Susanne Keiding, MD, Consultant, DMSci, Head of the Liver/PET Group at Aarhus University Hospital:
”As the first in the world we have developed a radiolabelled tracer which makes it possible to measure the hepatic bile excretion”.
Susanne Keiding, Consultant, DMSci and Head of the Liver/PET Group at Aarhus University Hospital in Denmark has recently made a breakthrough in liver research.
Her research group has developed a radiolabelled tracer which can be used for measuring liver uptake of bile acids from the blood and further excretion through the biliary system using non-invasive PET scanning – or in other words to see the back of the liver.
- This makes it possible to examine patients with diseases in the hepato-biliary excretory system, which has not been possible before; it will provide a rational basis for improved treatment.
- Bile acids are excreted from the liver with the bile to the intestines. Bile acids are needed for uptake of fat and fat-soluble vitamins from the ingested food. Defect excretion of bile acids – also called cholestasis – leads to digestive problems and accumulation of toxic bile acids in the body and especially in the liver. The patient suffers from malabsorption, severe itching of the skin and can develop severe liver diseases such as liver cirrhosis.
Inspiration from San Diego
Back in 2005, Susanne Keiding and other researchers from the Liver/PET Group Michael Sørensen, MD, PhD and Peter Ott, MD, Consultant, DMSci met Professor Alan Hofmann from University of California San Diego, USA. Alan Hofmann had previously developed a synthetic bile acid – cholylsarcosine – behaving like a natural bile acid in the body and being used to treat specific patients with diarrhoea due to defect bile acid excretion.
The researchers discussed the idea that this bile acid perhaps could be used to measure hepatic excretion of bile acids by PET/CT scanning; PET/CT is an advanced scanning technology for 3D imaging and quantification of physiological processes in living subjects. The challenge was that the tracer had to be radiolabelled by a positron to make it detectable by the PET/CT.
Grant from National Institutes of Health
In 2007, Susanne Keiding received a 5-year grant of DKK 6 million from the American medical research council, the National Institutes of Health (NIH). This made it possible in 2009 to employ chemist Kim Frisch full-time and after two years the breakthrough came. Kim Frisch had invented a new principle for radio-synthesis of 11C-marked cholylsarcosine – called 11C-CSar.
– It is great that we succeeded. A research group from Tokyo had worked on similar tracers for a long time, but we were the first, says Susanne Keiding.
– She expects 11C-CSar PET/C will provide a breakthrough in the knowledge of how the human liver takes up bile acids from the blood and how the liver excretes bile acids to the bile – in healthy human subjects and in patients with cholestatic liver disease.
– In clinical practice 11C-CSar PET/CT scans will considerably improve diagnostics and treatment of patients with cholestasis – that is diseases reduced bile excretion.
This is how 11C-CSar PET/CT works:
The small yellow arrows illustrate the transport of bile acids inside the liver: From blood in the liver –> liver cells –> bile capillaries. These pathways can be measured with the new PET/CT scanning using 11C-CSar.
From the bile ducts in the liver (green), the bile flows into the intestines (yellow) from where the bile acids are absorbed into the portal vein (blue) which brings them back to the blood in the liver.
Studies in pigs and human beings
However, it takes a while before 11C-CSar used in PET/CT scans can be implemented in clinical practice.
After the tracer was developed in 2011 it was tested in a number of animal studies in pigs. These studies showed the tracer was safe and effective to measure hepatic excretion of bile acids and the first studies in healthy subjects and patients with cholestasis have just been initiated at Aarhus University Hospital.
One of the patients examined so far presumably had a congenital defect in a transport protein (BSEP) responsible for transporting bile acid from the liver cells to the small bile duct within the liver tissues. The 11C-CSar PET/CT scan confirmed this diagnosis; 11C-CSar accumulated in the liver cells and was very slowly excreted to the small bile ducts in the liver.
Another patient developed suddenly severe itching of the skin and jaundice, which could be signs of hepatitis. Blood analyses showed no sign of acute hepatitis and the suspicion of drug-induced cholestasis was raised. A 11C-CSar PET/CT scan confirmed that the hepatic excretion of bile was affected.
Huge international attention
Aarhus University has applied for patent on the production and the clinical use of the tracer. And there is a huge international interest in implementing 11C-CSar PET/CT scans in human subjects. The Liver/PET Group is planning collaboration projects with hospitals and institutes in Copenhagen, Vienna, Zürich, Amsterdam, Maastricht, Oslo and Uppsala. When the tracer is approved for general use in humans in Denmark, it is expected that health authorities in other countries will join.
About the Liver/PET Group
- The Liver/PET Group is a research group at Aarhus University Hospital, Department of Hepatology and Gastroenterology, Department of Nuclear Medicine & PET Centre, and the Department of Surgery (section for upper gastrointestinal and hepatico-pancreatico-biliary surgery).
- The Liver/PET Group consists of a basis of approximately ten researchers in addition to visiting researchers.
- The Liver/PET Group’s goal is to improve the knowledge of regional liver blood perfusion, metabolic functions and biliary excretion in healthy subjects and patients with liver disease using non-invasive PET/CT scanning - and to implement the methods in the clinical management of patients with specific liver diseases. This will provide a rational basis for improved treatment of humans suffering from defect bile acid excretion.
- Website of the Liver/PET Group: www.liver.dk