Pathophysiology

Several hypotheses have been put forward to explain the cause of functional recurrent abdominal pain. We examine them in the following sections.

Visceral hyperalgesia

The visceral hyperalgesia hypothesis proposes that greater sensitivity of visceral afferent pathways or central amplification of visceral input lead to an enhanced perception of visceral stimuli. There is evidence that the pain and discomfort of IBS might be due to hyperalgesia and allodynia of the gut. While in hyperalgesia a painful stimulus is perceived as even more painful, in allodynia a non-painful stimulus becomes painful.30 A noxious stimulus applied to a particular area of the gut may sensitize primary afferent fibers and noci-ceptors of adjacent areas, causing painful sensations with a low-intensity stimulus, resulting in primary hyperalgesia.

Most IBS patients experience rectal discomfort at lower intraluminal volumes or pressures31,32 and have diminished tolerance to intestinal gas.33 Trimble et al31 found that patients presenting with one functional bowel disorder frequently had additional symptoms referable to other parts of the digestive system, suggesting that enhanced visceral nociception may be a pan-intestinal phenomenon. For example, it has been reported that in addition to the features of rectal hyperalge-sia, IBS patients have a decreased sensory threshold to balloon distension of the esophagus. Children with functional abdominal pain exhibited generalized visceral hyperalgesia, whereas IBS patients had rectal but not gastric hyperalge-sia.32 Different GI symptoms were reproduced by stimulation of the predominant site of hyperalge-sia, providing a physiological explanation of symptoms in children who have distinct phenotypic presentations.

Dysmotility

In addition to a greater intestinal sensitivity, patients with functional bowel disorders may display abnormal motility. Various types of motor disturbances have been documented in IBS, apparently reflecting dysfunction at one or more levels of the brain-gut axis.34 Although the pathophysiology of IBS is commonly attributed to dysfunction of the large intestine, evidence exists to incriminate the small bowel as well.35 Postprandial motor dysfunction in the small bowel appears to be more prevalent among IBS patients who exhibit underlying visceral hypersensitivity in the fasting state. Abdominal cramping has been associated with the passage of high-amplitude contractions through the ileocecal region.36 Bloating has been explained by an abnormal transit and pooling of gas in conjunction with gut hypersensitivity.33 Manometric studies have demonstrated postprandial antral hypomotility in children and adults with functional dyspepsia.37 However, not all studies have demonstrated differences between patients and control subjects.38,39 Motility changes in IBS are neither specific nor predictable and do not serve as a diagnostic marker or as an aid to the selection of treatment.40 It has been suggested than, rather than having a persistent motility abnormality, patients with functional bowel disorders exhibit an abnormal motor response to a variety of physiological stimuli.41

Brain-gut interaction

The shortcomings of isolated experimental or observational models in explaining the complex nature of functional bowel disorders have led research to focus on the alterations in the communications between the CNS and the GI tract, hence the term 'brain-gut' interaction.6,42 There are multiple examples of brain-gut interaction, the most common being the subjects who, under emotionally stressful situations, develop diarrhea, nausea or vomiting. Anger and aggression increase colonic motility, while hopelessness results in decreased motility.43 The brain-gut model links alterations in peripheral sensory afferent communication from the gut (e.g. visceral hyperalgesia) to CNS processing of the sensory stimuli and its efferent signaling to the gut. In IBS patients multiple studies have shown that both gut and brain show an exaggerated responsiveness to different stimuli. Patients with IBS have significantly greater electroencephalogram (EEG) abnormalities than controls.44 Dynamic brain imaging technologies such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have recently been applied to the study of the gut-brain axis in order to identify the areas of the brain activated by visceral sensations. Studies with these techniques have suggested an abnormal cerebral processing of visceral stimuli in patients with functional bowel disorders.27,28

Inflammation

There is evidence that IBS can occur following a gastrointestinal infection resulting in transient inflammation. Gwee et al reported that 20-25% of patients admitted to the hospital for bacterial gastroenteritis developed symptoms consistent with IBS in the first 3 months.45 Rectal biopsies prospectively obtained during and after acute gastroenteritis from patients who developed post-infectious IBS and a control group, showed that the former group exhibited significantly greater expression of interleukin (IL)-ip mRNA.46 A recent study examining full-thickness biopsies from the jejunum of patients with severe IBS revealed inflammation and neuronal degeneration in the myenteric plexus, suggesting a possible patho-genetic role of inflammation.47 Animal studies also seem to indicate that inflammation may produce persistent neuromuscular gut dysfunction.48 Mild mucosal inflammation may perturb neuromuscu-lar function also at remote non-inflamed sites. The gut dysfunction may persist even after reduction of the mucosal inflammation. Substances that mediate these changes are not fully understood, but there is growing recognition of the role of serotonin as a sensitizing agent.

Immunity

The mucosal immune system mediates the clinical impact of stress and other psychological factors on the gut. Vagal afferents can be activated by products of mast cell degranulation, resulting in sensi-tization of silent nociceptors. Mast cell mediators may be released in response to luminal macro-molecules, a phenomenon that could explain brain-immune system interactions within the gut. A descending input by the vagus nerve may also reciprocally affect mast cell degranulation, resulting in local effects on secretomotor activity.

Stressors

Stressful events have long been believed to be important in the development of symptoms in functional bowel disorders.49 Physiological reactions to stressors should be considered as attempts by the body to adapt - a natural coping mechanism, in which, if stressors are not too extreme or long standing, the subject is usually successful in reaching a homeostatic state. However, at times the body loses the capacity to adapt and deleterious behavioral responses may arise. Chronic exposure to threat is associated with alterations in the autonomic outflow, resulting in activation of the hypothalamic-hypopituitary-adrenal axis with alteration in pain modulation. Corticotropin releasing hormone seems to be the hormonal mediator of the stress response. Intracerebroventricular injection of corticotropin releasing factor, which mimics the responses to stress in animals, exacerbates nociceptive responses associated with increased release of histamine.50 In humans, possibly as a primitive response to danger, stress induces delayed gastric emptying, slower small-bowel activity and accelerated colonic transit.51-54

These alterations may presumably cause diarrhea, constipation or abdominal distension depending on the predominant abnormality.

Genetics

A recent study showed a significant association between subjects with abdominal pain or bowel disturbances and first-degree relatives with IBS and dyspepsia.55 Twin studies have shown a 17% concordance for IBS in monozygotic patients with only 8% concordance in dizygotic twins. Although these data suggest a specific role for heredity in the development of IBS, the same study showed a higher correlation of IBS with parental symptoms, suggesting that social learning from the patient's environment has an equal or greater influence.56

Biopsychosocial model

The biopsychosocial model57 provides a framework to integrate the biological and psychosocial processes, in an attempt to understand the underlying pathophysiological mechanisms determining disease susceptibility, and to explain the clinical variability and outcome among individuals.

The biopsychosocial model, proposed as an alternative to the traditional biomedical model, conceptualizes the general state of health as resulting from the integration of medical and psychosocial factors. To understand this model, one should differentiate between disease, which is the abnormality of the structure and/or function of organs and tissues (physical component), and illness, defined as the patient's perception of health and bodily dysfunction (psychological component). In Engel's model,57 illness and disease result from interactions at the cellular, tissue, interpersonal and environmental levels resulting in a clinical outcome. The biopsycho-social model assumes that genetic influences on disease susceptibility and behavior result in a biological and psychosocial predisposition that will influence later psychosocial experiences, physiological functioning, or susceptibility to a pathological condition. This particular background is affected by physical and environmental exposures such as infection, food intolerance and social exposures including friends, family and community to influence the patient's attitude towards illness.58 Stress acting on a vulnerable GI tract leads to an imbalance in the system, resulting in an alteration of the brain-gut axis. Multiplicity of stressors reinforces and up-regulates the response. It is well recognized that some IBS patients report initiation or exacerbation of symptoms at times of stress, trauma and major loss.59 Traumatic early life events such as child abuse may predispose to functional bowel disorders.60 There have been reports of a greater prevalence of sexually and physically abusive experiences in individuals with IBS than in patients with organic gastrointestinal disorders and non-patient popula-tions.61 The interaction of the previously described subsystems with psychosocial modifiers (concurrent psychiatric diagnosis, life stress, social support, coping mechanisms) affects the behavior of the individual, the biological nature of the condition and, ultimately, the clinical outcome. New or uncontrollable threatening situations may result in emotional and physiological arousal. Psychosocial factors may affect the end result (clinical presentation and outcome) acting on gut physiology, modulating symptoms experience, and influencing health behavior and therapeutic interventions (Figure 14.1). The relative contribution of the medical and psychosocial factors varies among patients. This model should be considered when

Figure 14.1 Proposed pathophysiological model for functional bowel disorders.

planning therapy, as failure to link the disease and illness components will reduce the likelihood of an effective treatment.

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