Pruritus in cholestasis: No direct causative role for bile acid retention

Freedman, Marc R.; Holzbach, Rüdiger; Ferguson, Damien

doi:10.1016/0002-9343(81)90857-3

Cited by 70 publications

(20 citation statements)

References 13 publications

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“…More importantly, although bile acid levels vary among itchy patients with liver diseases both from our data ( Fig. 7a, b ) and previously reported results 32-34 , we found that the total plasma bile acids, as well as the individual levels of GCDCA, TCDCA, TCA, and GCA, significantly decreased in 11 out of 13 patients following itch relief ( Fig. 7c, d and Supplementary Fig.…”

Section: Resultssupporting

confidence: 79%

MRGPRX4 is a novel bile acid receptor in cholestatic itch

Zhao

Liu

et al. 2019

Preprint

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Patients with liver diseases often suffer from chronic itch or pruritus, yet the itch-causing pruritogen(s) and their cognate receptor(s) remain largely elusive. Using transcriptomics and GPCR activation assays, we found that an orphan, primate specific MRGPRX4 is expressed in human dorsal root ganglia (hDRG) and selectively activated by bile acids. In situ hybridization and immunohistochemistry revealed that MRGPRX4 is expressed in ∼7% of hDRG neurons and co-localizes with HRH1, a known itch-inducing GPCR. Bile acids elicited a robust Ca2+ response in a subset of cultured hDRG neurons, and intradermal injection of bile acids and an MRGPRX4 specific agonist induced significant itch in healthy human subjects. Surprisingly, application of agonist for TGR5, a known sequence conserved bile acid receptor previously implicated in cholestatic itch, failed to elicit Ca2+ response in cultured hDRG neurons, nor did it induce pruritus in human subjects. In situ hybridization and immunostaining results revealed that hTGR5 is selectively expressed in satellite glial cells, unlike mTGR5 (in mouse DRG neurons), likely accounting for the inter-species difference functionally. Finally, we found that patients with cholestatic itch have significantly higher plasma bile acid levels compared to non-itchy patients and the bile acid levels significantly decreased after itch relief. This elevated bile acid level in itchy patients is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch, providing a promising new drug target for anti-itch therapies.

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Section: Resultssupporting

confidence: 79%

MRGPRX4 is a novel bile acid receptor in cholestatic itch

Zhao

Liu

et al. 2019

Preprint

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“…Its relief with SAMe was well accepted by patients. to the fall of serum bile acids since previous investigations showed a poor correlation between pruritus and serum levels of bile acids (22,23). Even if the reason for the SAMe-induced relief from pruritus remains unclear, it may be tentatively related to the antidepressant effects which accompany the use of the drug (24).…”

Section: Resultsmentioning

confidence: 98%

Reversal of Intrahepatic Cholestasis of Pregnancy in Women after High Dose S-Adenosyl-L-Methionine Administration

et al. 1984

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Previous investigations have indicated that S-adenosyl-L-methionine (SAMe) leads to reversal of estrogen-induced bile flow impairment in rats. This randomized, single-blind clinical trial was performed to determine whether SAMe reverses intrahepatic cholestasis of pregnancy (ICP) which occurs in hypersensitive women associated with increased estrogen levels in late pregnancy. Eighteen women with ICP were randomly divided into three groups of six and treated for 20 days as follows: Group I received 200 mg per day of i.v. SAMe; Group II received 800 mg per day of i.v. SAMe; Group III served as control. At the beginning of the study, clinical and biochemical parameters were similar among groups. After 10 and 20 days of treatment with the higher dose of SAMe, the mean values of serum transaminases, conjugated bilirubin and total bile acids fell significantly in respect to initial levels; opposite results were found in the other two treatment groups. The final values of these selected parameters were lower in the group of subjects treated with 800 mg per day SAMe than in the other two groups of women. Pruritus graded on a 0 to 4+ scale significantly was reduced only in patients treated with the higher dose of SAMe. These results indicate a trend toward remission of ICP in women treated with 800 mg per day SAMe and suggest that SAMe administration may be a new therapeutic modality for ICP.

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“…However, this occurs at bile salt concentrations that are well above those at which cholestatic itch is observed. Furthermore, a relation between serum bile salt levels and the extent of itch has never been established [5,13].…”

Section: The Role Of Lpa In (Cholestatic) Itchmentioning

confidence: 99%