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

Autotaxin/Lysophosphatidic Acid Theory

The enzyme ATX generates a potent itch mediator, LPA, from extracellular lysophosphatidylcholine. LPA was originally understood to be involved with cell proliferation and oncogenesis;[58] however, in recent years, studies have demonstrated a significant role for LPA in cholestatic pruritus.[20] ATX and LPA serum levels are higher in cholestatic pruritus and levels have been found to correlate directly with pruritus intensity.[20] Increased levels are not seen in pruritus of other causes, indicating that these are specific markers of itch in cholestasis.[20] When injected intradermally, LPA causes a dose-dependent scratching behaviour in mice.[59] Despite these findings, the mechanism underpinning the role of ATX/LPA in cholestatic pruritus remains unclear.

We propose two original potential mechanisms by which LPA may cause pruritus in cholestatic disease (Figure 2).

Figure 2.

The role of lysophosphatidic acid (LPA)/autotaxin (ATX) in itch. Circulating LPA, generated by ATX, acts on LPA receptors (LPARs) on the keratinocyte membrane and activates nuclear factor of activated T cells (NFAT) via the STIM1 and store-operated calcium channel (ORAI1) system. NFAT activation results in keratinocyte secretion of thymic stromal lymphopoietin (TSLP). TSLP acts on the TSLP receptor (TSLPR) on a subset of sensory neurons in the skin. These sensory neurons express both TSLPRs and the receptor TRPA1. TRPA1 is thought to be activated downstream of TSLPR. Tryptase, released from cutaneous mast cell degranulation, which is increased in cholestatic disease and possibly triggered by ATX, activates protease-activated receptor (PAR)2 signalling on sensory neurons. PAR2 signalling also plays a significant role in the keratinocyte production of TSLP via the ORAI1/NFAT pathway.

Lysophosphatidic Acid Itch Mechanism

Increased circulating LPA acts on LPA receptors (LPAR) on the keratinocyte membrane and activates nuclear factor of activated T cells (NFAT) via the STIM1 and ORAI1 systems (Figure 2).[60] NFAT activation causes the keratinocyte to produce the calcium-dependent cytokine, thymic stromal lymphopoietin (TSLP), which plays a key role in several pruritic diseases.[59] TSLP acts on the TSLP receptor (TSLPR) on a subset of sensory neurons in the skin, thus mediating itch. These sensory neurons express both TSLPRs and the receptor TRPA1. TRPA1 is thought to be activated downstream of TSLPR.[61]

However, alternative studies have demonstrated a more direct activation of TRPA1 and transient receptor potential vanilloid (TRPV)1 intracellularly by cytoplasmic LPA. These studies confirm the role of LPA in cholestatic itch, but clearly our understanding of the precise mechanism remains incomplete.[62]

The Role of Protease-activated Receptor 2 and Tryptase

The GPCR protease-activated receptor (PAR)2 plays a significant role in the keratinocyte production of TSLP. PAR2 activity strongly correlates with the TSLP levels in the skin.[63,64] Studies have demonstrated that the ORAI1/NFAT pathway is a key regulator of PAR2- mediated TSLP secretion by epithelial cells (Figure 2).[61] Itch mediated by PAR2 receptor activation has been demonstrated by several pruritogens and has been suggested as a potential target for treatment of chronic pruritus.[65] Among these puritogens is tryptase, released from mast cell degranulation, which is increased in cholestatic disease.[2,24,66] Tryptase, released from cutaneous mast cells in close proximity to nerve terminals, activates PAR2 signalling on sensory neurons, which increases activity of neuronal TRPV1 on mouse dorsal root ganglion neurons.[67] ATX is highly expressed in submucosal mast cells also containing tryptase, suggesting that ATX may play a role in mast cell degranulation leading to PAR2 activation via tryptase.[68]

Therefore, there are several distinct receptors that may be directly or indirectly activated by LPA, which could then result in increased TSLP production and activation of TRPA1-positive sensory neurons in skin.

Ultraviolet B Action on Autotaxin to Reduce Pruritus

As with TGR5, TSLPR causes pruritus via the coreceptor TRPA1.[47,61] While this may explain how pruritus occurs in cholestatic disease, it does not necessarily explain how phototherapy may affect it. Phototherapy exerts a plethora of molecular effects in skin and blood, including effects on enzymes such as nitric oxide synthase[69,70] and heme oxygenase.[71] As modulation of the ATX/LPA axis has been implicated in cholestatic pruritus, it is possible that narrowband UVB may result in reduced ATX enzymic activity or possibly increased activity of lipid phosphate phosphatase enzymes involved in degradation of LPA, leading to lower levels of serum LPA and reduced pruritus sensation. Additionally, it has also been shown that UVB reduces mast cell degranulation and secretion of tryptase.[72,73] It is therefore possible that narrowband UVB reduces tryptase release from mast cells, reducing PAR2 activation, thus reducing pruritus.

These hypotheses can be tested by measurement of tryptase and LPA/ATX serum levels during phototherapy, while simultaneously identifying skin neuron expression of TGR5, TSLPR and TRPA1 receptors and keratinocyte expression and intracellular localization of LPAR, ORAI1, TSLP and NFAT.

Combining the Bile Salt and Autotaxin/Lysophosphatidic Acid Theory

These two theories outlined above – the bile salt theory and the ATX/LPA theory – have recently been shown to be closely linked in the pathophysiology of itch. Keune et al., demonstrated that bile salts enhance LPA signalling and facilitate LPA crossing the HeLa cell membrane, prolonging the lifetime of the ATX–LPA complex and thus increasing its overall role in the pruritus pathway.[74] These data suggest that these two, previously separate, pathways are more likely to be intricately connected in cholestatic itch. Of note, paradoxically, this paper also demonstrated that bile salt activation of ATX subsequently inhibits LPA production, demonstrating bile salt action as a partial noncompetitive inhibitor of ATX.[74]

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