DOI: 10.1542/peds.2009-1878D 2010

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  • 1. Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDsTimothy Buie, George J. Fuchs, III, Glenn T. Furuta, Koorosh Kooros, Joseph Levy, Jeffery D. Lewis, Barry K. Wershil and Harland Winter Pediatrics 2010;125;S19-S29 DOI: 10.1542/peds.2009-1878D The online version of this article, along with updated information and services, is located on the World Wide Web at: is the official journal of the American Academy of Pediatrics. A monthlypublication, it has been published continuously since 1948. PEDIATRICS is owned, published,and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, ElkGrove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. Allrights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 2. SUPPLEMENT ARTICLERecommendations for Evaluation and Treatment ofCommon Gastrointestinal Problems in Children With ASDsAUTHORS: Timothy Buie, MD,a,b,c George J. Fuchs, III, MD,dGlenn T. Furuta, MD,e,f Koorosh Kooros, MD,g Joseph Levy,MD,h Jeffery D. Lewis, MD,i Barry K. Wershil, MD,j and abstractHarland Winter, MDa,c Children with autism spectrum disorders (ASDs) can benefit from ad-aDepartment of Pediatrics, Harvard Medical School, Boston, aptation of general pediatric guidelines for the diagnostic evaluation ofMassachusetts; bLearning and Development DisabilitiesEvaluation and Rehabilitation Services, Lexington, abdominal pain, chronic constipation, and gastroesophageal refluxMassachusetts; cDivision of Pediatric Gastroenterology and disease. These guidelines help health care providers determine whenNutrition, MassGeneral Hospital for Children, Boston,Massachusetts; dDivision of Pediatric Gastroenterology, gastrointestinal symptoms are self-limited and when evaluation be-Hepatology, and Nutrition, University of Arkansas for Medical yond a thorough medical history and physical examination should beSciences, UAMS College of Medicine and Arkansas Children’sHospital, Little Rock, Arkansas; eKeck School of Medicine of USC, considered. Children with ASDs who have gastrointestinal disordersLos Angeles, California; fSection of Pediatric Gastroenterology, may present with behavioral manifestations. Diagnostic and treatmentHepatology and Nutrition, Children’s Hospital Denver, Aurora,Colorado, Department of Pediatrics, National Jewish Health, recommendations for the general pediatric population are useful toDenver, Colorado; and Department of Pediatrics, University of consider until the development of evidence-based guidelines specifi-Colorado Denver School of Medicine, Aurora, Colorado; gDivisionof Pediatric Gastroenterology and Nutrition, Golisano Children’s cally for patients with ASDs. Pediatrics 2010;125:S19–S29Hospital at Strong, University of Rochester Medical Center,Rochester, New York; hDepartment of Pediatrics(Administration), NYU Lagone Medical Center, New YorkUniversity School of Medicine, New York, New York; iChildren’sCenter for Digestive Health Care, LLC, Atlanta, Georgia; andjDivision of Gastroenterology, Hepatology and Nutrition,Children’s Memorial Hospital, Northwestern University’sFeinberg School of Medicine at Northwestern, Chicago, IllinoisKEY WORDSautism spectrum disorder, abdominal pain, constipation,diarrhea, gastroesophageal reflux diseaseABBREVIATIONSASD—autism spectrum disorderGER— gastroesophageal refluxPEG—polyethylene glycolHLA— human leukocyte antigenLBT—lactose breath testIg—immunoglobulinGERD— gastroesophageal reflux diseasePPI—proton-pump inhibitorDrs Buie and Fuchs made equal contributions to thedevelopment and preparation of this manuscript.The guidance in this article is not intended to advocate for anexclusive course of treatment or to represent a standard ofmedical care. Individual circumstances will determine variationsthat may be for publication Sep 4, 2009Address correspondence to Harland Winter, MD, or TimothyBuie, MD, Mass General Hospital for Children, PediatricGastrointestinal Unit, CRPZ 5-560, 175 Cambridge St, Boston, MA02114. E-mail: or tbuie@partners.orgPEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).Copyright © 2009 by the American Academy of Pediatrics (Continued on last page) PEDIATRICS Volume 125, Supplement 1, January 2010 S19 Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 3. In 2008 a multidisciplinary panel that mendations as a guide for evaluation TABLE 1 Alarm Symptoms or Signs That Warrant Consideration of Diagnosticreviewed gastrointestinal aspects of of the child with an ASD who presents Testing in Typically Developingautism spectrum disorders (ASDs) with symptoms and/or signs that sug- Children Who Present With Chronicrecommended that “individuals with gest abdominal distress. We also dis- Abdominal Pain cuss the association of self-injurious Involuntary weight lossASDs who present with gastrointesti- Deceleration of linear growthnal symptoms warrant a thorough behavior and disturbed sleep with un- Gastrointestinal blood loss (visible or occult)evaluation, as would be undertaken for derlying gastrointestinal pathology in Significant vomiting, includingindividuals without ASDs who have the an effort to raise awareness of atypi- Bilious emesis Protracted vomitingsame symptoms or signs.”1 The preva- cal presentations of common gastroin- Cyclical vomitinglence of gastrointestinal symptoms in testinal problems in individuals with Chronic severe diarrheachildren with ASDs has been reported ASDs. Persistent right upper or right lower quadrant painto range from 9% to 70% or higher.1–3 Unexplained feverEvidence-based guidelines for the eval- CHRONIC ABDOMINAL PAIN Family history of inflammatory bowel diseaseuation of gastrointestinal symptoms Abnormal or unexplained physical findingsare not yet available for children with Differential Diagnosis Data source: American Academy of Pediatrics, Subcom- mittee on Chronic Abdominal Pain. Pediatrics. 2005;115(3):ASDs.1 For practical purposes, chronic ab- 812– 815.Consensus guidelines have been devel- dominal pain is defined as intermittentoped by medical societies for the man- or constant abdominal pain that ex-agement of commonly encountered ceeds 1 or 2 months in duration, but dominal pain in atypical behaviors orgastrointestinal symptoms in the for children with ASDs this remains a changes in state of being that may notgeneral pediatric population.4–7 Few, challenging assessment. Although un- be perceived as indicating the sourceif any, of these published documents derlying causes of chronic abdominal of the discomfort. These behaviors in-addressed modifications in the diag- pain are frequently benign, parents clude pressing on the abdomen andnostic evaluation based on the needs are often worried that their child with tapping on the areas of distress;of children with disabilities such as an ASD is in gastrointestinal distress changes in state of being include sleepimpaired language skills. Clearly, and that their practitioner should be disturbance,8 self-injurious behavior,evidence-based information is needed concerned about missing a serious and aggression. The presence of anyto guide therapy for children with disease. alarm symptom should initiate an eval-ASDs, but until these data exist, recom- uation, but even in the absence ofmendations will be supported by the Evaluation alarm symptoms, a diagnostic evalua-opinions of pediatric gastroenterolo- Generally, for children without ASDs tion (Table 2) or empiric trial of a ther-gists from practices across the United between the ages of 4 and 18 years, apeutic intervention (Table 3) may beStates with substantive experience in functional abdominal pain can be diag- considered.the care of children with ASDs. For this nosed correctly by the primary carearticle, 8 pediatric gastroenterologists practitioner when alarm symptomsreviewed published guidelines for the Treatment Considerations (Table 1)5 are absent, results of themanagement of gastrointestinal symp- physical examination are normal, and Education is an important part of treat-toms that occur frequently in the gen- stool does not contain occult blood. ment. In the absence of alarm symp-eral pediatric population. Then, on the Evaluation of abdominal pain in a child toms, after an unrevealing diagnosticbasis of their clinical experience, they with impaired communication skills is evaluation and failure of empiric treat-adapted current best practices to di- challenging. As yet there are no reli- ment to resolve the symptom or behav-agnostic evaluation and treatment for able signs or symptoms that enable ior, it may be helpful for the practition-children with ASDs. These expert- the health care provider to distinguish er to review with the family the child’sopinion recommendations are pre- between organic and functional disor- symptoms and explain that althoughsented for chronic abdominal pain, ders. Certain children with ASDs are the pain is real, there is no evidence atchronic constipation, chronic diar- able to communicate when they expe- present of a serious or chronic dis-rhea, and symptoms of gastroesoph- rience episodes of pain by using lan- ease. The clinical picture can changeageal reflux (GER). guage or other communication tools. over time, and individuals with ASDsThe primary care provider or special- However, others have limitations in should be reevaluated if their symp-ist is encouraged to use these recom- communication and may express ab- toms or signs change.S20 BUIE et al Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 4. SUPPLEMENT ARTICLETABLE 2 Adaptation of Diagnostic Tests for Evaluation of Abdominal Pain or Chronic Diarrhea in TABLE 4 Differential Diagnosis of Children With ASDs Constipation Tests That May Be Difficult to Complete Tests That May Be Easier to Complete Nonorganic (Be Selective) Developmental Cognitive handicapsNoninvasive tests Attention deficit disorders Upper gastrointestinal series with small- Stool for enteric pathogens, ova/parasites, Giardia Situational bowel follow-through antigen, C difficile toxin Coercive toilet training 72-h fecal-fat collection Stool: guaiac, electrolytes/osmolarity (if secretory Toilet phobia diarrhea), split and neutral fat, calprotectin, School bathroom avoidance lactoferrin, trypsinogen, -1-antitrypsin, Excessive parental interventions elastase Sexual abuse Other LBT Serum: electrolytes, liver function tests Depression Assessment of nutritional status (if appropriate): Constitutional anthropometry, 25-OH vitamin D Colonic inertia Abdominal radiograph (assessment of bowel gas Genetic predisposition pattern and retention of stool) Reduced stool volume and drynessTests that require anesthesia Low fiber in diet — Upper endoscopy: biopsy looking for enteritis; Dehydration disaccharidase assay (lactase or Underfeeding or malnutrition sucrase–isomaltase deficiency); secretin test Organic Anatomic malformations Colonoscopy: biopsy looking for colitis Imperforate anus Anal stenosis Anterior displaced anusTABLE 3 Empiric Treatments for Abdominal ranted or if functional constipation is Pelvic mass (sacral teratoma) Pain in Children With or Without Metabolic and gastrointestinal present (Fig 1).7 Determination of what Hypothyroidism ASDs the family or child means when they HypercalcemiaTrial of a strict lactose-free diet for 2 wk HypokalemiaTrial with a PPI for 2–4 wk use the term “constipation,” the fre- Cystic fibrosisTrial with PEG 3350 for 4 wk quency of bowel movements, the con- Diabetes mellitus Multiple endocrine neoplasia type 2B sistency and size of stools, and Gluten enteropathy whether the child experiences abdom- Neuropathic conditionsCONSTIPATION Spinal cord abnormalities inal pain is important. A history of Spinal cord traumaDifferential Diagnosis stool-withholding behavior reduces Neurofibromatosis the likelihood of there being a caus- Static encephalopathyConstipation is the occurrence for 2 Tethered cord ative organic condition. Intestinal nerve or muscle disordersweeks or so of a delay or difficulty in Hirschsprung diseasedefecation. The causes of constipation Components of a thorough physical ex- Intestinal neuronal dysplasiaare many and may be organic or non- amination are listed in Table 5.7 For Visceral myopathies Visceral neuropathiesorganic; medications can be a poten- children with ASDs, the physical exam- Abnormal abdominal musculaturetial cause (Table 4).7 Children with ination may not identify palpable stool Prune belly in the left lower quadrant, and a care- GastroschisisASDs can have sensory processing Down syndromeabnormalities and develop stool- ful rectal examination might not be Connective tissue disorders feasible. Every attempt should be Sclerodermawithholding behaviors or constipation Systemic lupus erythematosusrelated to altered pain responses. made to examine the rectum, although Ehlers-Danlos syndromeEven children with ASDs who have daily at times this cannot be accomplished. Drugs Opiatesbowel movements may have retention The rectal examination enables as- Phenobarbitalof stool that is not evident to parents, sessment of stool retention, anal tone, Sucralfate Antacidsteachers, or health care providers. and occult mass, as well as the pres- Antihypertensives ence or absence of blood, and helps to AnticholinergicsEvaluation Antidepressants reassure the family that their child’s SympathomimeticsThe evaluation of all children who anatomy is normal. It need not be re- Other peated on subsequent visits unless Heavy-metal ingestion (lead)present with constipation should in- Vitamin D intoxificationclude a thorough medical history there is a change in the history or Botulism physical examination. Cow’s milk protein intoleranceand physical examination. Information Reprinted, with permission from Constipation Guidelinesfrom the history and physical examina- A plain radiograph of the abdomen Committee of the North American Society for Pediatriction usually enables the physician to may reveal a rectal fecal mass not pal- Gastroenterology, Hepatology and Nutrition. J Pediatr Gas- troenterol Nutr. 2006;43(3):e6.determine if further evaluation is war- pable on the abdominal examination,9 PEDIATRICS Volume 125, Supplement 1, January 2010 S21 Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 5. from 21 Constipation: . History Delayed or difficult defecation . Physical exam . Occult blood (if indicated) Condition for > 2 weeks 1 2 Impacted? Excess retention? Question 22 Are there any red flags? Condition Yes e.g., fever, vomiting, bloody diarrhea, Abdominal x-ray failure to thrive, anal stenosis, Action tight empty rectum? 23 Question Evaluate further 3 No Excess Yes 4 No stool? Action 24 Functional . T4 . Celiac disease constipation Abnormal . TSH 5 antibodies Transit time study . Calcium (if not already done) 25 Consider trial of milk-free diet Yes Is there Normal 26 Disimpact with oral or rectal medication fecal impaction? 7 6 Yes No Soiling? No Hirschsprung 27 disease? No Yes 28 Functional constipation . Reassurance Effective? without impaction . Behavioral No 8 9 modification . Observation . Psych 30 Rectal manometry evaluation/Rx and/or biopsy Treatment: 29 31 . Education . Diet . Oral medication . Dairy Yes Positive for . Close follow-up Surgical management Hirschsprung 10 33 disease? 32 . Re-assessment . Adherence? No No Treatment . Re-education effective? . Different medication? 11 Consider time-limited Rx with: 12 . PEG solution . Bowel training Yes . Stimulant laxatives . Intensive psych . Biofeedback Treatment Yes 34 Maintenance therapy effective? 13 14 No Treatment Yes No effective? Yes Blood tests: Relapse? 35 . T4 . Celiac disease 15 . Maintain Rx . TSH antibodies Consider other tests: . Wean No . MRI of spine . Barium enema . Calcium . Lead 36 16 . Anorectal . Full-thickness biopsy . Wean manometry . Other metabolic tests . Observe . Colonic manometry . Psych evaluation/Rx Yes Relapse? 17 . Transit time . Inpatient observation Abnormal Yes 37 38 T4,TSH, Ca, No Pb? 18 Evaluate further Yes No No Abnormal? Observation 19 39 40 Consultation Has previous No with Pediatric treatment been Gastroenterologist sufficient? Treatment Re-evaluate 20 21 41 42 Yes to 22FIGURE 1Algorithm for the management of constipation in children 1 year of age and older. T4 indicates thyroxine; TSH, thyroid-stimulating hormone/thyrotropin; Ca,calcium; Pb, lead; Rx, therapy; psych, psychological management. (Reprinted with permission from Constipation Guidelines Committee of the NorthAmerican Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43(3):e3.)although evidence for the accuracy of tory of delayed passage of stool after drial disorders are heterogeneous buta radiologic diagnosis of constipation birth should raise suspicion of agan- characterized by impaired energy pro-is conflicting,10 and routine radiogra- glionosis. Anatomic abnormalities duction.15 There is no reliable biomark-phy is not recommended.11 If large such as an anterior displaced anus, er specific for the screening and diag-amounts of stool are found on rectal which is more common in girls than nosis of mitochondrial disorders.15 Theexamination, an abdominal radio- boys, can be diagnosed by careful in- primary care physician should be alertgraph is not needed to establish the spection of the rectum. Children with to the presence of “red-flag” findingspresence of fecal impaction.7 altered intestinal motility may have un- that raise clinical suspicion (Table 6)Diagnostic clues can help to identify derlying mitochondrial disease.12 and warrant a baseline diagnosticsome organic causes of constipation. Recent studies have suggested a fre- evaluation.15 Initial evaluation includesHirschsprung disease is no less com- quent association of ASDs and mito- metabolic screening of blood andmon in children with ASDs, and a his- chondrial dysfunction.13,14 Mitochon- urine for all patients, metabolicS22 BUIE et al Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 6. SUPPLEMENT ARTICLETABLE 5 Physical Examination of Children TABLE 6 “Red-Flag” Findings in Mitochondrial Disease With Constipation Organ System Selected FindingsGeneral appearance Neurologic Cerebral stroke-like lesions in nonvascular patternVital signs Basal ganglia disease Temperature Encephalopathy Pulse Neurodegeneration Respiratory rate Myoclonus Blood pressure Cardiovascular Hypertrophic cardiomyopathy with rhythm disturbance Growth parameters Unexplained heart block in childHead, ears, eyes, nose, throat Cardiomyopathy with lactic acidosis ( 5 mM)Neck Dilated cardiomyopathy with muscle weaknessCardiovascular Ophthalmologic Retinal degeneration with signs of night blindness, color-vision deficits,Lungs and chest decreased visual acuityAbdomen Ophthalmoplegia/paresis Distension Fluctuating, disconjugate eye movements Palpable liver and spleen Ptosis Palpable mass Gastrointestinal Unexplained or valproate-induced liver failureAnal inspection Severe dysmotility Position Pseudo-obstructive episodes Stool present around anus or on clothes Other Unexplained hypotonia, weakness, FTT, and a metabolic acidosis Perianal erythema (particularly lactic acidosis) in newborn, infant, or young child Skin tags Hypersensitivity to general anesthesia Anal fissures FTT indicates failure to thrive.Rectal examination Adapted with permission from Haas RH, Parikh S, Falk MJ, et al. Pediatrics. 2007;120(6):1326 –1333. Anal wink Anal tone Fecal mass Presence of stool Consistency of stool ethylene glycol (PEG), or a combina- Chronic nonspecific diarrhea of child- Other masses tion of lubricant (mineral oil) and hood can first present between 6 and Explosive stool on withdrawal of finger laxative is recommended for the 36 months of age and resolve by 60 Occult blood in stoolBack and spine examination daily management of constipation in months of age. It is characterized by Dimple children (Table 8).7 loose and sometimes frequent stools Tuft of hair and, importantly, the absence of otherNeurologic examination CHRONIC DIARRHEA Tone abnormalities such as growth failure, Strength Differential Diagnosis abdominal pain, and difficulty in pass- Cremasteric reflex ing stool. If the latter signs or symp- Deep tendon reflexes Chronic diarrhea occurs when loose stools persist for 2 weeks or longer, toms are present, other causes ofReprinted, with permission from Constipation GuidelinesCommittee of the North American Society for Pediatric with or without an increase in stool chronic diarrhea should be considered.Gastroenterology, Hepatology and Nutrition. J Pediatr Gas-troenterol Nutr. 2006;43(3):e6. frequency. Most episodes of acute di- arrhea resolve within a week’s time Evaluation and are frequently caused by self- Guidelines for the diagnostic evalua-screening of spinal fluid for patients limited infections. In contrast, the tion of chronic diarrhea have not yetwith neurologic symptoms, and clinical causes of chronic diarrhea are generally been developed, but recommendedneurogenetic evaluation for patients different and include more noninfec- approaches are available in standardwith a developmental delay (Table 7).15 tious causes than for acute diarrhea. pediatric gastroenterology texts.18,19In addition, neuroimaging, provocative In the US general pediatric population, These same approaches are relevanttesting, and DNA analysis may be part of the most common causes of chronic for the child with an ASD. A careful his-an extensive evaluation.16 The role of mi- diarrhea are functional disorders, tory and physical examination are im-tochondrial disorders in autism needs malabsorption syndromes, inflamma- portant and include definition of thefurther definition. tory bowel disease (Crohn disease or age at symptom onset and whether ulcerative colitis), and chronic infec- symptoms develop abruptly or gradu-Treatment Considerations tions.15 The causes of diarrhea in chil- ally. Causes of chronic diarrhea in chil-Pharmacotherapy added to behavior dren on the autism spectrum are likely dren are listed in Table 9.20,21 Familymanagement for constipation is often the same as in children without ASDs, history of allergy or atopic diseasebeneficial.17 Mineral oil, magnesium and the differential diagnosis should may increase the likelihood of cow’shydroxide, lactulose, sorbitol, poly- be approached with similar rigor. milk allergy. Celiac disease is more PEDIATRICS Volume 125, Supplement 1, January 2010 S23 Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 7. TABLE 7 Baseline Screening Tests For Mitochondrial Disease: Initial Evaluation Metabolic Screening of Blood Assessment of Systemic Metabolic Screening of Spinal Fluid Clinical Neurogenetic Evaluation for and Urine for All Patients Involvement for All Patients for Patient With Neurologic Patient With Developmental Delay SymptomsBasic chemistries Echocardiogram Lactate and pyruvate KaryotypeLiver enzymes and ammonia ECG Quantitative amino acids Fragile X syndrome testingCBC Ophthalmologic examination Routine studies, including cell count, Child neurology consult glucose, and protein measurementCreatinine kinase Audiology testing Genetics consultBlood lactate, pyruvate, and Brain MRI lactate/pyruvate ratioQuantitative blood amino acidsQuantitative urine organic acidsPlasma acylcarnitine analysisNegative test results have a high false-negative rate. Thus, if the results are abnormal or if mitochondrial disease is still suspected, refer the patient to a mitochondrial center. CBC indicatescomplete blood count; ECG, electrocardiogram; MRI, magnetic resonance imaging.Adapted with permission from Haas RH, Parikh S, Falk MJ, et al. Pediatrics. 2007;120(6):1326 –1333.TABLE 8 Medications for Use in Treatment of Constipation in Children Medication Dosage CommentsLactulose (70% solution) 1–3 mL/kg per d in divided doses Well toleratedSorbitol (70% solution) 1–3 mL/kg per d in divided doses Similar to lactulose but less expensiveMagnesium hydroxide (400 mg/5 mL, 800 3 mL/kg per d Monitor for Mg toxicity, hypophosphatemia, mg/5 mL, or tablets) hypocalcemiaMagnesium citrate (liquid, 16.17% Mg) 6 y of age: 1–3 mL/kg per d; 6–12 y of age: Monitor for Mg toxicity, hypophosphatemia, 100–150 mL/d in single or divided doses; 12 hypocalcemia y of age: 150–300 mL/d in single or divided dosesPEG 3350 1–1.5 g/kg per d for 3 d; maintenance: 1 g/kg per Palatable (can be dissolved in most fluids); not d (usual dose 17 g/d) approved for use in infantsPhosphate enemas 2 y of age: to be avoided; 2 y of age: 6 mL/kg May be psychologically traumatic; may damage up to 135 mL rectal wall; may cause abdominal distention or vomiting; tetany with hyperphosphatemia/ hypocalcemia; avoid if renal disease is presentPEG electrolyte solution For disimpaction: 25 mL/kg per h (maximum: Taste is an issue; may cause nausea, bloating, 1000 mL/h) via nasogastric tube until clear; cramps, vomiting maintenance: 10 mL/kg per dMineral oil 1 y of age: not recommended; 1 y of age: Safe alternatives are available; should be used only maintenance 1–3 mL/kg per d if other agents fail; lipoid pneumonia if aspirated; leakage of stool; concern about impairing absorption of fat-soluble vitamins has not been substantiated clinicallySenna (syrup, 8.8 mg sennosides per 5 mL) 2–6 y of age: 2.5 mL/d; 12 y of age: 5–15 mL/d May cause permanent nerve or muscle damage, hepatitis, melanosis coliBisacodyl suppository (10 mg) May irritate rectal mucosaBisacodyl tablets (5 mg) Abdominal pain, diarrhea, hypokalemiaGlycerin suppositories Minimal adverse effects except for stress caused from insertionMg indicates magnesium.Adapted with permission from Constipation Guidelines Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr.2006;43(3):e1– e13.common in individuals with specific malnutrition. Poor weight gain may be fants or children who appear to behuman leukocyte antigen (HLA) types a result of malabsorption or inade- thriving or overweight while sufferingand is, in part, genetically determined. quate or inappropriate feeding: de- from chronic diarrhea, a careful di-It is important to assess a child’s layed growth may then be the result of etary record for 1 week may determinegrowth and nutrition. Weight for length a child being fed a dilute, hypocaloric if a patient is being overfed or drinkingor height and BMI are the simplest in- formula or clear liquids in an effort to excessive amounts of apple juice, peardices of growth failure secondary to reduce diarrhea. In contrast, for in- nectar, or other fruit juices that areS24 BUIE et al Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 8. SUPPLEMENT ARTICLETABLE 9 Causes of Chronic Diarrhea in Children whom food choices are limited. In ad- Cause Comment dition, unless results are clear-cut,Enteric infection MAI, Isospora, and Microsporidia occur in other diagnostic tests may be neces- immunocompromised children, including sary. A lactose breath test (LBT), which those with inadequately treated HIV infection Giardia lamblia requires an overnight fast and re- Cryptosporidium parvum peated collection of breath samples Cyclospora cayetanensis over 3 hours, can be difficult to per- C difficile EAEC form on some children. An LBT is pos- EPEC sible, though, for many children with Mycobacterium avium-intracellulare complex ASDs if the child and family are ade- Isospora belli Microsporidia quately prepared and a tolerant, un-Immunodeficiency derstanding staff member performs Primary immunodeficiencies (enteric infection, Primary immunodeficiencies are uncommon the test. Similar information can be including small-bowel overgrowth) causes obtained at the time of an upper Secondary immunodeficiencies (protein energy and Secondary immunodeficiencies, including HIV micronutrient malnutrition, HIV infection) infection and malnutrition, are major causes endoscopy via tissue analysis for worldwide disaccharidase-specific activity.Abnormal immune response Celiac disease Food allergy, another but less frequent Colitis and enteropathy associated with food allergy cause of diarrhea, is often challenging Autoimmune disorders (autoimmune enteropathy, to diagnose because most instances of GVHD)Idiopathic inflammatory bowel disease More common in developed countries intestinal food allergy are cell medi- Crohn disease ated rather than mediated by immuno- Ulcerative colitis globulin E (IgE). IgE-based tests mayCongenital persistent diarrhea Structural defects? Microvillus inclusion disease Neonatal onset; rare not identify individuals who do not Tufting enteropathy have atopic or immediate reactions, Congenital chloride diarrhea and IgG-based tests are of no value in Congenital disaccharidase (lactase, assessing intestinal food allergy. Re- sucrase–isomaltase) deficiencies Congenital bile acid malabsorption ferral to an allergist for skin testingHereditary lactase deficiency Onset after 3 y of age may be appropriate. Screening instru-Chronic nonspecific diarrhea of childhood Onset between ages 6 and 36 mo and resolution ments are currently being developed by age 60 mo; child is otherwise thrivingSyndromic persistent diarrhea (associated with Of greatest importance in developing countries to identify children with ASDs who are malnutrition) and worldwide likely to have a food allergy.MAI indicates Mycobacterium avium-intracellulare; EAEC, enteroaggregative E coli; EPEC, enteropathogenic E coli; HIV,human immunodeficiency virus; GVHD, graft-versus-host disease. Assessment for celiac disease shouldAdapted from Gibbons T, Fuchs GJ. Chronic enteropathy: clinical aspects. In: Cooke RJ, Vandenplas Y, Wahn U, eds. Nutrition be performed for any child with an ASDSupport for Infants and Children at Risk. Vol 59. Basel, Switzerland: Vevey/S Karger AG; 2007:89 –104. Nutrition Institute and gastrointestinal symptoms. TestingWorkshop Series: Pediatric Program and Steiner TS, Lima AAM, Nataro JP, Guerrant RL. J Infect Dis. 1998;177(1):88 –96. at a minimum should include a total IgA level, tissue transglutaminase IgA anti-known to induce diarrhea. A functional challenging and traumatic for the bodies with or without endomysial IgAcause of chronic diarrhea is suggested child. A plain abdominal radiograph antibodies. Antigliadin antibodies areby protracted symptoms ( 12 months) may be useful but not reflect the extent less reliable and more likely to yield aor lack of significant weight loss, noctur- of retained stool. Frequently, an em- false-positive result. Testing must shownal diarrhea, and straining with piric trial with a stool softener, such as no evidence of insufficiency of IgA for an-defecation. PEG 3350 (Miralax) for 2 to 4 weeks, tibody testing to be deemed reliable.Loose stool in children with ASDs may supports the diagnosis by causing a Children on a gluten-free diet shouldbe misdiagnosed as diarrhea. Consti- change in behavior. consider testing for celiac diseasepation is a common, albeit somewhat Lactose intolerance can be difficult to when gluten is reintroduced. Alterna-paradoxical, cause of loose stool and diagnose. A diagnostic trial of a strict tively, even if a child is on a gluten-freemay be difficult to confirm by history lactose-elimination diet may identify diet, genetic testing for HLA-DQ2 andor physical examination. Stool might children who are suspected of having HLA-DQ8 is reliable if the results arenot be palpable in the left lower quad- lactose intolerance, but it is difficult to negative and largely exclude a diagno-rant, and a rectal examination may be maintain, especially for a patient for sis of celiac disease. Because 35% of PEDIATRICS Volume 125, Supplement 1, January 2010 S25 Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 9. the US population has DQ2 or DQ8 but TABLE 10 Therapeutic Options for Chronic Diarrhea in Childrennot celiac disease, the presence of Therapy Underlying Causethese alleles does not make a diagno- Symptomatic therapy with antisecretory Severe diarrheal disease as an empiric trial before end of medication diagnostic workupsis of celiac disease. Genetic testing is Severe idiopathic diarrheaespecially valuable for excluding celiac Drug therapy Chronic intestinal infections and small-bowel bacterialdisease in children on a gluten-free overgrowth Malabsorptiondiet in whom antibody testing is not Inflammatory bowel diseases and autoimmune enteropathyreliable. Short-bowel syndrome and other chronic secretory diarrheal disordersStool samples to test for enteric patho- Surgery Malrotationgens, ova/parasites, or occult blood Stenosiscan be obtained easily at the time of a Blind loops Intestinal transplantation Short-bowel syndromelower endoscopy but otherwise may be Intestinal pseudo-obstruction and other disorders ofdifficult to collect. Biopsies of the colon defective intestinal motilityand ileum are routinely obtained on Ultrastructural enterocyte abnormalitiesendoscopy and determine whether Data source: Canani RB, Cirillo P, Terrin G. Chronic and intractable diarrhea. In: Guandalini S, ed. Essential Pediatric Gastroenterology, Hepatology, and Nutrition. New York, NY: McGraw-Hill Medical Publishing Division; 2005:41– 42.there is acute or chronic mucosalinflammation. TABLE 11 Complications of GEROther relevant diagnostic tests are Treatment Considerations Symptomslisted in Table 2. Stool guaiac identifies Therapeutic interventions vary de- Recurrent vomitingblood in the stool and suggests inflam- pending on the cause of chronic diar- Weight loss or poor weight gain Irritability in infantsmatory bowel disease, Clostridium dif- rhea; children without ASDs may Regurgitationficile infection, or perhaps allergy as a receive a specific medical/surgical Heartburn or chest painpotential cause of the chronic diar- therapy or may be treated symptomat- Hematemesis ically (Table 10).18 Physicians should Dysphagia or feeding refusalrhea. Blood in the stool caused by coli- Apnea or ALTEtis is often associated with an increase exercise clinical judgment when con- Wheezing or stridorin fecal calprotectin and lactoferrin, sidering the appropriate treatment op- Hoarseness tion for children with ASDs. Coughproteins derived from polymorphonu- Abnormal neck positioning (Sandiferclear leukocytes. Split or neutral fat in syndrome) GASTROESOPHAGEAL REFLUXthe stool suggests malabsorption that Findings DISEASE Esophagitiscould be caused by pancreatic insuffi- Esophageal strictureciency (elevated neutral fat) or muco- GER, the term for passage of gastric Barrett’s esophagussal injury, such as in celiac disease contents into the esophagus, can pro- Laryngitis duce diverse symptoms and complica- Recurrent pneumonia(elevated split fat). Pancreatic insuffi- Hypoproteinemia tions, called gastroesophageal refluxciency should also be suspected if Anemia disease (GERD) (Table 11).4 Clinicaltrypsinogen or elastase levels in the ALTE indicates apparent life-threatening events. practice guidelines for the manage- Reprinted with permission from Rudolph CD, Mazur LJ,stool are decreased. Protein-losing ment of GERD in the general pediatric Liptak GS, et al; North American Society for Pediatric Gas-enteropathy that causes diarrhea is troenterology and Nutrition. J Pediatr Gastroenterol Nutr. population were published in 20014 2001;32(suppl 2):S4.usually associated with increased -1- and are currently being updated.22 Theantitrypsin in the stool and hypoalbu- following recommendations can be ap-minemia. If the total peripheral lym- plied to children with ASDs and are life-threatening events. As a childphocyte count is also decreased, one based on the 2001 publication, with matures, other symptoms and signsshould consider the rare condition modifications ensuing from the clini- of GERD include chest pain or heart-intestinal lymphangiectasia. The oc- cal experiences of the authors. burn, esophagitis, food refusal, andcurrence of diarrhea when a child is extraesophageal manifestations offasting is suggestive of secretory di- Manifestations of GERD the airway.arrhea, in which case stool electro- During infancy, in contrast to non- As in children without ASDs, the ex-lytes and osmolarity are diagnostic pathologic reflux, GERD presents most pression of disease related to GER canand an evaluation for hormonal frequently as an adverse effect of re- vary widely in children with ASDs. Thecauses should be considered. current vomiting but also as apparent manifestations listed in Table 11 mayS26 BUIE et al Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 10. SUPPLEMENT ARTICLEbe identifiable in children with ASDs. A diagnostic trial of acid suppression, Treatment ConsiderationsHowever, certain children may express with an appropriate dose of a proton- Treatment of GERD depends on thediscomfort through problem behaviors, pump inhibitor (PPI), should be consid- cause. Surgical therapy should be con-restriction of foods of specific texture, or ered before invasive studies. For many sidered with a diagnosis of anatomicsimply pointing to their chest. Objective children with ASDs, who may have abnormality such as malrotation,measures become important to elicit GERD undiagnosed for many years, a whereas esophagitis may be treatedfrom the patient and family, such as the trial of acid suppression is beneficial. best by prolonged acid suppressionfrequency and timing of regurgitation, PPI medications should be given 30 (see Table 12). Subsequent evaluationthe character and amount of material re- minutes before the first meal of the depends on the resolution and recur-gurgitated, and the kinds of foods that day and, if 2 doses are prescribed, 30 rence of an individual’s symptoms. Up-are tolerated by the child. minutes before the evening meal. As- per endoscopy should be considered sessment of response to a PPI trial is to follow children with long-standingUnderlying Cause somewhat subjective in children with GERD who may be at risk for develop-The presenting symptom or sign is a ASDs and might depend on changes in ing complications such as esophagealclue to the underlying cause. Children behavior as perceived by care provid- stricture, Barrett esophagus, andwith ASDs who have obstruction caused ers (parents, teachers, or health care esophageal, for example, malrotation or antral providers). As in children without ASDs, GERD inweb may regurgitate many times an If further diagnostic testing is pur- children with ASDs can be a chronichour, whereas those individuals who sued, upper gastrointestinal radio- problem, with waxing and waning ofhave typical GERD may experience symp- graphs can be challenging for many symptoms. The management of suchtoms when they lie down at night or after children who are unable to cooperate children often requires continuitymeals. The vomiting of undigested foods with drinking barium and lying down with advancing age and an apprecia-suggests a delay in gastric emptying; he- quietly for the procedure. Because of tion by the health care team of thematemesis suggests the presence of in- these potential barriers, it can be diffi- natural history of disorders that un-flammation or ulceration. In young chil- cult to identify anatomic abnormali- derlie GERD.dren, a preference for liquids or a ties, such as a malrotation, annularrefusal to eat textured foods or foods pancreas, or antral inflammation or CONCLUSIONSthat require chewing should raise suspi- narrowing, that may be the cause of Children with ASDs can benefit fromcion of esophagitis. GERD-like symptoms. the adaptation of general pediatric Most children with ASDs are unlikely guidelines for the diagnostic evalua-Evaluation to tolerate placement of a transnasal tion of abdominal pain, chronic consti-Diagnostic evaluation begins with a pH probe for a prolonged period. A pation, and other gastrointestinalcareful history and physical exami- Bravo pH probe (Given Imaging Ltd, symptoms. The diagnostic evaluationnation. In some children more than 2 Yoqneam, Israel), which is endoscop- begins with a thorough medical his-years of age, recurrent regurgitation ically attached to the distal esopha- tory and physical examination. The ex-or vomiting disrupts their participa- gus, may be better tolerated. For pression of disease can be as diversetion in childhood activities. As for such children, upper endoscopy un- in individuals with ASDs as in thechildren without ASDs, an empiric der general anesthesia is often the general pediatric population. Healthtrial of acid suppression may be of diagnostic test initially used and care providers also should be alertdiagnostic value, but then the clini- might provide information about to behavioral manifestations of gas-cian may want to order an upper gas- other gastrointestinal conditions trointestinal disorders in patientstrointestinal series to exclude an an- such as carbohydrate malabsorp- with ASDs. Information from theatomic abnormality, as well as upper tion or food allergy or intolerance. medical history, including the pres-endoscopy with biopsy to look for in- Endoscopy is usually reserved for ence of red-flag findings, the charac-flammation associated with GERD, al- children who are unresponsive to a terization or definition of a problemlergy, or eosinophilic esophagitis. diagnostic trial of gastric acid sup- (as for chronic constipation), andOther warning signals for additional pression or when other clinical fac- the age of symptom onset (as fordiagnostic testing include gastroin- tors, such as hematemesis or food chronic diarrhea), can clarify thetestinal bleeding, abdominal tender- refusal, support the scheduling of in- clinical picture and help determineness, and fever. vasive tests. the need for further evaluation. PEDIATRICS Volume 125, Supplement 1, January 2010 S27 Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 11. TABLE 12 Acid-Suppressive Medications for Use in Treatment of GERD in Children Medication Dosage Comments aOmeprazole (capsules and oral suspension ) a 1–16 y of age: 5 to 10 kg, 5 mg/d; 10 to 20 Adverse events of respiratory system, fever (from adult kg, 10 mg/d; 20 kg, 20 mg/d; adult dosing: studies: headache, abdominal pain, nausea, diarrhea); 20 mg/d for 4–8 wk capsules can be administered with applesauceLansoprazole (tabletsa, capsulesa, and oral 1–11 y of age: 30 kg, 15 mg/d for 12 wk; Constipation, headache, abdominal pain, nausea, suspensiona) 30 kg, 30 mg/d for 12 wk; 12–17 y of dizziness (from adult studies: diarrhea, abdominal age: 15–30 mg/d for 8 wk; adult dosing: pain, nausea, constipation); strawberry-flavored 15–30 mg/d for 8 wk SoluTabs do not need to be swallowed; capsules can be administered with apple, orange, or tomato juicePantoprazole (tabletsa and oral suspensiona) —b; adult dosing: 40 mg/d for 8 wk (From adult studies: headache, diarrhea, flatulence, abdominal pain)Rabeprazole (tabletsa) Adolescents 12 y of age: 20 mg/d for 8 wk; Headache, nausea (from adult studies: pain, pharyngitis, adult dosing: 20 mg/d for 4–8 wk flatulence, constipation)Esomeprazole (capsulesa and oral suspensiona) 1–11 y of age: 10 or 20 mg/d for 8 wk; 12–17 Headache, diarrhea, abdominal pain, nausea, somnolence y of age: 20–40 mg/d for 8 wk; adult (from adult studies: headache, diarrhea, nausea, dosing: 20 or 40 mg/d for 4–8 wk flatulence, abdominal pain, constipation, dry mouth)a Delayed-release formulations.b Safety and efficacy of pantoprazole have not been established for the pediatric population.Diagnostic trials with empiric therapy number of such tests are difficult to per- ACKNOWLEDGMENTS(eg, PEG 3350 for chronic constipation, form. For children who are unable to co- This article is sponsored by the Autismacid-suppressive therapy for GERD) operate, performance of multiple tests Forum. The forum’s goal in this initia-may establish or support a specific di- during a single examination under anes- tive is to establish best practices foragnosis. Supervision by an experi- thesia might be considered. the care of co-occurring medicalenced provider, including a nutritionist Well-designed trials are needed to de- conditions that may affect the devel-if the diagnostic trial is an elimination velop an evidence base for optimal di- opmental outcome of persons withdiet, is important for assessing the clini- agnostic and treatment strategies to ASDs. Autism Forum programs arecal response appropriately. manage gastrointestinal disorders in developed under the guidance of theMany tests commonly performed in children with ASDs. Until then, applica- Northwest Autism Foundation and intypically developing children, such as tion and, where necessary, adaptation association with, and support of, thethe LBT and standard pH probe monitor- of conventional recommendations for Autism Research Institute, Autisming, are challenging or not feasible for the general pediatric population are Society of America, and Easter Sealschildren with ASDs. In this population, a relevant to children with ASDs. Oregon.REFERENCES 1. Buie T, Campbell D, Fuchs GJ III, et al. Evalu- reflux in infants and children: recommen- infants and children: recommendations of ation, diagnosis, and treatment of gastroin- dations of the North American Society for the North American Society for Pediatric testinal disorders in individuals with ASDs: Pediatric Gastroenterology and Nutrition. Gastroenterology, Hepatology and Nutri- a consensus report. Pediatrics. 2009; J Pediatr Gastroenterol Nutr. 2001;32(suppl tion. J Pediatr Gastroenterol Nutr. 2006; 125(suppl 1):S1–S18 2):S1–S31 43(3):e1– e13 2. Black C, Kaye JA, Jick H. Relation of child- 5. American Academy of Pediatrics, Subcom- 8. Horvath K, Perman JA. Autism and gastroin- hood gastrointestinal disorders to autism: mittee on Chronic Abdominal Pain. Chronic testinal symptoms. Curr Gastroenterol Rep. nested case-control study using data from abdominal pain in children. Pediatrics. 2002;4(3):251–258 the UK General Practice Research Data- 2005;115(3):812– 815 9. Rubin G, Dale A. Chronic constipation in chil- base. BMJ. 2002;325(7361):419 – 421 6. Di Lorenzo C, Colletti RB, Lehmann HP, et al; dren. BMJ. 2006;333(7577):1051–1055 3. Valicenti-McDermott M, McVicar K, Rapin I, NASPGHAN Committee on Chronic Abdomi- Wershil BK, Cohen H, Shinnar S. Frequency nal Pain. Chronic abdominal pain in 10. Reuchlin-Vroklage LM, Bierma-Zeinstra S, of gastrointestinal symptoms in children children: a technical report of the American Benninga MA, Berger MY. 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  • 12. SUPPLEMENT ARTICLE12. Chitkara DK, Nurko S, Shoffner JM, Buie T, mitochondrial disease. Mol Genet Metab. Wahn U, eds. Nutrition Support for Infants Flores A. Abnormalities in gastrointesti- 2008;94(1):16 –37 and Children at Risk. Vol 59. Basel, nal motility are associated with diseases 17. Nolan T, Debelle G, Oberklaid F, Coffey C. Switzerland: Vevey/S Karger AG; 2007: of oxidative phosphorylation in children. Randomized trial of laxatives in treatment 89 –104. Nutrition Institute Workshop Am J Gastroenterol. 2003;98(4):871– 877 of childhood encopresis. Lancet. 1991; Series: Pediatric Program13. Oliveira G, Diogo L, Grazina M, et al. Mito- 338(8766):523–527 21. Steiner TS, Lima AAM, Nataro JP, Guerrant chondrial dysfunction in autism spectrum 18. Canani RB, Cirillo P, Terrin G. Chronic and in- RL. Enteroaggregative Escherichia coli pro- disorders: a population-based study. Dev tractable diarrhea. In: Guandalini S, ed. Essen- duce intestinal inflammation and growth Med Child Neurol. 2005;47(3):185–189 tial Pediatric Gastroenterology, Hepatology, impairment and cause interleukin-8 re-14. Weissman JR, Kelley RI, Bauman ML, et al. and Nutrition. New York, NY: McGraw-Hill Med- lease from intestinal epithelial cells. J Infect Mitochondrial disease in autism spectrum ical Publishing Division; 2005:25– 46 Dis. 1998;177(1):88 –96 disorder patients: a cohort analysis. PLoS 19. Guarino A, De Marco G. Persistent diarrhea. 22. Vandenplas Y, Rudolph CD, Di Lorenzo C, et ONE. 2008;3(11):e3815 In: Kleinman RE, Sanderson IR, Goulet O, al. Pediatric gastroesophageal reflux clini-15. Haas RH, Parikh S, Falk MJ, et al. Mitochon- Sherman PM, Mieli-Vergani G, Shneider BL, cal practice guidelines: joint recommenda- drial disease: a practical approach for pri- eds. Walker’s Pediatric Gastrointestinal tions of the North American Society of Pedi- mary care physicians. Pediatrics. 2007; Disease: Pathology, Diagnosis, Manage- atric Gastroenterology, Hepatology, and 120(6):1326 –1333 ment. 5th ed. Hamilton, Ontario, Canada: BC Nutrition and the European Society of Pedi-16. Mitochondrial Medicine Society’s Commit- Decker Inc; 2008:265–274 atric Gastroenterology, Hepatology, and Nu- tee on Diagnosis; Haas RH, Parikh S, Falk MJ, 20. Gibbons T, Fuchs GJ. Chronic enteropathy: trition. J Pediatr Gastroenterol Nutr. 2009; et al. The in-depth evaluation of suspected clinical aspects. In: Cooke RJ, Vandenplas Y, In press(Continued from first page)FINANCIAL DISCLOSURE: Dr Winter has consulting agreements with AstraZeneca, P&G, Salix Pharmaceuticals, Ltd, Takeda Pharmaceuticals North America, Inc,and UCB Inc Pharma and has received research grants from AstraZeneca, Centocor, Inc, P&G, Nutricia North America Inc, SHS, Takeda Pharmaceuticals NorthAmerica, Inc, UCB Pharma, and Wyeth Pharmaceuticals; and the Autism Forum provided honoraria to all authors. PEDIATRICS Volume 125, Supplement 1, January 2010 S29 Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010
  • 13. Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDsTimothy Buie, George J. Fuchs, III, Glenn T. Furuta, Koorosh Kooros, Joseph Levy, Jeffery D. Lewis, Barry K. Wershil and Harland Winter Pediatrics 2010;125;S19-S29 DOI: 10.1542/peds.2009-1878DUpdated Information including high-resolution figures, can be found at:& Services 9References This article cites 17 articles, 5 of which you can access for free at: 9#BIBLSubspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Gastrointestinal Tract & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Downloaded from Provided by Massachusetts Gen Hosp on January 4, 2010