RATIONALE AND OBJECTIVES:Cardiac magnetic resonance imaging (CMR) is commonly obtained to evaluate for myocardial infiltrative disorders and fibrosis. Pre- and post-Gadolinium contrast T1-mapping sequences are employed to estimate interstitial expansion using extracellular volume fraction (ECV). Given the proximity of the liver to the heart, T1 and ECV quantification of the liver is feasible on CMR. The purpose of this study was to evaluate for hepatic measures of fibrosis and interstitial expansion in patients with amyloidosis or systemic disease on CMR. MATERIALS AND METHODS:Myocardial and hepatic native T1 values were measured retrospectively using a cardiac short axis modified Look-Locker inversion recovery sequence. Myocardial and hepatic ECV were calculated using pre- and post-contrast T1 and blood pool values according to the following formula: ECV = (Δ(1/T1) myocardium or liver and/or Δ(1/T1) blood)x(1 - hematocrit). Patients were divided into three cohorts by final diagnosis: amyloidosis, systemic disease (e.g. sarcoid, scleroderma), and controls (EF > 50, no ischemia). RESULTS:Of the 135 patients who underwent CMR, 22 had cardiac amyloidosis (age 59.9 ± 12.6 yrs, 41% female), 20 had systemic disease (age 50.9 ± 13.4 yrs, 35% female), and 93 were controls (age 49.5 ± 17.3 yrs, 50% female). Myocardial T1 and ECV values were highest for patients with amyloid, second highest for systemic disease, and least for controls (T1: 1169 ± 92 vs 1101 ± 53 vs 1027 ± 73 ms, p < 0.0001; ECV: 0.47 ± 0.11 vs 0.31 ± 0.05 vs 0.27 ± 0.04, p < 0.0001). Hepatic T1 and ECV were similarly higher in patients with amyloid and systemic disease compared to controls (T1: 646 ± 101 vs 660 ± 93 vs 595 ± 58 ms, p < 0.0001; ECV: 0.38 ± 0.08 vs 0.37 ± 0.05 vs 0.31 ± 0.03, p < 0.0001). There was a positive correlation between hepatic T1 and ECV (R = 0.282, p < 0.0001). No patients had abnormal liver function tests or clinical liver disease. CONCLUSION:Hepatic ECV quantification on CMR in patients with amyloidosis and systemic disorders is feasible. Further longitudinal investigation regarding detection of early or subclinical liver disease is warranted.

PURPOSE:To analyze the predictive value of ΔT1 of the liver and spleen as well as the extracellular volume fraction (ECV) of the spleen as noninvasive biomarkers for the determination of clinically significant portal hypertension (CSPH) on routine Gd-EOB-DTPA liver MRI. METHOD:195 consecutive patients with known or suspected chronic liver disease from 9/2018 to 7/2019 with Gd-EOB-DTPA liver MRI and abdominal T1 mapping were retrospectively included. Based on the presence of splenomegaly with thrombocytopenia, ascites and portosystemic collaterals, the patients were divided into noCSPH (n = 113), compensated CSPH (cCSPH, ≥1 finding without ascites; n = 55) and decompensated CSPH (dCSPH, ascites ± other findings; n = 27). T1 times were measured in the liver, spleen and abdominal aorta in the unenhanced and contrast-enhanced T1 maps. Native T1 times and ΔT1 of the liver and spleen as well as ECV of the spleen were compared between groups using the Kruskal-Wallis test with Dunn's post hoc test. Furthermore, cutoff values for group differentiation were calculated using ROC analysis with Youden's index. RESULTS:ΔT1 of the liver was significantly lower in patients with cCSPH and dCSPH (p < 0.001) compared to patients with noCSPH. In the ROC analyses for differentiation between noCSPH and CSPH (cCSPH + dCSPH), a cutoff of < 0.67 for ΔT1 of the liver (AUC = 0.79) performed better than ΔT1 (AUC = 0.69) and ECV (AUC = 0.63) of the spleen with cutoffs of > 0.29 and > 41.9, respectively. CONCLUSION:ΔT1 of the liver and spleen in addition to ECV of the spleen allow for determination of CSPH on routine Gd-EOB-DTPA liver MRI.

OBJECTIVES:To evaluate the ability of iodine uptake parameters from hepatic multiphasic CT to predict liver fibrosis, and compare absolute contrast enhancement (ΔHU) with dual-energy iodine density (ID) methods. METHODS:One hundred seventeen patients with pathologically proven liver fibrosis who underwent dual-energy CT during portal-venous phase (PVP) and 3-min delayed phase (DP) between January 2017 and Octotber 2019 were retrospectively included. Two radiologists measured the hepatic and blood-pool iodine uptake using ΔHU and ID methods; extracellular volume fraction (ECV) and the iodine washout rate (IWR) calculated with both methods were compared between different fibrosis stages (F0-1 vs. F2-4, F0-2 vs. F3-4, or F0-3 vs. F4). The inter-observer reproducibility (intraclass correlation coefficients [ICCs]) for ECV and IWR was compared between the ΔHU and ID methods. The areas under the receiver operating characteristic curves (AUCs) to predict liver fibrosis severity were calculated for serum and imaging fibrosis markers. To identify independent predictors, multivariable logistic regression analysis was performed, and combined performance was assessed for the ΔHU and ID models. RESULTS:Patients with F ≥ 2 (n = 70), F ≥ 3 (n = 51), and F4 (n = 29) had higher ECV and lower IWR than those with F ≤ 1, F ≤ 2, and F ≤ 3, respectively (all p < 0.001). ICCs were higher in the ID method than in the ΔHU method (ECV: p = 0.045; IWR: p < 0.001). The AUC ranges of ECV, ECV, IWR, and IWR for predicting liver fibrosis severity were 0.65-0.71, 0.67-0.73, 0.76-0.81, and 0.81-0.85, respectively. IWR and fibrosis-4 index were independent predictors, with combined AUCs of 0.82-0.87 for the ΔHU model and 0.86-0.89 for the ID model. CONCLUSIONS:IWR more accurately predicted liver fibrosis than ECV in routine multiphasic CT. The dual-energy ID method yielded higher inter-observer reproducibility and predictive values than the single-energy ΔHU method. KEY POINTS:• The IWR calculated from hepatic iodine uptake during PVP and 3-min DP predicted liver fibrosis (AUC, 0.76-0.85), while the ECV had a relatively limited predictive value (ACU, 0.65-0.73). • Compared with the conventional ΔHU method, the dual-energy ID method provided superior inter-observer reproducibility for measurement of ECV (p = 0.046) and IWR (p < 0.001). • The IWR and FIB-4 served as independent predictors of liver fibrosis; their combination yielded the high diagnostic performance particularly when using the ID method (combined AUCs of 0.86-0.89).

AIM:To investigate whether iodine density measurements from contrast-enhanced dual-energy computed tomography (CT) data can non-invasively stage liver fibrosis. METHODS:This single-center, prospective study was approved by our IRB with written informed consent. Forty-seven consecutive patients (26 men and 21 women; mean age, 63.1 years) with chronic liver disease underwent contrast-enhanced dual-energy CT of the liver (non-contrast, arterial, portal venous, and equilibrium phase images), followed by liver biopsy. Iodine density of liver and aorta were obtained by two independent observers. Iodine uptake of the liver (Δ Liver), representing the difference in iodine density between equilibrium phase and non-contrast images, was calculated and normalized by aorta (Δ Liver/Aorta). We accounted for contrast agent distribution volume by using hematocrit level. Accuracy of iodine density measurements for staging liver fibrosis was assessed by using receiver operating characteristic (ROC) curves. Multivariate linear regression analysis was used to assess the impact of independent variables (liver fibrosis stage and patient-related confounders) on iodine uptake. RESULTS:The Δ Liver/Aorta significantly increased and moderately correlated with METAVIR liver fibrosis stage (ρ = 0.645, P < 0.001). Areas under the ROC curve ranged from 0.795 to 0.855 for discriminating each liver fibrosis score (≥F1-F4). METAVIR fibrosis stage was the most significant independent factor associated with Δ Liver (P = 0.005) and Δ Liver/Aorta (P < 0.001). CONCLUSION:Hepatic extracellular volume fraction with contrast-enhanced dual-energy CT can non-invasively stage liver fibrosis in chronic liver diseases. This technique could prove useful for monitoring disease progression and treatment response, potentially reducing the need for liver biopsy.

Purpose To evaluate MRI T1 and T2 mapping with calculation of extracellular volume (ECV) for diagnosis and grading of liver fibrosis. Materials and Methods Different grades of fibrosis were induced in 60 male Sprague-Dawley rats by bile duct ligation (BDL) and carbon-tetrachloride (CCl) intoxication. Portal pressure was measured invasively, whereas hepatic fibrosis was quantified by hydroxyproline content, Sirius red staining, and α smooth muscle actin staining. T1 values, T2 values, and ECV were assessed by using quantitative MRI mapping techniques. Results T1 values in animals 4 weeks after BDL were greater than in control animals (718 msec ± 74 vs 578 msec ± 33, respectively; P < .001). T2 values at 4 weeks were also greater in animals that underwent BDL than in control animals (46 msec ± 6 vs 29 msec ± 2, respectively; P < .001). Similar T1 and T2 findings were observed after CCl intoxication. ECV was greater in animals 4 weeks after BDL compared with control animals (31.3% ± 1.3 vs 18.2% ± 3.5, respectively; P < .001), with similar results after CCl intoxication. High correlations were found between ECV and hepatic hydroxyproline content (BDL: r = 0.68, P < .001; CCl: r = 0.65, P < .001), Sirius red staining (BDL: r = 0.88, P < .001; CCl: r = 0.82, P < .001), α smooth muscle actin staining (BDL: r = 0.70, P < .001; CCl: r = 0.73, P < .001), and portal pressure (BDL: r = 0.54, P = .003; CCl: r = 0.39, P = .043). Conclusion Elevation of T1 and T2 values and ECV was associated with severity of liver fibrosis and portal hypertension in an experimental animal model.

OBJECTIVE:To evaluate the value of MR liver extracellular volume (ECV) in assessment of liver fibrosis with chronic hepatitis B (CHB), and to compare its performance with two-dimensional (2D) shear-wave elastography (SWE). MATERIALS AND METHODS:A total of 68 CHB patients who were histologically diagnosed as fibrosis stages F0 to F4 were retrospectively analyzed. All patients underwent gadopentetate dimeglumine-enhanced T1-mapping and 2D SWE. ECV and liver stiffness were measured and compared between fibrosis subgroups; their correlations with histologic findings were evaluated using Spearman correlation test and multiple regression analysis. Diagnostic performance in evaluating liver fibrosis stages was assessed and compared using receiver-operating characteristic analysis. RESULTS:Both ECV and liver stiffness increased as the fibrosis score increased (F = 17.08 to 10.99, P < 0.001). ECV displayed a strong correlation with fibrosis stage (r = 0.740, P < 0.001), and liver stiffness displayed a moderate correlation (r = 0.651, P < 0.001); multivariate analysis revealed that only ECV was independently correlated with fibrosis stage (P < 0.001). Univariate analyses showed significant correlations of ECV with fibrosis stage, inflammatory activity, and platelet count; among all, the fibrosis stage had the highest correlation coefficient and was the only independent factor (P < 0.001). Overall, ECV had no significant different performance compared with 2D SWE for the identification of both fibrosis stage s ≥ F2 and F4 (P = 0.868 and 0.171). CONCLUSION:MR ECV plays a promising role in the prediction of liver fibrosis for patients with CHB, comparable to 2D SWE.

OBJECTIVES:This study was to evaluate the diagnostic value of liver extracellular volume (LECV) for the staging of liver fibrosis in a cynomolgus monkey model of nonalcoholic steatohepatitis (NASH). METHODS:Forty-eight cynomolgus monkeys were enrolled in this prospective study. There are 17 healthy monkeys and 31 monkeys with NASH. Ten of these monkeys were used for repeatability assessment. The remaining 38 monkeys were used to compare LECV with other indicators including pathology fibrosis score, native T1, and serum chemical indexes by Spearman, Pearson correlation test, and ROC curves. The inter-reader variability was assessed by interclass correlation. The repeatability measurement of LECV was analyzed using Bland-Altman plots and the coefficient of variation. Partial correlation analysis was performed to assess the effects of fat content and inflammation scores on the correlation between LECV/T1 and liver fibrosis score. RESULTS:This study demonstrated a good intra-reader agreement (intraclass correlation = 0.79) of LECV in all monkeys and an excellent repeatability in 10 monkeys (coefficient of variation = 2.01%). The LECV has a strong correlation with the fibrosis score (r = 0.949; p < 0.0001), low-density lipoprotein (r = 0.72; p < 0.0001), and cholesterol (r = 0.70; p < 0.0001). LECV showed high diagnostic efficacy in the diagnosis of liver fibrosis (area under the curve of ROC, 0.945~1; p < 0.001). CONCLUSIONS:LECV may serve as a noninvasive valuable biomarker for the quantification and differentiating of the non-severe liver fibrosis (stage ≤ F3). However, circulating serum markers low-density lipoprotein and cholesterol (CHO) may not serve for this purpose. KEY POINTS:• This paper demonstrated the excellent repeatability (intraclass correlation coefficient = 0.79) of LECV in monkey animal model. • LECV-MRI has a strong correlation with histopathological fibrosis score stage (r = 0.949; p < 0.0001) and shows high diagnostic efficacy in the staging of non-severe liver fibrosis (the area under ROC curve ≥ 0.945). • The new fibrosis score maps appeared to provide a better imaging tool for the spatial assessment of liver fibrosis. It may eventually facilitate the diagnosis of liver fibrosis distribution.

OBJECTIVES:To investigate equilibrium contrast-enhanced CT (EQ-CT) measurement of extracellular volume fraction (ECV) in patients with systemic amyloid light-chain (AL) amyloidosis, testing the hypothesis that ECV becomes elevated in the liver and spleen and ECV correlates with other estimates of organ amyloid burden. METHODS:26 patients with AL amyloidosis underwent EQ-CT, and ECV was measured in the liver and spleen. Patients also underwent serum amyloid P (SAP) component scintigraphy with grading of liver and spleen involvement. Mann-Whitney U test was used to test for a difference between patients with amyloid deposition (SAP grade 1-3) and those without (SAP grade 0). Variation in ECV across SAP grades was assessed using the Kruskal-Wallis test and association between ECV and SAP grades with Spearman correlation. RESULTS:Mean ECV in the spleen and liver was significantly greater (p < 0.0005) in amyloidotic organs (SAP grade 1-3) [spleen, liver: 0.430, 0.375] compared with healthy tissues [spleen, liver: 0.304, 0.269]. ECV increased with increasing amyloid burden, showing positive correlation with SAP grade in both the liver (r = 0.758) and spleen (r = 0.867). CONCLUSION:In patients with systemic AL amyloidosis, EQ-CT can demonstrate increased spleen and liver ECV, which is associated with amyloid disease burden.

PURPOSE:To determine the performance of quantification of liver extracellular volume fraction (fECV) using dual-energy CT (DECT) compared with CT imaging for ruling out high-riskesophageal varices(HRV) in cirrhotic patients. METHODS:We retrospectively analyzed 229 cirrhotic patients (training [n = 159] and internal validation cohorts [n = 70]) who underwent dual-source DECT, serum marker assessment, and esophagogastroduodenoscopy (EGD) from 2017 to 2020. The fECV score was measured using iodine maps from 3-minute delayed, equilibrium-phase images at 100/140 Sn kVp. The association of CT parameters and serum markers with HRV was investigated. Criteria combining the fECV score (≤ 25.1%) or CT imaging with platelet count (> 150,000/mm) were created and compared to rule out HRV. RESULTS:In the training cohort, the fECV score (odds ratio (OR), 1.20; 95% confidence interval (CI), 1.09, 1.32) and CT imaging (OR, 28.21; 95% CI, 9.31, 85.93) were independent predictors of HRV, along with platelet count (OR, 0.85 and 0.78). Criteria combining the fECV score with platelet count showed significantly better performance than those combining CT imaging with platelet count in ruling out HRV (p < 0.001). Applying the criteria could have safely avoided an additional 10.7% and 8.6% of EGDs in the training and validation cohorts, respectively, achieving a final value of 36.5% and 35.7% spared EGDs (0 HRV missed) compared to CT imaging with platelet count. CONCLUSIONS:The combined DECT-based fECV score with platelet count is useful for ruling out HRV and can safely avoid more EGDs than CT imaging with platelet count.

INTRODUCTION:This study aimed to compare the correlation between the computed tomography (CT) enhancement rate of the venous to portal venous phase (VP-ER) and the extracellular volume (ECV) fraction with shear-wave ultrasound elastography (USE) findings in patients with liver fibrosis. METHODS:We included 450 patients with clinically suspected liver cirrhosis who underwent triphasic dynamic CT studies and USE. We compared the USE results with the unenhanced CT phase, with enhancement in the hepatic artery phase (HAP), portal venous phase (PVP), and venous phase (VP), and with the ECV fraction and the VP-ER. We also compared the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the ECV fraction and VP-ER with that of the values obtained with USE. RESULTS:The VP-ER was the most highly correlated with the liver stiffness value determined with USE (Pearson's correlation coefficient: r = 0.37), followed by enhancement in the PVP (r = -0.25), CT number on unenhanced CT scans (r = -0.22), the ECV fraction (r = 0.19), enhancement in the VP (r = 0.059), and enhancement in the HAP (r = -0.023) (all p < 0.01). The VP-ER showed a significantly higher AUC than the ECV fraction (0.75 vs 0.62) when the liver stiffness was >15 kPa in USE studies (p = 0.04). CONCLUSION:Compared to the ECV fraction, the VP-ER is more useful for predicting all degrees of liver fibrosis on routine triphasic dynamic CT images. IMPLICATIONS FOR PRACTICE:Although improvement is needed, the VP-ER has a higher diagnostic ability for liver fibrosis than the ECV fraction in clinical practice.

PURPOSE:Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that leads to severe fibrosis and cirrhosis. The aim of this study was to determine the diagnostic value of T1 and T2 mapping as well as extracellular volume fraction (ECV) for non-invasive assessment of liver fibrosis in AIH patients. METHODS:In this prospective study, 27 patients (age range: 19-77 years) with AIH underwent liver MRI. T1 and T2 relaxation times as well as ECV were quantified by mapping techniques. The presence of significant fibrosis (≥ F2) was defined as magnetic resonance elastography (MRE)-based liver stiffness ≥ 3.66 kPa. MRE was used as reference standard, against which the diagnostic performance of MRI-derived mapping parameters was tested. Diagnostic performance was compared by utilizing receiver-operating characteristic (ROC) analysis. RESULTS:MRE-based liver stiffness correlated with both, hepatic native T1 (r = 0.69; P < 0.001) as well as ECV (r = 0.80; P < 0.001). For the assessment of significant fibrosis, ECV yielded a sensitivity of 85.7% (95% confidence interval (CI): 60.1-96.0%) and a specificity of 84.6% (CI 60.1-96.0%); hepatic native T1 yielded a sensitivity of 85.7% (CI 60.1-96.0%); and a specificity of 76.9% (CI 49.7-91.8%). Diagnostic performance of hepatic ECV (area under the curve (AUC): 0.885), native hepatic T1 (AUC: 0.846) for assessment of significant fibrosis was similar compared to clinical fibrosis scores (APRI (AUC: 0.852), FIB-4 (AUC: 0.758), and AAR (0.654) (P > 0.05 for each comparison)). CONCLUSION:Quantitative mapping parameters such as T1 and ECV can identify significant fibrosis in AIH patients. Future studies are needed to explore the value of parametric mapping for the evaluation of different disease stages.

PURPOSE:To assess hepatocellular carcinoma (HCC) risk after sustained virologic response (SVR) through clinical data analyses, including evaluation of liver fibrosis using the extracellular volume fraction (ECV) obtained from dual-energy computed tomography (DECT). METHODS:Ninety-two patients (52 men and 40 women; mean age, 69.9 years) with hepatitis C virus infection after SVR underwent DECT of the liver (3-minute equilibrium-phase images) between January 2020 and March 2022. The ECV was calculated by measuring iodine density; fibrous markers, including ECV, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, and platelet count, were statistically analyzed (p < 0.05). The risk factors associated with HCC were analyzed using univariate and multivariate logistic regression analyses. RESULTS:The ECV (26.1 ± 4.6 %) in patients with HCC (n,21) was significantly larger than the ECV (20.7 ± 3.3 %) in patients without HCC (n = 71) (p < 0.001). The cutoff value for the ECV was 24.3 %. The area under the operating characteristic curve of the ECV was 0.857, which was higher than that of the serum fibrosis markers. Older age, SVR achieved with interferon, alpha-fetoprotein level (>5 ng/mL), advanced fibrosis before treatment (>F3), and ECV were associated with HCC according to the univariate analysis. Multivariate analyses showed that ECV was the only factor independently associated with HCC (odds ratio 0.619, 95 % confidence interval 0.482-0.795, p < 0.001). CONCLUSION:Liver fibrosis estimated using ECV can be a predictive marker in patients with HCC after SVR.

We aimed to investigate the diagnostic utility of MRI extracellular volume fraction (ECV) for the assessment of liver cirrhosis severity as defined by Child-Pugh class. In this retrospective study, 90 patients (68 cirrhotic patients and 22 controls), who underwent multiparametric liver MRI, were identified. Hepatic T1 relaxation times and ECV were assessed. Clinical scores of liver disease severity were calculated. One-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test, Spearman's correlation coefficient, and receiver operating characteristic (ROC) analysis were used for statistical analysis. In cirrhotic patients, hepatic native T1 increased depending on Child-Pugh class (620.5 ± 78.9 ms (Child A) vs. 666.6 ± 73.4 ms (Child B) vs. 828.4 ± 91.2 ms (Child C), P < 0.001). ECV was higher in cirrhotic patients compared to the controls (40.1 ± 11.9% vs. 25.9 ± 4.5%, P < 0.001) and increased depending of Child-Pugh class (33.3 ± 6.0% (Child A) vs. 39.6 ± 4.9% (Child B) vs. 52.8 ± 1.2% (Child C), P < 0.001). ECV correlated with Child-Pugh score (r = 0.64, P < 0.001). ECV allowed differentiating between Child-Pugh classes A and B, and B and C with an AUC of 0.785 and 0.944 (P < 0.001, respectively). The diagnostic performance of ECV for differentiating between Child-Pugh classes A and B, and B and C was higher compared to hepatic native T1 (AUC: 0.651 and 0.910) and MELD score (AUC: 0.740 and 0.795) (P < 0.05, respectively). MRI-derived ECV correlated with Child-Pugh score and had a high diagnostic performance for the discrimination of different Child-Pugh classes. ECV might become a valuable non-invasive biomarker for the assessment of liver cirrhosis severity.

OBJECTIVES:In patients with advanced liver disease, portal hypertension is an important risk factor, leading to complications such as esophageal variceal bleeding, ascites, and hepatic encephalopathy. This study aimed to determine the diagnostic value of T1 and T2 mapping and extracellular volume fraction (ECV) for the non-invasive assessment of portal hypertension. METHODS:In this prospective study, 50 participants (33 patients with indication for trans-jugular intrahepatic portosystemic shunt (TIPS) and 17 healthy volunteers) underwent MRI. The derivation and validation cohorts included 40 and 10 participants, respectively. T1 and T2 relaxation times and ECV of the liver and the spleen were assessed using quantitative mapping techniques. Direct hepatic venous pressure gradient (HVPG) and portal pressure measurements were performed during TIPS procedure. ROC analysis was performed to compare diagnostic performance. RESULTS:Splenic ECV correlated with portal pressure (r = 0.72; p < 0.001) and direct HVPG (r = 0.50; p = 0.003). No significant correlations were found between native splenic T1 and T2 relaxation times with portal pressure measurements (p > 0.05, respectively). In the derivation cohort, splenic ECV revealed a perfect diagnostic performance with an AUC of 1.000 for the identification of clinically significant portal hypertension (direct HVPG ≥ 10 mmHg) and outperformed other parameters: hepatic T2 (AUC, 0.731), splenic T2 (AUC, 0.736), and splenic native T1 (AUC, 0.806) (p < 0.05, respectively). The diagnostic performance of mapping parameters was comparable in the validation cohort. CONCLUSION:Splenic ECV was associated with portal pressure measurements in patients with advanced liver disease. Future studies should explore the diagnostic value of parametric mapping accross a broader range of pressure values. KEY POINTS:• Non-invasive assessment and monitoring of portal hypertension is an area of unmet interest. • Splenic extracellular volume fraction is strongly associated with portal pressure in patients with end-stage liver disease. • Quantitative splenic and hepatic MRI-derived parameters have a potential to become a new non-invasive diagnostic parameter to assess and monitor portal pressure.

Aims:To characterize changes in the myocardium in subjects with prediabetes, diabetes, and healthy controls with preserved left ventricular ejection fraction (LVEF) by using cardiac magnetic resonance imaging (CMR) in a sample from the general population. Methods and results:Subjects without history of cardiovascular disease and preserved LVEF but established diabetes, prediabetes, and controls from a population-based cohort underwent contrast-enhanced CMR. Obtained parameters included left ventricular (LV) function and morphology, late gadolinium enhancement as well as T1-mapping and derivation of extracellular volume fraction (ECV) by modified Look-Locker inversion recovery for diffuse fibrosis in a subset of patients. Fibrosis volume and cell volume were calculated and LV remodelling index was calculated by dividing the LV mass by its end-diastolic volume. Among 343 subjects (56.1 ± 9.2 years, 57% males), 47 subjects were classified as diabetes, 78 as prediabetes, and 218 as controls. Haematocrit values and thus ECV parameters were available in 251 subjects. LV remodelling index was significantly higher in participants with prediabetes and diabetes, independent of body mass index (BMI), hypertension, age, and sex. ECV was decreased in subjects with prediabetes and diabetes compared with healthy controls (23.1 ± 2.4% and 22.8 ± 3.0%, both P < 0.007). In contrast, cell volume was significantly higher in subjects with prediabetes and diabetes as compared with controls (109.1 ± 23.8 and 114.9 ± 32.3 mL vs. 96.5 ± 26.9 mL, both P < 0.03, respectively). However, differences in ECV and cell volume attenuated after the adjustment for cardiometabolic risk factors, including age, sex, BMI, and hypertension. Conclusion:Subjects with prediabetes and diabetes but preserved LVEF had higher LV remodelling indices, suggesting early detectable changes in the disease process, while diffuse myocardial fibrosis appears to be less relevant at this stage.

PURPOSE:To determine whether hepatic extracellular volume fraction (ECV) obtained from iodine density map (ECV-iodine) can be used to estimate hepatic fibrosis grade and to compare performance with ECV measured using Hounsfield units (ECV-HU). METHODS:From December 2016 to March 2019, patients who underwent liver resection or biopsy within four weeks after spectral liver CT were included. ECV-iodine and ECV-HU were calculated using the equilibrium phase. Within each of these, comparison of ECVs was made for different fibrosis grades (F0 - 1 vs. F2 - 3 vs. F4) and also for patients with compensated and decompensated cirrhosis. The diagnostic performance of ECVs in detecting clinically significant fibrosis (≥ F2) and cirrhosis (F4) was assessed using ROC analysis. RESULTS:A total of 144 patients (men = 98, mean age 58.1 ± 11.5 years) were included. The ECV-iodine value was significantly higher in cirrhosis (33.6 ± 6.8 %) than those with F0 - 1 (25.0 ± 3.7 %) or F2 - 3 (28.3 ± 3.4 %, P < 0.001 for all). It was significantly higher in decompensated cirrhosis than those with compensated cirrhosis (36.5 ± 7.2 % vs. 30.7 ± 5.0 %, respectively; P < 0.001). The AUC of ECV-iodine was 0.82 for detecting F2 or above (cut-off value, > 26.9 %) and 0.81 for detecting cirrhosis (cut-off value, > 29 %). ECV-iodine had a significantly higher AUC than ECV-HU for detecting F2 or above (AUC: 0.69, P <  0.001) and cirrhosis (AUC: 0.74, P =  0.04). CONCLUSIONS:ECV-iodine from spectral CT was able to detect clinically significant hepatic fibrosis and cirrhosis.

BACKGROUND:Evaluate equilibrium contrast-enhanced CT (EQ-CT) texture analysis (EQ-CTTA) against histologically-quantified fibrosis, serum-based enhanced liver fibrosis panel (ELF) and imaging-based extracellular volume fraction (ECV) in chronic hepatitis. METHODS:This study was a re-analysis of image data from a previous prospective study. Pre- and equilibrium-phase post-IV contrast CT datasets were collected from patients with chronic hepatitis with contemporaneous liver biopsy and serum ELF measurement between April 2011 and July 2013. Biopsy samples were analysed to derive collagen proportionate area (CPA). EQ-CTTA was performed with a filtration histogram technique using texture analysis software, with texture quantification using statistical and histogram-based metrics (mean, skewness, standard deviation, entropy, etc.). Association between pre-contrast and EQ-CTTA against CPA, ECV and ELF was evaluated using Spearman's rank correlation coefficient (r). RESULTS:Complete datasets collected in 29 patients (16 male; 13 female), mean age (range): 49 (22-66 years). Liver ECV, CPA and ELF had a median (interquartile range) of 0.26 (0.24-0.29); 5.0 (3.0-13.7) and 9.71 (8.39-10.92). Difference in segment VII hepatic CTTA (medium texture scale) between EQ-CT and pre-contrast images was significantly and positively associated with ELF score (mean: r = 0.69, < 0.001; skewness: r = 0.57, = 0.007). Significant negative associations were observed between pre-contrast and EQ-CT whole hepatic CTTA (coarse texture scale) with CPA (pre-contrast, SD: r = -0.66, < 0.001) and ECV (EQ-CT, entropy: r = -0.58, = 0.006). CONCLUSIONS:Hepatic EQ-CTTA demonstrates significant association with validated markers of liver fibrosis, suggesting a role in non-invasive quantification of severity in diffuse fibrosis.

PURPOSE:To investigate whether the iodine density of liver parenchyma in the equilibrium phase and extracellular volume fraction (ECV) measured by deep learning-based spectral computed tomography (CT) can enable noninvasive liver fibrosis staging. METHOD:We retrospectively analyzed 63 patients who underwent dynamic CT using deep learning-based spectral CT before a hepatectomy or liver transplantation. The iodine densities of the liver parenchyma (I-liver) and abdominal aorta (I-aorta) were independently measured by two radiologists using iodine density images at the equilibrium phase. The iodine-density ratio (I-ratio: I-liver/I-aorta) and CT-ECV were calculated. Spearman's rank correlation analysis was used to evaluate the relationship between the I-ratio or CT-ECV and liver fibrosis stage, and receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performances of the I-ratio and CT-ECV. RESULTS:The I-ratio and CT-ECV showed significant positive correlations with liver fibrosis stage (ρ = 0.648, p < 0.0001 and ρ = 0.723, p < 0.0001, respectively). The areas under the ROC curve for the CT-ECV were 0.882 (F0 vs ≥ F1), 0.873 (≤F1 vs ≥ F2), 0.848 (≤F2 vs ≥ F3), and 0.891 (≤F3 vs F4). CONCLUSIONS:Deep learning-based spectral CT may be useful for noninvasive assessments of liver fibrosis.

BACKGROUND:Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by bile duct inflammation and destruction, leading to biliary fibrosis and cirrhosis. The purpose of this study was to investigate the utility of T1 and T2 mapping parameters, including extracellular volume fraction (ECV) for non-invasive assessment of fibrosis severity in patients with PSC. METHODS:In this prospective study, patients with PSC diagnosis were consecutively enrolled from January 2019 to July 2020 and underwent liver MRI. Besides morphological sequences, MR elastography (MRE), and T1 and T2 mapping were performed. ECV was calculated from T1 relaxation times. The presence of significant fibrosis (≥ F2) was defined as MRE-derived liver stiffness ≥ 3.66 kPa and used as the reference standard, against which the diagnostic performance of MRI mapping parameters was tested. Student t test, ROC analysis and Pearson correlation were used for statistical analysis. RESULTS:32 patients with PSC (age range 19-77 years) were analyzed. Both, hepatic native T1 (r = 0.66; P < 0.001) and ECV (r = 0.69; P < 0.001) correlated with MRE-derived liver stiffness. To diagnose significant fibrosis (≥ F2), ECV revealed a sensitivity of 84.2% (95% confidence interval (CI) 62.4-94.5%) and a specificity of 84.6% (CI 57.8-95.7%); hepatic native T1 revealed a sensitivity of 52.6% (CI 31.7-72.7%) and a specificity of 100.0% (CI 77.2-100.0%). Hepatic ECV (area under the curve (AUC) 0.858) and native T1 (AUC 0.711) had an equal or higher diagnostic performance for the assessment of significant fibrosis compared to serologic fibrosis scores (APRI (AUC 0.787), FIB-4 (AUC 0.588), AAR (0.570)). CONCLUSIONS:Hepatic T1 and ECV can diagnose significant fibrosis in patients with PSC. Quantitative mapping has the potential to be a new non-invasive biomarker for liver fibrosis assessment and quantification in PSC patients.

Objective:The aim of the study was to analyze the efficacy of double-low dynamic contrast-enhanced CT (DCE-CT) and hepatic extracellular volume fraction (fECV) in the diagnosis of liver fibrosis (LF). Methods:A total of 200 patients with LF and cirrhosis who underwent the histopathological examination of liver biopsy and multiphase DCE-CT of the liver at the same time in our hospital (January 2020-December 2020) were selected as the research subjects, and the degree of liver fibrosis was staged according to pathological criteria to analyze the clinical diagnostic value of double-low DCE-CT and fECV. Results:Compared with the S2-S4 group, the S1 group had obviously higher Eaorta and HCT values ( < 0.05), a lower fECV value ( < 0.001), and lower serum IVC and LN levels ( < 0.001). Serum IVC and LN levels were positively correlated with fECV (  = 0.803 and  = 0.890; < 0.001). The fECV had the highest specificity and negative predictive value in the diagnosis of S1 and had the highest sensitivity and positive predictive value in the diagnosis of S2-S4. Conclusion:The double-low DCE-CT and fECV can provide a reliable basis for the clinical diagnosis of LF, and their results will provide a new direction for the treatment of LF and have a high application value in the clinical practice.

OBJECTIVES:To determine whether quantification of liver extracellular volume fraction (fECV) using dual-energy CT (DECT) allows prediction of liver-related events (LREs) in cirrhotic patients. METHODS:This retrospective study included 305 cirrhotic patients who underwent dual-source DECT imaging and had serum markers analyzed within 2 weeks of initial CT imaging. The fECV score was measured using an iodine map of equilibrium-phase images obtained 3 min after contrast injection at 100/140 Sn kVp. The association of the fECV score and serum markers with LREs was investigated. A risk model combining the fECV score (< 27 versus ≥ 27%) and serum albumin level (< 4 versus ≥ 4 g/dL) was constructed for LRE prediction. RESULTS:An increased fECV score (odds ratio, 1.27; 95% confidence interval (CI), 1.15, 1.40) was independently associated with decompensated cirrhosis at baseline (n = 85) along with the Model for End-Stage Liver Disease score (odds ratio, 1.32; 95% CI, 1.07, 1.63). Among patients with compensated cirrhosis, 10.5% (23 of 220) experienced LREs during the median follow-up period of 2.0 years (decompensation, n = 14; hepatocellular carcinoma, n = 9). The fECV score (hazard ratio, 1.40; 95% CI, 1.22, 1.62) and serum albumin level (hazard ratio, 0.26; 95% CI, 0.09, 0.73) were independent predictors of LRE. The mean times to LRE among the high (16.5 months, n = 18)-, intermediate (25.6 months, n = 44)-, and low (30.5 months, n = 158)-risk groups were significantly different (p < 0.001). CONCLUSIONS:The fECV score derived from DECT allows prediction of LREs in cirrhotic patients. KEY POINTS:• The extracellular volume fraction (fECV) score derived from the iodine map of dual-energy CT (DECT) was independently associated with the presence of hepatic decompensation. • The fECV score derived from the iodine map of DECT can predict liver-related events (LREs) in patients with cirrhosis. • Equilibrium-phase scanning in dual-energy mode is recommended as part of liver CT in cirrhotic patients because it can provide a prognostic indicator for LRE development.

OBJECTIVES:Most existing models that are in use to model hepatic function through assessment of hepatic gadoxetic acid enhancement kinetics do not consider quantitative measures of gadoxetic excretion. We developed a model that allows a simultaneous quantitation of uptake and excretion of liver specific contrast agents. The aim was to improve the assessment of hepatic synthetic function, and provide quantitative measures of hepatic excretion function. METHODS:Sixteen patients underwent dynamic T1-weighted turbo gradient echo imaging at 1.5 T prior and after bolus injection of gadoxetic acid at 0.1 ml/kg. DCE-images were obtained for 30 min after injection. A dual-inlet two-compartment model was then used to fit the measured liver signal values. Four tissue parameters (extracellular volume fraction, arterial flow fraction, uptake rate and excretion half-time) were extracted for each liver segment. RESULTS:The proposed model provided a good fit to acquired data. Mean values for arterial flow fraction (0.08+-0.04), extracellular volume (0.20±0.08) and uptake rate (4.02 ±1.32 /100 ml/min) were comparable to those obtained with the conventional model (0.08±0.05, 0.21±0.12, and 4.93±1.74), but exhibited significantly less variation and improved fit quality. CONCLUSIONS:The proposed model is more accurate than existing conventional models and provides an additional excretion parameter. KEY POINTS:• Models of hepatic contrast agent uptake can be extended to include excretion. • Including an additional excretion parameter improves accuracy of the model. • Standard diagnostic sequences can be extended to incorporate the model.

PURPOSE:To assess the segmental difference of liver fibrosis during the progression of chronic liver disease (CLD) using hepatic extracellular volume fractions (fECVs) obtained by dual-energy CT. METHODS:A total of 218 patients (92 men and 126 women; mean age, 67.8 ± 11.7 years) with CLD and 85 patients (44 men and 41 women; mean age, 62.8 ± 13.7 years) without CLD as a control underwent dual-energy computed tomography (CT) of the liver (5-min equilibrium phase images). The iodine densities of the lateral, medial, anterior, and posterior segments and the aorta were measured, and fECVs were calculated. Comparisons of the fECV of each segment and for each albumin-bilirubin (ALBI) grade were then statistically analyzed. RESULTS:In the control group and ALBI grades 1 and 3, no significant difference in fECV was found between each segment, whereas in ALBI grade 2, the fECVs were significantly larger in the medial and anterior than in the other segments (p < 0.001). The fECVs of the lateral and posterior segments significantly increased with higher ALBI grade (p < 0.001). The fECVs of the medial and anterior segments were significantly increased with higher ALBI grade, up to grade 2 (p < 0.001), but no significant difference was found between ALBI grades 2 and 3. CONCLUSION:During the progression of CLD, fibrosis antecedently progressed in the medial and anterior segments, followed by the other liver segments.

BACKGROUND:Patients with single ventricle physiology are at increased risk for developing liver fibrosis. Its extent and prevalence in children with bidirectional cavopulmonary connection (BCPC) and Fontan circulation are unclear. Extracellular volume fraction (ECV), derived from cardiovascular magnetic resonance (CMR) and T1 relaxometry, reflect fibrotic remodeling and/or congestion in the liver. The aim of this study was to investigate whether pediatric patients with single ventricle physiology experience increased native T1 and ECV as markers of liver fibrosis/congestion. METHODS:Hepatic native T1 times and ECV, using a cardiac short axis modified Look-Locker inversion recovery sequence displaying the liver, were measured retrospectively in children with BCPC- and Fontan circulations and compared to pediatric controls. RESULTS:Hepatic native T1 time were increased in Fontan patients (n = 62, 11.4 ± 4.4 years, T1 762 ± 64 ms) versus BCPC patients (n = 20, 2.8 ± 0.9 years, T1 645 ± 43 ms, p = 0.04). Both cohorts had higher T1 than controls (n = 44, 13.7 ± 2.9 years, T1 604 ± 54 ms, p < 0.001 for both). ECV was 41.4 ± 4.8% in Fontan and 36.4 ± 4.8% in BCPC patients, respectively (p = 0.02). In Fontan patients, T1 values correlated with exposure to cardiopulmonary bypass time (R = 0.3, p = 0.02), systolic and end diastolic volumes (R = 0.3, p = 0.04 for both) and inversely with oxygen saturations and body surface area (R = -0.3, p = 0.04 for both). There were no demonstrable associations of T1 or ECV with central venous pressure or age after Fontan. CONCLUSION:Fontan and BCPC patients have elevated CMR markers suggestive of hepatic fibrosis and/or congestion, even at a young age. The tissue changes do not appear to be related to central venous pressures. TRIAL REGISTRATION:Retrospectively registered data.

OBJECTIVE:To evaluate time-dependent changes in hepatic extracellular volume (ECV) fraction using contrast-enhanced CT (CECT) and serological liver fibrosis markers, the fibrosis-4 (FIB-4) index and aspartate aminotransferase to platelet ratio index (APRI), before and after direct-acting antiviral therapy (DAA) for hepatitis C virus (HCV) infection. METHODS:41 HCV-infected patients who achieved sustained virological response (SVR) after DAA (SVR group) and 10 control patients (untreated or unresponsive to treatment) who underwent CECT and serum biochemical tests before or after the first examination/DAA (T1) and at intervals thereafter (T2:<6 months after T1, T3: at 6-12 months, T4: at 12-24 months, and T5:>24 months) were evaluated. RESULTS:In the control group, ECV fractions remained relatively unchanged through the study, and significant differences in FIB-4 index comparisons and APRI comparisons were only seen between the T2 and T4 values ( = 0.046 and = 0.028, respectively). In the SVR group, ECV fractions were significantly different between T1 and T4 and T1 and T5 ( = 0.046 and 0.022, respectively), and both FIB-4 index and APRI were significantly different between T1 and all other time points ( = 0.017 to < 0.001 and = 0.001 to < 0.001, respectively). CONCLUSION:After DAA, ECV fraction decreased slowly, suggesting an improvement in hepatic fibrosis, while serological liver fibrosis markers decreased immediately, probably due to improvement in hepatic inflammation. ADVANCES IN KNOWLEDGE:ECV fraction has the potential to be a non-invasive biomarker for the assessment of liver fibrosis after direct-acting antiviral therapy.

OBJECTIVES:To assess whether extracellular volume fraction (ECV) obtained from routine liver CT equilibrium phase data utilizing new subtraction algorithm is useful in estimating the degree of liver fibrosis. MATERIALS AND METHODS:Consecutive 41 patients, 21 men and 20 women, with chronic liver diseases who underwent quadri-phase liver CT and MR elastography within 3 months were retrospectively enrolled. Subtraction image of unenhanced from equilibrium phase (240 s) images using conventional and new algorithms were made. We firstly assessed the quality of these subtraction algorithms using patients in whom anatomical misregistration between the two image sets were prominent. Then, ECVs were calculated using both subtraction data sets (ECV-convSub, and ECV-newSub, respectively). ECV were also calculated by traditional manual method (ECV-man). Correlation coefficients of 3 types of ECV were compared using liver stiffness (kPa) as measured by MR elastography and pathologically proven fibrosis grades as reference standards. RESULTS:For eleven patients with prominent anatomical misregistration between the unenhanced and equilibrium phases, new algorithm provided significantly better subtraction images than the conventional one (p = 0.001, Wilcoxon's signed rank test). As for correlation with liver stiffness, R for ECV-man, ECV-convSub, and ECV-newSub, were 0.57, 0.59, and 0.66, respectively (all p < 0.0001, Pearson's correlation). Histological assessment for fibrosis grades were available in 20 patients, and rho values for these three ECVs were 0.66, 0.61, and 0.71, respectively (all p < 0.01, Spearman's rank correlation). CONCLUSION:ECV-newSub showed better correlation to liver stiffness and pathological fibrosis grades than ECV-convSub and ECV-man, which could be a reliable biomarker of liver fibrosis obtained from routine clinical diagnostic imaging data, where equilibrium phase delay time was set at 240 s.

[This corrects the article DOI: 10.3389/fonc.2023.1214977.].

PURPOSE:To assess whether extracellular volume fraction (ECV) calculated from iodine(-blood) density images (I-B) of dual-energy liver CT (DECT) equilibrium phase data (EqD) is useful in estimating the degree of liver fibrosis. MATERIALS AND METHODS:Consecutive 52 patients with chronic liver disease who underwent fast kV switching DECT and liver MR elastography (MRE) were retrospectively enrolled. Iodine(-water) density images (I-W) and I-B generated from EqD and ECV were calculated. As blood pools, abdominal aorta (Ao) and suprahepatic inferior vena cava (IVC) were chosen, and, therefore, 4 types of ECV (ECV, ECV, ECV, ECV) were obtained. ECV was also calculated using conventional method (ECV). The correlation coefficients (R or rho) of these five ECVs versus liver stiffness (MRE) or pathologically proven fibrosis grades were compared. RESULTS:As for correlation with liver stiffness, R for ECV, ECV, ECV, ECV, and ECV, were 0.26, 0.34, 0.44, 0.39, and 0.52, respectively (all p < 0.0001). Histopathological correlation was available in 28 patients, and rho values were 0.61, 0.60, 0.71, 0.68, and 0.76, respectively (all p < 0.001). CONCLUSION:ECV calculated from EqD of DECT is useful in estimating the degree of liver fibrosis.

AIM:To investigate the value of hepatic extracellular volume fractions (fECVs) measured using routine liver computed tomography (CT) evaluating liver fibrosis (LF). MATERIALS AND METHODS:A total of 60 patients (male:female ratio, 39:21; mean age, 42.4 years) histologically diagnosed with LF underwent routine liver CT. Absolute enhancement (in Hounsfield units) of the liver parenchyma (E) and aorta (E) 3 minutes after contrast medium administration was calculated using precontrast and equilibrium phase scans. The fECV was calculated using the following equation: fECV (%)=E× (100 - haematocrit [%])/E. Correlation between fECV and LF stage was evaluated using the Spearman correlation coefficient. The fECVs were compared between each stage of LF. The diagnostic performance of fECV was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS:The difference among the groups was statistically significant (p<0.05). The fECVs were significantly different (p<0.05) between F0 versus F4, F1 versus F4, and F2 versus F4. The fECVs showed a significant correlation with pathological LF staging (r=0.468, p=0.001). The sensitivity and specificity were 0.76 and 0.68 for severe LF (F≥3); and 0.89 and 0.63 for cirrhosis (F=4). The areas under the ROC curve (AUCs) for F≥3 and F=4 were 0.757 and 0.775, respectively. CONCLUSIONS:Calculation of fECV during routine contrast-enhanced liver CT may provide a non-invasive means of assessing LF.

OBJECTIVE:The purpose of this study was to determine whether hepatic extracellular volume fractions (fECVs) measured using multiphasic liver computed tomography (CT) can be used to quantify the severity of hepatic fibrosis (HF). MATERIALS AND METHODS:This retrospective study was approved by our institutional review board, and the requirement for informed consent was waived. A total of 141 patients (male-female ratio, 109:32; mean [SD] age, 59.4 [11.4] years) histologically diagnosed with HF (F0-F1 = 33 and F2-F4 = 108) underwent multiphasic liver CT. Absolute enhancements (in Hounsfield unit) of the liver parenchyma (Eliver) and aorta (Eaorta) 3 minutes after contrast administration were measured on subtraction images of precontrast and equilibrium phase scans using nonrigid registration software. The fECV was calculated using the following equation: fECV (%) = Eliver/Eaorta × (100 - Hematocrit [%]). Correlation between fECV and HF stage was evaluated using the Spearman correlation coefficient. The fECVs were compared between F0-F1 and ≥F2 as well as between child A and child B or C. Diagnostic performance of fECV in predicting significant HF (≥F2) was assessed using receiver operating curve analysis. RESULTS:The fECVs showed a significant correlation with pathologic HF staging (r = 0.493, P < 0.001). The F2-F4 showed significantly higher fECVs than did F0 to F1 (33.6% [4.7%] vs 27.7% [4.4%]; P < 0.001). The fECVs were significantly higher in the patients with child B or C than those with child A (35.2% [7.0%] vs 31.3% [4.2%]; P < 0.001). The fECV values higher than 28.76% provided 87.5% sensitivity and 71.0% specificity in detecting significant HF (area under the curve, 0.832; P < 0.0001). CONCLUSIONS:Because fECV was shown to increase along with HF progression, the estimation of fECV using routine multiphasic liver CT may have the potential to detect significant HF.

Purpose:This study aimed to investigate the value of quantified extracellular volume fraction (fECV) derived from dual-energy CT (DECT) for predicting the survival outcomes of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). Materials and methods:A total of 63 patients with HCC who underwent DECT before treatment were retrospectively included. Virtual monochromatic images (VMI) (70 keV) and iodine density images (IDI) during the equilibrium phase (EP) were generated. The tumor VMI-fECV and IDI-fECV were measured and calculated on the whole tumor (Whole) and maximum enhancement of the tumor (Maximum), respectively. Univariate and multivariate Cox models were used to evaluate the effects of clinical and imaging predictors on overall survival (OS) and progression-free survival (PFS). Results:The correlation between tumor VMI-fECV and IDI-fECV was strong (both < 0.001). The Bland-Altman plot between VMI-fECV and IDI-fECV showed a bias of 5.16% for the Whole and 6.89% for the Maximum modalities, respectively. Increasing tumor VMI-fECV and IDI-fECV were positively related to the effects on OS and PFS (both < 0.05). The tumor IDI-fECV-Maximum was the only congruent independent predictor in patients with HCC after TACE in the multivariate analysis on OS ( = 0.000) and PFS ( = 0.028). Patients with higher IDI-fECV-Maximum values had better survival rates above the optimal cutoff values, which were 35.42% for OS and 29.37% for PFS. Conclusion:The quantified fECV determined by the equilibrium-phase contrast-enhanced DECT can potentially predict the survival outcomes of patients with HCC following TACE treatment.

PURPOSE:Assess the relationship between liver T1 relaxation time and extracellular volume (ECV) fraction and the disease severity of primary sclerosing cholangitis (PSC). METHODS:This retrospective study included 93 patients with PSC and 66 healthy patients in the control group. T1 relaxation times were measured in the right and left lobe, as well as in the area of stricture. T1 and ECV were calculated by averaging T1 and ECV of both lobes and stricture site. T1 and ECV were compared between the two groups and according to PSC phenotypes and severity based on Mayo Risk Score (MRS). We also examined the relationship between T1 and ECV with non-invasive measures of fibrosis such as Fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM) by transient elastography. RESULTS:Mean liver T1 (774 ± 111 ms, p < 0.001) and liver ECV (0.40 ± 0.14, p < 0.05) were significantly higher with both large-duct and small-duct-type PSC which may lack classic imaging findings on MRCP compared to the control group (p < 0.001). T1 and ECV showed weak-moderate correlation with LSM, FIB-4, and MRS (p < 0.05). Cut-off values of liver T1 to detect patients in low-risk and high-risk MRS groups were 677 ms (AUC: 0.68, sensitivity: 76%, specificity: 53%, p = 0.03) and 743 ms (AUC: 0.83, sensitivity: 79%, specificity: 76%, p < 0.001), respectively. CONCLUSION:T1 relaxation time and ECV fraction can be used for quantitative assessment of disease severity in patients with PSC.

PURPOSE:To verify the hypothesis that extracellular volume fraction (ECV) and precontrast CT density are the main determinants of washout of hepatocellular carcinoma (HCC) at the equilibrium phase CT. MATERIALS AND METHODS:Between 2018 and 2020, patients with surgically resected HCC were recruited who had undergone preoperative 4-phase CT. Those larger than 6 cm were excluded to minimize the possibility of intratumoral hemorrhage or degeneration. Two radiologists reviewed the whole images in consensus and divided cases into washout positive and negative groups. Washout positive group at the equilibrium phase was defined as "HCC showing relatively low density as compared to the surrounding background liver (BGL), irrespective of the presence of early enhancement or fibrous capsule". Several clinico-pathological and radiological features, including ECV and precontrast CT density, were correlated to the presence of washout, using uni- and multi-variable analyses. RESULTS:27 HCC in 24 patients met the inclusion criteria. 22 (82%) and five HCC belonged to washout positive and negative groups, respectively. Univariable analysis revealed ECV of HCC and BGL, ECV difference between HCC and BGL, and presence of fibrous capsule on the equilibrium phase CT were the significant factors. Multivariable analysis showed ECV of HCC and BGL, and precontrast CT density of BGL, were the independently significant factors related to washout, suggesting washout is more likely observed with lower HCC ECV, higher BGL ECV, and higher BGL precontrast CT density. CONCLUSION:Major determinants of washout of HCC may be ECV of HCC and BGL, and precontrast CT density of BGL.

Purpose: To compare the accuracy of liver fibrosis staging with MR elastography and of staging with extracellular volume fraction (fECV) analysis using contrast-enhanced CT. Methods: This retrospective study included 60 patients who underwent both MR elastography and contrast-enhanced CT before liver surgery between October 2013 and July 2020. Two radiologists independently measured liver stiffness of MR elastography and fECV of CT images. Accuracy for liver fibrosis staging was assessed using receiver operating characteristic (ROC) analysis. Correlations between liver stiffness or fECV and liver fibrosis were also evaluated by means of the Spearman rank correlation coefficient. Results: The areas under the ROC curves for MR elastography for each stage differentiation of ≥F1 (0.85, 0.82 for the two radiologists), ≥F2 (0.88, 0.89), ≥F3 (0.87, 0.86), and F4 (0.84, 0.83) were greater than those for fECV analysis with CT (0.64, p = 0.06, 0.69, p = 0.2; 0.62, p < 0.005, 0.63, p < 0.005; 0.62, p < 0.005, 0.62, p < 0.01; and 0.70, p = 0.08, 0.71, p = 0.2, respectively). The correlation coefficients between liver stiffness and liver fibrosis in A0 (0.67, 0.69 for the two radiologists), A1 (0.64, 0.66) and A2 group (0.58, 0.51) were significantly higher than those between fECV and liver fibrosis (0.28, 0.30; 0.27, 0.31; and 0.23, 0.07; p < 0.05 for all comparisons). Conclusion: MR elastography allows for more accurate liver fibrosis staging compared with fECV analysis with CT. In addition, MR elastography may be less affected than fECV analysis by the inflammatory condition.

BACKGROUND:To determine the utility of single-contrast-bolus hepatic extracellular volume (ECV) fraction measurement at different time points to detect and quantify hepatic fibrosis. METHODS:Different grades of liver fibrosis were induced in 23 male Sprague-Dawley rats by carbon-tetrachloride (CCl) intoxication. In ten control rats, no fibrosis was induced. Native T1 values and ECV fraction were assessed by using quantitative magnetic resonance imaging (MRI) mapping; only one contrast bolus was applied (gadobutrol 0.1 mmol/kg). ECV values were determined 5, 15, and 25 min after injection. Hepatic fibrosis was quantified histologically by Sirius red staining. RESULTS:For the 8-week-CCl group, the ECV fraction values obtained 5 (23.5 ± 4.8%, mean ± standard deviation), 15 (23.6 ± 4.8%), and 25 min (23.7 ± 4.7%) after injection were constant over time (p = 0.998); constant data 5-25 min after injection were also observed for the 16-week-CCl group and controls. Liver ECV after 15 min significantly increased with the severity of fibrosis: 18.0 ± 3.0% (controls) versus 23.6 ± 4.8% (8-week-CCl4) versus 30.5 ± 3.3% (16-week-CCl4) (p <  0.001). ECV values after 5, 15, and 25 min significantly correlated with Sirius red staining (p <  0.001 for all parameters). CONCLUSIONS:Hepatic ECV obtained using a single-contrast-bolus technique can be measured 5, 15, and 25 min after injection, obtaining constant values over time, each of them being suitable to detect diffuse hepatic fibrosis. In clinical practice, post-contrast T1 relaxation times for liver ECV fraction determination might be obtained at only one time point.

BACKGROUND:Chronic liver diseases pose a major health problem worldwide, while common tests for diagnosis and monitoring of diffuse hepatopathy have considerable limitations. Preliminary data on the quantification of hepatic extracellular volume fraction (ECV) with magnetic resonance imaging (MRI) for non-invasive assessment of liver fibrosis are encouraging, with ECV having the potential to overcome several of these constraints. PURPOSE:To clinically evaluate ECV provided by quantitative MRI for assessing the severity of liver disease. MATERIALS AND METHODS:In this prospective study, multiparametric liver MRI, including T1 mapping and magnetic resonance elastography (MRE), was performed in subjects with and without hepatopathy between November 2018 and October 2019. T1, T2, T2*, proton density fat fraction and stiffness were extracted from parametric maps by regions of interest and ECV was calculated from T1 relaxometries. Serum markers of liver disease were obtained by clinical database research. For correlation analysis, Spearman rank correlation was used. ROC analysis of serum markers and quantitative MRI data for discrimination of liver cirrhosis was performed with MRE as reference standard. RESULTS:109 participants were enrolled (50.7 ± 16.1 years, 61 men). ECV, T1 and MRE correlated significantly with almost all serum markers of liver disease, with ECV showing the strongest associations (up to r = 0.67 with MELD, p < 0.01). ECV and T1 correlated with MRE (0.75 and 0.73, p < 0.01 each). ECV (AUC 0.89, cutoff 32.2%, sensitivity 85%, specificity 87%) and T1 mapping (AUC 0.85, cutoff 592.5 ms, sensitivity 83%, specificity 75%) featured good performances in detection of liver cirrhosis with only ECV performing significantly superior to model of end stage liver disease (MELD), AST/ALT ratio and international normalized ratio (p < 0.01, respectively). CONCLUSION:Quantification of hepatic extracellular volume fraction with MRI is suitable for estimating the severity of liver disease when using MRE as the standard of reference. It represents a promising tool for non-invasive assessment of liver fibrosis and cirrhosis.

Background:Oxaliplatin (OX)-based chemotherapy induces sinusoidal obstruction syndrome (SOS) in the nontumorous liver parenchyma, which can increase the risk of liver resection due to colorectal liver metastasis (CRLM). The extracellular volume (ECV) calculated from contrast-enhanced computed tomography (CT) has been reported to reflect the morphological change of hepatic fibrosis. The present retrospective study aimed to evaluate the ECV fraction as a predictive factor for OX-induced SOS. Methods:Our study included 26 patients who underwent liver resection for CRLM after OX-based chemotherapy with a preoperative dynamic CT of appropriate quality. We investigated the relationship between the pathological SOS grade and the ECV fraction. Results:Overall, 26 specimens from the patients were graded with the SOS classification of Rubbia-Brandt et al. as follows: grade 0,  = 17 (65.4%); grade 1,  = 4 (15.4%); and grade 2,  = 5 (19.2%). No specimens showed grade 3 SOS. In a univariate analysis, the ECV fraction in grade 0 SOS was significantly lower than that in grade 1 + 2 SOS (26.3 ± 3.4% vs. 30.6 ± 7.0%;  = 0.025). The cutoff value and AUC value of the ECV fraction to distinguish between grades 0 and 1 + 2 were 27.5% and 0.771, respectively. Conclusions:Measurement of the ECV fraction was found to be a potential noninvasive diagnostic method for determining early-stage histopathological sinusoidal injury induced by OX-based chemotherapy.

BACKGROUND:Dual-Energy Computed Tomography (DECT) enables the direct measurement of iodine accumulation in the extracellular space. OBJECTIVE:To compare measures of liver fibrosis and function with Extracellular Volume (ECV) from iodine/water images using DECT. METHODS:Data was obtained from 119 consecutive patients who underwent abdominal DECT. A region of interest was set in the right lobe of the liver, pancreas, spleen, and aorta on iodine density images. ECV was calculated using the following formula: ECV = (1 - hematocrit) × [iodine concentration in the liver (or pancreas, spleen) / iodine concentration in the aorta]. The severity of liver fibrosis was estimated using the aminotransferase/platelet ratio index (APRI) and the Fibrosis-4 (FIB-4) index. Liver function was assessed by the Child-Pugh classification and albumin-bilirubin (ALBI) grade. Data were analyzed by the Spearman rank correlation coefficient, one-way analysis of variance, and post hoc analysis. RESULTS:The correlation between ECV and fibrosis indices (APRI and FIB-4) was only significant, with a weak magnitude for liver ECV quantification at the equilibrium phase (r=0.25 and r=0.20, respectively). The correlations between liver function index and ECV quantification were more robust than with fibrosis index. The highest correlations (r=0.50) were found between ALBI grade and liver ECV at the equilibrium phase. Liver ECV values at the equilibrium phase had a significant difference between ALBI grade 1 vs. 2 and grade 1 vs. 3. CONCLUSION:Liver ECV quantification by DECT is more suitable for evaluating liver function than liver fibrosis severity.

Objectives:To evaluate whether tumor extracellular volume fraction (fECV) on contrast-enhanced computed tomography (CT) aids in the differentiation between intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Methods:In this retrospective study, 113 patients with pathologically confirmed ICC (n = 39) or HCC (n = 74) who had undergone preoperative contrast-enhanced CT were enrolled. Enhancement values of the tumor (E) and aorta (E) were obtained in the precontrast and equilibrium phase CT images. fECV was calculated using the following equation: fECV [%] = E/E × (100 - hematocrit [%]). fECV values were compared between the ICC and HCC groups using Welch's -test. The diagnostic performance of fECV for differentiating ICC and HCC was assessed using receiver-operating characteristic (ROC) analysis. fECV and the CT imaging features of tumors were evaluated by two radiologists. Multivariate logistic regression analysis was performed to identify factors predicting a diagnosis of ICC. Results:Mean fECV was significantly higher in ICCs (43.8% ± 13.2%) than that in HCCs (31.6% ± 9.0%, p < 0.001). The area under the curve for differentiating ICC from HCC was 0.763 when the cutoff value of fECV was 41.5%. The multivariate analysis identified fECV (unit OR: 1.10; 95% CI: 1.01-1.21; p < 0.05), peripheral rim enhancement during the arterial phase (OR: 17.0; 95% CI: 1.29-225; p < 0.05), and absence of washout pattern (OR: 235; 95% CI: 14.03-3933; p < 0.001) as independent CT features for differentiating between the two tumor types. Conclusions:A high value of fECV, peripheral rim enhancement during the arterial phase, and absence of washout pattern were independent factors in the differentiation of ICC from HCC.

OBJECTIVES:To compare the predictive ability of liver fibrosis (LF) by CT-volumetry (CTV) for liver and spleen and extracellular volume fraction (ECV) for liver in patients undergoing liver resection. METHODS:We retrospectively analysed 90 consecutive patients who underwent CTV and ECV. Manually placed region-of-interest ECV (manual-ECV), rigid-registration ECV (rigid-ECV), and nonrigid-registration ECV (nonrigid-ECV) were calculated as ECV(%) = (1-haematocrit) × (ΔHU/ΔHU), where ΔHU = subtraction of unenhanced phase from equilibrium phase (240 s). Manual-ECV was compared with CTV for the estimation of LF. The total liver volume to body surface area (TLV/BSA), splenic volume to BSA (SV/BSA), ratio of TLV to SV (TLV/SV), ratio of right liver volume to SV (RV/SV), and liver segmental volume ratio (LSVR) were measured. ROC analyses were performed for ECV and CTV. RESULTS:After excluding 10 patients, seventy-eight (97.5%) out of 80 patients had a Child-Pugh score of 5 points, and two (2.5%) patients had a Child-Pugh score of 6 points. AUC of ECV showed no significant difference among manual-ECV, rigid-ECV, and nonrigid-ECV. TLV/BSA, SV/BSA, TLV/SV, and RV/SV had a higher correlation with LF grades than manual-ECV. AUC of SV/BSA was significantly higher than that of manual-ECV in F0-1 vs F2-4 and F0-2 vs F3-4. AUC of SV/BSA (0.76-0.83) was higher than that of manual-ECV (0.61-0.75) for all LF grades, although manual-ECV could differentiate between F0-3 and F4 at high AUC (0.75). CONCLUSIONS:In patients undergoing liver resection, SV/BSA is a better method for estimating severe LF grades, although manual-ECV has the ability to estimate cirrhosis (≥ F4). KEY POINTS:The splenic volume is a better method for estimating liver fibrosis grades. The extracellular volume fraction is also a candidate for the estimation of severe liver fibrosis.

Background Right heart failure may lead to impaired liver perfusion and venous congestion, resulting in different extents of liver fibrosis. However, whether hepatic tissue deterioration determined by native T1 mapping and extracellular volume fraction using cardiac magnetic resonance imaging is associated with poor outcomes in patients with pulmonary arterial hypertension remains unclear. Methods and Results A total of 131 participants with pulmonary arterial hypertension (mean age, 36±13 years) and 64 healthy controls (mean age, 44±18) between October 2013 and December 2019 were prospectively enrolled. Hepatic native T1 and extracellular volume fraction values were measured using modified Look-Locker inversion recovery T1 mapping sequences. The primary end point was all-cause mortality; the secondary end point was all-cause mortality and repeat hospitalization attributable to heart failure. Cox regression models and Kaplan-Meier survival analysis were used to identify the association between variables and clinical outcome. During a median follow-up of 34.5 months (interquartile range: 25.3-50.8), hepatic native T1 (hazard ratio per 30-ms increase, 1.22 [95% CI, 1.07-1.39]; =0.003) and extracellular volume fraction (hazard ratio per 3% increase, 1.18 [95% CI, 1.04-1.34]; =0.010) values were associated with a higher risk of death. In the multivariate Cox model, hepatic native T1 value (hazard ratio per 30-ms increase, 1.15 [95% CI, 1.04-1.27]; =0.009) remained as an independent prognostic factor for the secondary end point. Conclusions Hepatic T1 mapping values were predictors of adverse cardiovascular events in participants with pulmonary arterial hypertension and could be novel imaging biomarkers for poor prognosis recognition.

BACKGROUND:Children with Fontan circulation are at risk of developing hepatic fibrosis/cirrhosis. Reliable noninvasive monitoring techniques are lacking or under development. OBJECTIVE:To investigate surrogate indicators of hepatic fibrosis in adolescents with Fontan circulation by evaluating hepatic magnetic resonance (MR) T1 mapping and extracellular volume fraction measurements compared to US shear-wave elastography. MATERIALS AND METHODS:We analyzed hepatic native T1 times and extracellular volume fractions with modified Look-Locker inversion recovery. Liver stiffness was analyzed with shear-wave elastography. We compared results between 45 pediatric patients ages 16.7±0.6 years with Fontan circulation and 15 healthy controls ages 19.2±1.2 years. Measurements were correlated to clinical and hemodynamic data from cardiac catheterization. RESULTS:MR mapping was successful in 35/45 patients, revealing higher hepatic T1 times (774±44 ms) than in controls (632±52 ms; P<0.001) and higher extracellular volume fractions (47.4±5.0%) than in controls (34.6±3.8%; P<0.001). Liver stiffness was 1.91±0.13 m/s in patients vs. 1.20±0.10 m/s in controls (P<0.001). Native T1 times correlated with central venous pressures (r=0.5, P=0.007). Native T1 was not correlated with elastography in patients (r=0.2, P=0.1) or controls (r = -0.3, P=0.3). Extracellular volume fraction was correlated with elastography in patients (r=0.5, P=0.005) but not in controls (r=0.2, P=0.6). CONCLUSION:Increased hepatic MR relaxometry and shear-wave elastography values in adolescents with Fontan circulation suggested the presence of hepatic fibrosis or congestion. Central venous pressure was related to T1 times. Changes were detected differently with MR relaxometry and elastography; thus, these techniques should not be used interchangeably in monitoring hepatic fibrosis.

PURPOSE:To assess etiological differences in extracellular volume fraction (ECV) and evaluate its influence on staging performance. METHODS:A total of 166 patients with normal liver (n = 14) and chronic liver disease related to viral hepatitis (n = 71), alcohol (n = 44), and nonalcoholic steatohepatitis (NASH) (n = 37) underwent dual-energy CT (DECT) of the liver (5-min equilibrium-phase images) between January 2020 and July 2022. The iodine densities of the parenchyma and aorta were measured and ECV was calculated. Comparisons of ECV between each etiology and METAVIR fibrosis stage were statistically analyzed (p < 0.05). RESULTS:ECV in each etiology and all patients significantly increased with higher fibrosis stage (p < 0.001) and showed a strong or moderate correlation with fibrosis stage (Spearman's ρ; all patients, 0.701; viral hepatitis, 0.638; alcoholic, 0.885; NASH, 0.791). In stages F2-F4, ECV in alcoholic liver disease was significantly larger than those for viral hepatitis and NASH (p < 0.05); however, no significant difference in stage F1 was found among the three etiologies. The cutoff values and areas under the receiver operating characteristic curve (AUC-ROCs) for discriminating fibrosis stage (≥ F1- ≥ F4) were higher for alcohol (cutoff values and AUC-ROC; 20.1% and 0.708 for ≥ F1, 23.8% and 0.990 for ≥ F2, 24.3% and 0.968 for ≥ F3, and 26.6% and 0.961 for ≥ F4, respectively) compared with those for the others. CONCLUSION:ECV in alcoholic liver disease is higher than that in other etiologies in the advanced stages of fibrosis, and etiological differences in ECV affect the staging performance of fibrosis.

PURPOSE:Calculation of extracellular volume fraction (ECV) currently receives increasing interest as a potential biomarker for non-invasive assessment of liver fibrosis. ECV calculation requires hematocrit (Hct) sampling, which might be difficult to obtain in a high-throughput radiology department. The aim of this study was to generate synthetic ECV for hepatic applications without the need for Hct sampling. METHODS:In this prospective study participants underwent liver MRI. T1 mapping was performed before and after contrast administration. Blood Hct was obtained prior to MRI. We hypothesized that the relationship between Hct and longitudinal relaxation rate of blood (R1 = 1/T1) could be calibrated and used to generate the equation for synthetic Htc and ECV calculation. Conventional and synthetic ECV were calculated. Pearson correlation, linear regression and Bland-Altman method were used for statistical analysis. RESULTS:180 consecutive patients were divided into derivation (n = 90) and validation (n = 90) cohorts. In the derivation cohort, native R1 and Hct showed a linear relationship (Hct = 98.04 × (1/T1) - 33.17, R = 0.75, P < 0.001), which was used to calculate synthetic ECV in the validation and whole study cohorts. Synthetic and conventional ECV showed significant correlations in the derivation, validation and in the whole study cohorts (r = 0.99, 0.97 and 0.99, respectively, P < 0.001, respectively) with minimal bias according to the Bland-Altman analysis. CONCLUSION:Synthetic ECV seems to offer an alternative method for non-invasive quantification of the hepatic ECV. It may potentially overcome an important barrier to clinical implementation of ECV and thus, enable broader use of hepatic ECV in routine clinical practice.