change in 2–3 weeks, sigmoidoscopy can document the presence of eosinophilic inflammation as well as exclude other disorders. MILK PROTEIN-INDUCED ENTEROPATHY • Milk protein-induced enteropathy typically occurs in infants fed cow’s milk formula although it has also been described in soy protein- and breast-fed infants. In the latter, transmission of maternal dietary antigens through breast milk has been conjectured. The pri- mary symptoms of vomiting, diarrhea, and growth failure usually begin soon after birth (Table 73-1). • Small bowel injury can present with vomiting, diar- rhea, anemia, poor growth from malabsorption, and protein-losing enteropathy. Peripheral eosinophilia can be a clue, and histologic villous atrophy and intraepithelial lymphocytes help to confirm the diag- nosis. A higher prevalence of atopic dermatitis has been reported. Some studies have shown that atopy can be circumvented if predisposed infants are fed breast milk or hydrolysate formulas and introduction of high-risk food antigens (milk, soy, egg, gluten, and peanut) is delayed. •Traditional tests for allergy such as IgE-RAST (radioal- lergosorbent test) and skin prick testing are generally not useful in allergic bowel disorders. Avoidance of intact cow’s milk protein through a switch to soy pro- tein or protein-hydrolysate formulas is effective in the majority of infants; if successful it can obviate the need for further evaluation. Because up to 35% of infants with cow’s milk sensitivity have a concomitant soy allergy, soy formulas are not always effective. Those who do not respond to hydrolysate formulas (hexapep- tide) may require more complete elimination of cow’s milk antigens in peptide (tripeptides) or amino acid- based formulas. • Most affected infants will require cow’s milk protein elimination for the first year of life and outgrow the intolerance by 1–2 years of age. A cow’s milk protein challenge may be attempted after a year of age with appropriate monitoring in a medical setting. EOSINOPHILIC ESOPHAGITIS AND GASTROENTEROPATHY • EE is a distinct clinical entity with a gastroesophageal reflux disease (GERD)-like presentation whereas eosinophilic gastroenteropathy (EG) presents more like gastritis. EE is characterized by severe eosinophilic inflammation of the esophageal mucosa presumably due to multiple food allergies (Table 73-2). EG is char- acterized by eosinophilic infiltration of the gastric antrum, duodenum, and other distal parts of the GI tract. It is less common yet more difficult to treat than EE. EE has a bimodal distribution peaking in toddlers and teenagers. • EE should be considered when patients with refractory “GERD” fail maximal acid suppression and have normal 24-hour pH studies. Suggestive esophageal find- ings include erythema and edema, furrowing, nodular- ity, rings, strictures, adherent white plaques, and ulcerations more commonly in the mid than distal esophagus. This is confirmed by a higher density of mucosal eosinophils (≥20/hpf) compared to GERD. Unfortunately, identifying the offending food antigens can be problematic. Only some patients can identify food antigens based on symptoms but IgE-RAST and skin testing are typically normal. • Although dietary elimination for EE can be guided by symptoms and allergy testing results, the absence of identifiable food antigens necessitates a complete elimination diet consisting of an elemental (amino acid) formula. In most cases, there is symptomatic and pathologic resolution; however, because of diffi- culties associated with the poor tasting formula, lack of food, and nasogastric tube feeds, some opt for short- term systemic corticosteriod therapy or medium-term topical (swallowed) steroids. In EG, systemic corti- costeriod therapy is generally required but, because the effect is not sustained, it often has to be repeated. 310 SECTION 10 • GASTROINTESTINAL AND LIVER DISEASE TABLE 73-1 Symptoms and Presentation of Cow’s Milk Protein Allergy SYMPTOMS PRESENTATION Emesis Anemia Diarrhea Hypoalbuminemia Failure to thrive (FTT) Protein-losing enteropathy Abdominal distention Atopic dermatitis Hematochezia Irritability/colic TABLE 73-2 Symptoms and Findings of Eosinophilic Esophagitis (EE) and Eosinophilic Gastroenteropathy (EG) SYMPTOMS FINDINGS Emesis (often mucoid) Male preponderance Nausea Poor growth Abdominal pain Food allergy Anorexia Concurrent asthma Allergy in first-degree relative Peripheral eosinophilia Dysphagia (EE) Elevated IgE Esophageal stricture (EE) Gastric outlet obstruction (EG) Hypoalbuminemia (EG) Refractory to therapy (EG) Ascites (EG) (EE): Specific for EE only (EG): Specific for EG only CHAPTER 74 • DIARRHEA AND MALABSORPTION SYNDROMES 311 IgE-MEDIATED ANAPHYLAXIS •Anaphylactic reactions to food antigens can be life- threatening events. These are typically IgE-mediated reactions that cause immediate and potentially life- threatening symptoms with the most serious being upper airway obstruction (Table 73-3). Evaluation of suspected foods including common food allergens (milk, soy, egg white, peanut, shellfish, and wheat) should be tested by skin prick that carries a greater than 90% sensitivity. IgE-RAST testing may also be helpful in identifying the offending agent. In non-IgE- mediated hypersensitivities, symptoms are usually delayed. Treatment consists of eliminating the offend- ing food from the diet and supplying the patient with injectable epinephrine for emergency use. BIBLIOGRAPHY Furuta GT. Clinicopathologic features of esophagitis in children. Gastrointest Endosc Clin N Am 2001;11(4):683–715. Kelly KJ, et al. Eosinophilic esophagitis attributed to gastroe- sophageal reflux: Improvement with an amino acid-based for- mula. Gastroenterology 1995;109:1503–1512. Orenstein SR, et al. The spectrum of pediatric eosinophilic esophagitis beyond infancy: A clinical series of 30 children. Am J Gastroenterol 2000;95:1422–1430. 74 DIARRHEA AND MALABSORPTION SYNDROMES Rohit Kohli and B U.K. Li EPIDEMIOLOGY • Childhood diarrhea is a common but lethal problem in the United States, with 170,000 hospitalizations and up to 300 deaths a year. Worldwide it plays a central role in the vicious cycle of nutrient malabsorption, ensuing malnutrition and susceptibility to systemic infections such as measles. It is particularly problem- atic in infants because of their propensity to undergo acute volume and nutrient depletion during a phase of rapid somatic and brain growth. Diarrhea represents an excessive loss of fluid and electrolytes in stool and is defined quantitatively as a total daily volume exceeding 20 g/kg. ACUTE DIARRHEA • Acute diarrheal illnesses generally last less than 2 weeks and are caused by viral, bacterial, and parasitic infec- tions (Table 74-1). Viral diarrheas usually produce small bowel mucosal injury that results in carbohydrate mal- absorption and osmotic loss of fluids and electrolytes. In contrast, bacterial pathogens often produce toxins (e.g., cholera and verotoxins) that stimulate intestinal chloride secretion via second messenger pathways (e.g., cAMP and cGMP). In osmotic diarrheas, fasting eliminates the osmotic load from luminal carbohydrates and thus reduces fluid loss. In secretory diarrheas, fasting does not eliminate toxins that act as secretagogues and fluid loss continues unchanged (Table 74-2). •A positive effect has been seen on both diarrhea and short-term weight gain with early refeeding of soy- based or low-lactose formulas following 6 hours of oral or parenteral rehydration. Oral probiotic and zinc supplementation have also had positive effects on recovery. TABLE 73-3 Presentations of IgE-Mediated Food Allergy GENERALIZED GI RESPIRATORY Anaphylaxis Vomiting Rhinitis Urticaria Diarrhea Wheezing Orofacial edema Malabsorption Stridor Atopic dermatitis GI bleeding Upper airway obstruction TABLE 74-1 Etiologies of Acute Diarrhea VIRUS BACTERIA PROTOZOA Rotavirus Shigella Giardia Enteric adenovirus Salmonella Cryptosporidia Norwalk virus Campylobacter Entamoeba Calcivirus Yersinia Astrovirus E. coli TABLE 74-2 Osmotic vs. Secretory Diarrhea NORMAL OSMOTIC SECRETORY Etiology Rotavirus Cholera Response to IV/NPO Stops Persists Stool volume mL/kg/day 5–10 20–30 >50 Stool Na + (meq/L) 40 20 120 Stool K + (meq/L) 80 40 10 Stool osmotic gap (mOsm/L) 40 160 20 VIRAL DIARRHEAS •Viral-induced diarrheas are self-limited illnesses that produce watery, nonbloody diarrhea. Most are osmotic in mechanism, driven by unabsorbed luminal carbohydrates that can be detected by a high osmotic gap [stool osmolality ≈ 280 – (stool [Na + ] + [K + ]) × 2; normal <50 mOsm)], positive reducing substances and a low pH ≤5.5. Rotavirus is the most common viral cause with a characteristic winter peak. Day care centers are common sources of outbreaks in toddlers and Norwalk-like viruses have been implicated in confined community outbreaks. BACTERIAL D IARRHEAS • Bacterial diarrheas usually cause a colitis manifested by bloody, mucousy diarrhea associated with cramping and tenesmus. Because the yield from stool cultures is often low some advocate screening with stool leuko- cyte smears or fecal lactoferrin assays. Salmonella has been associated with pet turtles and Shigella outbreaks with public swimming pools. The following bacteria are associated with specific foods: Yersinia—pork; Campylobacter—dairy, poultry; E. coli 0157:H7— ground beef; and Salmonella—dairy, eggs, or meat. • Recent travel to endemic areas merits multiple samples for Giardia, Cryptosporidia, and other ova and para- sites. Antibiotic use in children over a year of age should always prompt testing for Clostridium difficile toxin. C OMPLICATIONS •Although dehydration is the principal complication of acute diarrhea, many other complications can occur (Table 74-3). Infants and toddlers are more susceptible because of their heightened intestinal secretory response to enterotoxins, incomplete colonic fluid reabsorption, and larger mucosal sur- face area relative to body fluid volume. Clinical con- firmation of dehydration is made by the presence of lethargy, depressed anterior fontanel, sunken eyes, dry mucous membranes, skin tenting, and delayed capillary refill. CHRONIC DIARRHEAS • Chronic or persistent diarrhea is a label applied when symptoms last longer than 4 weeks and is responsible for the largest share (c.f. acute diarrhea) of the diar- rhea-associated mortality in developing countries. It is especially important in immunocompromised patients (e.g., human immunodeficiency virus/acquired im- munodeficiency syndrome [HIV/AIDS] patients) who have an increased risk of chronic diarrhea from microsporidium, blastocystis, cyclospora, isospora, and the like. E TIOLOGIES • The etiology of chronic diarrhea changes significantly with age (Table 74-4). In early infancy, formula pro- tein sensitivities are common causes. Congenital transport defects of amino acids (Hartnup disease), car- bohydrate (glucose-galactose malabsorption), fat (lipase deficiency), and electrolytes (chloride-losing diarrhea) are rare. In toddlers, toddler’s diarrhea (chronic nonspecific diarrhea of infancy) and “day care giardiasis” are common. In the school age child and adolescent, irritable bowel syndrome and acquired lac- tase deficiency are common whereas inflammatory bowel disease is the most serious. Acquired lactase deficiency is very common and affects 80–90% of African- and Asian-Americans as lactase activity is downregulated after weaning. Sexually active adoles- cents have an increased incidence of proctocolitis caused by Campylobacter, Shigella, and Chlamydia. MALABSORPTION • Malabsorptive disorders result from impaired diges- tion (intraluminal defects) and/or impaired absorption (mucosal defects) of nutrients (fat, carbohydrate, and proteins) that result in impaired growth. Because both 312 SECTION 10 • GASTROINTESTINAL AND LIVER DISEASE TABLE 74-3 Specific Complications of Pathogens Causing Diarrhea ORGANISM COMPLICATIONS Shigella Seizures, hemolytic anemia, meningitis, reactive arthritis Salmonella Sepsis, pneumonia, meningitis, osteomyelitis, cholelithiasis Campylobacter Meningitis, pneumonia, Guillain-Barré syndrome Yersinia Intussusception, peritonitis, Reiter syndrome Enterohemorragic E. Coli Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura TABLE 74-4 Etiologies of Chronic Diarrhea INFANCY TODDLERS SCHOOL AGE Cow’s milk protein Irritable bowel Irritable bowel sensitivity syndrome syndrome Soy protein Giardiasis Acquired lactase sensitivity deficiency Congenital transport Sorbitol and Inflammatory defects fructose excess bowel disease Microvillous inclusion Celiac disease Encopresis (not disease true diarrhea) CHAPTER 74 • DIARRHEA AND MALABSORPTION SYNDROMES 313 are not degraded by colonic bacteria, fat and α 1 -antit- rypsin are the best markers of luminal nutrient loss and endogenous (serum) protein loss, respectively. Intraluminal defects include insufficient secretion of pancreatic enzymes and bile salts in cholestatic disor- ders that lead to maldigestion and impaired emulsifi- cation of fat, respectively (Table 74-5). Mucosal defects include loss of surface area in celiac disease that leads to impaired nutrient absorption (Table 74-6). E TIOLOGIES • Based on the gene frequency in Caucasians, the most common cause of malabsorption in the United States is cystic fibrosis (CF), an intraluminal defect. CF constitutes 95% of pancreatic insufficiency while Schwachman-Diamond comprises 3%. The most common global mucosal defect is celiac disease, gluten-sensitive enteropathy, but includes rare disor- ders such as microvillous inclusion disease. A third mechanism includes impaired removal of dietary long-chain fats through the lymphatic system in intes- tinal lympangiectasia. DIAGNOSIS •A detailed dietary history is important as to age of onset, number, and character of stools, relation to dietary intake, associated symptoms (pulmonary), and growth parameters. The growth curve is the most important data and, if normal, can exclude chronic severe malabsorption. • Initial screening should include a complete blood count, sedimentation rate, albumin, D -xylose absorption, and stool for ova and parasites, blood, leukocytes, fat stain (free fatty acids or split fat = poor absorption; neutral or large droplets = poor digestion) or steatocrit, pH and reducing substances (carbohydrate). Reflecting the jeju- nal surface area, the D-xylose absorption requires a 1- hour serum level after an oral load 14.5 g/m 2 or 0.3 g/kg in 10% solution following a 4-hour fast. Pancreatic insufficiency can now be suspected based on low-serum trypsinogen and elevated fecal elastase. • Definitive testing includes quantitative fat analysis, CF testing, celiac serology, and endoscopy with biopsies. The 72-hour fecal fat, expressed as the coefficient of fat absorption (≥95%) = (dietary fat intake – stool fat output)/(dietary fat intake) × 100%, is difficult to com- plete in infants and toddlers. In CF, an abnormal quan- titative sweat Cl − (>60 mmol/L) can be confirmed by the ∆508 mutation on CF transmembrane conductance regulator (CFTR) gene analysis. In Shwachman syn- drome, neutropenia and skeletal metaphyseal dysos- toses accompany exocrine pancreatic insufficiency. The celiac serology includes the highly specific IgA class antiendomysial and antitissue transglutaminase antibodies; however, endoscopic biopsies must be per- formed to confirm the inflammatory loss of villi and to exclude disorders such as eosinophilic gastroenteritis. Celiac disease is an immune-mediated inflammatory response to gluten in wheat, barley, and rye and is associated with type I diabetes, Down syndrome, and other autoimmune disorders. B IBLIOGRAPHY Dennison BA. Fruit juice consumption by infants and children: A review. J Am Coll Nutr 1996;15(Suppl. 5):4S–11S. Fayad IM, Hashem M, Hussein A, et al. Comparison of soy-based formulas with lactose and with sucrose in the treatment of acute diarrhea in infants. Arch Pediatr Adolesc Med 1999;153:675–680. Rothbaum R. Shwachman-Diamond syndrome: report from an international conference. J Pediatr 2002;141:266–270. Saavedra JM. Clinical applications of probiotics agents. Am J Clin Nutr 2001;73:1147S–1151S. Santosham M, Keenan EM, Tulloch J, Broun D, Glass R. Oral rehydration therapy for diarrhea: An example of reverse trans- fer of technology. Pediatrics 1997;100:e10. TABLE 74-5 Etiologies of Malabsorption INTRALUMINAL MUCOSAL OTHER Cystic fibrosis Celiac disease Intestinal lymphangiectasia Schwachman-Diamond Cow or soy milk enteropathy Congenital Cl – diarrhea Zollinger-Ellison syndome Crohn disease Glucose-galactose malabsorption Cholestatic liver disease Microvillus inclusion disease Hartnup (amino acid transport) TABLE 74-6 Comparison of Celiac Disease and Cystic Fibrosis CHARACTERISTIC CELIAC CYSTIC FIBROSIS Defect Mucosal Intraluminal Qualitative stool fat ↑ free fatty acids ↑ neutral fat Quantitative stool fat CFA <95% CFA <<95% D-Xylose (mg%) <20 >20 Serum trypsinogen both normal both ↓ and fecal elastase Sweat Cl – (meq/L) <60 ≥60 Celiac antibodies ↑ anti-EMA, anti-TTG normal Endoscopy flat villi, inflammation normal Sherman PM, Petric M, Cohen MB. Infectious gastroenterocoli- tides in children: An update on emerging pathogens. Pediatr Clin North Am 1996;43:391–407. 75 RECURRENT ABDOMINAL PAIN AND IRRITABLE BOWEL SYNDROME B U.K. Li RECURRENT ABDOMINAL PAIN • Recurrent abdominal pain (RAP) is a descriptive term currently defined as three episodes of abdominal pain recurring over a 3-month period sufficiently severe to disrupt usual activities. This symptom pattern affects 10–15% of children ages 5–14 years, it is the most common chronic complaint evaluated by pediatricians. Due to the advent of endoscopic assessment of upper gastrointestinal (GI) tract and hepatobiliary tree, and radiographic evaluation of GI tract and abdominal vis- cera by barium contrast, ultrasound, computerized tomography, magnetic resonance imaging, and scintig- raphy, the prevalence of identified underlying causes has increased sharply. In the 1960s, based on history, physical examination, complete blood counts, and uri- nalyses, Apley found only 5% of children to have a spe- cific organic etiology, whereas in 1995, Hyams et al. found 33% to have an organic basis (Table 75-1). • The majority of pediatric abdominal pain is functional rather than structural in origin. The clinical challenge is to differentiate—by history, red flags, laboratory screening, and response to empiric therapy—those with functional disorders (e.g., irritable bowel syn- drome) in need of less testing from those having an organic disorder (e.g., peptic esophagitis) that requires further testing and GI consultation (Table 75-2). This challenge is compounded by the fact that the abdomen is targeted not only by GI disorders, but also by extrain- testinal diseases (e.g., hydronephrosis) and psychologic stress. In addition, most children under 9 years of age localize pain to the umbilicus, wherever the actual origin, because of an undeveloped body image. In Table 75-3, specific red flags that warrant consideration of organic disorders and further testing are listed. • The most common disorders causing epigastric pain include peptic, allergic, and infectious disorders or injuries in the upper GI tract (Table 75-4). Functional dyspepsia is defined as epigastric pain, nausea, satiety, and bloating associated with eating in the absence of laboratory findings. The most common functional dis- orders involving the lower abdomen include motility disorders of the colon such as constipation and irrita- ble bowel syndrome, causing paroxysmal, midline pain, abdominal migraine is common and character- ized by sudden onset/offset, stereotypical pattern (e.g., time of onset, length, symptoms) that includes nausea, pallor and lethargy, and a family history of migraine. Other underappreciated disorders causing abdominal pain include peptic disease associated with endoscopi- cally-confirmed H. pylori gastritis that requires triple therapy, giardiasis associated with anorexia, nausea, vomiting, halitosis, and bloating without diarrhea in 50% of cases; and gallbladder dyskinesia diagnosed by scintigraphy (<40% emptying following cholecys- tokinin stimulation) characterized by right upper quad- rant pain, nausea, fatty food intolerance, and a clinical response to laparoscopic cholecystectomy. •Empiric therapy of undifferentiated recurring abdomi- nal pain in the absence of red flags is an appropriate initial approach in both primary and tertiary care set- tings (Table 75-5). In the case of epigastric pain related to meals or dyspepsia, an initial 2–4-week trial of H 2 - receptor antagonists is warranted. If lower abdominal or right lower quadrant pain and increased stool is detected on rectal, a trial of stool softeners or laxatives is warranted. If the pattern fulfills the criteria for irri- table bowel syndrome, those with pain and/or diarrhea can be treated with antispasmodics. Suspected lactose intolerance can be treated with lactose elimination or lactase enzyme supplements. 314 SECTION 10 • GASTROINTESTINAL AND LIVER DISEASE TABLE 75-1 Rome Criteria for Functional Abdominal Pain and Irritable Bowel Syndrome • Recurrent abdominal pain—three episodes of pain over a 3-month period, causing disruption in daily activities • Functional abdominal pain—6 months of nearly continuous pain, little relationship to eating or defecation, some loss of daily function, and no other functional GI disorder to explain symptoms •IBS—≥12 weeks of pain over 1 year mos plus two of three symptoms (relief by defecation, associated change in stool frequency or stool form) and no structural or metabolic abnormalities to explain symptoms. TABLE 75-2 Clinical Features to Help Differentiate Functional from Organic Disorders FUNCTIONAL ORGANIC Age <5 years – + Eccentric pain Less likely More likely Nocturnal pain Less likely More likely Upper abdominal pain Dyspepsia GE reflux disease Lower abdominal pain Constipation and IBS – CHAPTER 75 • RECURRENT ABDOMINAL PAIN AND IRRITABLE BOWEL SYNDROME 315 TABLE 75-4 Differential Diagnosis—Organic Causes Dyspepsia or epigastric pain Disorders GERD, eosinophilic esophagitis, peptic ulcer (±H. pylori), giardiasis, celiac disease, Crohn, chronic hepatitis, cholecystitis, biliary dyskinesia, chronic pancreatitis Screening tests CBC, ESR, hepatic and pancreatic enzymes, celiac screening, IBD serology Definitive tests small bowel radiography, endoscopy, ultrasound, GB scintigraphy (with CCK stimulation) Periumbilical/lower abdominal pain Disorders Hydronephrosis, malrotation, intussception, Crohn, ulcerative colitis, chronic appendicitis, lactose intolerance, abdominal migraine, constipation, gynecologic disorders, acute intermittent porphyria, musculoskeletal pain Screening tests CBC, ESR, lactose breath hydrogen, flat plate Definitive tests Small bowel radiography, ultrasound, computerized tomography, barium enema, colonoscopy, gynecology consult ABBREVIATIONS: GERD, gastroesophageal reflux disease; CBC, complete blood count; ESR, erythrocyte sedimentation rate; CCK, cholecystokinin. TABLE 75-3 Red Flags for Organic Disease SYMPTOMS CONSIDER Eccentric pain, pain that radiates to shoulder, back, side GI and hepatobiliary and pancreatic causes Constitutional symptoms—fever, malaise, arthralgias Infectious, inflammatory disorders e.g., IBD Vomiting, diarrhea Peptic/H. pylori, allergic, infectious, celiac disease, IBD Pain related to meals Peptic disorders, allergic, GB and pancreatic disorders, IBS, lactose intolerance Constipation, rectal bleeding Functional constipation, IBD, intussception Weight loss or growth failure Celiac disease, IBD Nocturnal occurrence Peptic and migraine disorders Progressive symptoms over time Celiac disease, IBD Family history of peptic ulcer disease Peptic disease/H. pylori Family history of inflammatory bowel disease IBD School absenteeism Dysability, school phobia ABBREVIATION: IBD, inflammatory bowel disease. TABLE 75-5 Initial Therapy of Undifferentiated Abdominal Pain POTENTIAL CAUSE THERAPY GOAL Acid-peptic disorder H 2 blockers, proton pump inhibitors Acid suppression Constipation Milk of magnesia, PEG 3350 Laxation Irritable bowel syndrome Antispasmodics Reduce colonic spasm Lactose intolerance Lactose elimination Stop lactose malabsorption NOTE: Do not treat H. pylori gastritis empirically. IRRITABLE BOWEL SYNDROME • Based on studies by Hyams et al. (1995, 1996, 1998), half of those who present with recurrent abdominal pain meet the criteria for irritable bowel syndrome. The current pathophysiologic understanding involves a triad of triggering psychologic or physiologic stress, altered GI motility (i.e., cramping or spasm) and intensified sensation, so-called visceral hypersensitiv- ity. There are three main patterns of irritable bowel syndrome (IBS) that are found in children including pain-, diarrhea-, constipation-predominant whereas alternating diarrhea and constipation tends to affect adults. The two most common triggers in children include psychologic stress and high-fat foods (e.g., fast foods). •Treatment can be directed toward any part of the triad including relief of stress through use of stress man- agement techniques or anxiolytics, reduced colonic spasm with fiber and antispasmodics, and attenuation of afferent pain transmission by tricyclic antidepres- sants and alosetron (Table 75-6). In infants, in whom the primary manifestation is diarrhea, so-called tod- dler’s diarrhea or chronic nonspecific diarrhea of infancy, it is important to reduce intake of poorly absorbed sugars in fruit juices and to normalize the dietary fat and fiber content. REFERENCES Hyams JS, Burke G, Davis P, et al. Abdominal pain and IBS in ado- lescents: A community-based study. J Pediatr [Demonstrates the real population-based prevalence of IBS] 1996;129:220–226. Hyams JS, Hyman PE. RAP and the biopsychosocial model of medical practice. J Pediatr 1998;133:473–478. Hyams JS, Treem WR, Justinich CJ, et al. Characterization of symptoms in children with RAP: Resemblance to IBS. J Pediatr Gastroenterol Nutr [Delineates the overlap between RAP and IBS—outstanding article] 1995;20:209–214. Macarthur C, Saunders N, Feldman W. Helicobacter pylori, gas- troduodenal disease and recurrent abdominal pain in children. JAMA [The causal relationship between Hp abdominal pain is unclear] 1995;273:729–734. Rasquin-Weber A, Hyman PE, Cucchiara S, et al. Childhood functional GI disorders. Gut [Includes Rome criteria for pedi- atric IBS] 1999;45(Suppl. II):II60– II68. 76 INFLAMMATORY BOWEL DISEASE Jeffrey B. Brown and B U.K. Li EPIDEMIOLOGY • Inflammatory bowel disease (IBD) refers to two spe- cific disorders, Crohn disease (CD) and ulcerative coli- tis (UC), but more realistically describes a continuum of chronic intestinal inflammatory disease. Although the etiology remains unclear, these disorders are thought to represent an aberrant mucosal immune response to normal enteric bacteria in genetically sus- ceptible individuals. The majority of IBD is acquired during two periods, the mid-to-late teens and during the fourth and fifth decades of life. Relevant to pedi- atrics, 25% of all cases are diagnosed before 20 years of age. Males and females are evenly affected and carry a lifetime risk of 0.5% in North America and Western Europe. Although the onset of disease is rare before 5 years of age, it has been described in infants. PATHOPHYSIOLOGY • Although there is no Mendelian pattern of inheritance, genetics play an important role in susceptibility. IBD is clustered in families with first-degree relatives car- rying a 4–20-fold increased risk of disease vs. the general population that has an absolute risk of 5–9%. Monozygotic twins carry a higher rate of concordance than do dizygotic twins. Among populations, Whites and Jews (especially Ashkenazi) have a higher prev- alence than non-Whites and non-Jews, respectively. 316 SECTION 10 • GASTROINTESTINAL AND LIVER DISEASE TABLE 75-6 Therapy of Irritable Bowel Syndrome MEASURES MEDICATIONS Pain-predominant Stress management Antispasmodics Diarrhea-dominant Reduce fructose, sorbitol, Antidiarrheals, tricyclic antidepressants, alosetron (in adult women only) Constipation-dominant Stool softeners, fiber Laxatives, tegasarod (in adult women) CHAPTER 76 • INFLAMMATORY BOWEL DISEASE 317 Work in progress has identified patients carrying muta- tions within chromosome 16, termed the IBD I locus (NOD2 gene). Finally, numerous genetically-altered animal models spontaneously develop colitis that is similar to human Crohn disease. Additional factors important to the development of IBD include the envi- ronment, luminal flora, and a dysregulated immune response. Environmental factors include the use of nonsteroidal agents that can exacerbate disease, and smoking, which increases the risk of CD while appar- ently acting protectively in UC. The fact that suscep- tible mice remain healthy in germ-free environments and only develop colitis when colonized with normal bacteria suggests that enteric flora is necessary for disease to occur. Finally, there is a sustained, chronic activation of the mucosal immune system that is a target of evolving therapies. Whether this activation results from enhanced mucosal permeability to bacte- rial antigens, inappropriate presentation of antigen to lymphocytes, or an aberrant T-cell response is not clear. CLINICAL PRESENTATION DIAGNOSTIC TESTING • The suspicion of IBD is based on combinations of the clinical features described in Table 76-1 and laboratory findings of anemia, elevated sedimentation rate, and low albumin. The radiographic and endoscopic evaluations are necessary to evaluate macroscopic distribution, appearance of disease, and histopathologic findings. • Infectious colitis must be ruled out prior to making a definitive diagnosis. These include bacterial and para- sitic infections (e.g., C. difficile, Yersinia, Shigella, Salmonella, Entamoeba, and Giardia) as well as viral and fungal infections in the immunocompromised. Endoscopic evaluation helps to exclude other diseases such as allergic colitis, eosinophilic gastroenteropathy, vasculitis (e.g., HSP, SLE), and chronic granulomatous disease. Up to 10% of children with disease confined to the colon remain difficult to categorize and are labeled “indeterminate colitis.” Even under the best diagnostic TABLE 76-1 Comparison of Clinical Features of Ulcerative Colitis and Crohn Disease ULCERATIVE COLITIS CROHN’S DISEASE Clinical features Diarrhea, often bloody Abdominal pain, often RLQ ± palpable mass Lower crampy abdominal pain, Diarrhea, can be bloody especially with defecation Weight loss Weight loss Growth failure Fever Fever Arthralgia, arthritis Fatigue Chronic anemia Perianal disease Anorexia Arthralgia, arthritis Pyoderma gangrenosum Chronic anemia Anorexia Nephrolithiasis Protein-losing enteropathy Erythema nodosum Anatomic location Limited to the colon with nearly Ileal disease in two-thirds 100% rectal involvement Colonic disease in two-thirds Upper GI disease in one-third Endoscopic findings Continuous involvement from Rectum often spared the rectum Discontinuous lesions Friable mucosa Aphthous lesions and linear ulceration Pseudopolyps Cobblestoning Microscopic Mucosal/submucosal inflammation Transmural inflammation description Cryptitis with crypt abscesses Distorted crypt architecture Distorted crypt architecture Noncaseating granulomas Radiologic findings Continuous involvement Segmental involvement with skip lesions Loss of haustra Stenotic areas, ileal string sign Complications Perforation Intestinal strictures Toxic megacolon Fistulizing disease Sclerosing cholangitis Colon cancer Colon cancer ABBREVIATION: RLQ, right lower quadrant. approach, 15% initially diagnosed as UC may be redi- agnosed as CD based on the course or subsequent test- ing. Adjunct serologic screening currently available includes testing to detect serum antibodies pANCA, present in about 65% of UC, and ASCA, present in about 50% of CD. Because these antibodies are rela- tively insensitive markers that are even less reliable in children, they must be cautiously interpreted in relation to the larger clinical picture and should not be used rou- tinely to diagnose IBD. TREATMENT • The treatment of IBD is complex and not standard- ized. The current medical therapies for IBD, their mechanism of action, indications, and side effects are summarized in Table 76-2. Good nutrition is critical to treatment and achieving optimal linear growth poten- tial of affected adolescents. Occasionally, the severity of growth retardation and anorexia necessitates tem- porary parenteral nutrition. An elemental diet can be 318 SECTION 10 • GASTROINTESTINAL AND LIVER DISEASE TABLE 76-2 Current Medical Therapy of Inflammatory Bowel Disease MECHANISM OF DRUG ACTION INDICATION SIDE EFFECTS ABBREVIATIONS: TNF, tumor necrosis factor; IL-2, interleukin2. * Numerous preparations exist to enhance delivery to specific areas of the intestine and colon. ** Oral budesonide is available for isolated ileal/right colon disease with high first-pass metabolism limiting many side effects; however, long-term use may result in growth suppression similar to prednisone. Peripheral neuropathyBacterial overgrowth in CD; perianal CD; broad spectrum antibiotics for CD- related abscesses or with fulminant colitis Antibacterial or undescribed immunosuppressive effect Antibiotics (e.g., Metronidazole) Hypersensitivity, infection susceptibility Fistulizing or moderate- to-severe CD refractory to conventional therapy Chimeric monoclonal antibody with anti- TNFα effects Infliximab Nephrotoxicity, hypertension, hirsuitism, gingival hyperplasia, seizures, infection susceptibility Severe/fulminant colitis refractory to high- dose IV corticosteroids Calcineurin inhibitor (inhibits production and release of IL-2) Cyclosporin Bone marrow suppression, interstitial pneumonitis, hepatic fibrosis Maintenance therapy in moderate-to-severe or corticosteroid- dependent UC and CD or CD problematic in the upper GI tract Antimetabolite with nonspecific immunosuppressive T-cell effects Methotrexate Bone marrow suppression, hepatitis, pancreatitis Blood levels can be measured Maintenance therapy in moderate-to-severe or corticosteroid- dependent UC and CD or CD problematic in the upper GI tract Antagonizes purine metabolism, possibly resulting in a suppressive effect on T cells Azathioprine/6-MP Cushingoid appearance, obesity, growth inhibition, osteoporosis, hypertension, diabetes, cataracts Induction therapy orally for moderate-to-severe UC and CD, or IV when ill enough to be hospitalized, followed by prescribed taper Nonspecific, broad anti- inflammatory action Corticosteroids ** (Prednisone) Nausea, vomiting, anorexia, headache, fever, rash, and abdominal pain Induction and maintenance of mild- to-moderate UC and CD. Can be given orally or rectally for isolated left colon disease Likely block action of prostaglandins and leukotrienes; inhibit neutrophil chemotaxis; inhibit activation of nuclear factor-kB 5-aminosalicyclic acid (5-ASA) compounds (Mesalamine * ) CHAPTER 77 • CONSTIPATION 319 efficacious short-term therapy by itself, but compli- ance limits its practicality (Table 76-2). • When initially diagnosed or during flare-ups in dis- ease, induction therapy is necessary to bring the inflammation under rapid control and is followed by chronic maintenance therapy. Oral or parenteral high- dose corticosteroids are the most effective induction, but the myriad of side effects limits their long-term use. Mild disease may be maintained on oral or topical (enema or suppository) 5-aminosalicylate preparations and moderate-to-severe disease is currently managed by azathioprine or 6-mercaptopurine. Numerous other therapies are under investigation including probiotics, short-chain fatty acids, growth hormone, thalidomide, tacrolimus, various antibodies to interleukins, myco- phenolate mofetil, and stem-cell transplantation. • Although a detailed discussion is beyond the scope of this chapter, surgical intervention may be necessary. Ultimately, total colectomy is curative for refractory UC or in those with evidence of colonic dysplasia. Indications for resection in CD include fixed stric- tures, refractory fistulous tracts, and rarely fulminant colitis. Surgery is generally avoided with CD until other interventions have been exhausted due to the possibility of disease recurrence at sites proximal to the resection. In spite of this, the majority of CD patients will need some surgical intervention by 20 years of disease duration. PROGNOSIS • Normal quality of life, good nutritional status, optimal growth, prevention of osteoporosis, and limitation of drug-related side effects remain the goals of therapy for childhood IBD. Because development of dysplasia is rare in childhood, there is a limited role for surveil- lance colonoscopy until 10 years of disease duration. For UC, the lifetime risk of colon cancer after 10 years is 1–2% per patient per year. The risk in CD is lower but less clear. In addition, 2–3% of patients with UC will develop hepatic involvement with sclerosing cholangitis. Although severe cases of IBD carry the risk of significant morbidity, most children with IBD who receive and take appropriate therapy are expected to live full, productive lives. B IBLIOGRAPHY Griffiths AM, Buller HB. Inflammatory bowel disease. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB (eds.), Pediatric Gastrointestinal Disease. Hamilton, ON: BC Decker, 2000, pp. 613–651. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6- mercaptopurine and prednisone in children with newly diag- nosed Crohn’s disease. Gastroenterology 2000;119: 895–902. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347(6):417–429. Sentongo TA, Semeao EJ, Piccoli DA, et al. Growth, body com- position, and nutritional status in children and adolescents with Crohn’s disease. J Pediatr Gastroenterol Nutr 2000;31:33–40. Stephens MC, Shepanski MA, Mamula P, et al. Safety and steroid-sparing experience using infliximab for Crohn’s dis- ease at a pediatric inflammatory bowel disease center. Am J Gastroenterol 2003;98(1):104–111. 77 CONSTIPATION Ruba Azzam and B U.K. Li EPIDEMIOLOGY • Functional constipation in childhood is currently defined by the Rome criteria as 12 weeks over 12 months of straining with bowel movements, hard stools, or fewer than three defecations per week (Table 77-1). As many as 10% of children are brought to medical attention because of a defecation disorder. Most suffer from functional (nonanatomic) constipation. Functional constipation is a common problem and comprises 3–5% of all visits to pediatricians and up to 25% of referrals to pediatric gastroenterologists. PHYSIOLOGY • Normal defecation is a complex and coordinated action involving the pelvic floor musculature, the TABLE 77-1 Rome Criteria for Constipation At least 12 weeks, which need not be consecutive, in the preceding 12 months, of two or more of: Straining > 1 / 4 of defecations Lumpy or hard stools > 1 / 4 of defecations Sensation of incomplete evacuation > 1 / 4 of defecations Sensation of anorectal obstruction/blockage > 1 / 4 of defecations Manual maneuvers to facilitate > 1 / 4 of defecations (e.g., digital evacuation, support of the pelvic floor) <3 Defecations per week Loose stools are not present, and there are insufficient criteria for irritable bowel syndrome (IBS). [...]... RETARDATION a-Iduronidase a-Iduronidase a-Iduronidase Iduronate sulfatase Iduronate sulfatase Heparan N-sulfatase a-N-acetylglucosaminidase Acetyl-CoA:a-glucosaminide acetyltransferase N-acetylglucosamine-6sulfatase Galactose -6 - sulfatase b-Galactosidase ENZYME DEFICIENCY ABBREVIATIONS: D = dermatan sulfate; K = keratan sulfate; H = heparan sulfate; C = chondroitin sulfate NAME TYPE TABLE 8 8-1 Characteristics... commonly contains either two normal X chromosomes or one normal X chromosome and a second structurally abnormal X chromosome such as an isochromosome of the long arm of the X These karyotypes are designated as 45,X/ 46, XX and 45,X/ 46, X,i(Xq) In some cases, a second cell line with a 46, XY complement will be identified In these cases, the streak gonads must be surgically removed because of the risk of development... hypernasal speech 5 Hypocalcemia • The first letters of the above features led initially to the use of the term CATCH-22 to describe the disorder Certainly any child with one or more of these findings should be tested for the 22q11 deletion; however, it is now clear that there are many more features that may be associated with this deletion Common ones are listed below 3 36 SECTION 11 • GENETIC DISEASES... ACIDOSIS • Methylmalonic acidemia and propionic acidemia are the most common disorders and will be summarized here; others include isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3methylglutaryl-CoA lyase deficiency, glutaric aciduria, and many others • Children with these disorders typically are normal at birth, but in the first few days of life develop profound ketoacidosis,... and excess mucosal acetylcholinesterase • The therapy of Hirschsprung disease is surgical including the Swenson, Duhamel, and Soave procedures that perform side-to-side anastomosis, excision of segment with side-to-side anastomosis, and pulling-through of ganglionated segment through the aganglionic segment REFERENCE Swenson O Hirschsprung’s disease: A review Pediatrics 2002;109:914–918 79 UPPER AND... referred to as the adult type, this is a misnomer, since nearly 50% of cases are diagnosed before the age of 10 years Deficient glucocerebrosidase activity results in accumulation of GC in the lysosomes of monocyte-derived macrophages in tissues of the reticuloendothelial system Accumulation in splenic macrophages and in the Kupffer cells of the liver is associated with enlargement of these organs The resulting... a previously healthy school-aged child with an unremarkable medical past who develops acute viral hepatitis Unexpectedly, they fail to recover, and worsen to the point of severe jaundice and altered mental status Patients may have a normal-, large-, or small-sized liver On examination, they may demonstrate evidence of hemorrhage from the nose, needle puncture sites, and/or the gastrointestinal tract... having another affected child Prenatal diagnosis should be offered Approximately 5% of patients with Down syndrome have a translocation involving the number 21 chromosome In such cases, the infant has only 46 chromosomes but has the equivalent of 47 chromosomes since one of these chromosomes is a translocation chromosome involving the number 21 chromosome attached to another chromosome— either a D group... yields a hypercontracted segment secondary to the inhibition of the parasympathetic nerves in the myenteric plexus These aganglionic segments have a higher content of acetylcholinesterinase and reduced amounts of nitric oxide synthase EPIDEMIOLOGY • The incidence of the disease is estimated to be 1:5000 live births The male to female ratio is 3.8:1 and there is no racial predilection A family history... school-age children and adolescents The dose is titrated according to treatment response If the response is suboptimal on high doses, a stimulant may be added to the regimen In order to reestablish colorectal tone and sensitivity, maintenance therapy is often required for 4 6 months • The child who fails to respond despite compliance with therapy requires testing to exclude organic disease (Table 7 7-5 ) . higher prev- alence than non-Whites and non-Jews, respectively. 3 16 SECTION 10 • GASTROINTESTINAL AND LIVER DISEASE TABLE 7 5 -6 Therapy of Irritable Bowel Syndrome MEASURES MEDICATIONS Pain-predominant. factor-kB 5-aminosalicyclic acid (5-ASA) compounds (Mesalamine * ) CHAPTER 77 • CONSTIPATION 319 efficacious short-term therapy by itself, but compli- ance limits its practicality (Table 7 6- 2 ). •. surgical including the Swenson, Duhamel, and Soave proce- dures that perform side-to-side anastomosis, excision of segment with side-to-side anastomosis, and pulling-through of ganglionated segment through the aganglionic