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Background This study examined the longitudinal changes in metabolic liver function and MR-morphological dilatation of intrahepatic bile ducts in patients with stereotactic body radiation therapy (SBRT) for liver metastases. Methods This retrospective study included 64 patients with SBRT of 84 liver metastases between February 2005 and January 2019. To evaluate hepatobiliary toxicity, the laboratory parameters albumin, alanine-transaminase (ALAT), aspartate-transaminase (ASAT), bilirubin and gamma-glutamyltransferase (GGT) and the qualitative dilatation of MR-morphological peritumoural, intrahepatic bile ducts were analyzed from pre- up to 12 months post-SBRT. Results The liver metastases were irradiated with a median D50 to the GTV of BED α/β=10 Gy = 134 Gy (range 51–219 Gy) resulting in a median mean dose D mean -L-EQD2 α/β=3 Gy = 11.8 Gy (range 0.4–65.6 Gy) to the total liver. The central hepatobiliary tract (cHBT) was exposed to a median D mean -cHBT-BED α/β=10 Gy = 8.3 Gy (range 0.1–81.6 Gy). Significant decreases in albumin and increases in GGT and bilirubin were observed up to 12 months post-SBRT. D mean -L-EQD2 α/β=3 Gy , D mean -cHBT-BED α/β=10 Gy and VBED α/β=10Gy 66Gy-cHBT and VBED α/β=10Gy 72Gy-cHBT were significant cofactors influencing the course of GGT, ASAT and bilirubin, but not for albumin and ALAT. MR-morphological, short- and long-term dilatation of peritumoural bile ducts were associated with significant higher VBED α/β=10Gy 66Gy-cHBT and VBED α/β=10Gy 72Gy-cHBT values and were significantly more frequent for SBRT of target volumes with < 3 cm distance to the cHBT. Conclusion SBRT of liver metastases was associated with minor alterations in metabolic liver function. High dose exposure and proximity of the liver metastases to the cHBT may lead to locoregional bile duct dilatation after SBRT. Further evaluation of metabolic and MR-morphological changes in liver function is recommended in personalised oncological treatment approaches for liver-directed therapies.

Background The effect of different locoregional treatments for hepatocellular carcinoma (HCC) on metabolic liver function is largely unknown. This information is crucial, particularly for patients with cirrhosis. We applied [ 18 F]-fluoro-2-deoxy- D -galactose ( 18 F-FDGal) positron emission tomography (PET) to determine the contribution of large HCCs to total metabolic liver function and the changes in metabolic liver function post-treatment. Results We included 29 patients with HCC treated with resection ( n  = 8), radiofrequency ablation (RFA) ( n  = 8), transarterial chemoembolization (TACE) ( n  = 9), and selective internal radiation therapy (SIRT) ( n  = 4). In patients with HCCs > 3 cm, the liver’s total metabolic activity was significantly higher when including the metabolically active tumor areas compared to when the tumor was excluded ( p  = 0.0002). The median percent change in mean metabolic activity in the liver after locoregional treatment was 5.1% in patients without cirrhosis as compared to -6.0% in patients with cirrhosis ( p  = 0.05). The distribution of cirrhosis ( n  = 15 in total) among treatment groups was uneven. After treatment, seven of eight patients who underwent resection showed increased or stable mean metabolic liver function, while responses for those treated with RFA, TACE, or SIRT were mixed. Changes in mean metabolic liver function and liver volume did not correlate. Conclusions HCCs > 3 cm contributed substantially to the liver’s galactose metabolism, suggesting that this would also apply to other substrates used for measuring metabolic liver function. Changes in metabolic capacity following treatment depend on cirrhosis status and type of treatment. Changes in functional liver volume do not necessarily reflect total metabolic capacity. The study underlines the power of imaging-based quantification of metabolic liver function.

Background Increasing incidence of non-alcoholic fatty liver disease (NAFLD) calls for improved understanding of how the disease affects metabolic liver function. Aims To investigate in vivo effects of different NAFLD stages on metabolic liver function, quantified as regional and total capacity for galactose metabolism in a NAFLD model. Methods Male Sprague Dawley rats were fed a high-fat, high-cholesterol diet for 1 or 12 weeks, modelling early or late NAFLD, respectively. Each NAFLD group (n = 8 each) had a control group on standard chow (n = 8 each). Metabolic liver function was assessed by 2-[ 18 F]fluoro‐2‐deoxy‐D-galactose positron emission tomography; regional galactose metabolism was assessed as standardised uptake value (SUV). Liver tissue was harvested for histology and fat quantification. Results Early NAFLD had median 18% fat by liver volume. Late NAFLD had median 32% fat and varying features of non-alcoholic steatohepatitis (NASH). Median SUV reflecting regional galactose metabolism was reduced in early NAFLD (9.8) and more so in late NAFLD (7.4; p = 0.02), both significantly lower than in controls (12.5). In early NAFLD, lower SUV was quantitatively explained by fat infiltration. In late NAFLD, the SUV decrease was beyond that attributable to fat; probably related to structural NASH features. Total capacity for galactose elimination was intact in both groups, which in late NAFLD was attained by increased fat-free liver mass to 21 g, versus 15 g in early NAFLD and controls (both p ≤ 0.002). Conclusion Regional metabolic liver function was compromised in NAFLD by fat infiltration and structural changes. Still, whole liver metabolic function was preserved in late NAFLD by a marked increase in the fat-free liver mass.

Purpose Stereotactic body radiotherapy (SBRT) is increasingly used for treatment of liver tumors but the effect on metabolic liver function in surrounding tissue is largely unknown. Using 2-deoxy-2-[ 18 F]fluoro- d -galactose ([ 18 F]FDGal) positron emission tomography (PET)/computed tomography (CT), we aimed to determine a dose–response relationship between radiation dose and metabolic liver function as well as recovery. Procedures. One male subject with intrahepatic cholangiocarcinoma and five subjects (1 female, 4 male) with liver metastases from colorectal cancer (mCRC) underwent [ 18 F]FDGal PET/CT before SBRT and after 1 and 3 months. The dose response was calculated using the data after 1 month and the relative recovery was evaluated after 3 months. All patients had normal liver function at time of inclusion. Results A linear dose–response relationship for the individual liver voxel dose was seen until approximately 30 Gy. By fitting a polynomial curve to data, a mean TD 50 of 18 Gy was determined with a 95% CI from 12 to 26 Gy. After 3 months, a substantial recovery was observed except in tissue receiving more than 25 Gy. Conclusions [ 18 F]FDGal PET/CT makes it possible to determine a dose–response relationship between radiation dose and metabolic liver function, here with a TD 50 of 18 Gy (95% CI 12–26 Gy). Moreover, the method makes it possible to estimate metabolic recovery in liver tissue.

Background Hepatic macrophage (Kupffer cell) hyperplasia is often described in Wilson’s disease (WD). In many liver diseases, Kupffer cell activation is related to disease severity, liver function, and fibrosis but the importance in WD is unknown. Kupffer cell activation can be assessed by the P-concentration of soluble (s)CD163, metabolic liver function by the galactose elimination capacity (GEC), and fibrosis by Fibroscan. We investigated the associations between sCD163, selected inflammatory cytokines, GEC, and liver fibrosis in Danish WD patients. Methods In a cross-sectional design, we studied 29 stable and well-treated patients (male/female15/14) with a median age of 35 years (IQR 24–50). P-sCD163 and cytokines were measured by ELISA. The GEC was measured by intra-venous galactose loading. Results The median P-sCD163 value at 2.96 mg/L (1.97–3.93) was high in the normal range (0.7–3.9) and seven patients (24%) had a value above the upper normal value. sCD163 correlated with TNF-α, IL-6 and IL-8 (rho> 0.50, p  < 0.005). A higher sCD163 value was closely associated with a lower GEC (rho = − 0.51, p  = 0.02). sCD163 was not related to the liver fibrosis indices. Conclusions Stable WD patients showed various degrees of Kupffer cell activation which was accompanied by loss of metabolic liver function. Neither activation nor liver function was related to liver fibrosis. The findings suggest that in WD inflammatory Kupffer cell activation may be involved in the loss of liver function over time. sCD163 may serve as a non-invasive biomarker of loss of liver function in WD, which the degree of fibrosis evidently may not. This study is registered at clinical trials with name: “sCD163 and sMR in Wilsons Disease - Associations With Disease Severity and Fibrosis”, NCT02702765. Date of registration: 26.02.16. Date of enrolment of the first participant to the trial: 17.03.16. ULR: https://clinicaltrials.gov/ct2/show/NCT02702765 .

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.

Metabolic liver function can be measured by dynamic PET/CT with the radio-labelled galactose-analogue 2-[(18)F]fluoro-2-deoxy-D-galactose ((18)F-FDGal) in terms of hepatic systemic clearance of (18)F-FDGal (K, ml blood/ml liver tissue/min). The method requires arterial blood sampling from a radial artery (arterial input function), and the aim of this study was to develop a method for extracting an image-derived, non-invasive input function from a volume of interest (VOI). Dynamic (18)F-FDGal PET/CT data from 16 subjects without liver disease (healthy subjects) and 16 patients with liver cirrhosis were included in the study. Five different input VOIs were tested: four in the abdominal aorta and one in the left ventricle of the heart. Arterial input function from manual blood sampling was available for all subjects. K*-values were calculated using time-activity curves (TACs) from each VOI as input and compared to the K-value calculated using arterial blood samples as input. Each input VOI was tested on PET data reconstructed with and without resolution modelling. All five image-derived input VOIs yielded K*-values that correlated significantly with K calculated using arterial blood samples. Furthermore, TACs from two different VOIs yielded K*-values that did not statistically deviate from K calculated using arterial blood samples. A semicircle drawn in the posterior part of the abdominal aorta was the only VOI that was successful for both healthy subjects and patients as well as for PET data reconstructed with and without resolution modelling. Metabolic liver function using (18)F-FDGal PET/CT can be measured without arterial blood samples by using input data from a semicircle VOI drawn in the posterior part of the abdominal aorta.

Dietary lipids favor the growth of the pathobiont Bilophila wadsworthia, but the relevance of this expansion in metabolic syndrome pathogenesis is poorly understood. Here, we showed that B. wadsworthia synergizes with high fat diet (HFD) to promote higher inflammation, intestinal barrier dysfunction and bile acid dysmetabolism, leading to higher glucose dysmetabolism and hepatic steatosis. Host-microbiota transcriptomics analysis reveal pathways, particularly butanoate metabolism, which may underlie the metabolic effects mediated by B. wadsworthia. Pharmacological suppression of B. wadsworthia-associated inflammation demonstrate the bacterium's intrinsic capacity to induce a negative impact on glycemic control and hepatic function. Administration of the probiotic Lactobacillus rhamnosus CNCM I-3690 limits B. wadsworthia-induced immune and metabolic impairment by limiting its expansion, reducing inflammation and reinforcing intestinal barrier. Our results suggest a new avenue for interventions against western diet-driven inflammatory and metabolic diseases.

The complex interplay between the gut microbiota, the intestinal barrier, the immune system and the liver is strongly influenced by environmental and genetic factors that can disrupt the homeostasis leading to disease. Among the modulable factors, diet has been identified as a key regulator of microbiota composition in patients with metabolic syndrome and related diseases, including the metabolic dysfunction-associated fatty liver disease (MAFLD). The altered microbiota disrupts the intestinal barrier at different levels inducing functional and structural changes at the mucus lining, the intercellular junctions on the epithelial layer, or at the recently characterized vascular barrier. Barrier disruption leads to an increased gut permeability to bacteria and derived products which challenge the immune system and promote inflammation. All these alterations contribute to the pathogenesis of MAFLD, and thus, therapeutic approaches targeting the gut-liver-axis are increasingly being explored. In addition, the specific changes induced in the intestinal flora may allow to characterize distinctive microbial signatures for non-invasive diagnosis, severity stratification and disease monitoring.

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.