Pruritus Secondary to Primary Biliary Cholangitis

A Review of the Pathophysiology and Management With Phototherapy

A.B. Hussain; R. Samuel; V.S. Hegade; D.E. Jones; N.J. Reynolds

Disclosures

The British Journal of Dermatology. 2019;181(6):1138-1145. 

In This Article

The Role of Bile Salts in Cholestatic Pruritus

Bile salts accumulate in the skin and blood of patients with cholestasis,[30,31] cause pruritus in healthy volunteers upon intradermal injection and, if ingested, will worsen pruritus in patients with cholestasis.[32] Treatments that reduce pruritus such as nasobiliary drainage and cholestyramine (which binds bile salts in the gut lumen) have been shown to reduce serum bile salt levels.[33–35] Furthermore, interrupting enterohepatic circulation of bile salts by inhibiting ileal bile acid transporters has been demonstrated to improve pruritus in PBC.[36]

Primary bile salts are formed in hepatocytes and are metabolized by gut bacteria to form secondary bile salts. These bile salts have variable properties, including water and fat solubility, and therefore are likely to exert different effects on pruritus-mediating receptors, including the G-protein-coupled bile acid receptor, Gpbar1 (TGR5) and farnesoid X receptor (FXR). The composition of bile salts in the body varies between individuals and is known as the 'bile salt profile'. This may help to explain the paradoxical therapeutic benefit of administering the bile salt ursodeoxycholic acid (UDCA) in PBC to treat a disease where bile salt levels are already raised.[3] UDCA administration has been shown to alter the bile salt profile (i.e. the relative concentration of each of the other bile salts), which may result in altered activation and intracellular signalling cascades in sensory neurons and subsequently reduce pruritus.[37] We propose testable mechanisms centred around this theory to investigate how phototherapy might reduce bile salt activation of TG5 and FXR, and thus pruritus.

How do Bile Salts Cause Itch?

Bile salts are thought to mediate their pruritic effects through the following two key receptors: TGR5, expressed on sensory neurons, and the nuclear transcription factor FXR, present in enterohepatic tissues, skin and brain neurons.[38–40] Bile salts bind to these receptors, activating signalling cascades and transcriptional networks intracellularly, which is thought to contribute to pruritus.

Exposure to high doses of bile salts results in FXR activation and increases pruritus, the mechanism of which is unexplained.[41] As FXR is highly expressed in enterohepatic cells and to a lesser extent in skin, two possible pathways are hypothesized (Figure 1).[39] Bile salt activation of FXR on enterohepatic cells is thought to result in reduced bile salt synthesis[42] via negative feedback mechanisms which downregulate the enzyme cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in biosynthesis of bile salts.[43]

Figure 1.

Bile salt itch pathways. Bile salts mediate their pruritic effects through the G-protein-coupled bile acid receptor, Gpbar1 (TGR5) receptor and the nuclear transcription factor farnesoid X receptor (FXR). High-dose bile salts activate FXR and increase pruritus, the mechanism of which is unexplained. In primary biliary cholangitis, treatment with FXR agonists worsens pruritus. Receptor stimulation is hypothesized to occur in enterohepatic cells and the skin. Enterohepatic FXR stimulation provides negative feedback mechanisms that downregulate the enzyme cholesterol 7-hydroxylase (CYP7A1), the rate-limiting enzyme in biosynthesis of bile salts, and hence reduce bile salt synthesis. Bile salts activate TGR5, which induces pruritus through activation of transient receptor potential ankyrin (TRPA)1 on cutaneous afferent neurons. Bile salt binding initiates TGR5 coupling with Gβγ and protein kinase C (PKC), which activates and sensitizes TRPA1. TRPA1 activation causes influx of extracellular calcium ions, subsequently activating voltage-sensitive channels and eventual central transmission to the spinal cord via the dorsal root ganglion (DRG). Secondary neurons are activated via glutamate and neuropeptide natriuretic polypeptide (Npp)b release. Nppb receptors on the secondary neuron are subsequently suspected to release gastrin-releasing peptide (GRP), which activates the GRP receptor on the third neuron in the spinal cord.

Scratching responses following intradermal injection of bile acids are attenuated in TGR5 knockout mice and augmented in TGR5 transgenic mice.[38] TGR5 is proposed to induce pruritus through activation of transient receptor potential ankyrin (TRPA)1 on cutaneous afferent neurons that signal to the dorsal horn of the spinal cord, ultimately leading to itch sensation (Figure 1).[37,44–47] The role of TRPA1 is supported by the finding that TRPA1 antagonism in TGR5 transgenic mice prevents bile-acid-induced pruritus.[47]

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