Mechanisms of DiseaseSensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency
Introduction
Faecal urgency is a distressing, debilitating disorder that is not fully understood and is inadequately treated. Although it could be a well recognised feature of disorders such as rectal cancer and inflammatory bowel disease, in many patients faecal urgency has no obvious underlying cause. Some patients are affected so severely that they have incontinence even when the anal sphincter mechanism is intact. Many patients are dismissed because their symptoms are thought to be psychogenic, whereas others are diagnosed with irritable bowel syndrome.
Physiological data show that many patients with idiopathic faecal urgency have rectal hypersensitivity, as shown by low distension volumes, low rectal compliance, and high pressure propagating rectal contractions.1 To treat these physiological abnormalities, we developed a new surgical procedure known as rectal augmentation, in which we created a stapled ileorectal pouch to increase rectal capacity and compliance.2 This procedure was effective in a small selected group of patients with severe intractable urgency, and gave the opportunity to obtain full-thickness rectal biopsy samples to investigate a neurogenic basis for this disorder. Further, techniques are now available to visualise key signalling molecules expressed by visceral sensory fibres, such as the capsaicin receptor vanilloid receptor 1 (trpv1). Our hypothesis was that rectal hypersensitivity and subsequent faecal urgency was due to sensitisation, sprouting, or phenotypic changes of nerves in transmission of visceral sensation.
Rectal sensation is thought to be conveyed by polymodal unmyelinated C fibres and thinly myelinated A fibres.3 Most primary colonic afferents are polymodal sensory fibres, and can encode all types of stimulation.4
Polymodal C fibres can be subdivided on the basis of histological markers into two main groups. One group contains the neuropeptides substance p and calcitonin gene-related peptide (cgrp), which are regulated by NERVE GROWTH FACTOR (NGF). NGF is a molecule that promotes survival and differentiation of sensory and sympathetic neurons5 and elicits many of its classical neurotrophic actions through its high affinity receptor tyrosine kinase receptor A.6 The other group of polymodal C fibres contains enzymes such as fluoride resistant acid phosphatase or have binding sites for the isolectin B4. These fibres are dependent on GLIAL CELL-LINE-DERIVED NEUROTROPHIC FACTOR (GDNF) for regulation of their physiological properties.7 Both groups of C fibres can respond to similar types of stimulation and most express the capsaicin receptor TRPV1, which transduces chemical and thermal stimuli.8
We aimed to determine whether changed peripheral neural mechanisms had a histological basis in rectal hypersensitivity, and whether such changes correlated with physiological or psychological abnormalities.
Section snippets
Patients
We investigated consecutive patients referred to a tertiary coloproctology centre with severe faecal urgency (inability to inhibit defaecation for more than a few seconds), increased stool frequency, and faecal incontinence. We excluded patients if they had any organic gastrointestinal pathology. All patients had a detailed clinical history and investigations to exclude organic colorectal disorders, coeliac disease, and malabsorption of bile salt. All patients underwent detailed anorectal
Results
Over 3 years, nine patients (seven female; median age 42 years [range 32–56]) met the study criteria of severe faecal urgency, rectal hypersensitivity on balloon distension, lowered rectal compliance, and presence of high amplitude pressure waves in the rectum temporally associated with symptoms of urgency,2 and underwent a “rectal augmentation” procedure (table 2). Patients were classified as having rectal hypersensitivity when the defaecatory desire volume was less than 70 mL in a man and 60
Discussion
Faecal urgency with rectal hypersensitivity is a distressing disorder frequently dismissed by doctors. The lack of clinical recognition is due in part to an inadequate understanding of its pathogenesis and an absence of satisfactory treatments. Our results have shown increased nerve fibres immunoreactive to TRPV1 in the mucosal, submucosal, and muscle layers of patients with rectal hypersensitivity and faecal urgency.
The increased immunoreactivity to TRPV1 in hypersensitive rectums was related
GLOSSARY
- capsaicin
- The pungent fiery ingredient of chilli peppers.
- nerve growth factor (ngf)/glial cell line-derived neurotrophic factor (gdnf)
- Small protein growth factors produced by tissues that maintain nerve fibres and TRPV1 expression.
- polymodal sensory fibres
- Nerve fibres that respond to different stimuli—eg, mechanical, thermal, chemical.
- resiniferatoxin
- A plant extract similar to capsaicin in action, but more potent.
- substance p/calcitonin gene-related receptor protein (cgrp)
- Small peptides released by
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