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

Ultraviolet B Action on Bile Salts to Reduce Pruritus

Ultraviolet B Promotes Increased Urinary Excretion of Bile Salts

In neonatal jaundice, phototherapy reduces serum bilirubin levels by enhancing formation of a bilirubin isomer with increased water solubility and, hence, increased urinary secretion.[48] After phototherapy, urinary excretion of bile salts is also increased in cholestatic disease.[49] We hypothesize that this occurs by altering the bile salt profile, thereby increasing water solubility and subsequent urinary excretion. A lower level of total serum bile salts would subsequently reduce activation of TGR5 and FXR, and therefore reduce symptoms of pruritus. This proposal is readily testable in patients and, if supported, could be followed by action spectrum studies to define the optimal wavelength of UVB that promotes enhanced urinary excretion of bile salts and consequently more effective reduction in itch.

Ultraviolet B Alters Bile Salt Structure

UVB converts previtamin D3 (7-dehydrocholesterol) to D3 (cholecalciferol) in the skin.[50,51] Vitamin D and bile salts are both derived from cholesterol and have similar structures.[52] Although the exact mechanism is unclear, it is possible that the bile salt molecular structure is altered by phototherapy, resulting in reduced receptor binding/activation, whilst not necessarily reducing total bile salt levels. Again, this hypothesis is readily testable in patients, for example using mass spectrometry to study potential changes in bile salt structure.

Bile Salt Synthesis is Reduced Via Increased Vitamin D Levels

As previously discussed, bile salts activate FXR to induce pruritus.[41] FXR stimulation reduces bile salt synthesis through downregulation of CYP7A1, the bile salt synthesis rate-limiting enzyme.[42,43] In patients with PBC, treatment with obeticholic acid, an FXR agonist, has been shown to worsen pruritus, although the mechanism is unclear.[53]

Vitamin D has been shown to be involved in the regulation of bile salt synthesis, by suppressing hepatic expression of CYP7A1, and consequently bile salts, through signalling pathways involving the intestinal enzyme FGF15.[54] Given that UVB increases vitamin D levels and subsequent vitamin D receptor expression,[55] it is possible that UVB could reduce bile salt synthesis through the involvement of vitamin D in the regulation of CYP7A1. This is testable using CYP7A1 enzyme assays.[56]

Clearly, the role of bile salts in the pathophysiology of pruritus is complex, and the pathways involved are not yet fully clear. Various clinical scenarios provide further interesting observations. Firstly, in clinical practice, patients with end-stage liver failure often find that pruritus is not a burdensome symptom, although bile salts are maximally elevated.[30] Secondly, the level of pruritus can fluctuate independently of total serum bile salt concentration, and thirdly, not all patients with cholestasis who have high bile salt concentrations report itch. In line with the theory described above, this may reflect differing bile salt profiles in these situations and differing ability to activate TGR5 and FXR receptors. Alternatively, a pathological upregulation of TGR5 and FXR receptors, independent of elevated bile acid levels, may be sufficient to induce pruritus.

Interestingly, Bouslimani et al. recently demonstrated that bile acids are detectable from skin swabs of healthy individuals.[57] This supports findings that bile acids have a role within the skin and highlights that it is in fact possible to detect these directly on the skin surface.[57] It is possible that the levels or composition of the detected bile salts may differ in cholestatic disease vs. normal skin and that phototherapy may further alter skin swab findings.

We plan to test the above hypotheses by measuring serum and urinary bile salt profile, vitamin D levels, and skin swab bile acids before and after phototherapy and assessing how they correlate with intensity of pruritus.

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