The intestine is a complex organ system with the unique ability to digest and absorb food while also coordinating complicated motility and hosting a distinctive immune system. When abnormalities occur in any of these intestinal functions, diarrhea can ensue. Diarrheal illness is a common childhood event that can lead to significant morbidity and even mortality. Infectious diarrhea remains the leading cause of childhood mortality worldwide. Furthermore, chronic diarrhea can lead to malnutrition and micronutrient deficiencies that further impart risk of comorbidities with other diseases.
In recent years, there has been a reduction in child mortality caused by severe diarrheal disease, which is hypothesized to be secondary to vaccines that target two common diarrheal pathogens worldwide—rotavirus and Vibrio cholerae . However, two-thirds of severe diarrheal episodes are not vaccine-preventable, and there are parts of the world where these vaccines are still not widely available. Furthermore, in developed countries, the incidence of inflammatory and allergic causes of chronic diarrhea is increasing. For example, in children and adolescents, inflammatory bowel diseases (IBDs), including Crohn’s disease, ulcerative colitis, and indeterminate colitis, are common causes of chronic diarrhea. In addition, food allergies, which are on the rise, can cause diarrhea, especially in infants, through non-immunoglobulin E (IgE)–mediated mechanisms.
The differential diagnosis of chronic diarrhea is broad and can vary according to the age of the child. A careful history and physical examination in combination with laboratory studies, stool analyses, breath testing, and endoscopy can lead to the diagnosis. As the scientific understanding of the many etiologies of diarrheal disease has expanded, genetic analysis has also become a key component in the diagnostic approach. Furthermore, over the last decade, significant advances in DNA sequencing technology now permit an assessment of the complex bacterial community that exists in the intestinal tract. Our improved understanding of the gut microbiota and the functions encoded by the genomes of the gut microbes has shed light on the pathogenesis of certain chronic diarrheal disorders.
This chapter defines protracted diarrhea and reviews the etiologic spectrum ( Box 32-1 ). The focus of this chapter, however, is on congenital diarrheal disorders that are not covered in other chapters. It should be emphasized that although rare causes of intractable diarrhea contribute little to the global burden of disease, they provide a unique insight into our understanding of human physiology and are deserving of detailed descriptions.
Infection
Bacterial: Vibrio cholerae , Escherichia coli (e.g., enteropathogenic, enteroaggregative), Salmonella , Campylobacter
Viral: HIV, rotavirus, norovirus, adenovirus Parasite: Cryptosporidium parvum , Giardia lamblia Others
Small bowel bacterial overgrowth
Postenteritis enteropathy
Tropical sprue
Food-Sensitive Diseases
Celiac disease
Allergic and eosinophilic enteropathies
“Toddler’s diarrhea”
Sucrase-isomaltase deficiency
Lactase deficiency
Immune-Mediated Or Inflammatory Enteropathies
Inflammatory bowel disease: Crohn’s disease, or ulcerative colitis Behcet’s disease
Celiac disease
Primary immunodeficiencies: common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), IgA deficiency
AIDS enteropathy
Autoimmune enteropathy including IPEX and APECED (also called autoimmune polyglandular syndrome 1 or APS-1) intestinal graft-versus-host disease
Anatomic Abnormalities
Malrotation
Short gut syndrome
Intestinal lymphangiectasia
Pancreatic Insufficiency
Cystic fibrosis
Shwachman-Diamond syndrome
Primary Metabolic Diseases
Mitochondrial cytopathies, mucopolysaccharidosis syndromes, congenital disorders of glycosylation
Malignancy
VIPoma
Carcinoid syndrome
Small bowel lymphoma
Multiple endocrine neoplasia (MEN)
Other Etiologies
Chronic nonspecific diarrhea of childhood
Irritable bowel syndrome
Factitious diarrhea or Munchausen’s syndrome by proxy
Laxative abuse
Nonabsorbable dietary substitutes: sorbitol, Olestra
Polyposis syndromes
Hirschsprung’s disease
Constipation with overflow incontinence
Hyperthyroidism
Definition and Epidemiology
Diarrhea can be defined by measured stool volume of greater than 10 mL/kg/day or 200 g/day for an older child. Although practical definitions of diarrhea can vary, the World Health Organization (WHO), for example, defines diarrhea as the “passage of loose or watery stools at least 3 times in a 24 hour period.” WHO emphasizes the change in consistency over frequency and allows flexibility for the provider to decide whether the child has true diarrhea. An arbitrary limit has been set at 14 days to delineate acute from chronic diarrheal episodes, although it is recognized that even episodes of 7 to 14 days can carry a nutritional penalty. The terms chronic, persistent, and protracted diarrhea are often used interchangeably. Persistent or protracted can infer a more acute onset initially. The term intractable diarrhea of infancy was first used by Avery and colleagues in 1968 and was thought to describe a single, but unexplained, clinic entity. It is now used to describe a symptom complex comprising multiple etiologies.
Mortality from diarrheal diseases has decreased from 4.6 million deaths per year in the early 1980s to the most recent estimate in 2011 of 700,000 diarrhea-related deaths in children younger than 60 months of age. Nearly 75% of these deaths occurred in children younger than 2 years of age. This decrease in mortality is due mainly to improved sanitation practices, but also to the introduction of oral rehydration therapy in 1979. The major burden of diarrheal disease continues to be carried by developing countries with an excess of infectious etiologies. Reducing the rates of malnutrition and provision of safe water, better sanitation, and better hygiene are expected to continue to reduce the inequalities between developing and developed countries.
Classification of Protracted Diarrhea
Two core processes are classically described: secretory and osmotic diarrhea. Each mechanism can occur separately or together, as is often the case in severe enteropathies ( Figure 32-1 ). Classically, osmotic and secretory diarrhea can be differentiated through calculation of the stool osmotic gap. The equation utilized is stool osmolality (290 is often substituted) minus twice the sum of the stool concentrations of sodium and potassium (2 × [Na + K]). When there is a high osmotic gap (greater than 100 mOsm), then an osmotic diarrhea is present. This result suggests that there is either an exogenous substance or a nutrient that is not being absorbed. If there is a low osmotic gap (less than 50 mOsm), then a secretory diarrhea is suspected. In addition, a high stool sodium (e.g., greater than 90 mM) is also suggestive of a secretory component. In practice, these definitions are not always helpful, as many disorders lead to a mixed secretory and osmotic diarrhea. Particularly important in the outpatient setting is the ability to characterize the stool frequency and consistency, in addition to the volume. A variety of factors contribute to increasing stool output beyond improperly digested material such as altered dietary intake, increased motility, diminished pancreatic function, medications, hormonal signaling, bile salt secretion, and an altered or “dysbiotic” gut microbiome. If diarrhea stops with bowel rest or is not present at night, an osmotic diarrhea is most likely. Nocturnal defecation is a sign of a secretory diarrhea. Stool consistency can be reliably assessed by the modified Bristol Stool Form Scale for children older than 6 to 8 years of age. This scale identifies five different stool types, with type 3 considered standard with smooth and soft log formation. Type 4 is fluffy pieces with ragged edges and mushy consistency and type 5 is watery without any solid pieces.
Osmotic diarrhea results when a substance in the intestinal lumen is not able to be absorbed, draws water into the lumen, and is excreted. Homeostasis dictates that fluid shifts will neutralize osmotic gradients between the intraluminal and extraluminal spaces of the intestinal tract. In the proximal small bowel, where the intraluminal osmolality is high from recently ingested meals, water is secreted into the lumen and an isotonic balance can be achieved as early as the proximal jejunum. In adults, approximately 120 mL/kg per day of fluid (±8 L in a 65-kg adult) can pass through the duodenum and 285 mL/kg per day in an infant. As nutrients are absorbed along the length of the small bowel, the osmolality decreases and water is reabsorbed, such that in the adult only 25 mL/kg per day enters the cecum and 61 mL/kg per day in the infant. The colon, through several efficient Na transport mechanisms operating within the apical membranes of colonocytes, both on the colonic surface and within the crypts, can extract daily an additional 20 to 30 mL/kg of water in the adult and 50 mL/kg in the infant. Osmotic diarrhea occurs when intraluminal solutes are not sufficiently absorbed because of maldigestion and/or malabsorption, creating an osmotic gradient that can be neutralized only by maintaining excessive amounts of water within the intestine.
An example of an osmotic substance is a malabsorbed macronutrient such as carbohydrates or fats. The substance could also be exogenous such as polyethylene glycol or lactulose—medications that are purposely used to induce an osmotic effect for the treatment of constipation. Carbohydrate malabsorption is a common cause of osmotic diarrhea. Colonic bacteria metabolize indigestible or malabsorbed carbohydrates that reach the colon to produce organic acids including lactic acid and short-chain fatty acids (SCFAs). The majority of these organic acids are absorbed or “salvaged” by the colonic mucosa. However, when there are significant amounts of malabsorbed carbohydrate in the colon (more than 45 g in healthy adults), the system becomes overwhelmed. Ultimately, this process leads to osmotic release, and thus diarrhea, and high gas production by the colonic bacteria. Indeed, the salvage mechanism can also be affected by antibiotics, which alter the colonic microbiota, thereby reducing bacterial carbohydrate metabolism.
Secretory diarrhea occurs when there is excess fluid secretion compared to absorption, most often the result of impaired electrolyte transport. The activation of chloride channels (e.g., the cystic fibrosis transmembrane regulator, or CFTR) is a common final pathway resulting in increased electrolyte and water secretion. Phosphorylation-induced activation of these channels may be mediated by increased intracellular concentrations of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and calcium. This cascade of intracellular processes may be triggered by either exogenous or endogenous substances. Exogenous mediators classically include bacterial toxins such as Vibrio cholerae toxin or heat-stable Escherichia coli toxin, but may also involve viruses (e.g., rotavirus, human immunodeficiency virus [HIV]) or parasites (e.g., Cryptosporidium parvum and Giardia lamblia ). Endogenous mediators may be endocrine, such as vasoactive intestinal peptide (VIP) or serotonin, or released by the immune system, such as histamine, serotonin, prostaglandins, or interleukin 1 (IL-1). Finally, loss of tight junction integrity with increased intestinal permeability can also contribute to increased intestinal fluid secretion. Mediators of this mechanism may be again exogenous (e.g., zonula occludens toxin of Vibrio cholerae , Salmonella , or Shigella ) or endogenous (e.g., epidermal growth factor).
Decreased absorptive area through either decreased intestinal length (e.g., short bowel syndrome) or inflammation (e.g., celiac disease) can also lead to malabsorption and osmotic diarrhea. Increased motor activity of the gut can lead to malabsorption by functionally decreasing the absorptive surface through decreased contact time between chyme and the intestinal epithelial lining. Diarrhea caused primarily by abnormal motor activity ( diarrhee motrice ) is rare but may contribute to the diarrhea seen in diseases of autonomic dysfunction and diarrhea-predominant irritable bowel syndrome. Allergic dysmotility due to non–IgE-mediated food allergy has been described and involves antigen-induced degranulation of mast cells and eosinophils leading to abnormal gut motility. In most cases, however, abnormal motor activity is secondary, aggravating existing diarrhea that is the result of increased fluid secretion and inflammation.
Assessment of the Patient with Protracted Diarrhea
Given the large number of diagnostic possibilities for protracted diarrhea, it is important to utilize a systematic approach when ordering testing. At every age, chronic infection or infectious enteritis with postinfectious complications must be considered. In addition to infection, toddlers most commonly have toddler’s diarrhea, celiac disease, and allergic enteritis. For older children, inflammatory bowel disease becomes more common, although celiac disease and irritable bowel syndrome are also prevalent. The evaluation for an infant with protracted diarrhea that begins when the infant is 6 months of age is different from that of a toddler or an older child and will be explored in the next section of this chapter.
Clinical History and Physical Examination
A careful history and then physical examination is the first critical piece in the evaluation of a pediatric patient with chronic diarrhea. The history is able to distinguish timing and severity of symptom onset. The history is also important to understand the character of the stools. Large volume, watery stools often point to a small bowel etiology with inability to absorb nutrients that then pass into the colon. Smaller volume stools with blood can suggest colonic inflammation. Stools that float and that are increased in frequency with high-fat diet point to steatorrhea. Nocturnal bowel movements are associated with a secretory diarrhea and is a concerning element in the history. The presence of weight loss or poor growth is extremely important in recognizing the possibility of an underlying inflammatory or autoimmune component. Furthermore, the presence of blood in the stool elicits a higher level of concern.
Extraintestinal symptoms must also be assessed, such as corresponding rash that can be seen in allergic disorders or the characteristic dermatitis herpetiformis of celiac disease. Inflammatory bowel disease extraintestinal manifestations such as aphthous ulcers, arthritis, erythema nodosum, or pyoderma gangrenosum can be identified by physical examination. A history of diarrhea plus frequent infections, especially respiratory infections, could suggest pancreatic insufficiency related to cystic fibrosis or a primary immunodeficiency.
A careful dietary history can help the provider to recognize carbohydrate malabsorption including excessive fructose intake leading to toddler’s diarrhea or excessive sorbitol intake found in beverages in adolescents. In addition, symptoms that correlate with dairy intake can uncover lactose intolerance. Furthermore, it is always important to ask about fever. If a fever was present at the start of the illness, this finding suggests an acute infectious enteritis. Often a history of fever, vomiting, and diarrhea followed by weeks of persistent diarrhea can be consistent with a postinfectious enteritis. Persistent diarrhea in a daycare or school setting can suggest a parasitic infection such as Giardia .
In the evaluation of chronic diarrhea, family history is also important, as there are genetic contributions to several of the diarrheal disorders. Although most diarrheal disorders are inherited in a Mendelian fashion, it is generally accepted that the greatest single risk factor for the development of IBD is having a family member with IBD. Similarly, there are multiple genes involved in the development of celiac disease. It is well known that the prevalence of celiac disease is increased in first-degree relatives of patients with celiac disease. Finally, many of the congenital diarrheal disorders have a genetic basis. An example is the newly recognized familial diarrheal syndrome caused by an activating mutation in the GUCY2C gene leading to increased production of cGMP and activation of CFTR (cystic fibrosis transmembrane receptor). Thus, it is important to ask about family history of diarrheal disorders. Of course, a negative family history does not rule out the possibility of an inherited diarrheal disorder.
Nutritional assessment as part of the physical examination is necessary and should include height, weight, and global nutritional appearance. The numerical data should be plotted on normative, relevant percentile graphs including the body mass index for age (or weight for length index in infants). Past growth parameters are helpful in constructing growth curves and estimating growth velocities: a body mass index for age that has fallen from the 75th percentile to the 15th percentile over one year is suspicious of organic disease and more worrisome than a child who has maintained the same low percentile over the same period.
Often neglected by physicians in training is an examination of the perianal area, which can provide important diagnostic clues. The presence of significant diaper dermatitis in infants can be suggestive of a carbohydrate intolerance brought on by the acidic quality of the stools. In the older child, the presence of anal fissures, a skin tag, or drainage, in the absence of constipation, is suggestive of Crohn’s disease. A digital rectal examination may be helpful when considering inflammatory bowel disease or to distinguish between the child with true diarrhea and the child with overflow incontinence.
After completing the history and physical examination, the diagnostic evaluation will focus the differential diagnosis. The evaluation can take place in a stepwise fashion with the least invasive testing performed first, especially for children and adolescents who have normal weight gain. For children with weight loss, an endoscopy and colonoscopy may be prioritized, although laboratory testing, stool studies, and imaging are still often performed.
Diagnostic Stool Studies
Regardless of diarrhea severity, diagnostic stool studies are a critical part of the evaluation. Although infectious diarrhea is most often thought of as an acute process, chronic, persistent infections with certain pathogens are possible. Specifically, diarrhea secondary to infection with Clostridium difficile and also parasitic infections can be prolonged. In addition, infections that are most commonly acute in healthy patients may become chronic in a patient with an underlying immunodeficiency. The clinician must keep in mind that the immunodeficiency may have been previously undiagnosed.
It is also important to note that certain infections, specifically parasitic infections, may require that more than one sample be submitted for detection. In addition, if there is suspicion for a particular pathogen, it is imperative to communicate with the laboratory if testing for nonroutine pathogens is required.
Once infection has been ruled out, the diagnostic workup should proceed with stool studies to evaluate the digestive and absorptive functions of the small intestine and also the presence of inflammation. As mentioned previously, in cases of severe diarrhea, stool osmolality should be obtained to distinguish osmotic diarrhea from secretory diarrhea. Table 32-1 lists the nutrient absorption tests that are typically performed on the stool. Stool pH is not listed in this table as the sensitivity is poor and the available literature has revealed variable results, but a low stool pH (<5.5) provides supporting evidence for carbohydrate malabsorption. The fecal calprotectin is not a nutrient absorption test, but rather a marker of inflammation in the intestinal tract. Calprotectin is a protein that is found in neutrophils and it is commonly elevated in the stool of patients with IBD. The sensitivity to detect mucosal inflammation ranges from 70% to 100%. In addition, routine laboratory evaluation of the stool may include an examination for fecal leukocytes, also indicative of inflammation, and a stool sample for occult blood, which could be helpful in the setting of suspected allergy or inflammation.
| Elevated stool α1-antitrypsin | Barrier disruption, loss of protein-positive stool reducing substances |
| Carbohydrate malabsorption Elevated fecal fat | Fat malabsorption |
| Low stool elastase | Pancreatic insufficiency |
| Elevated stool calprotectin | Inflammatory or infectious etiology |
Finally, it is important to note that to perform diagnostic stool testing, an adequate sample must be obtained. This acquisition may be difficult, especially when treating children who are not toilet-trained, as the liquid component of the stool may be absorbed into the diaper. In addition, it may be difficult to prevent urine and stool from mixing in children who are in diapers. The issue of absorption can be circumvented by turning the diaper inside out or by lining the inside of the diaper with plastic wrap. In severe cases of diarrhea, when it is impossible to prevent mixing of urine and stool and a precise quantification of stool volume is required, red rubber catheters can be utilized.
Hematologic Studies
The initial approach to the pediatric patient with chronic diarrhea may also include laboratory testing. A standard laboratory evaluation includes complete blood count (CBC), comprehensive metabolic panel (CMP), prealbumin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level. A CBC may show anemia, and the red blood cell indices may indicate iron-deficiency, which can be seen in the setting of small intestinal inflammation and poor absorption of iron. Inflammatory markers such as ESR, CRP, and platelet count may be elevated in Crohn’s disease, ulcerative colitis, or other inflammatory conditions. The CMP and prealbumin are important to assess for nutritional deficits. The prealbumin assay is particularly useful to distinguish malnutrition from protein-losing enteropathy in the hypoalbuminemic child. However, it is important to note that protein-losing enteropathy and malnutrition can coexist. Depending on the clinical scenario, other electrolyte, vitamin, or mineral levels may be considered. If steatorrhea is suspected, levels of fat-soluble vitamins will be important to assess.
Celiac disease is a very common cause of malabsorptive diarrhea, and so any child who is on a gluten-containing diet and who presents with chronic diarrhea should undergo screening for celiac disease with serology. The combination of the tissue transglutaminase antibody (TTG IgA) and anti-endomysial antibody (EMA IgA) offers the greatest sensitivity and specificity. However, these are both IgA-based serologies, and therefore an IgA level must be obtained as IgA deficiency is common in patients with celiac disease. In the setting of IgA deficiency, there are IgG-based serologies that can be obtained. In addition, there can be false negatives in young children with traditional serologic testing and so anti-gliadin antibodies should be considered in this age group.
Finally, protracted diarrhea may be an important manifestation of underlying immunodeficiency, especially in the setting of recurrent infections or skin rashes. In the appropriate clinical scenario, basic immunologic testing could be considered including quantitative immunoglobulin, T-cell, and IgG subsets. In terms of autoimmune conditions, anti-enterocyte antibodies should be requested from the blood, especially if there is a personal or family history of autoimmune disorders. However, these studies would not be part of the initial evaluation.
Hydrogen Breath Test
When there is evidence of reducing substances in the stool or when there is a high suspicion for carbohydrate malabsorption, a hydrogen breath test may be indicated. The hydrogen breath test is noninvasive and it relies on the ability of colonic bacteria to release hydrogen through fermentation of carbohydrates that reach the colon, instead of being absorbed. Hydrogen is absorbed by the colonocytes and excreted in the breath. Different substrates (e.g., lactose, fructose) are administered to assess for malabsorption of the respective carbohydrate. The hydrogen breath test, with a glucose or lactulose load, can also be used to identify small bowel bacterial overgrowth, another common cause of chronic diarrhea. Breath testing can be valuable in the cooperative child in whom no other disease other than a carbohydrate-sensitive enteropathy is suspected. It is important to keep in mind that if there is carbohydrate malabsorption secondary to small intestinal inflammation and villous blunting, positive results may be misleading, as the patient may not have a primary enzyme deficiency. In addition, up to 25% of humans have a non–hydrogen-producing fecal flora, which will lead to false-negative results.
The hydrogen breath test may be of particular importance in the diagnosis of sucrose malabsorption secondary to sucrase-isomaltase deficiency. This disorder causes a spectrum of disease from severe diarrhea in infancy to intermittent diarrhea, cramps, and increased flatulence in the older child. It is generally considered to be a rare disorder; however, the heterozygote frequency is thought to be higher—about 2%. Because there is such a wide spectrum of presentations, sucrase-isomaltase deficiency may be misdiagnosed as toddler’s diarrhea or irritable bowel syndrome. Sucrose is not a reducing sugar and so in these patients, the fecal reducing substance test will often be normal. When the diagnosis is suspected, a breath hydrogen test after an oral sucrose load will suggest the diagnosis. The diagnosis is confirmed by abnormal sucrase-isomaltase activity on disaccharidase analysis from a small intestine biopsy.
Sweat Test
In a child with failure to thrive and protracted diarrhea, it is important to rule out cystic fibrosis (CF). Today, there is widespread newborn screening operational in Western countries, which depends on high values of immunoreactive trypsinogen (IRT) in the blood of infants. In most states, a positive newborn screen is followed by either a repeat IRT measurement or DNA testing to identify known CFTR gene mutations. Either of these strategies provides about 90% to 95% sensitivity. However, these are screening programs only and the diagnosis of CF requires direct diagnostic testing. Sweat chloride testing remains the gold standard for the diagnosis of CF. In newborns, collecting adequate sweat for analysis can be challenging, and so sweat testing should only be performed at Cystic Fibrosis Foundation–certified laboratories. In infants who have intermediate sweat chloride testing results, analysis for CFTR gene mutation can be performed or a sweat chloride test can be repeated at 2 to 6 months of age.
Endoscopy and Histologic Sampling
A stepwise approach, as described here, has been shown to reduce the need for invasive procedures in pediatric patients who present with protracted diarrhea. However, endoscopy with biopsy may be required when less invasive, routine studies do not suggest a diagnosis or an inflammatory condition or congenital diarrheal disorder is suggested. Endoscopy with biopsy remains the cornerstone for diagnosis of diseases that require confirmation with a tissue sample such as in Crohn’s disease, ulcerative colitis, celiac disease, graft-versus-host disease (GVHD), microvillous inclusion disease, and tufting enteropathy. Upper endoscopy is indicated in the patient with protracted diarrhea who has weight loss, signs/symptoms of malabsorption or vitamin deficiencies, high inflammatory markers, or positive celiac serology. In some disorders, biopsy findings may provide a specific diagnosis such as in certain infections (e.g., Giardia ), common variable immunodeficiency, and GVHD. In other disorders, biopsy findings are supportive or suggestive. There have been reports of celiac disease with patchy villous atrophy, and so it is recommended to obtain multiple duodenal biopsies from different sites including at least one biopsy from the duodenal bulb. Regardless of the suspected diagnosis, multiple and adequate-sized biopsies should be obtained. In addition to routine histology, a sample can be obtained for disaccharidase analysis. In cases of a suspected congenital diarrheal disorder, additional biopsies should be processed for electron microscopy. It is also important to mention that during upper endoscopy, a duodenal aspirate can be obtained, if indicated, for culture. Duodenal aspirate is currently the “gold standard” diagnostic test for small bowel bacterial overgrowth. Ileocolonoscopy is also a tool available to pediatric gastroenterologists and it may be particularly helpful for patients who present with watery or inflammatory/bloody diarrhea. Biopsies from the terminal ileum, left colon, and right colon should be obtained. Ileocolonoscopy is the gold standard for the diagnosis of IBD.
Most chronic diarrhea caused by small bowel pathology can be diagnosed using standard upper endoscopy. However, with the advent of wireless capsule endoscopy, it is now possible to examine the small bowel in its entirety. The downside to capsule endoscopy is that biopsies cannot be obtained. However, it may still be a useful tool in patients with small bowel Crohn’s disease. When small bowel tissue located beyond the reach of the upper endoscope is required, push enteroscopy or balloon-assisted enteroscopy can be considered. These modalities are becoming more commonly available in pediatric centers.
Radiology imaging has a limited but useful role in the evaluation of a pediatric patient with protracted diarrhea. Imaging is most helpful when an anatomic abnormality is suspected or when there is concern for small bowel Crohn’s disease. In the evaluation of Crohn’s disease, most pediatric centers use upper gastrointestinal series with small bowel follow through or magnetic resonance (MR) enterography for small bowel assessment. The advantage of MR enterography is the lack of radiation. Small bowel ultrasound is also becoming an important modality. It allows assessment for small bowel wall thickening and hyperemia and it is an inexpensive test that also lacks radiation. However, small bowel ultrasound is operator dependent. In pediatric patients with Crohn’s disease, it is important to limit radiation exposure, as lifetime exposure may be great.
Causes of Protracted Diarrhea
The causes of protracted diarrhea are numerous. Reviewed herein are those that are most important from an epidemiologic standpoint, are frequently encountered in pediatric gastroenterology practice, or, even though rarely encountered, provide valuable insight into the pathophysiology of diarrheal syndromes ( Box 32-2 ). A nonexhaustive listing is provided in Box 32-1 .
6 to 24 Months
Postinfectious enteritis
Chronic infection
Celiac disease food allergy, excessive juice intake
Chronic nonspecific diarrhea
2 to 18 Years
Celiac disease
Inflammatory bowel disease
Irritable bowel syndrome
Carbohydrate intolerance, usually lactose
Chronic infection
Postinfectious enteritis
Infection-Induced Enteropathies
Worldwide, the most common etiology of diarrhea is infectious. The majority of bacterial and viral enteric pathogens cause an acute diarrheal illness. However, there are many pathogens, commonly associated with acute illnesses, which are capable of causing a chronic disease under certain high-risk conditions. Examples include Salmonella , Shigella , Campylobacter , Yersinia , and enterotoxigenic E. coli . Likely, a “vicious cycle” ensues where the initial infection leads to malnutrition and malnutrition increases the risk of infection. Chronic infection may also be perpetuated by factors such as environmental contamination and poor hygiene. In developing nations, perhaps the most important causes of persistent diarrhea in children are two serotypes of E. coli —enteropathogenic E. coli (EPEC) and enteroaggregative E. coli (EAEC).
Postenteritis syndrome is a chronic small intestinal condition with a worldwide distribution. It remains an important clinical problem in developing countries where access to medical care and adequate nutrition and hygiene are limited. Its clinical and histologic features can overlap with those of tropical sprue, which is perhaps its adult equivalent. The downward spiral of postenteritis syndrome may begin with a persistent infection or a sequence of infections, following one after the other, and providing an apparent clinical picture of a single continuing illness. The sequential nature of these infections can be determined only by repeated testing for infective agents. Enteric infection with inflammation and resulting loss of intake can lead to disaccharidase deficiency (so-called postinfectious or secondary lactase deficiency) in its mildest form and profound, generalized malabsorption in its most severe forms.
Diarrhea caused by food can occur under different guises: antigen sensitivities, carbohydrate intolerance, or feeding mismanagement due to issues of either excess or composition. It has been recognized for many years that food antigens may induce chronic small intestinal enteropathy presenting as persistent diarrhea. The most important specific enteropathy in this category is celiac disease. This immune-mediated disease is covered in depth in its own chapter of this book. It is now recognized that this classic clinical presentation of failure to thrive, bloating, and malnutrition is only the tip of the celiac disease iceberg and that many other presentations exist.
True food allergies and eosinophilic gastroenteritis should be part of the differential diagnosis of children with chronic diarrhea and are covered in another chapter of this textbook. Cow’s milk protein intolerance of infancy is a well-documented cause of enterocolitis in children. It typically presents with diarrhea and hematochezia within days to months after exposure to cow’s milk protein in neonates and young infants. Approximately 10% to 14% of young infants may also be allergic to soy secondary to cross-reactivity. In addition to formula-fed infants, cow’s milk protein intolerance may also be seen in exclusively breast-fed babies through transfer of dietary antigens through the breast milk. Treatment of cow’s milk protein intolerance includes exclusion of the offending proteins in the diet of the formula-fed infant and in the maternal diet of the breast-fed infant, which may involve transitioning to a protein-hydrolysate formula, or to an amino acid–based formula. In the great majority of cases, soy and cow’s milk protein can be reintroduced into the diet after one year of age without recurrence.
Chronic nonspecific diarrhea of childhood is a common cause of protracted diarrhea. It is also known as toddler’s diarrhea and typically presents in otherwise healthy children between the ages of 1 and 5 years. It can be continuous or episodic with usually variable stool consistencies from watery to soft. In many instances, the consumption of excessive quantities of hypertonic fluids such as fruit juices is identified. Certain juices such as apple, grape, or peach contain large amounts of poorly absorbable fructose and sorbitol. In some children, the juice intake can be so excessive that failure to thrive can ensue. Another subset of children, however, may be exquisitely sensitive to juices such that a single 240-mL serving causes carbohydrate malabsorption as evidenced by diarrhea and abnormal breath hydrogen testing. Diagnosis is often suspected by a careful history and a physical examination supporting good health. It is confirmed by an empiric trial of therapy without any need for further testing. Treatment involves parental reassurance, removing or severely limiting hypertonic juices from the diet, decreasing excessive volume intake to a reasonable amount, and removing any unfounded food restrictions. A balanced diet is recommended. This should include encouraging the consumption of fiber-rich and fatty foods (e.g., cheeses, whole milk). Increased dietary fat may be helpful, as fat is known to slow gastric emptying and to increase small-intestinal transit time by activating the “ileal brake” and decreasing colonic motility.
Rarely, infants may present with chronic diarrhea due to errors in formula mixing because inexperienced parents reconstitute formula from powder, creating a concentrated, hypertonic feeding. This diagnosis is again made by taking a careful history.
Immune-Mediated Enteropathies
It is well recognized that infants and children who have severe immunodeficiency syndromes may present with chronic diarrhea and failure to thrive. Primary immunodeficiency syndromes are thought to cause persistent diarrhea either by enteropathy or by chronic infection. These syndromes include common variable immunodeficiency (CVID), IgA deficiency, chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome, immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), and others. The first presentation of an immunodeficiency may be a major pathogen identified in the stool, and subsequently, immunodeficiency is suspected when the illness becomes persistent and difficult to treat with accompanying failing health, or when there are unexplained repeated infections with different or unusual organisms. The histology of the intestinal mucosa may be normal or may show variable abnormalities (e.g., villous blunting and absent plasma cells). Acquired immunodeficiencies, such as HIV/AIDS, can also lead to protracted or relapsing diarrhea secondary to enteropathy or chronic infection.
Autoimmune enteropathy (AIE) is a rare disorder recognized since the early 1980s and characterized by intractable diarrhea, histologic changes on small intestine biopsy, and lack of response to dietary manipulation. It occurs most commonly in infants and young children, although adult-onset cases have been described. The symptoms associated with AIE can be severe, and malabsorption leading to profound weight loss necessitating treatment with total parenteral nutrition (TPN) is not uncommon. An improved understanding of AIE pathophysiology, including disease-causing genetic mutations, allows us to recognize at least four types:
- 1.
Isolated AIE with typical anti-enterocyte antibodies occurring in both sexes
- 2.
IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) occurring only in males
- 3.
IPEX-like syndrome occurring in both sexes
- 4.
APECED syndrome (APS-1)
The pathogenesis of AIE continues to be elucidated, but it appears that a common pathway is the disruption of normal regulatory T-cell homeostasis. The histopathology of AIE, central to the diagnosis, can be confused with celiac disease demonstrating villous atrophy, but with a paucity of intraepithelial lymphocytes. Also described is a dense lymphoplasmacytic infiltration of the lamina propria, and crypt abscesses can be demonstrated in the most severe cases ( Figure 32-2 ). The well-documented anti-enterocyte antibodies of AIE are now thought to be an epiphenomenon of intestinal inflammation, rather than its cause. They are also no longer thought to be pathognomonic of AIE because they can be also seen in low titers in other intestinal diseases such as Crohn’s disease or cow’s-milk protein allergy. Anti-enterocyte antibodies may also be found in first-degree asymptomatic relatives. In the APECED syndrome (also called autoimmune polyglandular syndrome 1 or APS-1), AIE is associated with the multisystem extraintestinal manifestations, polyendocrinopathy, mucocutaneous candidiasis, and ectodermal dysplasia. The gene associated with the disease, AIRE (autoimmune regulator), has been mapped to the chromosome 21q22.3. The AIRE gene encodes a protein needed in gene transcription regulation. In patients with APECED syndrome, the clinical manifestations may be milder because the immune target is within the enteroendocrine cells rather than the absorptive cells. However, the gastrointestinal manifestations, in general, are quite variable ranging from Candida esophagitis to chronic gastritis and pernicious anemia to a multifactorial chronic diarrhea.
