Chronic abdominal pain is common in children. The majority of children with chronic abdominal pain have an abdominal pain–related functional gastrointestinal disorder (AP-FGID). AP-FGIDs are frequently and generically referred to as functional abdominal pain, although AP-FGID is a more precise term. AP-FGID is a substitute for the old term, recurrent abdominal pain, which was considered a basket term with poor specificity. The AP-FGID diagnosis is based on the interview of mother and child. Children who fulfill criteria for AP-FGIDs are subcategorized in various diagnoses according to the Rome criteria. The Rome committee has defined a set of diagnostic criteria that allows a positive clinical diagnosis of FGIDs. The first pediatric version of this symptom-based criteria was formulated in 1999 (Rome II criteria), with a subsequent revision in 2006 (Rome III criteria); a novel set of criteria is expected in 2015 (Rome IV). According to the Rome III criteria, AP-FGIDs are subdivided into four pediatric disorders: Irritable Bowel Syndrome (IBS), Functional Dyspepsia (FD), Abdominal Migraine (AM), and Childhood Functional Abdominal Pain (FAP), the latter with its own subdiagnosis: Functional Abdominal Pain Syndrome (FAPS) ( Figure 6-1 and Table 6-1 ). The hallmark of these disorders is the presence of at least 2 months of chronic abdominal pain and no evidence of anatomic, metabolic, infectious, or inflammatory pathology to explain the symptoms, which does not imply that routine diagnostic testing is necessary to exclude organic pathology.
| Functional Dyspepsia | All Criteria Must be Fulfilled: |
|---|---|
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| Irritable Bowel Syndrome | All Criteria Must be Fulfilled: |
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| Abdominal Migraines | All Criteria Must be Fulfilled: |
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| Childhood Functional Abdominal Pain | All Criteria Must be Fulfilled: |
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| Childhood Functional Abdominal Pain Syndrome | All Criteria Must be Fulfilled: |
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Large community-based studies conducted in geographically and socioculturally diverse areas have found a similar prevalence of abdominal pain and AP-FGIDs in children. Thirty-eight percent of American school-age children and 35% of Colombian children report abdominal pain weekly. A subset of these children meets criteria for an AP-FGID according to the Rome criteria. Most school-aged children with abdominal pain never seek medical attention for their symptoms. Only 3% of all children complaining of abdominal pain at the community level seek consultation. Despite this low ratio of consultation, children with chronic abdominal pain represent 2% to 4% of all pediatric office visits and 25% of pediatric gastroenterology consultations. Abdominal pain is associated with high anxiety and depression scores. The presence of abdominal pain greatly disrupts the child’s life; children with abdominal pain frequently miss school, sports, and social activities. Children diagnosed with an AP-FGID have poor quality of life, with quality of life scores as low as those reported by children with inflammatory bowel disease (IBD). FGIDs have important economic and social implications to families. In addition to the direct costs associated with medical consultations, testing, and treatment, parents frequently miss work to care for their children, which leads to additional economic and social disruption. Parent and primary care frustration with the course of the child’s symptoms frequently results in referrals to a tertiary care center.
The health-care costs of caring for a child with chronic abdominal pain are higher when children are referred to a pediatric gastroenterologist. Children referred to a tertiary care provider frequently undergo extensive and expensive diagnostic testing. Costs associated with the evaluation of children with similar severity of symptoms by a gastroenterologist are fivefold higher than when children are cared for by general pediatricians. The average cost to care for a child with abdominal pain in a tertiary care center in the United States exceeds $6000 USD. A study conducted in Uruguay showed that the direct health-care costs associated with a single pediatric consultation for abdominal pain accounted for 4% of the per capita health-care spending in one year. The cumulative lifetime health-care costs associated with FGIDs are even more substantial. Long-term follow-up studies have shown that adolescents and young adults with a history of AP-FGIDs are likely to report other somatic complaints including chronic abdominal pain and headache several years after the initial presentation. Thirty-five percent of patients who were diagnosed and treated for AP-FGIDs as children continue to meet criteria for an AP-FGID after 10 years. Children with a history of chronic abdominal pain have a high prevalence of psychiatric conditions and use of medications as adults. Almost one-third of all the adults who seek care for FGIDs began experiencing their gastrointestinal symptoms in childhood. The high personal, familial, and societal burden associated with FGIDs has raised great interest in unveiling their pathogenesis and pathophysiologic mechanisms.
Pathophysiology of AP-FGIDs
The pathophysiology of AP-FGIDs remains incompletely understood. FGIDs are heterogeneous disorders with a multifactorial origin. The most accepted theoretical framework to conceptualize FGIDs is the biopsychosocial model, which proposes a dysregulation of the bi-directional relationship between mind (thoughts, emotions, and behaviors) and body to explain symptoms, severity, and clinical outcome ( Box 6-1 ). The biopsychosocial model conceptualizes chronic pain as a centrally mediated phenomenon, shaped jointly by genetic susceptibility, physiologic, psychological, social, and environmental factors, and individual coping mechanisms. The role of inflammation, visceral hyperalgesia, central processing of pain, infection, diet, and gut flora in the development of AP-FGIDs is being increasingly understood, with hundreds of studies published in the last few years. This chapter provides up-to-date information on the possible role of each of these factors and their mutual interaction to improve understanding of the pathophysiology and treatment of AP-FGIDs in children.
Early Life
Genetic factors
Social learning
Abuse, neglect, and other adverse early life experiences
Psychosocial Factors
Life stress
Psychological state
Anxiety disorder
Panic disorder
Personality
Physiology
Abnormal motility and sensitivity
Brain–gut interaction
Regional brain activation
Hypothalamic-pituitary-adrenal axis
Postinfectious AP-FGIDs
Noninfectious postinflammatory AP-FGIDs (i.e., cow’s milk allergy, Henoch-Schönlein purpura, and probably others)
Postsurgical AP-FGIDs (i.e., pyloric stenosis, umbilical hernia and probably others)
Nature versus Nurture
Twins and familial aggregation studies support a genetic contribution to IBS. Genes that influence neural, barrier, mast cell, or immune function show univariate association with altered colonic transit in IBS. The presence of susceptibility genes may predispose to local immune activation, altered barrier function, increased permeability, and enteric nervous system signaling, leading to motor and sensory intestinal dysfunction. The most convincing evidence of gene susceptibility associated with increased risk of IBS is the TNFSF15 polymorphism, which has been observed in three independent cohorts in the United States and Europe. TNFSF15 polymorphism has been associated with a modest but significant increase in risk of IBS constipation (IBS-C), IBS diarrhea (IBS-D), and postinfectious IBS (PI-IBS) phenotypes. The TL1A protein encoded by TNFSF15 modulates inflammatory responses. This supports the role of immune activation in IBS. Gene polymorphisms involved in immune and inflammatory responses (interleukin 2 [IL-2], IL-4, IL-6, IL-10, Toll-like receptor 9 [TLR9], and tumor necrosis factor α [TNF-α]) were also found to be associated with IBS.
It has been shown that distinct gene polymorphisms implicated in serotonin (5-HT) metabolism were more frequently present in patients with IBS. 5-HT, a key signaling molecule in the gut, is an enteric neurotransmitter released from enterochromaffin cells (ECCs), which have the largest concentration of 5-HT in the body. 5-HT release activates neural reflexes associated with peristalsis, vascular perfusion, secretion, and sensation in the gastrointestinal system.
Patients with IBS-D have increased levels of mucosal 5-HT. Studies on patients with IBS suggest that 5-HT release plays a role in the development of abdominal pain and that a probable mechanism of action is through mucosal immune activation. Platelet 5-HT transporter (serotonin reuptake transporter, SERT) and the uptake of 5-HT by platelets are reduced in IBS-D. SERT terminates the signaling of 5-HT in the intestinal mucosa by transporting released 5-HT into epithelial cells, where it is metabolized to 5-hydroxyindole acetic acid. Lower SERT levels that result in impaired uptake of 5-HT correlate with duodenal immune activation (increased mast cells and intraepithelial lymphocytes). A study found that gene variants that encode TLR9, interleukin 6 (IL-6), and a gene that encodes a tight junction protein (E-cadherin, which forms the apical junctional complex required for adequate intestinal barrier function) are independent risk factors for the development of PI-IBS. However, not all the studies were able to isolate genes associated with IBS or have shown a familial concordance that could be explained by a genetic contribution. Guanine nucleotide binding protein (G-protein) beta polypeptide 3 (GNB3) C825T polymorphisms that were presumed to be associated with FGIDs were found to be equally present in cases and controls.
A large twin study found a similar prevalence of IBS among monozygotic twins (17%) and dizygotic twins (16%), and no significant difference in concordance rates between monozygotic and dizygotic twins. Another twin study that assessed the relative contribution of genetic and environmental (social learning) factors found that having a parent with IBS is a stronger predictor of IBS than having a co-twin with IBS. In this study, although concordance for IBS was significantly more common among monozygotic (17.2%) than dizygotic twins (8.4%), there was greater concordance between the dizygotic twins with their mothers than with their co-twin. This suggests that although a genetic contribution may exist, social learning may play an equal or greater role. Most experts believe that the genetic contribution to the development of FGIDs is likely to be modest, as none of the genetic findings can solely explain the pathophysiology of FGIDs. Nongenetic factors such as household environmental exposures, diet, lifestyle behaviors, shared exposure to microorganisms, adverse life events, and learned cognitions about disease and illness behavior may contribute to explain familiar clustering. Children from families with a maternal or paternal history of IBS and children from families with higher rates of illnesses and anxiety have more symptoms (gastrointestinal and nongastrointestinal), disability days, and medical consultations. Parental protective responses to pain (e.g., frequent attending to pain symptoms, granting permission to avoid regular activities) function as positive reinforcement of the illness behavior. Parental anxiety and preoccupation with physical health may help reinforce the child’s own concerns about physiologic or minor body sensations, resulting in worsening symptoms and disability.
Psychological Comorbidities
Clinic and community-based studies have found an association between anxiety and depression and AP-FGIDs The presence of anxiety and depression has prognostic implications. Higher levels of anxiety or depression are associated with a longer duration of symptoms. The temporal relation between anxiety and depression with the onset of pain is not well established. Studies suggest that anxiety may precede abdominal complaints by providing heightened attention to the child’s pain and lead to negative coping mechanisms, whereas the onset of depression frequently follows the onset of pain. An alternative explanation for the comorbidity between psychological disorders and FGIDs is that anxiety and depression could share common underlying risk factors or constitute different manifestations of a singular causal process.
Maladaptive coping is associated with worse symptoms. Children with a combination of severe abdominal pain and maladaptive coping skills are at increased risk for comorbid anxiety or depressive psychiatric disorders. Passive coping strategies (isolation from others, catastrophizing, behavioral disengagement) is associated with depressive symptoms. Catastrophizing (worrying and imagining the worst possible outcome) is thought to link pain and poor quality of life. A study of 230 school children showed that somatization may mediate the association between anxiety, depression, and passive coping with abdominal pain. Another study seems to confirm these findings by showing that although trait anxiety and somatization are significantly related to severity and frequency of pain, in children with AP-FGIDs, somatization explained the variance. These and other studies showing that greater somatization is associated with worse pain in children with AP-FGIDs (children who report multiple somatic complaints have worse abdominal pain) suggest that the assessment of somatization constitutes an important aspect in the planning of treatment in children with functional abdominal pain and supports the need for combined interdisciplinary pain programs to care for children with severe symptoms and functional disabilities.
Autonomic Dysfunction
The autonomic nervous system is involved in controlling the visceral function. The autonomic nervous system links the psychosocial aspects of the biopsychosocial model with pathophysiologic gastrointestinal symptoms. Studies have demonstrated autonomic dysfunction in adults and children with AP-FGIDs. Patients with AP-FGIDs have a higher heart rate variation in response to laboratory-induced stress compared to patients with organic abdominal pain and healthy controls. Children with severe AP-FGIDs frequently report symptoms of orthostatic intolerance. Gastrointestinal and extraintestinal symptoms of autonomic dysfunction (light-headedness, exercise intolerance, near syncope, fatigue, tremor, anxiety, sweating, and palpitations occurring in upright position and relieved on supine position) are common in patients with postural orthostatic tachycardia syndrome (POTS). Extraintestinal symptoms have been explained by redistribution of blood volume to the peripheral circulation with dependent pooling in the legs and decreased venous return. Manometric and radiologic abnormalities suggest the existence of gastrointestinal dysmotility in patients with POTS. Abnormal antroduodenal manometric tracings, abnormal anorectal manometry, radiographic changes (dilated intestinal loops or air-fluid levels), and delayed gastric emptying and colonic transit time are frequently found in adult patients diagnosed with POTS. Patients with FGIDs and POTS have unique electrogastrographic abnormalities. Changes in gastric electrical activity in the upright position (tilt-table test) were found in patients who had POTS and FGIDs but were not present in patients with FGIDs without POTS. Frequent gastrointestinal symptoms reported by patients with POTS include bloating, constipation, abdominal pain, nausea, and vomiting. A review of 24 children with abnormal tilt-test results who were referred for gastroenterology consult showed that abdominal pain was the most commonly reported gastrointestinal symptom (71%), followed by nausea (56%) and vomiting (50%), with 87% of these patients having experienced gastrointestinal symptoms for more than one year. A study of patients diagnosed with POTS at a large center treating autonomic disorders found similar results. Almost 80% of children who were diagnosed with POTS reported abdominal pain, and 36% of these patients reported at least one episode of abdominal pain weekly in a 2-month period, fulfilling criteria for an AP-FGID. Most of the patients (74%) reported changes in color or sensation with cold temperature and 85% complained of headaches. Most patients (73%) in whom the upright position during tilt-table testing reproduced their gastrointestinal complaints (mostly abdominal pain) improved their symptoms when prescribed fludrocortisone.
Early Life Events and AP-FGIDs
The early life is a period of particular vulnerability, characterized by incomplete maturation of the descending inhibitory systems and great neural plasticity of somatic and visceral sensory systems. Early exposure to physical and psychologic stressors may have long-lasting effects in brain development, programming of stress systems, and pain perception that can persist into adulthood. Preterm and term neonates who were admitted to the neonatal intensive care unit (NICU) exhibit an abnormal response to painful thermal stimulation, with greater perceptual sensitization to tonic heat than controls at 14-year follow-up. Several animal studies have linked neonatal colorectal chemical inflammation to the development of long-term visceral hypersensitivity (hyperalgesia—increased perception of a pain stimulus; and allodynia—nonpain stimulus being felt as pain). The same phenomenon is not present if the chemical inflammation is applied in adulthood. Various putative mechanisms have been proposed to explain this phenomena including sensitization of primary sensory or spinal neurons, altered stress response, and/or impaired descending inhibitory control.
In a series of studies by our group, we have demonstrated that these findings are not limited to animals. Colonic inflammation predisposes infants to abdominal pain and FGIDs later in life. Children with cow’s milk protein hypersensitivity are at risk of developing chronic abdominal pain and FGIDs (IBS, FD, and FAP). Inflammation of the gastrointestinal tract later in life (infectious and noninfectious) can also predispose to abdominal pain. Acute bacterial gastroenteritis in childhood predisposes to the development of long-lasting postinfectious FGIDs, including IBS (PI-IBS) months to years later. Children with a past history of Henoch-Schönlein purpura (HSP) are at increased risk of developing chronic abdominal pain and AP-FGIDs. Traumatic events such as surgery in infancy and childhood predispose children to the development of chronic abdominal pain. A study of children who underwent surgery for pyloric stenosis 7 years earlier found that chronic abdominal pain was four times more common and FGIDs seven times more common in the index group than in the control group. Abdominal surgery without gastrointestinal incision also increases the risk of developing AP-FGIDs. A pediatric study found that AP-FGIDs were significantly more common in children who underwent umbilical hernia repair than in nonsurgical controls. The same phenomenon does not occur in children who had an extraabdominal surgery of similar complexity. Central viscerosomatic convergence at the spinal segments responsible for the somatic and visceral nociception may contribute to these findings. Another example of viscerosomatic convergence and spinal sensory sensitization is illustrated by the hypersensitivity to cutaneous stimuli found in infants with a prenatal diagnosis of unilateral hydronephrosis.
Extraintestinal inflammation may also predispose children to AP-FGIDs. Children who had urinary tract infections in infancy are at a significantly higher risk of developing chronic abdominal pain years later. Viscerovisceral central convergence may play a role in explaining these findings. A study on neonatal rats subjected to chemical cystitis found long-term hypersensitivity to colonic balloon distention thought to be related to microRNA (miRNA)–mediated posttranscriptional suppression of the spinal γ-aminobutyric acid (GABA)ergic system. These series of studies illustrate the likely multiplicity of noxious agents and mechanisms involved in the development of chronic abdominal pain and AP-FGIDs in children (and possibly in adults).
Early life psychological stress may also contribute to sensitization to visceral pain. Some of the strongest evidence comes from the association between prior childhood abuse, neglect, or loss of a parent and the development of FGIDs later in life. Abnormal activation of central stress circuits with altered pain perception during visceral stimulation is found in patients with IBS. Neonatal maternal separation (a commonly used model of stress) predisposes rats to develop features that mimic IBS, such as visceral hyperalgesia, increased colonic motility, changes in microbiota, dysregulation of hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress, higher plasma cortisol levels (product of the HPA axis), and reduced somatic analgesia when exposed to an acute stressor.
The expression of 5-HT, 5-HT3 receptors, 5-HT transporter in brain and spinal tissue, and the 5-HT content in the colon is significantly increased in rats that are separated from their mothers compared with controls. Neonatal maternal separation sensitizes the anterior cingulate cortex (ACC: the pain critical center) and up-regulates the activity of the ascending pathway at the spinal level, as well as the thalamal-corticoamygdala pathway, in response to colorectal distension. It has been postulated that the sensitization of these pathways may be responsible for the development of visceral hypersensitivity in IBS. An increased expression of corticotropin-releasing factor (CRF), which is the main regulator of the HPA axis and CRF type 1 receptor (CRF-R1) was found in the thalamus of neonatal rats exposed to maternal separation. Chronic CRF release causes mucosal mast cell hyperplasia that may lead to colonic barrier dysfunction (increased paracellular permeability), afferent neuronal excitability, and visceral hyperalgesia. Together these results suggest that in line with the biopsychosocial model, animals exposed to early life stress develop brain–gut axis dysfunction.
Role of Infections
Mathematical modeling suggests that a substantial proportion of cases of IBS occur after an episode of acute gastroenteritis. Acute gastroenteritis increases the risk of AP-FGIDs. A likely mechanism for this effect is by triggering inflammation, increasing intestinal permeability, and altering the gut flora. Several studies have found a significant increase in cases of FGID following gastrointestinal infections in adults and children. Adult studies have shown that the risk of developing IBS increases 10-fold after a confirmed acute bacterial gastroenteritis. About 10% to 30% of children develop AP-FGIDs after an episode of acute gastroenteritis. A study of 44 children with a history of acute bacterial gastroenteritis 8 years earlier, showed a significant increase in incidence and prevalence of FGIDs compared with healthy controls of similar age and sex. Thirty-six percent of exposed patients and 11% of control subjects reported abdominal pain ( p < 0.01). An epidemiologic study conducted in children who experienced acute gastroenteritis as a result of an outbreak of bacterial contamination in the municipal water in Ontario, Canada, confirmed these findings. IBS symptoms are more likely to be present among children who are assessed closer to the time of infection than among those whose first assessment is delayed, indicating that some cases of PI-IBS resolve over time. It is not known how many children with AP-FGIDs have onset of symptoms following a gastrointestinal infection. Although it is likely that parasitic, protozoal, and viral infections that were shown to precede the onset of AP-FGIDs in adults likely do so in children too, no studies have proven these relations in the pediatric population. Some of the risk factors that predispose children to develop IBS after acute gastroenteritis have been identified. A large study showed that girls were six times more likely than their male counterparts to develop PI-IBS. An interesting question that remains to be answered is why the prevalence of FGIDs is similar among regions with different rates and types of infections if those are thought to precede a large proportion of cases of AP-FGIDs.
Role of Visceral Hypersensitivity
Altered central processing of pain perception, abnormal gastrointestinal motility, and visceral hypersensitivity (state of increased or abnormal perception of pain) are key pathophysiologic factors in the development of IBS symptoms. Studies in adult patients with IBS have shown that they are more likely than healthy controls to perceive intestinal contractions and gas. Patients with IBS are frequently hyperaware of their body signals, which results in amplified pain perception. There is controversy about whether this heightened pain perception is limited to visceral pain or cutaneous areas related to the organs involved (viscerosomatic convergence), with some studies showing that patients with IBS have higher somatic pain thresholds than healthy controls. The exact mechanisms involved in visceral hypersensitivity and in abnormal somatic referral of visceral sensations in patients with FGIDs are not clearly known but may involve sensitization of enteric neurons, sensitization of spinal cord neurons, abnormal modulation in ascending pathways, abnormal integration at the cortical level, and altered inhibitory descending pathways. The mechanical stimulation of the rectum results in activation of local peripheral mechanoreceptors and amygdala, a region known to facilitate HPA output, which in turn can affect the activity of the hypothalamic paraventricular nucleus (PVN). Patients with IBS have abnormal regulation of the HPA axis, with heightened cortisol response to visceral stimulation. Acute physical or psychological stress significantly reduces the rectal sensory pain threshold in IBS patients but not in controls. There have been numerous studies in adults and children demonstrating a lower rectal sensory threshold for pain in patients with IBS and FAP.
Visceral hypersensitivity has been shown to be organ specific, and patients with FD have lower gastric sensitivity threshold but normal rectal sensory threshold for pain. These studies have also shown aberrant projection of local pain in these patients. Sensations from rectal distension in normal children are referred to the S3 dermatome (perineal area), but in children with IBS or FAP (but not FD) these sensations resulted in viscerosomatic projections to dermatomes T8 to L1. Abnormal somatovisceral projections have also been demonstrated in adults with IBS after colonic, rectal, or jejunal distension.
Transient receptor potential (TRP) channel subunits play an important role in regulating pain, gastrointestinal motility, absorption, and secretory processes. TRPs are expressed by specific neurons and cells within the gastrointestinal tract. TRPM8 and TRPA1 modulate the signaling of painful visceral events. TRPM8 is expressed in visceral organs and the sensory pathways supplying them including the colonic wall, colonic primary afferent neurons, and colonic dorsal root ganglia (DRG) neurons. TRPV1 (transient receptor potential cation channel subfamily V member 1) is a cation-selective ion channel expressed on primary afferent neurons associated with visceral pain and hypersensitivity states. TRPV1 and TRPA1 (cation-selective ion channel associated with visceral pain and hypersensitivity states) show up-regulation in colonic afferent neurons and at the level of dorsal root ganglion, in animals subjected to stress (stress-induced visceral hyperalgesia). A significant increase in the number of TRPV1 nerve fibers is found following inflammation and in patients with IBS and quiescent IBD, with persistent IBS-like symptoms in comparison with patients with asymptomatic quiescent IBD.
Alterations in Motility
Alterations in motility and transit are found in some but not all patients with AP-FGIDs. An abnormal transit that may explain the pathophysiology of the different IBS subtypes is found in some patients. IBS-C is more frequently associated with delayed gut transit times, whereas IBS-D is more frequently associated with accelerated transit times. Colonic scintigraphy transit studies have shown that 33% of patients with IBS-D have accelerated transit time and 17.8% of patients with IBS-C have delayed colonic transit. Adult studies have shown delayed gastric emptying in patients with IBS.
A pediatric study found slower gastric emptying, lower amplitude of antral contractions, and lower antral motility index in children with FD compared with healthy controls. Gastric emptying rate and antral motility was also found significantly impaired in children with FAP compared with controls. These studies suggest a role of motility disturbances in the pathophysiology of a subset of children and adults with AP-FGIDs.
Increased Permeability
In healthy individuals, the intestinal barrier (intestinal secretions, microbiota, and epithelium), protects the body from the luminal contents of the gut and selectively regulates transcellular transport and intestinal permeability. Intestinal tight junctions control paracellular permeability, creating a selective diffusion barrier between epithelial and endothelial cells. Tight junctions have a complex protein system comprising integral membrane linker proteins (occludin, claudin), scaffold proteins (zonula occludens: ZO-1 and ZO-2), and regulatory kinases (myosin light-chain kinase). Central, or peripheral insults, or a combination of them, may result in increased permeability that facilitates access of luminal contents to the gastrointestinal wall, promoting inflammatory responses and modulating sensorimotor function. Increased small bowel and colonic permeability has been shown in both adult and pediatric patients with PI-IBS, food allergies, or food hypersensitivity. Analyses of colonic and jejunal biopsies from adult patients with IBS demonstrate disruption in the expression and distribution of tight junction proteins. Patients with IBS-D and patients with IBS-C have decreased expression of ZO-1 and occludin protein, and higher ubiquitin proteasome activity (degrades occluding-proteins) in the colonic mucosa. Colonic soluble mediators from the supernatant of colonic biopsies of patients with IBS have been shown to decrease transepithelial resistance, increase paracellular permeability, and activate human submucosal neurons, resulting in hyperalgesia. Increased luminal serine proteases, bile acids, and other organic acids including short-chain fatty acids found in the stool of patients with IBS-D, or deficiencies in glutamine, have been linked to the increased permeability.
Altered Microbiota
The gastrointestinal tract harbors a wide array of commensal microbes. The gut microbiota has an important role in promoting the development, maintenance, and function of the intestinal barrier by increasing IgA production and mucin expression, preventing intestinal epithelial cell apoptosis, inhibiting colonization by enteric pathogens, and promoting physiologic immune responses. The field of gut microbiology and the possible effects of quantitative and qualitative microbial changes on the pathogenesis of different diseases and disorders including FGIDs is rapidly evolving and not devoid of controversies. Emerging observations of alterations in composition of the intestinal microbiota, microbiota-related fermentation, disruption of intestinal barrier, and sensorimotor dysfunction in patients with IBS support the hypothesis that alterations in intestinal microbiota contribute to the pathophysiology of the disorder. Although studies on fecal microbiota composition in children and its possible role in IBS are still in the early stages, some studies suggest a possible role of specific microbiome signatures in children with IBS. The fecal microbiome composition of children with IBS patients differs from that of healthy controls. School-age children with IBS have a greater abundance of Gammaproteobacteria, and specific changes in gut microbiome composition (increased Alistipes ) have been associated with a greater frequency of abdominal pain in children.
The possible association between small intestinal bacterial overgrowth (SIBO) and IBS is still uncertain. Proponents of the role of SIBO in the pathogenesis of IBS state that the symptom overlap between SIBO in IBS and the improvement of symptoms with antibiotic treatment support the hypothesis that alterations in the intestinal microbiota play a role in the pathogenesis of IBS. Bloating is frequently reported by adults and some children with IBS. It has been argued that bloating and the increased gas production described in patients with IBS is secondary to the colonization of the proximal small bowel by fermenting bacteria. A study using the lactulose breath test to diagnose SIBO found a significantly higher prevalence of SIBO in children with IBS (65%) as compared to controls (7%; odds ratio [OR] 3.9, 95% confidence interval [CI] 7.3-80.1, p < 0.00001). Data from meta-analyses of adult studies indicate increased prevalence of SIBO in IBS. However, the tests employed and the diagnostic criteria used to diagnose SIBO are a matter of debate. There are no universally accepted gold standard methods or cut-off values for the diagnosis of SIBO. The prevalence of SIBO in cases with IBS varies with the criteria used to define SIBO, and the beneficial results of antibiotic treatment could not be replicated in some studies. A double-blind placebo-controlled study conducted in children with chronic abdominal pain showed no benefit with the use of a 10-day course of 550 mg of rifaximin three times daily compared to placebo in improvement of symptoms. A study in adult patients with abdominal bloating and flatulence that included patients with IBS found a beneficial effect of rifaximin using the same design and a lower dose of antibiotic (400 mg, three times daily). A study of patients with IBS who received a meal with lactulose and underwent lactulose breath hydrogen test and simultaneous orocecal transit determination of the meal by scintigraphy demonstrated that the abnormal rise in hydrogen found using a lactulose hydrogen breath test reflects variations in orocecal transit time. The study found that orocecal transit time was twice as long in IBS-C patients as in IBS-D patients and that the meal arrived to the cecum prior to the abnormal increase in hydrogen in the breath test. The results of this study contradict the hypothesis that SIBO explains the symptoms of IBS.
Immune Dysfunction
Immune activation and dysregulated intestinal immune response to microbiota are thought to play a role in the pathophysiology of IBS. Despite a lack of detectable inflammation on routine endoscopy and conventional histology, subtle changes including lymphocytes (CD3, CD4 and CD8 lymphocytes, and intraepithelial lymphocytes), mast cells, ECCs, and enteric nerves have been described in immunohistochemical and ultrastructural analyses in patients with PI-IBS. Increased concentrations of inflammatory/immune cells in intestinal tissue, altered levels of proinflammatory and antiinflammatory cytokines in the GI tract and peripheral blood ( Table 6-2 ), and IBS-associated polymorphisms on genes involved in immune and inflammatory responses were found in patients with IBS. Multiple studies (not all studies) have found an increased number of activated mast cells in proximity to colonic nerve endings in patients with IBS. Proximity of nerves and mast cells was strongly correlated with severity and frequency of pain. Activated mast cells secrete a complex mixture of inflammatory mediators, including proteases, prostaglandins, histamine, and cytokines/chemokines, many of which modulate the intestinal nerve activity. Patients with IBS have increased serum concentrations of IL-8, a chemokine primarily responsible for the attraction of mast cells and granulocytes. It has been proposed that the resulting mucosal inflammation sensitizes intestinal sensory endings, which leads to visceral hypersensitivity.
| Evidence | Change in IBS or PI-IBS vs. Healthy Controls |
|---|---|
| Altered concentrations or activation of immune cells | |
| GI tract | ↑ Activated (tryptase-positive) mast cells (11, 13, 24, 46, 89, 94, 121, 187) |
| ↑ IELs (36, 73, 89, 174, 185) | |
| T cells | |
| ↑ CD3+ (36, 46, 89, 94, 168) a | |
| ↑ CD4+ (46) | |
| ↑ CD8+ (46, 89, 123) | |
| B cells (62) | |
| ↓ IgA+ | |
| Peripheral blood | T cells (122) |
| ↑ activated CD4 + | |
| ↑ activated CD8 + | |
| B cells (124) a | |
| ↑ IgG+CD80 + | |
| ↑ IgG+CD86 + | |
| Altered levels of cytokines | |
| GI tract | ↑ IL-1β (75, 187) |
| ↓ IL-10 (102) | |
| Peripheral blood | |
| Baseline | ↑ IL-1β (98) |
| ↑ IL-6 (50, 51, 98) | |
| ↑ IL-8 (50, 51) | |
| ↓ IL-10 (118) | |
| ↑ IL-12 (118) | |
| ↑ TNF-α (98) | |
| In vitro stimulation | ↑ IL-1β (122) |
| ↑ IL-5 (90) | |
| ↑ IL-6 (98) | |
| ↓ IL-12 (90) | |
| ↑ IL-13 (90) |
TLRs play a key role in regulating innate immunity. They are expressed on mucosal immune cells that bind specific molecules of commensals and pathogens and thus mediate the interaction between enteric bacterial components and the immune response of the host. Altered TLR activity and elevated proinflammatory cytokine levels are found in patients with IBS. Brint et al. reported increased TLR4 and TLR5 and decreased TLR7 and TLR8 in patients with IBS. Colonic gene and protein expression of TLR2 and TLR4 differs in patients with IBS-M in relation to other IBS subtypes. Up-regulation of colonic expression of TLR2 and TLR4 was found in patients with IBS-M. TLR2 is required for the recognition of gram-positive bacteria and TLR4 is required for the recognition of gram-negative bacteria. Sensing of gram-positive and gram-negative bacteria by TLR2 and TLR4 could result in immune activation and secretion of proinflammatory cytokines. However, whether changes of TLRs are the cause or consequence of the dysbiosis found in some patients with IBS remains unclear.
Food and IBS
More than 60% of patients with IBS report the onset or worsening of symptoms with meals. Two-thirds of patients with IBS exclude food items from their diet in an attempt to alleviate symptoms. Self-reported food intolerance is associated with reduced quality of life and severity of symptoms. Foods rich in carbohydrates and fat are commonly perceived as triggering gastrointestinal symptoms. Dairy products are the most commonly reported culprit of gastrointestinal symptoms in adults and children. An investigation from Finland found that two-thirds of the children with gastrointestinal complaints who eliminated milk from their diet did not have lactose intolerance or cow’s milk allergy. A study of more than 100 children with recurrent abdominal pain who underwent lactose hydrogen breath testing found lactose intolerance in 24% of children. The study did not find an association between lactose intolerance and gastrointestinal symptoms. The frequency of abdominal pain, bloating, flatulence, and diarrhea was similar in the subgroup of children with or without lactose intolerance. Children who had an abnormal lactose breath hydrogen test were informed and recommended to avoid lactose-containing products; in a large percentage, their symptoms abated. However, an obvious limitation of the study was its unblinded nature, making it prone to bias and placebo effect. Another study assessed a similar group of children with recurrent abdominal pain with lactose breath hydrogen testing. Thirty percent of children were found to be lactose intolerant by breath hydrogen test and one in three of them was diagnosed as lactose deficient through biopsy. Different from the previous study, this investigation was blinded and had a control group. There was no significant difference in frequency of lactase deficiency between children with recurrent abdominal pain and healthy controls. There was no difference in pain outcome between lactose absorbers and malabsorbers who underwent a double-blinded lactose free diet trial. The fact that 20% of lactose absorbers with recurrent abdominal pain developed symptoms with a lactose-containing diet suggests that other factors could be responsible for the possible link between meals and gastrointestinal symptoms. Among those factors, it should be considered that the symptom experienced after intake of lactose is likely to be affected by psychological factors such as anxiety, depression, stress, classical conditioning, and pain expectation.
The ingestion of a high dose of carbohydrates, including fructose, a monosaccharide (and its chain form fructooligosaccharides—fructans found in wheat, apples, pears, watermelon, mango, asparagus, onion, rye, and garlic) and sorbitol have been shown to induce IBS symptoms. Research on adult patients with IBS and the effect of fructose, fructooligosaccharides, and lactose (disaccharide) led to the idea that restricting short-chain carbohydrates that can be poorly absorbed and are rapidly fermented in the intestine may help alleviate gastrointestinal symptoms in patients with IBS. The initial concept of restricting some short-chain carbohydrates was expanded to other food groups—including polyols, found in artificial sweeteners; sorbitol, found in stone fruits; and mannitol, found in mushrooms and cauliflower—which led to the acronym of FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) ( Table 6-3 ). FODMAPs are poorly absorbed in the small intestine. Malabsorbed sugars may lead to osmotic diarrhea. Poorly absorbed short-chain carbohydrates provide substrate for generation of short-chain fatty acids (SCFAs) by colonic bacterial fermentation. Increased gas production by colonic microbiota fermentation can result in bloating, distension, and abdominal pain. These symptoms can be more pronounced and distressing in patients with dysmotility and visceral hypersensitivity.
| Food Group | High in FODMAPs |
|---|---|
| Fruits | |
| Apples | |
| Apricots | |
| Cherries | |
| Blackberries | |
| Mangoes | |
| Nectarines | |
| Pears | |
| Plums | |
| Watermelons | |
| Vegetables | |
| Artichokes | |
| Asparagus | |
| Cauliflower | |
| Garlic | |
| Legumes | |
| Mushrooms | |
| Onions | |
| Grains | |
| Barley | |
| Rye | |
| Wheat | |
| Dairy | |
| Cottage cheese | |
| Ice cream | |
| Milk | |
| Yogurt | |
| Other | |
| Fructose | |
| High-fructose corn syrup | |
| Honey | |
| Sorbitol or mannitol |
Fecal SCFAs were found to be increased in patients with IBS. Animal studies demonstrate that SCFAs can initiate high-amplitude propagated colonic contractions, increase motility, and accelerate the gut transit via intestinal release of 5-HT. Other factors implicated in the pathophysiology of AP-FGIDs such as alterations in gut microbiota composition, visceral hypersensitivity, GI barrier defects, and abnormal immune function, may also serve as cofactors in symptom generation after intake of an excess of FODMAPs in the diet. Adults with IBS that consume a high-FODMAP diet had more GI hydrogen production but less flatus compared to controls, suggesting that the gas stays longer in the colon, which may contribute to abdominal pain.
Fructose is absorbed primarily in the small intestine via facilitated transport through the GLUT5 transporter (down-regulated in some individuals and can lead to fructose malabsorption). An alternative mechanism of fructose absorption is present when fructose is ingested with glucose through the opening of tight junctions (paracellular pathways), allowing small solutes including fructose to be passively absorbed with water. Malabsorption of fructose leads to fermentation by colonic bacteria and production of gas (hydrogen, methane, and carbon dioxide), SCFAs (acetate, butyrate, and propionate), and lactate. Fructose malabsorption has been associated with lower tryptophan levels (necessary for the biosynthesis of 5-HT) and higher depression scores. Fructose malabsorption is more common in adults with FGIDs (45%) than in healthy controls (34%). Fructose is naturally present in honey, fruits, fruit juices, and table sugar. In the form of high-fructose corn syrup, fructose is added to many foods including soft drinks, breakfast cereals, baked goods, candies, jams, and many packaged convenience foods. As a result, the amount of fructose in the average U.S. diet has increased substantially in the last 20 years, with a mean consumption of fructose among adolescents in the United States of 72.8 g per day. A pediatric study found an abnormal breath hydrogen test (fructose 1 g/kg) in 7 of 16 children diagnosed with IBS-D. Another pediatric study has shown that fructose can trigger symptoms of abdominal pain, nausea, flatulence, bloating, diarrhea, and belching in children with AP-FGIDs. In this unblinded study, 81% of children who had an abnormal breath hydrogen test using 15 or 45 g of fructose improved their symptoms with fructose restriction.
Sugar alcohols, also called polyols, include sorbitol, mannitol, xylitol, erythritol, lactitol, maltitol, isomalt, and hydrogenated starch hydrolysates. Polyols are poorly digested and absorbed in the gastrointestinal tract. Polyols are added to many prepared foods, especially “sugar-free” and diet products and liquid medications, to decrease energy content or add sweetness or bulk, and they occur naturally in some foods such as fruits. Ingestion of sorbitol has been shown to cause chronic abdominal pain in children.
Patients with self-perceived food allergies or sensitivities report a high prevalence of IBS symptoms and atopies. There is no clear evidence that patients with AP-FGIDs have food allergies. Diets based on food hypersensitivity via IgE or IgG tests are controversial. A study in adults demonstrated that a similar proportion of patients with IBS and healthy controls had positive IgG test results for yeast and foods. The study concluded that IgG tests are of little value in IBS management. A study in adult patients that found a positive effect from restricting IgG-positive foods, showed a beneficial effect that was only 10% greater than in the control group.
There has been increased interest in the possible association between nonceliac gluten sensitivity and IBS. It remains unclear whether the gastrointestinal (abdominal pain, bloating) and systemic symptoms (fatigue) that have been associated with gluten ingestion in patients without celiac disease are caused by gluten alone or another component of wheat such as fructans. Intestinal biopsies of nonceliac patients show a decrease in occluding and ZO-1 gene expression, decrease in zonulin release, and increased GI permeability after gliadin exposure. Patients with IBS-D who received a gluten-containing diet and tested positive for HLA DQ2 or HLA DQ8 (celiac genetic markers) have increased colonic mucosal permeability. These findings may suggest that patients with IBS-D who are positive for HLA DQ2 and HLA DQ8 are more likely to respond to a gluten-free diet than patients with IBS who are negative for these celiac genetic markers.
Clinical Evaluation
The initial evaluation of children with chronic abdominal pain should include a comprehensive interview with the child and parents and a thorough physical examination. Detailed characterization of the pain should include location, radiation, severity, timing of pain (daily, weekly, and seasonal), possible triggers, temporal relation to food intake, and associated symptoms of vomiting, nausea, diarrhea, and constipation. Of particular importance due to its worse prognostic factor is to inquire about autonomic symptoms, dizziness, and fatigue common in patients with autonomic dysfunction including POTS and presence of multiple comorbid non-GI symptoms such as headaches and chest and limb pain that may indicate somatization. Disability is another important aspect to be explored because patients with greater impairment frequently have a worse prognosis and require collaboration with a psychologist and school staff. The physician alone or in collaboration with a psychologist should investigate possible environmental stressors, social or emotional disturbances, and underlying psychiatric conditions. Adolescents should be interviewed without their parents and assured of complete confidentiality. An attempt must be made to elicit a possible history of physical or sexual abuse and disturbances in school and social functioning. A meticulous dietary history should be taken to uncover specific food intolerances if those are present. Frequently, by the time the family consults a specialist, the child has been subjected to multiple nonscientifically based exclusionary diets without success. Obtaining a detailed dietary history helps build trust and reassure parents that the physician listens and is open to their ideas and beliefs. Underscoring the lack of relation between the ingestion of each of the restricted food groups and the onset of symptoms and stressing that the child continues to have despite dietary restrictions helps demystify unnecessary dietary restrictions and allows returning to a normal diet when recommended.
Most children who present with chronic abdominal pain will have an FGID. The diagnosis of FGIDs is based on the Rome III criteria. Use of the Rome III criteria allows a clinical diagnosis to be established based on the clinical interview ( Table 6-1 ). A technical report from American Academy of Pediatrics (AAP) and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) stated that in the absence of red flags for an organic disease ( Box 6-2 ) and when an organic diagnosis is considered highly unlikely, laboratory testing may not be necessary. However, the level of evidence in which these alarm signs is based is low and the predictive of some alarm signs for the diagnosis of an organic condition has been put into question. Waking up at night, previously considered a red flag for an organic condition, is no longer considered so. Children with functional abdominal pain disorders frequently wake up at night. Children with AP-FGIDs are four times more likely than healthy children to have a behavioral sleep disorder, after controlling for psychopathology. Sleep is essential for optimal physical and mental functioning. A detailed sleep history frequently uncovers sleep fragmentation and less pain and better functioning on weekends when children are able to sleep late. In some cases, children with FAP who are allowed to have longer sleep hours during weekdays and start school late greatly improve their symptoms and functioning. Sleep—changes in neurohormones and endocrine factors have been associated with pain control. Animal studies have shown that rapid eye movement (REM) sleep deprivation increases the behavioral responses to noxious stimuli. Joint pains previously considered red flags for an organic disorder are also thought to be unspecific. Joint pains are equally present in children with abdominal pain of functional or organic origin. Isolated and occasional gastrointestinal blood loss can be seen in children with AP-FGIDs. Six percent of children diagnosed with IBS report blood in the stools. A family history of IBD is frequently found in children consulting for FGIDs. Parents with IBD may be more vigilant of their child’s symptoms and may be more prone to seek medical attention. The alarm signs may also vary by region and epidemiology. Ratios and type of infections can make some alarm signs more relevant in certain areas than others. However, certain red flags or the combinations of some red flags continue to be considered predictive for the diagnosis of an organic disease. The combination of anemia, hematochezia, and weight loss was found to be 94% sensitive for a diagnosis of IBD. In view of the relative low value of some of these red flags and the epidemiologic variability by region, the extent of testing will depend on the level of comfort of the practitioner and family with a functional diagnosis. In the event that any workup is indicated, the motives and expectations of the testing should be explained during the initial visit to avoid frustration and confusion once the likely normal results are obtained. In view of the absence of diagnostic markers of FGIDs, parents should be informed that a negative result only confirms the presumptive diagnosis of a FGID. This explanation will help reassure the parents of the functional diagnosis, maintain confidence in the doctor’s ability, and avoid the persistent pursuit of testing in search of an elusive diagnosis.
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