Approximately 2% to 4% of all pediatric outpatient visits are due to chronic or recurrent abdominal pain.1 More than 50 years ago, Apley2 proposed the classic definition of recurrent abdominal pain to describe children who experienced intermittent episodes of abdominal pain for at least 3 months that interfered with daily activities but had no identifiable cause. Recurrent abdominal pain represents a description rather than a diagnosis. Although many diseases cause recurrent abdominal pain, in clinical practice, the majority (70% to 90%) of children meeting Apley's criteria have no discernable organic cause for their pain and are considered to have abdominal pain of functional origin.3
In 1999, a group of expert pediatric gastroenterologists arrived at a consensus on symptom-based criteria for functional gastrointestinal disorders (FGjD) in children, known as Rome II criteria.4 As a result, Apley's original nomenclature that broadly defined a heterogenous group of patients has been replaced by more strictly defined criteria. These new criteria enable the clinician to make a positive diagnosis based more on clinical pattern and less on exclusion by costly laboratory testing. In addition, researchers are now able to investigate the physiology and treatment of disorders with similar phenotypes.
The Rome ? criteria take into consideration the location of pain and associated changes in bowel patterns (Sidebar 1, see page 250). According to these criteria, functional abdominal pain disorders now include functional abdominal pain (FAP), irritable bowel syndrome (IBS), functional dyspepsia (FD), abdominal migraine, and aerophagia. The fact that 27% of children diagnosed with the former definition of recurrent abdominal pain do not meet criteria for any Rome criteria-defined FGID underscores the importance of establishing common definitions of each FGjDs within the medical community.3
Reports from multiple countries reveal that the occurrence of abdominal pain of functional etiology is probably a global problem.5 In one community in the United States, symptoms consistent with IBS, one of the most common FGDs, occurred in 14% of all high school students and 6% of all middle school students.6 This prospective school-based study showed that abdominal pain persisted for 4 weeks or more in 23%, for 8 or more weeks in 10%, and for 12 weeks in 8% of children.
Interestingly, this study included children who were "healthy" enough to attend school, even though they had pain perceived in some cases to be both persistent and of high intensity. Due to the high prevalence of persistent abdominal pain in children, it is important to recognize that - as seen in the section on FAP - isolated episodes of abdominal pain only constitute FAP if they interfere with daily activity.
Functional abdominal pain greatly affects the child's quality of life. For example, in patients with IBS, quality of life was found to be substantially poorer than in the general population or those suffering from asthma or migraine.7 The social and economic effects includes school absences and loss of participation in extracurricular and social activities, as well as costs of medical visits, laboratory studies, drugs, and missed work days by the parents. In adults, cumulative medical expenses associated with IBS are comparable to those of asthma, stroke, hypertension and arthritis, estimated at up to $30 billion dollars a year.8 Although no cost studies have been performed in children, clinical practice indicates that both direct and indirect medical expenses incurred by evaluation and treatment of chronic abdominal pain are enormous.
Functional abdominal pain can become disabling, and may extend well beyond childhood and affect mental health in adults. Deleterious effects on academic and social competence and psychological state have been documented, with anxiety and depression lasting into young adulthood.9
Although the pathogenesis of painful FGDs is understood incompletely, most investigators agree on a multifactorial etiology and presence of an altered brain-gut interaction. A continuous interplay of genetic and environmental factors appears to shape the development of both central and enteric nervous systems. The biopsychosocial model provides a framework to understand the complex interaction among the biological, psychological, and social influences that result in the child's condition.10 The specific permutations of genetic susceptibility, early life experiences, sociocultural issues, and coping mechanisms could explain the variability in clinical presentation and outcome among individuals. For example, the combination of factors could explain why certain affected children attend school and daily activities full-time despite ongoing pain, while others are markedly incapacitated. The demonstration of a higher seasonal prevalence of abdominal pain symptoms during winter months indicates the role of additional modulating, potentially pathogenic factors such as school-related stressors, latitude, and daylight hours.
Multiple studies have demonstrated visceral hyperalgesia in patients with IBS and dyspepsia. This phenomenon can be explained by both heightened sensitivity of visceral afferent pathways and central amplification of visceral input, leading to enhanced and painful perception of visceral signals. Di Lorenzo et al.11 found that children with recurrent abdominal pain exhibited generalized visceral hyperalgesia, whereas patients with IBS had rectal but not gastric hyperalgesia.
The finding that specific GI symptoms frequently are reproduced by stimulation of the predominant site of hyperalgesia provides a possible explanation of the varied phenotypic presentations. Similarly, functional MRI and PET scanning studies have identified differential areas of brain activation in patients with IBS when compared with controls.12 In addition to greater sensory responses, patients with painful FGIDs may have abnormal GI motility. In patients with IBS, various types of motor disturbances have been documented that may correlate with specific symptoms.
Genetic factors contribute to susceptibility to developing FGIDs. Locke13 has reported a significant association between patients with abdominal pain or bowel disturbances and first-degree relatives with IBS and dyspepsia. A twin study showed a higher concordance for IBS in monozygotic than dizygotic twins.14 The same study also found a higher correlation of IBS with parental symptoms, reinforcing the importance of learned behaviors.
The hypothalamic-pituitary-adrenal (HPA) axis system regulates physiological processes to maintain homeostasis and facilitate adaptation to environmental stress. The stress response, although vital, can become pathogenic. Patients with IBS often become more symptomatic during stressful circumstances. In animal studies, hypothalamic secretion of corticotrophin-releasing factor has been shown convincingly to cause both gastric stasis and enhanced colonic motility.
Additional environmental insults have also been shown to predispose to IBS. There is evidence that a gastrointestinal infection resulting in transient mucosal inflammation can induce development of IBS. Multiple studies reported that 20% to 25% of adult patients hospitalized for bacterial gastroenteritis developed symptoms consistent with IBS within months after resolution of the acute infection.15 One possible explanation is that the inflammatory stimuli heighten enteric nerve sensitivity leading to a hyperalgesic state and altered gut motility.
TYPES OF FGID
Although each pain-related FGD possesses its own phenotypic characteristics, there is abundant overlap among them, and patients frequently migrate from one category to another over time. A common pathogenic pathway to all these FGDs provides a theoretical basis for this commonly described progression.
Although the terminology seems to overlap with recurrent abdominal pain, the term "functional abdominal pain" is one of the specific diagnoses within abdominal pain of functional origin (Table 1). The Rome II diagnostic criteria define FAP as a continuous or nearly continuous abdominal pain in school-aged children or adolescents, with only occasional relation of pain to physiological events, such as eating, menses, defecation, or changes in stool characteristics, in the absence of suspected malingering and insufficient criteria for other FGIDs.4
Although one community study found that almost 50% of otherwise healthy school-aged children suffer from abdominal pain,6 most would not qualify for a diagnosis of FAP because they attended school without loss of daily functioning - a key Rome ? criterion. Therefore, children with abdominal pain that does not impair their daily activities do not meet the Rome criteria and should not be considered to have FAR Children with FAP usually complain exclusively of diffuse or periumbilical pain occasionally accompanied by dizziness, headaches, nausea, and vomiting.
Alarm Symptoms for Organic Disease
Although there are few epidemiologic studies, one American community study has shown that IBS is the most prevalent pediatric FGID associated with pain. 16 The Rome ? diagnostic criteria for IBS entail at least 12 weeks of abdominal pain associated with bowel movements or with change in stool frequency or characteristics (Table 1).
Patients also may experience diarrhea or constipation, mucus in stools, straining, urgency, relief by evacuation or a sense of incomplete evacuation, bloating, gas, and abdominal distension. Most present with pain and either diarrhea or constipation, so-called diarrhea-predominant or constipation-predominant IBS, and some with alternating diarrhea and constipation.
Functional dyspepsia is defined as persistent or recurrent pain or discomfort centered in the upper abdomen (Sidebar 1). Associated symptoms may include belching, bloating, early satiety, nausea, retching, or vomiting. As opposed to IBS, patients suffering from dyspepsia have pain independent of stool pattern or characteristics. Although dyspeptic symptoms are common in children, neither FAP, IBS, nor functional dyspepsia results from the presence of gastric Helicobacter pylori. Therefore, testing for H. pylori is not recommended in the setting of patients with clinically evident abdominal pain of functional origin.
Abdominal migraine is characterized by discrete, paroxysmal episodes of severe abdominal pain between which the child is completely normal17 (Sidebar 1). These usually occur in children with either a personal or family history of migraines. As part of the Rome ? criteria, children may have aura, headaches, and photophobia. Apart from the criteria, affected patients also typically have stereotypical attacks (as to time of onset, duration, and symptoms), pallor, listlessness, and nausea. The abdominal pain may be acute, severe, and noncolicky, located in the midline. Among surveyed Scottish schoolchildren, abdominal migraine was diagnosed in 4%. 18 Antimigraine therapy is often used to prevent recurrences or abort acute attacks.
Figure. Algorithm for the initial management of chronic abdominal pain of functional origin.
FUNCTIONALVERSUS ORGANIC DISORDERS
Certain clinical features usually are considered suggestive of an organic etiology ("alarm symptoms") (Table, see page 25 1). In general, the presence of an isolated symptom (eg, isolated abdominal pain) is thought to be more consistent with a functional disorder, whereas multiple symptoms (eg, associated weight loss, vomiting, diarrhea) are more likely due to an organic condition.
A recent technical report of the American Academy of Pediatrics found sufficient evidence to consider the presence of persistent fever, weight loss, gastrointestinal bleeding, significant vomiting, and chronic diarrhea as alarm symptoms of organic disease.19 However, there was insufficient evidence to state that anorexia, nausea, headache, and joint pain should be used similarly. The awareness of these alarm symptoms may help the practitioner decide on further laboratory testing, radiologic testing, and GI consultation.
The differential diagnosis of abdominal pain conditions includes multiple conditions that we will describe briefly. A detailed description of each diagnosis is beyond the scope of this article.
Celiac disease now appears to be more common than has generally been recognized in the United States.20 The clinical presentation of celiac disease may be misleading, with patients often lacking the classical symptoms of diarrhea and growth failure and presenting with few symptoms. These children frequently present with abdominal pain (77%) and bloating or gas (73%), which are common clinical manifestations of FGIDs. An adult study found that patients with celiac disease initially were diagnosed with IBS in 37% of cases.21 Therefore, celiac disease should be included in the differential diagnosis of IBS. More information on celiac disease is provided in the article by Gelfond and Fasano (see page 275).
Inflammatory bowel disease was found in 3% to 4% of pediatric patients evaluated for IBS.22 Some patients complain for months of vague abdominal pain and intermittent diarrhea before being diagnosed with inflammatory bowel disease. The presentation of the abdominal pain is quite variable and may vary according to the site of bowel involvement. A decrease in height velocity preceded the onset of intestinal symptoms by at least 1 year in nearly half of children with Crohn's disease.23 Terminal ileum and cecal involvement in Crohn's disease often is associated with right lower quadrant discomfort and tenderness.
Peptic ulcer disease usually presents with epigastric pain, sometimes generalized or periumbilical in location, and can be accompanied by heartburn, nausea, and vomiting. These symptoms overlap with features commonly present in nonulcer dyspepsia. Although a favorable response to H2 blockers or proton pump inhibitors points towards peptic disease, these medications also may be partly effective in patients with functional dyspepsia. Because the symptoms and therapeutic responses between peptic ulcer disease and functional dyspepsia may be indistinguishable, on occasion the definitive diagnosis may require esophagogastroduodenoscopy Although H. pylori infections can cause peptic ulcers in children, most are asymptomatic. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition practice guidelines do not recommend universal testing or treatment of H. pylori in children with either recurrent periumbilical or epigastric pain.24
Carbohydrate intolerance in children can present with chronic abdominal pain, increased flatulence, and bloating. Although the breath hydrogen test can confirm the diagnosis of lactase deficiency, symptomatic improvement in response to lactose exclusion will establish it as the cause of abdominal symptoms (ie, lactose intolerance). One pediatric study found lactose-free elimination diets administered in a controlled, blinded trial did not show efficacy in resolution of symptoms of recurrent abdominal pain.25 It appears that, although lactase deficiency is quite common, lactose intolerance as a cause of abdominal pain is much less common.
Chronic constipation can overlap with constipation-predominant IBS and present similarly.26 Interestingly, because of the developing megacolon, children with chronic constipation often have little abdominal pain. In constipation, abdominal palpation may reveal a fecal mass in the left lower quadrant and suprapubic region and a fissure or a sentinel skin tag at the anus. Digital examination can reveal the presence of a hard fecal bolus in a distended rectum.
Cholelithiasis is considered uncommon in childhood and adolescence, but gallbladder dyskinesia is diagnosed with increasing frequency. Cholelithiasis is associated with obesity, ileal disease, hemolytic anemias, and a family history of childhood gallstones.27 Children with gallstones may have sudden onset of colicky or nonspecific pain localized to the right upper quadrant or epigastrium, occasionally radiating to the back or right shoulder. Nausea, vomiting, and fatty food intolerance may be present. Gallbladder dyskinesia is found in obese adolescent girls, with symptoms indistinguishable from those of cholelithiasis.28
Pancreatitis commonly presents with epigastric pain, nausea, and vomiting. The epigastric pain can radiate to the back or sides and typically is triggered or aggravated by meals. The physical examination is characterized by abdominal tenderness in the epigastric area and decreased bowel sounds.
Malrotation usually presents within the first year of life, but 20% in one series presented with chronic abdominal pain in children older than I.29 The pain typically is postprandial and associated with bilious emesis and diarrhea, with evidence of malabsorption or protein-losing enteropathy. Intestinal duplications also may result in vague pain and vomiting. In most cases, additional signs are present, such as decreased oral intake, bilious vomiting, gastrointestinal bleeding, abdominal masses, distention, and tenderness.
Urologie disorders including pyelonephritis, ureteropelvic junction obstruction, or extrinsic ureteral obstruction may present with recurrent colicky abdominal pain. Gynecologic disorders such as ovarian cysts, congenital uterine abnormalities, hematocolpos, endometriosis, and Mittelschmerz should be considered in the differential diagnosis of abdominal pain in a postmenarchal girl. Ovarian cysts tend to be rare in infancy and childhood.
Parasitic infections, including Giardia lamblia, Dientamoeba fragilis, Cryptosporidium and Blastocystis hominis may result in abdominal pain, mostly in association with anorexia, bloating, abdominal distention and diarrhea. One should consider these agents depending on the particular prevalence in each locale.
Trauma to the abdomen can cause localized pain, usually sharp in quality and exacerbated by movement. In adolescents, complaints of upper abdominal or chest pain should lead to consideration of costochondritis, especially when the pain is reproduced by palpating the affected costal cartilage.
Because of the possible common brain-gut pathogenesis among most of the pain-predominant FGEDs discussed above, we should review the evaluation and therapy of FAP along with function dyspepsia and IBS, all of which have recurring pain as a central feature. At present, there are no known biochemical or radiographic (structural) markers to identify patients with FGDDs. Although there are few pediatric studies validating the Rome criteria, adult studies show that, in patients without alarm symptoms, these criteria have a positive predictive value of approximately 98%, coupled with a low positive yield of additional diagnostic tests of less than 2%.30 Therefore, it appears that the diagnosis of these conditions can now be based on typical symptoms, with occasional support of negative results from limited testing (Figure, see page 252).
The exclusion of an organic condition usually can be accomplished through screening diagnostic tests such as complete blood cell count, erythrocyte sedimentation rate, liver transaminases, celiac antibodies, urinalysis and stool examination for blood, ova, or parasites. However, the practitioner should be cautious in performing multiple tests because that approach may yield findings that are either causally unrelated or irrelevant, as shown by the lack of response to specific therapy. Moreover, the repetition of tests may raise family concerns about the possibility of life-threatening conditions and may undermine attempts at reassurance.
There is no uniformly successful treatment for abdominal pain of functional origin. However, any therapeutic strategy should establish an effective physician-patient-family relationship and allocate sufficient consultative time to educate and reassure the child and parents. An essential aspect of the approach is to emphasize the normal aspects of the history, physical examination, and laboratory tests and to educate the family on the benign nature and natural history of these disorders. Comparison with other common symptoms such as headaches, muscle cramps, or stomach "butterflies" that have no objective findings may be helpful in clarifying the concept of functional conditions. It is important to validate the child's symptoms by stating that the pain is "real," not just "in the head." Finally, the family and child should be encouraged to ask questions to clarify misconceptions.
Once these essential steps are completed, the physician should review the different types of therapy available, and set goals and expectations (Figure 1). Alleviating symptoms is the main goal when treating the child with a functional disorder. Because complete eradication of pain often is impossible, from the medical viewpoint, the goals are to return the child to functional status, attending school and extracurricular activities. However, because few scientific data support a specific therapeutic approach, the strategy should be to tailor the therapy based on the health beliefs and levels of comfort of the child, parents, and physician.
In view of the paucity of controlled investigations in children with FGDs and the methodological flaws associated with other studies, no definitive recommendations can be given on effective pharmacotherapy. Therefore, current therapy of pain-predominant FGDs is based on personal preferences, anecdotal experience, and expert opinion (Sidebar 2, see page 254). However, despite these limitations, the practitioner should be aware of the most widely used therapies, the available evidence for each, the dosing and side effect profile, and the principal pharmacologic actions to inform families and guide day-to-day treatment decisions.
Anticholinergics, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin receptor modulators are used commonly. Because there is only one small randomized controlled trial in pediatric FAP, definitive support for the efficacy of any specific regimen is lacking. This single controlled trial found that 75% of children with IBS had reduced pain severity after 2 weeks of enteric-coated peppermint oil, a spasmolytic agent that relaxes gastrointestinal smooth muscle.31 Anecdotal experience appears to support the observation that some patients find relief using smooth muscle relaxants such as hyoscyamine or dicyclomine that act by reducing intestinal tone and motility. The sublingual, fast-acting form may be appropriate for relief of acute abdominal pain symptoms.
Tricyclic antidepressants used at lower doses than required in clinical depression have proven to be effective in adults for managing abdominal pain. Although there are no similar data on efficacy in children, a multicenter study is under way to answer this question. SSRIs seem to have therapeutic value in relieving FGD symptoms in adult inpatients.32 Despite the growing use of SSRIs in adults, no controlled studies have been published on their efficacy in children.
Patients with severe constipation or constipation-predominant IBS may find relief by combining fiber with or without a laxative. Although many other laxatives may be used, our preference is to use polyethylene glycol (0.5 mg/kg/day). Lactulose syrup should be avoided because increased gas production from colonic bacterial fermentation may trigger pain in patients with visceral hyperalgesia. Tegaserod, a 5HT4 receptor agonist that has not yet been studied in children, is being used increasingly with apparent good success by anecdote in therapy of abdominal pain with constipation. Patients with abdominal pain with diarrhea may find relief by using an antidiarrheal preparation containing fiber, diphenoxylate, or loperamide (1 to 2 mg once or twice a day). Based on the literature on therapy of functional disorders, one should also be aware that there is a high placebo response rate33 that can lead to initial efficacy of a treatment but subsequent relapse after a variable period of time.
Although the standard treatments for FGDs are pharmacologic, growing evidence supports the therapeutic value of psychological therapy such as cognitivebehavior treatment.34 There is increased investigation into diet supplements, probiotics, hypotherapy, and traditional modalities such as Chinese acupuncture. Hypnotherapy has been shown to have both short and long-term beneficial effects in the treatment of IBS in adults.35 There is no clear supportive evidence of the benefit and safety of "natural" and herbal medications. However, one should underscore that these medications are not without potential adverse effects and patients not take these them without appropriate supervision. Although recent controlled trials on the effects of probiotics in children did not show a beneficial effect on abdominal pain, they did relieve perceived abdominal distention.36 In an adult study, VSL#3, a combination of probiotic agents, reduced flatulence in patients with IBS37 but did not improve subjective outcomes such as relief of abdominal pain and bloating.
Many future investigations into FGDs are needed. These should focus on refining and validating the Rome diagnostic criteria, investigating possible biologic markers of these disorders, elucidating the role of the visceral afferent dysfunction or reflex motor responses that lead to symptoms, searching for new pathogenic factors (eg, corticotrophin-releasing factor), and evaluating therapies in prospective controlled trials. To tackle this challenging group of disorders successfully, there must be a broad collaboration among basic scientists, clinical investigators, physicians, psychologists, and practitioners of alternative and complementary medicine to develop and evaluate improved therapies. In the meantime, it is our duty as practitioners to keep updated and receptive to the needs of patients and families to reduce patient suffering, improve functioning, and control the costs to society.
1. Galler JR, Neustein S, Walker WA. Clinical aspects of recurrent abdominal pain in children. Adv Pediatr. 1980;27:31-53.
2. Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children. Arch Dis Child. 1958;33( 168): 165-170.
3. Walker LS, Lipani TA, Greene JW, et al. Recurrent abdominal pain: symptom subtypes based on the Rome ? Criteria for pediatric functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr. 2004;38(2): 187-191
4. Rasquin- Weber A, Hyman PE, Cucchiara S, et al. Childhood functional gastrointestinal disorders. Gut. 1999 Sep;45(Suppl 2):??60-?68.
5. Saps M, Di Lorenzo C. Functional abdominal pain and other functional bowel disorders. In: Guandalini S, ed. Textbook of Pediatric Gastroenterology and Nutrition. London, England: Taylor & Francis; 2004:213-232.
6. Saps M, Sztainberg MO, Di Lorenzo C. A prospective community based study of gastroenterological symptoms in school-age children. Gastroenterology. 2005;128(4 Suppl 2):A169.
7. Frank L, Kleinman L, Rentz A, et al. Healthrelated quality of life associated with irritable bowel syndrome: comparison with other chronic diseases. Clin Ther. 2002;24(4):675-689.
8. Talley NJ, Gabriel SE, Harmsen WS, Zinsmeister AR, Evans RW. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology. 1995;109(6):1736-1741.
9. Campo JV, Di Lorenzo C, Chiappetta L, et al. Adult outcomes of pediatric recurrent abdominal pain: do they just grow out of it? Pediatrics. 2001;108(1):E1.
10. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977; 196(4286): 129-136.
11. Di Lorenzo C, Youssef NN, Sigurdsson L, et al. Visceral hyperalgesia in children with functional abdominal pain. J Pediatr. 2001; 139(6): 838-843.
12. Silverman DH, Munakata JA, Ennes H, et al. Regional cerebral activity in normal and pathological perception of visceral pain. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology. 1997;112(l):64-72.
13. Locke GR 3rd, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ 3rd. Familial association in adults with functional gastrointestinal disorders. Mayo ClinProc. 2000;75(9):907-912.
14. Levy RL, Jones KR, Whitehead WE, et al. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology. 200 1 ; 1 2 1 (4):799 -804.
15. Gwee KA, Graham JC, McKendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet. 1996;347(8995): 150-153.
16. Hyams JS, Burke G, Davis PM, Rzepski B, Andrulonis PA. Abdominal pain and irritable bowel syndrome in adolescents: a communitybased study. J Pediatr. 1996;129(2):220-222.
17. Li BU, Balint JP. Cyclic vomiting syndrome: evolution in our understanding of a brain-gut disorder. Adv Pediatr. 2000;47:1 17-160.
18. Abu-Arafeh I, Russell G. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Arch Dis Child. 1995;72(5):413-417.
19. Di Lorenzo C, Colletti RB, Lehmann HP, et al.; AAP Subcommittee; NASPGHAN Committee on Chronic Abdominal Pain. Chronic Abdominal Pain In Children: a Technical Report of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40(3):249-261.
20. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and notat-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003; 163(3):286-292.
21. Zipser RD, Patel S, Yahya KZ, Baisch DW, Monarch E. Presentations of adult celiac disease in a nationwide patient support group. Dig Dis Sci. 2003;48(4):761-764.
22. Hyams JS, Treem WR, Justinich CJ, et al. Characterization of symptoms in children with recurrent abdominal pain: resemblance to irritable bowel syndrome. J Pediatr Gastroenterol Nutr. 1995;20(2):209-214.
23. KanofME,LakeAM,Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn's disease. Gastroenterology. 1988;95(6): 1523-1527
24. Sherman P, Czinn S, Drumm B, et al. Helicobacter pylori infection in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2002;35(Suppl 2):S 128-133.
25. Lebenthal E, Rossi TM, Nord KS, Branski D. Recurrent abdominal pain and lactose absorption in children. Pediatrics. 1981;67(6): 828-832.
26. Saps M, Di Lorenzo C. Interobserver and intraobserver reliability of the Rome ? criteria in children. Am J Gastroenterol. 2005; 100(9):2079-2082.
27. Wesdorp I, Bosman D, de Graaff A, et al. Clinical presentations and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr. 2000;3 1(4):41 1-417.
28. Dumont RC, Caniano DA. Hypokinetic gallbladder disease: a cause of chronic abdominal pain in children and adolescents. J Pediatr Surg. 1999;34(5): 858-861.
29. Spigland N, Brandt ML, Yazbeck S. Malrotation presenting beyond the neonatal period. J Pediatr Surg. 1990;25(1 1): 1 139-1 142.
30. Olden KW. Diagnosis of irritable bowel syndrome. Gastroenterology. 2002;122(6): 1701-1141.
31. Kline RM, Kline JJ, Di Palma J, Barbero GJ. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr. 2001; 138(1):125-128.
32. WaId A. Irritable Bowel Syndrome. Curr Treat Options Gastroenterol. 1999;2(1): 13-19.
33. Enck P, Klosterhalfen S. The placebo response in functional bowel disorders: perspectives and putative mechanisms. Neurogastroenterol Motil. 2005;17(3):325-331.
34. Heymann-Monnikes I, Arnold R, Florin I, et al. The combination of medical treatment plus multicomponent behavioral therapy is superior to medical treatment alone in the therapy of irritable bowel syndrome. Am J Gastroenterol. 2000;95(4):981-994.
35. Houghton LA, Calvert EL, Jackson NA, Cooper P, Whorwell PJ. Visceral sensation and emotion: a study using hypnosis. Gut. 2002;51(5):70 1-704.
36. Bausserman M, Michail S. The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial. J Pediatr. 2005; 147(2): 197-201.
37. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil. 2005;17(5):687-696.
Alarm Symptoms for Organic Disease