Aarhus University Seal / Aarhus Universitets segl

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Standard

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.

I: Journal of Hepatology, Bind 74, Nr. 1, 01.2021, s. 58-65.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

APA

CBE

MLA

Vancouver

Author

Bibtex

@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 farnesoid X receptor, 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). Methods: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period 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 of the liver using the conjugated bile acid tracer [N-methyl- 11C]cholylsarcosine ( 11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. Results: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. Conclusions: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Lay summary: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third. ",
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 = "2021",
month = jan,
doi = "10.1016/j.jhep.2020.07.028",
language = "English",
volume = "74",
pages = "58--65",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier BV",
number = "1",

}

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 - 2021/1

Y1 - 2021/1

N2 - Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, 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). Methods: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period 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 of the liver using the conjugated bile acid tracer [N-methyl- 11C]cholylsarcosine ( 11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. Results: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. Conclusions: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Lay summary: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

AB - Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, 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). Methods: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period 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 of the liver using the conjugated bile acid tracer [N-methyl- 11C]cholylsarcosine ( 11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. Results: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. Conclusions: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Lay summary: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

U2 - 10.1016/j.jhep.2020.07.028

DO - 10.1016/j.jhep.2020.07.028

M3 - Journal article

C2 - 32717289

VL - 74

SP - 58

EP - 65

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 1

ER -