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

Autor: Alan F. Hofmann, Mary Erickson, Kristoffer Kjærgaard, Susanne Keiding, David Shapiro, Michael Sørensen, Anna C. Schacht, Ole Lajord Munk, Jacob Horsager, Kim Frisch
Rok vydání: 2021
Předmět:
0301 basic medicine
INDOCYANINE GREEN
Receptors
Cytoplasmic and Nuclear
Chronic liver disease
Gastroenterology
chemistry.chemical_compound
0302 clinical medicine
CIRRHOSIS
GENE-EXPRESSION
Bile acid
Liver Cirrhosis
Biliary
Ursodeoxycholic Acid
Intrahepatic cholestasis
Obeticholic acid
Middle Aged
G protein-coupled bile acid receptor
Ursodeoxycholic acid
Treatment Outcome
FXR
HEPATOBILIARY SECRETION
CHOLYLSARCOSINE
Alkaline phosphatase
Female
030211 gastroenterology & hepatology
FARNESOID-X-RECEPTOR
medicine.drug
medicine.medical_specialty
medicine.drug_class
Bile acid-binding proteins
Molecular imaging
Chenodeoxycholic Acid
digestive system
Bile Acids and Salts
Excretion
03 medical and health sciences
Farnesoid X receptor
Double-Blind Method
Gastrointestinal Agents
Internal medicine
medicine
Humans
KINETICS
Aged
Hepatology
business.industry
Biological Transport
Alkaline Phosphatase
medicine.disease
URSODEOXYCHOLIC ACID
SALT EXPORT PUMP
Bile Ducts
Intrahepatic
030104 developmental biology
chemistry
Positron-Emission Tomography
Liver cirrhosis
Hepatocytes
business
Zdroj: Kjærgaard, K, Frisch, K, Sørensen, M, Munk, O L, Hofmann, A F, Horsager, J, Schacht, A C, Erickson, M, Shapiro, D A & Keiding, S 2021, ' Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis ', Journal of Hepatology, vol. 74, no. 1, pp. 58-65 . https://doi.org/10.1016/j.jhep.2020.07.028
ISSN: 0168-8278
DOI: 10.1016/j.jhep.2020.07.028
Popis: 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.
Databáze: OpenAIRE
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