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Chronic Abdominal Pain of Childhood and Adolescence
Introduction
Chronic abdominal pain, generally defined as long-lasting intermittent or constant abdominal pain, is a common complaint in children and adolescents. For the majority of children with chronic abdominal pain, the pain is functional in nature rather than the result of an underlying organic disease. Apley and Naish first described recurrent abdominal pain in a cohort of 1000 school children in 1958, defining recurrent abdominal pain as at least three episodes of pain severe enough to affect activities over a period of at least 3 months. Our terminology and definitions have changed over time, particularly with the adoption of the pediatric Rome criteria to define functional gastrointestinal disorders over the past two decades. The term “recurrent abdominal pain” is now regarded as a description rather than a diagnosis and is no longer in use. The Rome criteria classify children with abdominal pain for a period of 2 or more months without an underlying organic etiology to explain their symptoms as having a functional abdominal pain disorder (FAPD). Although children with other functional gastrointestinal disorders can complain of abdominal pain as well, children with FAPDs experience abdominal pain as their primary and most bothersome symptom. There have been multiple iterations of the Rome criteria. In the most recent iteration, the Rome IV criteria published in 2016, four diagnoses were established under the FAPD category: functional dyspepsia, irritable bowel syndrome (IBS), abdominal migraine, and functional abdominal pain–not otherwise specified (FAP-NOS). FAP and FAPDs are among the most common diagnoses seen in pediatrics. Nearly 90% of children who present to their primary care provider with abdominal pain are diagnosed with FAP and nearly 50% of these children will have pain long enough to fulfill criteria for an FAPD. Over half of the children who present to a pediatric gastroenterologist have a functional gastrointestinal disorder, and in children and adolescents found to have a functional gastrointestinal disorder, over two-thirds will have an FAPD. FAPDs are also very common at the community level, with population-based epidemiological studies from around the world showing an estimated pooled prevalence of 13.5%.
In addition to chronic symptoms that can range from bothersome to debilitating, children with FAP experience lower health-related quality of life compared not only to healthy children but also to children with organic gastrointestinal diseases like inflammatory bowel disease. , The medical and nonmedical costs associated with pediatric FAPDs are significant and appear to be increasing with time. Nearly a decade ago, the average cost of evaluation for a child with chronic abdominal pain was over $6000 in the United States, a staggering figure when the prevalence of abdominal pain in children is considered. This cost has almost certainly increased given the rising costs of healthcare over time. The cost of individual hospitalizations for children with functional gastrointestinal disorders in the United States nearly tripled from 1997 through 2009. Despite a decrease in pediatric hospitalizations overall, the number of hospitalizations for children with functional dyspepsia and IBS have been increasing over time. , Although outpatient and inpatient healthcare costs are responsible for the majority of the financial burden associated with FAPDs in children, nearly a quarter of the costs of care result from lost parental productivity. Children with functional gastrointestinal disorders miss more school, spend more days at home needing care, use more healthcare resources, and have parents who miss more work days with greater work impact than healthy children. The high prevalence of chronic abdominal pain and the substantial associated impact on quality of life and healthcare utilization emphasize the importance of evidence-based evaluation and management.
Pathophysiology
Our understanding of the pathophysiology of FAP has grown dramatically over the past few decades, and it is becoming clear that the pathogenesis of FAP and FAPDs is generally multifactorial, even in the individual patient. Over the past decade, research has led to significant advances in our understanding of the mechanisms that contribute to all functional gastrointestinal disorders, including FAPDs. In recognition of these advances and to establish a new conceptual approach to this group of disorders, the Rome Foundation has proposed changing the term functional gastrointestinal disorders to disorders of gut–brain interaction, one that more accurately represents the pathophysiology of these disorders. Functional gastrointestinal disorders are multifactorial in origin. The contribution of multiple factors in the development of FAPDs and other functional gastrointestinal disorders can be conceptualized by the biopsychosocial model ( Fig. 6.1 ). Within the biopsychosocial model, genetic factors, early life events, psychosocial factors, sensitizing medical events, and alterations in gastrointestinal physiology can all play a role in the individual child’s presentation.
Genetic Factors
Genetic factors are thought to increase the likelihood that a child develops an FAPD. Research evaluating the role of genetic influences on FAPD pathogenesis has been challenging, particularly as clinical phenotypes likely result from a variety of underlying mechanisms. Unlike monogenic diseases in which the phenotype is explained by mutation of a single gene, genetic influences in FAPDs are likely polygenic, in that the influence results from contributions of many genetic variations, each contributing a small amount to the variance of the clinical phenotype.
Several studies have shown that IBS tends to cluster in families. Relatives of patients with IBS are three times as likely to meet Rome criteria for IBS as relatives of healthy controls. However, familial aggregation can result from genetic influences as well as shared environmental factors. Twin studies of patients with IBS have suggested that the heritability of IBS ranges from 22% to 48%, but in one study, having a parent with IBS was a stronger independent predictor of developing IBS than having a twin with IBS. , Children of parents with IBS are more likely to be seen in clinic not only for chronic abdominal pain but also for all medical complaints.
Several candidate gene studies have been performed to evaluate an association between specific gene polymorphisms and IBS or IBS-related physiological alterations, like altered colonic transit, visceral sensation, or brain responses. The majority of investigators have selected genes encoding serotonin-related proteins, noradrenergic signaling-related proteins, or immune markers. Serotonin transporter-linked polymorphic region (5-HTT LPR) polymorphisms in the promoter region of the serotonin transporter gene SLC6A4 have been perhaps the most well-studied in relation to IBS, and have been studied in relation to psychiatric syndromes and fibromyalgia. , However, a meta-analysis of clinical studies evaluating a potential association between 5-HTT LPR polymorphisms and IBS did not find a significant association. More recently, several studies have identified an association between polymorphisms of the gene encoding tumor necrosis factor superfamily 15 (TNFSF15) and IBS, supporting the role of immune activation in IBS pathophysiology. , While there appears to be some genetic influence in the pathogenesis of IBS and FAPDs, its role remains unclear.
Early Life Events
Several murine studies have demonstrated visceral hypersensitivity in adult mice that were exposed to temporary irritation or inflammation of the stomach or colon early in life. Human studies have also demonstrated an association between a variety of physical stressors in infants and children and the development of FAPDs later in childhood, adolescence, and adulthood. This effect has been attributed to long-term alterations in nociceptive neuronal pathways during a critical period of development early in infancy, specifically through sensitization of spinal neurons, sensitization of primary sensory neurons, impairment of the hypothalamic-pituitary-adrenal axis and stress response, and alteration of descending inhibitory control.
Physical stressors later in infancy and childhood can also lead to lasting effects on visceral sensation, and it has recently been proposed that early life events may lead to increased sympathetic output and norepinephrine release that subsequently result in epigenetic changes that influence visceral sensation. , Children with a history of cow’s milk protein intolerance or allergic proctocolitis in infancy are more likely to report abdominal pain and meet criteria for an FAPD later in childhood or adolescence than siblings without the same history. , Gastrointestinal infection can predispose the patient to the development of FAPDs from months to years after recovery. , A study of a mixed sample of children and adults affected by a Salmonella outbreak 16 years prior showed that adults who had Salmonella infection as children were more likely to have developed IBS than matched controls, while those who had the infection in adulthood were not. Children with Henoch-Schönlein purpura are more likely to report abdominal pain months to years after recovery compared to controls, and nearly a quarter met criteria for an FAPD. There is evidence that abdominal surgery early in life, even without direct incision of the gastrointestinal tract, increases the likelihood of FAPDs as well. , Interestingly, children with a history of urinary tract infection in infancy are also significantly more likely to have chronic abdominal pain than controls, even nearly a decade after the infection. A larger, more recent study showed that while the risk of developing IBS in childhood was higher in those with a history of urinary tract infection in infancy, the risk was even higher in those with recurrent urinary tract infection or concurrent vesicoureteral reflux. These findings suggest that certain physical stressors may have effects across organ systems, perhaps related to the central convergence of shared afferent sensory nerves.
Psychosocial events and conditions throughout the patient’s life (e.g., stressful life events, anxiety, and depression) also play a role in the pathogenesis of FAPDs. Psychological stressors early in life have been associated with the development of FAPDs as children and adults. Patients with IBS are more likely to report a history of sexual, emotional, and physical abuse in childhood compared to patients with organic gastrointestinal disorders. A history of abuse in childhood seems to be more strongly associated with IBS development than abuse in adulthood. Interestingly, this study found that the association disappeared after controlling for psychological factors, leading the investigators to postulate that a history of abuse in childhood perhaps leads to psychological sequelae that in turn predispose the individual to FAPD development. Parental deprivation, an unsatisfactory relationship between parents, and losing a parent through death, divorce, or separation have also been associated with IBS development later in life. These findings underscore the multifactorial nature of FAPD pathogenesis and the role of alterations in brain–gut axis interaction.
Psychosocial Factors
Recognizing the role psychosocial factors play in a child’s presentation is critical to effective management. The brain–gut axis allows for constant communication between the emotional and cognitive centers of the brain and the peripheral functioning of the gastrointestinal tract and is the network by which psychosocial factors influence and are influenced by a child’s FAPD symptoms and illness. Through the brain–gut axis, emotional stimuli (e.g., anxiety and psychological stress) can lead to alterations in the physiological factors described later in this chapter, including visceral sensitivity, gastrointestinal motility, mucosal permeability, and the gut microbiome. Alterations in these physiological factors can also conversely affect the brain, leading to changes in pain processing and contributing to anxiety and depression. ,
Psychological stress and a child’s emotional response to stress can both contribute to FAPD pathogenesis and exacerbate FAPD symptoms. Children with higher levels of stress are more likely to develop IBS. However, the majority of children who experience stressful life events do not develop an FAPD, suggesting that exposure, response to stress, and resilience all play a role in changing the likelihood of developing an FAPD and modulating its severity. Children with FAPDs can be more susceptible to stress, and different coping methods and stress responses have been associated with symptom severity, functional disability, and measures of anxiety and depression in children with FAPDs. Due to the chronic and unpredictable nature of FAPDs, the illness experience of FAPDs in itself can generate associated psychosocial consequences. Emotional distress and maladaptive thoughts in response to symptoms can themselves contribute to the perpetuation or worsening of symptoms.
Children with FAPDs are more likely to have behavioral problems. Children with FAPDs also experience anxiety and depression more frequently than healthy children. Although there is some suggestion that anxiety often precedes FAPD development while depression often follows, the temporal relationship remains unclear and should be explored on a case-by-case basis. Studies have suggested that anxiety and depressive symptoms can be predictive of FAPD development and vice versa. ,
Sensitizing Medical Events
Medical events like infections and allergic conditions can lead to changes in pain processing and visceral sensitivity that subsequently result in gastrointestinal symptoms. Several studies have demonstrated an increase in FAPD development in children following enteric infections. , , In a recent prospective study, investigators found that nearly one-third of children who experience an enteric infection will have developed an FAPD 6 months afterwards. In a meta-analysis of studies on post-infectious FAPDs, it appears that while both functional dyspepsia and IBS are increased at 6 months after an enteric infection, the likelihood of developing IBS was higher than functional dyspepsia (odds ratio [OR] 3.51 vs. OR 2.54, respectively). Postinfectious FAPDs can be seen after infection by a variety of pathogens, including bacterial infections like Salmonella enteritidis, Escherichia coli, Shigella, and Campylobacter species, viral infections like norovirus, and parasitic infections like Giardia lamblia . , In children, the evidence is perhaps strongest for the development of FAPDs after bacterial infections, while the influence of viral infections is variable or perhaps short-lived. , ,
As described earlier, allergic conditions can increase the likelihood of FAPD development as well. Studies have demonstrated an increase in FAPDs in children with a history of cow’s milk protein intolerance or allergic proctocolitis in infancy. , There is recent evidence that children with atopic dermatitis have a greater risk of developing IBS than children without.
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