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BACKGROUND & AIMS: Wilson disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using positron emission tomography (PET) with copper-64 (64 Cu) as tracer. Furthermore, we assessed the diagnostic potential of the method.METHODS: Nine patients with WD, five healthy heterozygote subjects, and eight healthy controls were injected with an intravenous bolus of 64 Cu followed by a 90-min dynamic PET scan of the liver and static whole-body PET/CT scans after 1.5, 6, and 20 hours. Blood 64 Cu concentrations were measured in parallel. The hepatic copper retention and redistribution were evaluated by standardized uptake values (SUV).RESULTS: At 90 min, the hepatic SUVs were similar in the three groups. In contrast, at 20 hours post injection, the SUV in WD patient (Mean±SEM 31±4) was higher than in heterozygotes (24±3) or controls (21±4), (p < 0.001). An SUV-ratio of the hepatic 64 Cu concentration at 20 and 1.5 hours completely discriminated between the WD patients and control groups (p < 0.0001; ANOVA). By Patlak-analysis of the initial 90 min of the PET scan, the steady-state hepatic clearance of 64 Cu was estimated to be slightly lower in the patients with WD than in controls, (p = 0.04).CONCLUSIONS: 64 Cu PET imaging enables visualisation and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, which may assist the development of novel therapies, and accurate diagnosis.

Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA). Methods: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi, and bile ducts by positron emission tomography of the liver using the conjugated bile acid tracer [N-methyl- 11C]cholylsarcosine ( 11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. Results: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. Conclusions: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Lay summary: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

Wilson's disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper-64 (Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of

Purpose Copper is essential for enzymatic processes throughout the body. [64Cu]copper (64Cu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of 64Cu in healthy humans by both intravenous and oral administration. Methods Six healthy participants underwent PET/CT studies with intravenous or oral administration of 64Cu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs. Results After intravenous administration, 64Cu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/MBq (mean ± SD). After oral administration, 64Cu was almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of 64Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64Cu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min− 1. Conclusion 64Cu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, while after oral administration, 64Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64Cu yielded images of high quality for both administration forms with radiation doses of approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans. Trial registration number EudraCT no. 2016–001975-59. Registration date: 19/09/2016.

Background: PET/CT with the radioactively labelled galactose analogue 2-18F-fluoro-2-deoxy-D-galactose (18F-FDGal) can be used to quantify the hepatic metabolic function and visualise regional metabolic heterogeneity. We determined the day-to-day variation in humans with and without liver disease. Furthermore, we examined whether the standardised uptake value (SUV) of 18F-FDGal from static scans can substitute the hepatic systemic clearance of 18F- FDGal (Kmet, mL blood/min/mL liver tissue/) quantified from dynamic scans as measure of metabolic function. Four patients with cirrhosis and six healthy subjects underwent two 18F-FDGal PET/CT scans within a median interval of 15 days for determination of day-to-day variation. The correlation between Kmet and SUV was examined using scan data and measured arterial blood concentrations of 18F-FDGal (blood samples) from 14 subjects from previous studies. Regional and whole-liver values of Kmet and SUV along with total metabolic liver volume and total metabolic liver function (total SUV, average SUV multiplied by total metabolic liver volume) were calculated. Results: No significant day-to-day differences were found for Kmet or SUV. SUV had higher intraclass correlation coefficients than Kmet (0.92–0.97 vs. 0.49–0.78). The relationship between Kmet and SUV was linear. Total metabolic liver volume had non-significant day-to-day variation (median difference 50 mL liver tissue; P = 0.6). Mean total SUV in healthy subjects was 23,840 (95% CI, 21,609; 26,070), significantly higher than in the patients (P < 0.001). Conclusions: The reproducibility of 18F-FDGal PET/CT was good and SUV can substitute Kmet for quantification of hepatic metabolic function. Total SUV of 18F-FDGal is a promising tool for quantification of metabolic liver function in pre-treatment evaluation of individual patients. BACKGROUND: PET/CT with the radioactively labelled galactose analogue 2-(18)F-fluoro-2-deoxy-D-galactose ((18)F-FDGal) can be used to quantify the hepatic metabolic function and visualise regional metabolic heterogeneity. We determined the day-to-day variation in humans with and without liver disease. Furthermore, we examined whether the standardised uptake value (SUV) of (18)F-FDGal from static scans can substitute the hepatic systemic clearance of (18)F-FDGal (K met, mL blood/min/mL liver tissue/) quantified from dynamic scans as measure of metabolic function. Four patients with cirrhosis and six healthy subjects underwent two (18)F-FDGal PET/CT scans within a median interval of 15 days for determination of day-to-day variation. The correlation between K met and SUV was examined using scan data and measured arterial blood concentrations of (18)F-FDGal (blood samples) from 14 subjects from previous studies. Regional and whole-liver values of K met and SUV along with total metabolic liver volume and total metabolic liver function (total SUV, average SUV multiplied by total metabolic liver volume) were calculated.RESULTS: No significant day-to-day differences were found for K met or SUV. SUV had higher intraclass correlation coefficients than K met (0.92-0.97 vs. 0.49-0.78). The relationship between K met and SUV was linear. Total metabolic liver volume had non-significant day-to-day variation (median difference 50 mL liver tissue; P = 0.6). Mean total SUV in healthy subjects was 23,840 (95% CI, 21,609; 26,070), significantly higher than in the patients (P < 0.001).CONCLUSIONS: The reproducibility of (18)F-FDGal PET/CT was good and SUV can substitute K met for quantification of hepatic metabolic function. Total SUV of (18)F-FDGal is a promising tool for quantification of metabolic liver function in pre-treatment evaluation of individual patients.

Objective We aimed to improve prediction of outcome for patients with colorectal liver metastases, via prognostic models incorporating PET-derived measures, including radiomic features that move beyond conventional standard uptake value (SUV) measures. Patients and methods A range of parameters including volumetric and heterogeneity measures were derived from FDG PET images of 52 patients with colorectal intrahepatic-only metastases (29 males and 23 females; mean age 62.9 years [SD 9.8; range 32–82]). The patients underwent PET/CT imaging as part of the clinical workup prior to final decision on treatment. Univariate and multivariate models were implemented, which included statistical considerations (to discourage false discovery and overfitting), to predict overall survival (OS), progression-free survival (PFS) and event-free survival (EFS). Kaplan-Meier survival analyses were performed, where the subjects were divided into high-risk and low-risk groups, from which the hazard ratios (HR) were computed via Cox proportional hazards regression. Results Commonly-invoked SUV metrics performed relatively poorly for different prediction tasks (SUVmax HR = 1.48, 0.83 and 1.16; SUVpeak HR = 2.05, 1.93, and 1.64, for OS, PFS and EFS, respectively). By contrast, the number of liver metastases and metabolic tumor volume (MTV) each performed well (with respective HR values of 2.71, 2.61 and 2.42, and 2.62, 1.96 and 2.29, for OS, PFS and EFS). Total lesion glycolysis (TLG) also resulted in similar performance as MTV. Multivariate prognostic modeling incorporating different features (including those quantifying intra-tumor heterogeneity) resulted in further enhanced prediction. Specifically, HR values of 4.29, 4.02 and 3.20 (p-values = 0.00004, 0.0019 and 0.0002) were obtained for OS, PFS and EFS, respectively. Conclusions PET-derived measures beyond commonly invoked SUV parameters hold significant potential towards improved prediction of clinical outcome in patients with liver metastases, especially when utilizing multivariate models.

Background & Aims: Positron emission tomography (PET) with the liver-specific tracer [18F]-fluoro-2-deoxy-D-galactose (18F-FDGal) can be used for imaging of hepatocellular carcinoma (HCC). Curative intended and locoregional treatments of HCC require absence of extrahepatic disease. The aim of this prospective study was to determine whether adding 18F-FDGal PET/CT to standard work-up changes the planned treatment in patients with HCC deemed suitable for curative or locoregional treatment. Methods: Fifty patients with HCC were included at our tertiary liver centre. The primary study outcome was a change in treatment strategy. A subgroup of 29 patients was also examined with [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT for comparison. Results: 18F-FDGal PET/CT detected eight extrahepatic HCC metastases in six patients (12%), which were primarily not detected by ceCT or MRI. These findings led to a change in treatment in five patients (10%). One of the eight extrahepatic HCC foci was also detected by 18F-FDG PET/CT. A total of 85 malignant intrahepatic foci were examined, 12 of these were new findings by 18F-FDGal PET/CT which had a sensitivity of 71%, highest for large foci. None of the additional intrahepatic foci found by 18F-FDGal PET changed the planned treatment. Conclusions: For the detection of extrahepatic HCC metastases, 18F-FDGal PET/CT was superior both to standard clinical work-up with contrast-enhanced CT, and/or MRI, and to 18F-FDG PET/CT in patients deemed suitable for locoregional treatment. 18F-FDGal PET/CT led to a change in the planned treatment in 10% of the patients whereas 18F-FDG PET/CT did not change the planned treatment in any patient.

Positron emission tomography (PET) with 11 C-cholylsarcosine ( 11 C-CSar), a radiolabelled synthetic N -methylglycine (sarcosine) conjugate of cholic acid, is a novel molecular imaging technique that enables quantitative assessment of the individual transport steps involved in hepatic secretion of conjugated bile acids. Here, we present the method and discuss its potential clinical and scientific applications based on findings in the first human study of healthy subjects and patients with cholestasis. We also present a clinical example of a patient studied during and six months after an episode of drug-induced cholestatic liver injury.

Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for regulation of intracellular concentrations of bile acids and their function as detergents and signal carriers. Only few bile acid-derived imaging agents have been synthesized and hitherto none have been evaluated for studies of EHC. We hypothesized that N-(4-[A radiosynthesis of [[We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013.MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report.RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively.CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

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).

Positron emission tomography (PET) with

To assess the effect of propranolol treatment on the hepatic venous pressure gradient (HVPG) and the relationship between native HVPG and the effect of propranolol in patients with cirrhosis and portal hypertension in a prospective, observational, single-center study.The HVPG was registered prospectively in 124 consecutive cirrhosis patients with and without treatment with propranolol 80 mg daily. Results. 41% of the patients responded to the treatment with the intended reduction of HVPG to12 mm Hg and/or by20%. The HVPG reduction was larger for higher native HVPG values (p0.001). There was no significant relation between changes in heart rate and changes in HVPG (p = 0.8).The high fraction of hemodynamic non-responders supports the rationale of measuring the HVPG with and without propranolol treatment to assist the clinical assessment and avoid meaningless and potentially harmful treatment. The positive association between a high native HVPG and propranolol-induced HVPG reduction indicates that pharmacological treatment also benefits patients with advanced portal hypertension.

Background & Aims There is a clinical need for methods that can quantify regional hepatic function non-invasively in patients with cirrhosis. Here we validate the use of 2-[ 18 F]fluoro-2-deoxy-d-galactose (FDGal) PET/CT for measuring regional metabolic function to this purpose, and apply the method to test the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis. Methods Nine cirrhotic patients underwent dynamic liver FDGal PET/CT with blood samples from a radial artery and a liver vein. Hepatic blood flow was measured by indocyanine green infusion/Fick's principle. From blood measurements, hepatic systemic clearance ( K syst , Lblood/min) and hepatic intrinsic clearance ( V max / K m , Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma ( K met , mLblood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of K met . Results Mean approximation of K syst to V max / K m was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean K met was 0.157mLblood/mL liver tissue/min, which was lower than 0.274mLblood/mL liver tissue/min, previously found in healthy subjects ( p K met in liver tissue was 24.4% in patients and 14.4% in healthy subjects ( p p Conclusions A 20-min dynamic FDGal PET/CT with arterial sampling provides an accurate measure of regional hepatic metabolic function in patients with cirrhosis. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring.

Hepatic encephalopathy (HE) is associated with increased ammonia levels in plasma and brain. Different treatment strategies have been developed to ameliorate the detrimental effects of the ammonia load. One such strategy is based on the finding of a low level of the branched chain amino acids (BCAAs) in plasma of patients suffering from HE and the assumption that in particular isoleucine could be beneficial to brain energy metabolism as it is metabolized to the tricarboxylic acid cycle intermediate and precursor succinyl-CoA and acetyl-CoA, respectively. This would enable de novo synthesis of glutamine via α-ketoglutarate and glutamate and at the same time stimulate oxidative metabolism. The present mini-review summarizes the metabolic basis for this hypothesis delineating studies in the brain in vivo as well as in cultured neural cells aimed at elucidating the metabolism of the BCAAs focusing on isoleucine. The conclusion is that isoleucine appears at least partially to act in this fashion albeit its metabolism is quantitatively relatively modest. In addition, a short section on the role of the BCAAs in synaptic ammonia homeostasis is included along with some thoughts on the role of the BCAAs in other pathologies such as cancer.

Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to cognitive deficits. Different animal models for the study of HE have demonstrated learning and memory impairment and a number of neurotransmitter systems have been proposed to be involved in this. Recently, it was described that bile duct-ligated (BDL) rats exhibited altered spatio-temporal locomotor and exploratory activities and biosynthesis of neurotransmitter GABA in brain cortices. Therefore, the aim of this study was to evaluate cognition in the same animal model. Male adult Wistar rats underwent common bile duct ligation (BDL rats) or manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent object recognition behavioral task. The BDL rats developed chronic liver failure and exhibited a decreased discrimination index for short term memory (STM) when compared to the control group. There was no difference in long term memory (LTM) as well as in total time of exploration in the training, STM and LTM sessions between the BDL and control rats. Therefore, the BDL rats demonstrated impaired STM for recognition memory, which was not due to decreased exploration.

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-Nine healthy participants and eight patients with varying degrees of cholestasis were examined withResults 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 ofThis 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.Positron emission tomography (PET) using the radiolabelled bile acid (The trial is registered at ClinicalTrials.gov (NCT01879735).

INTRODUCTION: PET with [(18)F]fluoro-2-deoxy-D-galactose ((18)F-FDGal) is a promising imaging modality for detection of hepatocellular carcinoma (HCC). However, it can be difficult to distinguish small intrahepatic HCC lesions from surrounding liver tissue. Ut the competitive inhibition that galactose shows towards hepatic (18)F-FDGal metabolism, we tested the hypothesis that co-administration of galactose, at near-saturating doses, inhibits (18)F-FDGal metabolism to a greater extent in non-malignant hepatocytes than in HCC cells. This would increase the tumor to background ratio in the (18)F-FDGal PET scans with co-administration of galactose.METHODS: Three patients known to have HCC underwent two (18)F-FDGal PET/CT scans on consecutive days, one with and one without simultaneous constant intravenous infusion of galactose. On both days, (18)F-FDGal was injected in the beginning of a 45-min dynamic PET scan of the liver followed by a static PET scan from mid-thigh to the top of the skull starting 60-70min after (18)F-FDGal administration. Parametric images of the hepatic metabolic function expressed in terms of hepatic systemic clearance of (18)F-FDGal were generated from the dynamic PET recordings.RESULTS: Co-administration of galactose did not give significantly better discrimination of the HCC lesions from background. Parametric images of the hepatic metabolic function did not add additional useful information to the detection of HCC lesions compared to the static images of radioactivity concentrations.CONCLUSION: Co-administration of galactose did not improve the interpretation of the (18)F-FDGal PET/CT images and did not improve the detection of intrahepatic HCC lesions, either using static or parametric images.

The aim was to develop a method for quantification of hepatobiliary uptake and secretion of conjugated bile acids using 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 measurements of hepatic blood perfusion and (11)C-CSar concentrations in arterial, portal and hepatic venous blood. In three pigs (seven experiments) bile was collected from a catheter in the common hepatic duct (CHD). PET data were analyzed by a two-tissue compartmental model with calculation of rate constants for transport of (11)C-CSar between blood, hepatocytes and intra- and extra-hepatic bile ducts. PET results were validated against invasive blood and bile measurements.RESULTS: Directly measured secretion rate of (11)C-CSar into bile was equal to removal rate from blood at steady state. Hepatocytes accordingly did not accumulate bile acids but simply facilitated transport of bile acids from blood into bile against a measured concentration gradient of 4,000 from blood to bile. In experiments with catheter in CHD, rate constant for secretion of (11)C-CSar from hepatocytes into bile was 25% of that in experiments without a catheter (P < 0.05) which we interpreted as 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 experiment without catheter. The capacity of the overall transport of (11)C-CSar from blood into bile, as quantified by intrinsic clearance, was significantly lower in experiments with catheter than in pigs without catheter (P < 0.001). PET and blood measurements correlated significantly (P < 0.05).CONCLUSION: In vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic (11)C-CSar PET.

Highlights • Hepatic denervation results in a blunted counterregulatory response during insulin-induced hypoglycemia. • Fasting glucose concentration, glucose production and uptake are unaffected by hepatic denervation. • Insulin action and extrahepatic glucose uptake are unaffected by hepatic denervation., Objective The liver reacts to hypoglycemia by increasing its glucose output. This response is assumed to depend both on glucose sensing at the liver and the brain, as well as efferent impulses from the brain to the liver. We tested the importance of this signaling pathway by studying the hepatic response to insulin-induced hypoglycemia in hepatic complete denervated pigs. Materials/methods Two weeks prior to the metabolic study, 36-kg pigs underwent either total hepatic denervation (DN; n = 12) or sham operation (sham; n = 12). On the metabolic study day, measurements were performed at baseline conditions and during a hypoglycemic hyperinsulinemic (5 mU/kg/min) clamp. Endogenous insulin and glucagon secretions were inhibited by somatostatin, and glucagon was replaced at baseline levels. Endogenous glucose production (EGP) and glucose utilization (Rd) were determined by [3-3H] glucose infusion. Results Baseline plasma concentrations of glucose, insulin, EGP and Rd did not differ significantly between the two groups of animals. During insulin infusion, the plasma glucose concentration was clamped at ~3 mmol/L in both groups of animals resulting in an increase in plasma concentrations of epinephrine and norepinephrine in sham pigs (both P

Background: We have previously developed 11C-erlotinib as a new positron emission tomography (PET) tracer and shown that it accumulates in epidermal growth factor receptor (EGFR)-positive lung cancer xenografts in mice. Here, we present a study in patients with non-small cell lung cancer (NSCLC) investigating the feasibility of 11C-erlotinib PET as a potential method for the identification of lung tumours accumulating erlotinib. Methods: Thirteen patients with NSCLC destined for erlotinib treatment were examined by contrast-enhanced computed tomography (CT), 11C-erlotinib PET/low-dose CT and 18F-fluoro-2-deoxy--glucose (18F-FDG) PET/low-dose CT before start of the erlotinib treatment. After 12 weeks treatment, they were examined by 18F-FDG PET/contrast-enhanced CT for the assessment of clinical response. Results: Of the 13 patients included, 4 accumulated 11C-erlotinib in one or more of their lung tumours or lymph-node metastases. Moreover, 11C-erlotinib PET/CT identified lesions that were not visible on 18F-FDG PET/CT. Of the four patients with accumulation of 11C-erlotinib, one died before follow-up, whereas the other three showed a positive response to erlotinib treatment. Three of the nine patients with no accumulation died before follow-up, four showed progressive disease while two had stable disease after 12 weeks of treatment. Conclusion: Our data show a potential for 11C-erlotinib PET/CT for visualizing NSCLC lung tumours, including lymph nodes not identified by 18F-FDG PET/CT. Large clinical studies are now needed to explore to which extent pre-treatment 11C-erlotinib PET/CT can predict erlotinib treatment response.

The lumped constant is a proportionality factor for converting a tracer analogue's metabolic rate to that of its mother substance. In a uniform system, it is expressed as the ratio of the tracer analogue's extraction fraction (E⁎) to the extraction fraction of its mother substance (E). Here we show that, in capillary beds perfused by unidirectional blood flow, unequal concentration gradients of the tracer analogue and of the mother substance influence extraction fractions both locally and across the organ and that the direct proportionality of E⁎ and E must be replaced by ln(1−E⁎)/ln(1−E) to yield Λ, i.e. the lumped constant derived from first principles of bi-substrate enzyme and membrane kinetics. In other words, at a given capillary blood flow (F), the ratio of systemic clearances (FE⁎/FE), often used in compartmental kinetic analysis, must be replaced by the ratio of the intrinsic clearances, [−F ln(1−E⁎)]/[−F ln(1−E)]. The conclusion is supported by 2-[18F]fluoro-2-deoxy-d-galactose removal kinetics in pig liver in vivo from previous publications by the dependence of E⁎/E and the independence of Λ, on blood galactose concentration. Moreover, our corrections to the results of compartmental kinetics are quantified for comparing extraction fractions in different regions of interest (e.g. by positron emission tomography) and for calculating Λ using whole-organ E⁎ and E measured by arteriovenous concentration differences.

Branched-chain amino acids (BCAA) are used in attempts to reduce blood ammonia in patients with cirrhosis and intermittent hepatic encephalopathy based on the hypothesis that BCAA stimulate muscle ammonia detoxification. We studied the effects of an oral dose of BCAA on the skeletal muscle metabolism of ammonia and amino acids in 14 patients with cirrhosis and in 7 healthy subjects by combining [13N]ammonia positron emission tomography (PET) of the thigh muscle with measurements of blood flow and arteriovenous (A-V) concentrations of ammonia and amino acids. PET was used to measure the metabolism of blood-supplied ammonia and the A-V measurements were used to measure the total ammonia metabolism across the thigh muscle. After intake of BCAA, blood ammonia increased more than 30% in both groups of subjects (both P < 0.05). Muscle clearance of blood-supplied ammonia (PET) was unaffected ( P = 0.75), but the metabolic removal rate (PET) increased significantly because of increased blood ammonia in both groups (all P < 0.05). The total ammonia clearance across the leg muscle (A-V) increased by more than 50% in both groups, and the flux (A-V) of ammonia increased by more than 45% (all P < 0.05). BCAA intake led to a massive glutamine release from the muscle (cirrhotic patients, P < 0.05; healthy subjects, P = 0.12). In conclusion, BCAA enhanced the intrinsic muscle metabolism of ammonia but not the metabolism of blood-supplied ammonia in both the patients with cirrhosis and in the healthy subjects.

There is an unmet clinical need for an imaging method for quantification of hepatic blood perfusion. The purpose of the present study was to develop and validate a PET method using blood-to-cell clearance (K(1)) of (18)F-FDG, 3-O-(11)C-methylglucose ((11)C-MG), or 2-(18)F-fluoro-2-deoxy-D-galactose ((18)F-FDGal) as a measure of hepatic blood perfusion without the need for portal venous blood samples. We aimed to make the method as simple as possible with the prospect of future application to clinical studies. For this purpose, we examined the possibility of using a 3-min data acquisition and a model-derived dual input calculated from measurements of radioactivity concentrations in a peripheral artery.Pigs (40 kg) underwent dynamic PET of the liver with (18)F-FDG, (11)C-MG, or (18)F-FDGal with simultaneous measurements of time-activity curves in blood sampled from a femoral artery and the portal vein (PV); blood flow rates were measured in the hepatic artery (HA) and PV by transit-time flow meters. Two input functions were compared: A measured dual input and a model-derived dual input, the latter with the PV time-activity curve estimated from the measured arterial time-activity curve and a previously validated 1-parametric PV model. (K(1)) was estimated for each tracer by fitting compartmental models to the data, comparing 3-min and 60-min data acquisitions and the 2 dual-input time-activity curves.Agreement between (K(1)) estimated using the measured and the model-derived dual input was good for all 3 tracers. For (18)F-FDG and (11)C-MG, (K(1)) (3-min data acquisition, model-derived dual input, and 1-tissue compartmental model) correlated to the measured blood perfusion (P = 0.01 and P = 0.07, respectively). For (18)F-FDGal, the correlation was not significant.A simplified method for quantification of hepatic blood perfusion using 3-min dynamic (18)F-FDG PET or (11)C-MG PET with blood sampling from only a peripheral artery was developed. Parametric (K(1)) images were constructed and showed homogeneous blood perfusion in these normal livers.

Hepatic encephalopathy (HE) is a neuropsychiatric complication to liver disease. It is known that ammonia plays a role in the pathogenesis of HE and disturbances in the GABAergic system have been related to HE. Synthesis of GABA occurs by decarboxylation of glutamate formed by deamidation of astrocyte-derived glutamine. It is known that a fraction of glutamate is decarboxylated directly to GABA (referred to as the direct pathway) and that a fraction undergoes transamination with formation of alpha-ketoglutarate. The latter fraction is cycled through the neuronal tricarboxylic acid cycle, an energy-generating pathway, prior to being employed for GABA synthesis (the indirect pathway). We have previously shown that ammonia induces an elevation of the neuronal tricarboxylic acid cycle activity. Thus, the aims of the present study were to determine if increased levels of ammonia increase GABA synthesis via the indirect pathway in a rat model of HE induced by bile-duct ligation and in co-cultures of neurons and astrocytes exposed to ammonia. Employing (13) C-labeled precursors and subsequent analysis by mass spectrometry, we demonstrated that more GABA was synthesized via the indirect pathway in bile duct-ligated rats and in co-cultures subjected to elevated ammonia levels. Since the indirect pathway is associated with synthesis of vesicular GABA, this might explain the increased GABAergic tone in HE.

Objective. Galactose elimination capacity (GEC) is used as a quantitative measure of liver metabolic function with prognostic value in adults with acute and chronic liver failure. Almost no data are available regarding GEC in children, however. This study thus aims to meet the previously unmet clinical need for age-related data on GEC in children. Material and methods. We studied galactose elimination in 10 healthy children (median age 10.7 years; range 7 months to 16 years) and 30 children with chronic liver disease (median age 8.6 years; range 3 months to 16 years). GEC was estimated from the linear decrease in concentration of galactose in arterialized capillary blood from the ear following intravenous infusion of galactose. Results. In both groups of children, GEC (μmol/min/kg body weight) was highest in the youngest children and decreased with age, although at a significantly lower level in the children with liver disease (p = 0.05). GEC was significantly higher in healthy children than in healthy adults, diminishing to the adult level by the age of 16 years. Conclusions. GEC was found to be higher in children than in adults until the age of 16 years. Moreover, GEC was significantly lower in children with chronic liver disease than in healthy children, underlining that GEC testing also has potential clinical usefulness as a quantitative measure of liver metabolic function in children.

Polarographic oxygen-sensitive electrodes have demonstrated prognostic significance of hypoxia. However, its routine application is limited. (18)F-FMISO PET scans are a noninvasive approach, able to measure spatial and temporal changes in hypoxia. The aim of this study was to examine the association between measures of hypoxia defined by functional imaging and Eppendorf pO(2) electrodes.A total of 18 patients were included, nine squamous cell carcinoma of the head and neck and nine soft tissue tumors. The tumor volume was defined by CT, MRI, (18)FDG-PET or by clinical examination. The oxygenation status of the tumors was assessed using (18)F-FMISO PET imaging followed by Eppendorf pO(2) electrode measurements. Data were compared in a 'virtual voxel', resulting in individual histograms from each tumor.The percentages of pO(2) ≤ 5 mmHg ranged from 9 to 94% (median 43%) for all 18 tumors. For (18)F-FMISO PET the T/M ratio ranged from 0.70 to 2.38 (median 1.13). Analyzing the virtual voxel histograms tumors could be categorized in three groups: Well oxygenated tumors with no hypoxia and concordance between the (18)F-FMISO data and the Eppendorf measurements, hypoxic tumors likewise with concordance between the two assays and inconclusive tumors with no concordance between the assays.This study analyzed the relationship between (18)F-FMISO PET and Eppendorf pO(2) electrode measurements by use of a virtual voxel model. There was a spectrum of hypoxia among tumors that can be detected by both assays. However no correlation was observed, and in general tumors were more hypoxic based on Eppendorf pO(2) measurements as compared to (18)F-FMISO PET.

Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

The standard compartment model (CM) is widely used to analyze dynamic PET data. The CM is fitted to time-activity curves to estimate rate constants that describe the transport of tracer between well-mixed compartments. The aim of this study was to develop and validate a more realistic microvascular compartment model (MCM) that includes capillary tracer concentration gradients, backflux from cells into the perfused capillaries, and multiple re-uptakes during the passage through a capillary. The MCM incorporates only parameters with clear physiological meaning, it is easy to implement and it does not require numerical solution. We compared the MCM and CM for the analysis of 3-min dynamic PET data of pig livers (N=5) following injection of 11C-methylglucose. During PET scans, the tracer concentrations in blood were measured in the hepatic artery, portal vein, and liver vein by manual sampling. We found that the MCM outperformed the CM and that dynamic PET data include information, which cannot be extracted using standard CM. The MCM fitted dynamic PET data better than CM (Akaike values were 46 ± 4 for best MCM fits, and 82 ± 8 for best CM fits; mean ± standard deviation) and extracted physiologically reasonable parameter estimates such as blood perfusion that were in agreement with independent measurements. The difference between model-independent perfusion estimates and the best MCM perfusion estimates was -0.01 ± 0.05 mL/mL/min, whereas the difference was 0.30 ± 0.13 mL/mL/min using CM. In addition, the MCM predicted the time course of concentrations in the liver vein, a prediction fundamentally unobtainable using the CM as it does not return tracer backflux from cells to capillary blood. The results demonstrate the benefit of using models that include more physiology and that models including concentration gradients should be preferred when analyzing the blood-cell exchange of any tracer in any capillary bed.

The purpose of the present study was to define the elimination kinetics of phenazone (NFN) in the isolated perfused pig liver. In five experiments phenazone was administered as constant infusion to obtain steady-state periods over a wide range of concentrations. The elimination of phenazone followed saturation kinetics (concentrations 0.1–12 μmol × 1-1) and the maximal elimination rate (Vmax) was on average 102 μmol × min.-1 × kg-1 liver and the Michaelis-constant (Km) of 2.6 mmol × 1-1. Estimates of Vmax and Km for the microsomal phenazone hydroxylase activity measured in liver biopsies were found to be considerably lower than in the perfused liver. The hepatic elimination of phenazone during perfusion of pig liver at phenazone concentrations corresponding to human therapeutic doses follows first-order kinetics.

To address the question of whether increased ethanol elimination in alcoholics can be ascribed to increased metabolism via alcohol dehydrogenase (ADH; K(m) around 0.2 mM) or the microsomal ethanol-oxidizing system (MEOS; K(m) 10 mM) by kinetic analysis of hepatic ethanol elimination in recently drinking patients with alcoholic cirrhosis and healthy subjects. A further objective was to investigate whether systemic clearance of ethanol at low arterial ethanol concentrations can be used as a measure of hepatic blood flow.Six patients with alcoholic cirrhosis were enrolled after 2 days of abstinence, along with 6 healthy subjects. Ethanol was administered as 6 successive infusions in increasing doses. Arterial and hepatic venous blood concentrations of ethanol were measured; hepatic blood flow was measured simultaneously. Kinetic parameters were calculated according to the sinusoidal perfusion model of enzymatic elimination by the intact liver.Mean hepatic K(m) for ethanol was 0.16 mM (range 0.09-0.36) in healthy subjects and 0.36 mM (range 0.16-0.69) in patients with cirrhosis (p0.3), both compatible with the K(m) for ADH. The two groups of subjects had similar V(max) values (p0.3). Extrahepatic elimination of ethanol accounted for more than 50% of total elimination in both groups, which precludes the use of systemic clearance as a measure of hepatic blood flow.The results support the hypothesis that ADH remains the main pathway for hepatic elimination of ethanol in recently drinking patients with alcoholic cirrhosis. We interpret this as evidence against a significant contribution of MEOS in vivo.

Liver blood flow (Q) is often measured by constant infusion of ICG (i), concentration measurements in an artery (A) and a hepatic vein (V): Q = (A-V)/A. Some authors use ICG clearance, Cl = i/A, as a measure of Q assuming complete hepatic extraction. During the infusion, the ICG concentration often increases. The importance of this for calculated values of Q and Cl was examined, and the use of Cl as a measure of Q was reevaluated. ICG was given as 0.06-0.20 mumol/min to 52 subjects with liver disease, and about 0.20 mumol/min to 86 subjects with no liver disease. ICG concentration increased steeply during the first 90 min after start of the infusion; thereafter the increment was constant as evaluated in successive 40-min periods in eleven 320-min studies (analysis of variance P greater than 0.5); on average, 6 +/- 1% per hour (+/- SD). Q was not time-dependent (P greater than 0.5). ICG clearance decreased significantly, on average 5 +/- 2% per hour (+/- SD). Hepatic extraction fraction, (A-V)/A, (measurement period 90-130 min) was 0.34 +/- 0.21 in liver patients (+/- SD) and 0.61 +/- 0.80 in controls. Cl and Q were positively correlated in both groups but with substantial scatter. Thus, not only is the calculated ICG clearance time-dependent but the extraction fraction is further so low and variable, that any use of ICG clearance as a measure of liver flow is not justified.

Udgivelsesdato: 2009-Mar In patients with hepatic encephalopathy (HE) the blood concentration of ammonia is usually highly elevated. Ammonia readily enters brain cells from the blood, and toxic effects of ammonia on brain metabolism and neurotransmission are believed to play a key role in the pathogenesis of HE. It has, however, been a matter of great controversy whether backflux of unmetabolized ammonia (NH(3) + NH(4) (+)) from brain cells to the blood occurs in man. In the present analysis of data from a dynamic PET study of brain (13)N-ammonia metabolism in healthy subjects and cirrhotic patients with and without HE, we provide the first unambiguous evidence for backflux of ammonia from brain cells to the blood in man. The high temporal and spatial resolution of modern PET technology was employed to distinguish between unidirectional blood-brain transport of ammonia and subsequent metabolism of the ammonia in the brain. In all 16 subjects, clearance of the unidirectional transport of (13)N-ammonia from the blood to brain cells (K(1)) was higher than the metabolic clearance of (13)N-ammonia from the blood (K(met)=K(1) k(3)/(k(2)+k(3)). This can only be explained by backflux (k(2)) of ammonia from brain cells to the blood. In conclusion, backflux of ammonia from the brain to the blood does indeed occur in both healthy subjects and cirrhotic patients with and without hepatic encephalopathy.

The authors developed a transmission-dispersion model to estimate dispersion in blood sampling systems and to calculate dispersion-free input functions needed for kinetic analysis. Transport of molecules through catheters was considered in two parts: a central part with convective transmission of molecules and a stagnant layer that molecules may enter and leave. The authors measured dispersion caused by automatic and manual blood sampling using three PET tracers that distribute differently in blood (C15O, H215O, and 11C-methylglucose). For manual sampling, dispersion was negligible. For the automated sampling procedure, characteristic parameters were calibrated for each tracer, and subsequently used in calculating dispersion-free input functions following real bolus injections. This led to shapes of dispersion-free input functions Ci(t) that had sharper peaks than the measured Co(t), and the authors quantified the effect of correcting for dispersion before kinetic modeling. The transmission-dispersion model quantitatively takes apart effects of transmission and dispersion, it has transparent noise properties associated with each component, and it does not require deconvolution to calculate dispersion-free input functions. Once characteristic parameters are estimated, input functions can be corrected before applying kinetic models. This allows bias-free estimation of kinetic parameters such as blood flow.

BACKGROUND.: The benefit of a complementary fluorodeoxyglucose-positron emission tomography (FDG-PET) scan to standard workup for carcinoma of unknown primary (CUP) and metastatic neck lesions was prospectively studied. METHODS.: Sixty-seven patients underwent standardized diagnostic workup according to national guidelines including panendoscopies, multiple mucosal biopsies, and diagnostic CT/MRI scans. Median follow-up was 40 months (range, 2-65 months). RESULTS.: In 60 eligible patients, FDG-PET indicated a primary tumor or metastatic disease in 30 patients (50%). Additional investigations confirmed a primary tumor in 18 patients: hypopharynx in 5, oropharynx in 5, nasopharynx in 2, lung in 1, axilla in 1, bone in 1, rectum in 1, as well as multiple metastatic lesions from CUP in 2 patients. In retrospect, MRI was able to detect 1 of the PET-detected primaries, leading to an overall detection rate of PET of 29% in CUP. A therapeutic change of treatment was made in 25% as a consequence of FDG-PET. PET before panendoscopy demonstrated fewer false-positive pathological foci. CONCLUSION.: FDG-PET is a valuable tool in addition to conventional extensive workup in CUP and neck metastases. Consequently, FDG-PET is now recommended as an early diagnostic modality in the workup of these patients. (c) 2007 Wiley Periodicals, Inc. Head Neck, 2007.

Background and Aim: Colorectal cancer is a common cancer in the Nordic countries and 50% of the patients develop liver metastases. Liver resection may result in long term survival. Proper staging is therefore essential and CT is the standard imaging modality. We examined whether additional FDG-PET improves therapeutic management of patients with colorectal liver metastases. Patients and Methods: Fifty-four consecutive patients were enrolled. Each patient had a treatment plan made based on our standard evaluation. The patients then had a PET scan and the treatment plan was re-evaluated, taking these results into account. Results: In 76% of the cases, PET did not change the treatment plan due to complete concordance with CT. In another 19% of the cases, the plan was altered due to finding of more liver lesions by PET than by CT (four patients), fewer or no liver lesions (three patients), and extrahepatic lesions not visible on CT (three patients). In 5% of the cases, non-concordance between PET and CT did not change the therapeutic plan. Conclusion: Pre-treatment FDG-PET, used supplementary to CT, improved the treatment plan in one fifth of the patients with colorectal liver metastases.

It has been suggested that ammonia-induced enhancement of peripheral benzodiazepine receptors (PBRs) in the brain is involved in the development of hepatic encephalopathy (HE). This hypothesis is based on animal experiments and studies of post-mortem human brains using radiolabelled PK11195, a specific ligand for PBR, but to our knowledge has not been tested in living patients. The aim of the present study was to test this hypothesis by measuring the number of cerebral PBRs in specific brain regions in cirrhotic patients with an acute episode of clinically manifest HE and healthy subjects using dynamic 11C-PK11195 brain PET. Eight cirrhotic patients with an acute episode of clinically manifest HE (mean arterial ammonia 81 μmol/l) and five healthy subjects (22 μmol/l) underwent dynamic 11C-PK11195 and 15O-H2O PET, co-registered with MR images. Brain regions (putamen, cerebellum, cortex and thalamus) were delineated on co-registered 15O-H2 15O and MR images and copied to the dynamic 15O-H2O and 11C-PK11195 images. Regional cerebral blood flow (CBF) (15O-H2O scan) and the volume of distribution of PK11195 (11C-PK11195 scan) were calculated by kinetic analysis. There were regional differences in the CBF, with lowest values in the cortex and highest values in the putamen in both groups of subjects (p