Jacob Horsager

Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis

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Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. / Kjærgaard, Kristoffer; Frisch, Kim; Sørensen, Michael; Munk, Ole Lajord; Hofmann, Alan Frederick; Horsager, Jacob; Schacht, Anna Christina; Erickson, Mary; Shapiro, David A.; Keiding, Susanne.

In: Journal of Hepatology, 20.07.2020.

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@article{f96d797cdbc847708658243bece3aad2,
title = "Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis",
abstract = "Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor FXR, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA).Patients & Methods: Eight UDCA-treated PBC patients with alkaline phosphatase ≥ 1.5 ULN participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomized to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by one month washout without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi and bile ducts by positron emission tomography (PET) of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar), and the hepatic blood perfusionusing indocyanine green.Results: Compared to placebo, OCA increased the hepatic blood perfusion by median 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by median 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by median 73% (p = 0.03). This resulted in an OCA-induced decrease in hepatocyte residence time of 11C-CSar by median 30% (p = 0.01), from group median 11 min to 8 min.Conclusions: This study of UDCA-treated PBC patients showed that, compared toplacebo, OCA increased the transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. Thereby OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids.",
author = "Kristoffer Kj{\ae}rgaard and Kim Frisch and Michael S{\o}rensen and Munk, {Ole Lajord} and Hofmann, {Alan Frederick} and Jacob Horsager and Schacht, {Anna Christina} and Mary Erickson and Shapiro, {David A.} and Susanne Keiding",
year = "2020",
month = jul,
day = "20",
doi = "10.1016/j.jhep.2020.07.028",
language = "English",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis

AU - Kjærgaard, Kristoffer

AU - Frisch, Kim

AU - Sørensen, Michael

AU - Munk, Ole Lajord

AU - Hofmann, Alan Frederick

AU - Horsager, Jacob

AU - Schacht, Anna Christina

AU - Erickson, Mary

AU - Shapiro, David A.

AU - Keiding, Susanne

PY - 2020/7/20

Y1 - 2020/7/20

N2 - Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor FXR, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA).Patients & Methods: Eight UDCA-treated PBC patients with alkaline phosphatase ≥ 1.5 ULN participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomized to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by one month washout without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi and bile ducts by positron emission tomography (PET) of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar), and the hepatic blood perfusionusing indocyanine green.Results: Compared to placebo, OCA increased the hepatic blood perfusion by median 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by median 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by median 73% (p = 0.03). This resulted in an OCA-induced decrease in hepatocyte residence time of 11C-CSar by median 30% (p = 0.01), from group median 11 min to 8 min.Conclusions: This study of UDCA-treated PBC patients showed that, compared toplacebo, OCA increased the transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. Thereby OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids.

AB - Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor FXR, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA).Patients & Methods: Eight UDCA-treated PBC patients with alkaline phosphatase ≥ 1.5 ULN participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomized to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by one month washout without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi and bile ducts by positron emission tomography (PET) of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar), and the hepatic blood perfusionusing indocyanine green.Results: Compared to placebo, OCA increased the hepatic blood perfusion by median 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by median 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by median 73% (p = 0.03). This resulted in an OCA-induced decrease in hepatocyte residence time of 11C-CSar by median 30% (p = 0.01), from group median 11 min to 8 min.Conclusions: This study of UDCA-treated PBC patients showed that, compared toplacebo, OCA increased the transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. Thereby OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids.

U2 - 10.1016/j.jhep.2020.07.028

DO - 10.1016/j.jhep.2020.07.028

M3 - Journal article

C2 - 32717289

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

ER -