Non-alcoholic fatty liver disease (NAFLD) has emerged as the hepatic component of the metabolic syndrome and now seemingly affects one-fourth of the world population. Features associated with NAFLD and the metabolic syndrome have frequently been linked to cognitive dysfunction, i.e. systemic inflammation, vascular dysfunction, and sleep apnoea. However, emerging evidence suggests that NAFLD may be a cause of cognitive dysfunction independent of these factors. NAFLD in addition exhibits dysbiosis of the gut microbiota and impaired urea cycle function, favouring systemic ammonia accumulation and further promotes systemic inflammation. Such disruption of the gut–liver–brain axis is essential in the pathogenesis of hepatic encephalopathy, the neuropsychiatric syndrome associated with progressive liver disease. Considering the growing burden of NAFLD, the morbidity from cognitive impairment is expected to have huge societal and economic impact. The present paper provides a review of the available evidence for cognitive dysfunction in NAFLD and outlines its possible mechanisms. Moreover, the clinical challenges of characterizing and diagnosing cognitive dysfunction in NAFLD are discussed.

Hepatocytes Blood 11 C-CSar 11 C-CSar in bile ducts OCA-induced increase over placebo 0% 10% 70% PET of hepatic 11 C-CSar kinetics 11 C-CSar 11 C-CSar in biliary canaliculi Hepatocytes Highlights A randomised, placebo-controlled, crossover PET study of 8 patients with PBC.OCA enhances secretion of conjugated bile acids from hepatocytes into biliary canaliculi.OCA increases hepatic blood perfusion and uptake clearance of conjugated bile acids.OCA reduces the time hepatocytes are exposed to potentially toxic bile acids.

Purpose: Copper is essential for enzymatic processes throughout the body. [ 64 Cu]copper (64 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 64 Cu in healthy humans by both intravenous and oral administration. Methods: Six healthy participants underwent PET/CT studies with intravenous or oral administration of 64 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, 64 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, 64 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 64 Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64 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 − 1. Conclusion: 64 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, 64 Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64 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.

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 (64Cu) 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 64Cu 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 64Cu 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 64Cu 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 64Cu was estimated to be slightly lower in patients with WD than in controls (p = 0.04). Conclusions 64Cu 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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Normal liver tissue is highly vulnerable towards irradiation, which remains a challenge in radiotherapy of hepatic tumours. Here, we examined the effects of radiation-induced liver injury on two specific liver functions and hepatocellular regeneration in a minipig model. five Göttingen minipigs were exposed to whole-liver stereotactic body radiation therapy (SBRT) in one fraction (14 Gy) and examined 4-5 weeks after; five pigs were used as controls. All pigs underwent in vivo positron emission tomography (PET) studies of the liver using the conjugated bile acid tracer [N-methyl-11 c] cholylsarcosine ([ 11 C]CSar) and the galactose-analogue tracer [ 18 F]fluoro-2-deoxy-d-galactose ([ 18 f] FDGal). Liver tissue samples were evaluated histopathologically and by immunohistochemical assessment of hepatocellular mitosis, proliferation and apoptosis. Compared with controls, both the rate constant for secretion of [ 11 c]cSar from hepatocytes into intrahepatic bile ducts as well as back into blood were doubled in irradiated pigs, which resulted in reduced residence time of [ 11 c]cSar inside the hepatocytes. Also, the hepatic systemic clearance of [ 18 F]FDGal in irradiated pigs was slightly increased, and hepatocellular regeneration was increased by a threefold. In conclusion, parenchymal injury and increased regeneration after whole-liver irradiation was associated with enhanced hepatobiliary secretion of bile acids. Whole-liver SBRT in minipigs ultimately represents a potential large animal model of radiation-induced liver injury and for testing of normal tissue protection methods. Positron emission tomography (PET) has shown great potential for evaluating liver-specific functions in vivo, both regionally and for the whole liver 1. Excretion of bile acids and galactose metabolism are such liver-specific functions 2,3 that can be quantified using computed positron emission tomography (PET/CT) with the radiolabelled conjugated bile acid [N-methyl-11 C]cholylsarcosine ([ 11 C]CSar) 4,5 and the galactose analogue [ 18 F]fluoro-2-deoxy-d-galactose ([ 18 F]FDGal) 6,7 , respectively. Before use in humans, novel PET/CT methods assessing liver functions are validated in large animal models such as the pig, with blood sampling from the portal vein and direct measurement of hepatic blood flow 8,9. Because of the limited number of large animal models of parenchymal liver injury and fibrosis 10-12 , PET tracers have so far only been tested in healthy pigs. Stereotactic body radiation therapy (SBRT) is increasingly being used to deliver high doses of radiation to hepatic malignancies with precision 13. The liver parenchyma, however, is sensitive to irradiation 14,15 , and high

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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 of the radiotracer. Methods: Six healthy participants underwent PET/CT studies with intravenous or oral administration of 64Cu. A 90 min dynamic PET 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 residual 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 64Cu clearance 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 affected by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration; 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 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.