Nerve Fibers Regulating Cholestatic Itching
Cholestatic pruritus is mediated by unmyelinated C-fibers in the skin, which are distinct sensory neurons that transmit itch signals separately from pain pathways. 1
Neuroanatomical Basis
The British Association of Dermatologists guidelines establish that itch sensations arise from activation of distinct subpopulations of primary sensory neurons that are separate from pain-transmitting neurons, though some "cross-talk" exists between these neuronal circuits. 1 Specifically:
- Unmyelinated C-fibers in the skin serve as the primary itch receptors that detect pruritogenic substances accumulating during cholestasis 2
- These somatosensory neurons carry touch, pain, and itch sensations, with itch being transduced through specialized subpopulations 1
- The signal transmission follows a three-neuron pathway: primary sensory neurons in skin → secondary neurons in spinal cord → tertiary neurons projecting to the postcentral gyrus 2
Mechanism in Cholestasis
The current understanding is that pruritogenic compounds accumulating in cholestasis directly activate these unmyelinated nerve endings in the skin. 3, 4, 2 The most compelling evidence points to:
- Lysophosphatidic acid (LPA) as a key activator of these C-fibers, with cholestatic patients showing significantly elevated LPA levels that correlate with pruritus severity 3, 4
- LPA is generated by autotaxin (ATX), an enzyme markedly elevated in itchy cholestatic patients, which converts lysophosphatidylcholine into LPA near nerve endings 3, 4
- When LPA binds to its receptors on unmyelinated itch fibers, it potentiates action potentials that transmit itch signals centrally 3, 4
Additional Mediators
Beyond peripheral C-fiber activation, cholestatic pruritus involves both peripheral and central sensitization mechanisms 5:
- Peripheral factors affecting C-fibers include bile salts, sulfated progesterone metabolites, and other lysophospholipids (though bile acids and bilirubin alone are unlikely dominant pruritogens) 2, 5
- Central mechanisms involve altered opioid neurotransmission in the spinal cord, with endogenous opioid imbalance affecting itch perception 5, 6
Clinical Implications
Understanding that unmyelinated C-fibers are the primary mediators explains why:
- Cholestatic pruritus predominantly affects palms and soles (areas with high C-fiber density) and worsens at night 7, 8
- Treatment strategies targeting either peripheral pruritogen removal (cholestyramine, rifampicin) or central opioid modulation (naltrexone) can both be effective 7, 2
- The poor correlation between bile acid levels and itch intensity reflects the multifactorial nature of C-fiber activation 8
A critical pitfall is assuming bile salts alone activate these fibers—the evidence strongly supports LPA and the autotaxin-LPA pathway as more dominant mechanisms, with central opioid dysregulation playing an additional modulatory role. 3, 4, 2