Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[<sup>18</sup>F]fluoro-2-deoxygalactose positron emission tomography

Sørensen, Michael; Munk, Ole Lajord; Mortensen, Frank Viborg; Olsen, Annemarie; Bender, Dirk; Bass, L.; Keiding, Susanne

doi:10.1152/ajpgi.00004.2008

Cited by 36 publications

(68 citation statements)

References 36 publications

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“…This scenario was demonstrated in the comparison of bolus versus infusion administration of tracers; negative E* values were obtained when 18 F-FDG was administered as a bolus. Hexoses enter hepatocytes very efficiently, with a blood-to-hepatocyte clearance close to that of hepatic blood flow (5,6,15). Because of the relatively low phosphorylation rate, most of the 18 F-FDG remains nonmetabolized in hepatocytes and is thus subject to backward flux from hepatocytes to blood (5,6).…”

Section: Discussionmentioning

confidence: 99%

Methodologic Considerations for Quantitative ¹⁸F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

2015

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PET with the glucose analog 18 F-FDG is used to measure regional tissue metabolism of glucose. However, 18 F-FDG may have affinities different from those of glucose for plasma membrane transporters and intracellular enzymes; the lumped constant (LC) can be used to correct these differences kinetically. The aims of this study were to investigate the feasibility of measuring human hepatic glucose metabolism with dynamic 18 F-FDG PET/CT and to determine an operational LC for 18 F-FDG by comparison with 3 H-glucose measurements. Methods: Eight healthy human subjects were included. In all studies, 18 F-FDG and 3 H-glucose were mixed in saline and coadministered. A 60-min dynamic PET recording of the liver was performed for 180 min with blood sampling from catheters in a hepatic vein and a radial artery (concentrations of 18 F-FDG and 3 H-glucose in blood). Hepatic blood flow was determined by indocyanine green infusion. First, 3 subjects underwent studies comparing bolus administration and constant-infusion administration of tracers during hyperinsulinemic-euglycemic clamping. Next, 5 subjects underwent studies comparing fasting and hyperinsulinemic-euglycemic clamping with tracer infusions. Splanchnic extraction fractions of 18 F-FDG (E*) and 3 H-glucose (E) were calculated from concentrations in blood, and the LC was calculated as ln(1 -E*)/ln(1 -E). Volumes of interest were drawn in the liver tissue, and hepatic metabolic clearance of 18 F-FDG (mL of blood/100 mL of liver tissue/min) was estimated. Results: For bolus versus infusion, E* values were always negative when 18 F-FDG was administered as a bolus and were always positive when it was administered as an infusion. For fasting versus clamping, E* values were positive in 4 of 5 studies during fasting and were always positive during clamping. Negative extraction fractions were ascribed to the tracer distribution in the large volume of distribution in the prehepatic splanchnic bed. The LC ranged from 0.43 to 2.53, with no significant difference between fasting and clamping. Conclusion: The large volume of distribution of 18 F-FDG in the prehepatic splanchnic bed may complicate the analysis of dynamic PET data because it represents the mixed tracer input to the liver via the portal vein. Therefore, dynamic 18 F-FDG data for human hepatic glucose metabolism should be interpreted with caution, but constant tracer infusion seems to yield more robust results than bolus injection.

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Section: Discussionmentioning

confidence: 99%

Methodologic Considerations for Quantitative ¹⁸F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

2015

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“…Animals were sedated with an intramuscular injection of midazolam and S-ketamine; anesthetized with an infusion of midazolam, S-ketamine, and propofol; mechanically ventilated; and kept physiologically stable (17).…”

Section: Animal Preparationmentioning

confidence: 99%

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET

et al. 2016

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The aim of this study was to develop a method for the quantification of hepatobiliary uptake and secretion of conjugated bile acids with PET and the 11 C-labeled conjugated bile acid analog [N-methyl-11 C] cholylsarcosine ( 11 C-CSar). Methods: Six pigs (13 experiments) underwent dynamic 11 C-CSar PET of the liver with simultaneous measurements of hepatic blood perfusion and 11 C-CSar concentrations in arterial, portal, and hepatic venous blood. In 3 pigs (7 experiments), bile was collected from a catheter in the common hepatic duct. PET data were analyzed with a 2-tissue compartmental model with calculation of rate constants for the transport of 11 C-CSar among blood, hepatocytes, and intra-and extrahepatic bile ducts. PET results were validated against invasive blood and bile measurements. Results: The directly measured rate of secretion of 11 C-CSar into bile was equal to the rate of removal from blood at steady state. Accordingly, hepatocytes did not accumulate bile acids but simply facilitated the transport of bile acids from blood to bile against a measured concentration gradient of 4,000. The rate constant for the secretion of 11 C-CSar from hepatocytes into bile in experiments with a catheter in the common hepatic duct was 25% of that in experiments without a catheter (P , 0.05); we interpreted this result to be mild cholestasis caused by the catheter. The catheter caused an increased backflux of 11 C-CSar from hepatocytes to blood, and hepatic blood flow was 25% higher than in experiments without the catheter. The capacity for the overall transport of 11 C-CSar from blood to bile, as quantified by intrinsic clearance, was significantly lower in experiments with the catheter than in those without the catheter (P , 0.001). PET and blood measurements correlated significantly (P , 0.05). Conclusion: The in vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic 11 C-CSar PET.

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“…The hepatic systemic clearance of 18 F-FDGal per volume of liver tissue (K Ã 1gal ; L blood/min/L of liver tissue) was calculated as the asymptote fitted to Gjedde-Patlak (15,16) representation of time-activity curve blood and time-activity curve liver using data from 6 to 20 min after the 18 F-FDGal administration (quasi-steady-state metabolism) (3,7,17).…”

Section: Hepatic Removal Kinetics Of Galactose and Lc For 18 F-fdgalmentioning

confidence: 99%

“…The hepatic V max for galactose per volume of liver tissue (V PET max ; mmol/min/L of liver tissue) was calculated as follows (3,17):…”

Section: Hepatic Removal Kinetics Of Galactose and Lc For 18 F-fdgalmentioning

confidence: 99%

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

et al. 2014

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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...

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Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[¹⁸F]fluoro-2-deoxygalactose positron emission tomography

Cited by 36 publications

References 36 publications

Methodologic Considerations for Quantitative ¹⁸F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

Methodologic Considerations for Quantitative ¹⁸F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET

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

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Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[18F]fluoro-2-deoxygalactose positron emission tomography

Cited by 36 publications

References 36 publications

Methodologic Considerations for Quantitative 18F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

Methodologic Considerations for Quantitative 18F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET

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

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Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[¹⁸F]fluoro-2-deoxygalactose positron emission tomography

Methodologic Considerations for Quantitative ¹⁸F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

Methodologic Considerations for Quantitative ¹⁸F-FDG PET/CT Studies of Hepatic Glucose Metabolism in Healthy Subjects

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET

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