Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Background and Aims: A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients.
Method: Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms.
Results: There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients ( r (120) = -0.53, p < 0.001) but not healthy controls ( r (39) = -0.21, p = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition ( u  = 1034, p = 0.02), emotional ( u  = 1374, p = 0.004), and itch ( u  = 795, p = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u  = 423 p = 0.001).
Conclusion: Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.
Competing Interests: Torbjörn Bäckström is a board member and shareholder of Umecrine Cognition AB. Magnus Doverskog and Maja Johansson are current or recent employees of Umecrine Cognition AB. Professor David Jones has consulted for Intercept, Abbot, Calliditas, and GSK and received lecture fees from Intercept, Falk, Abbot, and Calliditas and received grant funding from Intercept. Dr. Jessica Dyson has received speaker fees from Dr. Falk Pharma and Intercept.
(Copyright © 2022 Aaron Wetten et al.)