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

Abstract and Introduction

Abstract

Background: Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood.

Objectives: To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch.

Methods: A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area.

Results: Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor.

Conclusions: Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC.

Introduction

Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of small intrahepatic bile ducts leading to chronic and progressive cholestasis. As with other cholestatic diseases, pruritus is a common symptom of PBC, with up to 80% of patients reporting this symptom.[1] Chronic intractable pruritus is a debilitating symptom with a profound effect on quality of life,[2] which can be particularly severe and difficult to manage in PBC, and when refractory to medical therapies is an accepted indication for liver transplant, even in the absence of liver failure.[2] Current therapies include cholestyramine, rifampicin, naltrexone and nasobiliary drainage.[3,4] No single therapy is entirely effective in managing cholestatic pruritus and patients often require a combination of management strategies in accordance with current treatment guidelines. For patients with refractory cholestatic pruritus, other available treatment options need to be considered, examples of which include phototherapy and plasmapheresis.[5,6]

Ultraviolet (UV)B radiation is currently used clinically in the U.K. for the treatment of refractory generalized pruritus and other inflammatory skin diseases, such as atopic dermatitis.[7–9] Although it is recognized that phototherapy is effective in reducing itch in these conditions, the mechanism of action remains unclear. Several theories about this mechanism of action have been proposed, for example, through the alteration of cytokine release in the skin and blood,[10,11] depletion of Langerhans cells, inducing T-suppressor and immunotolerant macrophages in the epidermis, and T-cell apoptosis and suppression of intercellular adhesion molecule-1 (a molecule required for inflammatory events in the epidermis) expression by keratinocytes.[12–14] Various physical changes to the skin have also been observed following phototherapy, including degeneration of Schwann and perineural cells in the dermis.[15]

In cholestatic pruritus, both broadband[6] and narrowband UVB[16] have been reported to reduce itch in several case studies, suggesting UVB therapy as a promising and potentially well-tolerated treatment for PBC. For example, Hanid et al. reported a reduction in pruritus in five of six patients with PBC undergoing phototherapy from a mercury vapour lamp within 1 week of exposure, and in four of these five patients, total serum bile acids were reduced.[17] A case study by Pinheiro et al. also reported improved pruritus, healing of excoriations and improvement in quality of life with narrowband UVB phototherapy, three times per week for 12 weeks.[16] Decock et al. reported that 10 of 13 patients with cholestatic pruritus had more than a 60% reduction in pruritus with broadband UVB phototherapy following 8 weeks of treatment;[6] treatment was well tolerated except in two patients who developed erythema and paraesthesia.[6] A recent survey of U.K. dermatologists found a favourable opinion on the use of phototherapy, particularly when longer courses are used.[18]

The mechanism of action of UVB in reducing cholestatic itch is unclear, but chemical modifications of pruritogens in the skin, and the reduction of skin sensitivity to pruritogens have been proposed.[16,19] As discussed in detail below, potential pruritogens include histamine, bile salts, and more recently the enzyme autotaxin (ATX) and its product lysophosphatidic acid (LPA).[20] Histamine is one of the most studied pruritogens and its role in allergic and inflammatory pruritus has been well documented.[21,22] For this reason, its role in cholestatic pruritus cannot be entirely disregarded. Certain bile salts cause histamine release and plasma histamine is noted to be higher in patients with cholestatic disease with pruritus.[2,23,24] However, the dose of bile salts needed to cause histamine release is far higher than that seen in cholestatic disease.[25] Histamine antagonists do not show much efficacy in treating cholestatic itch and have been reported to make other symptoms associated with PBC worse, such as dry eyes and dry mouth.[26,27] The characteristic welt and weal appearances of histamine-induced itch are not present in cholestatic pruritus. For this reason, we view histamine as a potential contributor but not the main driver of cholestatic pruritus.

Understanding the mechanism of action of narrowband UVB in cholestasis could be helpful not only to design optimal delivery protocols for UVB phototherapy, but perhaps ultimately to identify novel therapeutic targets and treatments. In this paper, we summarize the current literature and hypotheses regarding the effect of UVB on these mediators, and how this may contribute to the therapeutic relief of pruritus in cholestasis. We propose to address the hypotheses detailed in the paper by measuring specific parameters (e.g. serum bile salt levels) in serial samples being collected as part of a pilot prospective study of narrowband UVB, which will be published in due course.

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