Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1007/s12328-023-01914-7

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BACKGROUND: 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.

DOI： 10.4093/dmj.2023.0200

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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.

DOI： 10.15403/jgld-5045

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

DOI： 10.1038/s41598-023-36052-0

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Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009-2013, n = 86; period 2: 2014-2018, n = 132; period 3: 2019-2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1-3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin-bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.

DOI： 10.3390/cancers15215298

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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BACKGROUND: The chronological pattern of extrahepatic lymphatic vessel progression in the course of chronic liver disease has not been clarified. This study aimed to clarify the chronological changes in lymphatic vessels with liver disease progression. METHODS: This was a prospective cross-sectional study that enrolled a total of 199 patients. The maximum diameter of the cisterna chyli (CC) or terminal thoracic duct (tTD) was measured using computed tomography or ultrasonography, respectively. Changes in the maximum diameters of the CC and tTD were evaluated with patients with chronic liver disease as the pilot set (n = 138). Subsequently, we examined whether CC/tTD could be used to re-allocate unclassified patients by the Baveno-VII criteria to appropriately diagnose clinically significant portal hypertension (CSPH) in the pilot and validation sets. RESULTS: In the pilot set, a scatter-plot showed that both CC and tTD were narrowed as terminal features in chronic liver disease after dilation. Because there was a significant correlation between the CC diameter and hepatic venous pressure gradient (r = 0.724) in unclassified patients, the diagnostic value of CC and tTD for CSPH was good (AUC: 0.961 and 0.913, respectively). After re-allocation, 68 and 27 unclassified patients were reduced to 4 and 5 in the pilot and validation sets, respectively. CONCLUSION: Both the CC and tTD narrow in the course of liver disease after dilation. Moreover, the maximum diameter of the CC and tTD can be used to re-allocate patients who are unclassified according to the Baveno-VII criteria. CLINICAL TRIAL NUMBER: UMIN trial no. 000044857.

DOI： 10.1007/s12072-023-10563-4

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

DOI： 10.1038/s41598-023-36052-0

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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We herein report a 63-year-old man who presented with left lower jaw pain and was diagnosed with hepatocellular carcinoma with bone metastases post-examination. All tumors grew after immunotherapy with atezolizumab and bevacizumab, and his jaw pain worsened. After palliative radiation therapy, however, the tumors shrank markedly, with no recurrence seen after stopping immunotherapy. To our knowledge, this is the first case in which a radiotherapy- and immunotherapy-mediated abscopal effect facilitated tumor shrinkage and immunotherapy discontinuation.

DOI： 10.2169/internalmedicine.1844-23

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AIM: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

DOI： 10.1111/hepr.13925

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c+ M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.

DOI： 10.3390/ijms24032509

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Language：Japanese   Publisher：(一社)日本成人先天性心疾患学会  

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Aim: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. Methods: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. Results: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. Conclusions: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

DOI： 10.1111/hepr.13925

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Language：Japanese   Publisher：(一社)日本肝臓学会  

症例は70代女性.COVID19ワクチン2回目を接種2日後に黄疸が出現し,急性肝障害のため入院となった.各種ウイルスマーカーは陰性,抗核抗体陽性,抗平滑筋抗体陽性,IgG高値であった.肝生検組織では,肝実質に広範な壊死・炎症がみられた.門脈域にも炎症細胞浸潤がみられたが,線維化やinterface hepatitisは明らかでなかった.COVID19ワクチンに対するリンパ球刺激試験が陽性であり,当初は自己免疫機序の関与が示唆された薬物性肝障害と診断した.しかし,肝庇護療法では肝機能検査異常は改善せず,副腎皮質ステロイド投与を開始し改善した.改善後の肝生検ではロゼット形成,interface hepatitisや形質細胞浸潤が確認され,COVID19ワクチンに誘発された自己免疫性肝炎(AIH)と診断した.COVID19ワクチン投与後に発症したAIHの症例は極めてまれであり報告する.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00263&link_issn=&doc_id=20221111010003&doc_link_id=10.2957%2Fkanzo.63.491&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.63.491&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本肝臓学会  

症例は70歳男性.アルコール性肝硬変の経過中にアルコール性肝炎を合併し入院した.血尿を伴うネフローゼ症候群を呈しており,禁酒,利尿剤と栄養療法の導入により蛋白尿は改善した.顕微鏡的血尿が残存したため腎生検を実施し,血栓性微小血管障害症(TMA)と診断した.血漿ADAMTS13活性低下とvon Willebrand factor(VWF)抗原高値がみられ,肝星細胞減少によるADAMTS13産生低下がTMAの原因と想定された.ADAMTS13補充目的に新鮮凍結血漿(FFP)の投与,内皮細胞障害に対してトロンボモジュリン製剤(rTM)を開始した.FFPの漸減,中止後もADAMTS13活性の低下はみられず,腎機能が維持された.肝硬変の経過中に血尿が出現した場合,ADAMTS13活性低下とVWF抗原とのインバランスがある場合はTMAを疑い,FFPやrTMの投与を考慮する必要があると考えられた.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00263&link_issn=&doc_id=20221111010001&doc_link_id=10.2957%2Fkanzo.63.473&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.63.473&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.

DOI： 10.3390/biomedicines10102540

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BACKGROUND: The novel 2-D shear wave elastography (2D-SWE) can measure two ultrasound parameters: shear wave dispersion (SWD) and shear wave speed (SWS). We investigated the ability of 2D-SWE in measuring spleen stiffness using ultrasound multiparametric imaging. METHODS: This cross-sectional study included patients with chronic liver disease who underwent esophagogastroduodenoscopy and ultrasonographic examinations of the spleen between September 2018 and December 2021. In total, 157 patients were enrolled in this study: 81 and 67 patients were included in the pilot set for hepatic venous pressure gradient (HVPG) measurements and validation cohort without HVPG measurements, respectively. To confirm reproducibility between the two examiners, an additional 30 patients were enrolled. RESULTS: The Bland-Altman plots revealed no significant bias in the SWD as measured by two examiners. The splenic SWS (r = 0.752) and SWD (r = 0.444) were correlated with the HVPG. Regarding high-risk varices, as per the Youden index, the cut-off value for splenic SWS was 3.30 m/s, with a sensitivity of 85.7%, specificity of 92.5%, positive predictive value of 85.7%, and negative predictive value of 92.4% in the pilot set. In the validation set, good diagnostic performance by the splenic SWS was observed. However, SWD did not perform as well as SWS. CONCLUSIONS: The splenic SWS, measured using ultrasound multiparametric imaging, was closely correlated with the HVPG. Thus, SWS is a useful predictive marker for high-risk varices.

DOI： 10.1111/hepr.13841

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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For patients with cirrhosis, no definitive predictor of the efficacy and prognosis of tolvaptan treatment exists. We assessed the cisterna chyli's utility as an optimal marker. We retrospectively enrolled 172 patients with cirrhosis. The effect of tolvaptan was evaluated using post-treatment survival time. The overall response to tolvaptan was 52.3%. The median cisterna chyli diameter was 4.1 mm. Of 172 patients, 100 were included in the pilot set and 72 in the validation set. According to the Youden index, the cisterna chyli diameter's cutoff value was 4 mm, with a sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of 92%, 83%, 86%, 91%, 5.43, and 0.09, respectively, in the pilot set. The area under the curve of the cisterna chyli diameter for evaluating tolvaptan's effect was 0.911 and 0.988 in the pilot and validation sets, respectively. During multivariate analysis, cisterna chyli narrowing and furosemide treatment were significant predictive factors for tolvaptan's insufficient effect. Cumulative liver transplantation-free survival rates were significantly higher in patients with cisterna chyli dilatation than in those without (p = 0.028). Our findings suggest a strong association of cisterna chyli with tolvaptan treatment response in patients with cirrhosis and hepatic edema.

DOI： 10.1038/s41598-022-11889-z

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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INTRODUCTION: Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM. METHODS: This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.

DOI： 10.1007/s13300-022-01239-7

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The accuracy of attenuation coefficients and B-mode ultrasound for distinguishing between S0 (healthy, < 5% fat) and S1-3 (steatosis ≥ 5%) livers compared to a controlled attenuation parameter is unclear. This meta-analysis aimed to comprehensively assess the diagnostic performance of B-mode ultrasound imaging for evaluating steatosis of ≥ 5%. We searched the PubMed, Embase, and Web of Science databases for studies on the accuracy of B-mode ultrasound for differentiating S0 from S1-3 in adults with chronic liver disease. A bivariate random-effects model was performed to estimate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and diagnostic odds ratios (DORs). Subgroup analyses by attenuation coefficient, conventional B-mode ultrasound findings, and B-mode ultrasound findings without semi-quantification methods were performed. Liver steatosis was scored as follows: S0, < 5%; S1, 5-33%; S2, 33-66%; and S3, > 66%. Nineteen studies involving 3240 patients were analyzed. The pooled sensitivity and specificity of B-mode ultrasound for detecting S1 were 0.70 (95% confidence interval [CI], 0.63-0.77) and 0.86 (95% CI 0.82-0.89), respectively. The pooled PLR, NLR, and DOR were 4.90 (95% CI 3.69-6.51), 0.35 (95% CI 0.27- 0.44), and 14.1 (95% CI 8.7-23.0), respectively. The diagnostic accuracy was better in patients with attenuation coefficients (area under the curve [AUC], 0.89; sensitivity, 0.75; specificity, 0.86) than in those with conventional B-mode findings (AUC, 0.80; sensitivity, 0.59; specificity, 0.83). In particular, the diagnostic value was better when the attenuation coefficient guided by B-mode ultrasound was utilized. To screen patients with steatosis of ≥ 5%, attenuation coefficient should be used.

DOI： 10.1007/s10396-022-01196-5

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: To validate an appropriate spleen size measurement technique for the prediction of high-risk esophagogastric varices. METHODS: This retrospective cross-sectional study included 369 patients who underwent ultrasonography and computed tomography (CT) of the spleen and esophagogastroduodenoscopy between January 2018 and December 2020. Maximum spleen length, width, and craniocaudal length were measured in a longitudinal view. The two-dimensional (2D) spleen index (maximum length × maximum width in the longitudinal view) was calculated. A three-dimensional (3D) spleen index was then defined as follows: 2D spleen index × maximum length in the transverse view. The similarity in spleen volume measured by CT and ultrasonography (spleen index) was assessed by the correlation coefficient. The diagnostic accuracies of the spleen index, platelet/spleen length, and platelet/spleen index were calculated to determine the overall diagnostic accuracy. RESULTS: Compared to the other spleen indices, our 3D spleen index was significantly better correlated with spleen volume on CT (r = 0.91, 95% confidence interval 0.89-0.92, p < 0.001). Receiver-operating characteristic curve analyses revealed no significant difference between the 3D and 2D indices (p = 0.228) but did show a significant difference between the 3D and one-dimensional indices (p = 0.020). Although the area under the curve for the platelet count combined with the spleen index or length was higher than that for our 3D index, there was no significant difference between platelet count and spleen index or length (p = 0.078). CONCLUSIONS: Platelet/spleen length has a reasonable ability to predict high-risk esophagogastric varices, even though measurement of two or three factors can be correlated with spleen volume.

DOI： 10.1111/hepr.13716

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan–Meier Plotter. <italic>ASC</italic> expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high <italic>ASC</italic> expression in multiple PDAC cells, with <italic>ASC</italic> silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, <italic>ASC</italic> silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.

DOI： 10.1038/s41598-021-01465-2

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Other Link： https://www.nature.com/articles/s41598-021-01465-2

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Language：English   Publishing type：Research paper (scientific journal)  

Background and Aim: Spleen stiffness measurement (SSM) is useful for assessing portal hypertension. It is unclear whether SSM values are appropriate because vibration-controlled transient elastography (VCTE) does not generate B-mode images. This study aimed to confirm whether the controlled attenuation parameter (CAP) measured in the spleen can predict the accuracy of SSM. Methods: This retrospective study enrolled 349 patients who underwent SSM using VCTE from January 2012 to December 2020. Consecutive patients were classified into the pilot set (SSM and hepatic venous pressure gradient [HVPG] were measured) and the validation set (SSM was measured without HVPG). In the pilot set, scatter plots with a nonparametric contour line were created. Logistic regression analysis was performed to predict outliers outside the 50% contour line. Results: The values of CAP could distinguish the outliers in scatter plots between the HPVG and SSM in both univariate and multivariate analyses (cutoff, 118 dB/m). The correlation of SSM with HVPG (r = 0.718; P < 0.001) was significantly better in the low CAP (≤118 dB/m) group than in the high CAP (>118 dB/m) group (r = 0.330; P < 0.001). The area under the receiver operating characteristic curve of SSM in predicting high-risk varices was better in the low CAP group than in all patients or in the high CAP group in the pilot set (0.881, 0.854, and 0.843, respectively) and in the validation set (0.893, 0.821, and 0.814, respectively). Conclusion: For patients with CAP <118 dB/m, SSM is a feasible predictor of HVPG.

DOI： 10.1002/jgh3.12647

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Hepatocellular carcinoma has been considered to disseminate through the tumor blood drainage area. To improve curation rates, treatment should cover this area as it may contain satellite lesions. This retrospective study aimed to investigate whether radiofrequency ablation (RFA) completely covering the blood drainage area can improve the overall and disease-free survival. We enrolled 526 patients who underwent computed tomography during hepatic arteriography following RFA from April 2001 to May 2019. Patients were categorized into a covered group in which the blood drainage area was completely covered by RFA and a noncovered group in which coverage was incomplete. The primary endpoint was the overall survival rate; secondary outcomes included disease-free survival rate, distant intrahepatic and local recurrence rate, and changes in the Child-Pugh score. There were no significant differences in baseline characteristics between the two groups. Cumulative overall survival rates were significantly higher in the covered group than in the noncovered group (hazard ratio, 0.63; 95% confidence interval, 0.48-0.84; P = 0.002). On multivariate Cox proportional hazard model analysis, age <65 years, Child-Pugh class A, and coverage of the entire drainage area were independent protective factors. Child-Pugh worsened in 11 (4.2%) patients in the covered group compared to 18 (6.7%) patients in the noncovered group. Conclusion: RFA covering the complete drainage area improved overall survival without decreasing liver function.

DOI： 10.1002/hep4.1703

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. METHODS: Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as 'early recurrence', and recurrence more than 1 year after as 'late recurrence'. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. RESULTS: Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026-1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. CONCLUSION: Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

DOI： 10.1186/s12885-021-08401-7

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: The FibroScan-aspartate aminotransferase (FAST) score comprises an easy and feasible method for identifying advanced non-alcoholic steatohepatitis. Recently, shear-wave elastography and attenuation coefficient measurement on B-mode ultrasound (US) have become widely utilized. We investigated the diagnostic accuracy of the FAST score as calculated using US-elastography compared with that using vibration-controlled transient elastography (VCTE). METHODS: Patients with chronic liver disease who underwent VCTE, point-shear-wave elastography with attenuation coefficient measurement, and liver biopsy on the same day between January 2015 and September 2020 were retrospectively reviewed. RESULTS: Of 189 patients, 94 underwent VCTE using both M and XL probes. The C-statistics were similar for VCTE (0.846) and US-elastography (0.814; p = 0.251), and for M (0.857) and XL probes (0.833; p = 0.412). Scatter and Bland-Altman plots showed good reproducibility for the FAST score. For VCTE, a cut-off of ≤0.35 had a sensitivity of 92.3%, negative predictive value of 85.5%, and negative likelihood ratio of 0.14, and a cut-off of ≥0.67 had a specificity of 90.6%, positive predictive value of 88.1%, and positive likelihood ratio of 6.03, for ruling out and in advanced non-alcoholic steatohepatitis, respectively. For US-elastography, a cut-off of ≤0.35 had a sensitivity of 90.4%, negative predictive value of 83.3%, and negative likelihood ratio of 0.16, and a cutoff of ≥0.67 had a specificity of 91.8%, positive predictive value of 85.1%, and positive likelihood ratio of 4.67, for ruling out and in advanced non-alcoholic steatohepatitis, respectively. CONCLUSIONS: The FAST score is highly reproducible, even when different echo equipment or probes are used.

DOI： 10.1111/hepr.13646

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Causes of non-alcoholic fatty liver disease and its progression include visceral fat accumulation and loss of muscle mass; however, which of the two phenomena is more critical is unclear. Therefore, we intended to examine the relationship between body composition and non-alcoholic fatty liver disease progression as indicated by fibrosis and the non-alcoholic fatty liver disease activity score. METHODS: This cross-sectional study comprised 149 patients (55 men; age, 20-76 years) treated for non-alcoholic fatty liver disease between December 2010 and January 2020. Body composition measurements, histological examinations of liver samples, and comprehensive blood chemistry tests were performed. The relationship between body composition and non-alcoholic fatty liver disease histology findings was analyzed using the logistic regression model. RESULTS: Fibrosis was significantly and inversely correlated with muscle mass and appendicular skeletal muscle mass and significantly and positively correlated with fat mass, fat mass/height squared, visceral fat area, and waist-hip ratio (P < 0.05). After adjustment for sex, blood chemistry measurements, and body composition indices, fibrosis remained associated with appendicular skeletal muscle mass, fat mass, fat mass/height squared, and visceral fat area (P < 0.05). Non-alcoholic fatty liver disease activity score ≥ 5 significantly correlated with fat mass and fat mass/height squared in a univariate but not multivariate analysis. CONCLUSIONS: Fibrosis in non-alcoholic fatty liver disease, an indicator of unfavorable long-term outcomes, is associated with more indices of fat mass than of those of muscle mass. Hence, fat mass should be controlled to prevent non-alcoholic fatty liver disease progression.

DOI： 10.1186/s12876-021-01748-y

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Endoplasmic reticulum (ER) stress plays an important role in hepatocyte degeneration, especially in patients with chronic liver injury. Protein kinase R-like endoplasmic reticulum kinase (PERK) is a key molecule in ER stress. PERK may contribute to apoptotic cell death in HCC, however the details of the mechanism are not clear. In this study, we identified PERK-associated molecules using transcriptome analysis. We modulated PERK expression using a plasmid, tunicamycin and siRNA against PERK, and then confirmed the target gene expression with real-time PCR and Northern blotting. We further analyzed the apoptotic function. Transcriptome analysis revealed that expression of the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), which is a long noncoding RNA, was strongly correlated with the function of PERK. The expression of RMRP was correlated with the expression of PERK in experiments with the siRNA and PERK plasmid in both HCC cell lines and human HCC tissue. Furthermore, RMRP downregulation induced apoptotic cell death. RMRP is downregulated by PERK, which induces apoptosis in HCC. RMRP could be a new therapeutic target to regulate HCC in patients with chronic liver diseases associated with ER stress.

DOI： 10.1038/s41598-021-86592-6

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Patients with a Fontan circulation tend to develop liver fibrosis, liver cirrhosis and even hepatocellular carcinoma. A noninvasive ultrasound technique for liver fibrosis and cardiac function assessment in Fontan-associated liver disease (FALD) is needed to evaluate disease progression in real time. This study aimed to evaluate whether hepatic vein (HV) waveform analysis and elastography could be alternative markers to cardiac index (CI) in patients with FALD and assess factors influencing elastography measurements in FALD cases. METHODS: All patients underwent cardiac catheterization, B-mode ultrasound and ultrasound elastography measurement. Moreover, we measured serum markers related to fibrosis and examined HV blood flow using duplex Doppler ultrasonography. RESULTS: Forty-three patients (median age, 17 years; interquartile range, 12-25 years; 29 men, 6 with liver biopsy) were enrolled. The real-time tissue elastography (RTE) value was significantly higher in patients who underwent surgery > 7 years prior, suggesting that this value probably reflects the liver fibrosis due to FALD from the early fibrosis stage. The ultrasound elastography did not significantly correlate with hemodynamic parameters. The area under the receiver operating curve for the diagnosis of CI < 2.2 L/min/m2 using HV waveform was superior to the results from elastography and calculated fibrosis indices. CONCLUSION: HV waveform can be used as a noninvasive measurable surrogate marker for CI. The RTE value increased overtime after the operation and would reflect liver fibrosis. The combination of RTE and HV waveform type could be useful noninvasive tools to evaluate clinical conditions in FALD patients in real time.

DOI： 10.1007/s10396-020-01078-8

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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AIM: Liver stiffness measured using transient elastography (TE) is affected by tissue viscosity. The role of intrahepatic lymphatic fluid in liver stiffness is unclear. The present study aimed to investigate the effects of lymphatic vessel dilatation on liver stiffness. METHODS: Patients with chronic liver disease (n = 116) were enrolled from June 2018 to March 2020. All specimens were acquired by laparoscopic liver biopsy. Biopsy samples were stained with D2-40 for lymphatic vessel quantification based on a five-point scale for each specimen. Independent associations of liver stiffness measured by TE, strain elasticity (liver fibrosis index), and controlled attenuation parameter with fibrosis, lymphatic vessels, alanine aminotransferase, bilirubin, and steatosis were evaluated. RESULTS: Fibrosis, splenic stiffness measurement, and splenic volume were significantly correlated with the area of lymphatic vessels. Fibrosis, lymphatic vessels, and alanine aminotransferase were independent factors significantly associated with liver stiffness measurement (LSM; standardized coefficient [β] = 0.375, P < 0.001; β = 0.342, P < 0.001; and β = 0.359, P < 0.001, respectively). Fibrosis was the only independent factor significantly associated with liver fibrosis index (β = 0.360, P < 0.001), whereas the fat deposit area was the only independent factor significantly associated with controlled attenuation parameter (β = 0.455, P < 0.001). The areas under the receiver operating characteristic curves for diagnosing controlled ascites based on LSM, liver fibrosis index, splenic stiffness measurement, collagen proportionate area, and area of lymphatic vessels were 0.94, 0.66, 0.76, 0.64, and 0.79, respectively. CONCLUSIONS: Lymphatic vessel dilatation can affect liver stiffness measured using TE. Liver stiffness measurement is a predictive factor for ascites.

DOI： 10.1111/hepr.13610

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Language：Japanese   Publisher：(公社)日本超音波医学会  

症例は78歳,女性.他院で肺サルコイドーシスにて経過観察されていた.造影CTにて肝内に多発する乏血性結節がみられ,以前の画像に比べ増大があり精査目的に紹介された.エコー画像では造影エコー検査の後血管相においてのみ明瞭に描出可能であった.造影エコー下に生検し組織採取を行い,サルコイドーシスの確定診断が得られた.サルコイドーシスは様々な臓器に非乾酪性肉芽腫をきたす原因不明の疾患である.主として肺,リンパ節,皮膚などに肉芽腫がみられるが,時に肝内にも同様の病変がみられる.肝サルコイドーシスの確定診断や肝悪性腫瘍との鑑別のために生検による組織診断が必要となるが,腹部超音波Bモード検査では明瞭な結節としてとらえられない場合が多く,組織採取がしばしば困難となる.本症例では肝結節では貪食細胞の機能低下によると思われる,後血管相における造影欠損像を呈した.炎症期を過ぎた肝サルコイドーシスでは造影超音波検査の後血管相で欠損像を呈するため,造影エコー下での生検は診断確定のために有用な方法になりうることが示唆された.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00833&link_issn=&doc_id=20210318360005&doc_link_id=10.3179%2Fjjmu.JJMU.A.179&url=https%3A%2F%2Fdoi.org%2F10.3179%2Fjjmu.JJMU.A.179&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hepatic venous pressure gradient (HVPG) is the gold standard index for evaluating portal hypertension; however, measuring HVPG is invasive. Although transient elastography (TE) is the most common procedure for evaluating organ stiffness, accurate measurement of spleen stiffness (SS) is difficult. We developed a device to demonstrate the diagnostic precision of TE and suggest this technique as a valuable new method to measure SS. METHODS: Of 292 consecutive patients enrolled in this single-centre, translational, cross-sectional study from June through September in 2019, 200 underwent SS measurement (SSM) using an M probe (training set, n = 130; inspection set, n = 70). We performed TE with B-mode imaging using an ultrasound-fusion method, printed new devices with a three-dimensional printer, and attached the magnetic position sensor to the convex and M probes. We evaluated the diagnostic precision of TE to evaluate the risk of esophagogastric varices (EGVs). RESULTS: The median spleen volume was 245 mL (range, 64-1,720 mL), and it took 2 minutes to acquire a B-mode image using the ultrasound-fusion method. The median success rates of TE were 83.3% and 57.6% in patients with and without the new device, respectively (p<0.001); it was 76.9% and 35.0% in patients with and without splenomegaly (<100 mL), respectively (p<0.001). In the prediction of EGVs, the areas under the receiver operating characteristic curve were 0.921 and 0.858 in patients with and without the new device, respectively (p = 0.043). When the new device was attached, the positive and negative likelihood ratios were 3.44 and 0.11, respectively. The cut-off value of SSM was 46.0 kPa. Data that were similar between the validation and training sets were obtained. CONCLUSIONS: The SS can be precisely measured using this new device with TE and ultrasound-fusion method. Similarly, we can estimate the bleeding risk due to EGV using this method.

DOI： 10.1371/journal.pone.0246315

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title><sec>
<title>Background</title>
The effects of direct-acting antivirals (DAAs) on survival and recurrence rates after curative hepatocellular carcinoma (HCC) treatment in patients with hepatitis C virus (HCV) infection remain controversial.


</sec><sec>
<title>Methods</title>
This retrospective, multicenter study involved Child–Pugh class A patients within the Milan criteria who had a first diagnosis of HCC and survived 6 months or longer after undergoing hepatectomy or radiofrequency ablation (RFA). The DAA-treated group (DAA group) included 56 patients, and the DAA-untreated group (untreated group) included 261 patients. The study was conducted using the propensity score-matched (1:2) DAA group and untreated group, 56 and 112 patients, respectively.


</sec><sec>
<title>Results</title>
The survival rate at 48 months in the DAA group and the untreated group was 91.0% and 68.7%, respectively, showing significantly better survival in the DAA group (HR: 0.33; 95% CI 0.13–0.84; <italic>p</italic> = 0.021). The recurrence rate at 48 months was 36.7% and 66.7%, respectively, showing a significantly lower recurrence rate in the DAA group (HR, 0.46; 95% CI 0.27–0.77; <italic>p</italic> = 0.003). The median albumin–bilirubin (ALBI) score at 3 years post-HCC treatment was − 2.84 in the DAA group and − 2.34 in the untreated group. The ALBI score showed a significant improvement from baseline to 3 years post-HCC treatment (<italic>p</italic> = 0.001), whereas that in the untreated group showed a significant decline (<italic>p</italic> = 0.040).


</sec><sec>
<title>Conclusions</title>
DAAs after HCC treatment prevents deterioration of hepatic functional reserve and significantly improves both recurrence and survival rates.


</sec>

DOI： 10.1007/s00535-020-01747-y

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Other Link： http://link.springer.com/article/10.1007/s00535-020-01747-y/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

Hyperammonemia is an important stimulator of myostatin expression, a negative regulator of muscle growth. After splenectomy or partial splenic artery embolization (PSE), hyperammonemia often improves. Thus, we investigated changes in skeletal muscle index (SMI) in patients following an operation on the spleen and in patients who did not undergo an operation on their spleen. The study was designed retrospectively, in which we analyzed data collected between January 2000 and December 2015. Patients were assigned to the splenectomy/PSE or nontreatment group. Changes in SMI (ΔSMI), ammonia (Δammonia), myostatin (Δmyostatin), irisin (Δirisin), and branched-chain amino acids/tyrosine molar ratio (ΔBTR) were analyzed between baseline and 5-year follow-up both before and after inverse probability of treatment weighting adjustment (IPTW). Patients (102) were enrolled (splenectomy/PSE, n = 45; nontreatment group, n = 57) before IPTW adjustment: ΔSMI (2.6 cm2/m2 vs. -8.8 cm2/m2, respectively) (P < 0.001), Δmyostatin (-867 vs. -568, respectively) (P < 0.001), Δammonia (-34 and 16, respectively) (P < 0.001), and ΔBTR (0.89 and -0.665, respectively) (P < 0.001). There were no differences between splenectomy and PSE regarding these factors. Moreover, after IPTW adjustment, significant differences were observed between the splenectomy/PSE and nontreatment group for the median ΔBTR (0.89 and -0.64, respectively) (P < 0.001), Δammonia (-33 and 16, respectively) (P < 0.001), Δmyostatin (-894 and 504, respectively) (P < 0.001), and ΔSMI (1.8 cm2/m2 and -8.2 cm2/m2, respectively) (P < 0.001). Conclusions: Both splenectomy and PSE were associated with the prevention of secondary sarcopenia in patients with LC. Moreover, it can be expected that muscle volume loss is reduced by splenectomy or PSE in patients with hyperammonemia.

DOI： 10.1002/hep4.1604

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

Objective There is a paucity of information on whether the hepatitis B virus (HBV) vaccine, derived from HBV genotype C, can prevent mother-to-child transmission of HBV genotype D. The aim of this study was to clarify this issue. Methods The subjects consisted of 25 children (8.5±4.1 years old, 7 males, 18 females), born to 17 mothers who were chronically infected with HBV genotype D. Of these, 20 children were inoculated with the genotype C-derived vaccine, one was inoculated with the genotype A-derived vaccine, and one was inoculated with both the A- and C-derived vaccines. Information on the type of vaccine given to the remaining three children was not available. The serum levels of HB surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HB core (anti-HBc) of the children, as well as HBV markers of the mothers, were examined. Results All mothers were positive for HBsAg (6,563±11,005 IU/mL), negative for HBeAg, and positive for anti-HBe. HBV-DNA levels (log IU/mL) were <3.3 in 7 mothers, 3.3-4.3 in 9 mothers, and >4.3 in one mother. HBsAg and anti-HBc were negative in all children, regardless of the type of vaccine used. Anti-HBs were positive in 13 children and negative in 12. Conclusion All children born to mothers infected with genotype D, including 20 who were inoculated with the genotype C-derived vaccine, were negative for both HBsAg and anti-HBc. These results suggest that the genotype C-derived HB vaccine is effective in preventing mother-to-child transmission from mothers infected with HBV genotype D.

DOI： 10.2169/internalmedicine.5090-20

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

門亢症に伴う出血リスクとして門脈圧亢進症性胃症(PHG)、胃前庭部毛細血管拡張症(GAVE)は食道胃静脈瘤(EV)と同様に重要である。近年、門脈圧と肝・脾硬度の相関について報告されているが、本研究ではPHG、GAVEも含めた消化管出血リスクを評価し、肝・脾硬度との関連を調べた。対象は上部消化管内視鏡検査と肝・脾硬度を測定した92名。EV、PHG、GAVE、および治療歴から定義した門亢症関連消化管病変(PHRGL)と肝・脾硬度等の関連を解析した。EVは41.3%、PHG43.5%、GAVE9.8%に合併していた。PHRGL有無別での肝硬度は2.114 vs 1.802、脾硬度は2.621 vs 2.263と各々合併群が高かった(p<0.05)。PHRGL合併に寄与する因子は血小板数、脾硬度、アルブミンであった。PHRGLは肝・脾硬度と関連し、特に脾硬度がその囲い込みに有用であった。(著者抄録)

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

門亢症に伴う出血リスクとして門脈圧亢進症性胃症(PHG)、胃前庭部毛細血管拡張症(GAVE)は食道胃静脈瘤(EV)と同様に重要である。近年、門脈圧と肝・脾硬度の相関について報告されているが、本研究ではPHG、GAVEも含めた消化管出血リスクを評価し、肝・脾硬度との関連を調べた。対象は上部消化管内視鏡検査と肝・脾硬度を測定した92名。EV、PHG、GAVE、および治療歴から定義した門亢症関連消化管病変(PHRGL)と肝・脾硬度等の関連を解析した。EVは41.3%、PHG43.5%、GAVE9.8%に合併していた。PHRGL有無別での肝硬度は2.114 vs 1.802、脾硬度は2.621 vs 2.263と各々合併群が高かった(p<0.05)。PHRGL合併に寄与する因子は血小板数、脾硬度、アルブミンであった。PHRGLは肝・脾硬度と関連し、特に脾硬度がその囲い込みに有用であった。(著者抄録)

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

© 2020, The Author(s). The therapeutic effects of C16, which is an inhibitor of RNA-dependent protein kinase (PKR), on growth of hepatocellular carcinoma (HCC) cells and tumor progression in vitro and in vivo were evaluated. Huh7 cells, a human HCC cell line, were used. The effects of C16 on cell viability were evaluated with the MTT assay, and real-time RT-PCR was performed. Huh7 cells were grafted into immunodeficient mice, and the in vivo effects of C16 on tumorigenesis were examined. C16 suppressed proliferation of HCC cells in a dose-dependent manner in vitro. Mouse models with xenograft transplantation showed that the inhibitor suppressed the growth of HCC cells in vivo. Moreover, C16 decreased angiogenesis in HCC tissue in the xenograft model. Consistent with these results in mice, transcript levels of vascular endothelial growth factor-A and factor-B, platelet-derived growth factor-A and factor-B, fibroblast growth factor-2, epidermal growth factor, and hepatocyte growth factor, which are angiogenesis-related growth factors, were significantly decreased by C16 in vitro. In conclusion, the PKR inhibitor C16 blocked tumor cell growth and angiogenesis via a decrease in mRNA levels of several growth factors. C16 may be useful in the treatment of HCC.

DOI： 10.1038/s41598-020-61579-x

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct-acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log-rank test, P =  .007). On multivariate analysis, the fibrosis-4 index (HR = 1.11; 95%CI, 1.042-1.202, P =  .002) and posttreatment α-fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046-1.197, P  =  .001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR  =  1.090; 95%CI, 1.024-1.160, P  = .007) was an independent factor in male patients. The optimal posttreatment AFP cut-off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut-off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut-off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients.

DOI： 10.1002/jmv.25984

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jmv.25984

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD. METHODS: A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed. RESULTS: Serum Lp(a) levels in advanced fibrosis (stage 3-4) were lower than those in non-advanced fibrosis (stage 0-2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5-8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents. CONCLUSIONS: Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk.

DOI： 10.1016/j.atherosclerosis.2020.02.026

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：Japanese   Publisher：(一社)日本消化管学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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DOI： 10.2169/internalmedicine.3886-19

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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In the original publication of the article the formula under the heading "Three-point method" was incorrect, the correct formula is given in this correction.

DOI： 10.1007/s10396-019-00966-y

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Lenvatinib has anti-tumor activity against advanced hepatocellular carcinoma (HCC). Hypothyroidism is also a frequent complication in patients treated with lenvatinib. However, studies on lenvatinib-induced thyroid toxicity and destructive thyroiditis are limited. Therefore, this study aimed to clarify the frequency and timing of thyroid abnormalities in lenvatinib for unresectable HCC. This retrospective study enrolled 50 patients with advanced HCC treated with lenvatinib. Patients were classified to have euthyroid, subclinical hypothyroidism, overt hypothyroidism, and thyrotoxicosis. The timing of thyroid dysfunction was assessed, and risk factors for incident hypothyroidism or thyrotoxicosis were evaluated using multivariate models. Subclinical hypothyroidism, overt hypothyroidism, and thyrotoxicosis occurred in 7 (14.0%), 26 (52.0%), and 5 (10.0%) patients, respectively. In the 33 patients with hypothyroidism, 27 (84.4%) developed the condition within 2 weeks of starting lenvatinib treatment. Of the 5 patients with thyrotoxicosis, 3 developed the condition within 8 weeks of starting lenvatinib administration. One patient developed thyrotoxicosis in only 1 week of the initiation of treatment. No correlation between the presence of antibodies and the incidence and severity of thyroid dysfunction due to the autoimmune mechanism was observed. The progression-free survival was significantly better in the hypothyroidism group. Lenvatinib treatment for unresectable HCC not only causes hypothyroidism, but also thyrotoxicosis. Moreover, these thyroid conditions develop within the early period of treatment at a higher prevalence. Patients with thyroid dysfunction had better prognosis. Based on these results, in patients administered with lenvatinib, there is need for careful assessment for the possibility of thyroid dysfunction from the onset of treatment.

DOI： 10.1507/endocrj.EJ19-0140

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Schistosomiasis infection is a major cause of morbidity and mortality in endemic areas. Developed countries have declared that schistosomiasis has been eradicated; however, residents of these countries may travel and stay in endemic areas and the number of foreign travelers is increasing in the recent years. Thus, schistosomiasis is regarded as an imported infection. Ultrasonography and serum antibody titer tests are well established as diagnostic methods for schistosomiasis. However, a definitive diagnosis cannot be obtained using these tests in some cases. We herein report a case in which schistosomiasis was confirmed based on laparoscopic liver biopsy without a definitive diagnosis by blood test, fecal examination, or imaging.

DOI： 10.2169/internalmedicine.2776-19

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BACKGROUND AND AIM: Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon. METHODS: We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 103 /μL were identified. RESULTS: The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child-Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 103 /μL to 81.0 × 103 /μL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 103 /μL required baseline platelets > 30 × 103 /μL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 103 /μL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 103 /μL was required for patients administered with lusutrombopag. CONCLUSION: Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion.

DOI： 10.1111/jgh.14786

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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AIM: The predictors for the development of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment were investigated. METHODS: A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed. RESULTS: During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre- and post-treatment factors identified the Fibrosis-4 (FIB-4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021-1.178; P = 0.011) and post-treatment α-fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054-1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high-score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1- and 2-year cumulative incidence rates of HCC were 6.1% and 14.4%. CONCLUSIONS: A high FIB-4 index and a high post-treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed.

DOI： 10.1111/hepr.13278

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Obesity-induced adipose-tissue dysfunction is a critical contributor to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). B cell-activating factor (BAFF) is an adipokine related to impaired insulin sensitivity, and the serum BAFF concentration is associated with NAFLD severity. In this study, we aimed to determine the direct in vivo role of BAFF in the development of insulin resistance, adipocyte dysfunction, and hepatic steatosis using BAFF-/- mice fed a high-fat diet (HFD). HFD-fed BAFF-/- mice exhibited significantly improved insulin sensitivity despite their increased weight gain and adiposity relative to HFD-fed wild-type mice. Moreover, inflammation, especially the accumulation of CD11c+ adipose-tissue macrophages, and fibrosis of epididymal adipose tissue were reduced, contributing to healthy adipose-tissue expansion in obese BAFF-/- mice. In line with metabolically healthy obesity, hepatic steatosis also decreased, and we observed attenuated de novo lipogenesis in both the livers and hepatocytes of BAFF-/- mice. Our data revealed that BAFF serves as a potential stimulator of unhealthy adipose-tissue expansion by triggering inflammation and fibrosis and ultimately leading to enhanced insulin resistance and NAFLD. Therefore, these results suggest that BAFF is a promising target for diabetes and NAFLD treatment.

DOI： 10.1038/s41598-018-37403-y

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

We clarify the frequency of carnitine and zinc deficiency in chronic liver diseases. Carnitine and zinc as well as ammonia, albumin and BTR (BCAA/Tyr) were measured in 41 patients with chronic hepatitis (CH) and 88 with liver cirrhosis (LC) with or without hepatocellular carcinoma. No differences were found in free carnitine level among the three groups, but acylcarnitine was high and zinc was low in two LC groups. No cases fulfilled the criteria for carnitine deficiency, but mild deficiency was found in approximately 20% of LC cases. Zinc deficiency and mild zinc deficiency were found in 0% and 31.7% of CH cases, respectively, and in approximately 30% and 40% of LC cases, respectively. Correlation was found between zinc, acylcarnitine, and several biological markers described above, but not between free carnitine and these markers. Our study clarified the frequency of carnitine and zinc deficiency in chronic liver diseases.

DOI： 10.2957/kanzo.60.14

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Background: Although sorafenib-regorafenib sequential therapy improves the prognosis of patients with hepatocellular carcinoma (HCC), many patients abandon sequential therapy due to worsening hepatic reserve function. Thus, it is important to clarify which patients can be treated using regorafenib. The albumin-bilirubin score is a good biomarker for hepatic reserve function. The aim of this study was to determine whether patient albumin-bilirubin scores at the start of sorafenib treatment could be used to identify candidates for subsequent regorafenib therapy. Methods: This is a retrospective cohort study. From 2009 to 2017, 267 hepatocellular carcinoma patients treated with sorafenib were enrolled. After sorafenib therapy, 138 progressive disease patients were analyzed. The patients were divided in two groups: (i) regorafenib candidate group (Child-Pugh class A, Eastern Cooperative Oncology Group Performance Status ≤1, and maintained sorafenib tolerance); and (ii) regorafenib non-candidate group. The primary endpoint was the albumin-bilirubin score. We assessed retrospectively whether albumin-bilirubin scores were useful for predicting regorafenib treatment regimen candidacy. Results: For the 138 analyzed patients, the median overall survival duration was 15.6 months in the regorafenib candidate group and 6.8 months in the regorafenib non-candidate group (P < 0.01). Using univariate analysis, etiology, aspartate aminotransferase ≥40 IU/L, prothrombin time ≥85% and albumin-bilirubin score <-2.53 at the start of sorafenib treatment were identified as predictors. Using multivariate analysis, albumin-bilirubin score <-2.53 was the only significant predictor. Conclusions: Based on the multivariate analysis results, albumin-bilirubin score at the start of sorafenib therapy is a useful marker for identifying candidate patients for starting regorafenib therapy.

DOI： 10.1093/jjco/hyy153

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

A 65-year-old woman was admitted with fever, abdominal pain, and laboratory markers indicating an inflammatory reaction. An abdominal ultrasound (US) showed a 60-mm hyperechoic lesion in the left lateral segment of the liver diagnosed as a liver abscess. Antibiotics were administered. Percutaneous drainage was attempted but was difficult because of poor liquefaction. On day 6, the abscess had enlarged and progressed to involve the medial segment. Hypermucoviscous Klebsiella pneumoniae was detected in blood and abscess cultures. Repeat US showed poor liquefaction, suggesting that percutaneous drainage would again fail. As the abscess was deemed resistant to medical treatment, a left hepatic lobectomy was performed. Postoperatively, the pa-tient’s general condition and inflammatory reaction quickly improved. Hypermucoviscous K. pneumoniae is often resistant to antibiotics because of the organism’s extremely mucoid capsule. Percutaneous drainage is also difficult, so surgical resection should be considered.

DOI： 10.2957/kanzo.60.427

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Hepatic stellate cells (HSCs) were reported to promote the progression of hepatocellular carcinoma (HCC), however its mechanism is uncertain. We previously reported that protein kinase R (PKR) in hepatocytes regulated HCC proliferation. In this study, we focused on the role of PKR in HSCs, and clarified the mechanism of its association with HCC progression. We confirmed the activation of PKR in a human HSC cell line (LX-2 cell). IL-1β is produced from HSCs stimulated by lipopolysaccharide (LPS) or palmitic acid which are likely activators of PKR in non-alcoholic steatohepatitis (NASH). Production was assessed by real-time PCR and ELISA. C16 and small interfering RNA (siRNA) were used to inhibit PKR in HSCs. The HCC cell line (HepG2 cell) was cultured with HSC conditioning medium to assess HCC progression, which was evaluated by proliferation and scratch assays. Expression of PKR was increased and activated in stimulated HSCs, and IL-1β production was also increased molecular. Key molecules of the mitogen-activated protein kinase pathway were also upregulated and activated by LPS. Otherwise, PKR inhibition by C16 and PKR siRNA decreased IL-1β production. HCC progression was promoted by HSC-stimulated conditioning medium although it was reduced by the conditioning medium from PKR-inhibited HSCs. Moreover, palmitic acid also upregulated IL-1β expression in HSCs, and conditioning medium from palmitic acid-stimulated HSCs promoted HCC proliferation. Stimulated HSCs by activators of PKR in NASH could play a role in promoting HCC progression through the production of IL-1β, via a mechanism that seems to be dependent on PKR activation.

DOI： 10.1371/journal.pone.0212589

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Language：English   Publisher：WILEY  

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PURPOSE: The aim of this study was to clarify whether ultrasound quantitative methods were positively correlated with volume of ascites evaluated by whole abdominopelvic CT. METHODS: Sixty-eight patients with cirrhotic ascites were retrospectively analyzed. First, to confirm that virtual ultrasonography (VUS) is an alternative method to conventional ultrasound, 22 patients underwent both conventional ultrasonography and VUS. Second, the efficacy of US quantitative methods (3-point method, 4-point method, 5-point method, and Matsumoto's method) was confirmed by VUS in 68 patients. We assessed whether the ascites volume predicted by VUS corresponded with that calculated by 3D-CT. Of the 68 patients, 23 patients were analyzed before and after administration of tolvaptan. RESULTS: The predictive volumes calculated by VUS were remarkably relative to those yielded by conventional US. Correlations between exact volume and those measured by VUS were significantly high (3-point method: r = 0.882, p < 0.001; 4-point method: r = 0.797, p < 0.001; 5-point method: r = 0.836, p < 0.001; Matsumoto's method: r = 0.453, p < 0.001). Correlations between decreasing volume on 3D-CT and that measured by VUS were also significantly high in patients with administration of tolvaptan. CONCLUSION: Ascites volume measured by ultrasound was effective, especially the 3-point and 5-point methods. It was useful to assess the efficacy of diuretics in cirrhotic patients.

DOI： 10.1007/s10396-018-0879-9

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Language：English   Publisher：WILEY  

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Language：English   Publisher：WILEY  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Double-stranded (ds) RNA-dependent protein kinase (PKR) is a ubiquitously expressed serine/threonine protein kinase. It was initially identified as an innate immune antiviral protein induced by interferon (IFN) and activated by dsRNA. PKR is recognized as a key executor of antiviral host defense. Moreover, it contributes to inflammation and immune regulation through several signaling pathways. In addition to IFN and dsRNA, PKR is activated by multiple stimuli and regulates various signaling pathways including the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. PKR was initially thought to be a tumor suppressor as a result of its ability to suppress cell growth and interact with major tumor suppressor genes. However, in several types of malignant disease, such as colon and breast cancers, its role remains controversial. In hepatocellular carcinoma, hepatitis C virus (HCV) is the main cause of liver cancer, and PKR inhibits HCV replication, indicating its role as a tumor suppressor. However, PKR is overexpressed in cirrhotic patients, and acts as a tumor promoter through enhancement of cancer cell growth by mediating MAPK or signal transducer and activator of transcription pathways. Moreover, PKR is reportedly required for the activation of inflammasomes and influences metabolic disorders. In the present review, we introduce the multifaceted roles of PKR such as antiviral function, tumor cell growth, regulation of inflammatory immune responses, and maintaining metabolic homeostasis; and discuss future perspectives on PKR biology including its potential as a therapeutic target for liver cancer.

DOI： 10.1111/cas.13551

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Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is often associated with type 1 autoimmune pancreatitis, and the frequency of isolated IgG4-SC seems to be quite low, making the diagnosis of isolated IgG4-SC challenging. A 63-year-old male was admitted to our hospital for frequent fever. Abdominal magnetic resonance cholangiopancreatography showed diffuse narrowing of the common bile duct and post-stenotic dilatation of the right posterior bile duct. Laboratory tests showed abnormalities in the levels of hepatobiliary enzymes and serum IgG4 levels. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of intrahepatic bile ducts and post-stenotic dilatation of the right posterior bile duct but no abnormalities in the pancreas. Intraductal ultrasonography showed symmetric circumferentially thickened walls of both narrowed and non-narrowed common bile ducts. Histologic examination of the common bile duct mucosa showed infiltration of IgG4-positive plasma cells. Laparoscopic observations showed discoloration with red lobular markings and multiple small depressed lesions. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. From these findings, the patient was diagnosed with isolated IgG4-SC. After treatment with a steroid, bile duct dilatations improved. Laparoscopy and intraductal ultrasonography were useful to diagnose isolated IgG4-SC.

DOI： 10.1007/s12328-017-0787-3

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

The aim of this study was to clarify the percentage of samples considered false positive for hepatitis B surface antigen (HBsAg) in relation to the HBsAg concentration. The HBsAg concentrations were measured in 41,186 samples using chemiluminescent enzyme immunoassay. Samples with a concentration of ≥0.05 IU/mL were considered positive. The criteria for classifying a result as false positive were as follows: negative for anti-HBc, HBeAg, anti-HBe, and HBV-DNA as well as negative for HBsAg examined with the sample obtained on other day. In total, 1147 samples were positive for HBsAg. Six subjects fulfilled the criteria of false positives. The HBsAg concentrations (IU/mL) were 0.05≤ ＜0.2 in 6 cases, and none of the samples with a value of ≥0.2 were false positive. The percentage of false positives among those with HBsAg 0.05≤ ＜0.2 was 25% (6/24). It should be remembered that samples with a low HBsAg concentration may contain false positives.

DOI： 10.2957/kanzo.59.641

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Tissue intrinsic emission fluorescence provides useful diagnostic information for various diseases. Because of its unique feature of spectral profiles depending on tissue types, spectroscopic imaging is a promising tool for accurate evaluation of endogenous fluorophores. However, due to difficulties in discriminating those sources, quantitative analysis remains challenging. In this study, we quantitatively investigated spectral-spatial features of multi-photon excitation fluorescence in normal and diseased livers. For morphometrics of multi-photon excitation spectra, we examined a marker-controlled segmentation approach and its application to liver fibrosis assessment by employing a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. We formulated a procedure of internal marker selection where markers were chosen to reflect typical biochemical species in the liver, followed by image segmentation and local morphological feature extraction. Image segmentation enabled us to apply mathematical morphology analysis, and the local feature was applied to the automated classification test based on a machine learning framework, both demonstrating highly accurate classifications. Through the analyses, we showed that spectral imaging of native fluorescence from liver tissues have the capability of differentiating not only between normal and diseased, but also between progressive disease states. The proposed approach provides the basics of spectroscopy-based digital histopathology of chronic liver diseases, and can be applied to a range of diseases associated with autofluorescence alterations.

DOI： 10.3389/fmed.2018.00350

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AimAssessing disease progression in patients with primary biliary cholangitis (PBC) is necessary in order to evaluate therapeutic effectiveness. Therefore, the aims of this study were to evaluate both the diagnostic accuracy of both real-time tissue elastography (RTE) and vibration-controlled transient elastography (VCTE), and the usefulness of hepatic and splenic elasticity as predictive markers for the progression of symptomatic PBC.
MethodsThe study participants were 44 patients with PBC. We assessed hepatic and splenic elasticity using RTE and VCTE and measured serum markers related to fibrosis and hepatic and splenic blood flow using Doppler ultrasonography. We then compared RTE and VCTE for diagnostic accuracy. Patients with asymptomatic PBC were followed every 1-3months.
ResultsBoth RTE and VCTE performed well and had superior diagnostic accuracy compared with biochemical markers. The areas under the receiver operating characteristic curve for RTE and VCTE were 0.92 and 0.92, 0.95 and 0.91, and 0.97 and 0.91 for F2, F3, and F=4, respectively. During follow-up, nine patients (25.0%) developed liver-related symptoms. Multivariate analysis revealed that splenic elasticity assessed using RTE was a significant independent factor for the development of liver-related symptoms (odds ratio, 2.19; P=0.024).
ConclusionsReal-time tissue elastography offered better diagnostic accuracy for severe fibrosis and cholangitis than VCTE. Splenic elasticity determined using RTE is a useful parameter for evaluating liver-related symptoms and an effective predictive marker of disease progression in patients with asymptomatic PBC.

DOI： 10.1111/hepr.12861

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Background and Aim: The aim of this study is to confirm the efficacy of multipolar ablation with a new simulator system, three-dimensional (3-D) sim-Navigator, for patients with hepatocellular carcinoma by assessing relapse-free survival and shape of the ablation volume under clinical conditions.
Methods: All participants provided written, informed consent, and study protocols were approved by the institutional ethics committee. Twenty-seven patients with 27 nodules were treated by no-touch ablation using the new simulator system. Another 21 patients with 21 nodules treated without the simulator system were enrolled as controls. Tumor progression and shape of ablation volume were assessed. Predictors of tumor progression were assessed by Cox proportional hazard model.
Results: No significant differences in clinical characteristics were seen between groups. Mean sphericity was 0.48 +/- 0.07 with 3-D sim-Navigator and 0.37 +/- 0.07 without 3-D sim-Navigator (P &lt; 0.001). Median surface-to-volume ratio and compactness were also significantly closer to those of a sphere with 3-D sim-Navigator (P = 0.017, P &lt; 0.001). Relapse-free survival rates at 1 and 1.5 years were 94.1% and 82.4%, respectively, with 3-D sim-Navigator, compared with 83.2% and 55.5% without (P = 0.056). The only independent factor predicting relapse-free survival was use of 3-D sim-Navigator (hazard ratio, 0.12; 95% CI, 0.01-0.87; P = 0.035).
Conclusions: Ideal ablation area was acquired by this simulation and navigation system in clinics. This system improved local tumor progression by facilitating appropriate insertion of multiple electrodes.

DOI： 10.1111/jgh.13772

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The tolerability and efficacy of sofosbuvir and ribavirin in patients infected with hepatitis C virus (HCV) genotype 2 were investigated under actual clinical conditions. A total of 208 patients with chronic HCV genotype 2 infection were treated with sofosbuvir 400 mg and ribavirin (weight-based dosing) for 12 weeks. Treatment discontinuation and sustained virological response 12 (SVR12) were evaluated. Moreover, factors associated with SVR12, hemoglobin decreasing to less than 10 g/dL during treatment, and alanine aminotransferase (ALT) non-normalization after treatment were evaluated. In all patients, SVR12 responses were 96.1% (200/208). About 6 of 8 patients (3.8%) who did not achieve SVR12 were re-treatment patients, and eight patients who did not achieve SVR all had liver cirrhosis. Multivariate analysis also identified body mass index (OR = 0.79; P &lt; 0.001), platelet count (OR = 0.88; P = 0.003), and estimated glomerular filtration rate (eGFR) (OR = 0.96; P = 0.007) as independent contributing factors associated with hemoglobin decreasing to less than 10 g/dL during treatment, and only Mac-2 Binding Protein Glycosylation isomer (M2BpGi) (OR = 2.46; P = 0.017) as an independent contributing factor associated with ALT non-normalization after treatment. Cirrhotic patients may have a relatively high rate of treatment failure. In patients whose M2BpGi levels are elevated, their ALT tended to not normalize after treatment completion. These patients who did not achieve normalization of ALT after sofosbuvir plus RBV treatment need more careful observation for emergence of hepatocellular carcinoma even after achievement of SVR.

DOI： 10.1002/jmv.24776

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A change in hepatic blood flow caused by the hepatic arterial buffer response (HABR) occurs as fatty liver disease progress. The aim of this longitudinal cohort study was to investigate whether fatty liver with the HABR induces metabolic disorders. In 2009 and 2010, 494 (89.5%) participants were enrolled. The median follow-up duration was 5.0 (interquartile range, 3.9-6.0) years. The hazard ratios of fatty liver with the HABR for incident metabolic disorders were assessed by Cox proportional hazard models. A non-fatty liver group (non-FL group, hepatorenal echo intensity ratio <1.12), a fatty liver without portal hypertension (FL group, hepatorenal echo intensity ratio ≥1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein <3.1) group, and a fatty liver with portal hypertension (FL-HABR group, hepatorenal echo intensity ratio ≥1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein ≥3.1) group were defined based on echo intensity and Doppler ultrasonography. Fatty liver with and without the HABR was significantly associated with the incidence of diabetes on multivariate analysis (non-FL versus FL group, hazard ratio, 3.36; 95% confidence interval, 1.05-12.85; FL versus FL with the HABR group, HR, 2.68; 95% confidence interval, 1.28-6.04). With respect to the incidence of hypertension and dyslipidemia, only FL with the HABR was a significant factor (hypertension, non-FL versus FL, P = 0.874, FL versus FL-HABR, P = 0.016, non-FL versus FL-HABR, P = 0.023; dyslipidemia, non-FL versus FL, P = 0.311, FL versus FL-HABR, P = 0.194, non-FL versus FL-HABR, P = 0.038). Conclusion: Fatty liver with the HABR is a high-risk condition for metabolic diseases. (Hepatology Communications 2017;1:623-633).

DOI： 10.1002/hep4.1070

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The acidic (leucine-rich) nuclear phosphoprotein 32 family member B (ANP32B), a highly conserved member of the acidic nuclear phosphoprotein 32 (ANP32) family, is critical for the development of normal tissue. However, its role in the development of hepatocellular carcinoma (HCC) is controversial. In this study, we elucidated the role of ANP32B in HCC cell lines and tissues. ANP32B expression in HCC cell lines was modulated using siRNA and ANP32B expression plasmids and lentiviruses. The levels of apoptosis-related proteins were analyzed by real-time RT-PCR and Western blotting. The expression of ANP32B in tissues from patients with HCC was investigated using real-time RT-PCR and immunohistochemistry. ANP32B knockdown by siRNA altered the expression of apoptosis-related proteins in HCC cell lines and reduced the expression of cleaved forms of caspase 3 and caspase 9, but not that of caspase 8, in HCC cells cultured with the pro-apoptotic agent staurosporine. Phosphorylated Bad was upregulated, whereas Bak was downregulated. Moreover, ABT-737, which binds to and inhibits anti-apoptotic proteins of the Bcl-2 family, rendered HCC cells resistant to apoptosis induced by ANP32B silencing. Conversely, ANP32B overexpression decreased Bad phosphorylation and upregulated Bak, but did not induce apoptosis because Bax expression was downregulated. In tissues from patients with HCC, a low tumor/non-tumor ratio of ANP32B mRNA expression was related to advanced UICC stage (p = 0.032). TUNEL-positive cells were observed in parallel with ANP32B expression in HCC tissues. ANP32B modulates Bad phosphorylation as well as Bak and Bax expression, resulting in regulation of apoptosis in HCC. These findings indicate the potential value of ANP32B as a therapeutic target for HCC.

DOI： 10.1371/journal.pone.0177343

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A 58-year-old man was diagnosed with advanced hepatocellular carcinoma with portal vein tumor thrombosis (PVTT). The tumors were multiple and existed in both lobes. Drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) was performed for the tumors in the left lobe. Embosphere and Hepasphere were selected for embolization of the arterioportal shunt, followed by loaded epirubicin infusion into the left hepatic artery. Computed tomography showed reduction of PVTT. However, liver failure progressed, and the patient died 67 days after DEB-TACE. Autopsy showed that the beads reached the tumor thrombosis in the portal vein. The prognosis of hepatocellular carcinoma with PVTT is poor. Although there are no established treatments for unresectable PVTT, DEB-TACE might be a useful option for such cases.

DOI： 10.1016/j.radcr.2016.11.006

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Hepatic aneurysms are rare, but can prove fatal once they rupture. Transcatheter arterial embolization (TAE) is performed as a prophylactic treatment. The position of the aneurysm determines the degree of difficulty of TAE. Maintaining blood flow to the liver can become difficult, particularly when the aneurysm is at an arterial junction. The patient was a 72-year-old man diagnosed with a hepatic aneurysm. The aneurysm was situated on the common hepatic artery at the junction of the gastroduodenal and proper hepatic arteries. TAE was performed with framing, followed by coil embolization. Blood flow to the liver was maintained via the gastroduodenal artery. Appropriate framing is important for safe and efficient TAE.

DOI： 10.11405/nisshoshi.114.99

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Non-alcoholic steatohepatitis (NASH) is a common liver disorder caused by fatty liver. Because NASH is associated with fibrotic and morphological changes in liver tissue, a direct imaging technique is required for accurate staging of liver tissue. For this purpose, in this study we took advantage of two label-free optical imaging techniques, second harmonic generation (SHG) and auto-fluorescence (AF), using two-photon excitation microscopy (TPEM). Three-dimensional ex vivo imaging of tissues from NASH model mice, followed by image processing, revealed that SHG and AF are sufficient to quantitatively characterize the hepatic capsule at an early stage and parenchymal morphologies associated with liver disease progression, respectively.

DOI： 10.1016/j.bbrep.2016.09.010

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Fatty liver disease is associated with glucose intolerance and hepatic insulin resistance. However, there are distinct etiologies for alcoholic versus non-alcoholic fatty liver disease (NAFLD), and it is unknown whether alcohol consumption influences the onset of glucose intolerance in fatty liver disease patients. Therefore, we investigated the relationship between fatty liver disease and the onset of impaired fasting glucose (IFG) with respect to alcohol consumption.
The records of 6804 Japanese subjects were reviewed to identify those meeting the criteria for IFG. Male and female subjects were classified into five and four groups, respectively, based on average alcohol consumption (g/week). IFG onset was defined as fasting plasma glucose levels aeyen110 mg/dl.
In the non-drinker, &gt; 0-70 g/week, &gt; 70-140 g/week, &gt; 140-210 g/week (men only), and &gt; 210 g/week (men only) or &gt; 140 g/week (women only) groups, 7.3, 6.7, 6.4, 9, and 6.4 % of men and 2, 1.7, 3.1, and 3.2 % of women, respectively, developed IFG. Fatty liver was positively associated with the onset of IFG in men of the &gt; 0-70 g/week group (adjusted hazard ratio [aHR], 2.808; 95 % confidence interval [CI] 1.605-5.049, p &lt; 0.001) and women of the &gt; 70-140 g/week group (aHR, 4.193; 95 % CI, 1.036-14.584, p = 0.045) after adjusting for previously reported IFG risk factors. No associations were observed in the other groups.
A small amount of alcohol consumption is a significant risk factor for the onset of IFG in NAFLD patients; onset risk differs according to the amount of alcohol consumption.

DOI： 10.1007/s00535-016-1194-0

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Purpose: The tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated.
Methods: A total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients.
Results: The rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naive, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged &lt;70 and &gt;= 70 years, but viral relapse after completing treatment was significantly more frequent in patients aged &gt;= 70 years (p = 0.012).
Conclusions: In simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.

DOI： 10.1186/s40064-016-2190-9

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Entecavir is one of the most-used nucleoside analogues for the treatment of patients with chronic hepatitis B virus (HBV) infection. The aim of this study was to clarify the effects of long-term entecavir treatment on the incidence of hepatocellular carcinoma (HCC).
The participants were 249 patients with chronic HBV infection who had been treated by entecavir for more than 2 years. Hepatic functional reserve and incidence of HCC were evaluated, and the factors that might contribute to the development of HCC were analyzed.
Prothrombin activity was significantly elevated at 60 months after starting entecavir (from 85.9 +/- A 17.4 to 97.0 +/- A 16.9 %, p &lt; 0.001). The albumin level was also significantly elevated at 60 months after starting entecavir (from 4.0 +/- A 0.5 to 4.3 +/- A 0.3 mg/dL, p &lt; 0.001). The annual incidence of HCC decreased over time, and the incidence of HCC was only 1.8 % at 5 years after starting entecavir. On multivariate analysis for HCC incidence, older age and low platelet count were significant, independent contributing factors.
Long-term treatment with entecavir improved hepatic functional reserve and decreased the incidence of HCC over time after 3 years. To decrease the incidence of HCC, careful induction of long-term entecavir treatment in younger patients with chronic HBV infection and better hepatic functional reserve would be important.

DOI： 10.1007/s12072-015-9647-8

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Multipuncture radiofrequency ablation is expected to produce a large ablated area and reduce intrahepatic recurrence of hepatocellular carcinoma; however, it requires considerable skill. This study evaluated the utility of a new simulator system for multipuncture radiofrequency ablation. To understand positioning of multipuncture electrodes on three-dimensional images, we developed a new technology by expanding real-time virtual ultrasonography. We performed 21 experimental punctures in phantoms. Electrode insertion directions and positions were confirmed on computed tomography, and accuracy and utility of the simulator system were evaluated by measuring angles and intersections for each electrode. Moreover, to appropriately assess placement of the three electrodes, puncture procedures with or without the simulator were performed by experts and non-experts. Technical success was defined as maximum angle and distance ratio, as calculated by maximum and minimum distances between electrodes. In punctures using 2 electrodes, correlations between angles on each imaging modality were strong (ultrasound vs. simulator: r = 0.991, p&lt;0.001, simulator vs. computed tomography: r = 0.991, p&lt;0.001, ultrasound vs. computed tomography: r = 0.999, p&lt;0.001). Correlations between distances in each imaging modality were also strong (ultrasound vs. simulator: r = 0.993, p&lt;0.001; simulator vs. computed tomography: r = 0.994, p&lt;0.001; ultrasound vs. computed tomography: r = 0.994, p&lt;0.001). In cases with 3 electrodes, distances between each electrode correlated strongly (yellow-labeled vs. red-labeled: r = 0.980, p&lt;0.001; red-labeled vs. blue-labeled: r = 0.953, p&lt;0.001; yellow-labeled vs. blue-labeled: r = 0.953, p&lt;0.001). Both angle and distance ratio (expert with simulator vs. without simulator; p = 0.03, p = 0.02) were significantly smaller in procedures performed by experts using the simulator system. The new simulator system appears to accurately guide electrode positioning. This simulator system could allow multipuncture radiofrequency ablation to be performed more effectively and comfortably.

DOI： 10.1371/journal.pone.0148298

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3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH.

DOI： 10.2169/internalmedicine.55.6640

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Bile duct injury is a potential complication of radiofrequency ablation (RFA). Bipolar RFA devices have recently become available. Because visibility of the bipolar RFA electrodes is not good on ultrasonography, more careful usage of the electrodes to avoid bile ducts is needed. We present a case with hepatocellular carcinoma (HCC) located near the B5 intrahepatic bile duct. To view the bile duct, we used contrast medium for ultrasonography, administered through a biliary drainage catheter for endoscopic nasobiliary drainage (ENBD). Infusing the contrast medium allowed clear visualization of the HCC adjacent to the major bile duct during RFA. We also used a navigation system for bipolar RFA to confirm positions of the electrodes and HCC. We confirmed complete ablation of the HCC while avoiding bile duct injury and late bile duct stenosis. Administration of contrast medium for ultrasonography through an ENBD tube appears useful to avoid bile duct injury during RFA.

DOI： 10.1007/s12328-015-0599-2

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

A 65-year-old female with hepatitis C (genotype 1b) was started on a planned 24-week course of daclatasvir (DCV) and asunaprevir (ASV) treatment. She was a treatment-naïve case of anti-hepatitis C virus (HCV). She was estimated to be interferon-intolerant. At 11 days after starting treatment, she had a high fever, slight elevation in total bilirubin, and prolonged prothrombin time. However, there was no elevation of AST or ALT. Additionally, she developed ascites after starting treatment, and her blood test results indicated eosinophilia and high levels of serum immunoglobulin E and C-reactive protein. The DCV_ASV therapy was discontinued at 17 days after starting treatment
after discontinuation of therapy, her fever resolved and her hepatic functional reserve improved.

DOI： 10.2957/kanzo.56.109

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A 36-year-old Japanese woman took over-the-counter (OTC) medication for headaches for 20 days. Subsequently, five days after discontinuing the medication, a skin rash developed over the patient's upper and lower limbs and face, in addition to a fever, brown urine and serious liver dysfunction. Drug lymphocyte stimulation tests implicated ibuprofen, a main component of the OTC drugs, which has the potential to induce this pathology, and a diagnosis of drug-induced liver injury with multiform exudative erythema was made. The patient's symptoms and liver function tests returned to normal following treatment with systemic steroids.

DOI： 10.2169/internalmedicine.54.3204

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A 62-year-old woman with hepatocellular carcinoma (HCC) and asthma presented with acute abdominal pain and a decreased hemoglobin level. Peritoneal fluid was detected around the lesion, and rupture was suspected based on the findings of computed tomography. Extravasation of the HCC tumor was not detected on angiography with iodine contrast agent; however, such extravasation was clearly observed on angiography with carbon dioxide (CO2). CO2 angiography is sometimes utilized in patients with arterial bleeding. This modality be more effective and safe than angiography with iodine contrast agent for assessing potential ruptured HCC lesions.

DOI： 10.2169/internalmedicine.54.3144

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The present report describes a case of a patient with hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infection who was treated with tenofovir disoproxil (TDF)-based highly active antiretroviral therapy (HAART) and who achieved HBs antigen (Ag)/antibody (Ab) seroconversion. An 18-year-old Japanese man with HIV and HBV co-infection presented to our hospital. His CD4 count was decreased, and TDF-based HARRT was started. At 30 months after initiation of therapy, HBsAg was not detected. At 36 months after initiation of therapy, HBsAb was detected. We conclude that TDF-based therapy is useful for the management of patients with HBV and HIV co-infection.

DOI： 10.2169/internalmedicine.53.2131

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1371/journal.pone.0067750

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Double-stranded RNA-activated protein kinase R (PKR) is known to be upregulated by hepatitis C virus (HCV) and overexpressed in hepatocellular carcinoma (HCC). However, the precise roles of PKR in HCC with HCV infection remain unclear. Two HCV replicating cell lines (JFH-1 and H77s), generated by transfection of Huh7.5.1 cells, were used for experiments reported here. PKR expression was modulated with siRNA and a PKR expression plasmid, and cancer-related genes were assessed by real-time PCR and Western blotting
cell lines were further analyzed using a proliferation assay. Modulation of genes by PKR was also assessed in 34 human HCC specimens. Parallel changes in c-Fos and c-Jun gene expression with PKR were observed. Levels of phosphorylated c-Fos and c-Jun were upregulated by an increase of PKR, and were related to levels of phosphorylated JNK1 and Erk1/2. DNA binding activities of c-Fos and c-Jun also correlated with PKR expression, and cell proliferation was dependent on PKR-modulated c-Fos and c-Jun expression. Coordinate expression of c-Jun and PKR was confirmed in human HCC specimens with HCV infection. PKR upregulated c-Fos and c-Jun activities through activation of Erk1/2 and JNK1, respectively. These modulations resulted in HCC cell proliferation with HCV infection. These findings suggest that PKR-related proliferation pathways could be an attractive therapeutic target. © 2013 Watanabe et al.

DOI： 10.1371/journal.pone.0067750

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Hepatitis C virus (HCV) infection alters fatty acid synthesis and metabolism in association with HCV replication. The present study examined the effect of serum fatty acid composition on interferon (IFN)-based therapy. Fifty-five patients with HCV were enrolled and received IFN-based therapy. Patient characteristics, laboratory data (including fatty acids), and viral factors that could be associated with the anti-HCV effects of IFN-based therapy were evaluated. The effects of individual fatty acids on viral replication and IFN-based therapy were also examined in an in-vitro system. Multivariate logistic regression analysis showed that the level of serum palmitic acid before treatment and HCV genotype were significant predictors for rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR). High levels of palmitic acid inhibited the anti-HCV effects of IFN-based therapy. HCV replication assays confirmed the inhibitory effects of palmitic acid on anti-HCV therapy. The concentration of serum palmitic acid is an independent predictive factor for RVR, EVR, and SVR in IFN-based antiviral therapy. These results suggest that the effect of IFN-based antiviral therapy in patients with HCV infection might be enhanced by treatment that modulates palmitic acid levels.

DOI： 10.1007/s11745-012-3716-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

Background. The manner in which ribavirin (RBV) enhances the antiviral effects of interferon (IFN) against hepatitis C virus (HCV) remains unknown. We investigated whether RBV modifies IFN-stimulated genes (ISGs) in vivo and in vitro.
Methods. We measured the messenger RNA (mRNA) levels of ISGs in T lymphocytes from patients with HCV infection who were receiving IFN-alpha therapy with or without RBV. We added RBV and/or IFN-alpha to a plasmid-based HCV replication system containing a full-length HCV genotype la sequence in HepG2 and Huh7 cell lines and the JFH-1 HCV genotype 2a sequence in Huh7 cell lines and measured levels of ISGs and autocrine IFN-beta.
Results. The expression of protein kinase R and myxovirus resistance A mRNA was enhanced more with IFN-alpha and RBV than by IFN-alpha alone in assays in vivo and in vitro. Such enhancement depended on autocrine IFN-beta being enhanced by RBV. RBV upregulated interleukin 8 (IL-8) in the absence of IFN-alpha. The IL-8 upregulation induced by RBV was responsible for the activation of activator protein 1 (AP-1).
Conclusions. Ribavirin augments the anti-HCV effects of IFN-alpha induced by ISGs through enhancing autocrine IFN-beta. Moreover, RBV can enhance IL-8 through activating AP-1. Improved understanding of ISG modulation by RBV would help to establish a means of eliminating HCV.

DOI： 10.1093/infdis/jis025

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Aim: Patients infected with hepatitis C virus (HCV) genotype 2 are more sensitive to interferon (IFN) therapy than those infected with genotype 1, but 10-20% of patients do not achieve a sustained viral response (SVR) to combination therapy with pegylated (PEG) IFN and ribavirin (RBV). This study examines the prognostic factors associated with SVR in patients infected with HCV genotype 2 treated with PEG IFN and RBV.
Methods: We treated 149 patients with chronic hepatitis C caused by HCV genotype 2. The patients received s.c. PEG IFN-alpha-2b (1.5 mu g/kg) and a weekly weight-adjusted dose of RBV (600, 800 and 1000 mg per &lt;60, 60-80 and &gt;80 kg, respectively) for 24 weeks and then prognostic factors associated with the SVR were examined.
Results: Among the 149 patients, 138 completed the combination therapy and a sustained viral response was achieved in 71.8% of them. Univariate analysis showed that age, as well as mean RBV and PEG IFN doses were factors affecting the SVR (P = 0.012, = 0.021, = 0.014). Multivariate analysis identified age and mean PEG IFN dose (P = 0.021, = 0.018, respectively) as factors involved in the SVR, but not mean RBV dose.
Conclusion: The SVR of patients infected with HCV genotype 2 depended on the dosage of PEG IFN, but not of RBV. Selecting sufficient doses of PEG IFN for combination with RBV is critical for treating such patients.

DOI： 10.1111/j.1872-034X.2011.00816.x

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A 77-year-old man with hypertension, diabetes mellitus, ischemic heart disease and a smoking habit presented at our hospital with sudden abdominal pain. Computed tomography indicated edematous swelling and pneumatosis of the intestinal wall in a localized area of the ascending colon with inflamed adipose tissue. Acute mesenteric ischemia was diagnosed. Abdominal angiography showed stenosis of the mesenteric arteries. Virtual histology-intravascular ultrasound imaging indicated a fibrous change in the superior mesenteric artery with a necrotic core. Endovascular treatment with stent placement after percutaneous transluminal angioplasty was effective. Surgery would usually be considered as the first choice for treating patients with acute mesenteric ischemia; however, when this condition is complicated with metabolic diseases, stenotic changes in the mesenteric arteries that would normally be found in patients with chronic mesenteric ischemia need to be considered to ensure optimal treatment.

DOI： 10.1007/s12328-011-0236-7

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/MPA.0b013e3181d269c0

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Language：Japanese   Publisher：(一社)日本肝臓学会  

A 51-year-old woman with a history of ocular sarcoidosis had started the treatment of PEG-interferon alfa 2b and ribavirin (PEG/RBV) combination therapy against chronic hepatitis C, however, this treatment was discontinued because of development of multiple liver tumors which were around 1 cm in diameter and detected clearly by enhanced CT. On abdominal ultrasonography (US), the tumors were very hard to be visualized, therefore, only small part of tumor could be obtained by a liver biopsy using US, and the specimen showed suspect of hepatic sarcoidosis, but no definite diagnosis was made. Because the tumors had not been changing during the 5 months observation, PEG/RBV combination therapy was started again and had been continued for 24 weeks. HCV was eradicated, but the tumors had been increasing in size on a CT scan taken 5 months after the end of the treatment. Because the tumors were clearly detected by enhanced US using Perflubutane, accurate tumor biopsy was possible and the diagnosis of hepatic sarcoidosis was fixed. Afterwards, the tumors in the liver had been decreasing in both size and number without any therapy, and eventually disappeared 12 months after the end of PEG/RBV therapy. Regarding PEG/RBV therapy against chronic hepatitis C, sustained virological response was achieved.<br> We conclude that patients should be monitored for sarcoidosis during the course of interferon and/or ribavirin therapy.<br>

DOI： 10.2957/kanzo.50.280

CiNii Books

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Language：Japanese   Publisher：(一財)日本消化器病学会  

DOI： 10.11405/nisshoshi.105.1787

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A 50-year-old man with chronic HCV infection had been received the injections of 12MU of Consensus-Interferon (C-IFN) three times a week in a previous hospital. Six months later, C-IFN therapy was terminated because of fever and massive ascites. Diuretics and antibiotics had not been effective against these symptoms. In the meantime, skin symptoms of purpura and giant ulcers in the extremities developed, and he was transferred to our hospital. Because skin biopsy revealed vasculitis and serum MPO-ANCA was positive, the diagnosis of ANCA associated vasculitis was made. Methylpredonizoron pulse therapy improved skin symptoms and massive ascites, and the skin ulcers eventually disappeared. ANCA is suggested to be responsible for this rare complication.

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PubMed

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症例は65歳女性、発熱と腹痛を主訴に前医受診。炎症反応の著明な上昇と肝外側区域に60mmの肝腫瘤を指摘され、肝膿瘍の診断で当科紹介となり抗生剤の投与を開始した。経過中画像所見で液状化が見られず持続排膿ドレナージは困難であった。生検を行い採取組織からstring test陽性のムコイド型Klebsiella pneumoniaeが検出された。抗生剤不応で膿瘍は増大したため内科的治療では救命困難と判断し、肝左葉切除術を施行した。切除後全身状態、炎症反応は著明に改善した。ムコイド型K.pneumoniaeは高病原性であり、しばしば重症化するため早急な確定診断が必要である。本症例のようにムコイド形成により細径針での膿汁吸引が困難な場合は生検による確定診断を行うべきである。抗生剤不応例やドレナージ不能症例が多く、早期に外科的切除を検討すべきである。(著者抄録)

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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DOI： 10.1016/S0618-8278(19)31636-6

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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肝疾患におけるカルニチン、亜鉛低下例の頻度と他の肝代謝マーカーとの関連を明らかにすることを目的とした。慢性肝炎(CH)41例、肝硬変(LC)88例(肝細胞癌非合併群60例、合併群28例)を対象に、カルニチン、亜鉛、アンモニア、BTR(BCAA/Tyr)、アルブミン(Alb)を測定し、低下例の頻度と互いの関連を検討した。カルニチン高度低下例はなく、軽度低下例はLCの23.9%にみられ、うち42.9%はアシルカルニチン/遊離カルニチン比&gt;0.4での基準合致例であった。亜鉛高度低下例はCH0%、LC30.7%、軽度低下例はCH31.7%、LC40.9%にみられた。アシルカルニチンと亜鉛はアンモニア、BTR、BCAAと相関があったが、遊離カルニチンはこれらと相関はなかった。以上よりカルニチンと亜鉛は慢性肝疾患例の一部で低下し、両者の動態と肝代謝マーカーとの関連には差異がみられた。(著者抄録)

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HBs抗原の測定法が改良され検出感度が高くなっているが、HBs抗原低値陽性例では偽陽性が危惧される。偽陽性の疑われる例を判定困難例とし、HBs抗原濃度別の判定困難例の頻度を明らかにすることを目的とした。41,186検体を対象にHBs抗原を化学発光免疫測定法で測定し、後方視的に検討した。判定困難例の基準をHBc抗体、HBe抗原・抗体、HBV-DNAすべて陰性、後日採血された検体でHBs抗原が陰性、の全条件を満たす例とし、HBs抗原濃度別の判定困難例の頻度を検討した。HBs抗原は1,147検体(2.8%)で陽性であった。判定困難例は6検体で、HBs抗原濃度(IU/ml)は、全例0.05以上0.20未満であり、0.20以上例には基準を満たす例はなかった。以上より、HBs抗原低値陽性例は偽陽性の可能性に留意する必要があることが示唆された。(著者抄録)

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DOI： 10.2337/db18-1666-P

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症例は20歳代男性で、1年前から倦怠感、体重減少があり、上部消化管内視鏡検査では異常はなかった。1ヵ月前より、四肢、体幹に皮膚そう痒感が出現し、肝生検では、非特異的な急性肝炎像であった。血清トランスアミナーゼ値は低下傾向であったが、血清ビリルビン値の上昇を認めた。皮膚、結膜の黄染があり、背部に10mm大の不整形の淡紅色斑が多発した。plasma reagin test(RPR)とTreponema pallidum hemagglutination assay(TPHA)が陽性、Fluorescent treponemal antibody-absorption(FTA-ABS)も陽性で、梅毒と診断した。梅毒性バラ疹がみられたことより、第II期梅毒と診断した。陰部に明らかな梅毒感染を示唆する所見は得られなかった。腹部超音波下肝生検組織では急性肝炎像を呈し、梅毒感染に伴う急性肝炎、早期梅毒性肝炎と診断した。アンピシリンを8週間投与し、黄疸、血清トランスアミナーゼ値は速やかに改善した。その後、全身倦怠感は改善、皮疹も消失し、全身状態の改善がみられたため、退院した。治療開始から10ヵ月後にRPRは陰性化した。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01159&link_issn=&doc_id=20180625160012&doc_link_id=10.2169%2Fnaika.107.1095&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.107.1095&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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肝硬変は肝不全とともに、高率に肝がんを来す。肝硬変の成因について現状と変遷は重要な情報である。C型肝炎に起因する肝硬変が依然最多ではあるが、近年減少しつつあり、B型肝炎の比率は変化なく、非B非C型肝硬変が増加している。その中で非アルコール性脂肪肝炎(NASH)が増加し、肝細胞がん発生リスクが高いと予想される。今後肝硬変の成因は大きく変化する可能性があり、定期的な全国調査、経過の追跡が必要とされている。(著者抄録)

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今回われわれは、固有肝動脈(PHA)と胃十二指腸動脈分岐部(GDA)の総肝動脈に存在する肝動脈瘤の症例を経験したため報告する。症例は72歳、男性。血管造影で、病変はGDA、PHAの分岐部に25mmの紡錘状動脈瘤として描出された。予後的治療の適応と判断し、動脈瘤辺縁のGDAからPHAへの経路を閉塞しないようframingした後コイルで塞栓した。塞栓後の造影では上腸間膜動脈経由で肝への血流が保たれていた。(著者抄録)

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Fontan術後の長期経過中に、Fontan循環に起因し肝線維化の進展と肝細胞癌の発症をきたすFontan術後肝合併症(Fontan-associated liver disease:FALD)が近年注目されている。FALD症例で肝線維化診断のため肝生検を施行した報告は少数ながらみられるが、腹腔鏡を施行し、肝の形態と組織評価の両方を行っている報告は無い。今回我々は腹腔鏡検査を施行しFALDを診断しえた3例を経験した。症例は34歳男性、33歳男性、25歳女性で、それぞれFontan術後から23年、17年、17年であった。腹腔鏡検査にて全例結節肝の所見であった。鬱血肝に対する肝生検では術後出血に注意する必要があるが、腹腔鏡では腹腔内出血の有無を詳細に観察可能であり、今回肝生検を施行した全例で出血が無く終了できた。肝組織所見は、中心静脈周囲を中心とした線維形成がみられ、鬱血による線維化進展に矛盾しない所見であった。Fontan術後症例では安全かつ確実な診断を行うためには従来の超音波ガイド下生検よりも腹腔鏡検査での施行が望ましい。FALDは術後経過により肝線維化が進展し肝発癌の高危険群になると考えられ、定期的な画像検査が必要である。(著者抄録)

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© 2016 The Japan Society of Hepatology. Patients with Fontan circulation tend to develop liver fibrosis, liver cirrhosis, and even hepatocellular carcinoma. The present study describes two male patients and one female patient with congenital heart defects who were treated with the Fontan procedure and who subsequently developed cardiac cirrhosis. The Fontan procedure diverts blood from the inferior vena cava and superior vena cava to the pulmonary arteries, thereby increasing survival in infants born with a single effective ventricle. However, as such patients live longer, the high pulmonary and right-sided heart pressure causes chronic passive hepatic congestion and definitive cardiac cirrhosis. The three patients were asymptomatic, and their liver function tests were within normal limits. However, laparoscopy showed nodular cirrhosis, lymph vesicles, and white icing sugar-like (Zuckerguss) plaques on the surface of the liver in all three patients. Therefore, these patients were diagnosed with liver cirrhosis secondary to Fontan-associated liver disease.

DOI： 10.2957/kanzo.57.656

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C型肝炎ウイルス(HCV)に直接作用するdirect-acting antivirals(DAA)のなかで、NS3プロテアーゼ阻害薬をペグインターフェロン(Peg-FIN)、リバビリンと併用する3剤併用治療により治療効果は向上し、80〜90%の患者でHCVを排除できる時代になった。特に、副作用の少ない第二世代プロテアーゼ阻害薬により忍容性も向上した。一方、複数のDAA製剤によるIFNを用いない治療法が開発されており、今後IFNを用いる治療の利点と欠点を見極めて、どのような症例に治療するか臨床的検討が必要とされている。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

65歳女。hepatitis C virus感染の既往があり、Child-Pugh分類Aの肝硬変に対してダクラタスビル(DCV)・アスナプレビル(ASV)併用療法を開始したが、治療開始11日より発熱が出現した。画像所見では腹水が出現し、血液検査所見ではAST、ALTの上昇は認めなかったが、急激なアルブミン値の低下、プロトロンビン時間(PT)の著明延長、T-Bil の上昇とCRPの軽度上昇を認め、特徴的な所見は血中好酸球分画の上昇と血中IgEの上昇であった。DCV・ASVを中止したところ、速やかに解熱してPTの改善、T-Bilの正常化と腹水の消失を認めた。

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Language：Japanese   Publisher：(一社)日本超音波医学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本超音波医学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本エイズ学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：愛媛医学会  

症例は77歳女性で、呼吸困難、意識障害を主訴に救急搬送となった。来院時、敗血症性ショックを呈し、ICU入室にて集中治療を開始した。胸部CTでは誤嚥性肺炎を認め、腹部CTでは胆嚢気腫と十二指腸球部に存在する結石が確認され、Bouveret症候群の診断に至った。集学的治療により全身状態は改善し、経過中の腹部CTで胆石の空腸内への移動が確認された。入院後第25病日に胆石イレウスに対し開腹手術を施行し、空腸切除、結石採石、再縫合、胆嚢摘出を行った。切除標本は6×3×3cmの巨大な胆嚢結石で、術後経過良好にて、第72病日にリハビリ目的で転院となった。

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：愛媛医学会  

C型肝炎患者を60歳未満群52例、60歳以上群36例に分け、Peg-IFN、RBV、TVR 3剤併用療法の安全性と治療効果について比較検討した。その結果、60歳以上群は60歳未満群に比べ、貧血、腎機能異常の副作用が多く出現した。また、副作用による治療中止例は60歳以上群で有意に多く、そのため治療効果も60歳未満群より低いことが明らかとなった。

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

Web of Science

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

症例1は62歳男で、肝細胞癌(病期IVb)の診断でソラフェニブ800mg/日内服を開始したところ、意識消失と下血が出現し、十二指腸下行脚の発赤からの出血が疑われた。症例2は81歳女で、肝細胞癌に対してソラフェニブ800mg/日を開始したところ、血便と貧血が出現し、大腸回盲部からの出血が疑われた。2症例ともソラフェニブ投与開始後、比較的早期に出血が出現したが、内服中止により速やかに出血は改善し、再出血は認めていない。また、2症例の内視鏡所見より、門脈圧亢進症粘膜病変のような血管拡張や発赤、または明らかな出血部位の同定が困難な粘膜病変がソラフェニブによる粘膜出血病変の特徴である可能性が示唆された。ソラフェニブを投与する際には、消化管出血の副作用を念頭に置いて経過観察を行い、出血出現後は速やかに服用を中止することが必要と考えられた。

DOI： 10.11280/gee.53.1626

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

Web of Science

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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