The Lumped Constant for the Galactose Analog 2-¹⁸F-Fluoro-2-Deoxy-d-Galactose Is Increased in Patients with Parenchymal Liver Disease

Abstract

The galactose analog 2-18 F-fluoro-2-deoxy-D-galactose ( 18 F-FDGal) is a suitable PET tracer for measuring hepatic galactokinase capacity in vivo, which provides estimates of hepatic metabolic function. As a result of a higher affinity of galactokinase toward galactose, the lumped constant (LC) for 18 F-FDGal was 0.13 in healthy subjects. The aim of the present study was to test the hypothesis of a significantly different LC for 18 F-FDGal in patients with parenchymal liver disease. Methods: Nine patients with liver cirrhosis were studied in connection with a previous study with determination of hepatic intrinsic clearance of 18 F-FDGal (V Ã max =K Ã m ). The present study determined the hepatic removal kinetics of galactose, including hepatic intrinsic clearance of galactose (V max /K m ) from measurements of hepatic blood flow and arterial and liver vein blood galactose concentrations at increasing galactose infusions. LC for 18 F-FDGal was calculated as (V. On a second day, a dynamic 18 F-FDGal PET study with simultaneous infusion of galactose (mean arterial galactose concentration, 6.1 mmol/L of blood) and blood samples from a radial artery was performed, with determination of hepatic systemic clearance of 18 F-FDGal (K Ã 1gal ) from linear analysis of data (Gjedde-Patlak method). The maximum hepatic removal rate of galactose was estimated from 18 F-FDGal PET data (V PET max ) using the estimated LC. Results: The mean hepatic V max of galactose was 1.18 mmol/min, the mean K m was 0.91 mmol/L of blood, and the mean V max /K m was 1.18 L of blood/min. When compared with values from healthy subjects, K m did not differ (P 5 0.77), whereas both V max and V max /K m were significantly lower in patients (both P , 0.01). Mean LC for 18 F-FDGal was 0.24, which was significantly higher than the mean LC of 0.13 in healthy subjects (P , 0.0001). Mean K Ã 1gal determined from the PET study was 0.019 L of blood/min/L of liver tissue, which was not significantly different from that in healthy subjects (P 5 0.85). Mean hepatic V PET max was 0.57 mmol/min/L of liver tissue, which was significantly lower than the value in healthy subjects (1.41 mmol/min/L of liver tissue (P , 0.0001)). Conclusion: Disease may change the LC for a PET tracer, and this study demonstrated the importance of using the correct LC. PET is an excellent noninvasive tool for in vivo studies of metabolic processes. The PET tracers used may be natural substrates radiolabeled with positron-emitting isotopes such as 11 C. However, analogs of natural substrates are commonly used, a well-known example being the glucose analog 18 F-FDG used for studies of glucose metabolism. Using an analog tracer is advantageous when its metabolism is simpler, such as the metabolism of 18 F-FDG, which, unlike that of glucose, essentially stops after 6-phosphorylation. Fewer kinetic parameters are thus required in the kinetic model fitted to the dynamic PET data. An important disadvantage of using an analog tracer is that it may differ from the natural substrate in its affin...

Effect of stereotactic body radiotherapy on regional metabolic liver function investigated in patients by dynamic [18F]FDGal PET/CT

“…Parametric images of K met (mL blood/min/mL liver tissue) were created using the PMOD software (PMOD Technologies Ltd, Zürich, Switzerland). In short, the kinetic model fitted to data assumes irreversible trapping of 18 F-FDGal in hepatocytes by phosphorylation in hepatocytes by galactokinase with quasi-steady state from 6 to 20 min after the bolus injection of [ 18 F]FDGal [ 11 – 14 ]. Using the MIM Software Version 6.5 (MIM Software Inc, Cleveland, OH, USA), the parametric images were deformably co-registered liver-to-liver with the planning CT scan with same voxel size as the original PET images, and K met values in regions receiving 0–5 Gy, 5–10 Gy etc.…”

“…Galactose is metabolized in the liver by the cytosolic enzyme galactokinase and the galactose elimination capacity test provides a robust measure of metabolic liver function as demonstrated by its high prognostic sensitivity [ 5 – 10 ]. The fluorine-18 labeled galactose analogue 2-deoxy-2-[ 18 F]fluoro- d -galactose ([ 18 F]FDGal) is also metabolized by galactokinase and is used for functional positron emission tomography (PET) studies of regional metabolic liver function [ 11 – 14 ]. From dynamic PET scans of the liver with intravenous bolus injection of [ 18 F]FDGal, so-called parametric images of the liver function can be created which provides voxel-by-voxel values of the hepatic systemic clearance of [ 18 F]FDGal ( K met , mL blood/min/mL liver tissue).…”

“…From dynamic PET scans of the liver with intravenous bolus injection of [ 18 F]FDGal, so-called parametric images of the liver function can be created which provides voxel-by-voxel values of the hepatic systemic clearance of [ 18 F]FDGal ( K met , mL blood/min/mL liver tissue). K met is a flow-independent measure of galactokinase capacity that provides an indirect measure of the maximum removal capacity of [ 18 F]FDGal regionally in the liver [ 12 – 14 ] with low individual day-to-day variation [ 15 , 16 ].…”

Cardiovascular Immunotherapy and the Role of Imaging

“…ImmunoPET can be complemented with computed tomography and/or magnetic resonance imaging (MRI) to determine pathological and morphological changes. 17–19 …”

How Should Lumped Constant Be Estimated for Hepatic 18F-FDG Glucose in Humans?

“…Consequently, we successfully estimated in vivo V max and K m for unlabeled galactose, using a wide range of steady-state concentrations of galactose in pigs (12) and humans (13,14). When combined with tracer studies using the galactose analog 2-18 F-fluoro-2-deoxy-D-galactose ( 18 F-FDGal) and calculation of values of -F ln(1 -E Ã 18F 2 FDGal ) from blood measurements, LC values for hepatic 18 F-FDGal-galactose were estimated; in normal pigs they were on average 0.14 (12), in healthy human subjects 0.13 (13), and in patients with cirrhosis 0.24 (14). Moreover, mean net hepatic metabolic clearance K Ã PET for 18 F-FDGal was lower in cirrhosis and with larger intrahepatic heterogeneity than in normal livers (15).…”