Chapter 408. Disorders of Digestion and Absorption

The assimilation of ingested nutrients involves a complex integrated process of digestion and absorption with subsequent transport of the breakdown products across the intestinal mucosa into the systemic circulation. Normal digestion and absorption is discussed in Chapter 381. The term malabsorption is broadly used to characterize abnormalities of both digestion and absorption. The schema in Table 408-1 lists the major pathogenic mechanisms of various specific malabsorptive disorders that are generally due to disorders in luminal digestion, mucosal function, or lymphatic transport. Malabsorption may involve multiple nutrients (as occurs with celiac disease or pancreatic insufficiency) or only a single molecule (as found in isolated glucose-galactose malabsorption or vitamin B12 malabsorption). Defects may be congenital, with onset of symptoms shortly after birth, or acquired, when the age of onset of symptoms is variable.

The nutritional consequences of malabsorption vary from mild or none to severe, with malnutrition and even death. Abnormalities that impair absorption tend to have greater nutritional consequences than those impairing digestion. In general, growth is affected, manifest first by poor weight gain or weight loss and subsequently by linear growth retardation. Additional consequences may involve specific nutrients causing conditions such as rickets, osteoporosis, or tetany (vitamin D and calcium deficiency), coagulation disturbances (vitamin K deficiency), or anemia (iron, folate, or vitamin B12 deficiency).

Clinical Features

The evaluation of children with chronic diarrhea is discussed in Chapter 385. The most prominent clinical manifestation of children with disorders of digestion or absorption is diarrhea, except in those conditions involving malabsorption of a single molecule such as vitamin B12. Diarrhea is often accompanied by symptoms of abdominal distension, excessive flatulence, and growth failure in the older infant, toddler, or child. In the newborn or in early infancy, growth failure may not be evident and diarrhea may lead to dehydration. Very watery stools may soak into the diaper and be mistaken for urine, especially in infants with disorders such as congenital chloride-losing diarrhea.1 Stools that are loose to watery in nature and passed in an explosive fashion with excess flatus suggest some form of carbohydrate malabsorption. Carbohydrate-containing stools are generally acidic and frequently excoriate the infant’s buttocks. Large volume or bulky loose stools that are pale and very malodorous characterize steatorrhea, or fat malabsorption, as occurs with pancreatic exocrine enzyme insufficiency or celiac disease.

The time of onset of diarrhea or growth failure may provide clues regarding the diagnosis. Diarrhea or poor weight gain that starts shortly after birth suggests a congenital as opposed to an acquired defect. Onset of symptoms associated with dietary changes may suggest a diagnosis. For example, with sucrase-isomaltase deficiency symptoms commence following ingestion of sucrose-containing formula or foods; in celiac disease, symptoms often follow the introduction of solid, gluten-containing foods into the infant’s diet.2 Exposure to potential pathogens may suggest an infectious etiology of new onset malabsorption.

Previous abdominal surgery can be associated with malabsorption due to short-bowel syndrome, a blind loop, or terminal ileum resection, or malabsorption following partial or complete gastrectomy. Chronic respiratory illnesses occur in cystic fibrosis, which can also cause malabsorption. Arthritis or arthralgia can accompany inflammatory disorders such as Crohn disease. A history of multiple infections raises the possibility of immune deficiency such as Shwachman-Diamond syndrome or HIV.

Growth failure secondary to malabsorption of nutrients usually affects weight first and only impacts linear growth and head circumference at a later stage. Physical examination may show evidence of specific nutrient deficiencies such as pallor (anemia iron deficiency or B12 deficiency), hyperkeratosis (vitamin A deficiency), bruising (vitamin K or C deficiency), glossitis (riboflavin deficiency), dermatitis (niacin or zinc deficiency), rickets (vitamin D and calcium deficiency), muscle wasting with edema (protein deficiency), or peripheral neuropathy (deficiency of vitamin B1, B6, B12). The abdominal examination should include inspection for distension (due to carbohydrate malabsorption and gas production) as well as careful palpation for abdominal masses (tuberculous nodes, lymphoma, neuroblastoma) that may also cause abdominal distension and diarrhea, and for organomegaly. Examination of other systems, such as the respiratory, cardiovascular, and endocrine, is an integral part of the evaluation.

Diagnostic Evaluation

The selection of laboratory studies to confirm the presence of malabsorption and establish an etiology will depend upon the most likely causes determined by the history and physical examination. If the history suggests a specific diagnosis such as cystic fibrosis, targeted testing is appropriate. When malabsorption is suspected due to growth failure and diarrhea, screening laboratories guide the subsequent choice of more specialized testing as shown in Table 408-2.3 A complete blood count and differential with smear looking for anemia (iron, folate, or B12 deficiency), acanthocytosis (abetalipoproteinemia), eosinophilia (eosinophilic gastroenteropathy), or lymphopenia (lymphangiectasia) is useful. Measurement of serum bilirubin, alanine aminotransferase, and gamma-glutamyl transpeptidase may identify liver disorders. Low albumin can be due to malnutrition or lymphatic disease. Serum triglycerides and cholesterol may be abnormal in various disorders associated with malabsorption. In most situations serum testing for celiac disease is performed as part of the initial evaluation (see below). An examination of stool for occult blood, fecal leukocytes, or lactoferrin to exclude inflammatory disorders; stool microscopy for parasites such as Giardia; measurement of stool pH and reducing substances to look for carbohydrate malabsorption; and a qualitative test for fecal fat globules (Sudan stain) to look for fat malabsorption may provide valuable information.4 Fecal elastase or chymotrypsin testing provides a useful screening evaluation of pancreatic function, and fecal α1-antitrypsin can identify protein-losing enteropathies. Sweat tests or genetic testing for cystic fibrosis is usually indicated. If the initial screening tests are suggestive of a malabsorption disorder, more specialized tests are usually required to identify the specific etiology.

In some instances radiologic imaging studies may help identify a specific cause for malabsorption. Barium contrast studies or computerized tomography can identify distal ileal disease as found with Crohn disease, intestinal lymphoma, or tuberculosis and are also useful for identifying malrotations, duplications, blind loops, intestinal strictures, or entero-enteral fistulas that may cause small bowel bacterial overgrowth. Computerized tomography and magnetic resonance imaging may identify abnormalities of the pancreas, including hypoplasia with lipomatous infiltration, intraductal or parenchymal calcifications, or fibrosis, as may occur in chronic pancreatitis.

Tests for Carbohydrate Malabsorption

Malabsorption of carbohydrates is suggested when stool pH is reduced or reducing substances are abnormal. Specific disaccharidase deficiencies can be identified using a breath test that measure hydrogen levels following ingestion of a specific carbohydrate (eg, lactose, sucrose, or fructose). Malabsorption of the carbohydrate is shown by a breath hydrogen level increase of more that 20 ppm due to metabolism of the nonabsorbed carbohydrate by colonic bacteria. Early rises in breath hydrogen suggest possible bacterial overgrowth of the small intestine, whereas a lack of rise may be associated with a lack of hydrogen-producing bacteria due to recent antibiotic usage or to a predominance of methane-producing bacteria. Malabsorption of multiple carbohydrates suggests a decrease in intestinal absorptive capacity as occurs with destruction of the intestinal mucosa. Definitive identification of a disaccharidase deficiency (eg, lactase, sucrase, or glucoamylase) requires endoscopic biopsy, usually from the second or third portion of the duodenum. Pathology reveals normal mucosa, but specific enzyme assays show reduced or absent mucosal enzyme concentrations. The d-xylose test was previously used to assess the integrity of the mucosal surface, but a lack of specificity and sensitivity has the frequent use of this test in contemporary practice.5

Tests for Fat Malabsorption

Low serum levels of vitamins A, D, E, and carotene6 provide indirect evidence for possible fat malabsorption in the child. Further evidence may be obtained through the qualitative determination of fecal fat on a single stool sample using the Sudan stain or by means of the acid steatocrit, which employs a simple, rapid gravimetric method to determine fat content in a small stool sample. This method is reasonably sensitive and specific,7 as are breath tests using carbon 14 triolein as a substrate.8 Definitive quantitative evaluation of fat absorption is unpleasant and inconvenient and is rarely performed in contemporary practice.3 It requires a complete 3-day collection of all stools to determine both total fat content and calculate the coefficient of fat absorption. For this test to be meaningful, fat intake during the study should be in the range of 2 to 3 g/kg/day (maximum 100 g/day). Normally, greater than 94% of ingested fat is absorbed (coefficient of fat absorption > 94%), and any less than this value is indicative of fat malabsorption. Once the presence of fat malabsorption is confirmed, additional tests may be required to identify the specific cause. Deficiencies in pancreatic enzymes cause fat maldigestion.9 The approach to evaluation for these disorders is discussed in Chapter 417. Fat malabsorption may also result from conditions associated with inadequate micelle solubilization: decreased biliary production or secretion (cirrhosis, biliary atresia, or bile duct obstruction), congenital absence of bile salt synthesis, deconjugation and dehydroxylation of bile salts secondary to small intestinal bacterial overgrowth, or depletion of bile salts due to excessive loss in the stools. Normally, bile salts are absorbed in the distal ileum and returned to the liver for reconstitution and excretion. Disruption in this enterohepatic cycle with progressive depletion of the bile salt pool may occur in diseases involving the distal ileum, such as Crohn disease, intestinal lymphoma or tuberculosis, following surgical resection of the distal ileum, or in rare cases, due to congenital defects in the ileal bile salt transporter. Direct assay of blood or duodenal bile salts concentrations is sometimes used to identify a deficiency. An indirect measure of bile salt malabsorption is possible using the 75-selenium-homotaurocholic acid-taurine test. This test measures retention of bile acid following ingestion of a selenium 75–labeled synthetic bile acid (selen-homotaurocholic acid).10 Because of the technical requirements for this test, it is not commonly used in clinical practice.

Evaluation of Small Bowel Mucosa

Endoscopic examination of the upper small intestine and colon may identify obvious structural or morphological abnormalities. In most cases, mucosal biopsy is required to identify a specific cause for malabsorption. Routine histologic and, in some cases, electron microscopy examination of small intestinal mucosa is critical for accurate diagnosis. Conditions that may be identified on histology or electron microscopy include celiac disease, protein-sensitive enteropathy, Crohn disease, abetalipoproteinemia, and eosinophilic infiltration. Intestinal biopsies are best performed by means of gastrointestinal endoscopy with multiple biopsies, even when the macroscopic appearance of the mucosa is normal. Table 408-3 lists conditions causing malabsorption that may be identified on small intestinal biopsy.

Additional specialized tests that may be ordered based on the index of clinical suspicion, and initial screening tests include the Schilling test for vitamin B12 malabsorption, and a fasting serum gastrin level and maximal acid output test for Zollinger-Ellison syndrome. These conditions are uncommon in children.

Treatment

In most cases a specific cause for maldigestion and malabsorption in children can be identified through the process of initial screening tests followed by targeted definitive testing, and treatment addresses the underlying cause. In some cases simple removal of the offending agent is curative, for example, lactose elimination for lactose malabsorption and a gluten-free diet that eliminates all products containing wheat, barley, and rye for celiac disease. In others, enzyme replacement of deficiencies is possible, for example, pancreatic enzyme supplements for cystic fibrosis. In addition to treating the underlying cause, attention should also be focused on correcting any macronutrient and micronutrient deficits that exist at the time of diagnosis in order to promote optimal growth and development of the individual. Periodic assessment of nutritional status and review of nutrient intake is mandatory in all patients with malabsorption syndromes.

Celiac disease is defined as a lifelong sensitivity to gluten found in wheat and related proteins found in barley and rye. It occurs in genetically predisposed individuals and is manifest as an immune-mediated enteropathy as defined by characteristic changes seen on small intestinal histology.2 The intestinal mucosal injury leads to varying degrees of malabsorption of nutrients. Removal of wheat gluten and related proteins from the diet usually leads to full clinical remission and restoration of the small intestinal mucosal damage to normality. The fascinating historical aspects of this disorder are found on the DVD.

Aretaeus, the Cappadocian, who lived in the 2nd century AD, first described the wasting and characteristic appearance of the stools that occurs in celiac disease. He referred to his patients as having koiliakos, which meant “suffering in the bowels.” In his translation of these observations from Greek to English, Francis Adams in 1856 first used the term “coeliacs,” which is derived from the Greek word koiliakos. Samuel Gee provided a detailed description of celiac disease and in his classic paper published in 1888, entitled “On the Coeliac Affection,” was first to emphasize that it affected children as well as adults. In addition to his accurate description of the clinical features, he was the first to suggest the disease could be cured by dietary therapy. This was in part based on his observations that symptoms in a child resolved when fed a quart of Dutch mussels daily, but relapsed once the mussel season was over. Following on the diet theme, Haas in 1924 recommended his famous banana diet. This was used for many years until the discovery that gluten products were the cause of celiac disease. The Dutch pediatrician, Willem Karel Dicke, is credited with recognizing the role of wheat in causing celiac disease. He first based this on his observations during World War II that affected children improved symptomatically once deprived of bread and other wheat products when these were in very short supply, and relapsed after the war when these products were once more available. He subsequently confirmed his clinical suspicion by withdrawing wheat from the diet of affected children and published his findings in his doctoral thesis in 1950. The characteristic histologic changes of celiac disease were first described from surgical specimens by Paulley in 1954, and in 1956 Margot Shiner developed a means of obtaining intestinal samples for biopsy by mouth. This provided physicians with a means to confirm the diagnosis and demonstrate on serial biopsies that histologic recovery occurred with treatment. At the beginning of the 1970s serologic markers of celiac disease were identified. Subsequent development and refinement of additional serologic tests in the 1980s and 1990s provided physicians with a powerful diagnostic modality to identify individuals who might have celiac disease and require an intestinal biopsy for confirmation. The use of serologic tests has also greatly enhanced our understanding of the epidemiology of celiac disease and the recognition of the highly variable clinical manifestations of the condition.

Epidemiology and Associated Disorders

Celiac disease is one of the most common chronic conditions affecting humans. A prevalence of 1:67 to 1:285 is reported in the European general population.11 A multicenter study involving a large number of individuals in the United States estimates a prevalence of 1:133.12 Celiac disease is diagnosed in North and South America, North Africa, the Middle East countries, India, Australia, and New Zealand, but is rare or nonexistent in black African, Japanese, and Chinese people. The reasons for this are unclear, but could be due to the lack of genetic potential in these populations or to the fact that wheat is not the staple diet in these regions.

Pathophysiology and Genetics

There is a strong genetic predisposition for celiac disease. It occurs in 10% to 20% of first-degree relatives, and there is concordance in 30% to 40% of HLA-identical siblings and 70% of homozygous twins.13 Celiac disease is strongly associated with the HLA-DQ2 molecule, which is present in over 90% of all individuals with confirmed disease.13 HLA-DQ2 is a heterodimer consisting of an α and β chain that is encoded by the alleles DQA1*05 and DQB1*02. The DQ2 molecule contains a peptide-binding groove that binds specific peptides in preparation for presentation to T cells. The HLA-DQ2 heterodimer can be encoded in cis (on the same haplotype) or in trans, where the subunits are encoded on separate haplotypes. Gene dose affect appears to influence both the risk and severity of celiac disease expression. Homozygosity for the cis haplotype, or a second DQB1*02 allele on the other haplotype, can increase the risk for celiac disease fourfold to sixfold and is associated with a more severe clinical form of the disease.14 Most individuals with celiac disease who do not possess the HLA-DQ2 molecule carry the HLA-DQ8 moleculeencoded by the alleles DQA1*03 and DQB1*0302. There also appears to be a gene dose effect with HLA-DQ8 similar to that for DQ2. Rare cases of celiac disease in the absence of either HLA-DQ2 or DQ8 have been described. Most of these possess a single DQA1*05 or DQB1*02 allele. While HLA-DQ2 is strongly associated with celiac disease, it is also found in 30% of the general population, hence it is not specific for celiac disease.

The presence of HLA-DQ2 and/or DQ8 is therefore necessary but not sufficient for the development of celiac disease. It is estimated the HLA factors account for only about 40% of the heritable risk for celiac disease, and other non-HLA genes are believed to play a major role. Linkage studies have identified promising regions on chromosomes 5 and 19. Specifically, in a Dutch cohort of celiac patients there was a significant linkage to chromosome 19p13.1, while in an Italian cohort there was linkage to a locus on chromosome 5q31-33. Other non-HLA areas of interest include the CTLA4 gene, chromosome 2q33, and chromosome 6q21-22 (distinct from the HLA region). Although all these non-HLA genes have shown promise, much work is still needed to clearly define the specific genes that play a role in the onset of disease.

Dietary Factors

Wheat, barley, and rye share a common taxonomy in the plant kingdom. The proteins derived from these grains initiate the immune processes that result in the intestinal damage found in celiac disease. Oats, once also believed capable of initiating disease, is more distantly related to these grains. There is now good evidence that oats can be safely ingested by the majority of patients with celiac disease and previous observations implicating oats in the disease process were due to contamination with wheat flour during harvesting and milling. Gluten is the term used to describe the entire protein component of wheat. It can be divided into an alcohol-soluble fraction called gliadin and an alcohol-insoluble fraction known as glutenin. Gluten is rich in the amino acids glutamine and proline, as are the proteins derived from barley and rye (known as hordeins and secalins, respectively). As such, these proteins are sometimes collectively referred to as prolamines. Although not strictly correct, the term gluten is often loosely used to refer to all the proteins derived from wheat, barley, and rye. The gliadin fraction of wheat gluten can be divided into fractions, one of which is α-gliadin. The complete amino acid sequence of α-gliadin has been identified and consists of some 262 amino acids. Analysis of this sequence reveals multiple repetitive motifs creating numerous peptides that have been identified both in vitro and in vivo as capable of initiating celiac disease in a susceptible individual.15 The human digestive tract is unable to completely digest gluten and related products from barley and rye, leaving several peptides of varying lengths that are resistant to further degradation by gastric, pancreatic, or intestinal brush border membrane proteases. These peptides pass through the epithelial barrier of the intestine to initiate the inflammatory process in celiac disease. Predigestion of these peptides with bacterial prolylendopeptidases has been shown to render them harmless and incapable of causing disease. This observation has raised the possibility of developing alternative therapeutic modalities for treating celiac disease in the future.

Because not all individuals with the known genetic markers develop celiac disease when exposed to gluten products, additional environmental trigger factors have been implicated in the pathogenesis of the disease. Principal among these are infectious agents. A high degree of amino acid sequence homology has been found between gliadin and viruses such as adenovirus type 12 and 7, rubella, and human herpes virus 1. This raises the possibility of infection by one of these viruses triggering celiac disease. There is also an association between previous rotavirus infection and onset of celiac disease.16 Other conditions that have been considered as a trigger factor are stress-related events such as pregnancy. The evidence for additional trigger factors in the pathogenesis of celiac disease remains circumstantial and has yet to be confirmed.

Immunologic Factors

Individuals with untreated celiac disease have increased intestinal permeability rendering their intestinal mucosa more permeable to the passage of harmful peptides. This increase may be related to an upregulation in zonulin that has been found in individuals with celiac disease.17 Zonulin is a protein that exerts an influence on the enterocyte microskeleton to control the tight junctions in the intestinal epithelial layer. Passage of certain peptides from gluten and related proteins across the enterocyte layer triggers the innate response in susceptible individuals that produces a lymphocytic cytotoxic reaction against enterocytes. One distinct peptide capable of triggering a response is the gliadin peptide 31-43.18 Production of IL-15 by enterocytes and lamina propria macrophages and dendritic cells appears to be an important factor in this response. IL-15 promotes migration of lymphocytes from the deeper layers of the lamina propria to intraepithelial compartment. This expansion of intraepithelial lymphocytes represents one of the earliest recognizable small intestinal mucosal changes seen on histology in celiac disease. IL-15 also stimulates intraepithelial lymphocytes expression of the innate immune receptor NKG2D and expression of MICA, the epithelial ligand of NKG2D. Binding of NKG2D to MICA triggers cytotoxicity of intraepithelial lymphocytes against enterocytes.18 Finally, cytokines including IL-15 and IFN-α promote upregulation of the DQ2 molecules on the antigen-presenting cells in preparation for the adaptive phase of the immune process.

In individuals with celiac disease, the gluten-derived peptides that traverse the intestinal mucosa are targeted by tissue transglutaminase, and glutamine molecules are deamidated to glutamic acid. This results in a great increase in the negative charge on the peptide being greatly enhanced and binding to the peptide groove on the DQ2 molecule of the antigen presenting cells is increased. The bound peptide antigen is presented to T lymphocytes, which in turn stimulate B lymphocytes to elaborate a number of antibodies to gliadin, endomysium, and tissue transglutaminase. T lymphocytes also elaborate additional cytokines, including IFN-α, which are believed to play a role in the mucosal remodeling that occurs in celiac disease.19

Clinical Features and Differential Diagnosis

The manifestations of celiac disease are protean with tremendous variation among affected individuals (Table 408-4).20 The “classic” constellation of symptoms composing malabsorptive-type diarrhea, poor weight gain, abdominal distension, and proximal muscle wasting in the child under 2 years of age is readily recognized as a manifestation of celiac disease. Today, this type of presentation accounts for a relatively small number of all newly diagnosed cases. In rare cases, very young children present with a celiac crisis characterized by severe diarrhea with electrolyte imbalance, hypoalbuminemia, and a shocklike state that can be fatal.

More commonly, symptoms of celiac disease are delayed until late childhood, adolescence, or even adulthood. Population-screening studies using serologic tests to identify those who might have celiac disease have led to the recognition that many individuals with characteristic changes seen by small intestinal biopsy are asymptomatic, indicating that the intestinal mucosal damage likely may precede onset of symptoms by many years. Most symptomatic children will have gastrointestinal symptoms as their initial manifestation of celiac disease. Diarrhea is frequently present, but may be mild or intermittent for prolonged periods of time. Abdominal pain, distension, and a feeling of bloating with flatulence are fairly frequent complaints in the older child and adolescent and may be incorrectly attributed to the irritable bowel syndrome or lactose intolerance. Nausea and vomiting occur less commonly, and in some cases, constipation has been the major complaint. In adolescents and adults, symptoms of celiac disease may be indistinguishable from those of irritable bowel syndrome, resulting in the delayed diagnosis of celiac disease in many individuals.

Nongastrointestinal Manifestations

Nongastrointestinal manifestations of celiac disease are being recognized with greater frequency, and in adults these may account for half of all newly diagnosed cases (Table 408-4). Decrease in linear growth velocity or delayed onset of puberty may be the initial manifestation of celiac disease in the pediatric population. Dental enamel hypoplasia, involving all 4 quadrants of the secondary dentition in a symmetrical distribution, is well described in celiac disease and may be the initial manifestation first recognized during a routine dental examination. Dermatitis herpetiformis, characterized by extremely itchy bullous lesions on the extensor surfaces of the limbs, trunk, and scalp, is a feature of celiac disease that is more common in adults and can occur without any intestinal symptoms (Fig. 408-1). Behavioral changes, fatigue, anorexia, and unexplained iron-deficiency anemia are additional initial manifestations.

Associated Conditions

Celiac disease is also strongly associated with a number of autoimmune conditions (Table 408-4).10,20 Up to 10% of patients with type 1 diabetes have been found to have celiac disease, and the condition occurs in about 12% of those with Down syndrome, leading to recommendations for routine screening in these and other high-prevalence populations.10 Selective IgA deficiency occurs in about 3% of patients with celiac disease as compared to about 1:500 of the general population, complicating the diagnosis of celiac disease with anti-IgA antibody–based diagnostic test.

Diagnostic Evaluation

Revised criteria for the diagnosis of celiac disease published by the European Society of Pediatric Gastroenterology and Nutrition in 199021,22 and endorsed by the North American Society of Pediatric Gastroenterology and Nutrition in 200510 list 2 mandatory requirements for the diagnosis of celiac disease: (1) identification of the characteristic histologic findings on small intestinal mucosal histology in a symptomatic patient and (2) complete symptom resolution on a strict gluten-free diet. The use of serologic tests may be used as supportive evidence for the diagnosis, but despite the improved sensitivity and specificity of new serologic tests, serology alone is considered inadequate for initiation of lifetime therapy that has substantial social and economic consequences.

Serologic tests are useful for screening of patients with possible celiac disease or high-risk groups that may have asymptomatic disease. Commercial laboratories offer a number of serologic tests for celiac disease. Those most readily available include the antigliadin antibodies which that are both IgA and IgG based, antiendomysium antibodies that are IgA based, and anti-tissue transglutaminase antibodies that are IgA based. The antigliadin antibody (AGA) tests are easy to perform and relatively inexpensive, but have highly variable sensitivities and specificities.23,24 Elevated levels of these antibodies have been found in a number of other conditions as well as healthy individuals. For these reasons AGA tests are no longer recommended for routine use as a screening test. The antiendomysium antibody test (EMA) and anti-tissue transglutaminase antibody test (TTG) are both highly sensitive (> 95%) and specific (> 98%) and are recommended as the test of choice for screening purposes. A TTG is performed by means of an ELISA or radioimmunoassay technique and is generally less expensive than the EMA, and less operator dependent, so it has become the preferred test. Current recommendations from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, the American Gastroenterology Association, and the NIH advocate use of either the TTG or EMA for routine screening of patients suspected of having celiac disease10,25,26 or in patients at risk of celiac disease (Fig. 408-2). Serum IgA level is recommended to be obtained at the time of testing to identify those who are IgA deficient since IgA-based serologic tests are of no use in such individuals, for whom IgG-based tests for EMA or TTG should be considered. EMA and TTG tests are also less reliable in children less than 2 years of age,23 so in this age group AGA tests combined with the TTG or EMA may increase sensitivity during screening, although if the diagnosis is likely, small bowel biopsy may be indicated.

Small intestinal biopsy remains the definitive test for the diagnosis of celiac disease.10 Intestinal biopsy specimens are usually obtained by means of an upper gastrointestinal endoscopy. Visual abnormalities of the mucosa may be recognized at endoscopy (Fig. 408-3). These include mucosal nodularity, scalloping along the borders of the folds, and a mosaic pattern. These changes have been shown to correlate with the degree of mucosal atrophy, but have not been shown to have adequate sensitivity or specificity for diagnosis. For these reasons, even if the endoscopic appearance is completely normal, multiple samples should be obtained from the second part of the duodenum or beyond. Characteristic histologic features of celiac disease are progressive and include an increase in the number of intraepithelial lymphocytes, an increase in plasma cells in the lamina propria, loss of enterocyte basal nuclear polarity, crypt hyperplasia with an increased crypt mitotic index, and villous blunting with reversal of the villous height-to-crypt depth ratio (Fig. 408-4).19 Disease severity is characterized by pathologists using the Marsh classification.27 Marsh 0 describes a normal small intestinal mucosa with tall fingerlike villi and a villous crypt depth ratio greater than 3:1. Marsh I refers to the presence of increased numbers of intraepithelial lymphocytes, with lymphocytes numbers in excess of 30 per 100 enterocytes. In Marsh II there is crypt hyperplasia in addition to the increased intraepithelial lymphocytes, whereas in Marsh III there is additional progressive flattening of the villi. Marsh III lesions are further divided into IIIa (partial villous atrophy), IIIb (subtotal villous atrophy), and IIIc (total villous atrophy). There is good evidence that Marsh III changes are strongly associated with celiac disease.10 In contrast, the evidence that Marsh I and II are diagnostic for celiac disease is not as strong, and these findings alone should not be used to make a positive diagnosis of celiac disease. Most pathologists readily recognize the presence of subtotal or total villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes as characteristic of celiac disease. It requires more experience to identify patients with less severe changes who are at an early stage of the disease. Other disorders such as autoimmune enteropathy and milk protein–sensitive enteropathy may cause flattening of the intestinal mucosa together with a mucosal inflammatory cell infiltrate that could be mistaken for celiac disease.

Treatment

The treatment approach to celiac disease is summarized in eFigure 408.1. A diagnosis of celiac disease mandates lifelong dietary exclusion of gluten found in wheat and related peptides in barley and rye. Previously, oats were excluded, but this does not appear to be necessary if the oats are milled separately from gluten-containing grains. Strict adherence to such a diet is difficult and requires constant vigilance on the part of the patient. For this reason, it is essential to confirm the diagnosis by means of an intestinal biopsy before starting an exclusionary diet. In the short term, dietary modification will result in rapid remission of symptoms and correction of growth and nutritional deficiencies.

Long-term benefits of adhering to the diet include preventing such complications as osteoporosis and reducing the risk for intestinal malignancies. Repeating the serologic tests at intervals may help the physician and patient monitor whether gluten and related products are being adequately excluded from the diet. Persistent elevation of a serologic marker, or recurrence of a positive test that had previously been negative, is indicative that the patient is knowingly, or unknowingly, continuing to ingest gluten. Elevation of serologic antibody levels and recurrence of significant small intestinal mucosal damage after initial recovery can precede symptoms by several years in those who do not strictly adhere to the diet.

Adherence to the diet can be particularly difficult in children, and consultation with an experienced pediatric dietician is recommended. Cookbooks and various gluten-free specialty items are available for patients with celiac disease and are easily accessed via the Internet, but strict adherence to the diet is challenging for those with limited resources. The American Dietetic Association has published evidence-based guidelines for treatment of celiac disease.28,29 Patients with celiac disease are also encouraged to join a local support group, as these provide valuable sources of education and dietary guidance. Children should see their physician on a regular basis to monitor their growth and general health. At these visits, the physician should take the opportunity to evaluate the patient’s adherence to the gluten-free diet and provide ongoing education on the long-term benefits of dietary compliance.30

Current research is aimed at finding alternative forms of therapy for patients with celiac disease. One possibility that is being explored is the use of bacterial prolyl endopeptidases with food to further digest the potentially harmful gluten peptides and render them nontoxic. Other possible forms of therapy involve the use of immune modulators to block specific inflammatory mediators that are involved in the immunopathogenesis of the disease. None of these alternative forms of therapy are yet available for use, and all will have to demonstrate that they are as effective and as safe as the gluten-free diet before they will be acceptable as a replacement form of therapy.

Complications

Untreated celiac disease has potential for long-term adverse health consequences.28 Mortality is increased twofold over the general population in those with symptomatic celiac disease who are noncompliant with therapy. Most of the excess deaths in these cases are related to malignanciess. Individuals with celiac disease are at significantly increased risk for intestinal lymphomas and in particular an enteropathy-associated T-cell lymphoma that carries a poor prognosis. In those who remain compliant with dietary therapy, the relative risk for intestinal cancers returns to that of the general population after a period of 5 years. In children with growth stunting due to celiac disease, early diagnosis and treatment usually results in catch-up growth. However, if the diagnosis and treatment is delayed beyond puberty, there may be permanent growth stunting, with the child failing to reach his or her true growth potential. A decrease in bone mineralization leading to osteopenia or frank osteoporosis is frequently present at the time of diagnosis in those with symptomatic celiac disease. In children, early diagnosis and treatment of celiac disease results in restoration of normal bone mineralization. In adults, treatment will improve osteopenia or osteoporosis in most cases, but bone mineralization seldom returns to that of healthy individuals without celiac disease. It has also been suggested that a delay in diagnosis and treatment of celiac disease may place the individual at increased risk for developing additional autoimmune disorders such as type 1 diabetes and autoimmune thyroiditis. However, the evidence supporting the concept that prolonged exposure to gluten is a cause for other autoimmune disorders is conflicting.

Chronic idiopathic diarrhea of infancy is also known as intractable diarrhea of infancy, protracted diarrhea of infancy, severe persistent diarrhea of infancy, and prolonged diarrhea of infancy.31 A number of new disorders that cause diarrhea during infancy have been recognized in recent years,32-35 but despite these advances there remains a group of infants for whom no specific etiology can be identified. The term chronic idiopathic diarrhea of infancy remains appropriate for these cases. In the past, this term was applied to infants less than 3 months of age, but it now is often used to describe any infant with otherwise unexplained chronic diarrhea, characterized by ongoing watery diarrhea lasting for more than 2 weeks. Stool losses often exceed 30 mL/kg/day. The volume of stool loss is usually of such magnitude that the infant is unable to maintain adequate hydration without additional intravenous fluids. Without appropriate management, mortality rates are exceedingly high, thus early recognition of the disorder is important to improve outcome.

Epidemiology and Pathophysiology

The commencement of diarrhea in this disorder resembles that in an acute infectious episode of either viral or bacterial gastroenteritis. Apparent risk factors for persistent diarrhea in an infant following such an illness include prematurity, early age of onset of the diarrhea, lack of breast-feeding, low socioeconomic circumstances with poor hygiene, and preexisting malnutrition. In most cases an inciting infectious agent is not identified, but even when a bacterial agent is identified and treatment administered, diarrhea may persist. Small intestinal mucosal biopsy of these infants consistently demonstrates subtotal to total villous atrophy, with an increased cellular infiltrate and cuboidal epithelial cells. It appears that in these infants villous repair is ineffective. Histologic evidence of intestinal mucosal injury can persist for several months following the initial clinical presentation, even in those who demonstrate clinical recovery from the diarrhea.36 The intestinal villous atrophy results in deficiencies of intestinal brush border enzymes. This leads to secondary disaccharide (and sometimes even monosaccharide) intolerance. Enterocyte destruction may also reduce enteric hormone secretion, resulting in a secondary pancreatic insufficiency that aggravates the malabsorption of fats, carbohydrates, and proteins. Nutrient absorption decreases to such an extent that mucosal healing is impaired due to a lack of nutrients, resulting in a spiraling downward course.37 Many of these infants also develop small intestinal bacterial overgrowth, possibly due to hypochlorhydria, which may further damage the intestinal mucosa and can deconjugate bile acids, causing increased fluid and electrolyte losses by the colon.38,39

Clinical Features and Differential Diagnosis

The diagnosis of idiopathic diarrhea of infancy is made by exclusion of other known causes of chronic diarrhea in an infant with a typical history and presentation.40 Conditions that cause severe ongoing diarrhea in the very young infant need to be excluded: enteropathies associated with the villous atrophy and transporter defects (see Table 408-5), pancreatic insufficiency (see Table 417-1) malrotation and Hirschsprung disease, and rarely, endocrinopathies such as those associated with hypoparathyroidism, hyperthyroidism, adrenal insufficiency, VIPomas, and neuroblastoma.32-35 Diarrhea that starts within the first few days of life should always raise suspicion for one of the congenital structural, metabolic, mucosal transport, or enzyme abnormalities. A preceding history of polyhydramnios in the mother may be a clue to the diagnosis of congenital sodium- or congenital chloride-losing diarrhea in the infant. Diarrhea that starts some months after birth is more likely to be due to an acquired disorder. Chronic diarrhea starting only after the introduction of solid foods may be indicative of celiac disease in the older infant, and, although very rare in the young infant, both Crohn disease and ulcerative colitis have been described.

Because of the complexity involved in reaching a final diagnosis and the potential high mortality associated with idiopathic diarrhea of infancy, infants with severe, persistent diarrhea should be referred to a center with the facilities and expertise necessary for investigation and treatment. Initial laboratory evaluation generally includes determination of serum electrolytes and acid-base status; stool microscopy for leukocytes, ova, and parasites; repeated bacterial culture; and reducing substances. Measurement of stool electrolyte content is often helpful to confirm or exclude a secretory-type diarrhea, which is characteristic of some congenital conditions causing chronic diarrhea. Differentiating a secretory-type diarrhea from that which is osmotically induced can also be determined on a clinical basis by temporarily withholding feeds from the infant and providing all fluids via the intravenous route. Stool output will persist unabated in those with a secretory-type diarrhea, whereas it will decrease dramatically in those with osmotically induced diarrhea, only to recur with reintroduction of feedings. Evaluation for other causes of chronic diarrhea, including infection, immunodeficiency, and pancreatic insufficiency, may be considered.

An intestinal biopsy is not always necessary to make a presumptive diagnosis and to initiate treatment. When a biopsy is obtained, it is used to rule out other diagnosis and should include specimens for both light and electron microscopy, as well as for Sudan fat and neurogenin-3 staining. Biopsy confirms findings of villous atrophy, but the cause of atrophy is nonspecific.

Treatment and Prognosis

Preventing the evolution of acute infectious diarrheal episodes into chronic “idiopathic diarrhea” should be a primary goal for infants who are at risk for this condition. Strategies that are of benefit in this regard include promoting breast-feeding in all cases and promoting continued feeding of children with acute diarrhea to prevent any deterioration in their nutritional status. In infants with persistent diarrhea, the first priority is to prevent dehydration and to correct electrolyte imbalance as discussed in Chapter 385. If diarrhea persists when enteral feeding ceases, a diagnostic workup should begin as discussed above. If diarrhea resolves, attempts to enterally feed should resume.

Often infants can tolerate smaller-volume feeds, particularly if delivered as a continuous nasogastric feeding. Modular formula with decreased carbohydrate or semielemental formula are often better tolerated than lactose-containing formula. If adequate calories can be delivered without substantial increases in stool volume and without dehydration, the enteral approach is preferable. If stool volume increases substantially as enteral feeding is attempted, the enteral feeding rate should be reduced to a smaller amount that is better tolerated and parenteral nutrition should be administered to provide additional nutritional support.

Usually, within 5 to 7 days of starting parenteral nutrition the infant will tolerate small-volume feeds of a reduced-carbohydrate modular formula, a semielemental, or elemental formula without any marked increase in stool output. The volume of formula feeds can then be slowly increased with simultaneous decrease in the amount of parenteral nutrition. In those infants showing steady improvement as demonstrated by the ability to receive an increasing proportion of calories enterally, expectant management is reasonable. In those infants who do not improve, small bowel biopsy should be performed to rule out other causes of persistent diarrhea.

Empirical treatment of small intestinal bacterial overgrowth with a combination of oral antibiotics (gentamicin 50 mg/kg/day in 6 divided doses for 3 days and metronidazole 15 mg/kg/day in 3 divided doses) and cholestyramine (0.5–1 g every 6 hours for 5 days) has proven highly beneficial and may result in a dramatic decrease in stool output in many cases.39 Underlying vitamin and mineral deficiencies also require correction. Both vitamin A and zinc deficiency are frequently documented in malnourished infants and are associated with prolongation of diarrhea in these cases. Complete recovery is now possible in the majority of infants with chronic idiopathic diarrhea who receive appropriate therapy.

There are a number of enteropathies associated with varying degrees of malabsorption of nutrients. In some there is histologic evidence of structural derangement characterized by decreased villus height with consequent loss of intestinal absorptive surface area. In others the mucosal architecture appears intact, and malabsorption results from a functional defect of the enterocyte (Table 408-5). Enteropathies associated with malabsorption can be congenital or acquired. Congenital enteropathies usually present early in infancy, and the underlying defect is generally not reversible. Acquired enteropathies can present at any age and are potentially reversible, depending on the underlying cause.

Congenital Enteropathies

Microvillus Inclusion Disease

Congenital microvillus inclusion disease has also been referred to as congenital microvillus atrophy and familial microvillus atrophy.41 It is believed to be inherited in an autosomal-recessive manner based on occurrence among siblings and clustering among infants of Navajo descent.42 The entity is characterized by watery diarrhea, with onset within the first days after birth, although about 20% present later over the first 2 months of life. Stool and electrolyte losses are of such magnitude that rapid dehydration and death will ensue unless appropriate treatment with intravenous fluid is initiated. Massive fecal losses (50 to 800 mL/kg/day) continue even when the infant is maintained on parenteral nutrition and given nothing by mouth. The diarrhea is secretory, with increased electrolyte concentrations without an anion gap. Most tests of intestinal absorption function, such as fecal fat analysis and d-xylose uptake, are abnormal, and stool electrolyte content is consistently high in keeping with a secretory-type diarrhea. Nutrition cannot be maintained via the enteral route, and parenteral nutrition is required. Without continued intravenous nutrition and fluid-replacement therapy or intestinal transplantation, the condition is almost always fatal.

Histologically, the small intestine demonstrates diffuse villus atrophy, but without crypt hypertrophy or an inflammatory cell infiltrate. The surface enterocytes are disorganized, with loss of brush border definition, and there is extensive apical cytoplasmic vacuolization (eFig. 408.2). Periodic acid Schiff staining may confirm the absence of apical brush border and demonstrates positive staining within the apical cytoplasm of the enterocytes.32 Electron microscopy reveals mucosal surface enterocytes that lack microvilli completely or that have sparse, shortened villi. The apical cytoplasm of the enterocyte contains a marked increase in electron-dense secretory granules of various sizes, some of which contain glycocalyx and brush border–related material (Fig. 408-5). The hallmark of the disease is the presence of microvilli within involutions of the apical membrane. The crypt epithelium is usually well preserved, as are other epithelial cells, such as goblet cells, Paneth cells, and enteroendocrine cells. Microvillus inclusions can also be demonstrated in colonocytes, gastric epithelial cells, renal tubules, and gallbladder. Another characteristic feature on electron microscopy is the presence of secretory granules within the apical cells of the surface epithelium. These secretory granules account for the periodic acid Schiff–positive staining of the enterocytes.

The differential diagnosis includes other causes of congenital diarrhea, such as congenital chloride-losing diarrhea, congenital sodium-losing diarrhea, primary bile acid malabsorption, and congenital short gut. Treatment has been largely unsuccessful. Many dietary manipulations and medications have been tried without benefit. Therapeutic agents that have been tried include corticosteroids, antibiotics, disodium cromoglycate, prostaglandin synthase inhibitors, and cholestyramine. The long-acting somatostatin analog octreotide may decrease the stool output but does not alter the course of the disease. In nearly all cases, life can be sustained only by parenteral nutrition unless the infant can undergo intestinal transplantation.

Tufting Enteropathy

Tufting enteropathy is also known as intestinal epithelial dysplasia. In some cases the infants may have characteristic dysmorphic facial features.43 The condition is characterized by chronic diarrhea beginning shortly after birth and is associated with poor growth. In some cases nutrition cannot be maintained via the enteral route alone, and additional parenteral nutrition is required for normal growth.

Histology of the small intestine reveals varying degrees of villus atrophy with crypt hyperplasia and a minimal increase in inflammatory cells in the lamina propria (Fig. 408-6). The characteristic feature is the presence of foci of closely packed enterocytes with rounding of the apical membrane resembling “tufts” that appear to be coming away from the epithelium. Unlike microvillus inclusion disease, periodic acid Schiff staining in tufting enteropathy demonstrates the presence of linear staining along the apical surface membrane without positive staining in the enterocyte cytoplasm. Because of the patchy nature of these findings, several intestinal biopsies may be needed in order to make the diagnosis. Biopsies may appear near normal early in life, showing only nonspecific signs of villous atrophy, with characteristic tufts on later biopsy. The disorder appears to be due to an abnormality of the basement membrane or cell-matrix interactions. Mice in which the gene encoding the transcription factor Elf3 is disrupted have morphologic features resembling tufting enteropathy.44

Based on occurrence in siblings and parental consanguinity, the condition is believed to be inherited in an autosomal recessive manner and is more common in those of Arab descent.45 The long-term prognosis is variable. A small number of affected individuals receive adequate nutrition via the enteral route, but most cases require parenteral nutrition. There is a report of a successful pregnancy in a woman with tufting enteropathy.46 In those cases requiring long-term supplemental parenteral nutrition, the only other therapeutic option is intestinal transplantation.

Ipex Syndrome

IPEX is characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linkage. It is caused by mutations in the Foxp3 gene (also see Chapter 188) carried in the pericentric region of the X chromosome, Xp11.23-Xp13.3.47 This gene is involved in the control of normal regulatory T-cell development. Mutations in the gene result in the inappropriate activation and dissemination of activated immune cells to multiple organ systems, including the intestinal tract (see also Chapter 188).

Male infants with IPEX present in infancy with chronic high-volume diarrhea together with type-1 diabetes, autoimmune hemolytic anemia, autoimmune thyroiditis, and a variety of skin manifestations including eczema and psoriasis. There may be associated food allergies, peripheral blood eosinophilia, and elevated levels of serum IgE. An exaggerated response to viral infections is described in some cases. The condition is associated with a high mortality.48 Supportive therapy with parenteral nutrition and insulin, together with prolonged immunosuppressive therapy, has been attempted with little success. There is one report suggesting allogeneic bone marrow transplant may offer the possibility of a cure.49

Histologic features in the small intestine are similar to those seen in other immune enteropathies and include villus atrophy and a prominent infiltration of activated T cells in the lamina propria. The diagnosis should be suspected in any infant with chronic diarrhea associated with autoimmune hemolytic anemia, type 1 diabetes, autoimmune thyroiditis, or eczematous type skin manifestations. Confirmation of IPEX requires identification of the mutation in the Foxp3 gene.

Intestinal Lymphangiectasia

Intestinal lymphangiectasia is characterized by ectasia of the enteric lymphatics. Congenital malformation of the lymphatic system results in a congenital or primary form of the disorder, whereas the acquired or secondary form is due to diseases causing obstruction of intestinal lymphatic drainage. Most cases of the primary abnormality are sporadic, but there are reports of occurrence in multiple siblings from several families, suggesting in certain cases there may be a genetic cause. Primary intestinal lymphangiectasia is often associated with lymphatic abnormalities elsewhere in the body. These include hypoplasia or aplasia of the peripheral lymphatic system with lymphedema, chylous ascites, and chylothorax, or the lymphangiectasia may be part of a syndrome such as Noonan, Klippel-Trenaunay-Weber, and Turner. Secondary diseases causing secondary obstruction to lymph flow include constrictive pericarditis, congestive heart failure, retroperitoneal fibrosis, retroperitoneal neoplasms, portal hypertension, and mesenteric tuberculosis.

In both the primary and secondary types of lymphangiectasia there is usually diffuse involvement of the intestine characterized by ectatic lymphatics located in the mucosa, submucosa or subserosa. Occasionally the disorder is localized to one or more areas of the small bowel. With the exception of long-chain fatty acids and fat-soluble vitamins, small intestinal absorptive function is usually intact. However, rupture of dilated mucosal lymphatics into the intestinal lumen leads to loss of protein-rich lymph containing albumin, globulins, and lymphocytes. The ensuing protein-losing enteropathy and lymphocyte loss leads to hypoproteinemia and an absolute lymphopenia in the peripheral blood.

In the primary form mean age of onset of symptoms is 11 years. The initial presentation is often with peripheral edema and hypoproteinemia without proteinuria or hepatic dysfunction. Gastrointestinal symptoms vary from none or mild to severe. Symptoms include diarrhea, nausea, vomiting, abdominal pain, and in some cases steatorrhea. Chylous ascites and chylous pleural effusions can occur in those with longstanding lymphangiectasia. Onset of symptoms in the first decade of life is often associated with growth failure.

The diagnosis of intestinal lymphangiectasia is based on the clinical presentation and laboratory and pathological findings. The presence of a protein-losing enteropathy can be confirmed by demonstrating elevated levels of fecal α1-antitrypsin. Protein-losing enteropathy associated with peripheral blood lymphocytopenia should suggest the possibility of intestinal lymphangiectasia. The diagnosis is confirmed on intestinal biopsy, which demonstrates dilated lymphatic vessels in the mucosa or submucosa of the small intestine. There is no inflammatory cell infiltrate. The villi show no signs of atrophy but are distorted, often appearing swollen and broad.

Treatment is dependent on the cause. In the small number of cases where the abnormality is localized to a section of the intestine, resection of this area is curative. When the lymphangiectasia is secondary to conditions such as constrictive pericarditis, treatment of the underlying disease will lead to resolution of the intestinal losses. In the diffuse primary form of lymphangiectasia, treatment requires limiting the amount of dietary long-chain fat to 5 to 10 g per day and providing a diet that is high in protein and medium-chain triglycerides.50 The medium-chain triglycerides are absorbed directly into the portal system, thereby minimizing distension of the lymphatics. Additional supplementation with calcium and water-soluble forms of fat-soluble vitamins may be required.

Acquired Enteropathies

Tropical Sprue

This malabsorption syndrome is seen in visitors or residents of endemic tropical regions of the world. These areas include India, parts of Asia, the Philippines, the northern part of South America, Central America, some Caribbean countries, and central and southern Africa. The condition occurs in children, but is more common in adults. It is most probably infectious in origin, but no specific pathogen has been identified.51 Damage to the intestinal mucosa progresses from the jejunum to the ileum. On small intestinal histology, there is flattening of the villi, crypt elongation, and chronic inflammatory cell infiltration of the lamina propria. These changes are similar to those found in celiac disease. Clinical symptoms are usually insidious in onset and evolve through stages. Fatigue, weakness, anorexia, and acute diarrhea characterize the early stage. The acute diarrhea progresses to a more chronic form with steatorrhea accompanied by abdominal cramps and flatulence. Signs of nutritional deficiencies appear, including night blindness, cheilosis, glossitis, stomatitis, and hyperkeratosis. In the final stage there is muscle wasting, edema, abdominal distension, and a macrocytic anemia. These changes occur over a period of several months to years. On occasion the presentation is more acute, and the stages are accelerated over a few months. The condition should be suspected in patients with diarrhea and malabsorption who have lived in or recently visited an endemic area. Differential diagnosis includes parasitic infestations (Giardia, Strongyloides stercoralis, Isospora, Capillaria philippinensis), celiac disease, HIV infection, tuberculous enteritis, and small intestinal bacterial overgrowth syndromes. Once diagnosed, tropical sprue can be treated by a course of the antibiotic tetracycline (doxycycline) or sulfamethoxazole/trimethoprim (cotrimoxazole), and vitamin B12 and folic acid, for at least 6 months, which will usually lead to dramatic improvement.

Whipple Disease

This rare, multisystem disorder virtually always involves the small intestine, causing a severe malabsorption syndrome.52 Other features commonly encountered are arthritis/arthralgia, polyserositis, fever, and central nervous system symptoms. It is caused by a gram-positive actinomycete, Tropheryma whippelii, which is a fastidious organism that has not yet been cultured. Small intestinal biopsy reveals villi that are flattened and wide. The lamina propria is extensively infiltrated with large macrophages containing periodic acid-Schiff-positive granules representing remnants of the cell walls of degenerated phagocytosed bacilli. Numerous tiny bacilli are located in the upper epithelium, most abundantly beneath the absorptive epithelium. Mucosal and submucosal lymphatics are dilated, probably because of lymphatic obstruction by enlarged mesenteric lymph nodes. Treatment with antibiotics produces dramatic improvement, but long-term therapy is necessary.

HIV Enteropathy

Gastrointestinal disorders are among the most common complaints in patients with human immunodeficiency virus (HIV) disease. These include diarrhea, nausea, vomiting, anorexia, weight loss, and abdominal pain. In some cases the gastrointestinal symptoms are clearly related to one of many opportunistic bacterial, viral, or parasitic infections, or are secondary to the effects of small intestinal bacterial overgrowth or gastrointestinal malignancies such as intestinal lymphomas or Kaposi sarcoma. In others there is evidence to suggest the HIV is an intestinal pathogen capable of causing diarrhea and malabsorption.53 The virus can be identified in macrophages within the lamina propria and enterochromaffin cells and is believed to exert an effect on local humoral immunity and impair motility.54,55 The term idiopathic AIDS enteropathy has been used to describe those patients with HIV disease who have chronic diarrhea with no other identifiable etiology. Histologic findings are variable, with varying degrees of villus blunting. Lamina propria cellularity ranges from normal in some cases to a severe increase in the density of lymphocytes and plasma cells in others.56

Clinically, HIV enteropathy is associated with chronic diarrhea, and this is often accompanied by anorexia. Weight loss and malnutrition are secondary to both inadequate nutrient intake and malabsorption of nutrients, and growth is frequently impaired in children. Diagnosis is dependent on careful exclusion of other identifiable causes of diarrhea. Treatment combines strategies to stimulate appetite using drugs such as megestrol acetate and to decrease stool output using antidiarrheal agents. Supplemental enteral nutrition by means of enteral tube feeding techniques may be needed in some cases to provide sufficient caloric intake. Parenteral nutrition may be necessary in some cases with severe diarrhea, but the decision to use this form of therapy needs to be carefully weighed against the potential risks that accompany central venous line placement in an immunocompromised individual.

Autoimmune Enteropathy

This potentially life-threatening disorder is characterized by chronic diarrhea beginning during the first year of life but usually after 8 weeks of age. There are rare reports of autoimmune enteropathy occurring in older children and adults.57 The condition is frequently associated with other autoimmune diseases, including membranous glomerulonephritis, insulin-dependent diabetes, collagen vascular disorders, hemolytic anemia, autoimmune hepatitis, and hypothyroidism. Most cases are sporadic but it rarely has been associated with a family history of unexplained chronic diarrhea in infancy.

Affected children present with chronic watery diarrhea. Because of the colonic involvement, there may be associated features of colitis with blood and mucus in the stools. Malabsorption of nutrients leads to malnutrition and impaired growth. Chronic diarrhea associated with other autoimmune disorders, including type-1 diabetes, autoimmune thyroiditis, or hemolytic anemia, should always raise suspicion for the diagnosis of autoimmune enteropathy.

Light microscopy of small intestinal biopsies demonstrates partial or complete villus atrophy, crypt hyperplasia, and a mononuclear cell infiltrate in the lamina propria. The features resemble those of celiac disease, except there is a relative paucity of intraepithelial lymphocytes. Furthermore, these histologic changes occur in the absence of any gluten ingestion in the majority of cases. The microscopic changes are not confined to the small intestine and can be seen in the colon and stomach as well.

The disorder appears to be autoimmune by virtue of the presence of autoantibodies to the enterocytes and other tissues (eg, antibodies to pancreatic islet cells, thyroid, parietal cells, and renal tubular epithelium). Diagnosis is dependent on (1) the clinical history of prolonged diarrhea with histologic features of small intestinal enteropathy, (2) lack of clinical or histologic response to an exclusion diet or a period of complete bowel rest with parenteral nutrition, and (3) the demonstration of circulating autoantibodies to gut and other tissues.

Parenteral nutrition is often necessary to prevent progressive malnutrition. Corticosteroids, azathioprine, cyclosporine, tacrolimus, and infliximab have been used with some success.58 Serial determination of enterocyte autoantibodies may be of benefit to monitor treatment efficacy. Declining or low titers are associated with recovery, whereas persistent high titers indicate a poorer prognosis with worse outcome for the patient.

Dietary carbohydrates are ingested predominantly as starches (consisting of linear and branched polymers of glucose) and sugars from dairy products (lactose) or fruits and vegetables (glucose, sucrose, and fructose). Details of the mechanisms of carbohydrate digestion and absorption are provided in Chapter 396. Intraluminal digestion of starch is initiated by salivary amylase but is predominantly completed by pancreatic amylase and results in production of oligosaccharides, maltotriose, maltose, and α-limit dextrins. These products of starch digestion, as well as any ingested disaccharides (lactose or sucrose), cannot be absorbed in their intact form and require further hydrolysis to their constituent monosaccharides. This hydrolytic process is dependent on the brush border membrane hydrolases lactase, sucrase, and maltase-glucoamylase and results in production of glucose, galactose, and fructose. Glucose and galactose are subsequently transported into the enterocyte via a sodium-glucose coupled cotransporter, SGLUT1, whereas fructose uptake is facilitated by the transporter GLUT5. All 3 monosaccharides subsequently leave the enterocyte to enter the systemic circulation via facilitated diffusion across the basolateral membrane.

Disorders of carbohydrate absorption can occur as a result of deficiencies in intraluminal digestion or from a defect in transport across the enterocyte. Problems related to defects in mucosal transport are discussed later in this chapter. Defects in digestion related to isolated pancreatic amylase insufficiency are extremely rare59 and will not be discussed further. Problems related to generalized pancreatic exocrine enzyme insufficiency are covered in Chapter 440.

Carbohydrate malabsorption is most commonly caused by a deficiency in one or more of the brush border membrane hydrolases such as lactase or sucrase. This may be due to a primary defect, as occurs with congenital enzyme deficiencies or adult-type hypolactasia, or an acquired defect secondary to intestinal mucosal damage resulting in decreased enzyme levels. Unabsorbed carbohydrates can exert significant osmotic pressure, which results in the secretion of fluid and electrolytes into the intestinal lumen. Carbohydrates entering the colon are fermented by colonic bacteria to produce lactic acid and other short-chain organic acids. These compounds may exacerbate symptoms through the production of gases, by adding further to the osmotic load, and by directly stimulating colonic motility. Symptoms of carbohydrate malabsorption may vary from none or mild to severe, with varying combinations of watery diarrhea, abdominal pain, bloating and flatulence.

Primary Disorders of Carbohydrate Malabsorption

Congenital Lactase Deficiency

Congenital lactase deficiency is a rare disorder inherited as an autosomal recessive condition caused by mutations in the translated region of the lactase gene (LCT), which maps to chromosome 2q21.60 The incidence is over 1:60,000, with the highest incidence in the Finnish population, although it has been reported elsewhere. It is characterized by watery diarrhea starting shortly after birth in infants fed breast milk or any lactose-containing milk formula. Stool water losses may be of such magnitude as to result in dehydration with acidosis, and the infant fails to gain weight. The diarrhea will cease promptly if enteral feeds are withheld, thus confirming the diarrhea is osmotically induced. Subsequent administration of a lactose-free formula is not associated with recurrence of diarrhea and should lead the physician to consider the diagnosis of congenital lactase deficiency. The diagnosis can be confirmed on duodenal biopsies that demonstrate normal histology but with isolated low levels of lactase activity on measurement of the intestinal mucosal disaccharidases. Treatment involves avoidance of all lactose-containing products or administration of supplemental lactase enzyme with ingestion of any dairy products. The prognosis is excellent, and individuals with congenital lactase deficiency are expected to lead normal lives.

Adult-Type Hypolactasia

Adult-type hypolactasia is inherited as an autosomal recessive trait as a result of polymorphisms in the region of the lactase phlorizin hydrolase gene.61 It is a normal physiologic condition characterized by downregulation of the lactase enzyme after the weaning period and is the most common enzyme deficiency in humans.62 The prevalence in Asian and African countries ranges from 80% to 100%, whereas in Europe it is usually less than 20%. The age of onset of symptoms varies widely among ethnic groups. In black populations symptoms manifest between 1 and 8 years of age, whereas in white populations low lactase levels are rare under 5 years of age. The reasons for this ethnic variation in timing of the decrease in enzyme activity are not known. Symptoms in affected individuals vary in severity and are in part related to the amount of lactose ingested. Typical symptoms include flatulence, abdominal pain, abdominal distension or bloating, and, in some cases, diarrhea. Confirmation of the diagnosis can be made indirectly by an exclusion diet or with a lactose breath test, or directly by measuring lactase levels in small intestinal mucosal tissue. Low levels of lactase activity occur in the absence of any structural mucosal damage. Some commercial companies now also offer genetic testing as a means of confirming the diagnosis.

In older children and adults with lactase deficiency, avoidance of milk and other foods that are rich in lactose often is sufficient, and total elimination of lactose or dairy products is rarely necessary. Patients who want to consume milk can ingest prehydrolyzed milk that has been treated with microbial-derived lactase enzyme (Lactaid) or ingest this enzyme with any dairy product intake. Several commercial preparations for lactase enzyme replacement are available over the counter. These preparations in caplet or tablet form can be crushed and sprinkled over lactose-containing foods and therefore are suitable for children who cannot chew or swallow the intact product. Yogurt containing active live culture from which microbial lactase is released is often well tolerated by lactase-deficient individuals and is an alternative source of calcium.

Congenital Sucrase-Isomaltase Deficiency

Congenital sucrase-isomaltase deficiency is a rare autosomal recessive condition due to mutations in the gene encoding sucrase-isomaltase, which maps to 3q25-q26. It is a lifelong condition resulting from complete absence of small intestinal sucrase and near complete absence of maltase enzyme activity.63 Affected individuals are intolerant of sucrose and of some starches that are high in amylopectin. Starch tolerance is dependent on the level of isomaltase activity as the 1,6 bonds require isomaltase for cleavage. Onset of symptoms usually occurs in infancy after the introduction of sucrose or starches into the diet. Some infants with sucrase-isomaltase deficiency develop severe diarrhea with ingestion of formula composed of carbohydrates such as corn syrup solids. Symptoms vary from severe diarrhea to loose stools associated with abdominal pain and flatulence. The diagnosis may be suspected on the basis of a breath test using sucrose as substrate. However, confirmation of the diagnosis requires demonstration of absence of sucrase enzyme activity in the presence of normal small intestinal mucosal structure.

Congenital sucrase-isomaltase deficiency is managed with lactose-containing formulas and avoidance of sucrose-containing foods. In children with sucrase-isomaltase deficiency, enzyme replacement therapy with a sucrase enzyme derived from the yeast Saccharomyces cerevisiae (Sucraid) is now available and offers an alternative to dietary avoidance.64

Fructose and Sorbitol Malabsorption

Isolated fructose malabsorption is a rare autosomal recessive disorder that is distinct from “physiological” malabsorption of fructose. The condition of isolated fructose malabsorption is a congenital transport defect and is described later in this chapter.

Fructose, and perhaps sorbitol, is absorbed across the mucosal surface by facilitated diffusion via a specific saturable carrier protein located on the apical membrane of the enterocyte (GLUT5).

Fructose and sorbitol are monosaccharides that may be malabsorbed if ingested in excessive quantities. These sugars are widely used in commercial food products as an inexpensive sweetener. Carbonated beverages, often consumed in significant amounts by children, contain large quantities of fructose as high-fructose corn syrup. Sorbitol is a poorly absorbed sugar that is used in many “diet” products as a sucrose substitute. Glucose and amino acids appear to facilitate the transport of fructose across the mucosal surface, so when fructose is ingested with equimolar amounts of glucose or amino acids, absorption is complete in most subjects.65 This explains why ingestion of fruit juices with a high-fructose/glucose ratio and in which sorbitol also is present (eg, apple, pear), as well as sorbitol-containing products such as chewing gum and candy, can cause symptoms such as chronic nonspecific diarrhea, flatulence, abdominal distension, and abdominal pain in some children.66 Diagnosis should be suspected on the basis of a dietary history that identifies ingestion of large amounts of fructose or sorbitol. The diagnosis can be confirmed by means of a breath test using the appropriate monosaccharide as substrate or by excluding the offending substance from the diet and documenting complete resolution of symptoms.

Secondary Disorders of Carbohydrate Malabsorption

Intestinal disorders that result in damage to the small bowel mucosa are commonly associated with secondary, or acquired, carbohydrate malabsorption, mainly due to a decrease in the intestinal brush border membrane hydrolases. In cases of severe mucosal damage, malabsorption may be aggravated by a decrease in absorptive surface area. In these cases there may also be malabsorption of monosaccharides in addition to disaccharides. Conditions associated with intestinal mucosal damage are listed in Table 408-5. Many of these are potentially reversible with appropriate treatment of the underlying condition. In such cases the carbohydrate malabsorption is transient.

Of the intestinal brush border membrane hydrolases, lactase has the lowest relative activity levels and therefore is most commonly first affected when there is damage to the intestinal mucosa. With progressive damage, sucrase is next affected, and in severe damage it is possible to have glucoamylase deficiency as well. Infectious agents, notably rotavirus and Giardia lamblia, commonly cause transient intolerance to lactose. Carbohydrate malabsorption also has been reported in HIV infection, and lactase deficiency is common in children with AIDS who have diarrhea. Mucosal damage that is immune mediated, as in milk protein–sensitive enteropathy and celiac disease, is frequently associated with sugar malabsorption. Small intestinal bacterial overgrowth, as occurs in children with short bowel syndrome or in disorders affecting intestinal motility, often leads to disaccharidase deficiencies. This occurs as a result of direct damage to the intestinal mucosa by the bacteria and from degradation of brush border enzymes by bacterial proteases.

Children with secondary or acquired carbohydrate malabsorption usually present with diarrhea as their major clinical symptom. Typically, the stools are watery and explosive in nature and frequently cause excoriation of the buttocks due to the acid content. Stool output decreases significantly or even ceases completely when enteral feeds are withheld or the offending carbohydrate is withdrawn from the diet. Treatment of the underlying cause of the intestinal damage will usually result in mucosal repair and regeneration of brush border membrane enzyme activity.

Congenital defects in enterocyte transport function are a rare group of disorders that are characterized by impaired transport of nutrients across the intestinal mucosa into the systemic circulation. In some there are visible histologic structural abnormalities, but in many the mucosa appears intact with normal-appearing villi and enterocytes. Symptoms associated with these deficiencies vary from none or mild to severe, with diarrhea, dehydration, failure to thrive, and systemic manifestations of specific nutritional deficiencies. Congenital defects in amino acid transport, including Hartnup disease, lysinuric protein intolerance, and blue diaper syndrome, are discussed in detail in Section 11. Of these, only lysinuric protein intolerance has gastrointestinal manifestations, often presenting with clinical features of recurrent vomiting, episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia (see Chapter 140).

Congenital Defects in Fat Transport

Intraluminal lipolysis of dietary fats generates free fatty acids and monoglycerides that are passively transported into the enterocyte. The mechanisms of fat digestion and absorption are described in Chapter 166, and shown in Figure 166-1. Beta-apolipoproteins are critical for the formation and secretion of chylomicrons and very low-density lipoprotein (VLDL) from the enterocyte and hepatocyte, respectively. There are two beta-apolipoproteins—B-100 and B-48. Apolipoprotein B-100 is synthesized in the liver and is carried on VLDL and apolipoprotein B-48 is derived from the enterocyte and is carried on chylomicrons. Defects in the production of these apoproteins result in abetalipoproteinemia and hypobetalipoproteinemia.

Abetalipoproteinemia

Abetalipoproteinemia, also known as Bassen-Kornzweig syndrome, is a rare disorder inherited in an autosomal recessive manner, with only about 100 cases described worldwide. It is characterized by congenital absence of apoprotein B, which results in an inability to synthesize chylomicrons. Microsomal triglyceride transfer protein is required for assembly of chylomicrons within the enterocyte. Several mutations within the microsomal triglyceride transfer protein gene (4q22-q24) have been identified that result in abetalipoproteinemia.67

Infants with abetalipoproteinemia present early in life with steatorrhea, characterized by pale, bulky, and offensive-smelling stools; abdominal distension; and failure to thrive. Associated deficiencies in fat-soluble vitamins result in devastating neurologic manifestations later in life that are largely due to vitamin E deficiency, including pigmented retinopathy and spinocerebellar degeneration with loss of deep tendon reflexes, progressive ataxia and spasticity, and peripheral neuropathy.

Diagnosis depends on recognition of the signs of fat malabsorption, usually associated with failure to thrive. Laboratory investigations demonstrate acanthocytes in the peripheral blood smear that result from membrane lipid abnormalities in the erythrocytes (eFig. 408.3). Often a finding of an extremely low level of plasma cholesterol (< 50 mg/dL) and triglycerides alerts the clinician to consider a diagnosis of abetalipoproteinemia. A fasting lipid profile reveals that chylomicrons and VLDLs are undetectable. Histology of small intestinal biopsy specimens reveals normal-appearing villi, but the enterocytes are filled with lipid droplets. The diagnosis can be confirmed by identifying specific mutations in the microsomal triglyceride transfer protein gene.

Treatment consists of restricting dietary long-chain fatty acids and supplementation with medium-chain triglycerides. Large doses of vitamin E (100–300 mg/kg/day) and water-soluble forms of vitamins A, D, and K should be supplied, together with routine monitoring of the blood levels of all fat-soluble vitamins.

Hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is a rare autosomal dominant disorder of apo-B metabolism caused by mutations in the APOB gene involving 1 or both alleles.67 To date, more than 30 mutations have been described. The most common mutations lead to truncations of the apolipoprotein-B molecules that result in either impaired synthesis of apolipoprotein-B–containing lipoproteins or their increased catabolism. Homozygotes for FHBL are clinically similar to those with abetalipoproteinemia (ABL) with impairment of chylomicron formation, consequent fat and fat-soluble vitamin malabsorption, similar intestinal biopsy findings, and sequelae due to fat-soluble vitamin deficiencies. A lipid profile on the parents of the affected child may help distinguish between ABL and FHBL because parents of children with ABL have normal cholesterol levels while those of a child with homozygous FHBL have lower than average levels. Aside from low plasma cholesterol and low to normal triglyceride levels, heterozygotes are asymptomatic, but they may have vitamin E deficiency. The diagnosis of FHBL can be confirmed by identifying specific mutations on the APOB gene.

Treatment for homozygous familial hypobetalipoproteinemia is the same as that for abetalipoproteinemia, involving dietary restrictions of long-chain fatty acids and high-dose supplementation of vitamins A, D, E, and K. Heterozygotes for familial hypobetalipoproteinemia should receive supplements of vitamin E to prevent neurological manifestations that occasionally occur.

Chylomicron Retention Disease

Chylomicron retention disease (CMRD) is also known as Anderson disease, is inherited as an autosomal recessive condition due to mutations in the SAR1B gene that maps to the 5q31.1 locus.68 CMRD appears to result from defective exocytosis of chylomicrons from the enterocyte, but the precise reason for this remains unknown.69 The condition is characterized by severe fat malabsorption with progressive neurologic degenerative disease, similar to that found in abetalipoproteinemia (ABL) and homozygous familial hypobetalipoproteinemia (FHBL).

The clinical presentation is the same as that found in children with ABL with onset of fat malabsorption and failure to thrive in early infancy. Acanthocytosis is present but usually less severe than in ABL. Unlike ABL and homozygous FHBL, the fasting lipid profile in CMRD reveals normal triglyceride levels and reduced levels of cholesterol and apoprotein B, with an absence of postprandial circulating chylomicrons in the blood. Intestinal biopsies reveal normal villous architecture with enterocytes filled with lipid droplets. Treatment is similar to that for ABL and consists of dietary restriction of long-chain fatty acids and supplementation with large doses of fat-soluble vitamins A, D, E, and K.

Congenital Defects in Carbohydrate Transport

Complete intraluminal hydrolysis of carbohydrates results in the production of the monosaccharides glucose, galactose, and fructose. Subsequent entry of these monosaccharides across the brush border into the enterocyte occurs via carrier molecules. Rare congenital defects in these carrier molecules result in malabsorption of these simple carbohydrates.

Congenital Glucose-Galactose Malabsorption

Congenital glucose-galactose malabsorption is caused by a mutation of the SGLT-1 gene. Affected infants present with explosive, watery diarrhea immediately following the commencement of enteral feeds. Untreated, the infants develop dehydration that can be severe and fail to gain weight. Diarrhea ceases promptly if enteral feeds are withheld or if glucose and galactose are removed from the diet.

Diagnosis is dependent on clinical suspicion, laboratory investigations, and response to therapy. The presence of an osmotic diarrhea is inferred based on cessation of stool output when enteral feeds are stopped and all fluids are delivered intravenously. An osmotic cause for the diarrhea can be confirmed by measuring stool electrolytes and osmolarity and calculating the osmotic gap. A positive test for reducing substances in the stools indicates the presence of a reducing sugar such as glucose or galactose. Histologic examination of small intestinal mucosa reveals normal villus structure and cellularity, which excludes secondary causes for carbohydrate malabsorption. Cessation of diarrhea in response to a therapeutic trial using feeds that contain fructose as the sole source of carbohydrates is strong supportive evidence for the diagnosis of congenital glucose-galactose malabsorption. The diagnosis can be confirmed on identification of a known mutation of the SGLT-1 gene, but this test is not widely available.

Treatment initially requires complete elimination of all carbohydrates other than fructose from the diet. As the infant grows, a gradual program involving the introduction of low-carbohydrate feeds into the diet is initiated and advanced as tolerated.70 With increasing age and colonic adaptation, the individual is able to tolerate greater amounts of other carbohydrates.

Congenital Isolated Fructose Malabsorption

Fructose uptake across the enterocyte is a facilitated process dependent on a hexose carrier, GLUT-5. Isolated fructose malabsorption is a clinical entity, with symptoms developing after a fructose load. No mutations on the GLUT-5 have yet been identified in affected individuals, and hence the mechanism for the malabsorption remains unknown.71 Symptoms appear to be dependent on the fructose load and are influenced by the ratio of glucose to fructose in the intestinal lumen. Fructose is best absorbed when combined with glucose in a 1:1 ratio. Malabsorption is characterized by abdominal discomfort, with gas production and diarrhea in some cases. Diagnosis can be confirmed by means of a fructose breath hydrogen test. Treatment involves dietary restriction of fructose-containing foods and fluids.

Enteric Anendocrinosis

Although this disorder, also known as enteroendocrine cell dysgenesis is not strictly a disorder of carbohydrate transport it presents similarly. This rare disorder results from disruption in the pathway of differentiation for enteroendocrine cells due to mutations in the neurogenin-3 gene. Affected infants present with vomiting, diarrhea, dehydration, and a severe hyperchloremic metabolic acidosis after the ingestion of formula. Diarrhea ceases during periods of fasting, or during administration of water. However, administration of substrate containing formulas (including carbohydrate free) leads to diarrhea. Diagnosis is made by intestinal biopsy. Villus structure appears normal with no pathologic infiltration of inflammatory cells.

Staining for chromogranin A, a marker for enteroendocrine cells, reveals a marked depletion of enteroendocrine cells. Normal mucosa contains 5 to 6 enteroendocrine cells per crypt. Electron microscopy reveals a normal mucosa. Treatment currently consists of parenteral nutrition, with consideration of small bowel transplant.72

Congenital defects in intestinal transport of electrolytes are rare disorders involving principally sodium and chloride absorption. They are characterized by large volume loss of watery stools beginning at the time of birth. Maintenance of hydration initially requires aggressive fluid and electrolyte replacement delivered via the intravenous route. Acrodermatitis enteropathica involves a defect in zinc transport.

Congenital Chloride Diarrhea

Congenital chloride diarrhea is an autosomal recessive condition caused by mutations in the SLC26A3 gene, which encodes a sodium independent Cl–/HCO3– exchanger found in the apical brush border membrane of the enterocyte in the ileum and colon. Multiple different mutations of the SLC26A3 gene have been identified.73

Infants present with watery diarrheal stools that contain a high-chloride and low-bicarbonate concentration and a low pH. Diarrhea is secretory in type, and there is persistent high-volume stool output even when the infant is given nothing via the enteral route and receives only intravenous fluids. Infants are often born prematurely, but are of normal size for gestational age. Polyhydramnios is a constant feature, indicative of the intrauterine onset of diarrhea. There is frequently abdominal distension with visible intestinal peristalsis that may lead one to suspect intestinal obstruction. The diarrhea rapidly causes dehydration and severe electrolyte disturbance characterized by hypochloremia, hyponatremia, and metabolic alkalosis. Treatment involves continuous replacement of the water and electrolyte losses. Initially, this needs to be delivered intravenously, but very soon after birth it can be delivered via the enteral route. With treatment, the prognosis is good, and most children eventually become continent for feces by 3 to 4 years of age.

Congenital Sodium Diarrhea

Congenital sodium diarrhea is a rare autosomal recessive condition characterized by a defect in intestinal sodium transport. The defect involves the Na+/H+ exchange transport system in the jejunum, ileum, and colon. To date no mutations in candidate genes for the known sodium-proton exchangers have been identified.74 Clinical features are similar to those of congenital chloride diarrhea. The pregnancy is often complicated by maternal polyhydramnios. Watery diarrhea starts at birth, and the stools characteristically have very high sodium content. In contrast to congenital chloride diarrhea, stool chloride concentration is lower than that of sodium, and the stools tend to be alkaline. The diarrhea rapidly causes dehydration and an electrolyte disturbance characterized by hyponatremia and hypochloremia, but unlike congenital chloride diarrhea, there is a metabolic acidosis. Treatment involves replacing the ongoing water and electrolyte losses. Provision of sodium in the form of sodium citrate alleviates the acidosis. With treatment, normal growth and development can be anticipated, and continence for feces can be expected by 3 to 4 years of age.

Acrodermatitis Enteropathica

Acrodermatitis enteropathica is an autosomal recessive disorder of zinc absorption caused by mutations in the SLC39A4 gene on 8q24.3.75,76 The gene appears to code for a transmembrane protein involved in the uptake of zinc. Symptoms of zinc deficiency develop in infancy, shortly after discontinuation of breast-feeding. This has led to the postulate that human milk contains a ligand that is beneficial for zinc absorption, but to date this has not been confirmed.

Clinical manifestations are characterized by dermatitis with bullous and pustular lesions; alopecia; ophthalmic manifestations including blepharitis, conjunctivitis, and corneal opacities; diarrhea; and growth retardation. The skin lesions are typically distributed around the mouth (Fig. 408-7); in the anogenital region; and on the face, scalp, hands and feet. Infants that are not breast-fed develop symptoms within 1 to 2 months after birth. Breast fed infants become symptomatic 2 to 3 weeks after weaning.

The differential diagnosis includes other causes of acquired zinc deficiency. These may occur in total parenteral nutrition, cirrhosis of the liver, renal disease (nephritic syndrome, renal tubular dysfunction), and malnutrition (kwashiorkor). Other skin disorders, such as atopic dermatitis, psoriasis, and burn injuries, as well as essential fatty acid deficiency or ingestion of foods that contain a large amount of phosphate, can produce similar skin lesions.

Diagnosis is based on the presence of clinical findings and documentation of chronic zinc deficiency with plasma zinc concentrations below 50 μg/dL. Other laboratory parameters that support the diagnosis include decreased activity of zinc-dependent enzymes such as serum alkaline phosphatase and low red blood cell and urinary zinc levels. Skin biopsies revealing the characteristic features seen in zinc deficiency are further supportive evidence. Often, the diagnosis can only be confirmed after attempts to discontinue zinc supplementation fail. Treatment requires administration of 35 to 100 mg elemental zinc per day delivered orally in divided doses. Zinc sulfate heptahydrate (50 mg elemental zinc in 220 mg) is commonly used, but other salts are available. The treatment must be continued indefinitely, with adjustments of dose for growth rates and stresses such as intercurrent illnesses. Although massive doses of zinc (12–24 g) can result in toxicity (nausea, vomiting, lethargy, muscular incoordination, dizziness, and renal failure), the safety and efficacy of zinc sulfate make it the treatment of choice for acrodermatitis enteropathica.

The short bowel syndrome (SBS) is defined as a functional impairment in intestinal absorption resulting from a critical reduction in intestinal length. Massive intestinal resection leads to malabsorption, chronic diarrhea, malnutrition, and micronutrient and electrolyte deficiencies. Malabsorption results mostly from the decreased villous absorptive surface, with contributions from mucosal injury, bile acid deficiency, and small intestinal bacterial overgrowth. SBS is the most common cause of intestinal failure and dependency on parenteral nutrition. Its prognosis is largely dependent on the functional capacity of the remaining bowel.

Epidemiology

Short bowel syndrome (SBS) is about twice as common in children as in adults, but the overall incidence is still only approximately 1 in 500,000.77 This number is projected to increase as the survival rates for many of the causes of SBS increase due to therapeutic advances. The most common causes of pediatric SBS are shown in Table 408-6. In infants, SBS is most often the result of congenital gastrointestinal anomalies or necrotizing enterocolitis.78 Multiple intestinal atresias, abdominal wall defects—gastroschisis and, to a lesser degree, omphalocele—account for most of the congenital anomalies causing SBS cases in infancy. Volvulus due to malrotation or to a Meckel diverticulum also may cause SBS. Necrotizing enterocolitis (NEC) accounts for about 40% of infant SBS. Almost 20% of infants with NEC requiring resection develop SBS. An uncommon cause of infant short bowel syndrome is severe aganglionosis involving the small bowel. Congenital short gut without atresias has been the subject of rare case reports and is postulated to be caused by in utero intestinal infarction.79

In older children and adolescents, causes of short bowel syndrome include massive abdominal trauma, intra-abdominal malignancy, midgut volvulus due to previously unrecognized malrotation, severe small intestinal Crohn disease, vascular anomalies requiring bowel resection, thrombotic disease, and radiation enteropathy from radiation usually administered for treatment of an abdominal neoplasm.80

Pathophysiology

The functional region and the length of the gastrointestinal tract that remains after resection determine the net balance of absorption and secretion, and hence the severity of short bowel syndrome. Duodenal resection, which is rare in pediatric short bowel syndrome, results in decreased absorption of iron, folate, and calcium, causing anemia and osteopenia. Isolated jejunal resection is well tolerated because the intact ileum adapts to absorb nutrients and excess fluid. In contrast, ileal resection has profound effects on absorption in that resection of more than 50% results in large water and electrolyte losses. The ileum also has two specialized functions—the absorption of bile salts and vitamin B12—that the more proximal small intestinal segments cannot adapt to perform. Ileal resection results in decreased intraluminal bile salt concentrations and hence fat malabsorption. The unabsorbed bile acids and long-chain fatty acids will in turn stimulate a secretory diarrhea. Vitamin B12 malabsorption can result in a macrocytic anemia. Resection of the ileocecal valve is associated with the development of bacterial overgrowth with subsequent mucosal damage. Absence of ileum, ileocecal valve, and colon removes the “ileal brake” mechanism, shortening intestinal transit time and further reducing contact between nutrients and absorptive surface.81 Loss of continuity with the colon impacts fluid balance and removes a nutrient source, the fermentation of unabsorbed carbohydrates by resident anaerobic bacteria.82 The clinical manifestations of short bowel syndrome alter with time due to a gradual process of intestinal adaptation, characterized by lengthening of villi and an increase in mucosal absorptive capacity. Small bowel dilation occurs and further increases the overall absorptive surface area.83 Adaptation is regulated by several enterocyte-derived mediators. Luminal nutrients, especially long-chain triglycerides and intact proteins, stimulate cellular hyperplasia and mucosal growth, underscoring the importance of enteral nutrition in the management of this disorder.

Management

The desired outcome of managing patients with short bowel syndrome is a transition from total parenteral nutrition to full enteral feeds. This is a gradual process that requires a great deal of patience as well as the expertise of a multidisciplinary team including pediatric surgeons, intensivists, gastroenterologists, nutritionists, and nurses. Management of these patients is typically divided into phases demarcated by nutritional input.

The initial period following intestinal resection requires decompression of the upper gastrointestinal tract while awaiting resolution of postoperative ileus. Fluid and electrolyte balance must be carefully maintained in the face of variable volume and electrolyte content of ongoing fluid losses. This is particularly important for patients with more proximal enterostomies predisposing them to high-volume secretory diarrhea. Fecal and urinary electrolytes should be monitored closely, and electrolyte losses should be replaced intravenously. A central venous line is usually placed at the original surgery or during this postoperative period. Management is simplified by the delivery of a prescribed solution of central parenteral nutrition that delivers maintenance fluid and electrolyte needs and separate administration (via a Y-injection port) of replacement fluids and electrolytes for ostomy or fecal water and electrolyte losses. Antisecretory therapy with proton-pump inhibitors may reduce gastric hypersecretion that can account for high fecal fluid losses and deactivate pancreatic digestive enzymes.84 Once the patient’s fluid and electrolyte status is stabilized on parenteral nutrition, enteral nutrition is gradually introduced. Enteral nutrition stimulates the process of intestinal adaptation or compensatory mucosal growth with enterocyte hyperplasia and villus lengthening and also mitigates against complications of parenteral nutrition (discussed below). Trophic feedings, delivered by continuous intragastric or transpyloric infusion (in order to maximize absorptive potential) should begin early, even in the setting of large fluid and electrolyte losses in the stool, as long as adequate replacement is provided.85 A marked increase in stool volume or evidence of marked carbohydrate malabsorption (manifested by a fecal pH < 5.5 or moderate reducing substances) contraindicates further advancement of feeds.

Controversy surrounds the optimal composition of enteral formula for short bowel syndrome, especially in infants. Breast milk, protein hydrolysate formula, amino acid–based formula, and various lipid blends have all been advocated and used by different centers. Fatty acids stimulate enterocyte hyperplasia, so they are a key component. Carbohydrate usually is provided as glucose polymers or sucrose because lactose is poorly tolerated, though this is more of a problem in proximal resections. Soluble fiber serves as a source of short-chain fatty acids as well as a stool-bulking agent. Protein hydrolysates are adequately absorbed; in rare cases, more elemental solutions may be required. In general, a diet higher in fat than in carbohydrate tends to be better tolerated in pediatric short bowel syndrome patients, mainly due to a lower luminal osmotic load. Remnant anatomy may be the best determinant of macromolecule tolerance. Patients with a terminal enterostomy will benefit from diets high in lipids, particularly long-chain triglycerides, which stimulate enterocyte adaptation while not increasing the osmolarity of luminal contents and consequent fecal water loss. In contrast, patients with a substantial length of colon in continuity with remnant small intestine tolerate complex carbohydrates better because of colonic bacterial fermentation to short-chain fatty acids.86 Also, a lipid blend rich in medium-chain triglycerides is better absorbed by patients with colonic continuity.87

Advancing enteral nutrition is based on tolerance—maintenance of hydration without excessive fecal losses. Stool or ostomy output greater than 50% over baseline, greater than 40 to 50 mL/kg/day, or with strongly positive reducing substances usually contraindicate further advancement of enteral feedings.88 The bowel adapts over a period of months to years, and reliance on parenteral nutrition for nutritional support decreases. As soon as feasible, a “window” period, or cycling of the parenteral nutrition solution, should be instituted to decrease hepatocellular injury and promote patient mobilization. Enteral nutrition is typically increased at a rate of 0.5 to 1.0 cal/kg every 1 to 3 days, and continued weight gain and tolerance dictates weaning of first, parenteral calories, then parenteral nutrition volume. Success is determined by a constant or increasing proportion of enteral nutrient absorption over time, accompanied by acceleration in weight velocity and linear growth. However, malabsorption makes the amount of energy needed from enteral nutrition greater than that needed from parenteral nutrition to achieve similar weight gain. It is important not to be overly aggressive and to make small frequent increases in enteric feeding to allow the small intestine to adapt to the increased nutrient administration.88 If fecal losses suddenly increase during advancement of enteral nutrition, intestinal absorption probably has reached its maximum and feedings should not be increased until further adaptation occurs. Intercurrent infection or bacterial overgrowth (see below) may also result in a reduction in feeding tolerance.

Home parenteral nutrition administration has become a safe and widespread practice in pediatric short bowel syndrome care, and provides a more cost-effective alternative89 to hospital confinement during the gradual transition to enteral nutrition.

Oral feedings, even in minute amounts, should be instituted as soon as feasible in order to preserve feeding skills and prevent development of oral feeding aversion. Oral glucose-electrolyte solutions can be used when fluid losses are an issue. Trace elements and vitamins are initially supplemented in parenteral nutrition solutions and then orally as parenteral nutrition is weaned, and serum levels are checked periodically. Zinc, calcium, and magnesium deficiencies are common among children with extensive small bowel loss. Zinc deficiency can perpetuate diarrhea and undernutrition. Vitamins B12, D, and E absorption is often impaired, even in those children who have achieved full oral nutrition, and levels should be monitored.

Adjunctive medical therapies are sometimes used in the management of short bowel syndrome in infants and children. Antimotility agents such as loperamide and diphenoxylate/atropine can help reduce fecal fluid losses, though in young children the relatively high doses required can lead to paralytic ileus, vomiting, and lethargy. Octreotide may reduce output from proximal ostomies but can predispose the child to gallstone formation.90 The bile acid sequestrant cholestyramine is used empirically to treat choleretic secretory diarrhea in patients with a limited ileal resection. Glutamine supplementation in theory would provide fuel and nucleotides for enterocyte and colonocyte growth, but no controlled studies have demonstrated efficacy of glutamine given enterally or in parenteral nutrition for shortening the duration of parenteral nutrition.91 Growth hormone alone or in combination with glutamine produced a modest improvement in electrolyte absorption, but no effect on small bowel morphology, stool losses, or macronutrient absorption.92 These therapies are considered experimental, as is the use of glucagon-like peptide-2, an enterocyte growth factor that improved nutrient absorption and nutritional status in a limited number of adult short-bowel patients with extensive ileocolonic resections.93

Complications

Table 408-7 lists the primary complications associated with short bowel syndrome. During the initial phase of management of short bowel syndrome, complications arise due to the necessity of a central venous catheter and total parenteral nutrition use. Central line infections with bacteria and fungi can lead to systemic sepsis and death, particularly in infants with extremely short bowel remnants, comorbidity, and liver disease. Infection rates in pediatric short bowel syndrome range between 1 and 6 per 1000 days of parenteral nutrition.94 Thrombotic and thromboembolic catheter problems occur, as do pleural effusions and luminal occlusions. Limited sites are available for the placement of infusion catheters during a patient’s lifetime, so aggressive treatment of potential line infections or thrombosis is mandatory before their removal is considered.

Chronic use of parenteral nutrition causes cholestasis and hepatocellular injury that can develop into progressive liver disease and liver failure as discussed in Chapter 422. Risk factors for parenteral nutrition–associated liver failure include extreme small bowel loss and sepsis in infants within a few months after resection.95 Minimizing catheter sepsis, aggressive use of enteral feedings, and careful attention to appropriate use of parenteral nutrition may help to reduce the risk. Ursodeoxycholic acid may help with choleresis and have cytoprotective effects, but significant long-term benefit has not been documented. Very recently, the substitution of a conventional parenteral nutrition fat emulsion with one containing primarily omega-3 fatty acids (Omegaven) has been reported to lead to resolution of parenteral nutrition–associated liver disease in 2 infants still on parenteral nutrition.96 Signs of progressive parenteral nutrition–related liver disease include persistent cholestasis despite full enteral feedings, thrombocytopenia, and splenomegaly. These signs should prompt early consideration of liver and small bowel transplantation. Ileal resection and prolonged parenteral nutrition also predispose the patient to formation of calcium bilirubinate gallstones,97 which can lead to cholecystitis and bile duct obstruction requiring surgical management. Prolonged parenteral nutrition and lipid malabsorption of short bowel syndrome (SBS) can lead to calcium oxalate renal stones. Small intestinal bacterial overgrowth (SIBO) is discussed below. In infants with SBS, the onset of lethargy and ataxia should raise suspicion of the development of d-lactic acidosis, especially if wide anion gap metabolic acidosis is noted. Treatment of SIBO relieves the symptoms.

Remnant bowel in SBS usually has ineffective peristalsis due to dilation, leading to recurrent symptoms of partial obstruction. This is aggravated by the development of anastomotic strictures. Dysmotility in SBS can be initially treated medically with antibiotics and prokinetics, but most often will require surgical intervention. Longitudinal intestinal lengthening (Bianchi procedure), antimesenteric longitudinal tapering, and serial transverse enteroplasty (STEP) are operations geared toward reducing bowel caliber and increasing bowel length The STEP procedure has shown promising short-term outcomes in SBS infants, including earlier weaning from parenteral nutrition and prevention of d-lactic acidosis,98 but long-term outcomes have not been reported.

Intestinal failure or inability to wean parenteral nutrition, parenteral nutrition–induced liver failure, and impending loss of central venous access sites are indications for consideration of intestinal transplantation, which is discussed in Chapter 131.

Prognosis

The survival rate for all pediatric patients with short bowel syndrome (SBS) is approximately 87%.99 Infants with extreme short bowel, defined as 95% or greater small bowel resection, are more predisposed to mortality related to liver failure and catheter sepsis. The factors that determine the ability to transition to enteral nutrition include small intestinal length, ileocecal and colonic anatomy, the function of the remnant bowel, and the process of adaptation. In infants, tolerance of enteral nutrition estimates remnant gut function; for example, an infant with 25 cm of small bowel remaining who tolerates 75% of calories enterally by age 3 months has a 90% chance of weaning parenteral nutrition.100 In contrast, the likelihood of becoming parenteral nutrition–independent decreases to 50% if only 25% of daily calories are effectively delivered through the gastrointestinal tract at 3 months of age. Children continuing to require parenteral nutrition 3 to 4 years after resection are likely to require parenteral nutrition indefinitely. The prognosis of SBS requires continuous reevaluation as the child transitions from inpatient intensive care to outpatient multidisciplinary management.

Small intestinal bacterial overgrowth (SIBO) is a condition characterized by an increased number and/or type of bacteria in the upper gastrointestinal tract. Under normal circumstances, the stomach and proximal small bowel are relatively sterile in comparison to the colon. SIBO is diagnosed when jejunal bacterial counts exceed 105 organisms/mL (normal concentration is 104 organisms/mL). Multiple organisms are typically present in varying numbers, and common species include streptococci, Bacteroides, Escherichia coli, and lactobacilli.101 Disruption of protective mechanisms such as gastric acid secretion, peristalsis, pancreatic secretions, the ileocecal valve, and the mucosal immune system may result in SIBO. Anytime a disease process interrupts or overwhelms the protective mechanisms discussed above, SIBO may ensue. The most common causes of SIBO are listed in Table 408-8. Disorders associated with bowel dilatation, blind loops, or reduced gastrointestinal motility impair the normal clearance of bacteria from the small bowel by the migrating motor complex during fasting. Other causes include malnutrition, immunodeficiency, and pancreatic insufficiency such as is seen with cystic fibrosis and chronic pancreatitis. Hypochlorhydria induced by acid blockade has been shown to significantly increase the mean bacterial count in the stomach, from 0 to over 106.102

Pathophysiology and Clinical Features

Patients with small intestinal bacterial overgrowth may be asymptomatic or have malabsorptive symptoms including abdominal pain, bloating, excessive flatulence or eructation, watery diarrhea, dyspepsia, and weight loss or failure to gain weight.103 Intraluminal bacteria metabolize carbohydrate and lead to excessive gas formation and subsequent abdominal distention and halitosis. Bacterial deconjugation causes bile acids and hydroxylated fatty acids to become unabsorbable by the ileum, and these induce a secretory diarrhea in the colon. Fat malabsorption may lead to steatorrhea and fat-soluble vitamin deficiency. Direct mucosal injury by bacteria can lead to brush border degradation and disaccharidase deficiency, as well as loss of villous absorptive capacity. Such mucosal injury can also cause protein loss and signs of hypoproteinemia such as edema. In severe instances patients may present with hypocalcemic tetany induced by malabsorption of vitamin D, night blindness due to vitamin A deficiency, and dermatitis related to zinc malabsorption. The bacteria also take up vitamin B12, leading to a deficiency state marked by anemia, weakness, and paresthesias. Ataxia and lethargy after carbohydrate ingestion may result from d-lactic acidosis, which most often occurs in short bowel syndrome.104 Inflammation and toxin production in response to bacterial antigens may manifest as large-joint arthritis. Physical examination often reveals abdominal distention with loud borborygmi and an identifiable succussion splash due to palpable soft, fluid-filled loops of bowel. Laboratory examination may show hypoalbuminemia or anemia, which can be macrocytic due to malabsorption of vitamin B12, normocytic due to chronic disease, or microcytic due to occult blood loss.

Diagnostic Evaluation

Frequently, small intestinal bacterial overgrowth (SIBO) is suspected based upon the presence of characteristic symptoms in an at-risk patient. Small intestinal biopsy, while not diagnostic of SIBO, may identify inflammation associated with overgrowth and helps to exclude other causes of malabsorption. In some cases, SIBO may be associated with subtotal villus atrophy and increased cellularity in the lamina propria, which may be confused with celiac disease. Other screening studies that may detect the presence of bacterial metabolites are serum d-lactate levels and urine indicans. The gold standard for diagnosis of bacterial overgrowth is quantitative culture from a jejunal aspirate. A bacterial concentration greater than 105 organisms/mL fluid is considered diagnostic; however, the collection and culture technique is rife with limitations, including the meticulous care required to avoid contamination, the vast microbial diversity in the bowel, the fastidious nature of anaerobic cultures, and the patchy nature of SIBO. The most practical alternative to jejunal culture is breath hydrogen analysis, performed by administering a test dose of carbohydrate and measuring a rise or early peak in breath hydrogen levels. Of the breath test substrates, carbon 14 d-xylose has the accuracy most comparable to the gold standard, but is not widely available and not routinely recommended for children.105 The glucose breath hydrogen test has lower false-negative rates than the lactulose breath test;106 both of these are safe, simple to perform, and generally available. The sensitivity of these tests may be augmented by concurrent testing with methane, pretest mouthwash to remove oral bacteria, and avoidance of starches and fiber, which may cause prolonged hydrogen secretion. Even with these measures, false negatives may occur in 30% to 40% of patients due to low anaerobic organism counts.106

Empiric treatment of SIBO when the index of suspicion is high has been advocated and used frequently in practice. Symptom resolution on therapy supports the presumptive diagnosis. Antibiotics are the cornerstone of therapy, but the adverse effects of these, including diarrhea and bloating, may mimic symptoms of bacterial overgrowth. Some patients with demonstrable SIBO are asymptomatic or their digestive symptoms are not due to the overgrowth. Intestinal inflammation in association with SIBO is more supportive of a causal relationship.

Treatment

Most patients with small intestinal bacterial overgrowth (SIBO) will require treatment with antibiotics targeting the predominant organisms, usually anaerobes, coliforms, and bacteria. The aim of therapy is to alter the microflora in order to reduce symptoms, rather than to achieve complete eradication of intestinal bacteria. Antimicrobial agents typically used to treat SIBO in children include metronidazole, oral gentamicin or tobramycin (requires toxicity monitoring), amoxicillin-clavulonic acid, and trimethoprim-sulfamethoxazole. Norfloxacin is an option for monotherapy, but potential adverse effects of the fluoroquinolone class in young children remain a concern. Recently, rifaximin, a nonabsorbable broad-spectrum antibiotic, has demonstrated efficacy and safety in treatment of adult patients with SIBO.107 A single course of antibiotic therapy for 7 to 10 days usually leads to clinical improvement, but some patients require prolonged therapy for 1 to 2 months before a response is seen. Some patients with recurrent SIBO require repeated courses, and others need treatment on a cyclical basis.

Underlying causes of SIBO should be addressed either medically or surgically. Discontinuation of antisecretory or antimotility agents when feasible, as well as periodic bowel lavage with polyethylene glycol solutions, may be of benefit. A high-fat, low-carbohydrate diet may help reduce bacterial proliferation as carbohydrate is the preferred metabolic substrate of bacteria. Nutritional support and correction of micronutrient deficiencies is important. Some have advocated that that supplementation with nonpathogenic strains of probiotic bacteria may be beneficial,108 but several case reports of probiotic bacteria causing sepsis should lead to caution in their use for treatment of SIBO.109,110