Publications by authors named "Susanne Keiding"

91 Publications

The pathophysiology of Wilson's disease visualized: A human Cu PET study.

Hepatology 2021 Nov 13. Epub 2021 Nov 13.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background And Aims: 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 ( Cu) as a tracer. Furthermore, we assessed the diagnostic potential of the method.

Approach And Results: Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of 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 h. Blood Cu concentrations were measured in parallel. Hepatic copper retention and redistribution were evaluated by standardized uptake values (SUVs). At 90 min, hepatic SUVs were similar in the three groups. In contrast, at 20 h postinjection, the SUV in WD patients (mean ± SEM, 31 ± 4) was higher than in heterozygotes (24 ± 3) and controls (21 ± 4; p < 0.001). An SUV-ratio of hepatic Cu concentration at 20 and 1.5 h completely discriminated between 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 Cu was estimated to be slightly lower in patients with WD than in controls (p = 0.04).

Conclusions: Cu PET imaging enables visualization and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, and may assist the development of therapies, and accurate diagnosis.
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http://dx.doi.org/10.1002/hep.32238DOI Listing
November 2021

Hepatic bile acid transport increases in the postprandial state: A functional C-CSar PET/CT study in healthy humans.

JHEP Rep 2021 Jun 15;3(3):100288. Epub 2021 Apr 15.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background & Aims: It is not known how hepatic bile acids transport kinetics changes postprandially in the intact liver. We used positron emission tomography (PET)/computed tomography (CT) with the tracer [-methyl-C]cholylsarcosine (C-CSar), a synthetic sarcosine conjugate of cholic acid, to quantify fasting and postprandial hepatic bile acid transport kinetics in healthy human participants.

Methods: Six healthy human participants underwent dynamic liver C-CSar PET/CT (60 min) during fasting and from 15 min after ingestion of a standard liquid meal. Hepatobiliary secretion kinetics of C-CSar was calculated from PET data, blood samples (arterial and hepatic venous) and hepatic blood flow measured using indocyanine green infusion.

Results: In the postprandial state, hepatic blood perfusion increased on average by 30% ( <0.01), and the flow-independent hepatic intrinsic clearance of C-CSar from blood into bile increased by 17% from 1.82 (range, 1.59-2.05) to 2.13 (range, 1.75-2.50) ml blood/min/ml liver tissue ( = 0.042). The increased intrinsic clearance of C-CSar was not caused by changes in the basolateral clearance efficacy of C-CSar but rather by an upregulated apical transport, as shown by an increase in the rate constant for apical secretion of C-CSar from hepatocyte to bile from 0.40 (0.25-0.54) min to 0.67 (0.36-0.98) min ( = 0.03). This resulted in a 33% increase in the intrahepatic bile flow ( = 0.03).

Conclusions: The rate constant for the transport of bile acids from hepatocytes into biliary canaliculi and the bile flow increased significantly in the postprandial state. This reduced the mean C-CSar residence time in the hepatocytes.

Lay Summary: Bile acids are important for digestion of dietary lipids including vitamins. We examined how the secretion of bile acids by the liver into the intestines changes after a standard liquid meal. The transport of bile acids from liver cells into bile and bile flow was increased after the meal.
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http://dx.doi.org/10.1016/j.jhepr.2021.100288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165435PMC
June 2021

Reply to: "Obeticholic acid and hepatic bile acids: Excellent study faulty conclusion".

J Hepatol 2021 05 20;74(5):1268-1269. Epub 2021 Feb 20.

Division of Gastroenterology, Department of Medicine, University of California at San Diego, San Diego, CA, USA.

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http://dx.doi.org/10.1016/j.jhep.2021.02.014DOI Listing
May 2021

Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis.

J Hepatol 2021 01 25;74(1):58-65. Epub 2020 Jul 25.

Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

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-C]cholylsarcosine (C-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 C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of C-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 C-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 C-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.
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http://dx.doi.org/10.1016/j.jhep.2020.07.028DOI Listing
January 2021

Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [Cu]copper PET/CT.

EJNMMI Radiopharm Chem 2020 Jun 18;5(1):15. Epub 2020 Jun 18.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark.

Purpose: Copper is essential for enzymatic processes throughout the body. [Cu]copper (Cu) 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 Cu in healthy humans by both intravenous and oral administration.

Methods: Six healthy participants underwent PET/CT studies with intravenous or oral administration of Cu. 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, Cu 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, Cu 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 Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of Cu 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.

Conclusion: Cu 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, Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq Cu 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.
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http://dx.doi.org/10.1186/s41181-020-00100-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303253PMC
June 2020

[ F]-Fluoro-2-deoxy-D-galactose positron emission tomography/computed tomography as complementary imaging tool in patients with hepatocellular carcinoma.

Liver Int 2020 02 25;40(2):447-455. Epub 2019 Nov 25.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark.

Background & Aims: Positron emission tomography (PET) with the liver-specific tracer [ F]-fluoro-2-deoxy-D-galactose ( F-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 F-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 [ F]-fluoro-2-deoxy-D-glucose ( F-FDG) PET/CT for comparison.

Results: F-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 F-FDG PET/CT. A total of 85 malignant intrahepatic foci were examined, 12 of these were new findings by F-FDGal PET/CT which had a sensitivity of 71%, highest for large foci. None of the additional intrahepatic foci found by F-FDGal PET changed the planned treatment.

Conclusions: For the detection of extrahepatic HCC metastases, F-FDGal PET/CT was superior both to standard clinical work-up with contrast-enhanced CT, and/or MRI, and to F-FDG PET/CT in patients deemed suitable for locoregional treatment. F-FDGal PET/CT led to a change in the planned treatment in 10% of the patients whereas F-FDG PET/CT did not change the planned treatment in any patient.
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http://dx.doi.org/10.1111/liv.14293DOI Listing
February 2020

Prognostic modeling for patients with colorectal liver metastases incorporating FDG PET radiomic features.

Eur J Radiol 2019 Apr 8;113:101-109. Epub 2019 Feb 8.

Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1016/j.ejrad.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507885PMC
April 2019

β-Blockers Improve Presinusoidal Portal Hypertension.

Dig Dis Sci 2018 11 12;63(11):3153-3157. Epub 2018 Jul 12.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99; C116, 8000, Aarhus, Denmark.

Background: Presinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas β-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown.

Aims: To evaluate the hemodynamic effect of β-blockers in non-cirrhotic patients with presinusoidal portal hypertension.

Methods: We measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off β-blocker treatment (random sequence).

Results: The β-blockers reduced the gradient from a mean off-treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%).

Conclusions: β-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic β-blockage in patients with presinusoidal portal hypertension.
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http://dx.doi.org/10.1007/s10620-018-5186-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182445PMC
November 2018

N-(4-[F]fluorobenzyl)cholylglycine, a novel tracer for PET of enterohepatic circulation of bile acids: Radiosynthesis and proof-of-concept studies in rats.

Nucl Med Biol 2018 06 4;61:56-62. Epub 2018 May 4.

Centre for Advanced Imaging, University of Queensland, St. Lucia, Brisbane, Australia.

Introduction: 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-[F]fluorobenzyl)cholylglycine ([F]FBCGly), a novel fluorine-18 labeled derivative of endogenous cholylglycine, would be a suitable tracer for PET of the EHC of conjugated bile acids, and we report here a radiosynthesis of [F]FBCGly and a proof-of-concept study by PET/MR in rats.

Methods: A radiosynthesis of [F]FBCGly was developed based on reductive alkylation of glycine with 4-[F]fluorobenzaldehyde followed by coupling to cholic acid. [F]FBCGly was investigated in vivo by dynamic PET/MR in anesthetized rats; untreated or treated with cholyltaurine or rifampicin. Possible in vivo metabolites of [F]FBCGly were investigated by analysis of blood and bile samples, and the stability of [F]FBCGly towards enzymatic de-conjugation by Cholylglycine Hydrolase was tested in vitro.

Results: [F]FBCGly was produced with a radiochemical purity of 96% ± 1% and a non-decay corrected radiochemical yield of 1.0% ± 0.3% (mean ± SD; n = 12). PET/MR studies showed that i.v.-administrated [F]FBCGly underwent EHC within 40-60 min with a rapid transhepatic transport from blood to bile. In untreated rats, the radioactivity concentration of [F]FBCGly was approximately 15 times higher in bile than in liver tissue. Cholyltaurine and rifampicin inhibited the biliary secretion of [F]FBCGly. No fluorine-18 metabolites of [F]FBCGly were observed.

Conclusion: We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [F]FBCGly, and shown by PET/MR that [F]FBCGly undergoes continuous EHC in rats without metabolizing. This novel tracer may prove useful in PET studies on the effect of drugs or diseases on the EHC of conjugated bile acids.
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http://dx.doi.org/10.1016/j.nucmedbio.2018.04.004DOI Listing
June 2018

Quantitative PET of liver functions.

Am J Nucl Med Mol Imaging 2018 25;8(2):73-85. Epub 2018 Apr 25.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital Aarhus, Denmark.

Improved understanding of liver physiology and pathophysiology is urgently needed to assist the choice of new and upcoming therapeutic modalities for patients with liver diseases. In this review, we focus on functional PET of the liver: 1) Dynamic PET with 2-deoxy-2-[F]fluoro--galactose (F-FDGal) provides quantitative images of the hepatic metabolic clearance (mL blood/min/mL liver tissue) of regional and whole-liver hepatic metabolic function. Standard-uptake-value () from a static liver F-FDGal PET/CT scan can replace and is currently used clinically. 2) Dynamic liver PET/CT in humans with C-palmitate and with the conjugated bile acid tracer [-methyl-C]cholylsarcosine (C-CSar) can distinguish between individual intrahepatic transport steps in hepatic lipid metabolism and in hepatic transport of bile acid from blood to bile, respectively, showing diagnostic potential for individual patients. 3) Standard compartment analysis of dynamic PET data can lead to physiological inconsistencies, such as a unidirectional hepatic clearance of tracer from blood (; mL blood/min/mL liver tissue) greater than the hepatic blood perfusion. We developed a new microvascular compartment model with more physiology, by including tracer uptake into the hepatocytes from the blood flowing through the sinusoids, backflux from hepatocytes into the sinusoidal blood, and re-uptake along the sinusoidal path. Dynamic PET data include information on liver physiology which cannot be extracted using a standard compartment model. , of non-invasive static PET with F-FDGal provides a clinically useful measurement of regional and whole-liver hepatic metabolic function. Secondly, assessment of individual intrahepatic transport steps is a notable feature of dynamic liver PET.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944823PMC
April 2018

Functional assessment of hepatobiliary secretion by C-cholylsarcosine positron emission tomography.

Biochim Biophys Acta Mol Basis Dis 2018 04 2;1864(4 Pt B):1240-1244. Epub 2017 Dec 2.

Department of Hepatology & Gastroenterology, Aarhus University Hospital, Denmark. Electronic address:

Positron emission tomography (PET) with C-cholylsarcosine (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.
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http://dx.doi.org/10.1016/j.bbadis.2017.11.016DOI Listing
April 2018

A microvascular compartment model validated using C-methylglucose liver PET in pigs.

Phys Med Biol 2017 12 29;63(1):015032. Epub 2017 Dec 29.

Department of Nuclear Medicine & PET Center, Aarhus University Hospital, 8000 Aarhus, Denmark. Author to whom any correspondence should be addressed.

The standard compartment model (CM) is widely used to analyse dynamic PET data. The CM is fitted to time-activity curves to estimate rate constants that describe the transport of a 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 C-methylglucose. During PET scans, the tracer concentrations in blood were measured in the abdominal aorta, 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 the 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 the 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 analysing the blood-cell exchange of any tracer in any capillary bed.
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http://dx.doi.org/10.1088/1361-6560/aa9475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968454PMC
December 2017

Hepatic metabolism of C-methionine and secretion of C-protein measured by PET in pigs.

Am J Nucl Med Mol Imaging 2017 1;7(4):167-173. Epub 2017 Sep 1.

Department of Nuclear Medicine and PET Centre, Aarhus University HospitalAarhus, Denmark.

Hepatic amino acid metabolism and protein secretion are essential liver functions that may be altered during metabolic stress, e.g. after surgery. We wished to develop a dynamic liver PET method using the radiolabeled amino acid C-methionine to examine this question. Eleven 40-kg pigs were allocated to either laparotomy or pneumoperitoneum. 24 hours after surgery a 70-min dynamic PET scanning of the liver with arterial blood sampling was performed immediately after intravenous injection of C-methionine. Time course of arterial plasma C-methionine concentration was used as input function and that of liver tissue C-concentration as output function in an extended Patlak analysis that accounted for irreversible metabolism of C-methionine (hepatic systemic metabolic clearance ) and secretion of C-protein + C-metabolites into blood (rate constant ). Appearance of C-proteins in arterial plasma was measured during the experiment. There were no statistically significant differences between the laparotomy group and the pneumoperitoneum group in any of the calculated parameters. Average mean hepatic systemic metabolic clearance was 0.212 mL plasma/mL liver tissue/min, secretion rate constant from liver to blood 0.0054 min, flux of methionine 3.59 μmol methionine/mL liver tissue/min, and the appearance rate of C-proteins in plasma 0.048 kBq/mL plasma/min. There was significant correlation between and . In conclusion, the hepatic systemic metabolic clearance of C-methionine was significantly correlated to the appearance rate of C-proteins in plasma. It would be interesting to translate the present method to human studies for the development of a clinical quantitative test of hepatic protein secretion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596319PMC
September 2017

Metabolic liver function in humans measured by 2-F-fluoro-2-deoxy-D-galactose PET/CT-reproducibility and clinical potential.

EJNMMI Res 2017 Aug 29;7(1):71. Epub 2017 Aug 29.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark.

Background: PET/CT with the radioactively labelled galactose analogue 2-F-fluoro-2-deoxy-D-galactose (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 F-FDGal from static scans can substitute the hepatic systemic clearance of F-FDGal (K , 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 F-FDGal PET/CT scans within a median interval of 15 days for determination of day-to-day variation. The correlation between K and SUV was examined using scan data and measured arterial blood concentrations of F-FDGal (blood samples) from 14 subjects from previous studies. Regional and whole-liver values of K 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 or SUV. SUV had higher intraclass correlation coefficients than K (0.92-0.97 vs. 0.49-0.78). The relationship between K 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 F-FDGal PET/CT was good and SUV can substitute K for quantification of hepatic metabolic function. Total SUV of F-FDGal is a promising tool for quantification of metabolic liver function in pre-treatment evaluation of individual patients.
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http://dx.doi.org/10.1186/s13550-017-0320-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574826PMC
August 2017

Hepatobiliary transport kinetics of the conjugated bile acid tracer C-CSar quantified in healthy humans and patients by positron emission tomography.

J Hepatol 2017 08 27;67(2):321-327. Epub 2017 Feb 27.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

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-C]cholylsarcosine (C-CSar) and positron emission tomography (PET).

Methods: Nine healthy participants and eight patients with varying degrees of cholestasis were examined with C-CSar PET and measurement of arterial and hepatic venous blood concentrations of C-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 C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min, 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 C-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 C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min 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 (C-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).
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http://dx.doi.org/10.1016/j.jhep.2017.02.023DOI Listing
August 2017

2-[(18)F]fluoro-2-deoxy-D-galactose PET/CT of hepatocellular carcinoma is not improved by co-administration of galactose.

Nucl Med Biol 2016 09 28;43(9):577-580. Epub 2016 Jun 28.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1016/j.nucmedbio.2016.06.002DOI Listing
September 2016

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

J Nucl Med 2016 06 10;57(6):961-6. Epub 2016 Mar 10.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Unlabelled: 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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http://dx.doi.org/10.2967/jnumed.115.171579DOI Listing
June 2016

Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs.

J Clin Transl Endocrinol 2015 Dec 25;2(4):131-136. Epub 2015 Sep 25.

Departments of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark.

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-H] 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 < 0.05), while this effect was abolished in DN pigs. While insulin action (P = 0.09) and glucose utilization (P = 0.44) were similar, EGP was markedly decreased in the DN pigs (P < 0.05).

Conclusion: The findings indicate a blunted hepatic counterregulatory response to hypoglycemia following complete hepatic denervation. This implies that intact neural impulses to and from the liver are necessary to maintain the increase in EGP that protects the organism against hypoglycemia.
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http://dx.doi.org/10.1016/j.jcte.2015.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685012PMC
December 2015

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

Authors:
Susanne Keiding

J Nucl Med 2015 Sep 9;56(9):1302-3. Epub 2015 Jul 9.

Department of Hepatology/Gastroenterology and PET Centre, Aarhus University Hospital, Aarhus, Denmark

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http://dx.doi.org/10.2967/jnumed.115.161422DOI Listing
September 2015

Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.

Scand J Gastroenterol 2015 Jun;50(6):797-808

Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital , Oslo , Norway.

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).
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http://dx.doi.org/10.3109/00365521.2015.1036359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487534PMC
June 2015

Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans.

Front Neurosci 2014 3;8:353. Epub 2014 Nov 3.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital Aarhus, Denmark ; Center of Functionally Integrative Neuroscience, Aarhus University Aarhus, Denmark ; Brain Research and Integrative Neuroscience Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark.

In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [(11)C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [(11)C]acetate. No significant differences of the rate constant of oxidation of [(11)C]acetate (k 3) were found among the three groups of subjects. The net metabolic clearance of [(11)C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P < 0.05), which we interpret to be an effect of reduced cerebral blood flow rather than a reflection of low [(11)C]acetate metabolism. We conclude that the characteristic decline of whole-brain oxidative metabolism in patients with cirrhosis with HE is not due to malfunction of oxidative metabolism in astrocytes. Thus, the observed decline of brain oxidative metabolism implicates changes of neurons and their energy turnover in patients with HE.
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http://dx.doi.org/10.3389/fnins.2014.00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217371PMC
November 2014

Biodistribution and PET imaging of a novel [68Ga]-anti-CD163-antibody conjugate in rats with collagen-induced arthritis and in controls.

Mol Imaging Biol 2015 Feb;17(1):87-93

Department of Biomedicine, Aarhus University, Ole Worms Alle 3, Blng 1170, 8000, Aarhus, Denmark.

Purpose: The hemoglobin scavenger receptor CD163 is exclusively expressed on monocytes and tissue macrophages, also at sites of inflammation. We examined whether gallium-68 (Ga-68)-labeled anti-CD163-antibody can detect the receptor in vivo.

Procedures: We radiolabeled anti-CD163 antibody with Ga-68 and evaluated stability and binding specificity of the conjugate ([(68)Ga]ED2) in vitro. Furthermore, tracer biodistribution was assessed in vivo in healthy rats and rats with acute collagen-induced arthritis (CIA) by MicroPET and tissue analysis.

Results: Radiosynthesis of [(68)Ga]ED2 antibody yielded a tracer with high-specific activity and radiochemical purity. [(68)Ga]ED2 bound specifically to CD163 in vitro. In rats, [(68)Ga]ED2 rapidly accumulated in macrophage-rich tissues. The arthritic paws exhibited a low but significant [(68)Ga]ED2 uptake. Interestingly, the systemic distribution was also changed in the sense that a significantly higher liver uptake and lower spleen uptake of [(68)Ga]ED2 was measured in CIA rats that accordingly showed a corresponding change in level of CD163 expression.

Conclusions: [(68)Ga]ED2 specifically binds CD163 in vitro and in vivo. Biodistribution studies in CIA rats suggest that this novel tool may have applications in studies of inflammatory diseases.
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http://dx.doi.org/10.1007/s11307-014-0768-6DOI Listing
February 2015

The lumped constant for the galactose analog 2-18F-fluoro-2-deoxy-D-galactose is increased in patients with parenchymal liver disease.

J Nucl Med 2014 Apr 3;55(4):590-4. Epub 2014 Mar 3.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.

Unlabelled: 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 ¹⁸F-FDGal (V*(max/K*(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 ¹⁸F-FDGal was calculated as (V*(max)/K*(m))/(V(max)/K(m)). On a second day, a dynamic ¹⁸-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 ¹⁸F-FDGal (K*(+gal) from linear analysis of data (Gjedde-Patlak method). The maximum hepatic removal rate of galactose was estimated from ¹⁸F-FDGal PET data (V(max)(PET)) 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 of healthy subjects, K(m) did not differ (P = 0.77), whereas both V(max) and V(max)/K(m) were significantly lower in patients (both P < 0.01). Mean LC for ¹⁸LF-FDGal was 0.24, which was significantly higher than the mean LC of 0.13 in healthy subjects (P < 0.0001). Mean K*(+gal) 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 = 0.85). Mean hepatic V(max)(PET) 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.
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http://dx.doi.org/10.2967/jnumed.113.125559DOI Listing
April 2014

Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats.

J Cereb Blood Flow Metab 2014 Mar 18;34(3):460-6. Epub 2013 Dec 18.

1] Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark [2] Department of Hepatology and Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark.

Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH(4)(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH(4)(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH(4)(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.
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http://dx.doi.org/10.1038/jcbfm.2013.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948122PMC
March 2014

Propranolol treatment of portal hypertension in cirrhosis patients is better the higher the untreated pressure: a single-centre prospective experience.

Scand J Gastroenterol 2013 Aug 11;48(8):969-73. Epub 2013 Jun 11.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Objective: 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.

Material And Methods: 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 to <12 mm Hg and/or by >20%. The HVPG reduction was larger for higher native HVPG values (p < 0.001). There was no significant relation between changes in heart rate and changes in HVPG (p = 0.8).

Conclusions: 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.
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http://dx.doi.org/10.3109/00365521.2013.805811DOI Listing
August 2013

Brain metabolism in patients with hepatic encephalopathy studied by PET and MR.

Arch Biochem Biophys 2013 Aug 30;536(2):131-42. Epub 2013 May 30.

Department of Hepato-Gastroenterology, Aarhus University Hospital, 8000 Aarhus, Denmark.

We review PET- and MR studies on hepatic encephalopathy (HE) metabolism in human subjects from the point of views of methods, methodological assumptions and use in studies of cirrhotic patients with clinically overt HE, cirrhotic patients with minimal HE, cirrhotic patients with no history of HE and healthy subjects. Key results are: (1) Cerebral oxygen uptake and blood flow are reduced to 2/3 in cirrhotic patients with clinically overt HE but not in cirrhotic patients with minimal HE or no HE compared to healthy subjects. (2) Cerebral ammonia metabolism is enhanced due to increased blood ammonia in cirrhotic patients but the kinetics of cerebral ammonia uptake and metabolism is not affected by hyperammonemia. (3) Recent advantages in MR demonstrate low-grade cerebral oedema not only in astrocytes but also in the white matter in cirrhotic patients with HE.
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http://dx.doi.org/10.1016/j.abb.2013.05.006DOI Listing
August 2013

Brain alanine formation as an ammonia-scavenging pathway during hyperammonemia: effects of glutamine synthetase inhibition in rats and astrocyte-neuron co-cultures.

J Cereb Blood Flow Metab 2013 Aug 15;33(8):1235-41. Epub 2013 May 15.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of (15)NH4(+) in alanine during acute hyperammonemia. We observed a fourfold increased amount of (15)NH4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to (15)NH4Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of (15)NH4 into alanine together with increased (15)N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy.
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http://dx.doi.org/10.1038/jcbfm.2013.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734774PMC
August 2013

Role of branched chain amino acids in cerebral ammonia homeostasis related to hepatic encephalopathy.

Metab Brain Dis 2013 Jun 31;28(2):209-15. Epub 2013 Jan 31.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1007/s11011-013-9381-7DOI Listing
June 2013

Regional metabolic liver function measured in patients with cirrhosis by 2-[¹⁸F]fluoro-2-deoxy-D-galactose PET/CT.

J Hepatol 2013 Jun 20;58(6):1119-24. Epub 2013 Jan 20.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark.

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 (Ksyst, Lblood/min) and hepatic intrinsic clearance (Vmax/Km, Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma (Kmet, mL blood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of Kmet.

Results: Mean approximation of Ksyst to Vmax/Km was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean Kmet was 0.157 mL blood/mL liver tissue/min, which was lower than 0.274 mL blood/mL liver tissue/min, previously found in healthy subjects (p<0.001), in accordance with decreased metabolic function in cirrhotic livers. Mean CoV for Kmet in liver tissue was 24.4% in patients and 14.4% in healthy subjects (p<0.0001). The degree of intrahepatic metabolic heterogeneity correlated positively with HVPG (p<0.05).

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.
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http://dx.doi.org/10.1016/j.jhep.2013.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660513PMC
June 2013
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