Single Breath-Hold MR Elastography for Fast Biomechanical Probing of Pancreatic Stiffness.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) stromal disposition is thought to influence chemotherapy efficacy and increase tissue stiffness, which could be quantified noninvasively via MR elastography (MRE). Current methods cause position-based errors in pancreas location over time, hampering accuracy. It would be beneficial to have a single breath-hold acquisition. PURPOSE: To develop and test a single breath-hold three-dimensional MRE technique utilizing prospective undersampling and a compressed sensing reconstruction (CS-MRE). STUDY TYPE: Prospective. POPULATION: A total of 30 healthy volunteers (HV) (31 ± 9 years; 33% male) and five patients with PDAC (69 ± 5 years; 80% male). FIELD STRENGTH/SEQUENCE: 3-T, GRE Ristretto MRE. ASSESSMENT: First, optimization of multi breath-hold MRE was done in 10 HV using four combinations of vibration frequency, number of measured wave-phase offsets, and TE and looking at MRE quality measures in the pancreas head. Second, viscoelastic parameters delineated in the pancreas head or tumor of CS-MRE were compared against (I) 2D and (II) 3D four breath-hold acquisitions in HV (N = 20) and PDAC patients. Intrasession repeatability was assessed for CS-MRE in a subgroup of healthy volunteers (N = 15). STATISTICAL TESTS: Tests include repeated measures analysis of variance (ANOVA), Bland-Altman analysis, and coefficients of variation (CoVs). A P-value <.05 was considered statistically significant. RESULTS: Optimization of the four breath-hold acquisitions resulted in 40 Hz vibration frequency, five wave-phases, and echo time (TE) = 6.9 msec as the preferred method (4BH-MRE). CS-MRE quantitative results did not differ from 4BH-MRE. Shear wave speed (SWS) and phase angle differed significantly between HV and PDAC patients using 4BH-MRE or CS-MRE. The limits of agreement for SWS were [-0.09, 0.10] m/second and the within-subject CoV was 4.8% for CS-MRE. DATA CONCLUSION: CS-MRE might allow a single breath-hold MRE acquisition with comparable SWS and phase angle as 4BH-MRE, and it may still enable to differentiate between HV and PDAC. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2.

MR Elastography of the Pancreas: Bowel Preparation and Repeatability Assessment in Pancreatic Cancer Patients and Healthy Controls.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) stromal viscoelasticity can be measured using MR elastography (MRE). Bowel preparation regimens could affect MRE quality and knowledge on repeatability is crucial for clinical implementation. PURPOSE: To assess effects of four bowel preparation regimens on MRE quality and to evaluate repeatability and differentiate patients from healthy controls. STUDY TYPE: Prospective. POPULATION: 15 controls (41 ± 16 years; 47% female), 16 PDAC patients (one excluded, 66 ± 12 years; 40% female) with 15 age-/sex-matched controls (65 ± 11 years; 40% female). Final sample size was 25 controls and 15 PDAC. FIELD STRENGTH/SEQUENCE: 3-T, spin-echo echo-planar-imaging, turbo spin-echo, and fast field echo gradient-echo. ASSESSMENT: Four different regimens were used: fasting; scopolaminebutyl; drinking 0.5 L water; combination of 0.5 L water and scopolaminebutyl. MRE signal-to-noise ratio (SNR) was compared between all regimens. MRE repeatability (test-retest) and differences in shear wave speed (SWS) and phase angle (ϕ) were assessed in PDAC and controls. Regions-of-interest were defined for tumor, nontumorous (n = 8) tissue in PDAC, and whole pancreas in controls. Two radiologists delineated tumors twice for evaluation of intraobserver and interobserver variability. STATISTICAL TESTS: Repeated measures analysis of variance, coefficients of variation (CoVs), Bland-Altman analysis, (un)paired t-test, Mann-Whitney U-test, and Wilcoxon signed-rank test. P-value<0.05 was considered statistically significant. RESULTS: Preparation regimens did not significantly influence MRE-SNR. Therefore, the least burdensome preparation (fasting only) was continued. CoVs for tumor SWS were: intrasession (12.8%) and intersession (21.7%), and intraobserver (7.9%) and interobserver (10.3%) comparisons. For controls, CoVs were intrasession (4.6%) and intersession (6.4%). Average SWS for tumor, nontumor, and healthy tissue were: 1.74 ± 0.58, 1.38 ± 0.27, and 1.18 ± 0.16 m/sec (ϕ: 1.02 ± 0.17, 0.91 ± 0.07, and 0.85 ± 0.08 rad), respectively. Significant differences were found between all groups, except for ϕ between healthy-nontumor (P = 0.094). DATA CONCLUSION: The proposed bowel preparation regimens may not influence MRE quality. MRE may be able to differentiate between healthy tissue-tumor and tumor-nontumor. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Marked difference in liver fat measured by histology vs. magnetic resonance-proton density fat fraction: A meta-analysis.

Background & Aims: Pathologists quantify liver steatosis as the fraction of lipid droplet-containing hepatocytes out of all hepatocytes, whereas the magnetic resonance-determined proton density fat fraction (PDFF) reflects the tissue triacylglycerol concentration. We investigated the linearity, agreement, and correspondence thresholds between histological steatosis and PDFF across the full clinical spectrum of liver fat content associated with non-alcoholic fatty liver disease. Methods: Using individual patient-level measurements, we conducted a systematic review and meta-analysis of studies comparing histological steatosis with PDFF determined by magnetic resonance spectroscopy or imaging in adults with suspected non-alcoholic fatty liver disease. Linearity was assessed by meta-analysis of correlation coefficients and by linear mixed modelling of pooled data, agreement by Bland-Altman analysis, and thresholds by receiver operating characteristic analysis. To explain observed differences between the methods, we used RNA-seq to determine the fraction of hepatocytes in human liver biopsies. Results: Eligible studies numbered 9 (N = 597). The relationship between PDFF and histology was predominantly linear (r = 0.85 [95% CI, 0.80-0.89]), and their values approximately coincided at 5% steatosis. Above 5% and towards higher levels of steatosis, absolute values of the methods diverged markedly, with histology exceeding PDFF by up to 3.4-fold. On average, 100% histological steatosis corresponded to a PDFF of 33.0% (29.5-36.7%). Targeting at a specificity of 90%, optimal PDFF thresholds to predict histological steatosis grades were ≥5.75% for ≥S1, ≥15.50% for ≥S2, and ≥21.35% for S3. Hepatocytes comprised 58 ± 5% of liver cells, which may partly explain the lower values of PDFF vs. histology. Conclusions: Histological steatosis and PDFF have non-perfect linearity and fundamentally different scales of measurement. Liver fat values obtained using these methods may be rendered comparable by conversion equations or threshold values. Impact and implications: Magnetic resonance-proton density fat fraction (PDFF) is increasingly being used to measure liver fat in place of the invasive liver biopsy. Understanding the relationship between PDFF and histological steatosis fraction is important for preventing misjudgement of clinical status or treatment effects in patient care. Our analysis revealed that histological steatosis fraction is often significantly higher than PDFF, and their association varies across the spectrum of fatty liver severity. These findings are particularly important for physicians and clinical researchers, who may use these data to interpret PDFF measurements in the context of histologically evaluated liver fat content.

Imaging in interventional oncology, the better you see, the better you treat.

Imaging and image processing is the fundamental pillar of interventional oncology in which diagnostic, procedure planning, treatment and follow-up are sustained. Knowing all the possibilities that the different image modalities can offer is capital to select the most appropriate and accurate guidance for interventional procedures. Despite there is a wide variability in physicians preferences and availability of the different image modalities to guide interventional procedures, it is important to recognize the advantages and limitations for each of them. In this review, we aim to provide an overview of the most frequently used image guidance modalities for interventional procedures and its typical and future applications including angiography, computed tomography (CT) and spectral CT, magnetic resonance imaging, Ultrasound and the use of hybrid systems. Finally, we resume the possible role of artificial intelligence related to image in patient selection, treatment and follow-up.

Viscoelastic properties of small bowel mesentery at MR elastography in Crohn's disease: a prospective cross-sectional exploratory study.

BACKGROUND: Creeping fat is a pathological feature of small bowel Crohn's disease (CD), with literature suggesting that bowel resection with extended mesenteric resection is related to less postoperative recurrences. Conventional imaging is unable to accurately quantify the disease involvement (i.e., fibrosis) of creeping fat. Quantification of disease involvement could be useful in decision-making for additional extended mesenteric resection. We investigated the feasibility of magnetic resonance elastography (MRE) of the mesentery and if MRE is capable to detect fibrotic disease involvement of mesentery in active CD. METHODS: Multifrequency MRE yielded spatial stiffness (shear wave speed, SWS, |G*|) and fluidity maps (φ). Viscoelastic properties of seven CD patients' mesentery were compared to age- and sex-matched healthy volunteers (HV) (Mann-Whitney U-test). Within CD patients, the affected and "presumably" unaffected mesentery were compared (Wilcoxon-signed rank test). Repeatability was tested in 15 HVs (Bland-Altman analysis, coefficient of variation [CoV]). Spearman rank correlations were used to investigate the relation between microscopically scored amount of mesenteric fibrosis and viscoelastic parameters. RESULTS: SWS, |G*|, and φ of affected mesentery in CD were higher compared to HV (p = 0.017, p = 0.001, p = 0.017). Strong correlations were found between percentage of area of mesenteric fibrosis and SWS and |G*| (p < 0.010). No differences were found within CD between affected and presumably unaffected mesentery. Repeatability of SWS showed 95% limits of agreement of (-0.09, 0.13 m/s) and within-subject CoV of 5.3%. CONCLUSION: MRE may have the potential to measure fibrotic disease involvement of the mesentery in CD, possibly guiding clinical decision-making with respect to extended mesenteric resection. TRIAL REGISTRATION: Dutch trial register, NL9105 , registered 7 December 2020. RELEVANCE STATEMENT: MRE may have the potential to measure the amount of mesenteric fibrosis of the affected mesenteric fat in active Crohn's disease, giving more insight into disease progression and could potentially play a role in clinical decision-making for extended mesenteric resection. KEY POINTS: • MRE of the mesentery in patients with active CD is feasible. • Fluidity and stiffness of the mesentery increase in active CD, while stiffness correlates with the histopathological amount of mesenteric fibrosis. • MRE provides biomarkers to quantify mesenteric disease activity in active CD.

Self-supervised neural network improves tri-exponential intravoxel incoherent motion model fitting compared to least-squares fitting in non-alcoholic fatty liver disease.

Recent literature suggests that tri-exponential models may provide additional information and fit liver intravoxel incoherent motion (IVIM) data more accurately than conventional bi-exponential models. However, voxel-wise fitting of IVIM results in noisy and unreliable parameter maps. For bi-exponential IVIM, neural networks (NN) were able to produce superior parameter maps than conventional least-squares (LSQ) generated images. Hence, to improve parameter map quality of tri-exponential IVIM, we developed an unsupervised physics-informed deep neural network (IVIM3-NET). We assessed its performance in simulations and in patients with non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R 2. IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with a significant increase in average parameter-map SNR from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R 2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM3-NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology similar to the bi-exponential neural network fit, while generating potentially complementary additional parameters.

Deep learning-based whole-heart segmentation in 4D contrast-enhanced cardiac CT.

Automatic cardiac chamber and left ventricular (LV) myocardium segmentation over the cardiac cycle significantly extends the utilization of contrast-enhanced cardiac CT, potentially enabling in-depth assessment of cardiac function. Therefore, we evaluate an automatic method for cardiac chamber and LV myocardium segmentation in 4D cardiac CT. In this study, 4D contrast-enhanced cardiac CT scans of 1509 patients selected for transcatheter aortic valve implantation with 21,605 3D images, were divided into development (N = 12) and test set (N = 1497). 3D convolutional neural networks were trained with end-systolic (ES) and end-diastolic (ED) images. Dice similarity coefficient (DSC) and average symmetric surface distance (ASSD) were computed for 3D segmentations at ES and ED in the development set via cross-validation, and for 2D segmentations in four cardiac phases for 81 test set patients. Segmentation quality in the full test set of 1497 patients was assessed visually on a three-point scale per structure based on estimated overlap with the ground truth. Automatic segmentation resulted in a mean DSC of 0.89 ± 0.10 and ASSD of 1.43 ± 1.45 mm in 12 patients in 3D, and a DSC of 0.89 ± 0.08 and ASSD of 1.86 ± 1.20 mm in 81 patients in 2D. The qualitative evaluation in the whole test set of 1497 patients showed that automatic segmentations were assigned grade 1 (clinically useful) in 98.5%, 92.2%, 83.1%, 96.3%, and 91.6% of cases for LV cavity and myocardium, right ventricle, left atrium, and right atrium. Our automatic method using convolutional neural networks performed clinically useful segmentation across the cardiac cycle in a large set of 4D cardiac CT images, potentially enabling in-depth assessment of cardiac function.

Assessment of Imaging Modalities Against Liver Biopsy in Nonalcoholic Fatty Liver Disease: The Amsterdam NAFLD-NASH Cohort.

BACKGROUND: Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD. PURPOSE: To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores. STUDY TYPE: Prospective, cohort. POPULATION: Thirty-seven patients with NAFLD. FIELD STRENGTH/SEQUENCE: Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi-echo stimulated-echo acquisition mode, magnitude-based and three-point Dixon using a two-dimensional multi-echo gradient echo, MR elastography (MRE) using a generalized multishot gradient-recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single-shot echo-planar sequence. ASSESSMENT: Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFFMRS ), magnitude-based MRI (PDFFMRI-M ), and three-point Dixon (PDFFDixon ), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH). STATISTICAL TESTS: Spearman's rank test, Kruskal-Wallis test, Dunn's post-hoc test with Holm-Bonferroni P-value adjustment, receiver operating characteristic curve analysis. A P-value <0.05 was considered statistically significant. RESULTS: Histological steatosis grade correlated significantly with PDFFMRS (rs  = 0.66, P < 0.001), PDFFMRI-M (rs  = 0.68, P < 0.001), and PDFFDixon (rs  = 0.67, P < 0.001), whereas no correlation was found with CAP. MRE and IVIM diffusion and perfusion significantly correlated with disease activity (rs  = 0.55, P < 0.001, rs  = -0.40, P = 0.016, rs  = -0.37, P = 0.027, respectively) and fibrosis (rs  = 0.55, P < 0.001, rs  = -0.46, P = 0.0051; rs  = -0.53, P < 0.001, respectively). MRE and IVIM diffusion had the highest area-under-the-curve for distinction between simple steatosis and NASH (0.79 and 0.73, respectively). DATA CONCLUSION: Multiparametric MRI is a promising method for noninvasive, accurate, and sensitive distinction between simple hepatic steatosis and NASH, as well as for the assessment of steatosis and fibrosis severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: 2.

Accuracy of controlled attenuation parameter compared with ultrasound for detecting hepatic steatosis in children with severe obesity.

OBJECTIVES: To determine the diagnostic accuracy of controlled attenuation parameter (CAP) on FibroScan® in detecting and grading steatosis in a screening setting and perform a head-to-head comparison with conventional B-mode ultrasound. METHODS: Sixty children with severe obesity (median BMI z-score 3.37; median age 13.7 years) were evaluated. All underwent CAP and US using a standardized scoring system. Magnetic resonance spectroscopy proton density fat fraction (MRS-PDFF) was used as a reference standard. RESULTS: Steatosis was present in 36/60 (60%) children. The areas under the ROC (AUROC) of CAP for the detection of grade ≥ S1, ≥ S2, and ≥ S3 steatosis were 0.80 (95% CI: 0.67-0.89), 0.77 (95% CI: 0.65-0.87), and 0.79 (95% CI: 0.66-0.88), respectively. The AUROC of US for the detection of grade ≥ S1 steatosis was 0.68 (95% CI: 0.55-0.80) and not significantly different from that of CAP (p = 0.09). For detecting ≥ S1 steatosis, using the optimal cutoffs, CAP (277 dB/m) and US (US steatosis score ≥ 2) had a sensitivity of 75% and 61% and a specificity of 75% and 71%, respectively. When using echogenicity of liver parenchyma as only the scoring item, US had a sensitivity of 70% and specificity of 46% to detect ≥ S1 steatosis. The difference in specificity of CAP and US when using only echogenicity of liver parenchyma of 29% was significant (p = 0.04). CONCLUSION: The overall performance of CAP is not significantly better than that of US in detecting steatosis in children with obesity, provided that the standardized scoring of US features is applied. When US is based on liver echogenicity only, CAP outperforms US in screening for any steatosis (≥ S1). KEY POINTS: • The areas under the ROC curves of CAP and ultrasound (US) for detecting grade ≥ S1 steatosis were 0.80 and 0.68, respectively, and were not significantly different (p = 0.09). • For detecting grade ≥ S1 steatosis in severely obese children, CAP had a sensitivity of 75% and a specificity of 75% at its optimal cutoff value of 277 dB/m. • For detecting grade ≥ S1 steatosis in clinical practice, both CAP and US can be used, provided that the standardized scoring of US images is used.

Donor Fecal Microbiota Transplantation Alters Gut Microbiota and Metabolites in Obese Individuals With Steatohepatitis.

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of . Conclusion: Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.

A pharmacokinetic model including arrival time for two inputs and compensating for varying applied flip-angle in dynamic gadoxetic acid-enhanced MR imaging.

PURPOSE: Pharmacokinetic models facilitate assessment of properties of the micro-vascularization based on DCE-MRI data. However, accurate pharmacokinetic modeling in the liver is challenging since it has two vascular inputs and it is subject to large deformation and displacement due to respiration. METHODS: We propose an improved pharmacokinetic model for the liver that (1) analytically models the arrival-time of the contrast agent for both inputs separately; (2) implicitly compensates for signal fluctuations that can be modeled by varying applied flip-angle e.g. due to B1-inhomogeneity. Orton's AIF model is used to analytically represent the vascular input functions. The inputs are independently embedded into the Sourbron model. B1-inhomogeneity-driven variations of flip-angles are accounted for to justify the voxel's displacement with respect to a pre-contrast image. RESULTS: The new model was shown to yield lower root mean square error (RMSE) after fitting the model to all but a minority of voxels compared to Sourbron's approach. Furthermore, it outperformed this existing model in the majority of voxels according to three model-selection criteria. CONCLUSION: Our work primarily targeted to improve pharmacokinetic modeling for DCE-MRI of the liver. However, other types of pharmacokinetic models may also benefit from our approaches, since the techniques are generally applicable.

Diffusion-weighted imaging of hepatocellular carcinoma before and after transarterial chemoembolization: role in survival prediction and response evaluation.

BACKGROUND: Survival outcomes of patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) are heterogeneous. Measuring the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI) may improve overall survival prediction. AIM: To assess the value of measuring the ADC before and after TACE in predicting overall survival. METHODS: A retrospective analysis was performed in HCC patients treated with TACE at a tertiary referral center between 2008 and 2017. The ADC values and changes in ADC value (ΔADC) of HCC lesions (≥ 1 cm) and liver parenchyma were assessed by DWI ≤ 3 months before and after first TACE. Pre- and post-TACE ADC values were compared with tumor response according to mRECIST and correlated with overall survival (OS) in a univariable and multivariable Cox-regression analysis. RESULTS: A total of 89 patients were included, mostly Child-Pugh A (85%) and BCLC stage B (53%) with a median OS of 21.7 months (95% CI 17.6-25.9). Tumor ADC increased from 1081 mm2/s before (IQR 964-1225) to 1328 mm2/s (IQR 1197-1560) after TACE (p < 0.001). Responders according to mRECIST showed a higher ΔADC after first TACE than non-responders (26 vs. 14%, p = 0.048). Pre-TACE ADC and ΔADC were not significantly associated with OS in both univariable and multivariable analysis, whereas response according to mRECIST remained an independent predictor of OS. CONCLUSION: mRECIST was confirmed as an independent prognostic factor of OS, but pre- or post-TACE ADC measurements were not. Response according to mRECIST was associated with a higher increase in ADC than non-response.

Pivotal role of glutamine synthetase in ammonia detoxification.

Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle. Using GS-knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that ∼35% of this ammonia is detoxified by hepatic GS and ∼35% by urea-cycle enzymes, while ∼30% is not cleared by the liver, independent of portal ammonia concentrations ≤2 mmol/L. Using both genetic (GS-knockout/liver and GS-knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia-detoxifying capacity through either the enteral or the intravenous route is ∼160 µmol/hour in control mice. Using stable isotopes, we show that disposal of glutamine-bound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from ∼7% in methionine sulfoximine-treated mice to ∼500% in dexamethasone-treated mice (control mice, 100%), without difference in total urea synthesis. CONCLUSIONS: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high-affinity ammonia-detoxifying system of the body. The dependence of glutamine-bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (Hepatology 2017;65:281-293).

Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice.

Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. AIM OF THIS STUDY: to evaluate the efficacy of selective agonists INT747/obeticholic acid (FXR) and INT777 (TGR5) as novel treatments for the metabolic effects of oestrogen deficiency. Ovariectomized (OVX) or sham-operated (SHAM) mice were fed a high-fat diet (HFD) for 5weeks. During the last 4weeks two groups of OVX and SHAM mice received either INT747- or INT777-supplemented HFD. OVX mice had significantly higher bodyweight gain than SHAM mice, which was attenuated by INT747- or INT777-treatment. No significant changes in food intake or physical activity were found. OVX mice had significantly lower energy expenditure than SHAM mice; INT747- and INT777-treated OVX mice had intermediate energy expenditure. Liver triglyceride and cholesterol content was significantly increased in OVX compared to SHAM mice, which was normalized by INT747- or INT777-treatment. Significant changes in metabolic gene expression were found in liver (Cpt1, Acox1), muscle (Ucp3, Pdk4, Cpt1, Acox1, Fasn, Fgf21), brown adipocytes (Dio2) and white adipocytes (c/EBPα, Pparγ, Adipoq). For the first time, expression of FXR and induction of its target gene Pltp1 was shown in skeletal muscle. BA receptor agonists are suitable therapeutics to correct postmenopausal metabolic changes in an OVX mouse model. Potential mechanisms include increased energy expenditure and changes in expression patterns of key metabolic genes in liver, muscle and adipose tissues.

Comparison of clinical MRI liver iron content measurements using signal intensity ratios, R 2 and R 2.

PURPOSE: To compare three types of MRI liver iron content (LIC) measurement performed in daily clinical routine in a single center over a 6-year period. METHODS: Patients undergoing LIC MRI-scans (1.5T) at our center between January 1, 2008 and December 31, 2013 were retrospectively included. LIC was measured routinely with signal intensity ratio (SIR) and MR-relaxometry (R 2 and R 2*) methods. Three observers placed regions-of-interest. The success rate was the number of correctly acquired scans over the total number of scans. Interobserver agreement was assessed with intraclass correlation coefficients (ICC) and Bland-Altman analysis, correlations between LICSIR, R 2, R 2*, and serum values with Spearman's rank correlation coefficient. Diagnostic accuracies of LICSIR, R 2 and serum transferrin, transferrin-saturation, and ferritin compared to increased R 2* (≥44 Hz) as indicator of iron overload were assessed using ROC-analysis. RESULTS: LIC MRI-scans were performed in 114 subjects. SIR, R 2, and R 2* data were successfully acquired in 102/114 (89%), 71/114 (62%), and 112/114 (98%) measurements, with the lowest success rate for R 2. The ICCs of SIR, R 2, and R 2* did not differ at 0.998, 0.997, and 0.999. R 2 and serum ferritin had the highest diagnostic accuracies to detect elevated R 2* as mark of iron overload. CONCLUSIONS: SIR and R 2* are preferable over R 2 in terms of success rates. R 2*'s shorter acquisition time and wide range of measurable LIC values favor R 2* over SIR for MRI-based LIC measurement.

Glycerophosphocholine and Glycerophosphoethanolamine Are Not the Main Sources of the In Vivo (31)P MRS Phosphodiester Signals from Healthy Fibroglandular Breast Tissue at 7 T.

PURPOSE: The identification of the phosphodiester (PDE) (31)P MR signals in the healthy human breast at ultra-high field. METHODS: In vivo (31)P MRS measurements at 7 T of the PDE signals in the breast were performed investigating the chemical shifts, the transverse- and the longitudinal relaxation times. Chemical shifts and transverse relaxation times were compared with non-ambiguous PDE signals from the liver. RESULTS: The chemical shifts of the PDE signals are shifted -0.5 ppm with respect to glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), and the transverse and longitudinal relaxation times for these signals are a factor 3 to 4 shorter than expected for aqueous GPC and GPE. CONCLUSION: The available experimental evidence suggests that GPC and GPE are not the main source of the PDE signals measured in fibroglandular breast tissue at 7 T. These signals may predominantly originate from mobile phospholipids.

Noninvasive Differentiation between Hepatic Steatosis and Steatohepatitis with MR Imaging Enhanced with USPIOs in Patients with Nonalcoholic Fatty Liver Disease: A Proof-of-Concept Study.

PURPOSE: To (a) study the optimal timing and dosing for ultrasmall superparamagnetic iron oxide particle (USPIO)-enhanced magnetic resonance (MR) imaging of the liver in nonalcoholic fatty liver disease, (b) evaluate whether hepatic USPIO uptake is decreased in nonalcoholic steatohepatitis (NASH), and (c) study the diagnostic accuracy of USPIO-enhanced MR imaging to distinguish between NASH and simple steatosis. MATERIALS AND METHODS: This prospective study was approved by the local institutional review board, and informed consent was obtained from all patients. Quantitative R2* MR imaging of the liver was performed at baseline and 72 hours after USPIO administration in patients with biopsy-proven NASH (n = 13), hepatic steatosis without NASH (n = 11), and healthy control subjects (n = 9). The hepatic USPIO uptake in the liver was quantified by the difference in R2* (ΔR2*) between the contrast material-enhanced images and baseline images. Between-group differences in mean ΔR2* were tested with the Student t test, and diagnostic accuracy was tested by calculating the area under the receiver operating characteristic curve. RESULTS: Patients with NASH had a significantly lower ΔR2* 72 hours after USPIO administration when compared with patients who had simple steatosis and healthy control subjects (mean ± standard deviation for patients with NASH, 37.0 sec(-1) ± 16.1; patients with simple steatosis, 61.0 sec(-1) ± 17.3; and healthy control subjects, 72.2 sec(-1) ± 22.0; P = .006 for NASH vs simple steatosis; P < .001 for NASH vs healthy control subjects). The area under the receiver operating characteristic curve to distinguish NASH from simple steatosis was 0.87 (95% confidence interval: 0.72, 1.00). CONCLUSION: This proof-of-concept study provides clues that hepatic USPIO uptake in patients with NASH is decreased and that USPIO MR imaging can be used to differentiate NASH from simple steatosis.

Minimizing the Acquisition Time for Intravoxel Incoherent Motion Magnetic Resonance Imaging Acquisitions in the Liver and Pancreas.

OBJECTIVES: The aim of this study was to determine the combination of b-values and signal averages for diffusion-weighted image acquisitions that render the minimum acquisition time necessary to obtain values of the intravoxel incoherent motion (IVIM) model parameters in vivo in the pancreas or liver with acceptable reproducibility. MATERIALS AND METHODS: For 16 volunteers, diffusion-weighted images, with 14 b-values and 9 acquisitions per b-value, were acquired in 2 scan sessions. The IVIM model was fitted to data from lesion-sized regions of interest (ROIs) (1.7 cm(3)) as well as organ-sized ROIs in the pancreas and liver. By deleting data during analyzes, the IVIM model parameters, D and f, could be determined as a function of the number of b-values as well as the number of measurements per b-value taken along. For the IVIM model parameters, we examined the behavior reproducibility, in the form of the within-subject coefficient of variation (CVw), as a function of the amount of data taken along in the fits. Finally, we determined the minimum acquisition time required as a function of CVw. RESULT: For the lesion-sized ROI, the intersession CVws were 8%/46% and 13%/55% for D/f in the pancreas and liver, respectively, when all data were taken along. For 1.2 times larger CVws, acquisition in the pancreas could be done in 5:15 minutes using 9 acquisitions per b-value at b = 0, 30, 50, 65, 100, 375, and 500 mm(-2)s and for the liver in 2:15 using 9 acquisitions per b-value at b = 0, 40, and 500 mm(-2)s. CONCLUSIONS: Acquiring 7 b-values in the pancreas and 3 b-values in the liver only decreases the reproducibility by 20% compared with an acquisition with 14 b-values. The understanding of the behavior of reproducibility as a function of b-values and acquisitions per b-values scanned will help researchers select the shortest IVIM protocol.

Short-Term Effect of Estrogen on Human Bone Marrow Fat.

Bone marrow fat, an unique component of the bone marrow cavity increases with aging and menopause and is inversely related to bone mass. Sex steroids may be involved in the regulation of bone marrow fat, because men have higher bone marrow fat than women and clinical observations have suggested that the variation in bone marrow fat fraction is greater in premenopausal compared to postmenopausal women and men. We hypothesized that the menstrual cycle and/or estrogen affects the bone marrow fat fraction. First, we measured vertebral bone marrow fat fraction with Dixon Quantitative Chemical Shift MRI (QCSI) twice a week during 1 month in 10 regularly ovulating women. The vertebral bone marrow fat fraction increased 0.02 (95% CI, 0.00 to 0.03) during the follicular phase (p = 0.033), and showed a nonsignificant decrease of 0.02 (95% CI, -0.01 to 0.04) during the luteal phase (p = 0.091). To determine the effect of estrogen on bone marrow fat, we measured vertebral bone marrow fat fraction every week for 6 consecutive weeks in 6 postmenopausal women before, during, and after 2 weeks of oral 17-ß estradiol treatment (2 mg/day). Bone marrow fat fraction decreased by 0.05 (95% CI, 0.01 to 0.09) from 0.48 (95% CI, 0.42 to 0.53) to 0.43 (95% CI, 0.34 to 0.51) during 17-ß estradiol administration (p < 0.001) and increased again after cessation. During 17-ß estradiol administration the bone formation marker procollagen type I N propeptide (P1NP) increased (p = 0.034) and the bone resorption marker C-terminal crosslinking telopeptides of collagen type I (CTx) decreased (p < 0.001). In conclusion, we described the variation in vertebral bone marrow fat fraction among ovulating premenopausal women. And among postmenopausal women, we demonstrated that 17-ß estradiol rapidly reduces the marrow fat fraction, suggesting that 17-ß estradiol regulates bone marrow fat independent of bone mass.