Pediatric Functional Gastrointestinal Disorders

Abstract

Functional gastrointestinal disorders continue to be a prevalent set of conditions faced by the healthcare team and have a significant emotional and economic impact. In this review, the authors highlight some of the common functional disorders seen in pediatric patients (functional dyspepsia, irritable bowel syndrome, functional abdominal pain) as well as one of the more intriguing (cyclic vomiting). The most recent Pediatric Rome Working Group has modified the definitions of functional gastrointestinal disorders. Current studies have used these categorizations to understand better the epidemiology, etiology, and treatment options for these disorders. As more data are available, children and their families will be offered a better understanding of the conditions and more effective treatments to overcome them. The importance of making an accurate diagnosis of a functional gastrointestinal disorder cannot be overemphasized.

Functional gastrointestinal disorders (FGIDs) are conditions that include a combination of symptoms that are chronic or recurrent and are not explained entirely with current structural or biochemical investigations. The term functional emphasizes that many of the symptoms may accompany normal development (eg, infant regurgitation) or may be a response to otherwise normal internal or external cues (eg, constipation following painful stooling).¹

Historically, one of the earliest descriptions of a FGID in children was by Apley,² who described a group of children in the community who complained of abdominal pain with no clear etiology that persisted and interfered with daily activities. He coined the phrase recurrent abdominal pain (RAP) to describe this condition. Using Apley’s definition, 10%-17% of school-aged children have RAP.^3-10 Now, however, the term RAP has been modified and subdivided into more defined groups. The most recent revision by the Rome Pediatric Working Group on Functional GI Disorders occurred in 2006.¹¹ The process involved group consensus using clinical experience as well as an extensive review of the literature.¹¹ The goal of this pediatric working group was to make the criteria more useful for both clinician and researcher, facilitating efforts to make an accurate and definitive diagnosis in these children as well as efforts to provide additional evidence-based data regarding FGIDs in children.¹¹ Two studies reviewed the classification of children who previously had been described as having RAP and divided them into subtypes according to the Pediatric Rome criteria (Table 1).^12,13 The majority of these RAP children met the criteria for irritable bowel syndrome (45%) or functional dyspepsia (16%), whereas the third most frequent was functional abdominal pain (7.5%).¹² Another recent study using prospective methods suggested that 65% of RAP children had irritable bowel syndrome and 35% had functional abdominal pain (the latter group may have included some children with functional dyspepsia).¹⁴

Table 1.

Pediatric Rome III Criteria for Functional Disorders

Functional Dyspepsia	Functional Abdominal Pain	Irritable Bowel Syndrome	Cyclic Vomiting Syndrome
Persistent or recurrent pain  or discomfort centered  in the upper abdomen	Episodic or continuous  abdominal pain	Abdominal discomfort or pain  associated with 2 or more of the  following (see below) at least  25% of the time	Two or more periods of  intense nausea or retching  lasting hours to days
Criteria fulfilled at least  once per week for at  least 2 months	Criteria fulfilled at least once  per week for at least  2 months	Criteria fulfilled at least once per  week for at least 2 months	Return to usual state of  health lasting weeks to  months
Does not meet criteria for  irritable bowel syndrome	Functional abdominal pain  syndrome: includes  functional abdominal pain  at least 25% of the time  and 1 or more of the  following:  – Some loss of daily   functioning  – Additional somatic   symptoms such as   headache, limb pain,   or difficulty sleeping	At least 2 of the following at least  25% of the time:  – Pain improved with defecation  – Pain onset associated with a change   in stool form  – Pain onset associated with a change   in stool frequency

In this review, we highlight some of the most common functional disorders seen in pediatric patients (functional dyspepsia, irritable bowel syndrome, functional abdominal pain) as well as one of the more intriguing (cyclic vomiting).

Functional Dyspepsia

The diagnosis of functional dyspepsia (FD) describes persistent or recurrent pain or discomfort localized to the upper abdomen.¹¹ The symptoms commonly occur after eating. Many children miss school because of the pain, nausea, and occasional vomiting attributed to functional dyspepsia. Studies cite a prevalence between 5% and 16% in the United States.^6,12

Unlike adults, in whom the differential diagnosis is more extensive, in children, cancer of the stomach and esophagus is almost nonexistent, and gastric and duodenal ulcers are much less common. The issue of Helicobacter pylori infection often is raised in individuals with upper GI pain. Although H pylori infection can cause pain as well as ulcers, in children in the United States, H pylori is an uncommon cause of dyspeptic symptoms.¹⁵

The etiologies of FD have not been fully elucidated. There is some evidence to show that dysmotility may be involved. Abnormal antral contractility was associated with postprandial nausea in some adults with FD.¹⁶ Adolescents with FD demonstrated delayed gastric emptying and decreased gastric volume accommodation after feeding.¹⁷ However, in adults, the impaired quality of life did not correlate with delayed gastric emptying.¹⁸ Psychological factors may play a role in symptom expression. In adults, patients with FD reported higher anxiety and stress than patients with ulcer disease.¹⁹

There are no specific diagnostic markers for FD, but careful history and physical exam (including evaluation of growth parameters and stool guaiac testing) can determine if additional testing may be required. As with other FGIDs, the presence of so-called red flag symptoms can suggest the need for further testing but should not exclude the diagnostic possibility of a FGID.²⁰ Historically, red flags included nocturnal symptoms that awaken the patient, involuntary weight loss, deceleration in linear growth, blood in the stool, fever, urinary complaints, pain away from the umbilicus (especially right lower/upper quadrant), family history of inflammatory bowel disease, and/or organomegaly. Although the presence of these findings may suggest a higher pretest probability of organic disease, the specificity and sensitivity of these findings for organic disease has not been determined in pediatric patients. Indeed, Shulman et al¹⁴ observed that children with RAP can present with pain remote from the umbilicus. A systematic review reported that frequency, severity, location, and timing of pain do not distinguish organic from functional abdominal pain.²¹

Because some studies have suggested abnormalities in motility in patients with FD,^16,17 some treatments have attempted to enhance gastric emptying. Erythromycin, used frequently to increase and synchronize antral motility, did enhance gastric emptying but was not associated with a beneficial effect on meal-related symptom severity in adults.²² Other motility agents have been used in adults with FD. Itopride, a dopamine agonist with antiacetylcholinesterase effects, significantly improves symptoms in adult patients with functional dyspepsia.²³ Studies in adults suggest that the use of a proton pump inhibitor is associated with improvement in symptoms in some individuals with FD in the absence of gastroesophageal reflux or ulcer disease.²⁴ Further studies are needed to find medications that could provide benefit to patients with FD, particularly children.

Alternative medicine approaches also are being used for patients with FD. Calvert et al²⁵ showed long-term benefit for patients with FD using hypnotherapy. A recent report demonstrated that acupuncture improves gastric emptying and relieves dyspeptic symptoms in adults with FD and normal gastric emptying.²⁶

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS), as described by the Rome criteria, includes weekly symptoms of abdominal pain or discomfort accompanied by changes in bowel patterns.¹¹ These include changes in bowel movement form or frequency at the onset of pain and/or relief of pain with defecation. In adults, the bowel symptoms are used to subclassify the IBS into diarrhea- or constipation-predominant IBS. A systematic review of the literature reported a prevalence of IBS in North American adults between 3% and 20%, with most reporting 10%-15%.²⁷ Interestingly, this percentage range is similar for pediatric patients with RAP around the world.²⁸

There appears to be a genetic component to IBS. This appears to be true for RAP as well and presumably IBS in children. IBS tends to “run in families,” and mothers of children with RAP are more likely to have a lifetime history of IBS compared with controls.²⁹ Concordance for IBS is greater in identical twins than in fraternal twins, highlighting the genetic influence of this disease.³⁰

Children and adults with IBS have evidence of visceral hypersensitivity. That is, a stimulus (usually measured in the laboratory as distention of the gut lumen) that does not elicit pain in control individuals will cause pain in an individual with IBS.³¹ Some of the visceral hypersensitivity appears to stem from a dysregulation in the communication between the enteric nerves of the intestine and the central nervous system.³² Using functional magnetic resonance imaging (MRI) that highlights activity in specific brain regions, studies have demonstrated that altered central nervous system processing of gut signals can play a major role in IBS.^33,34

The visceral hypersensitivity likely is multifactorial. Additional evidence suggests that physiologic stimuli (dietary, gut flora, hormonal), noxious stimuli (inflammation), altered motility, and/or psychological stress may be involved. The visceral hypersensitivity may come from an altered interaction between the gut bacteria and the enteric nervous system. Indeed, it has been demonstrated that the microbiota is significantly altered in adult patients with IBS compared with controls.³⁵ In adults (and no doubt in children), IBS may develop after an enteric viral, bacterial, or parasitic infection.^36,37 Despite resolution of the infection, the symptoms of IBS can persist for years.³⁷ It has been suggested that this so-called postinfectious IBS may be responsible for up to 30% of cases in adults.³⁸ Along these lines, some patients with IBS have demonstrated increased proinflammatory cytokines, suggesting that intestinal inflammation may play a role in IBS symptoms.³⁹ One particular type of inflammatory cell that has been studied in IBS is the mast cell, also involved in histamine reactions in allergic diseases. In animal studies, these cells can excite gut sensory nerves, leading to symptoms similar to IBS in humans.⁴⁰ Adults with diarrhea-predominant IBS have been noted to have a marked increase of mast cells in their small intestine.⁴¹ What role inflammation plays in the etiology of IBS symptoms in children requires further study.

Another important factor is the psychological component. The way children handle stressors may contribute to the development or expression of FGIDs, including IBS. Adults with high levels of stress and anxiety are more likely to develop IBS after a GI infection.⁴² Other studies have demonstrated that the way children handle their stressors may predispose them to FGID symptoms. For example, children with RAP were more likely to use less effective coping strategies to handle stress than control children.⁴³ In fact, the use of less effective coping skills also was associated with depressive symptoms, which may accompany many of the FGIDs.⁴⁴

Treatments for IBS have targeted the possible causes of the visceral hypersensitivity, including the potential role of small intestinal bacterial overgrowth. Pimentel et al⁴⁵ demonstrated in adults that the nonabsorbed oral antibiotic rifaximin can improve IBS symptoms. In addition, peppermint oil, a smooth muscle relaxant that also has antimicrobial properties, was effective in reducing severity of pain associated with IBS in children.⁴⁶ Probiotics, bacteria designed to repopulate the gut and possibly demonstrate anti-inflammatory effects, have been evaluated as treatments for IBS symptoms. In children and adults, the modest benefits appear to be species specific,^47-49 and further studies are awaited to establish the exact role that probiotics can play in treating IBS.

Serotonin, a hormone involved in gut motility, also has been targeted for treatment of IBS patients. Two examples include the serotonin receptor agonist tegaserod (recently taken off the market due to adverse side effects) used to treat constipation-predominant IBS, and the serotonin receptor antagonist alosetron, which is available on a restricted-use basis (again because of side effects) to treat diarrhea-predominant IBS. Another more central approach involves the selective serotonin reuptake inhibitor (SSRI) citalopram. In adults, citalopram was shown to improve IBS symptoms (but with less effect on stool pattern) compared with placebo. This effect was independent of its effect on anxiety or depression.⁵⁰ Similar benefits also were seen with citalopram in children with functional abdominal pain.⁵¹

The hormone melatonin also reduced IBS pain symptoms in adults, independent of its effect on sleep or psychological profiles when compared with placebo.⁵² The tricyclic antidepressant amitriptyline was shown to reduce brain activation during pain, especially during stress, suggesting a potential role in blunting pain and symptoms caused by stress in IBS.⁵³ Whether these treatments will be effective in children has yet to be elucidated, but studies are under way.

Fiber supplementation has proven beneficial in 1 double-blind, placebo-controlled trial in children with recurrent abdominal pain.⁵⁴ Further studies are anticipated to determine the benefit of fiber treatment in children with IBS.

Functional Abdominal Pain

According to the Rome criteria, functional abdominal pain (FAP) is characterized by weekly abdominal pain lasting at least 2 months.¹¹ It is distinguished from FD by the location of pain and from IBS by the lack of bowel symptoms. When the pain interferes with activities or is accompanied by other somatic symptoms (eg, headache, sleeping disturbance, extremity pain, or dizziness), it is labeled as functional abdominal pain syndrome (FAPS). A systematic review of the literature using the search criterion recurrent abdominal pain (the term that includes functional abdominal pain) found the prevalence in children of Western countries to range from 0.3% to 19%, with a median of 8.4%. The highest prevalence was in women and children older than age 4 years to adolescence.⁵⁵

As with IBS, children with FAP appear to have an underlying visceral hypersensitivity. For example, children with IBS and FAP have increased rectal sensitivity compared with controls. In addition, these children have abnormal pain referral after rectal distension, suggesting modified pain receptors and/or interpretation.³¹ DiLorenzo et al⁵⁶ demonstrated that sites of visceral hyperalgesia can differentiate FAP and IBS; IBS patients demonstrate more rectal hypersensitivity than children with FAP, and FAP patients demonstrate more gastric hypersensitivity than IBS patients.

Caring for children with FAP can be difficult for both the parent and the physician. Many parents provide extra attention to their children in hope of ameliorating the pain. In a study by Walker et al,⁵⁷ children with abdominal pain underwent water load testing (the children drank a volume of water that caused less intense but representative abdominal pain), and parents were randomly assigned to provide either attention to the pain with reassurance and sympathy or distraction away from the pain. The parents of children with abdominal pain rated that “distraction” would have a greater negative impact on their child than “attention.” Surprisingly, the children in the distraction group rated their parents as making them feel better compared with those from the attention group.

The treatments aimed at treating the abdominal pain in IBS also are used for patients with FAP (see above). Complementary medical approaches also have been used. Gut-directed hypnotherapy is highly effective in the treatment of children with longstanding FAP or IBS, demonstrating reduction in pain scores when compared with medical therapy.⁵⁸ Combination therapy with psychological treatment (ie, cognitive behavioral therapy) combined with medical treatment appears to be the most effective for helping children overcome these FGIDs.⁵⁹

Cyclic Vomiting Syndrome

Although cyclic vomiting syndrome (CVS) is not a very prevalent diagnosis (1%-3%), it merits special attention for its unique characteristics and predilection for children.^60,61 The Rome criteria describe a recurrent period of intense nausea and unremitting vomiting over hours to days separated by symptom-free intervals lasting weeks to months.¹ In a study that characterized the clinical features of CVS, the peak intensity of vomiting was ≥4/hour, but the frequency of episodes was ≤9/month.⁶²

The episodes often escalate rapidly and often terminate as abruptly as they started. It appears to be more prevalent in children than adults, especially children ages 2-7 years old, although the prevalence for adults is not well described.⁶³

Accompanying symptoms can include headache, phonophobia, photophobia, fever, loose stools, skin blotching, and leukocytosis. Given these associations, it should come as no surprise that many of these children have other pain syndromes, particularly migraine headaches (11%)⁶⁴ and IBS (62%).⁶⁵ In fact, family histories of IBS and/or migraine headaches are common. A recent study confirmed that patients with CVS, their mothers, and their grandmothers had twice the prevalence of migraine headaches compared with controls.⁶⁶

Similar to migraines, many of these children are able to identify circumstances that trigger the vomiting episodes. These can include anxiety, excitement, infections, or physical exhaustion.⁶⁷ Despite the identification, these triggers are often difficult to avoid.

The symptoms can lead some to pursue a path of investigation that can be costly in both time and money for the patients. This can include tests to exclude intracranial neoplasia, vestibulitis, obstructive uropathy, gastrointestinal obstruction, recurrent pancreatitis, metabolic and endocrine disease, and/or familial dysautonomia.⁶⁸ It is important to keep CVS on the differential when evaluating a child with recurrent vomiting episodes as recognition of the pattern will allow for earlier treatment of the disease and family relief.

Cyclic vomiting syndrome is related to repeated activation of the vomiting reflex. The vomiting reflex is associated with 2 centers in the brain, the chemoreceptor trigger zone and the central vomiting center. These centers receive input from visceral afferents as well as higher centers (thalamus, hypothalamus, inner ear, cerebral cortex). The input may include visceral, olfactory, or vestibular stimuli or stress interpretation. If the input to the vomiting center exceeds a certain threshold, the vomiting process is initiated with preejection autonomic activation (salivation, pallor, headache, nausea, etc). In many CVS patients, this autonomic activation can be intense with release of corticotropin, vasopressin, norepinephrine, and prostaglandin F. After this preejection phase, the ejection phase follows with repeated vomiting and retching.⁶³

The cause of CVS is not completely understood. Given the prevalence of maternal migraine headaches, studies have investigated the possible role of mitochondrial deoxyribonucleic acid (mtDNA) mutations.^61,69 The study by Wang et al⁶⁹ found differences in mtDNA sequences in children with CVS as well as migraine without aura (the headache type commonly associated with CVS) when compared with control children. They suggested that this mitochondrial component to the disease may imply that avoidance of fasting could prove helpful in these children.

The treatment for CVS involves a dual approach of abortive and preventive therapy depending on the severity of symptoms. The preventive approach includes tricyclic antidepressants (amitriptyline), cyproheptadine, phenobarbital, or propranolol. These medications decrease the sensitivity of the chemoreceptor trigger zone in the brain medulla that is partially responsible for the vomiting episodes. They have been shown to reduce or eliminate the vomiting episodes in many children with CVS.^70-72

Abortive therapy is best administered during the preceding prodrome before the nausea and vomiting start. Ondansetron, erythromycin, and ibuprofen also have been used. With the vomiting, an acid-blocking agent can help protect the esophagus and teeth but does not affect the symptoms. Lorazepam, an anxiolytic/sedative, also acts as an antiemetic and can be helpful early in the course. For some, intravenous fluids and treatment are needed. Intravenous combinations of ondansetron, granisetron, diphenhydramine, and chlorpromazine may be effective.^63,73

Considering the extensive and often expensive diagnostic workup that many patients with FGIDs can receive, Olson and Li⁷⁴ looked at the cost-effectiveness of different diagnostic and treatment options for CVS. They compared empiric treatment alone, upper GI radiographic series with small bowel follow-through, and empiric treatment vs extensive diagnostic evaluation. They found that this GI radiographic imaging modality plus empiric migraine therapy was the most cost-effective strategy for treating CVS. The cost of adding the GI radiographic imaging was less than the cost of complications from missing a GI obstruction.

Summary

FGIDs are a cause of great distress and morbidity in children and adults. We have learned a lot since Apley’s description of “recurrent abdominal pain” was published. As more data are available, we will offer these children and their families a better understanding of the conditions and more effective treatments to overcome them. The importance of making a positive diagnosis of a FGID cannot be overstressed. Children and their parents need to understand that they have a medical diagnosis and not one that is solely psychologically based. Management and treatment must take into account the physiological and psychological contributions to symptom expression.