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Spleen stiffness is increased in liver cirrhosis (LC). We attempted to characterize the pathological features of spleen in LC.We compared pathological findings of resected spleen tissues of 28 LC patients and those of six healthy controls. In addition, we measured spleen stiffness before splenectomy by shear wave elastography in nine LC patients. After splenectomy, we examined the relationship between spleen stiffness and pathological findings.Passive congestion of the spleen was more frequently observed in LC patients than in controls (P 0.01). The sinus was wider in LC patients than in controls (P 0.01). In the spleens of the LC patients, diffuse α-smooth muscle actin (αSMA) expression of sinusoidal mesenchymal cells and deposition of collagen fibers on the perisinusoidal wall were observed. In nine LC patients whose spleen stiffness was examined, the width of the sinus increased along with spleen stiffness (r = 0.89, P 0.01). Spleen stiffness was higher in the spleen tissues with diffuse αSMA expression of sinusoidal mesenchymal cells than in those with partial αSMA expression of sinusoidal mesenchymal cells (P = 0.01). The degree of fibrosis was higher in the LC patients with diffuse αSMA expression of the red pulp than in those with partial αSMA expression of the red pulp (P = 0.03).In the LC patients, spleen tissues showed passive congestion with a dilated sinus, diffuse αSMA expression of sinusoidal mesenchymal cells, and deposition of collagen fibers on the perisinusoidal wall. This contributed to spleen stiffness.

To develop and validate a simple predictive model using easily obtained clinical parameters to predict decreased skeletal muscle mass (DSMM) in chronic liver disease (CLD) patients (n = 652).Study subjects were divided into a training set (n = 326) and a validation set (n = 326). Decreased skeletal muscle mass was diagnosed based on skeletal muscle mass index measured by bioimpedance analysis. Variables significantly associated with DSMM were identified using univariate and multivariate analyses in the training set and used to construct a predictive formula. Receiver operating characteristic (ROC) curve analysis was carried out and the predictive model was validated in the validation set. Subgroup analyses were undertaken based on gender, age, or cirrhosis status of patients.Body mass index (BMI), age, serum albumin, and branched-chain amino acid to tyrosine ratio (BTR) were determined to be significant predictive factors for DSMM. A composite formula "BALB score" was constructed [-7.740 + (0.539 × BMI) + (-0.112 × age) + (1.358 × albumin) + (-0.264 × BTR)]. The BALB score had the best predictive characteristics among all variables in both population sets (area under the ROC curve, 0.877-0.898). Patients with DSMM were stratified into three BALB score categories (4, 0-4, and0). Subgroup analyses also showed that BALB scoring was predictive of DSMM irrespective of gender, age, or cirrhosis status. The BALB score significantly correlated with psoas muscle index on computed tomography (rThe BALB scoring system based on routinely used clinical parameters offers a convenient and non-invasive method for predicting DSMM in compensated CLD patients with high accuracy.

To investigate the impact of low skeletal muscle mass (LSMM) on survival as compared with protein-energy malnutrition (PEM) in patients with liver cirrhosis (LC).A total of 206 individuals with LC were analyzed. We retrospectively examined the impact of LSMM, as defined by psoas muscle mass at the third lumber on computed tomography, on survival as compared with PEM. In terms of comparison of the effects of LSMM and PEM on survival, we used time-dependent receiver operating characteristics (ROC) analysis.Our study cohort included 115 men and 91 women with a median age of 67 years. There were 140 patients with Child-Pugh A, 62 with Child-Pugh B, and 4 with Child-Pugh C. A total of 117 patients (56.8%) had LSMM and 52 patients (25.2%) had PEM. The proportion of PEM in patients with LSMM (31.62%, 37/117) was significantly higher than in patients without LSMM (16.85%, 15/89) (P = 0.0229). In the multivariate analysis for the entire cohort, the presence of hepatocellular carcinoma, lower body mass index, presence of LSMM, lower triglyceride value, poorer renal function, and higher des-γ-carboxy prothrombin value were found to be significant adverse predictors linked to overall survival, while presence of PEM tended to be significant. In the time-dependent ROC analysis, all area under the ROCs for survival in LSMM at each time point were higher than those in PEM except for Child-Pugh B patients.In this comparison of LSMM and PEM on clinical outcomes in LC patients, it was shown that LSMM may have stronger prognostic impact than PEM.

We aimed to construct a predictive model for advanced fibrosis containing Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFAA total of 386 patients with CHC were retrospectively analyzed. For the purpose of this study, we formed a training set (n = 210) and a validation set (n = 176). In the training set, we investigated variables linked to the presence of advanced fibrosis using univariate and multivariate analyses. We constructed a formula for predicting advanced fibrosis and validated its accuracy in the validation cohort. Receiver operating characteristic curve (ROC) analysis was carried out for calculating the area under the ROC (AUROC).In multivariate analyses, WFAOur proposed MPPH scoring system can be useful for predicting advanced fibrosis in patients with CHC.

This study aimed to compare the severity of sleep problems between chronic hepatitis C (CHC) patients treated with interferon (IFN)-based triple therapy (pegylated [Peg]-IFN plus ribavirin [RBV] plus simeprevir [SMV]) and those who received IFN-free direct-acting antiviral (DAA) therapy.Our study included 31 patients in group A (Peg-IFN/RBV/SMV combination therapy) and 41 patients in the group B (IFN-free DAA therapy). We prospectively compared the effect of each antiviral treatment regimen on sleep conditions between the two groups adding actigraphy data. Five parameters detected by actigraphy (objective assessment) and scores of the Pittsburgh Sleep Quality Index (subjective assessment, n = 30 [group A] and 35 [group B]) were estimated. The causal effect of each therapy on sleep disturbances was evaluated at baseline and at 4 weeks after commencement of therapy.In terms of baseline characteristics, no significant differences between groups were found, except for hepatitis C virus genotype. In group A, sustained virological response 12 rate was 83.9% (26/31), whereas in group B it was 95.1% (39/41). In group A, each score of waking after sleep onset, activity index, wake episodes, and Pittsburgh Sleep Quality Index at 4 weeks significantly increased compared to those evaluated at baseline. In group B, scores of all variables except for sleep episodes at 4 weeks did not significantly change compared to those at baseline.Interferon-based triple therapy in patients with CHC may cause significant sleep disturbances. Interferon-free DAA therapy is less likely to deteriorate sleep conditions in patients with CHC.

To examine the relationship between serum Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFAA total of 189 treatment naïve-CHB patients were analyzed. We examined the effect of pretreatment serum WFAThe WFAThe WFA

To examine the impact of pretreatment Wisteria floribunda agglutinin positive Mac-2-binding protein (WFAA total of 57 patients were analyzed. All subjects were initially treated with NUC. We examined the impact of pretreatment WFAThere were 36 men and 21 women (median age, 39 years). The WFAPretreatment WFA

To examine the relationship between the Wisteria floribunda agglutinin positive Mac-2-binding protein (WFAA total of 134 NASH patients (mean age, 51.7 years) were analyzed. We examined the effect of WFAThe WFASerum WFA

We aimed to examine the relationship between the Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA(+) -M2BP) level and high-sensitivity C-reactive protein (hCRP) concentration and liver histological findings for patients with autoimmune hepatitis (AIH).A total of 84 AIH patients (median age, 64 years) were analyzed. We examined the effect of pretreatment WFA(+) -M2BP level and hCRP concentration on histological findings of liver fibrosis and liver inflammation activity comparing with other laboratory markers. Receiver-operator curve (ROC) analysis was performed for calculating the area under the ROC (AUROC).The median WFA(+) -M2BP values in each fibrosis stage were: 1.5 cut-off index (COI) in F1, 2.1 in F2, 3.3 in F3 and 9.8 in F4 (P 0.001). The median WFA(+) -M2BP values in each liver inflammation stage were: 1.6 COI in A1, 2.5 in A2 and 5.4 in A3 (P 0.001). For predicting liver cirrhosis (F4), WFA(+) -M2BP yielded the highest AUROC (0.853). For predicting advanced liver fibrosis (F3 or F4), WFA(+) -M2BP, FIB-4 index and hyaluronic acid yielded the highest AUROC (0.747). For predicting severe liver inflammation activity (A3), WFA(+) -M2BP yielded the highest AUROC (0.739). The hCRP concentration in patients with A3 (median, 2230 ng/mL) was significantly higher than that in patients with A1 or A2 (median, 854.5 ng/mL) (P 0.01). WFA(+) -M2BP level significantly correlated with hCRP concentration (rs = 0.461, P 0.001).WFA(+) -M2BP can be a useful marker for assessing liver histological findings in AIH patients and it correlated well with hCRP concentration.

We aimed to examine the relationship between serum Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA(+) -M2BP) levels and serum interferon-γ-inducible protein-10 (IP-10) levels and liver histological findings for patients with primary biliary cirrhosis (PBC) compared with other laboratory fibrotic or inflammatory parameters.A total of 57 PBC patients were analyzed. Receiver-operator curve (ROC) analysis was performed for calculating the area under the ROC (AUROC) for WFA(+) -M2BP, IP-10 and four serum fibrosis markers for the presence of liver cirrhosis (F4) or advanced fibrosis (F3 or F4). Similarly, ROC analysis of WFA(+) -M2BP, IP-10, aspartate aminotransferase and alanine aminotransferase for the presence of severe inflammation activity (A3) was performed.There were eight men and 49 women (median age, 59 years). As for histological findings, F4 was observed in five patients, F3 in 11, F2 in 17, F1 in 24 and F0 in zero, whereas A3 was observed in seven patients, A2 in 27, A1 in 19 and A0 in four. The WFA(+) -M2BP levels ranged from 0.5 cut-off index (COI) to 13.6 COI (median, 1.8), while serum IP-10 levels ranged 121.9-1835.9 pg/mL (median, 571.5). For predicting liver cirrhosis, WFA(+) -M2BP yielded the highest AUROC (0.97, P 0.01). For predicting severe liver inflammation activity (A3), WFA(+) -M2BP and serum IP-10 yielded the highest AUROC with a level of 0.87. WFA(+) -M2BP levels significantly correlated with serum IP-10 levels (rs = 0.55, P 0.0001).Serum WFA(+) -M2BP and serum IP-10 can be useful markers for predicting histological findings in PBC patients.

In chronic liver disease associated with hepatitis C virus (HCV), a low platelet count is a major obstacle in carrying out interferon (IFN) treatment. We used a questionnaire to clarify the extent to which splenectomy/partial splenic embolization (PSE) is performed before IFN treatment, as well as the efficacy and complications thereof.Two questionnaires were distributed to 413 medical institutes in Japan specializing in the treatment of liver diseases, and responses were obtained from 204 institutes. Furthermore, a more detailed questionnaire was completed by 10 institutes that experienced cases of death.In patients with HCV genotype 1b and a high viral load (HCV1b/High), the sustained viral response (SVR) rate was 28% for the splenectomy group and 22% for the PSE group, with no significant difference between these groups. In patients that were not HCV1b/High, the SVR rate was higher in those that underwent splenectomy (71%) compared to the PSE group (56%; P = 0.025). There were cases of death in seven of 799 splenectomy cases (0.89%) and four of 474 PSE cases (0.84%). Infectious diseases were involved in nine of 11 cases of death, with a peculiar patient background of Child-Pugh B (6/10) and an age of 60 years or greater (7/11).The application of splenectomy/PSE before IFN treatment should be avoided in patients with poor residual hepatic function and/or elderly patients. In HCV1b/High patients, splenectomy/PSE should be performed only after selecting those in which IFN treatment should be highly effective.

Sonazoid is a new contrast agent for ultrasonography (US). Contrast-enhanced ultrasonography (CEUS) using Sonazoid enables Kupffer imaging, which improves the sensitivity of hepatocellular carcinoma (HCC) detection. However, there are no studies on the cost-effectiveness of HCC surveillance using Sonazoid. We constructed a Markov model simulating the natural history of HCV-related liver cirrhosis (LC) patients, and compared three strategies (no surveillance, US surveillance and CEUS surveillance). The transition probability and cost data were obtained from published data. The simulation and analysis were performed using TreeAge pro 2009 software. When compared to the no surveillance group, the US and CEUS surveillance groups increased the life expectancy by 1.67 and 1.99 quality-adjusted life-years (QALY), respectively, and the incremental cost effectiveness ratio (ICER) were 17 296 $US/QALY and 18 384 $US/QALY, respectively. These results were both less than the commonly-accepted threshold of $US 50 000/QALY. Even if the CEUS surveillance group was compared with the US surveillance group, the ICER was $US 24 250 and thus cost-effective. Sensitivity analysis showed that the annual incidence of HCC and CEUS sensitivity were two critical parameters. However, when the annual incidence of HCC is more than 2% and/or the CEUS sensitivity is more than 80%, the ICER was also cost-effective. Contrast-enhanced ultrasonography surveillance for HCC is a cost-effective strategy for LC patients and gains their longest additional life years, with similar degree of ICER in the US surveillance group. CEUS surveillance using Sonazoid is expected to be used not only in Japan, but also world-wide.

To evaluate the dynamics of Kupffer cell (KC) phagocytosis by performing both in vivo and in vitro studies using Sonazoid (GE Healthcare, Oslo) in a rat nonalcoholic steatohepatitis (NASH) model.Contrast enhanced ultrasonography (CEUS) was performed on a rat NASH model induced by a methionine choline deficient diet (MCDD) and control rats, and Sonazoid was used to measure the signal intensity in the liver parenchyma. The uptake of Sonazoid by the KCs was observed by intravital microscopy. Their phagocytic capability was evaluated in vitro using isolated and cultured KCs. The uptake of fluorescein isothiocyanate (FITC)-labeled latex beads was observed and quantitatively analyzed by flow cytometry.In the MCDD group, liver parenchymal enhancement was reduced 20 min after the Sonazoid injection. Microscopic observation of the isolated and cultured KCs revealed that the number of phagocytosed Sonazoid microbubbles was significantly decreased. Confocal laser scanning microscopic (CLSM) observation showed a decrease in the uptake of the latex beads. A decreased phagocytic capacity in the MCDD group was suggested by the quantitative analysis using flow cytometry, as well as by intravital microscopy.CEUS with Sonazoid is a powerful evaluation tool to diagnose NASH from an early stage of the disease.

Aim: To determine whether parametric imaging correlates with the degree of histological differentiation of hepatocellular carcinoma (HCC). Methods: The samples comprised 49 nodules diagnosed histologically as HCC: 19 well differentiated (w-HCC), 22 moderately differentiated (m-HCC), and eight poorly differentiated (p-HCC). The ultrasound (US) equipment used was SSA-770 A (Toshiba Medical Systems, Otawara, Japan) and the contrast agent was SonoVue (Bracco, Milan, Italy). After 1.5 mL of SonoVue was injected intravenously and staining of the tumors and parenchyma was confirmed, microbubbles in the scanned volume were eliminated using high mechanical index (MI) scanning frames. The “arrival time (TA) images,” reflecting β-values, were displayed with color codes at the phase after reperfusion. Images at the phase when the staining reached a plateau (90–180 s) were used as “A images,” reflecting A values. These images were compared between each histological grade of differentiation. Results: Analysis of TA images indicated that β-values in m-HCC were higher than those in the adjacent non-tumor parenchyma in all 22 samples and also were significantly higher than in the other HCCs (P

Aim: Non-alcoholic steatohepatitis (NASH) is one of the representative liver diseases in developed countries. Diagnosis of NASH is dependent on histological findings from liver biopsy. Methods: The usefulness of contrast ultrasound with Levovist for diagnosis of NASH is described. 2.5 g of ultrasound contrast agent Levovist was injected intravenously. The liver was scanned at 5, 10, 15, 20, 30, 40 and 50 min and changes in microbubble accumulation were evaluated. The signal intensity from regions of interest (ROI) on the contrast images was measured and estimated using time intensity curves (TICs). Twenty-one patients with NASH, 33 with non-alcoholic fatty liver disease (NAFLD) and 10 healthy volunteers (HV) were studied. The signal intensity was measured quantitatively at 5 and 20 min after injection. Results: There was a statistically significant decrease in NASH, when compared with NAFLD and HV groups. These changes in signal intensity were not correlated to the degree of fibrosis and steatosis in histological study. The sensitivity, specificity and overall accuracy obtained from the receiver operating characteristic (ROC) curve were 100% when the cut-off value was set at 43.6 of signal intensity at 20 min. Conclusion: The Levovist contrast study is a useful screening examination which picks up NASH among fatty liver patients.

We evaluated the time-intensity curves of the ultrasound contrast agent, Levovist, in the aorta, portal vein and liver parenchyma in order to define distribution of the agent when it is administered by an intravenous bolus injection. Twelve healthy volunteers were studied. All 12 subjects were examined for the study of vascular phase and five of the subjects were examined for the study of delayed parenchymal phase. To evaluate vascular enhancement, transverse abdominal scanning was performed. To evaluate parenchymal enhancement, liver scanning was done just once at 14 time points up to 60 min after injection. The time-intensity curves in the aorta and the portal vein indicated the conventional curves of blood pool agents such as iodine CT agents and gadolinium MRI agents. They showed steep initial rises and peaks at 20 s and 30 s after injection, respectively. Parenchymal enhancement reached a peak five minutes after injection, with a plateau for 20 min subsequently. It has been proved that there are two phases of Levovist contrast ultrasonography, the vascular phase and the delayed parenchymal phase.

Background and aims Non alcoholic steatohepatitis (NASH) is one of the representative liver diseases in the developed countries. Diagnosis of NASH is dependent on histological findings from liver biopsy. Usefulness of contrast ultrasound with Levovist for diagnosis of NASH is described. Methods and materials Clinical study : Ultrasound contrast agent, Levovist of 2.5 g was injected intravenously. The liver was scanned at 5, 10, 15, 20, 30, 40, and 50 min after Levovist injection in different planes using a contrast specific ultrasound mode. Changes in microbubble accumulation in the liver were evaluated. The signal intensity from regions of interest (ROI) on the contrast images was measured and accumulation and decrescence of microbubbles were estimated using the time intensity curves (TICs). The image data and TICs were evaluated by blind reviewers. Fifteen patients with NASH, 8 with alcoholic steatohepatitis (ASH), 45 with non alcoholic fatty liver (NAFL), 10 with chronic hepatitis C (CHC) and 10 healthy volunteers were studied. Animal study : Methionine–choline-deficient diet (MCDD) fed rats were used for NASH model. Correlation between microbubble accumulation and morphological and functional changes of sinusoidal endothelium and macrophage was evaluated. Results The maximum intensity of contrast ultrasound was decreased and time course decrescence was more rapid in NASH than the other groups. These changes were correlated to the degree of centrilobular and pericellular fibrosis but not to steatosis in histological study. Disturbance of microbubble accumulation was correlated with sinusoidal function rather than morphological changes such as fibrosis and parenchymatitis in the animal studies. Conclusions The Levovist contrast study enables differential diagnosis between NASH and other diseases that provoke steatosis and fibrosis.

Objective: The therapeutic response of radio-frequency ablation (RFA) for hepatocellular carcinoma (HCC) was evaluated by contrast-enhanced ultrasonography (US) using a new contrast mode, agent detection imaging (ADI), and its usefulness was compared with that of dynamic computed tomography (CT). Materials and methods: Forty patients with 64 nodules diagnosed as HCC histologically and/or by various imaging modalities were evaluated with ADI (1 and 7 days after treatment) and Dynamic CT (7 days after treatment). Results: ADI and dynamic CT revealed residual lesions in 15 and 12 nodules, and no residual lesions in 45 and 52 nodules, respectively. ADI yielded indeterminate findings in four nodules; although the vascular phase showed minute residual tumor vessels, the tumor appeared to be completely contained within the ablated area in the delayed phase. In these indeterminate cases, US-guided biopsies of the areas of residual vascularity revealed no viable cancer cells; only degenerated tissues. Conclusion: In assessing the therapeutic response of RFA for HCC, ADI has a similar competence to dynamic CT. Even if the vascular phase of contrast-enhanced US shows minute residual vessels, as long as the tumor is safely contained within the ablated area in the delayed phase, the cancer cells are likely to be degenerated.