nervous system, such as in Hirschsprung disease and chronic idiopathic intestinal pseudoobstruction (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.

Autoimmune processes may target the intestinal epithelium, alone or in association with extraintestinal symptoms. Autoimmune enteropathy is associated with the production of antienterocyte and antigoblet cell antibodies, primarily immunoglobulin A, but also immunoglobulin G, 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 gene mutations and phenotypes of chronic diarrhea. Other immunoregulatory defects, found in patients with agammaglobulinemia, isolated immunoglobulin A deficiency, and combined immunodeficiency disorders, may result in persistent infectious diarrhea.

Phenotypic diarrhea, also defined as syndromic diarrhea or trichohepatoenteric syndrome, is a rare disease presenting with facial dysmorphism, woolly hair, severe diarrhea, and malabsorption (Fig. 341-3). Half of the patients have liver disease.

Short bowel syndrome is the single most frequent etiology of chronic diarrhea and intestinal failure (see Chapter 338.7). Many intestinal abnormalities such as stenosis, segmental atresia, and malrotation may require surgical resection, but the most frequent primary cause of short bowel is necrotizing enterocolitis. In these conditions, the residual intestine may be insufficient to carry on its digestive–absorptive functions. Rarely, a child may be born with a congenitally short small bowel resulting in delayed growth. In rare cases of severe chronic diarrhea, the gastrointestinal symptoms may be the initial manifestation of mitochondrial disease, carbohydrate deficient glycoproteins, or a primary immune deficiency. Multiple food protein hypersensitivity also is included in the list of causes of protracted diarrhea syndrome. The disease is believed to be the result of a reaction against specific proteins contained in foods. Diarrhea often resolves with fasting or when an amino-acid–based formula is started. Although most children with food intolerance in infancy are eventually able to resume a regular diet, some require restrictions throughout their lives. When the cause of the diarrhea remains undetermined and the clinical course is inconsistent with organic disorders, factitious disorder by proxy should be considered.

Genetic and Molecular Basis of the Protracted Diarrhea Syndrome

The genetic and molecular basis of many causes of protracted diarrhea have been identified recently and a new classification of congenital diarrheal disorders (CDDs) has been proposed (Table 341-3). CDDs are a group of rare, but severe enteropathies, with a similar clinical presentation despite a different outcome. However, diarrhea is the result of structural and functional abnormalities resulting in either secretory or osmotic diarrhea. Often diarrhea presents at birth or shortly thereafter, but in milder forms diarrhea may go unrecognized for years. CDDs are rare diseases, however in most specific disorders the specific genetic defect and transmission are known. Hereditary fructose intolerance is associated with mutations in the ASDOB gene that encodes for the aldolase B enzyme that is found primarily in the liver and is involved in the metabolism of fructose. Individuals with hereditary fructose intolerance may have nausea, abdominal pain/bloating, vomiting, diarrhea, and hypoglycemia. Continued ingestion of fructose results in hepatomegaly and eventually cirrhosis. The incidence of hereditary fructose intolerance is estimated to be 1 in 20,000-30,000. In contrast, fructose malabsorption is common in Western countries with estimates as high as 40% of the population. These individuals cannot absorb fructose and often develop bloating, abdominal pain, diarrhea, and flatulence. They do not have liver disease.

The incidence of other genetic disorders associated with CDD ranges from 1 in 2,500 for cystic fibrosis, 1 in 5,000 for sucrose-isomaltase deficiency, 1 in 60,000 for congenital lactase deficiency, to 1 in 400,000 to trichohepatoenteric syndrome. For most CDDs, such as polyendocrinopathy, X-linked (IPEX) syndrome, or autoimmune polyglandular syndrome type 1, the clinical application of exome sequencing is likely to increase identification of more patients with these rare causes of chronic diarrhea.

Selected CDDs are more frequent in ethnic groups where consanguineous marriages are common, or in some geographic areas because of founder effects. For example, congenital lactase deficiency is more common in Finland; lysinuric protein intolerance has a higher incidence either in Finland and in Japan because of founder effect, and a specific mutation is typically found in each of the 2 ethnic groups. A defect in the DGAT1 gene was identified using whole-exome sequencing in an Ashkenazi Jewish family and associated with the early onset of vomiting and nonbloody diarrhea with protein-losing enteropathy.

Most cases of protracted diarrhea syndrome are not easily treated. The natural history of protracted diarrhea is related to the primary intestinal disease and the specific defect in nutrient absorption. Treatment is more favorable for motility disorders and autoimmune enteropathy than for structural enterocyte defects. Children with motility disorders may have persistent symptoms, but they are rarely fatal; whereas children with structural enterocyte defects have a more severe course, poorer prognosis, and are more likely to be candidates for intestinal transplantation (see Chapter 339). Some late-onset CDDs may be relatively mild and are recognized only later in life.

Evaluation of Patients

Because of the spectrum of etiologies, the medical approach should be based on diagnostic algorithms that begin with assessment for infectious causes, and then consider the age of the child, growth, and clinical and epidemiologic factors. Early onset may suggest a congenital or severe condition. In later infancy and up to 2 yr of age, infections and allergies are more common; inflammatory diseases are more frequent in older children and adolescents. Celiac disease and chronic nonspecific diarrhea should always be considered independently of age because of their relatively high frequency at all ages.

Specific clues in the family and personal history may provide useful indications, suggesting a congenital, allergic or inflammatory etiology. A history of polyhydramnios is consistent with congenital chloride-sodium diarrhea, or cystic fibrosis. An acute onset of diarrhea that runs a protracted course suggests post-enteritis diarrhea or small intestinal overgrowth or the onset of chronic nonspecific diarrhea (toddler's diarrhea). In children, with chronic nonspecific diarrhea there is often a history of an acute gastroenteritis. The association of diarrhea with specific foods may indicate a nutrient basis, such as intolerance to selected nutrients (fructose). Anthropometric evaluation is essential to understand if diarrhea has affected weight gain and growth. The amount of weight loss over time provides an estimate of the severity of diarrhea. Normal weight and growth strongly support functional diarrhea that may respond to simple dietary management.

Initial clinical examination should include the evaluation of general and nutritional status. Dehydration, marasmus, or kwashiorkor require prompt supportive interventions to stabilize the patient. Nutritional evaluation 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 a 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 may assist in grading malnutrition (Table 341-4) as the half-life of serum proteins may distinguish between short- 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 scans. Evaluation of micronutrient concentrations should always be considered. Zinc, magnesium, vitamin A, and folate deficiency are associated with chronic diarrhea and should be provided if needed.

Diagnosis of functional diarrhea is based on clinical assessment using established age-related criteria. It should be noted that a child with functional diarrhea may be inappropriately “treated” with a diluted hypocaloric diet in an effort to reduce the diarrhea, resulting in impaired growth.

The search for an etiology may be based on the relevant causes of diarrhea for the age of the child. Continued diarrhea with fasting or fecal electrolyte concentrations discriminate between secretory and osmotic diarrhea. Associated symptoms and selected investigations provide important diagnostic clues. Signs of general inflammation such as fever, mucoid or bloody stools, and abdominal pain may suggest inflammatory bowel disease. The presence of eczema or asthma is associated with an allergic disorder, whereas specific extraintestinal manifestations (arthritis, diabetes, thrombocytopenia, etc.) may suggest an autoimmune disease. Specific skin lesions may be suggestive of acrodermatitis enteropathica that might respond to zinc replacement. Typical facial abnormalities and woolly hair are associated with phenotypic diarrhea (see Fig. 341-3).

Investigations

Microbiologic investigation should include a thorough list of intestinal bacterial, viral, and protozoan pathogens. Proximal intestinal bacterial overgrowth may be determined using the hydrogen breath test, after an oral glucose or lactulose load, but either substrate may give false results.

Initial investigations of a child with chronic diarrhea should always include an assessment of intestinal inflammation using fecal calprotectin or lactoferrin, and serology for celiac disease (see Chapter 338.2). The role of a mucosal biopsy is determined by the noninvasive diagnostic evaluation in consultation with a pediatric gastroenterologist.

Noninvasive assessment of digestive-absorptive function and of intestinal inflammation plays a key role in the diagnostic work-up (Table 341-5). Abnormalities in the digestive–absorptive function tests suggest small bowel involvement, whereas intestinal inflammation, as demonstrated by increased fecal calprotectin or lactoferrin, supports colitis. Histology is important in establishing mucosal involvement, noting changes in the epithelial cells, or in identifying specific intracellular inclusion bodies caused by pathogens, such as cytomegalovirus, or the presence of parasites. Electron microscopy is essential to detect subcellular structural abnormalities such as microvillous inclusion disease. Immunohistochemistry allows the study of mucosal immunity as well as of other cell types (smooth muscle cells and enteric neuronal cells).

Imaging has a major role in the diagnostic approach. Abdominal ultrasound may help in detecting liver and pancreatic abnormalities or an increase in distal ileal wall thickness that suggests inflammatory bowel disease. A preliminary plain abdominal x-ray is useful for detection of abdominal distention, suggestive of intestinal obstruction, or increased retention of colonic feces. Intramural or portal gas may be seen in necrotizing enterocolitis or intussusception. Structural abnormalities such as diverticula, malrotation, stenosis, blind loop, inflammatory bowel disease, as well as motility disorders, may be investigated through a barium meal and a small bowel follow-through. Capsule endoscopy allows the exploration of the entire intestinal tract searching for structural changes, inflammation or bleeding and the new SmartPill measures pressure, pH, and temperature as it moves through the gastrointestinal tract, assessing motility.

Specific investigations should be carried out for specific diagnostic indications. Prick and patch test may support a diagnosis of food allergy. However, elimination diet with withdrawal of the suspected harmful food from the diet and subsequent challenge is the most reliable strategy by which to establish a diagnosis. 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 cell neoplastic proliferation. In other diseases, specific imaging techniques such as computed tomography, or nuclear magnetic resonance endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography may 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 causes of chronic diarrhea should be investigated, based on the features of the diarrhea and the specific nutrient(s) that is (are) affected. The use of whole-exome sequencing is of benefit in children suspected of having mendelian-related causes of chronic diarrhea. A step-by-step diagnostic approach is important to minimize the unnecessary use of invasive procedures as well as the cost, while optimizing the yield of the diagnostic work-up (Table 341-6).

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 medications. The latter include 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. Potentially harmful nutrients must be identified and avoided. 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 and is recommended by the World Health Organization. Lactose is generally replaced by maltodextrin or a combination of complex carbohydrates. A sucrose-free formula is indicated in sucrase-isomaltase deficiency. Semielemental or elemental diets have the dual purpose of overcoming food intolerance, which may be the primary cause of chronic diarrhea, particularly in infancy and early childhood, and facilitating nutrient absorption. The sequence of elimination should begin from less to more restricted diets, that is, cow's milk protein hydrolysate to amino-acid–based formulas, depending on the child's situation. In severely compromised infants, it may be prudent to start with amino-acid–based feeding.

When oral nutrition is not feasible or fails, enteral or parenteral nutrition should be considered. Enteral nutrition may be performed via nasogastric or gastrostomy tube and is indicated in a child who is not able to be fed orally, either because of inability to tolerate nutrient requirements or because of extreme weakness. Continuous enteral nutrition is effective in children with a compromised absorptive capacity, such as short bowel syndrome where the remaining mucosal surface is intact. In extreme wasting, enteral nutrition may not be tolerated and parenteral nutrition is required.

Micronutrient and vitamin supplementation are part of nutritional rehabilitation, especially in malnourished children in developing countries. Zinc supplementation is important in both prevention and therapy of chronic diarrhea, since it promotes ion absorption, restores epithelial proliferation, and stimulates immune response. Nutritional rehabilitation has a general beneficial effect on the patient's general condition, intestinal function, and immune response.

Functional diarrhea in children may benefit from a diet based on the “4 F” principles (reduce fructose and fluids, increase fat and fiber). Probiotics have been used with some success as adjunctive therapy based on the evidence that changes in intestinal microflora might be beneficial in several other intestinal diseases.

Pharmacologic therapy includes antiinfectious drugs, immune suppression, and drugs that may inhibit fluid loss and promote cell growth. If a bacterial agent is detected, specific antibiotics should be prescribed. Empiric antibiotic therapy may be used in children with either small bowel bacterial overgrowth or with suspected infectious diarrhea. Table 341-7 summarizes the treatment of postinfectious persistent diarrhea. Immune suppression should be considered in selected conditions such as autoimmune enteropathy.

Treatment may be also directed at modifying specific pathophysiologic processes. Secretion of ions may be reduced by proabsorptive agents, such as the enkephalinase inhibitor racecadotril. In diarrhea caused by neuroendocrine tumors, microvillus inclusion disease and enterotoxin-induced severe diarrhea, a trial of somatostatin analog octreotide may be considered. Zinc promotes both enterocyte growth and ion absorption and may be effective when intestinal atrophy and ion secretion are associated. However, when therapeutic attempts have failed, the only option to avoid intestinal failure may be parenteral nutrition or eventually intestinal transplantation.