Nikolaj Worm Ørntoft1, Ole Lajord Munk1, Kim Frisch1, Peter Ott2, Susanne Keiding3, Michael Sørensen4. 1. Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark. 2. Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. 3. Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. 4. Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: michsoer@rm.dk.
Abstract
BACKGROUND & AIMS: Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) and positron emission tomography (PET). METHODS: Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11C-CSar. RESULTS: Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion of 11C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min-1, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min-1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min-1, 2.3times higher than the rate constant for backflux to blood (0.05, 0.04-0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11C-CSar was 2.5 (1.6-3.1)min in healthy participants and 6.4 (3.1-23.7)min in patients. The rate constant for transport of 11C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min-1 in healthy participants and only slightly reduced in patients 0.039 (0.017-0.066). CONCLUSIONS: This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease. LAY SUMMARY: Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions. CLINICAL TRIAL REGISTRATION NUMBER: The trial is registered at ClinicalTrials.gov (NCT01879735).
BACKGROUND & AIMS:Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) and positron emission tomography (PET). METHODS: Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11C-CSar. RESULTS: Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion of 11C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min-1, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min-1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min-1, 2.3times higher than the rate constant for backflux to blood (0.05, 0.04-0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11C-CSar was 2.5 (1.6-3.1)min in healthy participants and 6.4 (3.1-23.7)min in patients. The rate constant for transport of 11C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min-1 in healthy participants and only slightly reduced in patients 0.039 (0.017-0.066). CONCLUSIONS: This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease. LAY SUMMARY: Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions. CLINICAL TRIAL REGISTRATION NUMBER: The trial is registered at ClinicalTrials.gov (NCT01879735).
Keywords:
Bile acid transporter; Bile acids and salts; Cholestasis; Functional molecular imaging of the liver; Hepatic transport kinetics; Hepatocytes; Kinetics; Positron-emission tomography
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