Diagnostic performance of shear wave measurement in the detection of hepatic fibrosis: A multicenter prospective study.

AIM: This study aimed to establish the shear wave measurement (SWM) cut-off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard. METHODS: We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61 kPa), F1 (≥2.61 kPa, <2.97 kPa, any fibrosis), F2 (≥2.97 kPa, <3.62 kPa, significant fibrosis), F3 (≥3.62 kPa, <4.62 kPa, advanced fibrosis), or F4 (≥4.62 kPa, cirrhosis). RESULTS: The median SWM values increased significantly with increasing fibrosis stage (p < 0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761-0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin-capsular distance; skin-capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut-off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89 kPa, respectively. CONCLUSIONS: This multicenter study in a large number of patients established SWM cut-off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut-off values will be applied to liver diseases in the future.

A case of hepatocellular carcinoma with pseudoaneurysm formation upon lenvatinib administration.

A 79-year-old man received treatment for multiple intrahepatic hepatocellular carcinoma with atezolizumab + bevacizumab. However, he developed lower back pain attributed to spinal metastases upon tumor enlargement; thus, he was admitted to our hospital for a change from atezolizumab + bevacizumab to lenvatinib and radiation therapy for the spinal metastases. On the 11th day after starting lenvatinib treatment, a pulsatile aneurysm appeared in the tumor, detected using abdominal ultrasonography Micro B-flow imaging, which visualized blood flow at a high frame rate; this was diagnosed as a pseudoaneurysm. The patient refused treatment for the pseudoaneurysm; therefore, he was carefully followed up. Fortunately, the pseudoaneurysm disappeared on the 17th day. One month later, the tumor had become completely necrotic. Lenvatinib demonstrated effectiveness in inhibiting angiogenesis in the tumor, as evidenced by a decrease in tumor blood flow. This case report suggests that pseudoaneurysm formation within the tumor occurs early after the administration of lenvatinib; thus, clinicians must be aware of the potential risk of pseudoaneurysm rupture.

Diagnostic accuracy of ultrasound-derived fat fraction for the detection and quantification of hepatic steatosis in patients with liver biopsy.

PURPOSE: This retrospective study was conducted to investigate the diagnostic accuracy of ultrasound-derived fat fraction (UDFF) for grading hepatic steatosis using liver histology as the reference standard. METHODS: Seventy-three patients with liver disease were assessed using UDFF and liver biopsy. Pearson's test and the Bland-Altman plot were used to assess the correlation between UDFF and histological fat content in liver sections. The UDFF cutoff values for histologically proven steatosis grades were determined using the area under the receiver operating characteristic curve (AUROC). RESULTS: The median age of the patients was 66 (interquartile range 54-74) years, and 33 (45%) were females. The UDFF values showed a stepwise increase with increasing steatosis grade (p < .001) and were strongly correlated with the histological fat content (r = .7736, p < .001). The Bland-Altman plot revealed a mean bias of 2.384% (95% limit of agreement, - 6.582 to 11.351%) between them. Univariate regression analysis revealed no significant predictors of divergence. The AUROCs for distinguishing steatosis grades of ≥ 1, ≥2, and 3 were 0.956 (95% confidence interval [CI], 0.910-1.00), 0.926 (95% CI, 0.860-0.993), and 0.971 (95% CI, 0.929-1.000), respectively. The UDFF cutoff value of > 6% had a sensitivity and specificity of 94.8% and 82.3%, respectively, for diagnosing steatosis grade ≥ 1. There was no association between UDFF and the fibrosis stage. CONCLUSION: UDFF shows strong agreement with the histological fat content and excellent diagnostic accuracy for grading steatosis. UDFF is a promising tool for detecting and quantifying hepatic steatosis in clinical practice.

iATT liver fat quantification for steatosis grading by referring to MRI proton density fat fraction: a multicenter study.

BACKGROUND: Several preliminary reports have suggested the utility of ultrasound attenuation coefficient measurements based on B-mode ultrasound, such as iATT, for diagnosing steatotic liver disease. Nonetheless, evidence supporting such utility is lacking. This prospective study aimed to investigate whether iATT is highly concordant with magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF) and could well distinguish between steatosis grades. METHODS: A cohort of 846 individuals underwent both iATT and MRI-PDFF assessments. Steatosis grade was defined as grade 0 with MRI-PDFF < 5.2%, grade 1 with 5.2% MRI-PDFF < 11.3%, grade 2 with 11.3% MRI-PDFF < 17.1%, and grade 3 with MRI-PDFF of 17.1%. The reproducibility of iATT and MRI-PDFF was evaluated using the Bland-Altman analysis and intraclass correlation coefficients, whereas the diagnostic performance of each steatosis grade was examined using receiver operating characteristic analysis. RESULTS: The Bland-Altman analysis indicated excellent reproducibility with minimal fixed bias between iATT and MRI-PDFF. The area under the curve for distinguishing steatosis grades 1, 2, and 3 were 0.887, 0.882, and 0.867, respectively. A skin-to-capsula distance of ≥ 25 mm was identified as the only significant factor causing the discrepancy. No interaction between MRI-logPDFF and MRE-LSM on iATT values was observed. CONCLUSIONS: Compared to MRI-PDFF, iATT showed excellent diagnostic accuracy in grading steatosis. iATT could be used as a diagnostic tool instead of MRI in clinical practice and trials. Trial registration This study was registered in the UMIN Clinical Trials Registry (UMIN000047411).

Glycemic Control Is Associated with Histological Findings of Nonalcoholic Fatty Liver Disease.

BACKGRUOUND: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD. METHODS: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%. RESULTS: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses. CONCLUSION: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma.

AIMS: The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment. METHODS: A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression-free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c-index) and Akaike information criterion (AIC) results. RESULTS: Cox-hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI-De) scoring system. For IMABALI-De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p < .001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c-index 0.606). PFS periods for those IMABALI-De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c-index 0.574). As compared with CRAFITY score, IMABALI-De score had better AIC and c-index results for both OS and PFS. CONCLUSION: The present results indicated that the proposed IMABALI-De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy.

Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306).

Background & Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvedilol-treating cohort. Results: In the meta-analysis with six studies (n = 819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n = 151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n = 1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvedilol-treated cohort, patients with high-risk CSPH treated with carvedilol (n = 81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n = 613 before propensity score matching [PSM], n = 162 after PSM). Conclusions: Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Outcomes of patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab in real-world clinical practice who met or did not meet the inclusion criteria for the phase 3 IMbrave150 trial.

BACKGROUND: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC). AIMS: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real-world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial. METHODS: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non-IMbrave150 group). RESULTS: Median progression-free survival (PFS) in the IMbrave150 and non-IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non-B, non-C HCC aetiology (hazard ratio [HR], 1.173), α-fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin-bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non-Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α-fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a. CONCLUSIONS: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival.

Clinical and Pathological Features of Immune Checkpoint Inhibitor-induced Liver Injury in Comparison with Drug-induced Liver Injury and Autoimmune Hepatitis.

BACKGROUND AND AIMS: Immune checkpoint inhibitors may cause various types of organ damage as immune-related adverse events, of which, liver damage is the most common. Herein, we evaluated the clinicopathological features of immune checkpoint inhibitor-related liver injury and investigated the differences between immune checkpoint inhibitor-related liver injury and drug-induced liver injury or autoimmune hepatitis. METHODS: We selected patients with ≥ grade 3 liver injury who were diagnosed with immune checkpoint inhibitor-related liver injury (n=15). Liver biopsies were performed in 10 of the 15 cases. We also selected cases in which a liver biopsy was performed and drug-induced liver injury (n=7) or autoimmune hepatitis [n=21: acute exacerbation (n=13) was diagnosed and cases of acute onset (n=8), in which liver function test results corresponded to ≥ grade 3]. RESULTS: Portal fibrosis and periportal activity scores were significantly higher in the acute exacerbation autoimmune hepatitis group than in the other groups. Portal and lobular activity were not different between the groups. Plasma cell infiltration showed a higher trend in the autoimmune hepatitis group than in the other groups. Granuloma formations were seen in 90% of immune checkpoint inhibitor-related liver injury cases. The CD4/8 ratio was significantly lower in the immune checkpoint inhibitor-related liver injury group than in the other groups. Patients with bile duct injury had poorer response to corticosteroid therapy than those without. CONCLUSIONS: There are some obvious differences among immune checkpoint inhibitor-related liver injury, drug-induced liver injury, and autoimmune hepatitis in liver histology. Liver biopsy is helpful for the diagnosis and severity evaluation of liver injury.