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

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

DOI： 10.1007/s10396-024-01472-6

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

DOI： 10.4093/dmj.2023.0200

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Double-stranded RNA-activated protein kinase R (PKR) is highly expressed in colorectal cancer (CRC). However, the role of PKR in CRC remains unclear. The aim of this study was to clarify whether C16 (a PKR inhibitor) exhibits antitumor effects and to identify its target pathway in CRC. We evaluated the effects of C16 on CRC cell lines using the MTS assay. Enrichment analysis was performed to identify the target pathway of C16. The cell cycle was analyzed using flow cytometry. Finally, we used immunohistochemistry to examine human CRC specimens. C16 suppressed the proliferation of CRC cells. Gene Ontology (GO) analysis revealed that the cell cycle-related GO category was substantially enriched in CRC cells treated with C16. C16 treatment resulted in G1 arrest and increased p21 protein and mRNA expression. Moreover, p21 expression was associated with CRC development as observed using immunohistochemical analysis of human CRC tissues. C16 upregulates p21 expression in CRC cells to regulate cell cycle and suppress tumor growth. Thus, PKR inhibitors may serve as a new treatment option for patients with CRC.

DOI： 10.1038/s41598-024-59671-7

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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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DOI： 10.1007/s10396-024-01423-1

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Background and objective Examining the factors influencing the career aspirations of medical students is imperative for understanding their orientation toward rural medicine. Such an investigation can serve as a basis for shaping medical education curricula dedicated to nurturing rural focus. Although previous studies have categorized students based on the presence or absence of orientation toward rural medicine and explored their sociodemographic characteristics, these students may not constitute a homogeneous group; their interests can range from aspiring to establish residence and professional practice in a specific region to being merely willing to endure brief regional placements. There is a scarcity of comprehensive examination of the extent and potential variations of rural orientation in the literature. Our survey addresses this gap by exploring the variations in rural orientation among medical students and the differences in their sociodemographic characteristics and preferred specialties based on their degree of rural orientation. Methods We classified medical students into four groups according to their levels of rural orientation: demonstrating proactive engagement towards it, considering it for a defined duration, indicating a preference for avoiding it, and considering it unfeasible. The distribution within each group was investigated. A subsequent analysis of rural orientation and its associated sociodemographic characteristics was performed: a conventional dichotomous study was conducted based on the presence or absence of rural orientation, and a focused study compared students actively interested in rural healthcare with other students. This approach enabled us to explore differences in the degree of rural orientation and associated factors. Results The study included 531 students, with 89 participants demonstrating proactive engagement towards rural medicine, 283 considering it for a defined period, 95 indicating an inclination to avoid it, and 63 students stating that it is unfeasible for them. Associated sociodemographic characteristics were explored based on the presence or absence of rural orientation and included recommendations for admission by a designated high school, the presence of a physician role model, and aspirations for obstetrics and gynecology departments. Conversely, when exclusively focusing on students with a desire for proactive engagement in rural medicine, positive correlations were observed with characteristics such as being from the same non-urban prefecture as that of the university where the study was conducted, having a history of residing in a rural area, having a physician role model, and expressing aspirations for general practice or family medicine. Aspiring to be an organ-specific specialist showed a negative correlation with high levels of rural orientation. Conclusions Based on our findings, rural orientation is not uniform among medical students; distinct levels of this aspect were observed, each associated with different sociodemographic factors.

DOI： 10.7759/cureus.55743

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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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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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

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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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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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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  

全国の肝疾患診療連携拠点病院21施設において2021年度現在勤務している肝炎医療コーディネーター(肝Co)の、人数(現職数)、実働率、職種、配属部署等についてアンケート調査を行った。21施設において肝Coは合計951名が養成され、現職数は714名(75.1%)であった。実働率は全体で83.6%であり、9施設が100%と回答したが、31.7%の施設もあった。肝Coの職種は看護師が最も多く(49%)、次いで臨床検査技師(11%)、薬剤師(10%)、管理栄養士(7%)の順であった。21施設中、前回調査(2019年度)にも参加した17施設の実働率平均は85.8%で、前回調査(84.2%)と比べてわずかに上昇しており、コロナ禍においても肝Co活動は維持されていると考えられた。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00263&link_issn=&doc_id=20231016030006&doc_link_id=10.2957%2Fkanzo.64.510&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.64.510&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  

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PURPOSE: We aimed to compare vibration-controlled transient elastography (VCTE) with shear wave elastography (SWE) without previous analysis and generate regression equations between VCTE and new point SWE using combination-elastography. METHODS: Overall, 829 patients with chronic liver disease were enrolled in this study. Patients with a skin-liver capsule distance > 25 mm were excluded. The reproducibility of VCTE and SWE was confirmed in a phantom study and a clinical study. Considering that combination-elastography allows measurement based on strain elastography, a similar analysis was performed for the liver fibrosis index (LFI), which is a quantitative value for evaluation of liver fibrosis calculated using strain elastography image features. Regression equations between the VCTE and SWE values were obtained based on linear regression analysis. RESULTS: In the phantom study and clinical study, there was a strong correlation between VCTE and SWE [r = 0.995 (p < 0.001) and r = 0.747 (p < 0.001), respectively). The regression equation between VCTE and SWE was VCTE (kPa) = 1.09 × point SWE (kPa) - 0.17. The Bland-Altman plots revealed no statistically significant bias. Meanwhile, there was no correlation between VCTE and LFI (r = 0.279). There was a statistically significant bias between VCTE and LFI in the Bland-Altman plots. The inter-operator reliability showed a good intraclass correlation coefficient of 0.760 (95% confidence interval: 0.720-0.779). CONCLUSION: Liver stiffness measured using point SWE was comparable to that measured using VCTE.

DOI： 10.1007/s10396-023-01333-8

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

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Hepatitis B vaccine induces the production of antibodies against hepatitis B surface antigen (anti-HBs) and prevents hepatitis B virus (HBV) infection. However, 5-10% of individuals cannot develop anti-HBs even after multiple vaccinations (HB vaccine non-responders). We developed an intranasal vaccine containing both HBs antigen (HBsAg) and HB core antigen (HBcAg) and mixed it with a viscosity enhancer, carboxyl vinyl polymer (CVP-NASVAC). Here, we investigated the prophylactic capacity of CVP-NASVAC in HB vaccine non-responders. Thirty-four HB vaccine non-responders were administered three doses of intranasal CVP-NASVAC. The prophylactic capacity of CVP-NASVAC was assessed by evaluating the induction of anti-HBs and anti-HBc (IgA and IgG) production, HBV-neutralization activity of sera, and induction of HBs- and HBc-specific cytotoxic T lymphocytes (CTLs). After CVP-NASVAC administration, anti-HBs and anti-HBc production were induced in 31/34 and 27/34 patients, respectively. IgA anti-HBs and anti-HBc titers significantly increased after CVP-NASVAC vaccination. HBV-neutralizing activity in vitro was confirmed in the sera of 26/29 CVP-NASVAC-administered participants. HBs- and HBc-specific CTL counts substantially increased after the CVP-NASVAC administration. Mild adverse events were observed in 9/34 participants; no serious adverse events were reported. Thus, CVP-NASVAC could be a beneficial vaccine for HB vaccine non-responders.

DOI： 10.3390/vaccines11091479

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

肝硬変の治療の基本は栄養療法である.わが国のガイドラインでは,低アルブミン血症,Child-Pugh分類B/C,サルコペニアを合併する肝硬変を積極的な栄養療法の対象としている.サルコペニアの発症抑制に就寝前捕食や分岐鎖アミノ酸製剤が有効であり,亜鉛,カルニチンなどを併用した栄養療法が肝疾患患者の予後改善に必要である.一方,わが国ではウイルス性肝硬変が減少し,アルコール性肝硬変,脂肪性肝疾患の増加が著しい.肝疾患の病態に直接的な傷害を引きおこすアルコールについて,早急な対策が必要とされている.近年発売された飲酒量低減薬を含めたアルコール対策を,有効に実施する必要がある.(著者抄録)

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Rural career preference is known to be affected by rural self-efficacy. This study aims to explore whether the presence of a physician role model and having a medical department of interest influence rural self-efficacy among medical students. The study sample comprised 813 students (464 male and 349 female). We assessed rural self-efficacy using a validated scale that comprised 15 questions. The effect of the presence of a physician role model and the choice of medical department on rural self-efficacy score was examined. Multivariable-adjusted regression analysis showed that the presence of a physician role model was significantly associated with the rural self-efficacy score (β = 0.236, p < 0.001), as were gender (β = -0.096, p = 0.004), admission while living in hometown (β = 0.077, p = 0.041), receiving a scholarship for regional duty (β = 0.079, p = 0.025), admission based on school recommendation (β = 0.077, p = 0.031), and subjective difficulty with living in a rural area (β = -0.201, p < 0.001). Moreover, a higher rural self-efficacy score was significantly associated with students who listed general medicine/family medicine (β = 0.204, p < 0.001), pediatrics (β = 0.098, p = 0.004), or obstetrics and gynecology (β = 0.108, p = 0.002) as their department of choice, while anesthesiology (β = -0.075, p = 0.023) was significantly associated with a lower rural self-efficacy score. These relationships were consistent for both males and females. The presence of a physician role model and the choice of medical department are important factors for higher rural self-efficacy scores.

DOI： 10.7759/cureus.46174

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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  

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

肝硬変の治療の基本は栄養療法である.わが国のガイドラインでは,低アルブミン血症,Child-Pugh分類B/C,サルコペニアを合併する肝硬変を積極的な栄養療法の対象としている.サルコペニアの発症抑制に就寝前捕食や分岐鎖アミノ酸製剤が有効であり,亜鉛,カルニチンなどを併用した栄養療法が肝疾患患者の予後改善に必要である.一方,わが国ではウイルス性肝硬変が減少し,アルコール性肝硬変,脂肪性肝疾患の増加が著しい.肝疾患の病態に直接的な傷害を引きおこすアルコールについて,早急な対策が必要とされている.近年発売された飲酒量低減薬を含めたアルコール対策を,有効に実施する必要がある.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20230921450003&doc_link_id=10.11405%2Fnisshoshi.120.717&url=https%3A%2F%2Fdoi.org%2F10.11405%2Fnisshoshi.120.717&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞栄養食事療法は肝硬変の基本的治療である.「肝硬変診療ガイドライン2020」では,サルコペニアの評価を含めた栄養アセスメントを速やかに行い,就寝前軽食や分岐鎖アミノ酸製剤を含めた栄養療法を早期から提供することを推奨している.また,肝硬変患者は高率にサルコペニアを合併し,その予後を悪化させる要因となるため,SARC-Fや指輪っか法による拾い上げが重要である.肝硬変患者に対する運動療法の重要性は指摘されているが,安全性への懸念などから,その研究は端緒についたばかりである.日本肝臓学会は肝疾患患者に対する運動療法,栄養療法などを包括した多職種連携プログラムである「肝臓リハビリテーション」の確立に向けて検討を開始している.

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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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BACKGROUND: Many of the existing research studies have shown that serum uric acid (SUA) is a predictor of renal disease progression. More recently, studies have suggested an association between renal function-normalized SUA and all-cause mortality in adults. This study aims to examine the association between the ratio of SUA to creatinine (SUA/Cr) and all-cause mortality with a focus on hypertensive patients. METHODS: This study is based on 2,017 participants, of whom 916 were male (mean age, 67 ± 11 years) and 1,101 were female (mean age, 69 ± 9 years). All participants were part of the Nomura Cohort Study in 2002 (cohort 1) and 2014 (cohort 2), as well as the follow-up period (2002 follow-up rate, 94.8%; 2014 follow-up rate, 98.0%). We obtained adjusted relative risk estimates for all-cause mortality from a basic resident register. In addition, we employed a Cox proportional hazards model and adjusted it for possible confounders to determine the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Of the total participants, 639 (31.7%) were deceased; of these, 327 (35.7%) were male and 312 (28.3%) were female. We found an independent association between a higher ratio of SUA/Cr and a higher risk of all-cause mortality in female participants only (HR, 1.10; 95% CI, 1.02-1.18). The multivariable-adjusted HRs (95% CI) for all-cause mortality across quintiles of baseline SUA/Cr were 1.28 (0.91-1.80), 1.00, 1.38 (0.95-1.98), 1.37 (0.94-2.00), and 1.57 (1.03-2.40) for male participants, and 0.92 (0.64-1.33), 1.00, 1.04 (0.72-1.50), 1.56 (1.06-2.30), and 1.59 (1.06-2.38) for female participants. When the data were further stratified on the basis of age (< 65 or ≥ 65 years), body mass index (< 22.0 or ≥ 22.0 kg/m2), estimated glomerular filtration rate (< 60 or ≥ 60 mL/min/1.73 m2), and presence of SUA-lowering medication, trends similar to those of the full population were found in all groups. CONCLUSION: Baseline SUA/Cr is independently and significantly associated with future all-cause mortality among hypertensive patients.

DOI： 10.1186/s40885-023-00235-8

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

【背景/目的】門脈圧亢進症合併症例の予後改善やサルコペニア進展阻止のため栄養介入をすべき症例の臨床像は未だ明らかではない.栄養介入を開始すべき臨床像を明らかとする.【対象/方法】2021年12月までに当院で診断した初発肝癌患者408例.肝予備能評価にはmALBIを用い,門脈圧亢進症(PHT)は食道胃静脈瘤F2以上/治療歴ありとした.BTR4.4以下をアミノ酸インバランス(AAI)と規定して後方視的に生命予後を解析した.【結果】多変量解析で75歳以上,mALBI 2b以下,MVL,PHTが予後因子であった.AAIを予測するALBIは-2.586(AUC 0.789)であった.【結語】PHTがあれば,Child-Pugh AでもmALBI 1から2aへの過渡期にAAIがすでに起こりはじめており,MVLへの進展を防ぐために栄養介入を積極的に行うべきである.(著者抄録)

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

AIMS: HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device. METHODS: A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints. RESULTS: Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 log10  IU/ml (p < 0.05) and -0.2677 log10  IU/ml (p < 0.05), respectively. Anti-HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP-NASVAC treatment. CONCLUSIONS: Anti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

DOI： 10.1111/hepr.13851

PubMed

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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

PubMed

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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

PubMed

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PURPOSE: Deep attenuation transducers (DAX) are capable of imaging at diagnostic depths of up to 40 cm. The feasibility of DAX for liver stiffness measurement (LSM) has not been reported clinically. We aimed to assess the feasibility and reliability of DAX for LSM. METHODS: Overall, 219 patients with chronic liver disease were enrolled. The success rate (acquired after ≥ 10 valid measurements) and inadequate measurements (interquartile range/median ≥ 0.3) for DAX were compared with those of conventional convex (c-convex) probes and M and XL probes of vibration-controlled transient elastography. RESULTS: LSM was successfully performed for all patients using DAX through all degrees of skin-to-liver capsular distance (SCD). Especially in patients with an SCD ≥ 30 mm, the difference in the rate of acquisition of 10 valid measurements was remarkable: M probe (8/33, 24.2%), XL probe (26/33, 78.8%), c-convex probe (33/43, 76.7%), and DAX (44/44, 100%). In patients with an SCD ≥ 30 mm, the inadequate measurement rate of M probe (1/8, 12.5%), XL probe (8/26, 30.8%), and c-convex probe (6/33, 18.2%) was higher than that of DAX (1/43, 2.3%). The areas under the curve for diagnosis of F4 with shear wave speed by c-convex and DAX were 0.916 and 0.918, respectively. Between DAX and c-convex probes, the intraclass correlation coefficient of 0.937 (95% CI 0.918-0.952) was excellent. Bland-Altman plots revealed that there was no statistically significant bias. CONCLUSION: Liver stiffness measured by DAX is feasible and reliable for all patient populations, while the XL probe is limited to use in obese patients.

DOI： 10.1007/s10396-022-01270-y

PubMed

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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

Scopus

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

DOI： 10.11405/nisshoshi.120.717

PubMed

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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

Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞エラストグラフィには,臓器に対して一定の力を加えた際に生じる歪み(stiffness)を「硬さ」として計測した"strain elastography"と,剪断波(shear wave)が臓器の中を伝播する速度を「硬さ」として計測した"shear wave elastography"に大きく分けられる.本稿ではstrain elastographyであるReal-time Tissue Elastography(RTE)の特徴と,shear wave elastography(SWE)であるtransient elastographyの違いについて概説する.

DOI： 10.19020/cg.0000002416

CiNii Research

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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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Language：Japanese   Publisher：(株)日本医事新報社  

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

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Language：Japanese   Publisher：(株)日本医事新報社  

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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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AIMS: To investigate whether fibrosis-4 index can help stratify the risk of diabetes mellitus in subjects with fatty liver disease. METHODS: Based on fatty liver disease and fibrosis-4 index (cutoff value, 1.3), we retrospectively divided 9,449 subjects, who underwent at least two annual health checkups, into four groups stratified by gender: normal, high fibrosis-4 indexwithout fatty liver disease, low fibrosis-4 index with fatty liver disease, and high fibrosis-4 index with fatty liver disease groups. RESULTS: Onset rates for diabetes mellitus in the normal, high fibrosis-4 index without fatty liver disease, low fibrosis-4 index with fatty liver disease, and high fibrosis-4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8%, and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3%, and 7.0%, respectively, in women. Compared with the normal group, the high fibrosis-4 index without fatty liver disease, low fibrosis-4 index with fatty liver disease, and high fibrosis-4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female subjects. Moreover, in both genders, high fibrosis-4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis-4 index with fatty liver disease group: adjusted harzard ratio, 95% confidence interval: 4.03, 2.19-7.42 [men] and 6.40, 1.77-23.14 [women]). CONCLUSIONS: Subjects with fatty liver disease and high fibrosis-4 index had a higher risk of diabetes mellitus onset. Therefore, fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention.

DOI： 10.1111/jdi.13812

PubMed

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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：(株)アークメディア  

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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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INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction-associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM. MATERIALS AND METHODS: We retrospectively assessed 9,459 participants who underwent two or more annual health check-ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non-overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants). RESULTS: The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre-diabetes (P < 0.01). CONCLUSIONS: Fatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.

DOI： 10.1111/jdi.13772

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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：(NPO)日本高齢消化器病学会  

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BACKGROUND: In Japan, community medicine clerkships facilitate positive attitudes toward rural medical practice and encourage rural recruitment. Rural self-efficacy has been shown to influence rural career intent following a rural clinical placement. However, the impact of subjective difficulties of living in a rural area on future rural career intent is also important. This study aims to explore whether rural self-efficacy influences the relationship between difficulty with living in a rural area and rural career intent.  METHODS: The subjects included 308 male and 255 female participants aged 20-41 [median (interquartile range): 22 (21-22)] years. Rural self-efficacy was based on a validated scale consisting of 15 questions. Difficulty with living in a rural area was measured asking students. A cohort survey was conducted to evaluate the effect of the rural self-efficacy score on the rural career intent of Japanese medical students after they completed their rural clinical training. RESULTS: The following variables were significantly associated with a higher rural self-efficacy score: female sex (p = 0.003), age < 21 years (p = 0.013), having a doctor as a role model (p < 0.001), gaining admission through a school recommendation (p = 0.016), living in a rural or remote area until the age of 18 years (p = 0.018), and orientation towards general medicine (p < 0.001). In addition, baseline difficulty with living in a rural area was significantly associated with a lower self-efficacy score (p < 0.001). Participants with a stronger intent to practice in a rural area before rural clinical training had higher rural self-efficacy and showed a stronger positive rural career intent after rural clinical training (p < 0.001). A multivariable logistic regression analysis demonstrated that difficulty with living in a rural area [odds ratio (OR): 0.61; 95% confidence interval (CI), 0.39-0.84] was still associated with lower rural career intent after rural clinical training, independent of all confounders such as gender, age, scholarship for regional duty, rural background, and orientation towards general medicine. However, when rural self-efficacy (OR, 1.12; 95% CI, 1.07-1.16) was added as a factor for rural career intent, difficulty with living in a rural area (OR, 0.68; 95% CI, 0.43-1.06) was no longer observed as an associated factor. CONCLUSION: Subjective difficulty with living in a rural area was shown to reduce future rural career intent, but high rural self-efficacy ameliorated this decline.

DOI： 10.1186/s12909-022-03511-7

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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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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

PubMed

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BACKGROUND: This study examined the relationship between survival prognosis and alanine aminotransferase (ALT), a critical factor contributing to aging-related health and mortality. The research is based on a follow-up study with 6- and 10-year intervals. METHODS: The participants included 1,610 males (63 ± 14 years old) and 2,074 females (65 ± 12 years old) who were part of the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort). The multivariable-adjusted hazard ratios (HRs) of death between the baseline health checkup and the end of the follow-up periods were estimated using a Cox proportional hazards model, controlling for potential confounding factors. RESULTS: The follow-up survey revealed 180 male deaths (11.2% of male participants) and 146 female deaths (7.0% of female participants). The univariate Cox regression analysis showed a significant increase in the HRs of all-cause mortality with decreasing ALT levels (p < 0.001). Furthermore, compared with individuals with ALT levels of 20-29 IU/L, the multivariable-adjusted HRs (95% confidence interval) for all-cause mortality were 2.73 (1.59-4.70) for those with ALT levels <10 IU/L, 1.45 (1.05-2.00) for those with ALT levels of 10-19 IU/L, and 1.63 (1.05-2.53) for those with ALT levels ≥30 IU/L. CONCLUSIONS: Our findings show that abnormally low ALT levels and high within the normal range were related to all-cause mortality in Japan's community-dwelling individuals. Especially, ALT activity may be an important biomarker for predicting the long-term survival of older adults.

DOI： 10.1002/jcla.24445

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

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

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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：医学図書出版(株)  

薬物性肝障害(drug-induced liver injury:DILI)は薬物副反応の肝臓における表現型である。ベッドサイドで遭遇する頻度が高く、他診療科から紹介を受けることが多い疾患である。特異的な症状、検査所見に乏しく、臨床経過の詳細な聴取と、他の肝疾患の除外が重要である。近年、多彩な作用機序の新薬に加え、複数薬の投与を受ける患者が多いため、起因薬物の同定が困難なケースが増えている。さらに、医薬品に限らず、日常生活のなかで使用している健康食品、サプリメントの成分により生じることもある。肝障害のコンサルテーションを受けたときには、常にDILIの可能性を念頭において鑑別を進めていくことが求められる。(著者抄録)

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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：(NPO)日本高齢消化器病学会  

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

【目的】高齢早期胃癌・内視鏡的非治癒切除例において、追加手術と低骨格筋量の予後への影響を明らかにする。【方法】内視鏡的根治度C-2と判定された75歳以上の早期胃癌患者55例を、追加手術の有無で検討した。また、サルコペニア関連因子としてCTで測定したPsoas muscle mass index(PMI)を用い、予後との関連を評価した。【結果】再発率は、両群間で差がなかった。腸腰筋体積は、追加手術群で経年的減少が見られた。予後は、追加手術の有無で差はなく、ESD3年後の低PMI群において予後不良傾向を認めた(P=0.068)。【結論】高齢早期胃癌において、予後は術後低栄養との関連が示唆された。(著者抄録)

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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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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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Language：Japanese   Publisher：(有)科学評論社  

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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：English   Publishing type：Research paper (scientific journal)  

The small intestinal mucosa-associated microbiota (MAM) can potentially impact the etiology of primary biliary cholangitis (PBC). Herein, we investigate the MAM profile to determine its association with liver pathology in patients with PBC. Thirty-four patients with PBC and 21 healthy controls who underwent colonoscopy at our hospital were enrolled in our study. We performed 16S ribosomal RNA gene sequencing of MAM samples obtained from the mucosa of the terminal ileum and examined the relationship between the abundance of ileal MAM and chronic nonsuppurative destructive cholangitis using liver specimens from patients with PBC. There was a significant reduction in microbial diversity within individuals with PBC (P = 0.039). Dysbiosis of ileal MAM was observed in patients with PBC, with a characteristic overgrowth of Sphingomonadaceae and Pseudomonas. Multivariate analysis showed that the overgrowth of Sphingomonadaceae and Pseudomonas is an independent association factor for PBC (P = 0.0429, P = 0.026). Moreover, the abundance of Sphingomonadaceae was associated with chronic nonsuppurative destructive cholangitis in PBC (P = 0.00981). The overgrowth of Sphingomonadaceae and Pseudomonas in ileal MAM was found in patients with PBC. Sphingomonadaceae may be associated with the pathological development of PBC.

DOI： 10.1038/s41598-021-99314-9

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞▼わが国の肝硬変・肝細胞がん患者の多くが高齢者である.▼高用量の利尿薬投与は電解質異常や腎機能増悪の危険性があり,高齢者ではtolvaptanの適用を利尿薬の増量前から検討する.▼高齢者に対する腹水排液は少量から開始し,輸液,アルブミン投与を併用する.▼サルコペニア合併例は分岐鎖アミノ酸製剤を含む栄養療法と運動療法を行う.ただし,運動は軽微な運動から段階的に強度を上げることが望ましい.▼加齢に伴う認知機能低下と肝性脳症の鑑別はしばしば困難である.▼高齢者の肝細胞がんでは,より侵襲の少ない治療が推奨される.個々の症例におけるperformance statusや合併疾患を考慮して,ガイドラインに沿った治療が可能か検討する.

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00974&link_issn=&doc_id=20211004160015&doc_link_id=10.15106%2Fj_naika128_843&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_naika128_843&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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

INTRODUCTION: Fatty liver disease (FLD) is a surrogate condition for glucose intolerance development. FLD may involve normal or abnormal liver enzyme levels. Whether FLD is a risk factor for glucose intolerance, regardless of liver enzyme levels, remains unknown. We assessed relationships between the development of impaired fasting glucose (IFG) and FLD, liver enzyme abnormalities, and alcohol consumption. MATERIALS AND METHODS: We retrospectively evaluated 8,664 participants with more than two annual health check-ups. Participants were classified according to sex, alcohol consumption, alanine aminotransferase (ALT) levels, and fatty liver status. RESULTS: In univariate analyses, IFG onset among men was related to normal or high ALT levels with FLD in the nonalcoholic and alcoholic groups (P-trend < 0.01). In multivariate analyses, IFG onset among nonalcoholic men was associated with normal or high ALT levels with FLD, independent of potential confounding factors (P-trend < 0.01). However, IFG onset was non-independently associated with any condition among alcoholic men. In univariate analyses, IFG onset among women was related to normal or high ALT levels with FLD in the nonalcoholic group (P-trend < 0.01) and high ALT levels with FLD in the alcoholic group (P-trend < 0.05). In multivariate analyses, IFG onset was independently associated with only normal ALT levels in nonalcoholic FLD women. CONCLUSIONS: Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk.

DOI： 10.1111/jdi.13548

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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   Publisher：WILEY  

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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：医歯薬出版(株)  

＜Key Point＞・「肝硬変診療ガイドライン2020」の栄養療法フローチャートは、実際の栄養指導で利用しやすい流れに改訂された。・蛋白低栄養状態、Child-Pugh分類BまたはC、サルコペニアのいずれかがある肝硬変患者には、分岐鎖アミノ酸を含めた栄養療法を行う。・肝硬変患者の栄養療法では、就寝前軽食や分割食を積極的に取り入れる。(著者抄録)

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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)  

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：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Serum uric acid (SUA) is a key risk factor contributing to renal failure, a serious public health problem. However, few studies have examined whether the interactive relationship between alcohol consumption and SUA is independently associated with the estimated glomerular filtration rate (eGFR). METHODS: Our sample comprised 742 men aged 69 ± 11 years (mean ± standard deviation) and 977 women aged 69 ± 10 years from a rural area. We cross-sectionally examined the relationships between the confounding factors of alcohol consumption and SUA with renal function denoted by eGFR estimated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations modified by a Japanese coefficient. RESULTS: In both genders, eGFR increased with a rise in alcohol consumption. This tendency was more pronounced in participants with hyperuricemia, where SUA was greater than 7.0 mg/dL in men and greater than 6.0 mg/dl in women (men: F = 41.98, p < 0.001; women: F = 41.98, p < 0.001). A multiple linear regression analysis showed that alcohol consumption (men: β = 0.112, p < 0.001; women: β = 0.060, p = 0.011) and SUA (men: β = -0.282, p < 0.001; women: β = 0.317, p < 0.001) were significantly and independently related to eGFR. Further, the interactive relationship between alcohol consumption and SUA (men: F = 6.388, p < 0.001; women: F = 5.368, p < 0.001) was a significant and independent indicator of eGFR. CONCLUSIONS: These results suggested that alcohol consumption and SUA were synergistically associated with renal dysfunction among community-dwelling persons.

DOI： 10.1002/jcla.23812

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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：愛媛医学会  

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

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 via 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 [LFI]), and controlled attenuation parameter (CAP) with fibrosis, lymphatic vessels, alanine aminotransferase (ALT), bilirubin, and steatosis were evaluated. RESULTS: Fibrosis, splenic stiffness measurement (SSM), and splenic volume were significantly correlated with the area of lymphatic vessels. Fibrosis, lymphatic vessels, and ALT were independent factors significantly associated with liver stiffness measurement (LSM) (β  =  0.375, P < 0.001; β  =  0.342, P < 0.001; β  =  0.359, P < 0.001). Fibrosis was the only independent factor significantly associated with LFI (β  =  0.360, P <0.001), whereas the fat deposit area was the only independent factor significantly associated with CAP (β  =  0.455, P <0.001). The areas under the receiver operating characteristic curves for diagnosing controlled ascites based on LSM, LFI, SSM, 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. LSM is a predictive factor for ascites. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13610

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

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BACKGROUND: 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. METHODS: 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. RESULTS: 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; p = 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; p = 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 (p = 0.001), whereas that in the untreated group showed a significant decline (p = 0.040). CONCLUSIONS: DAAs after HCC treatment prevents deterioration of hepatic functional reserve and significantly improves both recurrence and survival rates.

DOI： 10.1007/s00535-020-01747-y

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

肝硬変の診療にあたっては門脈圧亢進症、腹水、肝性脳症など多彩な合併症の適切な管理が生命予後の改善に直結する。わが国では腹水や肝性脳症に対する新規薬剤が使用可能となり治療選択肢が広がることで、肝硬変の合併症に対する治療戦略に大きな変化がみられている。一方で、肝硬変の合併症は多岐にわたり、サルコペニアや門脈肺高血圧症などのさらなる病態解明や治療法の開発が望まれる。本稿では肝硬変の合併症対策についてのクリニカルクエスチョンに対する回答として、新ガイドラインの考え方と今後の課題について概説する。(著者抄録)

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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：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11405/nisshoshi.118.30

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Language：Japanese   Publisher：愛媛医学会  

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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：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)日本肝臓学会  

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AIM: For radiofrequency ablation to treat patients diagnosed with liver cancer, the ablation area cannot be envisaged beforehand, even by experts. This study aimed to assess the clinical feasibility of applying a combination of electric (E)-field and coronal (C)-plane simulations to ultrasound-ultrasound (US-US) fusion images. METHODS: The study protocols were approved by the institutional ethics committee. Between October 2017 and July 2019, 151 patients with 151 hepatocellular carcinoma nodules (80 treated with navigation images and 71 without navigation images) were retrospectively compared in this cross-sectional study. The E-field, which is a simulated image that predicts the ablation area, was applied to the US-US fusion images. The C-plane is defined as a sagittal plane in relation to the original 2-D US images. The positions of each E-field area in the maximum cross-sectional area of the tumor were easily identified from C-plane results. The primary end-point of this study was achievement of an adequate safety margin (greater than 5 mm). The sphericity of the ablation volume was used as a secondary end-point. RESULTS: The rate of achieving a sufficient safety margin was significantly higher in the group treated with navigation images (71/80) than in the group treated without navigation images (31/71, P < 0.001). The median sphericity was 0.55 with navigation images and 0.42 without navigation images (P < 0.001). CONCLUSION: Using the combination of an E-field and a C-plane on US-US fusion images can be a feasible method for acquiring a sufficient safety margin.

DOI： 10.1111/hepr.13527

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

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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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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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© 2017 The Japan Society of Hepatology Aim: We examined the prognosis of liver cirrhosis (LC) patients with and without portal hypertension (PHT) and muscle volume loss (MVL). Methods: From 2006 to 2016, 346 LC outpatients (PHT/non-PHT = 173/173) were enrolled (median age, 69 years; men / women, 204/142; Child–Pugh A / B, 230/116; and presence of MVL 15.6% in each group) after propensity matching, following exclusion of those with hepatocellular carcinoma (HCC) beyond the Milan criteria and Child–Pugh C. Portal hypertension was defined as positive for significant esophagogastric varices; MVL was diagnosed based on a previously reported index using CT imaging. Overall survival rate (OSR) was evaluated from the viewpoints of PHT and MVL. Results: There were no significant differences in clinical background (age, gender, etiology, presence of HCC [within Milan criteria], or Child–Pugh class) between the groups. Although there was no significant difference regarding OSR between patients with and without MVL in the non-PHT group (P = 0.076, Holm's method), the OSR of patients with MVL in the PHT group was lower compared to those without MVL in both groups (P = 0.017 and P = 0.012, respectively, Holm's method). As a result, the OSR of patients with MVL (n = 54) was lower than the other patients (n = 292) (3- and 5-year OSR, 69.0% vs. 86.4% and 35.8% vs. 74.1%, respectively; P < 0.001). Multivariate Cox hazard analysis showed that positive for HCC (hazard ratio [HR], 2.028; 95% confidence interval [CI], 1.189–3.460; P = 0.009) and positive for MVL (HR, 2.768; 95% CI, 1.575–4.863; P < 0.001) were significant independent prognostic factors for death. Conclusion: Muscle volume loss and HCC, but not PHT, were found to be independent prognostic factors for death in LC patients.

DOI： 10.1111/hepr.12984

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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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AIM: Hypozincemia is associated with the progression of chronic liver diseases, but it is unknown whether hypozincemia promotes human hepatocarcinogenesis. Our aim is to evaluate the serum zinc levels in liver cirrhosis (LC) patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC). METHODS: Cirrhotic patients without HCC (n = 299) were enrolled from 14 medical institutes in Japan as a multicenter prospective study (No. 2028). Of the 299 patients, 157 were included in the present study based on reliable and consistent serum zinc levels and no history of oral zinc supplementation. Clinical parameters associated with the development of HCC were determined. Furthermore, the cumulative incidence of HCC was analyzed using Kaplan-Meier methods and was calculated using the log-rank test. A Cox regression analysis was utilized for the multivariate analysis to evaluate the predictors of hepatocarcinogenesis. RESULTS: Thirty of 157 patients (19.1%) developed HCC during an observation period of 3 years. Serum zinc levels were significantly decreased in hepatitis C virus-related LC (C-LC) patients with HCC (0.0180). The risk factors for incidence of HCC were hypozincemia (0.0014), high α-fetoprotein (0.0080), low branched chain amino acids-to-tyrosine ratio (0.0128), or female sex (0.0228). Hypozincemia (hazard ratio 1.61, 0.0324) was the only significant predictor of hepatocarcinogenesis by multivariate Cox regression analysis. CONCLUSIONS: Hypozincemia is associated with hepatocarcinogenesis in C-LC patients.

DOI： 10.1111/hepr.13388

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© 2018 The Japan Society of Hepatology 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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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：Japanese   Publisher：(一社)日本内科学会  

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Background: Patients with liver cirrhosis often exhibit zinc deficiency. Although zinc is involved in many bioactivities, many aspects of clinical implications of zinc deficiency in liver cirrhosis remain unclear. We aimed to reveal the prevalence and implications of zinc deficiency in liver cirrhosis by assessing associations with parameters such as clinical symptoms and laboratory data. Methods: In 235 cirrhosis patients enrolled at multiple medical institutions in 2009, we assessed how blood zinc levels were associated with their clinical symptoms, patients characteristics, and liver function test results. Results: Blood zinc levels were most strongly correlated with blood albumin levels among the study parameters (r = 0.587, P < 0.0001). When blood albumin levels were ≤ 3.5 g/dL, blood zinc levels were < 70 μg/dL in 88% of patients. Additionally, significant correlations were observed with age (r = -0.253, P = 0.0014), aspartate aminotransferase levels (r = -0.254, P = 0.0020), total bilirubin levels (r = -0.222, P = 0.0053), prothrombin time (r = -0.255, P = 0.0029), branched-chain amino acid to tyrosine ratio (r = 0.357, P < 0.0001), Child-Pugh score (r = 0.469, P < 0.0001), ammonia levels (r = -0.246, P = 0.0028), and total cholesterol levels (r = 0.314, P < 0.0001). Blood zinc levels were significantly lower in patients with edema/ascites (P < 0.0001), those with hepatic encephalopathy (P = 0.0215), those receiving oral diuretics (P = 0.0045), and those receiving oral branched-chain amino acids (P < 0.0001) than in those without these conditions. Conclusions: Zinc deficiency is prevalent in cirrhosis patients, whereas nitrogen metabolic disorders, particularly hypoalbuminemia, can be an indicator of zinc deficiency. Thus, cirrhosis patients exhibiting a nitrogen metabolic disorder should be examined for the presence of zinc deficiency.

DOI： 10.14740/jocmr3374w

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© 2017, Japanese Society of Gastroenterology. 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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© 2018 The Japanese Society of Internal Medicine. Objective Low urine pH is associated with several metabolic diseases, such as dyslipidemia, diabetes, and metabolic syndrome. However, the association between low urine pH and non-alcoholic fatty liver disease (NAFLD) remains unknown. Therefore, we conducted a community-based cross-sectional study to investigate this association. Methods Between April 2013 and March 2014, the records of 4,945 Japanese subjects who had undergone annual health checkups were reviewed to identify subjects who met the diagnostic criteria for NAFLD. Patients Based on urine pH, the participants were classified into four groups; a low urine pH was defined as ≤5.5. Of the 3,411 subjects who qualified for enrollment, 1,028 met the diagnostic criteria for NAFLD. Results The prevalence of NAFLD was significantly increased with decreasing urine pH in both men and women (p<0.01 and p=0.02, respectively). A multivariate analysis, including adjustments for age, metabolic markers, and the renal function, showed a significant association between low urine pH and NAFLD in men and women (odds ratio, 1.37; 95% confidence interval, 1.01-1.85, p=0.04 and odds ratio, 1.73; 95% confidence interval, 1.15-2.62, p<0.01, respectively). Conclusion Our study indicates that NAFLD is associated with a low urine pH in both sexes, findings that might help clinicians identify patients at high risk for NAFLD.

DOI： 10.2169/internalmedicine.0167-17

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© 2017 The Japan Society of Hepatology Aim: Assessing 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. Methods: The 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 1–3 months. Results: Both 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 F ≥ 2, F ≥ 3, 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). Conclusions: Real-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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© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd 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 < 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 < 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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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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© 2017 Wiley Periodicals, Inc. 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 < 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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© 2017, Japanese Society of Gastroenterology. Background: Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH. Methods: A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1–2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3–4 [advanced NASH (a-NASH)]. 13C-labeled palmitate was administered directly into the duodenum of all participants by gastrointestinal endoscopy. Breath 13CO2 levels were measured to quantify palmitic acid absorption, and serum Apolipoprotein B-48 (ApoB-48) concentrations were measured after a test meal to quantify absorbed chylomicrons. Expressions of fatty acid (FA) transporters were also examined. The associations of breath 13CO2 levels with hepatic steatosis, fibrosis and insulin resistance was evaluated using laboratory data, elastography results and liver histology findings. Results: Overall, 13CO2 excretion was significantly higher in e-NASH patients than in the control subjects and a-NASH patients (P < 0.01). e-NASH patients had higher serum ApoB-48 levels, indicating increased palmitic acid transport via chylomicrons in these patients. Jejunal mRNA and protein expressions of microsomal triglyceride transfer protein and cluster of differentiation 36 were also increased in both NASH patient groups. The 13CO2 excretion of e-NASH patients was significantly correlated with the degree of hepatic steatosis, fibrosis and insulin resistance (P = 0.005, P < 0.001, P = 0.019, respectively). Conclusions: Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.

DOI： 10.1007/s00535-016-1298-6

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© 2016 The Japan Society of Hepatology Aim: This study aimed to compare multipolar radiofrequency ablation (RFA) with monopolar RFA as the major treatment for nodules of hepatocellular carcinoma in the caudate lobe. Methods: This retrospective study was approved by the institutional review board. Data were reviewed from 101 patients who met the Milan criteria and were treated by multipolar RFA (n = 22) or monopolar RFA (n = 79). After propensity score matching, complications and local tumor progression were compared between the two groups. Results: Before propensity score matching (n = 101), the 2-year relapse-free survival rates for multipolar and monopolar RFA (65.1% vs. 38.8%, respectively; P = 0.064) and the local tumor progression rate (12.5% vs. 14.9%, respectively; P = 0.313) were not significantly different. There were no significant differences between the two RFA techniques by treatment efficacy of transcatheter hepatic arterial embolization, location of tumor, and puncture route. After matching (n = 44), the 2-year relapse-free survival rate for the multipolar and monopolar groups (65.1% vs. 22.7%, respectively; P = 0.004) was significantly different, and the local tumor progression rate (12.5% vs. 22.9%, respectively; P = 0.004) was significantly different. No severe complications occurred in the patients treated by multipolar RFA. Conclusion: Multipolar RFA appears to be a safe and effective method for hepatocellular carcinoma nodules in the caudate lobe.

DOI： 10.1111/hepr.12791

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© 2017 Ohno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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© 2016 The Authors 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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© Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved. Background/aim Sarcopenia is recognized as a condition related to quality of life and prognosis in patients with chronic liver disease, although no useful strategy for improving muscle volume and strength has been established. Here, we evaluated the efficacy of supplementation with branched-chain amino acid (BCAA) administration and walking exercise. Patients and methods From December 2015 to July 2016, 33 Japanese outpatients with liver cirrhosis were enrolled (median: 67 years, HCV: HBV: alcohol: others=26: 2: 2: 3, male: female=13: 20, Child-Pugh A: B=30: 3). None had a history of BCAA supplementation. After calculating the average number of daily steps using a pedometer for a 2-3-week period, BCAA supplementation (protein 13.5 g, 210 kcal/day) as a late evening snack and walking exercise (additional 2000 steps/day prescribed) were started. Body composition including muscle volume was analyzed using a bioelectrical impedance analysis method, and serological data and muscle strength (leg, handgrip) were evaluated at enrollment, and then 1, 2, and 3 months after starting the protocol. Results The median average number of daily steps was 3791 (interquartile range: 2238-5484). The average period of BCAA supplementation was 2.7±0.7 months. During the period from enrollment to 3 months after starting the protocol, HbA1c and NH 3 were not significantly changed, whereas the BCAA/tyrosine ratio improved (4.3±1.35 to 5.24±2.04, P=0.001). In addition, the ratios for average daily steps (1.595, P=0.02) as well as muscle volume, leg strength, and handgrip strength (1.013, 1.110, and 1.056, respectively; all P<0.01) were increased at 3 months. Conclusion BCAA supplementation and walking exercise were found to be effective and easily implemented for improving muscle volume and strength in liver cirrhosis patients.

DOI： 10.1097/MEG.0000000000000986

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© 2016 The Authors 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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER INTERNATIONAL PUBLISHING AG  

© 2016, Watanabe et al. 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-naïve, 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 <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥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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Language：Japanese   Publisher：(株)アークメディア  

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© 2016, Japanese Society of Gastroenterology. Background: 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. Methods: 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 ≥110 mg/dl. Results: In the non-drinker, >0–70 g/week, >70–140 g/week, >140–210 g/week (men only), and >210 g/week (men only) or >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 >0–70 g/week group (adjusted hazard ratio [aHR], 2.808; 95 % confidence interval [CI] 1.605–5.049, p < 0.001) and women of the >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. Conclusions: 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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Language：Japanese   Publisher：(株)日本メディカルセンター  

C型肝硬変に対するインターフェロン治療は,ウイルス排除率が低く,副作用が高率に出現することから適応は限定的であった.しかし,2014年にインターフェロンを使用せずに直接的にC型肝炎ウイルス(HCV)の複製を阻害するdirect-acting antivirals(DAA)が登場し,代償性肝硬変に対して保険適応となった.以後,DAAによる治療は代償性肝硬変に対する第一選択の治療と考えられている.海外ではさらに非代償性肝硬変を対象とした臨床試験が進行し,肝予備能の改善が報告されていることから,本邦での適応拡大も期待されている.しかし,肝硬変症例ではウイルス排除率が慢性肝炎に比べて低く,治療期間延長の必要性,リバビリンの併用,薬剤耐性変異の影響,肝不全などの有害事象への対応など解決が必要な問題もあり,安全かつ効果的な治療法が望まれている.(著者抄録)

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＜Point＞慢性肝不全では高率に蛋白・エネルギー低栄養を合併している。分岐鎖アミノ酸比率を高め、就寝前の補食を含めた分割食が推奨されている。分岐鎖アミノ酸製剤は、肝細胞がんの発症や総死亡を抑制し、予後を改善する。適切な栄養療法、指導により予後の改善が得られる。(著者抄録)

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Purpose The purpose of this study was to assess the accuracy and efficacy of a needle-tracking system in phantom and clinical studies using bipolar electrodes.
Methods To observe the tip of the electrode, a needle-tracking system with a volume navigation system was used. In the phantom study, the electrode was inserted at various angles and the error was verified. In the clinical study, 21 nodules close to extrahepatic organs or major vessels were enrolled between May and October 2014. After puncturing with the needle-tracking system, computed tomography (CT) was performed. The distances between the electrode tip and extrahepatic organs or major vessels were measured on both B-mode ultrasound (US) and CT. By comparing these distances, the accuracy of this system was evaluated.
Results In the phantom study, the deviation between the tip of the electrode and the virtual tip of the electrode was analyzed. The median values were within 2 mm at each puncture angle. In the clinical study, the difference between B-mode US and CT was less (mean value 1.17 +/- A 1.76 mm; range 0-3.5 mm).
Conclusion The needle-tracking system is an accurate and useful system for bipolar radiofrequency ablation.

DOI： 10.1007/s10396-015-0679-4

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© 2015, Asian Pacific Association for the Study of the Liver. Background and aim: 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). Methods: 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. Results: Prothrombin activity was significantly elevated at 60 months after starting entecavir (from 85.9 ± 17.4 to 97.0 ± 16.9 %, p < 0.001). The albumin level was also significantly elevated at 60 months after starting entecavir (from 4.0 ± 0.5 to 4.3 ± 0.3 mg/dL, p < 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. Conclusions: 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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© 2016 Hirooka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 threedimensional 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<0.001, simulator vs. computed tomography: r = 0.991, p<0.001, ultrasound vs. computed tomography: r = 0.999, p<0.001). Correlations between distances in each imaging modality were also strong (ultrasound vs. simulator: r = 0.993, p<0.001; simulator vs. computed tomography: r = 0.994, p<0.001; ultrasound vs. computed tomography: r = 0.994, p<0.001). In cases with 3 electrodes, distances between each electrode correlated strongly (yellowlabeled vs. red-labeled: r = 0.980, p<0.001; red-labeled vs. blue-labeled: r = 0.953, p<0.001; yellow-labeled vs. blue-labeled: r = 0.953, p<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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© 2016 The Japanese Society of Internal Medicine. 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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© 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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© 2015, Springer Japan. 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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© 2014, Springer Japan. Background: Epidemiologic studies show an association between short sleep duration and the presence of nonalcoholic fatty liver disease (NAFLD). This study examined the association between short sleep duration and the onset of NAFLD. Methods: This community-based, retrospective, longitudinal cohort study included 6,370 Japanese subjects who had undergone annual health check-ups more than twice at a single center between April 2003 and March 2010. After excluding 3,941 subjects, the records of 2,429 Japanese subjects were reviewed. Results: Two groups comprised the study cohort: those with short (≤6 h) sleep durations (n = 1,543) and those with moderate (7–8 h) sleep durations (n = 886). During the observation period, 296 subjects developed NAFLD. Multivariate analysis identified an association between short sleep duration and the reduced onset of NAFLD in men (odds ratio: 0.551, 95 % confidence interval 0.365–0.832, p = 0.005). There was no association between short sleep duration and NAFLD onset in women. The prevalence of NAFLD onset in men increased significantly as sleep duration increased, as follows: 12.5, 18.4, and 27.4 % among subjects who had sleep durations of ≤4, 5–6, and 7–8 h, respectively (p = 0.02). Conclusions: This study demonstrates an association between sleep duration and NAFLD onset. Short sleep duration reduced the risk of NAFLD onset in men. Correct recognition is important to prevent disease progression and further complications.

DOI： 10.1007/s00535-014-0989-0

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This study aimed at prospectively evaluating bile duct anatomy on ultrasonography and evaluating the safety and utility of radiofrequency ablation (RFA) assisted by virtual ultrasonography from gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI).
The institutional review board approved this study, and patients provided written informed consent prior to entry into the study. Bile duct anatomy was assessed in 201 patients who underwent Gd-EOB-DTPA-enhanced MRI for the evaluation of hepatic tumor. Eighty-one of these patients subsequently underwent RFA assisted by ultrasound imaging. In 23 patients, the tumor was located within 5 mm of the central bile duct, as demonstrated by MRI.
Virtual ultrasonography constructed by Gd-EOB-enhanced MRI was able to visualize the common bile duct, left hepatic duct, and right hepatic duct in 96.5, 94.0, and 89.6 % of cases, respectively. The target hepatic tumor nodule and biliary duct could be detected with virtual ultrasonography in all patients, and no severe complications occurred.
The running pattern of the bile ducts could be recognized on conventional ultrasound by referencing virtual ultrasonography constructed by Gd-EOB-DTPA-enhanced MRI. RFA assisted by this imaging strategy did not result in bile duct injury.

DOI： 10.1007/s10396-014-0598-9

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© 2014 RSNA. Purpose: To prospectively evaluate whether the characteristics of hepatic blood flow change during the early stages of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Materials and Methods: All participants provided written informed consent, and the study protocols were approved by the institutional ethics committee. A total of 121 patients with NAFLD that was diagnosed at histologic examination were enrolled. Hepatic blood flow was measured by means of Doppler ultrasonography (US), and the ratio of arterial to portal blood flow (arterioportal ratio) was calculated. Elasticity of the spleen was measured by means of real-time tissue elastography. The elastic ratio was measured as the value in the small splenic vessel divided by the value of the splenic parenchyma. The arterioportal ratio and splenic elasticity were compared in patients with all stages of fi-brosis (F0'F4) and with all levels of platelet counts. Correlations among the resistive index of the hepatic artery and that of the splenic artery, the fibrosis 4 index, hepatic elasticity, arterioportal ratio, splenic elasticity, and platelet counts were analyzed. Univariate and multivariate logistic regression analyses were performed. Correlations in patients with platelet counts greater than 200 000/mL also were analyzed. Results: The mean ± standard deviation arterioportal ratio was significantly higher at fibrosis stage 2 (2.4 ± 0.6) than at fibrosis stage 0 (1.8 ± 0.4) in patients with NAFLD (P <.01). Increased splenic stiffness at earlier stages of fibrosis also was observed in patients with NAFLD (fibrosis stage 2, 4.4 ± 2.3; fibrosis stage 0, 3.2 ± 1.9; P <.05). In patients with NAFLD with platelet counts higher than 200 000/mL, pericellular fibrosis was the only significant predictor of hepatic hemodynamic change at multivariate analysis (odds ratio, 7.17; 95% confidence interval: 1.33, 57.13; P =.021). Conclusion: Change in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD because of outflow block in the sinusoidal area.

DOI： 10.1148/radiol.14132952

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© 2015 The Japanese Society of Internal Medicine. 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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© 2015 The Japanese Society of Internal Medicine. 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 (CO<inf>2</inf>). CO<inf>2</inf> 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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© 2013 The Japan Society of Hepatology. Aim: The purpose of this study was to clarify the frequency of hypophosphatemia and other clinical features in patients with hepatitis B undergoing long-term therapy with adefovir dipivoxil (ADF). Methods: Seventeen hepatitis B patients treated with a combination of lamivudine and ADF were analyzed. They were divided into two groups: patients who developed hypophosphatemia (P<2.5mg/dL) (group A) and those who did not (group B). The frequency of hypophosphatemia and other clinical features were retrospectively analyzed. Results: There were six patients (35.3%) in group A. The treatment period was 57.3 ± 15.6 and 61.8 ± 25.7 months in groups A and B, respectively. No differences were found between the groups prior to treatment. Among the six patients in group A, osteomalacia was observed in two, while a pathological fracture of the scapula was found in one. Decreases in phosphate (96 weeks after starting ADF), estimated glomerular filtration rate (eGFR) (48 weeks) and uric acid (24 weeks) levels, and increases in creatinine and alkaline phosphatase were noted in group A. Conclusion: Hypophosphatemia occurred in 35% of the patients under the long-term treatment with ADF. Although it was not possible to predict the decrease in phosphate before ADF therapy, decreases in uric acid and eGFR may be the early events relating to low phosphatemia.

DOI： 10.1111/hepr.12226

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Background & Aims: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis. Methods: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n= 85) or no BCAAs (controls, n= 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis. Results: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P=.019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death wereChild-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P=.015) in both regression models. Conclusions: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis. © 2014 AGA Institute.

DOI： 10.1016/j.cgh.2013.08.050

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. HCC is generally considered to spread via the bloodstream and local recurrence often occurs in the blood drainage area determined by computed tomography during hepatic arteriography (CTHA), despite complete ablation of the primary nodule. This study was conducted in order to prospectively assess the rate of local recurrence in the blood drainage area depicted by delayed-phase CTHA. The participants comprised 364 consecutive patients (260 men and 104 women; mean age, 67.4±8.6 years), enrolled between April, 2002 and December, 2011. The participants were divided into two groups, according to whether the ablation area covered the entire blood drainage area as defined by delayed-phase CTHA (group A) or not (group B). Local tumor progression was compared between the two groups. The median time to recurrence was significantly shorter for group B (434 days) compared to that for group A (1,474 days; P=0.0037). The cumulative local recurrence rates for group A were 0, 0 and 1.5% at 1, 3 and 5 years postoperatively, respectively, whereas the recurrence rates for group B were 3.8, 17.0 and 22.8% at 1, 3 and 5 years, respectively (P<0.0001). In conclusion, the safety margin for radiofrequency ablation should be defined as the blood drainage area and ablation should aim at acquiring adequate safety margins.

DOI： 10.3892/mco.2013.229

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Background. Information regarding the progression of acute hepatitis B virus (HBV) infection to chronic infection in adults is scarce. Methods. Twenty-five adult patients with acute HBV infection (14 men and 11 women, 18-84 years old), whose clinical features progressed to those of chronic infection (group A) or did not (group B), were studied retrospectively. Results. There were 3 and 22 patients in groups A and B, respectively. Two of the 3 patients of group A lacked the typical symptoms of acute hepatitis. No differences were found between groups with respect to age, sex, or HBV genotypes. However, total bilirubin and alanine aminotransaminase levels were significantly lower in group A. Conclusions. Three of the 25 adult patients with acute HBV infection progressed to chronic infection. Hepatitis was mild in these patients. Patients with mild acute hepatitis B or unapparent HBV infection may have a higher risk of progressing to chronic infection.

DOI： 10.1155/2014/358206

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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. © 2014 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.53.2131

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© 2014, Springer Japan. Methods: Using a community-based, cross-sectional design, the records of 11,094 Japanese subjects who had undergone at least 1 annual health checkup were reviewed.Background: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for diabetes and cardiovascular disease that could progress to nonalcoholic steatohepatitis, cirrhosis, and liver failure. We aimed to assess the relationship between NAFLD and lifestyle habits.Results: Of the 6,370 subjects who qualified for enrolment, 1,346 met the diagnostic criteria for NAFLD. The prevalence rate (PR) of NAFLD increased significantly to 36.6, 41.5, and 41.1 % with no snacking, snacking less than once/day, and snacking ≥2 times/day, respectively, in men (P = 0.0495) and to 10.8, 11.7, and 15.3 %, respectively, in women (P = 0.002). In men, the NAFLD PR decreased significantly to 48.8, 36.9, and 29.9 % with no exercise, exercise consciousness, and periodical exercise, respectively (P < 0.001). In women, the NAFLD PR decreased significantly to 19.3, 13.5, 11, and 8 % with sleep durations of ≤4, 5–6, 7–8, and ≥9 h, respectively (P = 0.003). Periodical exercise was identified as an independent factor associated with NAFLD in men (odds ratio 0.707, 95 % confidence interval 0.546–0.914; P = 0.008).Conclusions: Performing regular exercise was associated with a reduced risk for NAFLD in men. Men with a high risk for NAFLD can be identified using questionnaires on exercise in an outpatient setting. Disease progression and further complications may be prevented by educating high-risk NAFLD patients about the importance of exercise.

DOI： 10.1007/s00535-014-0959-6

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Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma. In addition, NAFLD is a risk factor for the development of other serious diseases, such as diabetes or cardiovascular disease. Therefore, the detection of early-stage NAFLD is important. Many studies have described the factors that predict the presence of NAFLD and its onset, and several markers have been identified. These markers have enabled the identification of high-risk patients and have improved routine medical practice. To prevent advanced disease, clinicians need to have simple markers that predict the onset of NAFLD so that interventions can be started at much earlier stages of disease. This review summarizes the current state of knowledge regarding independent factors, as reported in large studies, that predict the presence of NAFLD and its onset, especially markers that can be used in daily medical practice, such as physical measurements and blood tests. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/jgh.12251

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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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Purpose: B cell-activating factor (BAFF) is expressed in adipocytes and affects lipogenesis and insulin sensitivity. In addition, the BAFF receptor is expressed in visceral adipose tissue and liver. The aim of this study was to analyze serum BAFF levels in patients with nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) and to compare their respective clinical and histological findings. Methods: A total of 96 patients with nonalcoholic fatty liver disease (20 with SS and 76 with NASH) were enrolled and their serum BAFF levels were analyzed. Comprehensive blood chemistry analysis and histological examination of liver samples were also conducted. Results: Serum BAFF levels were higher in patients with NASH than in those with SS (p = 0.016). NASH patients with ballooning hepatocytes and advanced fibrosis had higher levels of BAFF in sera (p = 0.016 and p = 0.006, respectively). In addition, the prevalence of NASH increased significantly as the serum BAFF level increased (p = 0.004). Higher serum BAFF levels were found to be an independent risk factor for development of NASH (OR 1.003, 95% CI 1.0003-1.006; p = 0.047). Conclusions: Nonalcoholic steatohepatitis patients had higher levels of serum BAFF than patients with SS, and higher levels were associated with the presence of hepatocyte ballooning and advanced fibrosis. The serum BAFF level may be a useful tool for distinguishing NASH from SS. © 2012 Asian Pacific Association for the Study of the Liver.

DOI： 10.1007/s12072-012-9345-8

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Portal biliopathy is a morphological abnormality of the biliary ductal and gallbladder wall associated with portal hypertension. A patient with essential thrombocythemia was initially diagnosed with extrahepatic portal vein obstruction (EHPVO). The contrast-enhanced computed tomography (CT) findings were similar to those of cholangiocarcinoma or sclerosing cholangitis. However, color Doppler and contrast-enhanced ultrasound (US) were more specific. The paracholedocheal veins around the bile ducts appeared as beads soon after the injection of contrast medium, followed by linear enhancement of the epicholedochal veins and the gradual enhancement of the whole bile ducts. These findings led to a diagnosis of portal biliopathy, which prevented the patient from having to endure hazardous procedures such as bile duct biopsies. Color Doppler and contrast-enhanced US findings are useful for diagnosing or ruling out portal biliopathy in patients who present with EHPVO. © 2013 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.52.8848

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Background and Aims: Serum des-γ-carboxy prothrombin (DCP) is an established tumor marker in patients with hepatocellular carcinoma (HCC), which can be identified by using MU-3 antibody. The MU-3 antibody mainly reacts with the 9-10 glutamic acid residues of DCP (conventional DCP). Since other variants of DCP with fewer glutamic acid residues can be detected using P-11 and P-16 antibodies (code name: NX-PVKA), we examined the clinical characteristics associated with NX-PVKA, and whether NX-PVKA is a useful measure in HCC patients. Methods: Participants comprised 197 HCC patients admitted to our hospital between 2001 and 2010. NX-PVKA, conventional DCP, alpha-fetoprotein, and L3 fraction of alpha-fetoprotein were measured prior to initiation of HCC treatment. Results: Of the tumor markers assessed, NX-PVKA was the only significant predictor of prognosis (hazard ratio, 81.32; P<0.0001). Patients with NX-PVKA level≥100mAU/mL showed significantly lower survival rates (P<0.0001). NX-PVKA level was also significantly associated with platelet count, prothrombin time, C-reactive protein, sex, maximum tumor size, number of nodules, and portal venous invasion by HCC. Finally, using NX-PVKA level and other clinical parameters, we established a prognostic model to estimate patient survival time. Conclusions: NX-PVKA offers the best marker of tumor prognosis among HCC patients, and is strongly associated with tumor factors and hepatic functional reserve. NX-PVKA could be useful for clinical evaluation of tumor severity, as well as the estimated duration of survival among patients with HCC. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/jgh.12076

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Chronic inflammation is an important contributor to the development and progression of metabolic syndrome. Recent evidence indicates that, in addition to innate immune cells, adaptive immune cells have an important role in this process. We previously showed that the serum level of B-cell-activating factor (BAFF) was increased in patients with nonalcoholic steatohepatitis. However, it is currently unknown whether BAFF and BAFF-R (BAFF-R) have a role in lipid metabolism in the liver. To address this issue, the role played by BAFF and BAFF-R signaling in the development of insulin resistance and hepatic steatosis was examined in BAFF-R-/- mice fed a high-fat diet (HFD). Furthermore, the effect of BAFF on lipid metabolism in hepatocytes was analyzed in vitro. BAFF-R-/- mice showed improvements in HFD-induced obesity and insulin resistance. In addition, the number of B cells, levels of serum IgG, and inflammation of visceral fat were reduced in these mice. However, the expression of steatogenic genes and fatty acid deposition in the liver was higher in these mice than in control mice. BAFF was also found to downregulate the expression of steatogenesis genes and enhance steatosis in hepatocytes through BAFF-R. Collectively, these data indicated that, in addition to its known functions in inflammation and glucose metabolism, BAFF has a protective role in hepatic steatosis by regulating lipid metabolism in the liver. © 2013 USCAP, Inc All rights reserved.

DOI： 10.1038/labinvest.2012.176

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Background Nonalcoholic fatty liver disease (NAFLD) can progress to advanced liver disease and non-liver-related diseases. To prevent NAFLD onset, clinicians must be able to easily identify high-risk NAFLD patients so that intervention can begin at an earlier stage. We sought to identify the predictive factors for NAFLD onset. Methods In a community-based, longitudinal design, the records of 6,403 Japanese subjects were reviewed to identify those meeting the criteria for NAFLD onset. Univariate and multivariate logistic regression analyses were used to identify predictive factors for NAFLD onset. The accuracy of different models was evaluated according to their areas under the receiver operating characteristic curves. Comparative risk analysis was performed using the Kaplan-Meier method. Results Multivariate analysis of 400 subjects who met the criteria for the onset of NAFLD during the observation period confirmed that body mass index (BMI) at baseline was the most useful predictive factor for NAFLD onset in both sexes. Cutoff levels of BMI for NAFLD onset were estimated at 23 kg/m2 for men and 22.2 kg/m2 for women. The cumulative onset rate of NAFLD was significantly higher in the high BMI group than in the low BMI group in both sexes (P <0.001). Conclusion BMI was confirmed as the most useful predictive factor for NAFLD onset in both sexes; its cutoff levels were similar to those recommended by the World Health Organization for helping to prevent metabolic disease. An accurate BMI cutoff level will enable clinicians to identify subjects at risk for NAFLD onset. © Springer 2012.

DOI： 10.1007/s00535-012-0650-8

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Background: The Wilms' tumor 1 (WT1) gene is known to be overexpressed in hepatocellular carcinoma (HCC) and to upregulate tumor growth and oncogenic potential, although the detailed mechanisms remain to be elucidated. Methods: We identified host genes involved in WT1 gene modulation of human liver cancer cell lines in vitro, and further characterized genes related to apoptosis. Moreover, we evaluated the alteration of genes by WT1 in 40 HCC and 58 non-HCC human liver samples collected at resection. Results: Analysis of the effect of small interfering RNAs-mediated knock-down of WT1 on apoptosis using an annexin V labeling assay, and on modulation of the activity of caspases-3, -8 and -9, indicated that WT1 has an anti-apoptotic role. We identified three apoptosis-related genes that were modulated by WT1; the cellular FLICE-inhibitory proteins (cFLIP) gene was upregulated, and Fas-associated death domain (FADD) and nuclear factor kappa B (NF-κB) were downregulated. Interestingly, knock-down of FADD or NF-κB resulted in the upregulation of WT1, and the expression of cFLIP changed in parallel with WT1 expression. We further evaluated WT1-mediated alteration of genes in HCC and non-HCC human liver samples. Both HCC and non-HCC tissues that expressed relatively high levels of WT1 showed cFLIP overexpression. Conclusions: WT1 modulates cFLIP, FADD and NF-κB, and has an anti-apoptotic role in HCC. This mechanism of action of WT1 could be related to the tumor growth and oncogenic potential of HCC. © 2012 Springer Japan.

DOI： 10.1007/s00535-012-0708-7

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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 viro-logical 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. © AOCS 2012.

DOI： 10.1007/s11745-012-3716-8

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The aim of this study was to prospectively measure liver stiffness with real-time tissue elastography in patients with nonalcoholic fatty liver diseases (NAFLD) and to compare the result with the clinical assessment of fibrosis using histological stage. One hundred and eighty-one prospectively enrolled patients underwent real-time tissue elastography, with the first 106 being analyzed as the training set and the remaining 75 being evaluated as the validation set. Hepatic and splenic elastic ratios were calculated and compared with stage of histological fibrosis. Portal hypertension (PH) was assessed. Real-time tissue elastography cut-off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut-off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%-96.0% in all stages. Only portal fibrosis correlated with the hepatic elastic ratio by multivariate analysis. The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages. Patients with PH, defined by splenic elasticity, had early fibrosis. Patients with severe PH were found only in the group with cirrhosis. Conclusion: Real-time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. © 2012 American Association for the Study of Liver Diseases.

DOI： 10.1002/hep.25756

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Background Untreated nonalcoholic fatty liver disease (NAFLD) may progress to liver cirrhosis or failure and is associated with the development of hepatocellular carcinoma, diabetes, and cardiovascular disease. It is therefore essential to diagnose and treat NAFLD at an early stage. To assist in this effort, this retrospective study explored the risk factors for NAFLD, and derived new surrogates, a revised alanine aminotransferase (ALT) cutoff level and a novel NAFLD index, to identify previously undiagnosed cases of NAFLD. Methods Using a community-based, cross-sectional design, the records of 6,370 Japanese subjects who had undergone at least 1 annual health check-up were reviewed for the identification of subjects meeting the diagnostic criteria for NAFLD and the variables associated with NAFLD for the estimation of ideal ALT cutoff levels. Results The results of multivariate analysis of the 1,346 subjects who met the diagnostic criteria for NAFLD confirmed that metabolic disease markers and a novel NAFLD index, using the variables derived from multivariate analysis, were also markers of NAFLD. The ALT cutoff levels for NAFLD diagnosis were estimated at 25 U/L for males and 17 U/L for females. Conclusions ALT level and the novel NAFLD index were confirmed to be surrogate markers for NAFLD in addition to metabolic disease markers. The ALT cutoff level used in NAFLD diagnosis should be revised downward to identify subjects at risk of NAFLD to prevent NAFLD progression and the development of associated diseases. © 2012 Springer.

DOI： 10.1007/s00535-012-0534-y

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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-α therapy with or without RBV. We added RBV and/or IFN-α to a plasmid-based HCV replication system containing a full-length HCV genotype 1a 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-β. Results. The expression of protein kinase R and myxovirus resistance A mRNA was enhanced more with IFN-α and RBV than by IFN-α alone in assays in vivo and in vitro. Such enhancement depended on autocrine IFN-β being enhanced by RBV. RBV upregulated interleukin 8 (IL-8) in the absence of IFN-α. 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-α induced by ISGs through enhancing autocrine IFN-β. 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. © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

DOI： 10.1093/infdis/jis025

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A 69-year-old man presented with multiple nodules on the spleen and liver that had been detected by computed tomography (CT). A liver tumor biopsy was performed, and the patient was diagnosed to have histiocytic sarcoma (HS). Splenectomy was performed, and the chemosensitivity of the spleen tumor was measured using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST). Hepatic arterial infusion chemotherapy was administered, based on the results of the CD-DST. The patient achieved complete remission (CR) after this therapy and remained alive without recurrence at the final follow-up. This is the first known case of CR in response to chemotherapy for advanced splenic HS. © 2012 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.51.8325

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Branched-chain amino acid (BCAA) supplements have mainly been administered as a nutritional intervention for decompensated liver cirrhosis. Several studies have shown that short-term BCAA supplementation improves insulin and glucose tolerance in patients with liver cirrhosis. However, the long-term effects of BCAA supplementation on glucose tolerance and in patients with nonalcoholic steatohepatitis (NASH)- related liver cirrhosis are unknown. Herein, we report 2 cases of NASH-related liver cirrhosis in which longterm BCAA supplementation improved glycemic control. We conclude that in the absence of an effective conventional therapy for NASH-related liver cirrhosis, BCAA supplementation should be considered as an alternative treatment. © 2012 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.51.7578

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Aim: Hepatitis C virus infection often complicates glucose intolerance, which can be caused by insulin resistance. Aerobic exercise can improve insulin resistance and decrease body fat in patients with diabetes. The aim of the present study is to clarify whether aerobic exercise improves insulin resistance and decreases body fat in patients with chronic hepatitis C (CH-C). Methods: Seventeen patients with CH-C received nutrition education at entry and every two months thereafter. The following were evaluated before and after 6months of walking at least 8000steps/day monitored using a pedometer that started 2months after entry: body composition, fat and muscle weight, visceral and subcutaneous fat areas (VFA and SFA, respectively), liver function tests, the Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR), serum tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, adiponectin, leptin and the Short Form-36. Results: Fifteen of the 17 patients completed the study protocol. Bodyweight, body mass index, fat weight, VFA, SFA, alanine aminotransferase level and HOMA-IR were significantly decreased at the end of the study (P=0.004, =0.004, =0.008, =0.041, =0.001, =0.023 and =0.002, respectively). Serum levels of TNF-α, IL-6 and adiponectin did not change, whereas those of leptin significantly decreased (P=0.002). Conclusion: Patients with CH-C could safely walk as aerobic exercise. Furthermore, walking improved insulin resistance and decreased body fat while lowering serum levels of leptin. © 2011 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2011.00833.x

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The present report represents the case of a 36-year-old woman with congenital hepatic fibrosis (CHF). She was admitted to our hospital because of gastric varices. She was asymptomatic and her liver function tests were within normal limits. Computed tomography showed hepatomegaly, splenomegaly and collateral circulation, but no evidence of liver cirrhosis. Real-time tissue elastography suggested severe fibrosis of the liver. Laparoscopy showed wide and discrete white markings on the surface of the liver and she was diagnosed with CHF based on the histological examination. The findings obtained from elastography and laparoscopy were useful for making the diagnosis of CHF. © 2010 Japan Gastroenterological Endoscopy Society.

DOI： 10.1111/j.1443-1661.2010.01033.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: We prospectively examined the effects of a reduced initial dose of ribavirin (RBV) combined with pegylated interferon (PegIFN) to prevent RBV discontinuation due to adverse events in patients with chronic hepatitis C (CH-C) infection aged >60y or with low hemoglobin values. Methodology: We enrolled 42 patients with hepatitis C virus (HCV) serotype 1. Twenty-one of them with hemoglobin values <14g/dl or who were aged >60y comprised group A. The other 21 patients (sex-and age-matched with group A) comprised group B, and received Peg-IFN (1.5μg/kg/week) and RBV (10-13mg/kg/day) for 48 weeks. Group A initially received 200mg less RBV than group B. Results: Higher hemoglobin values persisted at 16, 20, 24 and 44 weeks, and the sustained viral response (SVR) ratio was lower in group A than in group B (17% vs. 57%). RBV therapy was discontinued due to severe anemia in group B, but not in group A. Conclusions: The reduced initial dose of ribavirin prevented discontinuation due to anemia. However, this protocol cannot be recommended even for patients with CH-C accompanied by low hemoglobin or advanced age, since a sufficient SVR ratio is not achievable. © H.G.E. Update Medical Publishing S.A.

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Aim: The aim of this study is to clarify the amino acid imbalance in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC). Methods: We assayed total branched-chain amino acids (BCAA), tyrosine (Tyr) levels and their ratio (BTR) in sera of 101 patients with CH (37 in fibrosis stage F1, 23 in F2, 21 in F3) and 20 with LC (F4) who were diagnosed by liver biopsy. Their levels in relation to the staging of liver fibrosis were analyzed. Results: The percentage of patients whose BTR was less than the normal range was 32.1% in CH and 75.0% in LC. The levels of BTR and BCAA were significantly lower (. P < 0.001, . P < 0.05, respectively) and that of Tyr was significantly higher (. P < 0.001) in patients with LC than those in CH. The levels of BTR decreased according to the staging. The levels of Tyr increased according the staging, whereas the levels of BCAA deceased prominently in F4 (487 ± 103 in F1, 483 ± 122 in F2, 487 ± 111 in F3 and 423 ± 94 in F4). Conclusion: A considerable number of patients not only with LC but also with CH showed lower levels of BTR. It has been clarified that amino acid imbalance of Tyr was found in the early stage of liver disease, whereas decrease of BCAA was found mainly in F4 stage. © 2010 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2009.00614.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Background: Little is understood about worldwide changes in the epidemiological distribution of the etiology of liver cirrhosis (LC). The present study examines the etiology of liver cirrhosis in Japan using a nationwide survey. Methods: We analyzed data from 33,379 patients with LC at 58 hospitals and presented the findings in a poster symposium regarding the etiology and clinical features of LC in Japan that was included in the program of the 44th Annual Meeting of the Japan Society of Hepatology. We identified the distribution of the etiology of LC and compared the present with previous Japanese findings to estimate the future of etiological changes in LC. Results: The etiological agents were as follows: hepatitis B virus (HBV) 13.9%, hepatitis C virus (HCV) 60.9%, alcohol 13.6%, primary biliary cirrhosis (PBC) 2.4% and autoimmune hepatitis (AIH) 1.9%. Cirrhosis was considered to be related to nonalcoholic steatohepatitis (NASH) in 2.1% of the patients. The ratio of HCV-related LC was significantly higher among patients with hepatocellular carcinoma (HCC) (P < 0.0001) compared to those without, whereas the ratios of alcohol, PBC, AIH were lower. HCC was evident in 31.5% of NASH-related LC. Conclusions: The major etiology of liver cirrhosis in Japan remains HCV. Our survey revealed the prevalence of NASH-related LC in Japan and the frequency of HCC. Future changes in etiology must be considered in establishing preventive or educational strategies, as well as in developing new treatment strategies. © 2009 Springer.

DOI： 10.1007/s00535-009-0128-5

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Fibrosing cholestatic hepatitis (FCH) is a serious disease in patients with recurrent hepatitis C after liver transplantation (LTx). Antiviral therapy is indicated in these patients; however, it is not always effective, and the prognosis of FCH is generally poor. Double filtration plasmapheresis (DFPP) has been shown to be effective at eliminating hepatitis C virus (HCV) in patients with chronic hepatitis C. We report a case of FCH with severe cholestasis (total bilirubin 34.2 mg/dl) after LTx. Combination therapy with interferon (IFN) and ribavirin (RBV) was unsuccessful for improving cholestasis; however, the addition of DFPP to IFN and RBV alleviated cholestasis and improved renal function. Although IFN and RBV with DFPP could not eliminate HCV, results of liver function tests improved and remained stable for several months. This treatment with DFPP combined with IFN and RBV would be useful for resolving cholestasis due to FCH. Moreover, treatment of DFPP could improve liver and renal function test results and could stop the worsening condition of patients with FCH. © 2009 Springer.

DOI： 10.1007/s12328-008-0057-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

N,N-dimethylformamide (DMF) is a solvent used extensively in the chemical industry. The main toxic effect reported after exposure to DMF is hepatotoxicity. We encountered four patients with liver injury due to DMF exposure; the severity of the liver injury was related to the exposure levels. After removal of exposure, all patients recovered without specific treatment. A careful evaluation of occupational history is necessary when liver dysfunction develops in industrial workers. © 2009 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.48.2332

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

A derivative of soyasapogenol, 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-α (IFN-α) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-β (IFN-β) and of IFN-stimulated genes (2′-5′ oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-β knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-α. Conclusion: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-β suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-α. ME3738 might be a useful anti-HCV drug either with or without IFN-α. Copyright © 2008 by the American Association for the Study of Liver Diseases.

DOI： 10.1002/hep.22289

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background/aims: Wilms' tumour 1 gene (WT1) was originally isolated as a tumour-suppressor gene. We investigated the expression of WT1 in hepatocellular carcinoma (HCC; T) and in non-cancerous hepatic tissues (non-tumour: NT) from patients with chronic liver diseases, and then examined the role of WT1 in the carcinogenesis or prognosis of HCC. Methods: The expression of WT1 in T and NT from 50 patients with HCC was investigated using Western blotting, immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined whether WT1 expression was related to clinicopathological factors in individual patients in addition to prognostic factors in 50 patients with HCC and in 26 without HCC. Results: Western blotting and immunohistochemical staining showed that WT1 was overexpressed in T compared with NT (P < 0.001) and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) showed that WT1 mRNA expression was similarly increased. Overexpressed WT1 in HCC was significantly associated with T factors at the TNM stage, and short doubling time of HCC. Univariate and multivariate analyses revealed that WT1 overexpression was an independent prognostic factor for HCC. The disease-free survival period in patients with overexpressed WT1 in NT tissues was significantly reduced. Conclusion: The expression of WT1 is increased more in HCC than in non-tumour tissues. Moreover, overexpressed WT1 was associated with tumour growth, and resulted in a worsening prognosis of HCC. Our findings from NT tissues revealed that WT1 overexpression might contribute to oncogenic potential. © 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejca.2008.01.008

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Background: There is a lack of information regarding the laparoscopic features and interobserver variation of histological diagnosis in patients with non-alcoholic fatty liver disease (NAFLD). Methods: Thirty-five patients with NAFLD were studied for laparoscopic and histological findings. For the study of interobserver variation of histological diagnosis, two pathologists from different hospitals independently observed the 35 liver samples with patient names blinded to the pathologists. Assessment of laparoscopic findings on the diagnosis of non-alcoholic steatohepatitis (NASH) was also investigated. Results: Histological diagnoses of the two pathologists were identical in 28 (five fatty liver, 23 NASH) patients, whereas they were not identical in seven patients (20%). The difference of diagnosis was mainly caused by the difference of judgment of minimal fibrosis and minimal necroinflammatory grade. Analysis of the laparoscopic findings revealed that small regular depressions were frequently found on the liver surface in patients with NASH. Scatter of dye on the liver surface facilitated the observation of this finding. Sensitivity and specificity of small depressions in the diagnosis of NASH was 73.9% and 80.0%, respectively. Conclusion: Interobserver variation of the diagnosis was found in 20% of patients with NAFLD. Small regular depressions were characteristic findings of NASH. Laparoscopy is assessed to be useful for diagnosis of NAFLD, especially of early stage of NASH. © 2007 The Authors.

DOI： 10.1111/j.1443-1661.2007.00771.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim: The aim of this study is to clarify the cerebral functions in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC). Methods: We studied 58 patients with CH (20 in fibrosisstage F1, 20 in F2, 18 in F3), 77 with LC (46 rated as Child-Pugh class A, 24 as B, 7 as C), and 20 healthy volunteers (HV). Computer-aided quantitative neuropsychiatric function test systems, including eight neuropsychiatric tests were performed. Results: Subjects with results over the cut-off value for healthy subjects ranged from 11.1-28.6% in CH and 19.5-36.4% in LC. The percentages with abnormality in at least one test in CH and LC were 72.4% and 80.6%, respectively, which were significantly higher than that in the HV group (35.0%) (P = 0.003, P = 0.0003, respectively). Among CH subjects, those with three or more abnormal results in the F1, F2 and F3 subgroups were 15.0%, 20.0% and 38.9%, respectively. Among LC subjects, those with three or more abnormal results in the Child-Pugh class A, B and C subgroups comprised 30.4%, 50.0% and 57.1%, respectively. The rate in the CH F3 subgroup (P = 0.011) and in all three LC subgroups (P = 0.023, P = 0.001, P = 0.002, respectively) were significantly higher than that in the HV group. Conclusion: The percentage of patients with neuropsychiatric function impairment was high in both LC and CH, especially in stage F3. Neuropsychiatric dysfunction may initiate in CH in a considerable number of patients. © 2008 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2008.00374.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Interferon (IFN)-inducible double-stranded RNA-activated protein kinase (PKR) is thought to play a key antiviral role against hepatitis C virus (HCV). However, demonstrating the importance of PKR expression on HCV protein synthesis in the presence or absence of IFN has proven difficult invivo. In the present experiment, full-length HCV constructs were transiently transfected into two cell lines stably expressing T7 RNA polymerase. HCV expression was monitored under conditions of upregulated or downregulated PKR expression. In addition, IFN was monitored during downregulation of PKR. HCV expression effectively increased PKR expression, as well as that of its regulated proteins. PKR was obviously knocked down by PKR-specific siRNA, which resulted in significantly increased HCV core protein levels. Conversely, over-expression of PKR significantly suppressed HCV core levels in both cell lines. Furthermore, IFN induced high levels of PKR, whereas downregulation of PKR reversed IFN's antiviral effects and increased HCV core levels. Based on these results, it appears that HCV protein expression is directly dependent on PKR expression. PKR is antiviral toward HCV and responsible for IFN's effect against HCV. © 2007 Wiley-Liss, Inc.

DOI： 10.1002/jmv.20902

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Aim: Patients with chronic hepatitis C (CHC) often have diabetes mellitus (DM). However, it is unknown whether DM affects patient response to interferon (IFN) plus ribavirin therapy. Therefore, the aim of this study was to examine the influence of DM on the outcome of IFN-α2b plus ribavirin therapy. Methods: In a cohort of 110 patients with CHC, the outcome of 6 months of IFN-α2b plus ribavirin therapy was evaluated by comparing the patients with and without DM. Results: There were 46 sustained-responders; 64 patients did not become sustained responders. Higher age (P = 0.015), lower platelet counts (P = 0.036), hepatitis C virus (HCV) serotype 1 (P = 0.001), advanced liver fibrosis (P = 0.004), and the presence of DM (P = 0.007) were significantly associated with not becoming a sustained-responder. Seventeen CHC (15%) patients had DM. Sex ratio, age, body mass index, alanine aminotransferase levels, HCV-RNA titer, and HCV serotypes did not significantly differ between the patients with and without DM, while fasting plasma glucose, hemoglobin A1c and liver histological staging were significantly different. On multiple logistic regression analysis, HCV serotype 1 (odds ratio 8.743, 95% confidence interval 2.215-34.517; P = 0.002) and the presence of DM (odds ratio 8.657, 95% confidence interval 1.462-51.276; P = 0.014) were independently associated with not becoming a sustained-responder. Conclusions: The findings indicate thatDM reduces the response to IFN-α2b plus ribavirin therapy in CHC patients. © 2007 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2007.00052.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W J G PRESS  

It is controversial whether steroid therapy should be continued to prevent the recurrence of autoimmune hepatitis (AIH) in patients who have undergone liver transplantation (LTx) due to AIH. We report a case of recurrent autoimmune hepatitis after LTx despite a persistently normal range of alanine aminotransferase (ALT). A 50-year-old woman was admitted to our hospital because of jaundice and severe liver dysfunction, where she was diagnosed with liver failure due to AIH. Steroid therapy was not effective enough and the patient received living-donor LTx in 1999. Following the operation, the level of ALT was maintained within a normal range and anti-nuclear antibody (ANA) became negative, however, the serum level of IgG gradually elevated and ANA became positive, while platelets decreased. A liver biopsy performed 6 years after LTx showed histological findings of AIH and she was diagnosed with recurrent AIH. A recurrence of AIH may occur after LTx even if the level of ALT remains within a normal range. We consider that a protocol liver biopsy should be performed in patients who undergo LTx due to AIH to decide the indication for steroid therapy. © 2007 The WJG Press. All rights reserved.

DOI： 10.3748/wjg.v13.i10.1618

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 63-year-old man was admitted to hospital in 2003 for treatment of a hepatocellular carcinoma (HCC). He was negative for HBs antigen (HBsAg) and anti-HCV antibody, and positive for anti-HBs. He had a past history of chronic hepatitis B. In 1986, HBsAg had become negative with the development of anti-HBs. In 2003, an HCC was detected and liver resection was carried out. Histological examination revealed moderately differentiated HCC and slightly fibrotic liver. It is suggested that a diagnosis of HCC, combined with negativity for HBsAg and anti-HCV antibody, may include cases of past recovery from chronic hepatitis B, such as this case. © 2007 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.46.1586

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DOI： 10.2169/internalmedicine.46.0170

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A 59-year-old man developed acute hepatitis with reactivated hepatitis B virus (HBV) following administration of rituximab (anti-CD20 monoclonal antibody). The patient was diagnosed with malignant lymphoma in 1998, and virus marker testing indicated HBV surface antigen (HBsAg)-negative and anti-HBs antibody (anti-HBs)-positive results when chemotherapy including rituximab was started. Levels of aminotransferases were elevated, and HBsAg results turned positive. Despite therapy for late-onset hepatic failure, the patient died. Rituximab appears likely to have induced HBV reactivation in this case. Anti-viral agents should be administered for both HBsAg-positive and anti-HBs-positive patients who are scheduled to receive rituximab. © 2006 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.45.1590

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Language：Japanese   Publisher：大道学館出版部  

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

Objective: Genotypes B and C are the prevalent hepatitis B virus (HBV) genotypes in eastern Asia. Although very rare in this region of the world, genotype D was found to be prevalent in a small area of western Japan. In this study, we confirm the frequency and clinical significance of co-infection with different genotypes among patients from that area infected with genotype D. Methods: Twenty-three patients from the same area of western Japan infected with HBV genotype D, determined using a genotyping enzyme immunoassay, were studied. Cloning was done using DNA extracted from serum samples, and polymerase chain reaction assays with the restriction fragment length polymorphism for HBV genotyping were performed with 10 clones from each patient. Results: Four (17.4%) of the 23 patients were found to be co-infected with HBV genotype C, and the HB surface antigen subtype was ayw in both mono- and co-infected patients. No clinical differences were found between mono-infected and co-infected patients carrying genotype D. Conclusion: A significant number of patients from the study area found to be infected with HBV genotype D were co-infected with genotype C. Additional study with a larger number of patients is needed to elucidate the possible clinical significance. Copyright © 2005 S. Karger AG.

DOI： 10.1159/000084604

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

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We treated a 66-year-old woman with hepatic encephalopathy secondarily induced by an intrahepatic portosystemic venous shunt (IPSVS). In serial observations, the volume of the liver became smaller and encephalopathy could not be controlled with conservative therapy. We occluded the IPSVS successfully using percutaneous transcatheter embolization with micro coils. Following embolization, encephalopathy disappeared and blood flow of all branches of portal vein improved. In cases with an IPSVS without liver cirrhosis, blood flow in the portal vein and liver volume must be followed carefully, and interventional radiology may be considered effective in those who do not show a satisfactory response to conservative therapy.

DOI： 10.2169/internalmedicine.44.212

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Background: We carried out this study to evaluate recent clinical features of Wilson's disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC). Methods: Sixteen patients with hepatic manifestations were diagnosed with WD in the period 1976-2003. We divided this period into two periods, "past" and "recent". The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital. Results: Four patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects. Conclusions: Recently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication. © Springer-Verlag Tokyo 2004.

DOI： 10.1007/s00535-004-1466-y

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Language：Japanese   Publisher：大道学館出版部  

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A 12-year-old girl with Gianotti-Crosti syndrome caused by hepatitis B virus (HBV) infection was admitted due to eruption on her extremities. Laboratory findings revealed elevation of transaminase, positivity for HB surface antigen (HBsAg), and an IgM type anti-HB core. The eruption and level of transaminase improved, and HBsAg became negative within 2 months of onset. Analysis of the virus revealed it to be genotype D with a genomic length of 3,182 bases and the HBsAg serotype was ayw3, which is very rare in Japan. The possible relationship between Gianotti-Crosti syndrome and HBV genotype D infection is discussed.

DOI： 10.2169/internalmedicine.43.696

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Language：Japanese   Publisher：The Japan Society of Hepatology  

DOI： 10.2957/kanzo.45.373

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Other Link： http://search.jamas.or.jp/link/ui/2004309859

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 54-year-old Japanese woman with primary biliary cirrhosis (PBC) was admitted to our hospital due to hepatic coma and refractory pleural effusion. The physical examination revealed clubbed fingers and collateral veins. The patient had an increased alveolar-arterial oxygen gas tension difference. The levels of anti-mitochondrial antibody (AMA) and AMA M2 was 80 times normal. A technetium 99m-labeled macro-aggregated human albumin scintigram. showed uptake in the spleen and the kidneys. A diagnosis of hepatopulmonary syndrome (HPS) was made. HPS may be overlooked because of the lack of symptoms. We conclude that closer attention should be paid to the occurrence of HPS.

DOI： 10.2169/internalmedicine.43.458

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A 27-year-old Japanese man with no past history of liver disease was admitted to our hospital due to liver abnormalities. The patient was diagnosed with drug-induced hepatitis, as the three episodes of hepatitis occurred just after repeated use of hair dye. After cessation of the hair dye use, abnormal liver function tests improved to within the normal range. Although hair dyes contain various hepatotoxic compounds, hair dye is not known to cause drug-induced hepatitis. Thus, in cases of liver abnormality of unknown origin, the history of hair dye use should be investigated.

DOI： 10.2169/internalmedicine.42.1104

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG TOKYO  

Background. Many years have passed since various prophylactic policies for preventing hepatitis B virus (HBV) transmission were begun. We studied the chronological alterations in HBV infectious routes in patients with acute hepatitis B in the past 27 years. Methods. Seventy-two patients with acute HBV infection who were admitted to our hospital during the period 1976 to 2002 were enrolled in this study. This study was divided into two periods (first period, 1976-1990; and second period, 1991-2002), and the HBV infectious routes were studied. Results. Infectious routes have been changing. Posttransfusion hepatitis was seen only in the first period. In the second period, sexual transmission was the major infectious route (68%), followed by infection at a medical facility or occupational exposure such as needlestick injury (8%). Conclusions. Transmission from sexual contact has become the main infectious route of HBV in Japan.

DOI： 10.1007/s00535-003-1144-5

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A 42-year-old Japanese man was admitted to our hospital for investigation of abnormal liver function tests. He had no history of drug use, and drank little alcohol. Body mass index was 30. Serum was negative for viral markers and autoantibodies. Laparoscopy revealed diffuse small nodules on the liver surface. Liver biopsy revealed small nodules with pericellular fibrosis and macrovesicular fat deposition throughout the acini. Some inflammatory changes were observed. Liver cirrhosis due to non-alcoholic steatohepatitis (NASH) was diagnosed. NASH displays similar histological and laparoscopic characteristics to alcoholic liver diseases.

DOI： 10.1046/j.1443-1661.2003.00292.x

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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)日本医学教育学会  

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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：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)日本老年医学会  

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

Web of Science

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

Web of Science

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

Web of Science

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

Web of Science

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

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

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Language：Japanese   Publisher：(一社)日本プライマリ・ケア連合学会  

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

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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：(公社)日本超音波医学会  

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

Web of Science

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

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

Web of Science

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

Web of Science

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

Web of Science

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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：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：(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)日本門脈圧亢進症学会  

【背景・目的】原発性胆汁性胆管炎(PBC)における食道胃静脈瘤の評価は重要である。一方、門脈圧亢進症性胃症(PHG)も門脈圧亢進により発症し、無症候性PBCにも合併するが意義は不明で、それを明らかにするため検討を行った。【対象】PBCで食道胃静脈瘤、PHGを継続し評価しえた112例を調査した。【結果】PHG合併は、PBC診断時21例、観察期間中の出現例6例の計27例(21.9%)であった。PHG合併別では生命予後には有意な差異はなかったが、症候性への移行はPHG合併群が有意に早かった。症候性移行時点での食道胃静脈瘤合併はPHG合併群、非合併群でそれぞれ74%、40%であり、PHG合併群は門脈圧亢進症型への移行が多かった。また、PHG合併は症候性移行の独立した危険因子であった。【結語】PHGの合併は、症候性への進展、門脈圧亢進症型へ移行する可能性が高く、慎重な経過観察が必要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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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)日本門脈圧亢進症学会  

J-GLOBAL

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

J-GLOBAL

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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  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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

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

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

Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本移植学会  

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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  

J-GLOBAL

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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：(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)日本肝臓学会  

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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：(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：(一財)日本消化器病学会  

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

目的:本研究は,胆管の解剖学的構造を超音波検査で評価することと,Gd-EOB-DTPA(gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid)造影MRIの肝細胞相において肝内胆管の描出能を解析し,仮想超音波像を局所療法支援画像として用いたラジオ波焼灼術(RFA)の安全性と有用性を明らかにすることを目的とした.方法:本研究は施設内倫理審査委員会によって承認され,本研究に参加することに対するインフォームドコンセントを書面で得た.Gd-EOB-DTPA造影MRIを施行した肝腫瘍を有する201例で,胆管の解剖学的構造を評価した.これらの患者のうちの81例に,超音波とGd-EOB-DTPA造影MRIから構築した仮想超音波を支援画像に用いてラジオ波焼灼術(RFA)を施行した.また,23例で腫瘍が中部胆管から半径5mm以内に存在していた.結果:Gd-EOB-DTPA造影MRIで構築した仮想超音波画像によって,総胆管,左肝管,右肝管をそれぞれ96.5%,94.0%,89.6%で描出することができた.仮想超音波検査装置を使用して,標的とした肝細胞癌と胆管を全患者で描出することができ,重篤な合併症はみられなかった.結論:Gd-EOB-MRIによる仮想超音波像を構築することで腫瘍と胆管の位置関係を把握し胆管損傷を予防できる.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00833&link_issn=&doc_id=20170323360007&doc_link_id=%2Fed5choon%2F2017%2F004402%2F009%2F0167-0174%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fed5choon%2F2017%2F004402%2F009%2F0167-0174%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

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

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