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Protracted Diarrhea
Introduction
The intestine is a complex organ system holding 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 which can lead to significant morbidity and even mortality. Infectious diarrhea remains one of the leading causes 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 and this is hypothesized to be secondary to vaccines which target two common diarrheal pathogens worldwide—rotavirus and Vibrio cholerae . However, two thirds of severe diarrhea episodes are not vaccine-preventable and there are also parts of the world where these vaccines are still not widely available. , Further, in developed and developing 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 disease, ulcerative colitis, and indeterminate colitis, are common causes of chronic diarrhea. Additionally, food allergies, which are on the rise, can cause diarrhea, especially in infants, through non-IgE-mediated mechanisms.
The differential diagnosis of chronic diarrhea is broad and can vary based on the age of the child. A careful history and physical examination in combination with laboratories, 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 past 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 ( Table 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.
Table 32.1
Causes of Protracted Diarrhea Beyond Infancy
Infection
Food-sensitive diseases
Immune-mediated or inflammatory enteropathies
Anatomic abnormalities
Pancreatic insufficiency
Primary metabolic diseases
Malignancy
Other etiologies
See Table 32.4 for congenital diarrheal disorders |
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 three or more loose or liquid stools per day (or more frequent passage than is normal for the individual).” The WHO emphasizes the change in consistency over frequency and allows flexibility for the provider to decide whether or not 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, clinical entity. It is now used to describe a symptom complex comprising multiple etiologies.
Mortality from diarrheal diseases has overall decreased, with the most recent estimate in 2013 of 519,666 diarrhea-related deaths in children under the age of five. This decrease in mortality is mainly due to improved sanitation practices but also 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. In 2013, half of the world’s diarrheal deaths among children and adolescents occurred in just five countries—India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. Reducing the rates of malnutrition and provision of safe water, better sanitation, and better hygiene is 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 ( Fig. 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 (>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 (<50 mOsm), then a secretory diarrhea is suspected. Additionally, a high stool sodium (e.g., >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 over 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/day of fluid (±8 L in a 65-kg adult) can pass through the duodenum and 285 mL/kg/day in an infant. As nutrients are absorbed along the length of the small bowel, the osmolality decreases and water is reabsorbed such that only 25 mL/kg/day enters the cecum in the adult and 61 mL/kg/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 only be neutralized 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 also high gas production by the colonic bacteria. Indeed, the salvage mechanism can also be affected by antibiotics that alter the colonic microbiota, thus 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 cAMP, 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 V. 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, Giardia lamblia ). Endogenous mediators may be endocrine, such as vasoactive intestinal peptide or serotonin, or released by the immune system, such as histamine, serotonin, prostaglandins, or interleukin-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 V. cholerae , Salmonella, Shigella) or endogenous (e.g., epidermal growth factor).
Decreased absorptive area either through 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 (diarrhée motrice) is rare but may contribute to the diarrhea seen in diseases of autonomic dysfunction and diarrhea-predominant irritable bowel syndrome (IBS). 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
Due to 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, IBD becomes more common, though celiac disease and IBS are also prevalent. The evaluation for an infant with protracted diarrhea that begins under 6 months of age is different than 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 are the first critical pieces 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 very 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 points to steatorrhea. Nocturnal bowel movements are associated with a secretory diarrhea and are a concerning element in the history (commonly associated with infectious or inflammatory etiologies). The presence of weight loss or poor growth is extremely important in recognizing the possibility of an underlying inflammatory or autoimmune component. Further, 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. IBD 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 (CF) or a primary immunodeficiency.
A careful dietary history can help the provider to recognize carbohydrate malabsorption including excessive fructose intake or excessive sorbitol intake found in beverages in adolescents. Additionally, symptoms that correlate with dairy intake can uncover lactose intolerance. Further, 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 while patients with IBD can sometimes experience chronic, intermittent fevers.
In the evaluation of chronic diarrhea, family history is also important, as there are genetic contributions to several of the diarrheal disorders. While 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 familial diarrheal syndrome caused by an activating mutation in the GUCY2C gene leading to increased production of cGMP and activation of CFTR. 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 children under the age of 2). Past growth parameters are very 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 1 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 large or inflamed skin tag, or drainage, in the absence of constipation, is suggestive of Crohn disease. A digital rectal examination may be helpful when considering IBD 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 step-wise fashion with the least invasive testing performed first, especially for children and adolescents who have normal weight gain. For children with weight loss, an upper endoscopy and colonoscopy may be prioritized though laboratories, stool studies, and imaging are still often performed prior to endoscopy.
Diagnostic Stool Studies
Regardless of diarrhea severity, diagnostic stool studies are a critical part of the evaluation. While 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. Additionally, 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. Also, 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 work-up 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 in order to distinguish osmotic diarrhea from secretory diarrhea. Table 32.2 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%. Thus, fecal leukocyte stains have largely fallen out of favor secondary to lower diagnostic value. Additionally, routine laboratory evaluation of the stool may include a stool sample for occult blood which could be helpful in the setting of suspected allergy or inflammation.
Table 32.2
Diagnostic Stool Studies
|
Finally, it is important to note that in order 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. Also, 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. 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). 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 disease, ulcerative colitis, or other inflammatory conditions. The CMP and prealbumin are important in order to assess for nutritional deficits. The prealbumin assay is particularly useful to distinguish malnutrition from protein-losing enteropathy (PLE) in the hypoalbuminemic child. However, it is important to note that PLE 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 so 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. Additionally, there can be false negatives in young children with traditional serologic testing and so antigliadin 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, antienterocyte 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. Also, 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. Because there is such a wide spectrum of presentations, sucrase-isomaltase deficiency may be misdiagnosed as toddler’s diarrhea or IBS. There is also recent data that sucrase-isomaltase gene variants coding for disaccharidases with defective or reduced enzymatic activity may predispose to IBS. 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 and often by genetic testing.
Sweat Test
In a child with failure to thrive and protracted diarrhea, it is important to rule out CF. Today, there is widespread newborn screening operational in Western developed countries that 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 provide 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 CF 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 step-wise 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 Crohn disease, ulcerative colitis, celiac disease, graft versus host disease (GVHD), microvillus inclusion disease (MVID), 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 (CVID), and GVHD. In other disorders, biopsy findings are supportive or suggestive. There have been reports of celiac disease with patchy villous atrophy and so multiple duodenal biopsies from different sites is currently recommended, 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 to aid in the diagnosis of small bowel bacterial overgrowth. Ileocolonoscopy is also part of the pediatric gastroenterologist’s armamentarium and may be particularly helpful in 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.
The vast majority of chronic diarrhea caused by small bowel pathology can be diagnosed on 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 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.
Intestinal Imaging
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 disease. In the evaluation of Crohn disease, most pediatric centers use upper GI with small bowel follow through or 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. Some centers are now using contrast enhanced small bowel ultrasound, which allows the assessment of mural and mesenteric blood flow, important in determining IBD disease activity. In pediatric patients with Crohn disease, it is important to limit radiation exposure as lifetime exposure may be great.
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