Elevated density and plasticity of nerve fibres in anal fissures

Neural proliferative processes are regarded as a contributing factor in chronic inflammatory diseases and chronic pain. To elucidate whether neural proliferations occur in tissues surrounding chronic anal fissures and in the normal anal canal, the nerve fibre density was examined with the pan-neural marker protein gene product 9.5 (PGP) and the neural proliferative marker growth-associated protein 43 (GAP) by immunohistochemistry. GAP-immunoreactive nerve fibres in the uninflamed anal canal were distributed region specifically. The proportion of GAP-immunoreactive nerves in relation to the PGP-immunoreactive innervation exhibited regional differences. In tissue sections of chronic anal fissures, a marked increase in the density of PGP- and GAP-immunoreactive nerve fibres was noted, and PGP- and GAP-immunopositive nerve fibres displayed a neuroma-like appearance. Image analysis revealed that PGP- and GAP-immunoreactive innervation represented an area fraction of 0.5% (0.49 +/- 0.052; mean and SEM) and 0.1% (0.11 +/- 0.013) in the normal anal canal, respectively. In tissue sections of chronic anal fissures, PGP- and GAP-immunostained nerve fibres represented area fractions of 1.3% (1.32 +/- 0.12) and 0.6% (0.56 +/- 0.15), respectively. The increases in PGP- and GAP-immunopositive area fractions were highly significant (P > 0.01). The mean ratio of GAP to PGP immunoreactivities was not significantly increased in chronic anal fissures. The increase in pan-neural innervation and neuronal GAP immunoreactivity in tissues of anal fissures may imply that neuronal proliferation is involved in the pathogenesis of anal fissures. Neuronal proliferations may also be responsible for pruritus and severe pain in chronic anal fissures.