GASTROINTESTINAL UPDATE
From the 38th Annual Advances and Controversies in Clinical
Pediatrics, presented June 2-4, 2005, by the University of California, San
Francisco, School of Medicine, Department of Pediatrics
Frank R. Sinatra, MD, Professor of
Pediatrics, University of Southern California, Keck School of Medicine, Los
Angeles
| CELIAC DISEASE: UNDER THE ICEBERG
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| Case: girl 14 mo of age; 6-mo history of loose
foul-smelling stools and weight loss; 1-wk history of periorbital edema;
6- mo history of decreased activity level with increasing irritability; no
travel outside of California; no known exposure to gastrointestinal (GI)
infections; neonatal course unremarkable; breast-fed for first 7 mo, then
switched to cowís milk formula; solid food started at 6 mo of age; no
family history of cystic fibrosis or chronic GI disorders; maternal
grandfather died of small intestinal lymphoma; sister has type 1 diabetes;
physical examination (PE)óalert, irritable, pale infant; moderate
periorbital edema; height at fifth percentile; weight below fifth
percentile; abdomen protuberant without enlargement of liver or spleen;
generalized decrease in muscle mass and strength; gluteal wasting;
laboratory studiesó bacterial and parasitic pathogens negative;
anemia; hypoalbuminemia; stool qualitative fat stain positive; stool pH
normal; stool reducing substances negative; fecal α1
-antitrypsin (screen for protein-losing enteropathy); sweat
chloride test normal; classic celiac disease (CD) |
| Clinical presentations of CD: multiple
presentations; classic infantile formóoccurs in minority
of patients with celiac disease; poor weight gain or weight loss after
introduction of cereals or breads; previously well; anorexia; large, pale
stools; abdominal distention; irritability or lethargy; loss of muscle
mass or strength; protein-losing enteropathy with edema in severe cases;
early-infancy formóonset before 9 mo of age; possible association
with early exposure to gluten; vomiting; diarrhea (possibly severe;
increases with intercurrent infections); other
presentationsóconstipation, hypotonia, severe abdominal distention;
older childrenópresentations vary; often no overt GI symptoms;
unexplained short stature; iron-resistant (hypochromic, microcytic) anemia
or folate deficiency; poor bone mineralization (fractures); behavioral or
personality changes; asymptomatic siblings |
| Associated disorders: CD classified as autoimmune
disorder; immunologicótype 1 diabetes mellitus; selective IgA
deficiency; thyroiditis; chronic hepatitis; IgA nephropathy; cowís
milkñsensitive enteropathy; Sj–grenís syndrome; otheró Down
syndrome; Williams syndrome; Turnerís syndrome; α1
-antitrypsin deficiency; cystic fibrosis; dermatitis
herpetiformisóCD with cutaneous manifestation; severely pruritic;
symmetrical distribution (elbows and knees); erythematous macule that
becomes urticarial papule, then tense vesicles; 90% of patients have no GI
symptoms; 75% of patients have histologic changes in small bowel mucosa;
gluten-sensitive |
| Complications: short stature; osteoporosis;
dermatitis herpetiformis; dental enamel hypoplasia; recurrent stomatitis;
fertility problems; gluten ataxia and other neurologic disturbances;
refractory CD; intestinal lymphoma |
| CD (gluten-induced enteropathy):
definitionópermanent intolerance to dietary gluten
(major form of protein in wheat seed endosperm; found primarily in wheat,
barley, and rye); gliadin (alcohol-soluble component) toxic to small
intestine in susceptible individuals; pathogenesisógenetic
predisposition; environmental trigger (dietary and nondietary);
dietaryó33-amino acid peptide (33-mer peptide) in gliadin
contains critical epitopes (high in glutamine and proline); resistant to
digestion in lumen of gut; penetrates epithelial barrier; zonulin
activated, loosening tight junctions; toxic and nontoxic peptides allowed
through to submucosa where tissue transglutaminase deamidates glutamine to
glutamic acid, resulting in higher binding affinity to HLA DQ2 or DQ8
molecule on surface of antigen-presenting cells and initiating autoimmune
cascade; cellular and humoral response; cytokine response; inflammation
and mucosal atrophy; reduced surface area available for absorption;
surface cells change from tall columnar epithelial cells to cuboidal cells
(inefficient); disaccharidases and peptidases that normally reside in
brush border now unable to work; loss of normal villus structure and
inflammatory reaction result in decreased surface area, altered mucosal
integrity, and increased luminal osmolarity because of nutrient
malabsorption |
| Serologic screening tests: small-intestine biopsy
only test in past; serologic screening tests now provide ability to look
at large groups of people in noninvasive fashion; roleóidentify
symptomatic people who need biopsy; screen asymptomatic people considered
at risk (family history or other symptoms); use as supportive evidence of
CD; monitor dietary compliance; testsóantigliadin antibodies
(AGA-IgG and AGA-IgA); anti-endomysium antibodies (AEM); antitissue
transglutaminase antibodies (anti-tTG; human recombinant); HLA typing (DQ2
and DQ8); all IgA antibodies except antigliadin IgG; person possibly
IgA-deficient, must make sure person IgA-sufficient to interpret these IgA
antibody tests; sensitivity and specificity better with AEM and anti-tTG
than AGA-IgG and AGA-IgA; AEM observer-dependent; anti- tTG more reliable
and easier to perform; biopsyómore people biopsied as result of
screening tests; variations in gradation; CD patchy, need multiple samples
|
| Epidemiology: symptomatic and silent CD often have
mucosal lesions; latent CD often has normal mucosa; all share genetic
susceptibility with DQ2 or DQ8 HLA antigens; study estimating number of
diagnosed cases vs number that actually exist show that majority
of cases remain undiagnosed; multicenter epidemiologic studyó32
states; >13,000 people, 4500 of whom had first-degree relatives with
CD, 1300 had second-degree relatives with CD, 3200 symptomatic people (GI
symptoms or associated disorders), and 4100 people not at risk; screened
for AGA and AEM; anti-tTG, HLA DQ2 and DQ8, and intestinal biopsy
performed in AEM-positive people; results show that in at risk groups, 1
in 22 positive if first-degree relative with CD, 1 in 39 positive if
second-degree relative with CD, 1 in 56 positive in symptomatic group, and
1in 133 positive in group not at risk; 41% of AEM-positive people
asymptomatic; 100% of those who underwent intestinal biopsy had histologic
findings consistent with CD (34% had total or subtotal villus atrophy);
72% to 78% of AEM-positive HLA DQ2 haplotype; 16% to 20% HLA DQ8
haplotype; 6% to 8% HLA DQ2/DQ8 haplotype; no difference in prevalence
between ethnic groups; natural historyógenetically predisposed
person who, when exposed to environmental trigger (gluten load, intestinal
infections, pregnancy, or cancer), develops celiac type of enteropathy;
with time, some develop clinically overt CD or disease remains silent;
over time, more develop clinically overt CD, CD complications, or remain
persistently silent |
| Treatment: gluten-free diet for life; compliance
issue; education of family about hidden sources of gluten (prepared foods;
stabilizer in foods); support groups; American Dietetic Association has
guidelines on gluten-free diets; Celiac Disease Foundation and Gluten
Intolerance Group have websites; gluten in medications as stabilizer;
National Institutes of Health (NIH) Consensus Development Panel published
guidelines in 2004; Food Allergen Labeling and Consumer Protection Act
requires food statements list in plain language what if any of 8 main
allergens contained in product (milk, egg, peanuts, tree nuts, fish,
crustacean shellfish, soy, and wheat) |
| GASTROESOPHAGEAL REFLUX: DIAGNOSTIC PITFALLS AND APPROCH
TO MANAGEMENT |
| Case: girl 2 mo of age with 4-wk history of
postprandial emesis (effortless, consisting of undigested formula); emesis
never bilious or bloody; standard cowís milk formula diet; appetite good;
sleeps well; growth and weight gain appropriate for age; development
normal; no history of choking, pneumonia, or respiratory problems;
PEóhealthy appearance; weight and height appropriate for age;
chest sounds clear; abdominal examination unremarkable; neurologic
examination normal; stool negative for occult blood; key
findingsóemesis nonbilious and nonforceful; no evidence of
nutritional compromise, GI bleeding, or respiratory symptoms; no findings
to suggest infectious, metabolic, or neurologic disease;
diagnosisófunctional regurgitation |
| Functional regurgitation: gastroesophageal reflux
(GER); Rome Criteriaóinfants between 1 and 12 mo of age,
otherwise healthy; regurgitation twice daily for 3 wk; no retching,
hematemesis, aspiration, apnea, failure to thrive (weight loss), or
abnormal posturing; no clinical evidence to suggest metabolic, GI, or
central nervous system disease to explain symptoms |
| History and PE: feeding historyóamount and
frequency of feeds; type and preparation errors; positioning and burping;
psychosocial historyódifficulties in household; pattern of
vomitingófrequency and amount; infant distress; forceful; family
historyósignificant illness; GI, metabolic, or allergy problems;
medical historyóprematurity; growth and development problems;
surgery; PEógrowth chart (length; weight; head circumference);
warning signals suggestive of non-GER diagnosisóbilious or
forceful emesis; hematemesis or hematochezia; associated diarrhea;
abdominal tenderness or distention; onset of vomiting after 6 mo of age;
fever; lethargy; hepatosplenomegaly; macrocephaly; microcephaly; seizures
|
| Therapy: conservativeónormalize feeding
volume and frequency; consider thickened formula; positioning; consider
trial of hypoallergenic (no cow or soy protein) formula; thickened
formulaóstudy using tablespoon of cereal per ounce of formula
(changes caloric density from 0.67 cal/mL to 1 cal/mL) showed decreased
number of episodes of emesis, increased time of sleeping, and decreased
amount of crying; positioningóantrum becomes dependent part of
stomach in prone position and promotes gastric emptying; bolus of food in
cardiac portion of stomach when child in supine position or in infant
seat, making vomiting easier; sudden infant death syndrome (SIDS) data
reason not to recommend prone position; reflux index (percentage of time
distal esophageal pH <4, how much reflux) compared, using odds ratio,
to position and SIDS mortality, showed that in supine position, child
twice as likely to have reflux, but 14 times as likely to have SIDS
mortality; prone position considered if risk for death from GER outweighs
potential risk for SIDS (discuss implications with family and importance
of avoidance of soft bedding, pillows, and loose sheets near infant);
cowís milk allergyósymptoms of GER do not decrease in most
infants after changes; subset of infants with vomiting shown to have cowís
milk allergy; evidence to support 1- to 2-wk trial of hypoallergenic
formula in formula-fed infants with vomiting; eosinophilic
esophagitisóGI symptoms relating to eosinophilic esophagitis; no
response to typical therapy for GER; therapy for ìhappy spitterî (no
warning signals or signs of complicated GER)óhistory and PE usually
sufficient; parental education (warning signals; reassurance); consider
thickened or hypoallergenic formula; pharmacotherapy not recommended;
acid-reducing agents only effective pharmacotherapy available; cisapride
no longer used; speaker does not recommend metoclopramide (side effects
outweigh potential benefit); low-dose erythromycin effective in some
cases; upper GI series or other tests or GI referral if no resolution by
18 to 24 mo; prevalenceómost infants still spitting at 4 to 6 mo;
decrease in amount of emesis by 7 to 9 mo |
| Case: boy 6 wk of age with 3-wk history of forceful
postprandial emesis (immediately after feeding); nonbloody, nonbilious;
24-hr pH probe study revealed acid reflux during 37% of day; upper
endoscopy and biopsy revealed mild esophagitis; infant placed on cisapride
and ranitidine (2 days before this visit) with minimal improvement; weight
decrease from 4.8 kg to 4.4 kg in last 10 days; mother seeking second
opinion; key findingsóemesis forceful; weight loss; infant not
responding to pharmacologic therapy for GER; tests performed not specific
for uncomplicated GER and possibly positive in any disorder associated
with emesis; diagnosisópyloric stenosis |
| Diagnostic studies: barium swallow and upper GI
seriesóinitial study when emesis primary symptom (make sure anatomy
normal); high false-positive (30%) and false-negative (15%) rates in GER;
upper GI series not needed to make diagnosis of GER, but rule out other
problems; technical problems; gastroesophageal scintiscanómay be
more sensitive than barium swallow for evaluating GER; advantages of
scintiscan include providing information on gastric emptying, esophageal
motility, and pulmonary aspiration; esophageal pH monitoringógold
standard; not necessary for diagnosis of simple GER; primary role to
correlate changes in pH in distal esophagus with other findings;
simultaneously monitor for parameters of interest (eg,
respirations, heart rate, O2
saturation, chest wall movement, nasal air flow, and
electroencephalography [EEG]); temporal relationship to symptoms more
important than amount of GER; 24-hr monitoring looking at total time pH
<4 and number of GER episodes; use scoring system to determine normal,
borderline, or abnormal; reproducibility of data questionable;
endoscopy and esophageal biopsyóendoscopy used to evaluate
epigastric pain, dysphagia, or hematemesis; gross findings need
confirmation by histology; advantage of evaluating for peptic ulcer
disease and/or Helicobacter pylori; esophageal biopsy provides
information about esophageal histology and whether eosinophilic
esophagitis involved; GER complicationsóesophageal strictures;
Barrettís esophagus (intestinal metaplasia of esophageal mucosa;
potentially premalignant lesion) |
| Summary: not all vomiting in infants due to simple
GER; standard diagnostic tests in evaluation of GER not specific and
possibly positive in many conditions associated with recurrent emesis;
barium swallow and upper GI series first study performed in all cases
where investigation deemed necessary; GER not disease, but
pathophysiologic event |
Educational Objectives
| The goal of this program is to provide the listener with information
on celiac disease (CD) and gastroesophageal reflux (GER) in infants. After
hearing and assimilating this program, the clinician will be better able
to: |
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1. Describe the different presentations of CD.
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2. Discuss the pathogenesis of CD.
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3. Diagnose and treat children with CD.
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4. Discuss criteria for diagnosis and
treatment of GER. |
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5. Discuss diagnostic studies used in the
evaluation of emesis. |
Discussed on This Program
Cisapride [Propulsid]
Erythromycin [many trade names]
Metoclopramide [many trade names]
Ranitidine HCl [Zantac, Zantac 75, Zantac 150, Zantac EFFERdose]
Suggested Reading
Ciccocioppo R, Corazza GR: Is a
life-long gluten-free diet for patients with celiac disease successful? Nat
Clin Pract Gastroenterol Hepatol 2:290, 2005; Cornell HJ, et al:
Enzyme therapy for management of coeliac disease. Scand J
Gastroenterol 40:1304, 2005; Kripe C: Treating GER in
children younger than two years. Am Fam Physician 71:2091, 2005;
Kumar Y, Sarvananthan R: Gasto-oesophageal reflux in children
younger than two years. Clin Evid Jun:414, 2004;
Meize-Grochowski R: Celiac disease: a multisystem autoimmune
disorder. Gastroenterol Nurs 28:394, 2005; Naiyer AJ, Green PH:
How important is the timing of gluten introduction for children with
celiac disease? Nat Clin Pract Gastroenterol Hepatol 2:444, 2005;
Nisihara RM, et al: Celiac disease n children and adolescents
with Down syndrome. J Pediatr 81:373, 2005; Numanoglu A, et al:
Gastroesophageal reflux strictures in children,
management and outcome. Pediatr Surg Int 21:631, 2005;
Orenstein SR, et al: Nizatidine for the treatment of pediatric
gastroesophageal reflux symptoms: an open-label, multiple-dose, randomized,
multicenter clinical trial in 210 children. Clin Ther 27:472, 2005;
Raki M, et al: The effects of atorvastatin on gluten-induced
intestinal T cell responses in coeliac disease. Clin Exp Immunol
142:333, 2005; Ramaiah RN, et al: Hypopharyngeal and
distal esophageal pH monitoring in children with gastroesophageal reflux and
respiratory symptoms. J Pediatr Surg 40:1557, 2005; Simell S,
et al: Natural history of transglutaminase autoantibodies and mucosal
changes in children carrying HLA-conferred celiac disease susceptibility.
Scand J Gastroenterol 40:1182, 2005; Solid LM, Lie BA:
Future therapeutic options for celiac disease. Nat Clin Pract
Gastroenterol Heptol 2:140, 2005; Stordal K, et al: Acid
suppression does not change respiratory symptoms in children with asthma and
gastro-oesophageal reflux disease. Arch Dis Child 90:956, 2005;
Stordal K, et al: Gastroesophageal reflux disease in children:
association between symptoms and pH monitoring. Scand J Gastoenterol
40:636, 2005; Celiac disease: timing of gluten introduction in the infant
diet. Nat Clin Pract Gastroenterol Hepatol 2:294, 2005.
Faculty Disclosure
In adherence
to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to
disclose any significant financial relationship with the manufacturer or
provider of any commercial product or service discussed. The following has been
disclosed: Dr. Sinatra has received a research grant from the Schering-Plough
Research Institute (Interferon Ribavirin trial).
Dr. Sinatra was recorded at the 38th
Annual Advances and Controversies in Clinical Pediatrics,
held June 2-4, 2005, in San Francisco, and sponsored by the Department of
Pediatrics, University of California, San Francisco, School of Medicine. The
Audio-Digest Foundation thanks Dr. Sinatra and the University of California, San
Francisco, School of Medicine for their cooperation in the production of this
program.
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