Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C

Abstract

Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-THP) and isopregnanolone (3beta,5alpha-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased (P < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3alpha,5alpha-THP and pregnanolone (3alpha,5beta-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3beta,5alpha-THP, 3beta,5beta-THP and 3alpha,5alpha-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3alpha,5alpha-THP and 3alpha,5beta-THP were found to be significantly higher in patients with fatigue (P < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3alpha,5alpha-THP and 3alpha,5beta-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood-brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.

Liver-induced inflammation hurts the brain

“…Sickness behaviour in BDL mice was enhanced by depletion of Treg and diminished following Treg infusion. This interpretation is in accordance with data from PBC patients, in whom an increased plasma concentration of neurosteroids, which activate the GABA-A receptor and result in neuroinhibition, has been found [7]. No remarkable changes were found in TNFa or IL-1b levels.…”

Brain Perfusion Scintigraphy in Evaluation of Pathogenesis of Fatigue in Patients with Primary Biliary Cholangitis (PBC) – A Pilot Study

“…Some of progesterone metabolites are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood-brain barrier. It might be that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases [14].…”

“…Each item uses a 5-grade scale with higher scores denoting increased fatigue. Fatigue Impact Scale was applied in many studies regarding fatigue in PBC patients [1,10,[14][15][16][17][18][19][20][21][22][23].…”

Fatigue in primary biliary cirrhosis

“…48,49 progesterone metabolites a study has reported that levels of progesterone metabolites, such as allopregnanolone (also known as 3α, 5αtetrahydroprogestrone [3α, 5αtHP]) and iso pregnanolone (also known as 3α, 5βtHP) are increased in the plasma of patients with PBC. 50 the increased levels of these neuroinhibitory steroids may have a role in sleep disturbance and fatigue in patients with chronic liver disease. 18 intramuscular administration of progester one, which produces an increase in the plasma level of 3α, 5αtHP, to healthy individuals was shown to induce sedativelike effects and a feeling of fatigue in men and women.…”