Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT
Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT
This is an investigator-initiated, double-blind crossover study on the mechanism of OCA
 treatment of patients with PBC.

 Hypothesis and significance

 The investigators will test the hypothesis that OCA administration to patients with PBC
 increases hepatobiliary secretion of cholylsarcosine assessed by PET/CT using 11C-labeled
 cholylsarcosine (11C-CSar) as tracer.

 The results of this research project will elucidate the mechanism of the effect of using OCA
 therapeutically in patients with PBC.
Background

 Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by
 cholestasis and cirrhosis. Pathogenesis comprises impaired hepatobiliary secretion of bile
 acids to the bile. As a result bile flow reduces and diminished content of bile acids in the
 intestines leads to impaired absorption of lipids and lipid-soluble vitamins, diarrhea,
 general pruritus, and fatigue.

 Bile acids are transported from blood to hepatocytes by the transporter proteins
 Na+-taurocholate co-transporting polypeptide (NTCP) and Organic anion-transporting
 polypeptide (OATP) and secreted from hepatocyte to bile canaliculi by the Bile salt export
 pump (BSEP) and Multidrug resistance protein type 3 (MDR3). Dysfunction of BSEP most probably
 plays a key pathogenic role in PBC.

 Ursodeoxycholic acid (UDCA) is a dihydroxylated bile acid and the only approved drug for
 treatment of PBC today. In most cases UDCA can delay or prevent disease progression. However,
 a subgroup of patients does not respond adequately to UDCA and for these patients new
 therapies are needed.

 BSEP is induced by the nuclear bile acid receptor (BAR), also known as farnesoid X receptor
 (FXR). Obeticholic Acid (INT-747, Intercept) (OCA) is a FXR agonist and induces BSEP.

 OCA administration therefore may increase the hepatobiliary secretion of bile acids, being
 the mechanism behind beneficial therapeutic effects in PBC.

 Cholylsarcosine is a synthetic conjugated bile acid (sarcosine = methyl-glycine) that is
 non-toxic, not metabolized in the gut or liver, and transported by BSEP. The trans-hepatic
 transport of bile acids can be assessed in humans by PET/CT of the liver using 11C-labeled
 cholylsarcosine (11C-CSar) as tracer. 11C-CSar is handled by the liver as a natural bile acid
 in pig studies (1). Studies in humans (2) show that

 -  11C-CSar is taken up avidly by the liver and flow-determined

 -  11C-CSar secretion from hepatocytes to bile is reduced during cholestasis, and

 -  11C-CSar back flux from hepatocytes to blood during cholestasis

 Patients

 8 patients with PBC

 -  who are not responding adequately to treatment with UDCA, defined as ALP > 2 times upper
 normal level during a time period of 6 months

 -  Patients are recruited from Aarhus University Hospital, Department of Hepatology and
 Gastroenterology.

 Paired study design

 -  11C-CSar PET/CT before and after 3 months treatment with OCA or placebo.

 Methods

 PET/CT: Initial low-dose CT for anatomical definition of the PET findings and for attenuation
 correction of PET data. Dynamic 60-min PET recording of the tissue radioactivity
 concentration over time following iv bolus injection of 100 MBq 11C-CSar and iv infusion of
 100 MBq 11C-CSar. During the PET study, ICG is given as a constant iv infusion for
 measurements of hepatic blood flow, used in the kinetic analysis, and blood samples are
 collected from catheters in a radial artery and a liver vein (blood 11C-CSar concentrations
 for kinetic calculations, ICG, and blood gasses for monitoring purposes).

 Liver tests at the time points of the PET/CT study: Plasma ALT, ALP, GGT, bilirubin, bile
 salts, IRN, platelets, hemoglobin, mitochondrial antibodies; ICG clearance.

 Raw data comprise time-courses of the 11C-CSar concentrations in liver tissue and common
 hepatic bile duct (PET recordings) and blood concentrations of 11C-CSar in arterial and liver
 vein blood (blood samples); hepatic blood flow, hepatic venous pressure gradient (HVPG),
 splanchnic oxygen uptake.

 11C-CSar data comprise clearances of 11C-CSar from blood-to-hepatocytes and from
 hepatocytes-to-bile canaliculi, vascular extraction fractions, biliary secretion fraction,
 transit times, etc.
Inclusion Criteria:

 -  patients with PBC

 -  who are not responding adequately to treatment with UDCA, defined as ALP > 2 times
 upper normal level during a time period of 6 months

 Exclusion Criteria:

 -  Itching that requires medical treatment