Country：Japan

Country：Japan

DOI： 10.5009/gnl230072

PubMed

DOI： 10.1111/apt.17785

PubMed

DOI： 10.1016/j.jinorgbio.2023.112405

PubMed

DOI： 10.1159/000530441

PubMed

DOI： 10.1007/s00535-023-02039-x

PubMed

肝硬変の予後は肝機能により明確に層別化される。近年、直接作用型抗ウィルス薬(DAA)がC型肝炎ウィルス(HCV)排除のために用いられているが、DAA治療を行った非代償性肝硬変患者の予後が肝機能により層別化されるか否かに関しては明らかでない。2019年2月から2021年12月までの間に、日本の医療機関でDAA治療を開始したHCV関連非代償性肝硬変患者206例を前向きに登録した。年齢の中央値は68歳で、Child-Pugh分類のA(CP-A)、CP-B、CP-C症例はそれぞれ10%(20/206)、76%(156/206)、15%(30/206)であった。26例が死亡し、2例に肝移植(LT)が行われた。2年および3年無LT生存率は、それぞれ90.0%、83.2%であった。CPクラス(モデル1)またはMELDスコア(モデル2)の2種類のモデルを用いて、無LT生存期間に関連する因子について検討した。多変量Cox比例ハザード解析の結果、モデル1における治療終了(EOT)から12週間後のCPクラス、およびモデル2におけるEOTから12週間後のMELDスコアが有意な因子であり、一方、治療開始前のCPクラスおよびMELDスコアは有意な因子ではないことが示された。EOTから12週間後にCP-A、CP-B、CP-Cであった症例の2年間無LT生存率はそれぞれ100%、91.6%、60.4%、EOTから12週間後にMELD<15およびMELD≧15であった症例の2年間無LT生存率はそれぞれ95.2%、69.6%であった。以上より、非代償性肝硬変に対するDAA後の予後は、EOTから12週間後の肝機能により層別化されるが、治療前の肝機能によっては層別化されないことが示された。

DOI： 10.1097/HC9.0000000000000241

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.

DOI： 10.3390/cancers15153993

PubMed

DOI： 10.1111/hepr.13947

PubMed

DOI： 10.1111/apt.17551

PubMed

【背景】肝星細胞(HSC)は,肝細胞(Hep)との共培養により「静止型」フェノタイプを維持する.我々は,HSCの「静止型」の維持には肝細胞膜との直接的な結合が必要であり,HSCを脱活性化させる肝細胞膜因子が存在するとの仮説を立てた.【方法】野生型マウス(m)からmHepを単離して細胞膜を精製した.この肝細胞膜をプレートにコーティングし,そのプレート上にマウスから単離したmHSCやヒト胎児肝星細胞(HHSteC)を培養してタイムラプスを用いた形態観察および遺伝子発現解析を行った.【結果】肝細胞膜上に培養したmHSCは,通常プレート培養に比べて「静止型」フェノタイプである樹状突起に富んだ形態を示し,活性化マーカーであるActa2,Col1a1発現が抑制された.HHSteCでも同様にACTA2,COL1A1発現は抑制され,静止型マーカーであるMMP1発現が上昇した.【結語】HSCの「静止型」フェノタイプの維持に関与する肝細胞膜因子の存在が示唆された.今後,本肝細胞膜因子の探索を行う予定である.(著者抄録)

DOI： 10.1007/s12072-023-10547-4

PubMed

アテゾリズマブおよびベバシズマブ併用療法(Atezo+Bev)は、初めて認可された肝細胞癌(HCC)に対する免疫療法で、現行のガイドラインでは、切除不能例に対する一次療法と位置づけられている。Atezo+Bevにより、偽進行後に完全寛解に至った肝細胞癌の一例を報告した。症例は56歳男性で、中程度病期(バルセロナクリニック肝癌システム病期B)のHCCで、CT検査により肝内に多発病変が認められ、肝外病変は認められなかった。初回治療として、経カテーテル的動脈化学塞栓療法1(TACE)を施行したが、TACE施行2ヵ月後のCT検査で、多発遺残病変が認められた。TACEの4ヵ月後にAtezo+Bevを導入した。3回投与後、CTで肝内病変の進展が認められ、同時に血清腫瘍マーカーが上昇した。TACEを再度施行する予定としたが、入院待機中にはAtezo+Bevを継続した。Atezo+Bevの5回投与後、血清腫瘍マーカー値は正常化し、MRI検査で腫瘍径の著明な縮小が確認された。以上の経過から、Atezo+Bevを継続し、第8回投与後にはCT検査で全ての肝内病変の消失が確認され、完全寛解と判定した。免疫療法においては、偽進行と呼ばれるような、腫瘍病巣の増加や新規病変の発生により治療効果が非定型的に認められることがあるが、HCCでは稀である。

多施設共同コホート研究であるCLIONE(Clinical Outcome Nonalcoholic Fatty Liver Disease)研究のサブ解析を実施し、非アルコール性脂肪性肝疾患(NAFLD)患者における血小板数の予後予測能について検討した。NAFLD患者1398例(男性599例、平均54.5±14.2歳)を解析対象とした。評価項目は人口統計学的特徴、各種臨床所見(糖尿病、高血圧、脂質異常症などの有無)、各種検査データ(血小板数など)、病理学的データなどとした。その結果、追跡期間中央値4.6年、追跡期間は8874人・年に37例が肝細胞癌を発症していた。また、ベースラインの血小板数に基づき、血小板低値群495例、血小板高値群903例に分けて検討した。その結果、血小板低値群では血小板高値群と比較して、肝細胞癌発症率が高かった(6.7%対0.4%、p<0.001)。Kaplan-Meier曲線解析の結果、カットオフ値192×10^9/Lは肝細胞癌無イベント率を有意に層別化していた。血小板数低下と肝細胞癌発症リスク上昇には関連が認められた。血小板数192×10^9/Lと比較した場合の血小板数100×10^9/Lの交絡因子調整前ハザード比は7.37(95%CI 3.81～14.2、p<0.001)、調整後ハザード比は11.2(95%CI 3.81～32.7、p<0.001)であった。以上から、血小板数が肝細胞癌の発症に及ぼす潜在的な影響が示され、血小板数の少ない患者に対する積極的なサーベイランスを行う必要性が示唆された。

DOI： 10.1111/hepr.13884

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84-2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m2 (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m2 at baseline (p = .012; HR, 3.407) and albumin-bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.

DOI： 10.1111/jvh.13795

PubMed

C型肝炎による肝硬変患者20例を対象に、ソホスブビル/ベルパタスビル(SOF/VEL)12週間コースの安全性と有効性について検討した。治療後24週目に持続的ウイルス学的効果(SVR)を達成した患者(SVR24)において、テクネチウム(Tc)-99m-ガラクトシルヒト血清アルブミンシンチグラフィーによる肝細胞受容体指数(LHL15)と血液クリアランス指数(HH15)の変化、一過性エラストグラフィによる肝硬度測定(LSM)、肝静脈圧較差(HVPG)について検討した。直腸静脈瘤出血により1例が治療を中止し、19例が治療を完遂した。SVR24は17例(89%)で達成された。LHL15の中央値は治療前の0.72からSVR24後には0.82に増加し(p=0.012)、HH15の中央値は治療前の0.82からSVR24後には0.76に減少した(p=0.010)。LSM≧20kPaの患者の割合は治療前90%であり、SVR24後も90%であった。重症門脈圧亢進症(HVPG≧12mmHgと定義)の割合は、治療前の92%からSVR24後には58%に減少した(p=0.046)。治療前からSVR24後までにHVPGが減少した患者は、HVPGが増加した患者よりも治療前の脾臓容積が小さかった(中央値、252対537mL、p=0.028)。C型肝炎に関連した非代償性肝硬変患者において、SOF/VEL治療によりSVR24を達成することで、肝細胞機能と門脈圧亢進症の改善が期待できることが短期間の追跡調査により示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: It is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis. METHODS: We examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24). RESULTS: One patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028). CONCLUSION: Achieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.

DOI： 10.1007/s00535-023-01963-2

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIMS: Cell-cell interactions between hepatocytes and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes hepatocyte (Hep) dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of NO. Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression. RESULTS: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into neighboring hepatocytes to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. It's inhibitory action towards CcO specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo. INNOVATION AND CONCLUSION: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring hepatocyte dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO.

DOI： 10.1089/ars.2021.0279

PubMed

Publishing type：Research paper (scientific journal)  

<jats:p>It is not fully clear as to which dietary patterns are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in Asia. We conducted a cross-sectional study of 136 consecutively recruited patients with NAFLD (49% female, median age 60 years). Severity of liver fibrosis was assessed using the Agile 3+ score, a recently proposed system based on vibration-controlled transient elastography. Dietary status was assessed using the 12-component modified Japanese diet pattern index (mJDI12). Skeletal muscle mass was assessed by bioelectrical impedance. Factors associated with intermediate–high-risk Agile 3+ scores and skeletal muscle mass (75th percentile or higher) were analyzed by multivariable logistic regression. After adjustment for confounders, such as age and sex, the mJDI12 (OR: 0.77; 95% CI: 0.61, 0.99) and skeletal muscle mass (75th percentile or higher) (OR: 0.23; 95% CI: 0.07, 0.77) were significantly associated with intermediate–high-risk Agile 3+ scores. Soybeans and soybean foods were significantly associated with skeletal muscle mass (75th percentile or higher) (OR: 1.02; 95% CI: 1.00, 1.04). In conclusion, the Japanese diet pattern was associated with the severity of liver fibrosis in Japanese patients with NAFLD. Skeletal muscle mass was also associated with the severity of liver fibrosis, and intake of soybeans and soybean foods.</jats:p>

DOI： 10.3390/nu15051175

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Atezolizumab plus bevacizumab (Atezo + Bev) is the first immunotherapy for hepatocellular carcinoma (HCC), and in the current guidelines, it is positioned as the first-line chemotherapy for unresectable cases. Herein, we report a case of HCC with pseudoprogression followed by a complete response to Atezo + Bev. A 56 year-old man was diagnosed with intermediate-stage HCC, as defined by the Barcelona Clinic Liver Cancer system stage B. Computed tomography (CT) revealed multiple lesions in the liver without any extrahepatic lesions. First, he was treated with transcatheter arterial chemoembolization (TACE); however, multiple residual lesions were observed on CT scan 2 months after TACE. Therefore, treatment with Atezo + Bev was initiated 4 months after TACE. After the third administration of Atezo + Bev, a CT scan showed progressive disease in intrahepatic lesions, along with increased serum levels of tumor markers. Although TACE was planned again, Atezo + Bev was continued while the patient was waiting for hospitalization. After the fifth administration of Atezo + Bev, serum levels of tumor markers decreased to the normal range. Magnetic resonance imaging showed prominently reduced tumor size. Therefore, Atezo + Bev was continued, and after the eighth administration, the CT scan showed the disappearance of all the liver lesions, indicating a complete response. In immunotherapy, the therapeutic response can sometimes be obtained in an atypical pattern due to either an increase in tumor burden or the appearance of new lesions, called "pseudoprogression," which is rare in HCC.

DOI： 10.1007/s12328-023-01761-6

PubMed

DOI： 10.1016/j.cgh.2022.01.002

PubMed

DOI： 10.1016/j.gastha.2023.07.018

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12072-023-10488-y

PubMed

Other URL： https://link.springer.com/article/10.1007/s12072-023-10488-y/fulltext.html

DOI： 10.21873/anticanres.16113

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/2211-5463.13489

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND AND AIM: We evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness. METHODS: We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first-line systemic therapy. We reviewed the clinical backgrounds and courses of the patients. RESULTS: In total, 25 patients underwent rechallenge TACE after LEN due to LEN-refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P = 0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08-0.69, P = 0.008) and multivariate analyses (HR 0.26, 95% CI 0.08-0.80, P = 0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P = 0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P = 0.36). We did not observe a decrease in the ALBI score after TACE. CONCLUSION: Rechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis.

DOI： 10.1002/jgh3.12819

PubMed

健康人の唾液蛋白質(SP)がアンジオテンシン変換酵素2(ACE2)に結合する能力を評価し、新型コロナウイルス(SARS-CoV-2)スパイク蛋白質S1(S1)受容体結合ドメインとACE2の間の結合に及ぼすSPの影響を測定した。SPはACE2に結合し、S1のACE2への結合を妨害し、S1-ACE2相互作用を阻害するカチオン性ヒストンH2Aと好中球エラスターゼを含む4種類のACE2結合性SPを同定した。ウシ胸腺ヒストン(CTH)もH2Aと同じく効果的に結合を阻害した。CTHはACE2発現宿主細胞へのSARS-CoV-2偽ウイルス性侵入を抑制した。ε-ポリ-L-リジンなどの合成ポリペプチドもS1-ACE2結合を妨害し、ACE2結合におけるSPの重要性が示された。以上より、正荷電のSPはACE2の負荷電表面をクローキングしてSARS-CoV-2の侵入に対する障壁になり、カチオン性ポリペプチドは新型コロナウイルス感染症に対する予防的・治療的手法になり得ると考えられた。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.

DOI： 10.1016/j.ajpath.2022.07.003

PubMed

Publishing type：Research paper (scientific journal)  

Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23–dependent tumor necrosis factor–α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.

DOI： 10.1126/sciadv.abo5525

PubMed

DOI： 10.1093/jb/mvac054

PubMed

DOI： 10.1002/hep4.1954

PubMed

DOI： 10.1126/sciimmunol.abl7209

PubMed

DOI： 10.1002/poh2.4

DOI： 10.1016/j.redox.2022.102286

PubMed

DOI： 10.1016/j.redox.2022.102286.

DOI： 10.1038/s41389-022-00389-4

PubMed

DOI： 10.1038/s41389-022-00389-4.

DOI： 10.1111/liv.15158

PubMed

<p><b>Objective </b>Mapping the long-term prognosis of Budd-Chiari syndrome (BCS) is difficult, as the prognosis is associated with changes in the liver function. The present study evaluated the time course changes in the liver function in a treatment group with percutaneous old balloon angioplasty (POBA) and a non-treatment group using the albumin-bilirubin score (ALBI) and Child-Pugh score during long-term follow-up. </p><p><b>Methods </b>In this retrospective study, 13 consecutive patients diagnosed with BCS at our hospital between 2007 and 2020 were categorized into a treatment group (n=8), which received POBA, and a non-treatment group (n=5). Differences in the liver function in the ALBI and Child-Pugh scores between the initial visit and one- and three-year follow-up were calculated and statistically evaluated. We investigated the changes in the liver function during the long-term follow-up, including events such as re-stenosis and re-treatment. </p><p><b>Results </b>While the Child-Pugh scores in the treatment group did not differ significantly between the initial visit and 1- or 3-year follow-up, the ALBI scores in this group improved significantly between the initial visit and the 1- or 3-year follow-up visit (p=0.0078 and 0.0156, respectively). The liver function according to the ALBI score in the treatment group showed gradual improvement from the initial value but gradual worsening in the non-treatment group. The ALBI scores also revealed that the liver function varies according to re-stenosis and re-POBA in BCS patients. </p><p><b>Conclusion </b>Unlike the Child-Pugh score, the ALBI score was able to capture changes in the liver function of BCS patients during the long-term course of BCS. </p>

DOI： 10.2169/internalmedicine.8020-21

PubMed

CiNii Article

2007〜2020年に単施設でBudd-Chiari症候群(BCS)と診断された連続患者13例(男性6例、女性7例、中央値46歳)を対象に後方視的研究を行い、長期経過中の肝機能変化の評価におけるアルブミン-ビリルビン(ALBI)スコアとChild-Pughスコアの有用性を評価した。8例は経皮的バルーン血管形成術(POBA)による治療を行い(治療群)、5例はPOBAによる治療を行っていなかった(非治療群)。追跡期間中央値は2315日であった。治療群において、Child-Pughスコアは初回受診時と1年後または3年後で有意差を認めなかったが、ALBIスコアは1年後または3年後に有意に改善した。ALBIスコアで分類した肝機能は、治療群では初回受診時から徐々に改善したが、非治療群では徐々に悪化した。POBA後に再狭窄を認めたために再POBAを行った治療群の3例では、再狭窄時のALBIスコアで分類した肝機能は不良であったが、再POBA後に改善した。Child-Pughスコアとは異なり、ALBIスコアはBCSの長期経過における肝機能変化を捉えることができることが示された。

DOI： 10.1007/s00535-021-01845-5

PubMed

直接作用型抗ウイルス薬(DAA)を投与した、代償性および非代償性肝硬変患者350例(Child-PughクラスA(CP-A)195例、CP-B 131例、CP-C 24例)を検討対象とした。CP-A、CP-B、CP-C群のウイルス学的持続陰性化(SVR)率はそれぞれ96.9%、93.1%、83.3%であった(P=0.006)。70例に肝細胞癌(HCC)が発生し、多変量解析の結果、男性、HCC治療既往、血小板数<10.0×10^4/μl、AFP値≧5.0ng/mlおよびCP-Cが有意な関連因子であった。累積1年HCC発生/再発率は6.6%/45.2%であった。1年間の、入院が必要な非代償性肝硬変発症率は9.1%であった。多変量解析の結果、CP-BおよびCP-Cが有意な関連因子であった。経過観察期間の中央値は14.9ヵ月で、その間に13例が死亡し、1例が肝移植を受けた。CP-A、CP-B、CP-C症例の1年全生存率はそれぞれ98.4%、96.4%、85.6%であった(CP-A対CP-B、P=0.759、CP-A対CP-C、P=0.001、CP-B対CP-C、P=0.005)。CP-A症例とCP-B症例に関してはHCC発生率および死亡率に有意な差は認められなかったが、CP-C症例ではHCC発生、入院を要する肝硬変併発、死亡が多く認められた。

DOI： 10.2169/naika.111.15

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

DOI： 10.1038/s41598-021-03706-w

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on HCC progression remains uninvestigated. We conducted a retrospective cohort study of patients with hepatitis C virus-related HCC with BCLC stage 0/A diagnosed for the first time and treated by curative resection or ablation. Using a time-varying method, we estimated the risk of tumour progression (defined as progression to BCLC stage B-D) and liver-related death and the characteristics of repeated recurrence. Overall, 165 patients were enrolled. Following curative HCC treatment, 72 patients received DAA therapy (DAA-treated group), whereas 93 did not (untreated group). Approximately 75% of the recurrences were at an early stage and expected to be disease-free by retreatment. We recorded 56 tumour progressions, of which 60.7% were observed after second recurrence. Multivariate adjusted time-varying Cox regression analysis showed that the DAA-induced SVR significantly reduced the risk of tumour progression (hazard ratio [HR] 0.28; p = .001) and liver-related death (HR 0.12; p < .001). The annual incidence of HCC treatment until tumour progression was 82.8% and 23.9% in the untreated and DAA-treated groups, respectively (HR 0.30; p < .001). DAA-induced SVR significantly reduced the risk for tumour progression and liver-related death and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A.

DOI： 10.1111/jvh.13627

PubMed

DOI： 10.1007/s00535-021-01836-6

PubMed

原発性胆汁性胆管炎(PBC)の発症には環境因子の関与が示唆されている。日本の21医療機関で前向きに548例のPBC症例(男性78例、女性470例、年齢中央値66歳)、および年齢と性別を一致させた対照群を登録した。人口統計、人体測定、社会経済的因子、生活様式、既往歴、家族歴、および女性に関しては出産歴を含む121項目の質問紙調査を行い、条件付きロジスティック回帰分析により解析した。PBCと関連する因子として、生活様式では、小児期の汲み取り便所、小児期自宅付近の非舗装道路、喫煙歴、毛染め使用が、既往歴、家族歴関連では自己免疫性疾患既往、帝王切開既往、第一度近親者のPBC罹患が同定された。以上より、小児期の不衛生な環境および化学物質(喫煙および毛染め)曝露がPBC発症と関連があることが示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.1016/j.jcmgh.2022.07.006

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>Glecaprevir/pibrentasvir (GLE/PIB) is a pan-genotype anti-hepatitis C virus (HCV) therapy with high efficacy and safety. However, evidence supporting retreatment following failure of the GLE/PIB regimen is limited. We herein report 3 non-cirrhotic cases involving two men aged 51 and 58 years old and a woman aged 68 years old infected with HCV genotype 1a, 2a, and 3b respectively who failed anti-HCV therapies including GLE/PIB therapy. With combination therapy of sofosbuvir/velpatasvir plus ribavirin (SOF/VEL+RBV) for 24 weeks, all 3 patients had achieved a sustained viral response (SVR) at 24 weeks after completing treatment. SOF/VEL+RBV therapy was effective for retreatment of HCV after failure of GLE/PIB therapy. </p>

DOI： 10.2169/internalmedicine.7028-21

PubMed

CiNii Article

DOI： 10.1111/hepr.13709

PubMed

C型肝炎ウイルス感染に関連した肝細胞癌(HCC)に対し、肝切除後の直接作用型抗ウイルス薬(DAA)治療でウイルスが排除され、持続的ウイルス学的著効(SVR)を達成した患者の転帰を後方視的に検討した。術後のDAAによりSVRが得られた18例(HCC-DAA群)の手術成績を、術前のDAAによりSVRが得られた23例(DAA-HCC群)およびDAA療法を受けなかった10例(対照群)の手術成績と比較した。アミノトランスフェラーゼの血清中濃度は、HCC-DAA群、DAA-HCC群共に術後1年で改善した。HCC-DAA群の4例でアルブミン-ビリルビン(ALBI)のグレード2が1へ変化し、結果としてALBIグレード1のHCC-DAA患者が11例から15例に増加した。3年無病生存率は、HCC-DAA群(60%)と他の2群(DAA-HCC群92%、対照群60%)で差はなかった。3年全生存率は、DAA-HCC群(84%)とHCC-DAA群(100%)で対照群(46%)に比べて良好であった(ホルムの検定p<0.05)。多変量解析の結果、腫瘍のステージは術後再発の独立した危険因子であり、術後1年のALBIグレードは術後生存率を予測したが、DAAによるSVRは関連していなかった。以上より、術後のDAA投与による肝機能の改善は術後生存期間を延長させる可能性が示唆された。

症例1は58歳男性で、C型肝炎ウイルス(HCV) genotype 1aに感染し、グレカプレビル/ピブレンタスビル(GLE/PIB)療法を8週行ったが、無効であった。ソホスブビル/ベルパタスビル(SOF/VEL)+リバビリン(RBV)併用療法を24週行い、24週後に持続的ウイルス学的著効(SVR24)を達成した。治療終了後48週時点でHCV RNAは検出されなかった。症例2は51歳男性で、HCV genotype 2aに感染し、GLE/PIB療法が無効であった。SOF/VEL+RBV併用療法を24週行った。治療中に体重が5kg減少したが完遂し、SVR24を達成した。症例3は68歳女性で、HCV genotype 3bに感染しGLE/PIB療法を行ったが、4週目にHCVブレークスルーが発生した。GLE/PIB療法の無効後、SOF/VEL+RBV併用療法を開始し、SVR24を達成した。軽度のそう痒と頭痛を認めたが、重篤な有害事象は観察されなかった。

大阪市立大学医学部附属病院では、これまで腹部超音波検査(Ultrasonography;US)手技トレーニングを対面で実施してきた。今回、新型コロナウイルス感染症をきっかけに、受講者(初期臨床研修医)と指導者が、遠隔でリアルタイムにUS手技トレーニングを実施することとし、課題画像を対面時の10種類から13種類に増補して講習会を開催し、全受講者(5名)が課題画像の描出に成功した。US手技遠隔トレーニングは、感染症の流行下においても実施が可能であるだけでなく、1)遠隔地でのトレーニングを可能とし、2)1度に複数名の指導が実現できるため、医療手技教育の発展に有効な手段であることが示唆された。(著者抄録)

DOI： 10.1111/jgh.15436

PubMed

DOI： 10.1148/radiol.2021204727

PubMed

DOI： 10.1016/j.amsu.2021.102644

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>An 87-year-old man with hepatocellular carcinoma (HCC) presented with right-sided chest pain. Computed tomography revealed right bloody pleural effusion and an extravasation from an arterially enhanced mass in the right seventh posterior intercostal space. These findings indicated hemothorax from a rupture of HCC metastasis to the chest wall. Angiography of the intercostal arteries confirmed a hypervascular tumor, and transcatheter arterial embolization resulted in hemostasis. He was discharged with palliative care and remains alive after 9 months. Although hemothorax represents an unusual, life-threatening complication of HCC, our case suggests that transcatheter treatment can achieve hemostasis and a favorable survival even in elderly patients. </p>

DOI： 10.2169/internalmedicine.6003-20

PubMed

CiNii Article

DOI： 10.1038/s41598-021-93435-x

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIM: Hepatic venous pressure gradient (HVPG) measurement is a gold standard for the diagnosis of portal hypertension but can be invasive and difficult to conduct. Per-rectal portal scintigraphy (PRPS) can estimate portal haemodynamics noninvasively. However, no report to date has examined the association between HVPG and PRPS in patients with chronic liver disease, including cirrhosis. METHODS: This single-centre study included a total of 21 patients with chronic liver disease who underwent HVPG measurement and PRPS. For PRPS, the transit times from injection of the radiotracer to its inflow into the liver (TTL) and heart (TTH) were set and the time difference between TTL and TTH (TDLH) was calculated, while the shunt index (SI) was measured. RESULTS: Cirrhosis was observed in 18 cases (86%), and the median HVPG was 13 mmHg. HVPG (p = 0.028), TTL (p = 0.018), TDLH (p = 0.003) and SI (p = 0.033) were higher in patients with oesophageal varices (EV). Considering the diagnostic ability for EV, the area under the curve was 0.88 for TDLH and 0.80 for HVPG. TDLH was significantly correlated with the risk of EV rupture (p = 0.004). CONCLUSION: Patients with chronic liver disease should undergo upper gastrointestinal endoscopy when the TDLH is high.

DOI： 10.1111/cpf.12703

PubMed

DOI： 10.3350/cmh.2020.0187

PubMed

症例は87歳男性で、持続性の右側胸痛が突然出現した。4年前に肝細胞癌(HCC)を発症し、経皮的高周波アブレーションを受けていた。CTで大量の右胸水が認められ、出血が疑われた。ダイナミックCTでは、右第7肋間腔の動脈造影腫瘤が胸腔に膨隆しており、病変前面には点状溢出が認められた。HCCの肝内再発を示唆する所見はなかった。胸壁へのHCC転移の自然破裂により引き起こされた血胸が示唆された。肋間動脈の血管造影によりhypervascular腫瘍が判明し、肝動脈塞栓術を行って止血した。発熱、呼吸困難、胸痛などの症状は解消した。ヘモグロビンと血清アルブミンが低下していたが、他の肝機能検査は安定していたため、血胸に伴う失血により引き起こされたものであると考えられた。胸腔転移は唯一検出されたHCC病変であったが、機能状況が不良で高齢であったため、追加の抗癌治療は行わなかった。9ヵ月後の時点で生存している。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background and Aim: The Gut and Obesity in Asia Workgroup recently reported that a two-step approach using fibrosis scores followed by liver stiffness measurement (LSM) could accurately detect patients with non-alcoholic fatty liver disease (NAFLD) having advanced fibrosis in low-risk fibrosis populations. This study aimed to validate the utility of this approach using a Japanese health checkup registry. Methods: This cross-sectional study included subjects who underwent a health checkup from 2014 to 2019. Using estimated fibrosis stage measured by LSM as a standard, we calculated the percentage of misclassification from assessments made based on fibrosis scores (NAFLD fibrosis score [NFS] or Fibrosis-4 score [FIB-4]) and LSM, alone or in combination. Results: Of 630 subjects with NAFLD, 4 (0.8%) had advanced fibrosis. In the first-step evaluation, only 21.4-38.0% of subjects needed further testing. This approach was associated with a high specificity of approximately 100% and a negative predictive value of 99.7%. The percentage of misclassification based on NFS or FIB-4 values followed by LSM in all subjects and using LSM after NFS or FIB-4 determination only in subjects with indeterminate/high NFS or FIB-4 values (two-step approach) was 0% and 0.3% and 0.16% and 0.3%, respectively. In addition, very few false negatives occurred for both NFS and FIB-4. Conclusion: The two-step approach helps to identify the subjects with NAFLD who have advanced fibrosis during a routine health checkup and is associated with only a few false negatives.

DOI： 10.1002/jgh3.12590

PubMed

DOI： 10.14309/ajg.0000000000001157

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Preventive or on-demand nucleos(t)ide analog (NA) therapy can prevent severe hepatitis related to hepatitis B virus reactivation (HBV-R). However, it is unclear if NA can be safely stopped in such patients after cytotoxic therapies or during immunosuppressive therapies. We retrospectively evaluated 133 patients who initiated NA therapy between 2007 and 2018. A total of 103 patients were positive for HBV surface antigen (HBsAg) at baseline, and NA therapy was started before cytotoxic or immunosuppressive therapy (preventive group). Thirty patients with resolved HBV infection were treated with NA therapy after HBV reactivation (on-demand group). Virological relapse was defined as a serum HBV DNA level >20 IU/ml. NA therapy was stopped in 12 (12%) patients (preventive group), and in 16 (53%) patients (on-demand group). After the cessation of NA therapy, the cumulative rates of relapse were 36% and 39% at 12 and 24 months, respectively. High levels of HBsAg both at baseline and at the cessation of NA therapy were related to the occurrence of relapse. Relapse did not occur in patients with HBsAg levels <20 IU/ml (preventive group). HBV relapse occurred in five (33%) patients in the on-demand group. Relapse occurred only in anti-HBs-negative patients at the cessation of NA therapy. There were no cases of hepatitis flare after the cessation of NA therapy. HBsAg predicted HBV relapse after the cessation of NA therapy in HBsAg-positive patients. Anti-HBs could be a predictive marker for NA therapy cessation in patients with resolved HBV.

DOI： 10.1002/jmv.26526

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CiNii Article

DOI： 10.1002/hep.31752.

DOI： 10.1136/gutjnl-2020-322367

PubMed

DOI： 10.1002/hep.31752

PubMed

DOI： 10.1007/s00535-021-01782-3

PubMed

組織学的に診断された、慢性C型肝炎(HCV)1029例および慢性B型肝炎(HBV)384例を対象として、多施設後方視的(14年間)および前向き(12年間)コホート研究を行った。組織学的に肝硬変と診断された症例に関して、APRIおよびFIB-4の経時的変化を後方視的に検討し、METAVIRスコアがF3と診断された症例に関して前向き検討を行った。HCV患者のAPRIおよびFIB-4の平均値は経時的に増加していた(APRI 0.09/年、FIB-4 0.29/年)。未治療のHCV症例では、APRIの増加は0.14/年、FIB-4の増加は0.40/年であった。HBV患者および治療を受けたHCV症例では、平均APRI、FIB-4共に一定の傾向を示さなかった。APRIおよびFIB-4は、未治療のHCV症例において肝線維化の遷移指標となる可能性が示された。

好酸球性食道炎(EoE)患者43名(男性28名、平均46.7歳)および無症候性食道好酸球症(aEE)患者18名(男性10名、平均47.1歳)の食道生検試料を用いて、免疫組織化学染色により免疫関連組織バイオマーカーを定量した。BMIを除き患者群間に臨床的、内視鏡および組織学的な有意差はなかった。免疫関連組織バイオマーカーである主要塩基性タンパク質、好酸球由来ニューロトキシン、エオタキシン-3および免疫グロブリンG4についてEoEとaEEとの間に有意差はなかった。EoEとaEEは同様の免疫組織学的プロファイルを示すことから、両者は共通する病態メカニズムを有する近縁の疾患と考えられた。本研究の結果から、aEE患者でも病理組織学的に食道の炎症を有することが示唆された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>Patients with asymptomatic esophageal eosinophilia (aEE) do not exhibit clinical symptoms because of esophageal dysfunction, although they have endoscopic and histological findings similar to those of eosinophilic esophagitis (EoE). The cause of the symptoms and the differences between aEE and EoE are unclear. The aim of this study is to determine whether aEE and EoE are same disease entities by comparing immune-related tissue biomarkers using immunohistological staining. Esophageal biopsy specimens from 61 patients, including 18 with aEE and 43 with EoE, were analyzed. Immunofluorescence staining was performed to quantify the immune-related tissue biomarkers such as major basic protein, eosinophil-derived neurotoxin, eotaxin-3, and immunoglobulin G4. Data are presented as median (interquartile range). There were no significant differences in clinical, endoscopic, or histological features, between patients with aEE and EoE, with the exception of body mass index. There were no significant differences in all immune-related tissue biomarkers between both groups. In conclusions, EoE and aEE displayed similar immunohistological profiles. Hence, they may be similar disease entities with some common pathogenic mechanisms. Our findings suggest that patients with aEE also have histopathological esophageal inflammation.</p>

DOI： 10.3164/jcbn.20-49

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CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.14309/ajg.0000000000000747

PubMed

DOI： 10.14309/ajg.0000000000000747

PubMed

DOI： 10.1515/cclm-2020-0563

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant <i>Enterobacter cloacae</i> bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice. </p>

DOI： 10.2169/internalmedicine.5097-20

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.

DOI： 10.3390/ijms22031456

PubMed

DOI： 10.1007/s12072-021-10135-4

PubMed

DOI： 10.1136/gutjnl-2020-321666

PubMed

症例は82歳男性で、肝細胞癌に罹患していたが、上腹部痛と嘔吐を認めた。3ヵ月前からレンバチニブ(8mg/日)が投与されており、有害事象は認めていなかった。3年前に狭心症のため冠動脈ステント留置術を行っており、低用量アスピリンを服用していた。造影CTでは総胆管の拡張が認められた。急性胆管炎を疑ったが、画像検査では胆管閉塞の原因が判明しなかった。レンバチニブとアスピリンを中止後、内視鏡的逆行性胆管膵管造影を行ったところ、十二指腸の球部と下行部に多発性潰瘍が認められた。十二指腸潰瘍の一つはファーター乳頭上で形成されており、感染性胆汁が漏出していた。胆管造影の所見をあわせ、十二指腸潰瘍による浮腫性乳頭が胆汁うっ滞の原因であることが示唆された。血液と胆汁の培養でEnterobacter cloacae菌血症が特定されたが、内視鏡的胆管ドレナージを行い、セフェピムとメトロニダゾールを投与したところ改善した。十二指腸潰瘍の治療としては、ラベプラゾールをボノプラザン+ミソプロストールに変更した。

DOI： 10.1038/s41374-020-00509-x

PubMed

DOI： 10.1038/s41374-020-00509-x

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Stress can affect our body and is known to lead to some diseases. However, the influence on the development of nonalcohol fatty liver disease (NAFLD) remains unknown. This study demonstrated that chronic restraint stress attenuated hepatic lipid accumulation via elevation of hepatic β-muricholic acid (βMCA) levels in the development of nonalcoholic steatohepatitis (NASH) in mice. Serum cortisol and corticosterone levels, i.e., human and rodent stress markers, were correlated with serum bile acid levels in patients with NAFLD and methionine- and choline-deficient (MCD) diet-induced mice, respectively, suggesting that stress is related to bile acid (BA) homeostasis in NASH. In the mouse model, hepatic βMCA and cholic acid (CA) levels were increased after the stress challenge. Considering that a short stress enhanced hepatic CYP7A1 protein levels in normal mice and corticosterone increased CYP7A1 protein levels in primary mouse hepatocytes, the enhanced Cyp7a1 expression was postulated to be involved in the chronic stress-increased hepatic βMCA level. Interestingly, chronic stress decreased hepatic lipid levels in MCD-induced NASH mice. Furthermore, βMCA suppressed lipid accumulation in mouse primary hepatocytes exposed to palmitic acid/oleic acid, but CA did not. In addition, Cyp7a1 expression seemed to be related to lipid accumulation in hepatocytes. In conclusion, chronic stress can change hepatic lipid accumulation in NASH mice, disrupting BA homeostasis via induction of hepatic Cyp7a1 expression. This study discovered a new βMCA action in the liver, indicating the possibility that βMCA is available for NAFLD therapy.

DOI： 10.1038/s41374-020-00509-x

PubMed

DOI： 10.1038/s41374-020-00509-x

2019年2月から8月までの間に直接作用型抗ウイルス薬を導入した肝硬変患者(代償性108例、非代償性82例)を対象として検討を行った。治療終了後12週間目において血清HCV-RNAが同定されない場合を持続的ウイルス学的反応(SVR12)と定義した。SVR12が得られたのは、代償性群では92.6%、非代償性群では90.2%であった。それぞれの治療完遂率はそれぞれ98.1%、96.3%であった。非代償性群では、3例が治療を中断し、2例が肝臓関連死した。SVR12が得られた非代償性群では、治療開始時Child-PughクラスB症例の50%がクラスAへ、治療開始時クラスCの症例のうち27%がクラスBへ、9%がクラスAへと改善がみられた。SVR12が得られた症例では、治療終了時に血清アルブミン値が上昇し、SVR12値に更なる上昇がみられた。しかし、治療開始時の血清アルブミン値が2.8g/dl未満であった症例では治療終了後の血清アルブミン値の上昇は認められなかった。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND AND AIM: The evaluation of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection is important as it is a risk factor for hepatocellular carcinoma. In the recent years, autotaxin (ATX) has been established as a new noninvasive biomarker to predict liver fibrosis. However, antiviral treatment has been reported to decrease serum ATX, but it is unclear whether posttreatment ATX levels reflect liver fibrosis. In the present study, the correlation between ATX and liver fibrosis in pretreatment and posttreatment patients with HCV infection was analyzed. METHODS: A total of 199 samples from 136 patients with HCV infection who had undergone hepatic biopsy before and/or after antiviral treatment at Osaka City University Hospital were used. Posttreatment patients included 38 interferon-treated patients and 80 interferon-free direct-acting antiviral-treated patients; all patients achieved a sustained virological response (SVR). Serum ATX levels were determined by enzyme immunoassay with an AIA-2000 analyzer. RESULTS: Serum ATX levels were largely correlated with liver fibrosis stage in patients with HCV infection before and after antiviral treatment. The measured values decreased even in similar liver fibrosis stages after treatment. The area under the receiver operating characteristic curve for the ability of ATX to diagnose above F2 stage before treatment was 0.81 (both male and female) and that after achieving SVR, it was 0.71 (male) and 0.72 (female). CONCLUSIONS: Serum ATX levels were correlated with histological liver fibrosis stage after achieving SVR. However, separate cutoff values before and after antiviral therapy should be established.

DOI： 10.1111/jgh.15114

PubMed

DOI： 10.1007/s00535-020-01733-4

PubMed

DOI： 10.1111/hepr.13709.

DOI： 10.1371/journal.pone.0257166

PubMed

We held an abdominal ultrasonography(US)training seminar using by remoted WEB system. Trainees were instructed to acquire several target images and worked on their respective US simulators. Their ultrasound images were shared to the instructor simultaneously. All the trainees have successfully achieved the goals. Not only can this attempt be carried out under viral epidemic, but also it demonstrates possibilities of 1) distant area training, 2) parallel personalized teaching with multiple trainees. The study suggest that the method can be an effective means for the development of skills education in medicine.

DOI： 10.50950/jasehp.2021-09-06

CiNii Article

Authorship：Last author  

DOI： 10.1038/s41598-021-93435-x.

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

INTRODUCTION: Lenvatinib has been approved as a systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). We recently experienced lenvatinib-induced tumor-related hemorrhage in patients with HCC. The full details of tumor-related hemorrhage as a lenvatinib-related adverse event have not been elucidated. METHODS: This was a retrospective single-center study that enrolled consecutive patients treated with lenvatinib for unresectable HCC from April 2018 to February 2020. RESULTS: Sixty-eight consecutive patients were enrolled in this study. Among them, 5 cases developed intraperitoneal or intratumoral hemorrhages. The patients with hemorrhage had larger tumors (maximum tumor size, 97.5 ± 46.4 and 38.2 ± 28.8 mm, respectively; p = 0.009) than the patients without hemorrhage. The dosing period of lenvatinib (median, 3 and 93 days, respectively; p < 0.001) and the survival time from initial administration of lenvatinib (median, 77 and 495 days, respectively; p < 0.001) of the patients with hemorrhage were shorter than those of the patients without hemorrhage. Especially, in 4 cases with large HCCs (maximum tumor diameter was >90 mm), tumor hemorrhage with vascular lake-like phenomenon was evident, although most tumor blood flow was suppressed. DISCUSSION/CONCLUSION: It becomes clear that lenvatinib treatment brings about tumor-related hemorrhages despite rapid suppression of tumor blood flow. We speculate that lenvatinib quickly blocks the feeding circulation, resulting in tumor hemorrhage by necrosis. Clinicians should pay careful attention to the development of life-threatening hemorrhages when treating large HCCs with lenvatinib.

DOI： 10.1159/000510911

PubMed

DOI： 10.3350/cmh.2020.0187.

DOI： 10.31557/APJCP.2020.21.12.3647

PubMed

International / domestic magazine：International journal  

BACKGROUND: MicroRNAs (miRNAs) in exosomes represent disease-specific profiles and are applied as biomarkers in oncology. However, in functional dyspepsia (FD), the role of exosomal miRNAs has not been fully elucidated. AIMS: To investigate exosomal miRNAs as potential biomarkers of FD using liquid biopsy. METHODS: This retrospective cohort study included 11 subjects with FD and 11 age- and sex-matched healthy controls (HCs). We collected gastric juice and isolated exosomal miRNAs. In a discovery cohort, expression levels of 2565 miRNAs were evaluated by 3D-Gene® microarray. miRNA expression profiles from exosomes of subjects with FD and HCs were compared by two normalization methods: (1) global normalization and (2) normalization by internal control. Subsequently, in a validation cohort, the expression levels of miRNAs were validated by quantitative reverse transcription PCR (RT-qPCR). RESULTS: Through microarray analysis using the two methods, we identified 39 miRNAs that were consistently and significantly downregulated in FD cases compared with those in HCs. Of these, 12 miRNAs (hsa-miR-933, hsa-miR-345-5p, hsa-miR-708-5p, hsa-miR-203a-3p, hsa-miR-619-5p, hsa-miR-4294, hsa-miR-4481, hsa-miR-196a-5p, hsa-miR-3918, hsa-miR-372-3p, hsa-miR-658, and hsa-miR-3654) were further validated by RT-qPCR. Our results indicated that hsa-miR-933 was significantly downregulated in FD compared with HCs (0.317 ± 0.205-fold, P = 0.0317). Furthermore, the expression level of hsa-miR-933 was negatively associated with dyspepsia score and the frequency of epigastric pain and/or burning (P < 0.01, r = - 0.835; P = 0.0280, r = - 0.688, respectively). CONCLUSIONS: Exosomal hsa-miR-933 in gastric juice could be a candidate biomarker for FD.

DOI： 10.1007/s10620-020-06096-7

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVE: To investigate the postoperative recurrence of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after liver resection in patients with and without the achievement of sustained virologic response (SVR) through the administration of direct-acting antivirals (DAA). METHODS: Among 28 patients with HCC detected after DAA-SVR (DAA group) and 197 patients with HCC who did not receive treatment for HCV infection or who did not achieve an SVR (control group) between January 2000 and July 2019, we performed propensity score matching (PSM) to avoid confounding differences between the two groups. RESULTS: After PSM, 28 patients in each group were selected for analysis. The DAA-SVR patients showed improved liver function at operation and at recurrence in comparison to the control group. The disease-free survival rate at 3 years after surgery was 69% in the DAA group and 35% in the control group, respectively (P = .021). In the DAA group, all three patients with recurrence met the Milan criteria and could be managed by curative treatments and none died of liver failure during the follow-up period. CONCLUSIONS: SVR status suppresses postoperative recurrence of HCV-related HCC detected after DAA-SVR. Improved liver function may contribute to the successful treatment and prevention of liver failure.

DOI： 10.1002/jso.26184

PubMed

<p>A 59 year-old-Japanese female was referred to our hospital for tumor-induced abdominal pain. Dynamic computed tomography (CT) demonstrated a tumor, 88×73 mm in diameter, which was adherent to the caudate lobe of the liver and pancreas. Based on these findings, we performed a laparotomy with a preoperative diagnosis of hepatocellular carcinoma (HCC) originating from the caudate lobe of the liver. The tumor could be dissected from the liver, however, it had infiltrated into the common hepatic artery, leading to incomplete extirpation of the tumor. Histological examination revealed that the tumor was an ectopic HCC. Lenvatinib mesylate (lenvatinib) was used as systemic therapy for growth of the remnant tumor 16 days after surgery. CT performed during two months after initiating lenvatinib revealed that the tumor size had reduced with a decrease in vascularity, which was deemed to be a partial response. CT performed three months after the initiation of lenvatinib demonstrated regrowth of the tumor. The patient died of HCC 164 days after surgery.</p>

DOI： 10.2957/kanzo.61.597

CiNii Article

症例は59歳、女性。腹腔内腫瘤の精査・加療目的で入院となった。腹部ダイナミックCT像上にて肝外側区域背側から膵上縁におよぶ、動脈相で辺縁が不均一に濃染し、門脈相でwash outを呈する90mm大の腫瘤を認めた。AFPおよびPIVKA-IIの上昇もあり、尾状葉原発肝外突出型肝細胞癌と診断し開腹したところ、腫瘤は肝と線維性癒合のみであったが、総肝動脈が腫瘤を貫いており、同部位を遺残する摘出術を施行した。病理学的に低分化型異所性肝細胞癌と診断した。遺残部位の増大に対しレンバチニブメシル酸塩(レンバチニブ)を導入し、開始2ヵ月間の画像検査で部分奏効と判定したものの、開始後3ヵ月には腫瘍が増大したため進行(PD)と判断し、Best supportive careに移行した。レンバチニブ開始後132日で癌死した。進行異所性肝細胞癌に対してレンバチニブを投与した報告はなく、貴重な症例と考えられた。(著者抄録)

症例は59歳、女性。腹腔内腫瘤の精査・加療目的で入院となった。腹部ダイナミックCT像上にて肝外側区域背側から膵上縁におよぶ、動脈相で辺縁が不均一に濃染し、門脈相でwash outを呈する90mm大の腫瘤を認めた。AFPおよびPIVKA-IIの上昇もあり、尾状葉原発肝外突出型肝細胞癌と診断し開腹したところ、腫瘤は肝と線維性癒合のみであったが、総肝動脈が腫瘤を貫いており、同部位を遺残する摘出術を施行した。病理学的に低分化型異所性肝細胞癌と診断した。遺残部位の増大に対しレンバチニブメシル酸塩(レンバチニブ)を導入し、開始2ヵ月間の画像検査で部分奏効と判定したものの、開始後3ヵ月には腫瘍が増大したため進行(PD)と判断し、Best supportive careに移行した。レンバチニブ開始後132日で癌死した。進行異所性肝細胞癌に対してレンバチニブを投与した報告はなく、貴重な症例と考えられた。(著者抄録)

Other URL： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00263&link_issn=&doc_id=20201111080007&doc_link_id=10.2957%2Fkanzo.61.597&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.61.597&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

ピロリ菌抗体価が陰性高値と判定された被験者におけるピロリ菌感染診断のための胃炎の京都分類の有用性を調べた。研究デザインは単施設後ろ向き観察研究とした。健診でピロリ菌のIgG抗体価を測定した13203名のうち1690名に陰性高値が認められ、そのうちの当院を受診した111名について13C尿素の呼気試験(UBT)または糞便中の抗原検査(HpSA)、内視鏡検査を行った。評価者3名による所見の評価には木村-竹本分類の他に胃炎の京都分類を用いた。UBT陽性者またはHpSA陽性者を現感染者と判定した。胃炎の京都分類に基づく内視鏡5所見(び漫性発赤、粘膜浮腫、ひだ肥厚蛇行、粘稠性粘液、結節形成)の有(1)無(0)スコアを合計した「ピロリ菌感染スコア」を開発した。ROC曲線を描いて最適なカットオフ値を設定した。111名のピロリ菌抗体価中央値は4.0、UBT陽性10名、HpSA陽性3名で、13名(11.7%)が現感染、54名(48.6%)は除菌後の既感染、44名(39.6%)はその他であった。ピロリ菌感染スコアのROC曲線下面積は0.92で、感度と特異度が最大となるピロリ菌感染スコアのカットオフ値は1であった(内視鏡5所見のうちの1所見が確認されることを意味する)。多変量ロジスティック回帰分析により、ピロリ菌感染スコアがピロリ菌感染を予測する独立因子であることが判明した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>Subjects with a high-negative titer (3–9.9 U/ml) of serum anti-<i>Helicobacter pylori</i> (<i>H. pylori</i>) antibody represent a heterogeneous group of currently <i>H. pylori</i>-infected, <i>H. pylori</i>-uninfected, and previously <i>H. pylori</i>-infected cases. We investigated the characteristics of subjects with a high-negative titer during a medical check-up and the utility of <i>H. pylori</i> infection score, the sum of scores of endoscopic findings based on the Kyoto Classification of Gastritis, for diagnosing <i>H. pylori</i> infection. Subjects with ¹³C-urea breath test-positive or <i>H. pylori</i> stool antigen test-positive were diagnosed as currently <i>H. pylori</i>-infected. Although around half of subjects with a high-negative titer were after eradication therapy (48.6%), currently <i>H. pylori</i>-infected were considerably confirmed (11.7%). <i>H. pylori</i> infection score showed a high value of area under the receiver operating characteristic curve [0.92; 95% confidence interval (CI), 0.84–1.00] with the most suitable cut-off value of 1.0 (sensitivity: 0.92; specificity: 0.90). Multivariate logistic regression analysis revealed that <i>H. pylori</i> infection score was an independent factor associated with increased prevalence of <i>H. pylori</i> infection (odds ratio, 9.53; 95% CI, 2.64–34.40; <i>p</i><0.001). Currently <i>H. pylori</i>-infected subjects were considerably included among the subjects with a high-negative titer, and the Kyoto Classification of Gastritis was useful to predict current <i>H. pylori</i> infection.</p>

DOI： 10.3164/jcbn.20-21

PubMed

CiNii Article

DOI： 10.14670/HH-18-257

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background and Aim: The purpose of this study was to identify lifestyle risk factors, such as cigarette smoking and alcohol consumption, in relation to the development of hepatocellular carcinoma (HCC) among chronic hepatitis C patients who have achieved a sustained virologic response (SVR). Methods: This cross-sectional study was conducted between 2014 and 2017 using self-administered questionnaires and medical information at two tertiary hospitals in Osaka, Japan. Study subjects were chronic hepatitis C patients who had achieved SVR without HCC following antiviral treatment that was completed more than 1 year earlier. A logistic regression model was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the development of post-SVR HCC for each factor. Results: Of 202 participants, 18 patients were diagnosed with post-SVR HCC. After considering potential confounders, former drinkers at the time of SVR (OR, 9.51; 95% CI, 1.08-83.90) and patients with a history of gastric or duodenal ulcer (OR, 4.14; 95% CI, 1.37-12.46) were significantly associated with HCC. In addition, among patients with severe fibrosis, current smokers at the time of SVR had an increased OR for HCC compared with never smokers, with marginal significance (OR, 5.61; 95% CI, 0.97-32.63). Conclusions: In chronic hepatitis C patients with severe fibrosis, continuing smoking after achieving SVR could be a risk factor for post-SVR HCC. The relationship between gastric or duodenal ulcer history and post-SVR HCC should be investigated further.

DOI： 10.1002/jgh3.12331

PubMed

症例は74歳男性で、腹痛の精査目的に当院に紹介された。造影CTで肝両葉の肝細胞癌(HCC)と腹部大動脈・左腎動脈に隣接するリンパ節の腫大を認め、血清中α-フェトプロテイン(AFP)とデス-γ-カルボキシプロトロンビン(DCP)は著明に上昇し、甲状腺機能に異常はみられなかった。肝内病変は腹部血管造影によってHCCと診断され、経カテーテル動脈化学塞栓術(TACE)を開始した。また、PET/CTでは傍大動脈リンパ節と前立腺におけるF-18 FDGの異常集積が認められ、偶然発見された局所前立腺癌に対してリュープロレリンの投与を開始した。TACE開始2ヵ月後の造影CTでは傍大動脈リンパ節のサイズ増大がみられ、HCCの転移が疑われた。このため、レンバチニブ12mg/日を開始したところ、全身疲労と動悸をきたし、臨床検査でTSHの著明な減少と血清FT4の軽度上昇がみられた。超音波検査では甲状腺実質に異常はみられなかったが、カラードプラー検査で甲状腺血流の低下が明らかになり、レンバチニブに起因する甲状腺中毒症と判断して同薬を中断した。甲状腺関連パラメータは一旦回復するも甲状腺機能低下症を示唆する所見を認め、レボチロキシンの補助投与下にレンバチニブを継続したが、第146病日には血清TSHは31830μIU/mLまで上昇した。第148病日にレンバチニブを中止し、他院にて傍大動脈リンパ節症に対する外照射療法が開始され、血清TSHの著明な減少が得られた。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND & AIMS: Cytoglobin (CYGB) is a respiratory protein that acts as a scavenger of reactive oxygen species. The molecular role of CYGB in human hepatic stellate cell (HSC) activation and human liver disease remains uncharacterised. The aim of this study was to reveal the mechanism by which the TGF-β1/SMAD2 pathway regulates the human CYGB promoter and the pathophysiological function of CYGB in human non-alcoholic steatohepatitis (NASH). METHODS: Immunohistochemical staining was performed using human NASH biopsy specimens. Molecular and biochemical analyses were performed by western blotting, quantitative PCR, and luciferase and immunoprecipitation assays. Hydroxyl radicals (•OH) and oxidative DNA damage were measured using an •OH-detectable probe and 8-hydroxy-2'-deoxyguanosine (8-OHdG) ELISA. RESULTS: In culture, TGF-β1-pretreated human HSCs exhibited lower CYGB levels - together with increased NADPH oxidase 4 (NOX4) expression - and were primed for H2O2-triggered •OH production and 8-OHdG generation; overexpression of human CYGB in human HSCs reversed these effects. Electron spin resonance demonstrated the direct •OH scavenging activity of recombinant human CYGB. Mechanistically, pSMAD2 reduced CYGB transcription by recruiting the M1 repressor isoform of SP3 to the human CYGB promoter at nucleotide positions +2-+13 from the transcription start site. The same repression did not occur on the mouse Cygb promoter. TGF-β1/SMAD3 mediated αSMA and collagen expression. Consistent with observations in cultured human HSCs, CYGB expression was negligible, but 8-OHdG was abundant, in activated αSMA+pSMAD2+- and αSMA+NOX4+-positive hepatic stellate cells from patients with NASH and advanced fibrosis. CONCLUSIONS: Downregulation of CYGB by the TGF-β1/pSMAD2/SP3-M1 pathway brings about •OH-dependent oxidative DNA damage in activated hepatic stellate cells from patients with NASH. LAY SUMMARY: Cytoglobin (CYGB) is a respiratory protein that acts as a scavenger of reactive oxygen species and protects cells from oxidative DNA damage. Herein, we show that the cytokine TGF-β1 downregulates human CYGB expression. This leads to oxidative DNA damage in activated hepatic stellate cells. Our findings provide new insights into the relationship between CYGB expression and the pathophysiology of fibrosis in patients with non-alcoholic steatohepatitis.

DOI： 10.1016/j.jhep.2020.03.051

PubMed

DOI： 10.1111/hepr.13546

PubMed

Publishing type：Research paper (scientific journal)  

Background and Aim: We assessed direct-acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV) and a history of injection drug use (IDU) in Japan.Method: This retrospective observational study was based on clinical records. Overall, 804 DAA-naive HCV-infected patients were enrolled, treated with a 12-week regimen of DAAs, and had available information about a history of IDU. Anti-HCV efficacy was defined as a sustained viral response 12 weeks post-treatment (SVR12) only in patients who were assessed after 12 weeks [modified intention-to-treat (ITT) analyses]. We compared the antiviral effect between patients with (past-IDU) and without a history of IDU (non-IDU). We also evaluated the characteristics of each group, including the overall dropout rate and economic background.Results: Overall, 78 (9.7%) patients had a history of IDU. Compared to the non-IDU group at baseline, the past-IDU group consisted of predominantly male and younger patients infected with HCV genotype 2. Overall, 3% (3/78) and 16% (116/726) of the patients had cirrhosis in the past-IDU and non-IDU group, respectively. There was a significantly higher rate of welfare recipients in the past-IDU group. SVR rate was 97% (59/61) in the past-IDU group and 99% (689/699) in the non-IDU group. The cumulative rate of dropout from an aftercare program was high in the past-IDU group (P < 0.01).Conclusions: DAAs had a remarkable anti-HCV effect in patients with past-IDU who continued in an aftercare program. It is necessary to understand the characteristics of past-IDU patients to establish a support system for aftercare programs.

DOI： 10.1002/jgh3.12376

PubMed

アジア太平洋地域におけるレジパスビル・ソホスブビル配合錠(LDV/SOF)の第II/III相試験3件の統合解析を行い、genotype 2型のC型慢性肝炎患者(代償性肝硬変症例と非肝硬変症例を含む計200例、男性46%、平均59±11.3歳)に対する有効性と安全性を評価した。12週後のウイルス学的著効(SVR12)率は98%と高く、これは線維化のステージ、治療歴、genotype 2型のサブタイプ、ベースラインのnon-structural protein 5A resistance-associated substitution(NS5A RAS)の有無にかかわらず同様であった。LDV/SOFの忍容性は良好であった。これらの結果より、線維化進展例を含めたgenotype 2型のC型慢性肝炎患者に対するLDV/SOF 12週投与の高い有効性と安全性が示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Hypothyroidism is a common adverse event of lenvatinib therapy for hepatocellular carcinoma (HCC), whereas thyrotoxicosis has rarely been reported in clinical trials. A 74-year-old man complaining of abdominal pain was found to have liver tumors and paraaortic lymphadenopathy. The intrahepatic lesions were diagnosed as HCC by angiography and treated with transcatheter arterial chemoembolization. Although localized prostate cancer was discovered incidentally, the etiology of paraaortic lymphadenopathy was assumed to be metastatic HCC. Lenvatinib 12 mg/day was started when his thyroid function tests were almost normal but was interrupted because of thyrotoxicosis. The patient was negative for tested thyroid autoantibodies. Color Doppler ultrasonography detected reduced thyroid blood flow, suggesting destructive thyroiditis. Although he resumed lenvatinib at 8 mg/day once his serum level of free thyroxine normalized, thyrotoxicosis recurred. Subsequently, he suffered hypothyroidism, which exacerbated despite levothyroxine replacement. Lenvatinib was discontinued as it was ineffective against the paraaortic lymph node metastasis, and external-beam radiotherapy was performed. After the completion of radiotherapy, the thyroid dysfunction significantly improved. In summary, lenvatinib for HCC can induce transient thyrotoxicosis followed by hypothyroidism, which is compatible with destructive thyroiditis. During lenvatinib therapy, close monitoring of thyroid function and appropriate management of thyrotoxicosis as well as hypothyroidism are essential.

DOI： 10.1007/s12328-020-01107-6

PubMed

DOI： 10.1111/liv.14534

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC who underwent lenvatinib (n = 24) or TACE (n = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased (p = 0.040) and levels of sCD40 (p = 0.014) and sTIM-3 (p < 0.001) were increased at Week 1, while levels of sCD27 (p < 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 (p = 0.028), sCD40 (p < 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain-3) (p < 0.001), levels of sHVEM (soluble herpesvirus entry mediator) (p = 0.003), sTLR-2 (soluble Toll-like receptor 2) (p = 0.009), sCD80 (p = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) (p = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) (p = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) (p = 0.090), and sPD-L1 (soluble programmed death-ligand 1) (p = 0.070) also increased. The fold-changes in soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86 and sPD-1 (soluble programmed cell death domain-1) with sPD-L1 were positively correlated in both the lenvatinib and TACE treatment groups. Our results suggest that there are some limited differences in immunomodulatory effects between anti-angiogenic agents and TACE. Further studies from multicenters may help to identify an effective combination therapy.

DOI： 10.3390/cancers12082045

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.14309/ajg.0000000000000747

PubMed

DOI： 10.3350/cmh.2020.0037

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

INTRODUCTION AND OBJECTIVES: We examined whether Mac-2-binding protein glycosylation isomer (M2BPGi) levels could be a predictive marker for the presence of esophagogastric varices (EGV) in cirrhotic patients after hepatitis C virus (HCV) eradication with direct-acting antivirals (DAAs). PATIENTS AND METHODS: A total of 102 cirrhotic patients with HCV infection treated with DAAs were enrolled. Esophagogastroduodenoscopy was performed in 84 of the patients before treatment (Cohort A), in 66 after treatment (Cohort B), and in 48 at both time points (Cohort C). We examined factors associated with EGV before and after DAA treatment. RESULTS: In Cohort A, M2BPGi levels and liver stiffness were significantly higher in the EGV-positive group than the EGV-negative group (p=0.034, and p=0.042, respectively). The proportion of EGV-positive patients with before-treatment levels of M2BPGi ≧ 7.3 C.O.I. was significantly higher than in patients with M2BPGi levels<7.3 C.O.I. (p=0.015). In Cohort B, M2BPGi levels were significantly higher in the EGV-positive group than EGV-negative group (p=0.003). The proportion of EGV-positive patients with after-treatment levels of M2BPGi ≧ 3.4 C.O.I. was significantly higher than in patients with M2BPGi levels<3.4C.O.I. (p=0.001). In Cohort C, M2BPGi levels decreased during DAA treatment regardless of EGV development, but there was no significant difference in the reduction of M2BPGi among the EGV-improvement, EGV-invariant, and EGV-exacerbation groups (p=0.659). CONCLUSIONS: M2BPGi levels may be a novel serum marker for the presence of EGV before and after DAA treatment.

DOI： 10.1016/j.aohep.2020.04.002

PubMed

DOI： 10.1007/s12072-020-10051-z

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70-0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection.

DOI： 10.3390/ijms21124517

PubMed

DOI： 10.1089/ars.2019.7868

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms21113863

PubMed

DOI： 10.2957/kanzo.61.244

CiNii Article

DOI： 10.1007/s10620-019-06035-1

PubMed

DOI： 10.1038/s41598-020-63866-z

PubMed

DOI： 10.1007/s12072-020-10028-y

PubMed

慢性肝疾患患者における痒みの実態を明らかにするために、患者および看護師にアンケート調査を実施した。慢性肝疾患患者のべ1,043名のうち380名(36.4%)が痒みありと回答し、80%以上は夜間に痒みを感じていた。特に肝硬変で痒みの自覚が多かった(P<0.01)が、治療介入されていたのは半数以下であった。一方、看護師が考える「痒みのある患者」の割合は24%であり、痒みの問診頻度も低かった。これら結果をもとに、痒みの問診方法を見直したところ、看護師による痒みの把握、医師への処方依頼は増加した。慢性肝疾患の痒みに対する積極的な治療介入のためには、医療者の痒みに対する理解、かつ、医療者間の連携が不可欠である。(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

In hepatocellular carcinoma (HCC), the clinical significance of soluble immune checkpoint protein levels as predictors of patient outcomes or therapeutic responses has yet to be defined. This study profiled the baseline levels of sixteen soluble checkpoint proteins and their changes following sorafenib treatment for HCC. Plasma samples were obtained from 53 patients with advanced HCC at baseline, week 1, 2 and 4 of sorafenib treatment and tested the concentrations of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays. Multivariate analysis showed high sBTLA levels at baseline were an independent predictor of poor overall survival (p = 0.038). BTLA was highly expressed in T cells and macrophages in peritumoral areas. At week 2, sCD27 levels were decreased compared to baseline. By contrast, the concentrations of most inhibitory proteins, including sBTLA, sLAG-3, sCTLA-4, sPD-1, sCD80, sCD86 and sPD-L1, had significantly increased. The fold-changes of soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86, sPD-1 with sPD-L1; and the fold-changes of sCTLA-4 with sBTLA or sPD-1 were positively correlated. sBTLA may be a good biomarker for predicting overall survival in HCC patients. Sorafenib treatment in patients with advanced HCC revealed dynamic changes of soluble checkpoint protein levels.

DOI： 10.1038/s41598-020-60440-5

PubMed

DOI： 10.1038/s41598-019-56842-9

PubMed

妊娠中に慢性B型肝炎に対してテノホビルジソプロキシルフマル酸塩(TDF)が投与された日本人妊婦5例(21歳、30歳、31歳、27歳、41歳)について報告した。全例でTDF 300mgを1日1回経口投与した。2例は、B型肝炎ウイルス母子感染予防についての全国プログラムが導入された1986年以降の出生であった。エンテカビル投与歴がある妊婦、ヌクレオシドアナログ投与歴のない妊婦のいずれにおいても、TDFはB型肝炎ウイルス(HBV)複製を抑制し、重篤な有害事象は認めなかった。全例が妊娠39〜41週で分娩した。TDFに関連すると思われる症状や分娩異常は認めなかった。出生児5例のすべてにおいて、先天性障害、成長障害、HBV感染を認めなかった。慢性B型肝炎を有する妊婦において、TDF投与は安全かつ有効であることが示された。

DOI： 10.11405/nisshoshi.117.52

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>The appropriate management of hepatitis B virus (HBV) infection during pregnancy has not been established in Japan. We herein report five HBV-infected pregnant Japanese women who received tenofovir disoproxil fumarate (TDF). Two of them had been born after the introduction of nationwide immunoprophylaxis and were vertically infected with HBV, highlighting the need to address mother-to-child transmission further. In both entecavir-experienced and nucleoside/nucleotide analog-naïve mothers, TDF suppressed HBV replication without serious adverse events. All five children were free from congenital disorders, growth impairment, and HBV infection. TDF showed safety and efficacy for pregnant woman with chronic hepatitis B and might have helped prevent mother-to-child transmission. </p>

DOI： 10.2169/internalmedicine.3504-19

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.13410

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.13190

PubMed

DOI： 10.1002/hep.30552

PubMed

慢性C型慢性肝炎ウイルス(HCV)感染患者に対するグレカプレビル+ピブレンタスビル併用療法の有効性をITT分析により評価し、この直接作用型抗ウイルス(DAA)療法開始後に治療を中止した患者の特性について検討した。本レジメンを8週間1日1回投与したHCV感染患者群246例(A群:男性129例、女性117例、年齢24〜89歳)と、12週間投与した患者群177例(B群:男性99例、女性78例、年齢26〜88歳)を対象とした。抗HCV作用の有効性は、治療後12週間の持続性ウイルス陰性化(SVR12)と定義した。評価は、ITT群および同群からSVR12評価前に治療を中止した患者を除いた群(修正ITT集団)で行った。ITT群では、A群の220例(89%)、B群の164例(90%)がSVR12を達成した。治療中止患者は30例(A群24例、B群6例)で、主として男性およびHCV遺伝子型(GT)2保有の患者であった。DAA未治療のGT1保有患者は全てSVR12を達成した。B群では修正ITT集団において、GT保有2患者41例全例がSVR12を達成した。治療中139例に有害事象(AE)が見られ、このうち7例が重篤なAEで4例が75歳以上であった。本レジメンは、GT1およびGT2患者で顕著な抗HCV効果を示したが、GT-3b患者では効果は見られなかった。また高齢者には十分な注意が必要であった。

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.13190

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIMS: We assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world. METHOD: A total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300 mg) and pibrentasvir (120 mg) were given once daily for 8 weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or -2, and for 12 weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12 weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population). RESULTS: In the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects were more than 75 years old. CONCLUSIONS: Glecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.

DOI： 10.1111/hepr.13410

PubMed

症例1は55歳男性で、C型肝炎治療のため入院した。静注薬物乱用の既往があった。HCVの遺伝型は1b、HCV RNAは5.6log IU/mLであった。オムビタスビル(25mg)、パリタプレビル(150mg)、リトナビル(100mg)の配合剤を12週間投与した。投与開始から4週間後にHCV-RNAは検出限界未満となったが、12週間後に陽性となり再燃を認めた。治療失敗時におけるHCVの遺伝型は2aで、治療開始時と異なった。精査の結果、患者は1b型と2a型を有していた。2a型HCVのNS5A領域でDAA剤による薬剤耐性変異が検出された。グレカプレビル(100mg)とピブレンタスビル(40mg)を12週間投与し、SVR12を達成した。症例2は60歳女性で、HCVの遺伝型は2a、HCV RNAは5.7log IU/mLであった。ソホスブビル(400mg)とリバビリン(600mg)を12週間投与した。SVR24を達成したが、48週間後に再燃を認めた。パートナーがHCV感染者であった。その後HCV-RNAは低下し、ALT値も正常化した。パートナーはソホスブビル/リバビリンによりSVRを達成した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

We experienced two patients with chronic hepatitis C (HCV) in whom it was difficult to distinguish between relapse and reinfection after interferon-free direct-acting antiviral (DAA) therapy. Case 1 was a 55-year-old man infected with HCV genotype 1b, at 5.6 log IU/mL, with a history of injecting drug use. He was treated with ombitasvir/paritaprevir/ritonavir for 12 weeks. After DAA therapy, recurrent HCV showed the genotype 2a differed from the baseline genotype. Close examination for baseline sample showed that he was coinfected with HCV genotype 1b and 2a. Case 2 was a 60-year-old woman with HCV2b, at 5.7 log IU/mL. She was treated with sofosbuvir/ribavirin for 12 weeks and achieved a sustained virological response (SVR) at 24 weeks. Even after SVR24, her serum alanine aminotransferase levels remained fluctuated. HCV RNA was detected again at 48 weeks. She had a sexual partner who was also infected with HCV2b. The phylogenetic tree analysis revealed a high degree of homology among the three strains: pre- and post-HCV treatment, and her partner. After HCV recurrence, HCV RNA level decreased spontaneously below the limit of detection and serum ALT levels normalized. It is important to make a precise diagnosis regarding reemerged HCV after DAA therapy.

DOI： 10.1007/s12328-019-01001-w

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection patients (CH) results in a sustained viral response (SVR) in over 95% of patients. However, hepatocellular carcinoma (HCC) occurs in 1-5% of patients who achieved an SVR after treatment with interferon. We attempted to develop a minimally invasive and highly reliable method of predicting the occurrence and recurrence of HCC in patients who achieved an SVR with DAA therapy. The exosomal miRNA expression patterns of 69 CH patients who underwent HCC curative treatment and 70 CH patients were assessed using microarray analysis. We identified a miRNA expression pattern characteristic of SVR-HCC by using machine learning. Twenty-five of 69 patients had HCC recurrence. The expression of four exosomal miRNAs predicted HCC recurrence with 85.3% accuracy. Fifteen of 70 patients had HCC occurrence. The expression of four exosomal miRNAs predicted the onset of HCC with 85.5% accuracy. The expression patterns of miR-4718, 642a-5p, 6826-3p, and 762 in exosomes were positively correlated with those in the liver, and downregulation of these miRNAs induced cell proliferation and prevented apoptosis in vitro. Aberrant expression of four miRNAs, which was used for prediction, was associated with HCC onset after HCV eradication. Expression patterns of exosomal miRNAs are a promising tool to predict SVR-HCC.

DOI： 10.3390/biomedicines7040087

PubMed

<p>Sarcoidosis is typically characterized by the presence of lesions in the lungs, heart, eyes, and skin. However, in some cases, lesions have also been found in the liver. Although the diagnosis of hepatic sarcoidosis is difficult, liver biopsy can occasionally offer a definite diagnosis when blood test results indicate liver dysfunction of an unknown etiology. We encountered five cases of hepatic sarcoidosis at our hospital that were diagnosed based on liver dysfunction and compared these cases with previously reported cases. In our case series, hepatic sarcoidosis was predominantly diagnosed in middle-aged women, and biliary enzymes were elevated in most cases. Corticosteroids, ursodeoxycholic acid, or both were used for treatment. Despite the application of these therapies, some patients progressed to showing cirrhosis or even died. Thus, in cases with severe hepatitis, steroid therapy may not be effective and cirrhosis may develop. Moreover, the findings suggest that ursodeoxycholic acid can help in delaying the progression of hepatic sarcoidosis.</p>

DOI： 10.2957/kanzo.60.405

CiNii Article

サルコイドーシスは肺、心臓、眼、皮膚等に病変が見られることが多いが、肝臓に病変を有する症例も存在する。肝サルコイドーシスの診断はしばしば難渋することが多いが、肝機能障害が契機となり、確定診断には肝生検が有用である。今回、当院にて肝機能障害を契機に診断されたサルコイドーシスの5例を既報例と併せて検討した。頻度は中年女性に多く、多くの症例でALP異常優位の肝機能障害を認めた。治療としてステロイドやウルソデオキシコール酸が用いられたが、肝硬変へ進展し死亡する症例も認められた。組織学的に炎症が強い場合、ステロイド投与にも関わらず肝硬変へ進展する症例がある。またウルソデオキシコール酸には病状の進行を遅延させる可能性が示唆されている。(著者抄録)

J-GLOBAL

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12328-019-00983-x

PubMed

DOI： 10.1111/jgh.14595

PubMed

症例は59歳男性で、2年前に肝硬変および両肝葉の多発性肝細胞癌(HCC)と診断された。HCCは切除不能であり、Barcelona Clinic Liver Cancer分類の進行期であった。B型肝炎(HB)ウイルス表面抗原は陽性であった。最初の外来診察でHBe抗原陰性、HBe抗体陽性であり、エンテカビルの投与を開始した。HCCに対してシスプラチン(CDDP)を用いた肝動脈化学塞栓療法および肝動注化学療法を行ったが、CDDPに対してアレルギー反応が起こった。ソラフェニブの投与を開始したが、CTにてHCCの増大と左肺転移が認められたため、レゴラフェニブに変更した。その後、HCCの進行が認められたためレゴラフェニブの投与を中止した。その時点のCTで両下肺野の網状影が示唆された。レンバチニブ投与により部分奏効となったが、グレード3の労作時呼吸困難となり投与を中止した。胸部CTにて両下肺野の網状影の増大が認められ、間質性肺炎の治療のため入院した。低酸素血症とKL-6値の上昇が続いた。肺炎の原因となりうる自己抗体の陽性反応はなく、血液および痰培養、CTから感染性である証拠は示されなかった。チロシンキナーゼ阻害剤に起因する急性間質性肺炎が疑われたため、ステロイドパルス療法を行った。ステロイド療法を開始してから1週間以内に呼吸状態と低酸素血症が徐々に改善し、両下肺野の網状影の濃度が低下した。2週間ごとにステロイドの投与量を徐々に減らし、32日目に退院した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Recently, three tyrosine kinase inhibitors (TKIs) have become available for treatment of unresectable hepatocellular carcinoma (HCC). We herein report a case of a 59-year-old man with interstitial pneumonia that was suspected during regorafenib administration and was exacerbated by subsequent lenvatinib treatment for advanced HCC. After sorafenib was discontinued due to progressive HCC, regorafenib treatment was started. Progressive HCC was again noted and reticular shadows were suspected in both lower lung fields at 2 months after starting regorafenib administration. Subsequent treatment with lenvatinib obtained a partial response for HCC, but the reticular shadows became marked and dyspnea on effort emerged, followed by hypoxemia and an increased Krebs von den Lungen-6 (KL-6) value. Because we suspected acute interstitial pneumonia, due to these TKIs, intravenous pulse steroid therapy was started immediately after discontinuing lenvatinib. Within 1 week after starting steroid therapy, the patient's respiratory condition and hypoxemia gradually began improving. No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported. This case emphasizes that it is necessary to observe the patient's respiratory condition and to perform imaging examinations to monitor for adverse events during TKI treatment.

DOI： 10.1007/s12328-019-00983-x

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10388-019-00662-3

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

No controlled trial in patients with chronic hepatitis B virus (HBV) infection on long-term entecavir (ETV) treatment, comparing switching to tenofovir disoproxil fumarate (TDF) with continuing the therapy, has been reported. Twenty-seven nucleos(t)ide-naïve patients with chronic HBV who underwent ETV therapy for ≥5 years and maintained virological response were included and randomized into two groups: one group continued ETV, and the other switched to TDF, in a 1:2 ratio. The primary endpoint was changed from baseline in serum hepatitis B surface antigen (HBsAg) level at week 48. The baseline characteristics were not different between nineteen patients in the TDF group and eight patients in the ETV group. Mean decreases in HBsAg level at week 48 were 0.023 and 0.042 log10  IU/mL in the TDF and ETV groups, respectively (P = 0.94). The mean drops in hepatitis B core-related antigens were also not different between the TDF and ETV groups at week 48 (P = 0.80). HBV DNA was sustainedly <2.1 log 10  copies/mL in all patients throughout the study period. In contrast, the mean aminotransferase levels were significantly higher in the TDF group than in the ETV group at weeks 12, 24, and 36, although being within the reference range. Estimated glomerular filtration rate was lower in the TDF group than in the ETV group at weeks 24 (P = 0.016) and 48 (P = 0.003). In conclusion, we could not find the effect on reducing HBsAg level by switching to TDF in chronic hepatitis B patients with maintained virological response to ETV for ≥5 years.

DOI： 10.1002/jmv.25442

PubMed

食道好酸球浸潤(EE)の非アレルギー性危険因子について横断研究により検討した。健康診断において消化管内視鏡検査を受けた被検者を対象とした。EE被験者(男性15名、女性12名、年齢中央値45歳)と非EE被験者(男性2803名、女性3134名、年齢中央値51歳)の臨床的特徴を比較した。EEの検出率は0.45%であった。EE被験者の20名は症候性、7名は無症候性であった。単変量解析の結果、非EE被験者と比較してEE被検者はBMIが有意に高かった。内視鏡所見において、EE被検者は裂孔ヘルニアの割合が有意に高かった。EE被検者は年齢が有意に若く、気管支喘息の割合が高かった。多変量解析の結果、非EE被験者と比較してEE被検者はBMIおよび裂孔ヘルニアと正に関連していた。傾向検定において、高いBMI分類は有意なEE有病率増加傾向を示した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

There have been a few reports on the treatment of patients infected with recombinant hepatitis C virus (HCV) genotype 2/1 strains with direct-acting antivirals (DAAs). We experienced three patients, with genotype 2/1 recombinant HCV, treated with DAAs successfully. The first, a 39-year-old man, was infected with recombinant HCV genotype 2a/1b, a rare variant. The sequence of the relapsed virus showed chimeric HCV 2a/1b with the recombinant breakpoint found at nucleotide +49 from the start of the NS3 region. Sofosbuvir plus ribavirin, a regimen recommended for HCV genotype 2, did not lead to a sustained viral response (SVR). Retreatment with grazoprevir plus elbasvir resulted in an SVR. The second case, a 70-year-old woman, was infected with recombinant HCV genotype 2b/1b. DAA therapy with sofosbuvir plus ledipasvir resulted in an SVR. The third case, a 48-year-old woman, was also infected with recombinant HCV genotype 2b/1b. DAA therapy with daclatasvir plus asunaprevir resulted in an SVR. The baseline sequences of the viruses from both the second and third cases showed chimeric HCV 2b/1b with the recombinant breakpoint found at nucleotide +10 from the NS3 start. We report three cases with 2/1 chimeras and discuss the prevalence and response to therapy.

DOI： 10.1007/s12328-018-0922-9

PubMed

直接作用型抗ウイルス剤(DAA)投与が奏効したジェノタイプ2/1組み換えC型肝炎ウイルス(HCV)患者3例を報告した。症例1は39歳男性で、慢性C型肝炎に対しインターフェロンベースの治療を行ったが無効であった。当院に紹介され、組み換えHCVジェノタイプ2a/1bへの感染を認めた。再燃ウイルスはキメラHCV2a/1bであり、組み換えブレイクポイントはNS3領域開始のヌクレオチド+49に認めた。グラゾプレビルとエルバスビルを投与したところ、持続性ウイルス学的著効(SVR)に至った。症例2は70歳女性で、組み換えHCVジェノタイプ2b/1bに感染し、ソホスブビルとレジパスビルによるDAA療法によりSVRを得た。症例3は48歳女性で、組み換えHCVジェノタイプ2b/1bに感染し、ダクラタスビルとアスナプレビルによるDAA治療を実施しSVRに至った。症例2と症例3からのウイルスのベースライン配列は組み換えブレイクポイントがNS3からヌクレオチド+10のキメラHCV 2b/1bを示した。

DOI： 10.15106/j_naika123_1081

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s11010-018-3466-x

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.14454

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.14454

PubMed

Other URL： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jgh.14454

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Senescent hepatic stellate cells (senescent HSCs) are found in patients with liver cirrhosis and have been thought to be involved in the development of hepatocellular carcinoma (HCC) in mice via the senescence-associated secretory proteins. However, in humans, which secretory proteins are involved and what regulate their expression remain unclear. In the current study, we characterized senescence-associated β-galactosidase-positive senescent human HSCs (hHSCs) induced by repetitive passaging. They exhibited enhanced expression of 14 genes for secretory protein and persistent phosphorylation of ERK1/2 protein but not JNK or p38 MAPK proteins. Enhanced nuclear ERK1/2 phosphorylation was observed in senescent hHSCs. Treatment of the senescent hHSCs with ERK1/2 inhibitor, SCH772984, significantly decreased the levels of angiopoietin like 4 (ANGPTL4), C-C motif chemokine ligand 7 (CCL7), Interleukin-8 (IL-8), platelet factor 4 variant 1 (PF4V1), and TNF superfamily member 15 (TNFSF15) mRNA levels in a dose-dependent manner. The enhanced phosphorylation of ERK1/2 and expression of ANGPTL4, IL-8 and PF4V1 genes were observed in both of senescent human dermal fibroblasts and X-ray-induced senescent hHSCs. However, transient ERK1/2 activation induced by epidermal growth factor could not mimic the gene profile of the senescent hHSCs. These results revealed involvement of ERK1/2 signaling in the regulation of senescence-associated secretory factors, suggesting that simultaneous induction of ANGPTL4, IL-8, and PF4V1 genes is a marker of hHSC senescence. This study will contribute to understanding roles of senescent hHSCs in liver diseases.

DOI： 10.1007/s11010-018-3466-x

PubMed

DOI： 10.1002/hep4.1331

PubMed

Publishing type：Research paper (scientific journal)  

<p><b>Objective </b>The association between functional dyspepsia (FD) and endoscopic findings has not been fully elucidated. <i>Helicobacter pylori</i> infection is considered a key factor in the pathophysiology of FD. The Kyoto Classification of Gastritis (KCG) was proposed in 2014 to evaluate endoscopic findings based on the <i>H. pylori</i> status. We investigated the endoscopic findings associated with FD according to the KCG. </p><p><b>Methods </b>This cross-sectional study included subjects who underwent esophagogastroduodenoscopy during a medical health check-up. We compared the endoscopic findings between subjects with FD and healthy controls (HCs) according to the KCG. </p><p><b>Results </b>A total of 456 subjects were analyzed. Among them, the detection rate of FD was 5.5% (25/456 persons). In a univariate analysis of the endoscopic findings, a significantly lower proportion of subjects with FD had gastric red streak in comparison to HCs (0% vs. 18.6%, respectively; p=0.0124). Subjects with FD were more likely to have gastric depressive erosion (20.0% vs. 7.9%; p=0.0522). A higher proportion of the erosion-positive subjects had FD in comparison to erosion-negative subjects (12.8% vs. 4.8%). There were no significant differences in the other endoscopic findings, including gastric atrophy, intestinal metaplasia, enlarged fold, nodularity, and diffuse redness. A multivariate analysis revealed that gastric depressive erosion was significantly and independently associated with FD (odds ratio, 2.92; 95% confidence interval, 1.03-8.26; p=0.0436). In contrast, gastric red streak was not associated with FD (p=0.989). </p><p><b>Conclusion </b>Gastric depressive erosions may be associated with dyspepsia. </p>

DOI： 10.2169/internalmedicine.1325-18

PubMed

CiNii Article

機能性ディスペプシア(FD)の自験例を対象に、FDに関連する内視鏡所見を胃炎の京都分類に従って調査する横断研究を施行した。当院にて上部消化管内視鏡検査を施行された健診受診者のうち、器質的疾患がみられた例などを除外した456名を解析対象とした。そのうち5.5%に当たる25名(女性14名、年齢中央値47.0歳)がFDと診断され(罹患群)、残りの431名は健康と判定された(健康対照群)。両群の内視鏡検査所見を単変量解析にて比較した結果、稜線状発赤がみられた被験者の割合は罹患群で0%、健康対照群で18.6%と罹患群の方が有意に低く、逆に陥凹型びらんの割合はそれぞれ20.0%、7.9%と罹患群の方が高く、そのp値は0.0522であった。びらんが陽性の集団におけるFD罹患者の割合は12.8%で、びらん陰性集団での4.8%よりも高かった。胃炎の京都分類に記載されているその他の内視鏡所見に関しては両群間で有意差は示されなかった。単変量解析で関連性が示された2種の所見に関し多変量解析を行ったところ、陥凹型びらん所見陽性のみがFD罹患に対する独立関連因子であることが有意に示された(オッズ比2.92、95%信頼区間1.03〜8.26)。以上の結果から、陥凹型びらん所見はFDと関連していると考えられた。

DOI： 10.1016/j.humpath.2018.08.016

PubMed

Publishing type：Research paper (scientific journal)  

<p><b>Objective </b>The association between functional dyspepsia (FD) and endoscopic findings has not been fully elucidated. <i>Helicobacter pylori</i> infection is considered a key factor in the pathophysiology of FD. The Kyoto Classification of Gastritis (KCG) was proposed in 2014 to evaluate endoscopic findings based on the <i>H. pylori</i> status. We investigated the endoscopic findings associated with FD according to the KCG. </p><p><b>Methods </b>This cross-sectional study included subjects who underwent esophagogastroduodenoscopy during a medical health check-up. We compared the endoscopic findings between subjects with FD and healthy controls (HCs) according to the KCG. </p><p><b>Results </b>A total of 456 subjects were analyzed. Among them, the detection rate of FD was 5.5% (25/456 persons). In a univariate analysis of the endoscopic findings, a significantly lower proportion of subjects with FD had gastric red streak in comparison to HCs (0% vs. 18.6%, respectively; p=0.0124). Subjects with FD were more likely to have gastric depressive erosion (20.0% vs. 7.9%; p=0.0522). A higher proportion of the erosion-positive subjects had FD in comparison to erosion-negative subjects (12.8% vs. 4.8%). There were no significant differences in the other endoscopic findings, including gastric atrophy, intestinal metaplasia, enlarged fold, nodularity, and diffuse redness. A multivariate analysis revealed that gastric depressive erosion was significantly and independently associated with FD (odds ratio, 2.92; 95% confidence interval, 1.03-8.26; p=0.0436). In contrast, gastric red streak was not associated with FD (p=0.989). </p><p><b>Conclusion </b>Gastric depressive erosions may be associated with dyspepsia. </p>

DOI： 10.2169/internalmedicine.1325-18

PubMed

CiNii Article

<p>Sarcoidosis is typically characterized by the presence of lesions in the lungs, heart, eyes, and skin. However, in some cases, lesions have also been found in the liver. Although the diagnosis of hepatic sarcoidosis is difficult, liver biopsy can occasionally offer a definite diagnosis when blood test results indicate liver dysfunction of an unknown etiology. We encountered five cases of hepatic sarcoidosis at our hospital that were diagnosed based on liver dysfunction and compared these cases with previously reported cases. In our case series, hepatic sarcoidosis was predominantly diagnosed in middle-aged women, and biliary enzymes were elevated in most cases. Corticosteroids, ursodeoxycholic acid, or both were used for treatment. Despite the application of these therapies, some patients progressed to showing cirrhosis or even died. Thus, in cases with severe hepatitis, steroid therapy may not be effective and cirrhosis may develop. Moreover, the findings suggest that ursodeoxycholic acid can help in delaying the progression of hepatic sarcoidosis.</p>

DOI： 10.2957/kanzo.60.405

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-018-36215-4

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Cytoglobin (CYGB), discovered in hepatic stellate cells (HSCs), is known to possess a radical scavenger function, but its pathophysiological roles remain unclear. Here, for the first time, we generated a new transgenic (TG) mouse line in which both Cygb and mCherry reporter gene expression were under the control of the native Cygb gene promoter. We demonstrated that the expression of Cygb-mCherry was related to endogenous Cygb in adult tissues by tracing mCherry fluorescence together with DNA, mRNA, and protein analyses. Administration of a single dose (50 mg/kg) of thioacetamide (TAA) in Cygb-TG mice resulted in lower levels of alanine transaminase and oxidative stress than those in WT mice. After 10 weeks of TAA administration, Cygb-TG livers exhibited reduced neutrophil accumulation, cytokine expression and fibrosis but high levels of quiescent HSCs. Primary HSCs isolated from Cygb-TG mice (HSCCygb-TG) exhibited significantly decreased mRNA levels of α-smooth muscle actin (αSMA), collagen 1α1, and transforming growth factor β-3 after 4 days in culture relative to WT cells. HSCsCygb-TG were resistant to H2O2-induced αSMA expression. Thus, cell-specific overexpression of Cygb attenuates HSC activation and protects mice against TAA-induced liver fibrosis presumably by maintaining HSC quiescence. Cygb is a potential new target for antifibrotic approaches.

DOI： 10.1038/s41598-018-36215-4

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00280-018-3681-x

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

PURPOSE: This study aimed to identify a biomarker for predicting the response to sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: Of 100 patients with unresectable HCC who received sorafenib treatment in our institute (Cohort A), 48 had stored plasma samples collected within 28 days before the start of treatment (Cohort B). Concentrations of 18 plasma cytokines were measured in plasma samples using a sandwich immunoassay with multiplexed fluorescent bead-based technology. Among 27 patients with follow-up plasma samples taken at 5-10 days of treatment (Cohort C), changes in the 18 cytokines were also evaluated. RESULTS: In Cohort A, progressive disease (PD) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) was associated with poor overall survival by multivariate analysis (p = 0.024). In Cohort B, no significant differences in baseline concentrations of α-fetoprotein, des-γ-carboxy prothrombin, or the 18 cytokines were found between patients with PD and those with stable disease (SD) or partial response (PR). In Cohort C, the increase in interleukin-8 and tumor necrosis factor-α (TNF-α) was significant in the PD group (p = 0.0063 and p < 0.001, respectively) but not in the SD + PR group (p = 0.67 and p = 0.15, respectively). In addition, the fold changes in interleukin-8 and in TNF-α were correlated (p < 0.001, r = 0.67). CONCLUSIONS: Changes in plasma interleukin-8 and TNF-α levels during the first few days could predict the response to sorafenib therapy in HCC patients.

DOI： 10.1007/s00280-018-3681-x

PubMed

DOI： 10.1177/2050640618791053

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/liv.13685

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000486902

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MD.0000000000011765

PubMed

Publishing type：Research paper (scientific journal)  

Tc-99m-galactosyl human serum albumin (GSA) scintigraphy is used to assess the hepatic functional reserve, and allows for visual assessment of the residual hepatocyte distribution on single-photon emission computed tomography/computed tomography (SPECT/CT) images. The association between heterogeneous liver uptake of Tc-99m-GSA and liver fibrosis remains to be studied in detail. We analyzed this association.Fifty-one patients with chronic hepatobiliary disease undergoing a Tc-99m-GSA scintigraphy were included in this study. The receptor (LHL15) and blood clearance (HH15) indexes (the uptake ratios of the liver and heart) were obtained from dynamic planar images. The liver uptake count maximum-to-mean ratio (LUC Max/Mean) was calculated from single-photon emission computed tomography/computed tomography (SPECT/CT) images as an indicator of the Tc-99m-GSA liver uptake heterogeneity. We assessed the relationship between these quantified values and liver fibrosis.There were 30 Child-Pugh classification grade A patients, 16 grade B patients, and 5 grade C patients. Among the 30 patients whose liver histopathology was evaluable, those with advanced liver fibrosis (F2-4) had a lower LHL15 than those with mild liver fibrosis (F0-1) (median, 0.90 vs. 0.92, P=.04), and a higher LUC Max/Mean (median, 1.80 vs. 1.70, P=.02). The multivariate analysis identified platelets (P=.04) and the LUC Max/Mean (P=.04) as contributing factors of advanced liver fibrosis.These findings suggest that Tc-99m-GSA SPECT/CT can be used not only to assess the hepatic functional reserve, but also to evaluate a degree of liver fibrosis.

DOI： 10.1097/MD.0000000000011765

PubMed

DOI： 10.11477/mf.1542201610

Publishing type：Research paper (scientific journal)  

<p> B型，C型慢性肝疾患の治療はめざましい進歩を遂げ，肝炎ウイルスの制御が可能となった．しかしながら，肝硬変，アルコール性・非アルコール性脂肪肝炎（non-alcoholic steatohepatitis：NASH），原発性胆汁性胆管炎や原発性硬化性胆管炎等肝線維化が鍵となる疾患に対する治療はunmet medical needsにとどまっている．これを解決するためには，肝線維化の病態を分子細胞論的に細密に解析し，その情報をもとにした標的治療薬の開発が必須である．肝臓における細胞外マトリックス物質（extracellular matrix materials：ECMs）の産生細胞は星細胞や門脈周囲の線維芽細胞が主体であり，それらが活性化すると筋線維芽細胞（myofibroblast：MFB）として線維化の増幅のみならず，炎症や免疫反応制御，さらには肝癌の微小環境構成の主役となる．従って，肝線維化の治療には，肝細胞障害の阻止と同時に活性化星細胞の機能制御が必要である．近年，線維化誘導分子の解析が進展し，それらをターゲットとした臨床試験が始まっている．</p>

DOI： 10.2169/naika.107.938

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.7326/L17-0613

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.7326/L17-0613

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Aim: The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB). Methods: In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36–52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks. Results: A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient. Conclusion: The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.

DOI： 10.1111/hepr.13050

PubMed

日本人B型肝炎エンベロープ抗原(HBeAg)陽性または陰性慢性B型肝炎(CHB)患者における、エンテカビルからペグインターフェロンα(Peg-INFα)への早期切り替えを伴う逐次療法の有効性を評価した。更に、本療法に対して持続的応答を示す患者(応答患者)と示さない患者(非応答患者)の特性を比較した。HBeAg陽性CHB患者14例と陰性CHB患者10例に対し、エンテカビルを36〜52週、その後エンテカビルとPeg-IFNα2aを4週間、最後にPeg-IFNα2aを44週間それぞれ投与した。患者は少なくとも48週経過観察し、治療に対する血清アラニンアミノトランスフェラーゼの減少による生化学的応答、B型肝炎ウイルスDNAの減少によるウイルス学的応答、血清HBeAgの消失による血清学的応答を評価した。治療後48週における各持続的治療応答は、HBeAg陽性患者14%(2/14例)、HBeAg陰性患者50%(5/10例)で達成された。応答患者は、非応答患者よりもベースラインにおけるγ-グルタミルトランスフェラーゼ値が有意に低く、アスパラギン酸アミノトランスフェラーゼ-血小板比率とα-フェトプロテインも低かった。応答患者における、最初の24週間のPeg-IFNα2a治療中でのB型肝炎表面抗原(HBsAg)の減少は、非応答患者よりも大きかった。HBsAgの血清クリアランスは、両群の患者で1例ずつ達成した。本逐次療法の治療成績は満足すべきものではなかった。またウイルス因子、宿主代謝特性などが、治療に対する持続的応答予測に利用可能であるが、正確な予測は困難であった。

DOI： 10.14740/jocmr3374w

PubMed

Publishing type：Research paper (scientific journal)  

It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naïve patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P =.0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P =.0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naïve patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy.

DOI： 10.1111/jvh.12850

PubMed

Publishing type：Research paper (scientific journal)  

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level &lt
2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P =.79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level &lt
2000 IU/mL before DAA therapy.

DOI： 10.1111/jvh.12840

PubMed

DOI： 10.1124/dmd.118.080408

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)   Kind of work：Single Work  

DOI： 10.2169/naika.107.938

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000491637

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000486902

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0201423

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVE: Pancreatic cancers are characterized by dense stroma. To estimate the degree of interference by coexisting noncancer cells in molecular analyses, we aimed to develop a DNA methylation marker that assesses a cancer cell fraction in DNA samples. METHODS: The microarray data of 22 pancreatic cancer tissues from the The Cancer Genome Atlas database and 9 noncancer tissues were used for genome-wide screening. Thirty-one surgical tumor samples (10 intraductal papillary mucinous neoplasms [IPMNs] and 21 pancreatic cancers), 4 normal, and 26 nontumor samples were used for validation. Gene-specific methylation analysis was conducted by bisulfite pyrosequencing. RESULTS: Genome-wide screening isolated SIM1, MIR129-2, NR1I2, and HOXB-AS4, as specifically methylated in pancreatic cancer cells. Bisulfite pyrosequencing validated that one or more of three genes (SIM1, MIR129-2, and NR1I2) were methylated in 22 (71.0%) tumor samples (8 IPMNs and 14 cancers), and all showed low levels of methylation in 26 (86.7%) normal and nontumor samples. Therefore, the three genes collectively constituted one marker for a pancreatic cancer cell fraction. The cancer cell fraction estimated by the marker was highly correlated with that estimated using the KRAS mutant allele frequency (R = 0.79). CONCLUSION: The DNA methylation marker is useful to estimate the pancreatic cancer cell fraction in DNA samples.

DOI： 10.1159/000491637

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

[This corrects the article DOI: 10.1371/journal.pone.0194163.].

DOI： 10.1371/journal.pone.0201423

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background: Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients. Methods: Of 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ±11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed. Results: At baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p &lt
0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group. Conclusion: Stagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.

DOI： 10.1371/journal.pone.0194163

PubMed

Introduction: Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-) is to prevent the development of end-stage liver diseases.Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017.Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon- is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.

DOI： 10.1080/17474124.2017.1361822

PubMed

Publishing type：Research paper (scientific journal)  

Cytoglobin (CYGB) belongs to the mammalian globin family and is exclusively expressed in hepatic stellate cells (HSCs) in the liver. In addition to its gas-binding ability, CYGB is relevant to hepatic inflammation, fibrosis, and cancer because of its anti-oxidative properties; however, the regulation of CYGB gene expression remains unknown. Here, we sought to identify factors that induce CYGB expression in HSCs and to clarify the molecular mechanism involved. We used the human HSC cell line HHSteC and primary human HSCs isolated from intact human liver tissues. In HHSteC cells, treatment with a culture supplement solution that included fibroblast growth factor 2 (FGF2) increased CYGB expression with concomitant and time-dependent -smooth muscle actin (SMA) down-regulation. We found that FGF2 is a key factor in inducing the alteration in both CYGB and SMA expression in HHSteCs and primary HSCs and that FGF2 triggered the rapid phosphorylation of both c-Jun N-terminal kinase (JNK) and c-JUN. Both the JNK inhibitor PS600125 and transfection of c-JUN-targeting siRNA abrogated FGF2-mediated CYGB induction, and conversely, c-JUN overexpression induced CYGB and reduced SMA expression. Chromatin immunoprecipitation analyses revealed that upon FGF2 stimulation, phospho-c-JUN bound to its consensus motif (5-TGA(C/G)TCA), located -218 to -222 bases from the transcription initiation site in the CYGB promoter. Of note, in bile duct-ligated mice, FGF2 administration ameliorated liver fibrosis and significantly reduced HSC activation. In conclusion, FGF2 triggers CYGB gene expression and deactivation of myofibroblastic human HSCs, indicating that FGF2 has therapeutic potential for managing liver fibrosis.

DOI： 10.1074/jbc.M117.793794

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Long-term surgical outcomes after hepatic resection for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in patients who achieved a sustained virological response (SVR) to interferon (IFN) therapy remain inconclusive. Clinical records of 277 patients who underwent hepatic resection for HCV-related early stage HCC (met the Milan criteria) between 1993 and 2012 were retrospectively reviewed. Thirty-seven patients achieved the SVR during HCC detection (pre-SVR group), whereas 23 achieved SVR using adjuvant interferon therapy after hepatic resection (post-SVR group). The control group included remaining 217 patients. We investigated the SVR effects on surgical outcomes. Disease-free survival (DFS) rates at 5/10/15 years after hepatic resection were significantly greater in the pre and post-SVR groups than in the control group (46/30/30per cent and 61/36/27 per cent vs 23/7/7 per cent, respectively; P &lt; 0.001). Overall survival (OS) rates at 10/15 years after hepatic resection were better in the pre-and post-SVR groups than in the control group (68/68 percent and 78/78 per cent vs 13/11 per cent, respectively; P &lt; 0.001). On multivariate analysis, pre-and post-SVR were independent factors for no recurrence (pre-SVR: hazard ratio (HR), 0.48, P = 0.002; post-SVR: HR, 0.41, P = 0.001) and improved survival (pre-SVR: HR, 0.36, P = 0.002; post-SVR: HR, 0.122, P &lt; 0.001). Achievement of SVR in patients with HCV-related HCC was associated with long-term disease-free survival and OS after hepatic resection.

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

In contrast to patients with viral hepatitis, patients with nonalcoholic fatty liver disease (NAFLD) can progress to hepatocellular carcinoma during the initial stages of liver fibrosis. Development and implementation of noninvasive methods for diagnosis and progression prediction are important for effective NAFLD surveillance. Mac-2 binding protein (Mac-2bp) is a useful nonalcoholic steatohepatitis (NASH) diagnosis biomarker and a powerful prediction biomarker for NAFLD fibrosis stage. Wisteria floribunda agglutinin (WFA)-positive Mac-2bp (WFA+-M2BP) is a novel serum fibrosis biomarker for chronic hepatitis C that has clinical validity. Mac-2bp and WFA+-M2BP are also clinical NAFLD biomarker candidates. We examined the efficacy of Mac-2bp and WFA+-M2BP for NAFLD assessment using patients with biopsy-proven NAFLD (n = 510; NAFLD cohort) and subjects who received a health check-up (n = 2,122; check-up cohort). In the NAFLD cohort, we set the fibrosis predicting cutoff values as 1.80 (F1), 2.21 (F2), and 2.24 μg/mL (F3). In the subjects with fatty liver from the check-up cohort (n = 1,291), the serum Mac-2bp levels were >1.80 μg/mL in 38.6% of the subjects (n = 498), and >2.24 μg/mL in 24.6% of the subjects (n = 318). The NAFLD cohort results indicated that Mac-2bp and WFA+-M2BP were equally useful for NASH diagnosis. During the early stages of fibrosis (F1, F2), the increase in Mac-2bp was statistically significant but WFA+-M2BP did not increase. Logistic regression analysis revealed that Mac-2bp was an independent determinant for the prediction of advanced fibrosis stage (≥F2), even when adjusted for WFA+-M2BP. Immunohistochemical staining of Mac-2bp revealed that hepatocytes strongly expressed Mac-2bp in patients with NAFLD. Conclusion: Our results indicated that hepatocyte-derived Mac-2bp would be a useful single biomarker for NASH diagnosis and fibrosis stage prediction in patients with NAFLD. (Hepatology Communications 2017;1:780-791).

DOI： 10.1002/hep4.1080

PubMed

DOI： 10.1161/ATVBAHA.117.309410

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Recently, the MICA rs2596542 and DEPDC5 rs1012068 variants in Japanese individuals as well as the HCP5 rs2244546 and PNPLA3 rs738409 variants in European individuals have been found associated with hepatocellular carcinoma (HCC). The present study determined which single nucleotide polymorphism (SNP) is the most predictive for developing hepatitis C virus (HCV)-related HCC in a Japanese cohort. Of the 4 SNPs analysed, only the MICA genotypes were significantly associated with development of HCC (p = 0.0185). The major (MA), hetero (HE), and minor (MI) genotypes occurred in 40%, 41%, and 19% of HCC patients and in 43%, 47%, and 10% of non-HCC patients, respectively. Interestingly, the MICA genotype was significantly correlated with MICA mRNA and soluble protein levels. In patients older than 70 years, the MI genotype was significantly associated with HCC development. In addition, the MI genotype was related to HCC development when the platelet count range was 10-15 x 10(4)/mu L, corresponding with the fibrosis stage; but not when the range was less than 10, indicating advanced fibrosis; or greater than 15 x 10(4)/mu L, as mild fibrosis. Thus, polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with HCC development in Japanese patients with chronic HCV infection.

DOI： 10.1038/s41598-017-10363-5

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbagen.2017.06.019

PubMed

Publishing type：Research paper (scientific journal)  

目的:人間ドックでの胃がん発見精度の評価方法として胃がん発見率が挙げられるが、母集団の性差、年齢分布により影響を受ける。そこで我々は標準化発見比を指標として用い、細径内視鏡を用いた当院人間ドックでの胃がん発見精度を調査した。方法:2016年1月4日から1年間、当院人間ドックで上部消化管内視鏡検査を施行された4,927例において、胃がんの標準化発見比、発見率等を検討した。結果:男性における胃がん存在期待値合計は3.48であり、胃がん発見症例数は13例であった。すなわち、男性での標準化発見比は3.74であった。特に65〜69歳では存在期待値0.95に対して7例の胃がんを発見した。一方、女性での胃がん存在期待値合計は1.12、胃がん発見症例数は1例であり、標準化発見比は0.89であった。また、男女合算では、存在期待値4.60に対して14例の胃がんを発見しており、標準化発見比は3.04であった。さらには、胃がん発見率は男女合算で0.28%、年代別に解析すると、50〜59歳では0.21%、60歳以上では0.78%であった。結論:当院での人間ドックにおいて、胃がんの標準化発見比を検討することにより、罹患率が高い年齢層で確実に胃がんの発見、診断がなされていることが示された。(著者抄録)

Publishing type：Research paper (scientific journal)  

Background. The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). Material and methods. A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). Results. The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cirrhotic patients (10/49
20.4%) than in non-cirrhotic patients (10/96
10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). Conclusion. RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.

DOI： 10.5604/01.3001.0010.2732

PubMed

Publishing type：Research paper (scientific journal)  

Background Tensioned collagen gels with dermal fibroblasts (DFs) as a dermis model are usually utilized in a static culture (SC) that lacks medium flowing. To make the model closer to its in vivo state, we created a device to perfuse the model with media flowing at a physiological velocity and examined the effects of medium flow (MF) on the cultures. Methods We constructed a medium perfusion device for human DF-embedded stretched collagen gels (human dermis model), exposed the model to media that flows upwardly at ~ 1 mL/day, and examined water retention of the gels, cells' growth ability, metabolic activity, expression profiles of nine extracellular matrix (ECM)-related genes. The obtained data were compared with those from the model in SC. Results MF increases the gels' water retention and cells' growth potential but had little effect on their metabolic activities. MF robustly enhanced hyaluronan synthase 2 (HAS2) and matrix metalloprotease 1 (MMP1) gene expressions but not of the other genes (MMP2, HYAL1, HYAL2, HYAL3, COL1A1, COL3A1, and CD44). MF significantly increased the amounts of cellular hyaluronan and adenosine triphosphate. Conclusions The MF at a physiological speed significantly influences the nature of ECMs and their resident fibroblasts and remodels ECMs by regulating hyaluronan metabolism. General significance Fibroblasts in tensioned collagen gels altered their phenotypes in a MF rate-dependent manner. Collagen gel culture with tension and MF could be utilized as an appropriate in vitro model of interstitial connective tissues to evaluate the pathophysiological significance of mechanosignals generated by fluid flow and cellular/extracellular tension.

DOI： 10.1016/j.bbagen.2017.06.019

PubMed

目的:人間ドックでの胃がん発見精度の評価方法として胃がん発見率が挙げられるが、母集団の性差、年齢分布により影響を受ける。そこで我々は標準化発見比を指標として用い、細径内視鏡を用いた当院人間ドックでの胃がん発見精度を調査した。方法:2016年1月4日から1年間、当院人間ドックで上部消化管内視鏡検査を施行された4,927例において、胃がんの標準化発見比、発見率等を検討した。結果:男性における胃がん存在期待値合計は3.48であり、胃がん発見症例数は13例であった。すなわち、男性での標準化発見比は3.74であった。特に65〜69歳では存在期待値0.95に対して7例の胃がんを発見した。一方、女性での胃がん存在期待値合計は1.12、胃がん発見症例数は1例であり、標準化発見比は0.89であった。また、男女合算では、存在期待値4.60に対して14例の胃がんを発見しており、標準化発見比は3.04であった。さらには、胃がん発見率は男女合算で0.28%、年代別に解析すると、50〜59歳では0.21%、60歳以上では0.78%であった。結論:当院での人間ドックにおいて、胃がんの標準化発見比を検討することにより、罹患率が高い年齢層で確実に胃がんの発見、診断がなされていることが示された。(著者抄録)

Publishing type：Research paper (scientific journal)  

目的:人間ドックでの胃がん発見精度の評価方法として胃がん発見率が挙げられるが、母集団の性差、年齢分布により影響を受ける。そこで我々は標準化発見比を指標として用い、細径内視鏡を用いた当院人間ドックでの胃がん発見精度を調査した。方法:2016年1月4日から1年間、当院人間ドックで上部消化管内視鏡検査を施行された4,927例において、胃がんの標準化発見比、発見率等を検討した。結果:男性における胃がん存在期待値合計は3.48であり、胃がん発見症例数は13例であった。すなわち、男性での標準化発見比は3.74であった。特に65〜69歳では存在期待値0.95に対して7例の胃がんを発見した。一方、女性での胃がん存在期待値合計は1.12、胃がん発見症例数は1例であり、標準化発見比は0.89であった。また、男女合算では、存在期待値4.60に対して14例の胃がんを発見しており、標準化発見比は3.04であった。さらには、胃がん発見率は男女合算で0.28%、年代別に解析すると、50〜59歳では0.21%、60歳以上では0.78%であった。結論:当院での人間ドックにおいて、胃がんの標準化発見比を検討することにより、罹患率が高い年齢層で確実に胃がんの発見、診断がなされていることが示された。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.13743

PubMed

Publishing type：Research paper (scientific journal)  

Background and Aim: It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates to the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. This study investigated the effects of the ITPA polymorphism on Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy. Methods: In 106 patients treated with SOF/RBV therapy, this study assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response. Results: Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (P = 0.010). In multivariate analysis, age ≥ 65 years (P = 0.011) and the ITPA CC genotype (P &lt
 0.0001) were factors significantly associated with anemia throughout the treatment course. Sustained virological response was achieved in 99.0% of all patients: 98.7% of patients with the CC genotype and 100% of patients with a non-CC genotype. Conclusions: Inosine triphosphatase polymorphism appeared to correlate with anemia incidence and RBV dose reduction during SOF/RBV therapy, but not the clinical outcome. Careful monitoring of Hb concentrations and prompt adjustment of RBV doses are required for successful treatment, particularly in patients harboring the ITPA CC genotype or age ≥ 65 years.

DOI： 10.1111/jgh.13743

PubMed

当院で2014年9月から2016年8月までに直接作用型抗ウイルス薬治療を施行したC型慢性肝疾患患者616例及び2007年5月以降に経験したC型急性肝炎患者8例に対し、感染経路の実態を調査し再感染の可能性について検討した。616例のうち感染経路を推定しえた症例は372例(60.4%)であり、その内訳は輸血歴/手術歴/薬物使用歴/家族歴/刺青:189/279/30/18/24例(51.3%/75.8%/8.2%/4.9%/6.5%)であった(重複回答含む)。薬物使用歴、刺青を有する患者の特徴として若年、男性、genotype 2があげられた。また、外来治療を自己中断した症例の特徴も同様に若年、男性、genotype 2であった。観察期間内に再感染例はみられなかったが、今後再感染を予防する上で、これらに対する慎重な経過観察と患者教育が重要な課題である。(著者抄録)

当院で2014年9月から2016年8月までに直接作用型抗ウイルス薬治療を施行したC型慢性肝疾患患者616例及び2007年5月以降に経験したC型急性肝炎患者8例に対し、感染経路の実態を調査し再感染の可能性について検討した。616例のうち感染経路を推定しえた症例は372例(60.4%)であり、その内訳は輸血歴/手術歴/薬物使用歴/家族歴/刺青:189/279/30/18/24例(51.3%/75.8%/8.2%/4.9%/6.5%)であった(重複回答含む)。薬物使用歴、刺青を有する患者の特徴として若年、男性、genotype 2があげられた。また、外来治療を自己中断した症例の特徴も同様に若年、男性、genotype 2であった。観察期間内に再感染例はみられなかったが、今後再感染を予防する上で、これらに対する慎重な経過観察と患者教育が重要な課題である。(著者抄録)

Other URL： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00263&link_issn=&doc_id=20170830080002&doc_link_id=10.2957%2Fkanzo.58.435&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.58.435&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

DOI： 10.1053/j.gastro.2017.03.075

PubMed

Publishing type：Research paper (scientific journal)  

We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p &lt
0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

DOI： 10.3390/ijms18050962

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1053/j.gastro.2017.01.041

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms18050962

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10-8). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

DOI： 10.1053/j.gastro.2017.01.041

PubMed

Superb Microvascular Imaging(SMI)の加算画像を用いて肝表面近傍の血管構築を観察し、C型慢性肝疾患患者と健常者において見られた血管構築の違いを検討したので報告する。健常人と比較して、肝硬変患者では屈曲蛇行する血管が多く観察され、細血管の増生、多分枝化、径の不整や枯れ枝様の像も認められた。また、C型慢性肝疾患患者17例、健常者12名を対象に、各症例での5本あたりの屈曲蛇行血管数を比較したところ、患者群3.23±0.67、健常者群1.52±0.83であり、患者群で有意に屈曲蛇行血管数が多かった。SMIを用いた肝表面近傍の血管構築評価は非侵襲的な検査であり、患者や検者に負担をかけずに有用な情報を得ることができるため、その手法の確立は臨床的意義が大きいと考えられた。

Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v23.i15.2651

PubMed

Publishing type：Research paper (scientific journal)  

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and the second most common cause of cancer deaths worldwide. The top three causes of HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease. Owing to recent advances in direct-acting antiviral agents, HCV can now be eradicated in almost all patients. HBV infection and alcoholic liver disease are expected, therefore, to become the leading causes of HCC in the future. However, the association between alcohol consumption and chronic hepatitis B in the progression of liver disease is less well understood than with chronic hepatitis C. The mechanisms underlying the complex interaction between HBV and alcohol are not fully understood, and enhanced viral replication, increased oxidative stress and a weakened immune response could each play an important role in the development of HCC. It remains controversial whether HBV and alcohol synergistically increase the incidence of HCC. Herein, we review the currently available literature regarding the interaction of HBV infection and alcohol consumption on disease progression.

DOI： 10.3748/wjg.v23.i15.2651

PubMed

DOI： 10.1038/ncomms14807

PubMed

DOI： 10.1007/s00535-016-1285-y

PubMed

欧米では有効性が実証されているグラゾプレビル(GZR)とエルバスビル(EBR)の併用について、日本人慢性HCV感染患者に対する安全性と有効性を調べた。まず、非肝硬変の慢性HCV感染患者63例を2群に無作為に割り付け、GZRを50mg(31例)または100mg(32例)と組み合わせてEBR(50mg)を1日1回12週間投与した。SVR12率は50mg GZRで100%、100mg GZRで96.8%であり、忍容性は両者で同等であった。また、非肝硬変患者を3:1に無作為化し、EBR(50mg)およびGZR(100mg)による即時治療(227例)または遅延治療(74例)を12週間行い、肝硬変患者35例にはオープンラベルの即時治療を行った。治療後12週間の持続的ウイルス学的応答(SVR12)の割合はそれぞれ96.5%および97.1%であった。安全性は即時治療と遅延治療でほぼ同様であった。日本人の慢性HCV感染患者では12週間のGZRと併用したEBRによる治療は有効であり、十分な忍容性があることが示された。

Publishing type：Research paper (scientific journal)  

目的:胸部単純X線検査は肺疾患、特に肺がんのスクリーニング検査として検診や健診において重要である。その一方で、胸部単純X線検査には診断の限界があり、陳旧性肺結核などの病変がある場合、肺がんの指摘が困難な場合もある。当施設では有所見者に対する積極的受診勧告を行っており、今回はその有効性について検討した。方法:2015年1月1日から1年間に、胸部単純X線検査を施行した5,603例の胸部D2判定者(要精密検査)の画像所見の内訳、最終診断病名、発見率を検討した。結果:D2判定者は230例(4.1%)、呼び出しシステムにより197例(85.7%)に電話にて受診勧告を行った。また、32例(13.9%)に対して健診当日に胸部X線検査に異常ありと説明した。174例(75.7%)が当施設にてCT検査を施行した。肺野陰影は156例(89.7%)、そのうち結節影は106例、すりガラス陰影は17例であった。経過観察必要な陰影は20例、4例が肺がんと診断された。肺がん発見率は0.07%であった。集積症例の肺がん存在期待値は3.93人であり、標準化発見比は1.02であった。結論:当施設における胸部単純X線検査にてD2判定となった症例の実態と呼び出しシステムの有効性を明らかにした。当施設のような最終診断、治療まで可能な施設では再受診率が高い傾向にあり、二次予防として肺がんの早期発見、早期治療に有効であると考えられた。(著者抄録)

目的:胸部単純X線検査は肺疾患、特に肺がんのスクリーニング検査として検診や健診において重要である。その一方で、胸部単純X線検査には診断の限界があり、陳旧性肺結核などの病変がある場合、肺がんの指摘が困難な場合もある。当施設では有所見者に対する積極的受診勧告を行っており、今回はその有効性について検討した。方法:2015年1月1日から1年間に、胸部単純X線検査を施行した5,603例の胸部D2判定者(要精密検査)の画像所見の内訳、最終診断病名、発見率を検討した。結果:D2判定者は230例(4.1%)、呼び出しシステムにより197例(85.7%)に電話にて受診勧告を行った。また、32例(13.9%)に対して健診当日に胸部X線検査に異常ありと説明した。174例(75.7%)が当施設にてCT検査を施行した。肺野陰影は156例(89.7%)、そのうち結節影は106例、すりガラス陰影は17例であった。経過観察必要な陰影は20例、4例が肺がんと診断された。肺がん発見率は0.07%であった。集積症例の肺がん存在期待値は3.93人であり、標準化発見比は1.02であった。結論:当施設における胸部単純X線検査にてD2判定となった症例の実態と呼び出しシステムの有効性を明らかにした。当施設のような最終診断、治療まで可能な施設では再受診率が高い傾向にあり、二次予防として肺がんの早期発見、早期治療に有効であると考えられた。(著者抄録)

Publishing type：Research paper (scientific journal)  

目的:胸部単純X線検査は肺疾患、特に肺がんのスクリーニング検査として検診や健診において重要である。その一方で、胸部単純X線検査には診断の限界があり、陳旧性肺結核などの病変がある場合、肺がんの指摘が困難な場合もある。当施設では有所見者に対する積極的受診勧告を行っており、今回はその有効性について検討した。方法:2015年1月1日から1年間に、胸部単純X線検査を施行した5,603例の胸部D2判定者(要精密検査)の画像所見の内訳、最終診断病名、発見率を検討した。結果:D2判定者は230例(4.1%)、呼び出しシステムにより197例(85.7%)に電話にて受診勧告を行った。また、32例(13.9%)に対して健診当日に胸部X線検査に異常ありと説明した。174例(75.7%)が当施設にてCT検査を施行した。肺野陰影は156例(89.7%)、そのうち結節影は106例、すりガラス陰影は17例であった。経過観察必要な陰影は20例、4例が肺がんと診断された。肺がん発見率は0.07%であった。集積症例の肺がん存在期待値は3.93人であり、標準化発見比は1.02であった。結論:当施設における胸部単純X線検査にてD2判定となった症例の実態と呼び出しシステムの有効性を明らかにした。当施設のような最終診断、治療まで可能な施設では再受診率が高い傾向にあり、二次予防として肺がんの早期発見、早期治療に有効であると考えられた。(著者抄録)

Publishing type：Research paper (scientific journal)  

To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV+ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV+ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor , SMAD family member 3, -catenin, Nrf2, SREBP-LXR and nuclear receptor-interacting protein 1 (NRIP1), and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis.

DOI： 10.3390/ijms18020434

PubMed

DOI： 10.1038/srep41888

PubMed

DOI： 10.1111/liv.13272

PubMed

DOI： 10.1111/hepr.12730

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/hep.28849

PubMed

DOI： 10.1007/s10396-016-0736-7

PubMed

今回、超音波照射による温度変化から、組織深部のインドシアニングリーン(ICG)蛍光強度の変化を検出する、新しい蛍光イメージング法を開発した。なお、本法に用いるプローブでは、レーザーからの励起光、ライトパイプを介した蛍光感知および超音波による加熱を利用した。本法をウシ肝臓に適用し、ICGの集積を画像化したところ、ICGに783nm光を照射すると820nmの蛍光を発し、温度が1℃上昇すると、ICGの蛍光強度が0.85%低下し、ICGの分布は、本プローブの超音波加温を利用することにより、検出することが可能となった。以上より、超音波を利用した温度変化で蛍光を調節することにより、組織深部のICG堆積部位が明瞭に観察され、これら手法は、肝細胞癌の癌病巣特定に有用と考えられた。

DOI： 10.11423/jsph.23.149

CiNii Article

<b>Objective:</b> Chest X-ray is the most common screening procedure for detection of lung cancer. They play a significant role in both private and public health screening programs. However, if subjects have old inflammatory shadows, such as those due to tuberculosis, this will make it difficult to detect lung cancer. <br><b>Methods:</b> Our clinic, MedCity21, was established as an outpatient clinic to provide complete health check-ups aiming at pre-emptive preventive medicine. Examinees with abnormalities detected in chest X-rays are announced by our calling system and invited to our clinic for further examinations (exams). Here, we report the chest X-ray results for the complete health check-ups. <br><b>Results:</b> 5,603 subjects who underwent private health screening programs including chest X-ray exams at our clinic between January 1st and December 31st 2015 were enrolled in this study. Abnormalities were detected in X-rays for 230 (4.1%) individuals and 174 (76%) of them underwent a chest CT scan at our clinic. Abnormal shadows, including those for 106 nodules and 17 ground glass opacities, were detected in 156 (89.7%) of these examinees. Four examinees were diagnosed as lung cancer within 12 months of the health check-up. The lung cancer detection rate was 0.07%. The standardized detection ratio: “number of individuals with detected lung cancer” divided by “expected lung cancer presence” was 1.02.<br><b>Conclusions:</b> Chest CT scans clarified the details of abnormal lung shadows in 174 examinees. Our findings may contribute to the early prevention and treatment of lung cancer.

DOI： 10.11320/ningendock.31.661

CiNii Article

DOI： 10.11405/nisshoshi.114.43

PubMed

CiNii Article

<b>Objective: </b>Detection rate is one of the criteria used to evaluate the quality of gastric cancer screening programs that use esophagogastroduodenoscopy. However, the detection rate is biased by the age distribution and sex ratio of the population undergoing endoscopy. Therefore, we assessed the quality of our screening program using a standardized detection ratio adjusted for age and sex. <br><b>Methods: </b>Between January 4 and December 28, 2016, 4,927 persons who underwent a health check-up including ultra-slim endoscopy at our clinic, MedCity21, were enrolled in this study. We determined standardized detection ratios and gastric cancer detection rates.<br><b>Results: </b>Gastric cancer was detected in 13 male subjects and the value of the standardized detection ratio was 3.74. In contrast, gastric cancer was only detected in one female subject and the value of the standardized detection ratio was 0.89. Among all subjects, the value of the standardized detection ratio was 3.04 and the gastric cancer detection rate was 0.28%.<br><b>Conclusions: </b>Gastric cancer was detected successfully in our health check-ups based on assessment using the standardized detection ratio.

DOI： 10.11320/ningendock.32.537

CiNii Article

<p>We analyzed 616 chronic hepatitis C patients who were treated with DAAs from Sep 2014 to Aug 2016 and eight acute hepatitis C patients after May 2007 in our hospital. 372 patients (60.4%) identified their infection routes via a blood transfusion, surgery, intravenous drug use (IDU), family history, and tattooing in 189, 279, 30, 18, and 24, respectively. There were no patients who were reinfected with HCV during the observation period of 34 months. Infection via IDU and tattooing still have a possibility for reinfection after SVR. These were predominant routes in young, male, and genotype 2 patients. In addition, patients who were lost to follow-up treatment showed the same backgrounds. Our data indicated that they may be candidates in a high risk group of HCV reinfection. We should observe and educate them more intensely.</p>

DOI： 10.2957/kanzo.58.435

CiNii Article

Publishing type：Research paper (scientific journal)  

Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon alpha 2a + ribavirin (P2aR) and with peginterferon alpha 2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection.
Methods: Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24).
Results: In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively.
Conclusion: Peginterferon alpha 2a or alpha 2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.

DOI： 10.1111/hepr.12689

PubMed

日本人のC型肝炎ウイルスジェノタイプ1b感染患者におけるシメプレビル+ペグインターフェロンα2a+リバビリン併用療法(P2aR)およびSMV+ペグインターフェロンα2b+リバビリン併用療法(P2bR)の有効性と安全性を前向きに評価した。当該患者を、P2aR群73例(男性37例、女性36例、年齢30〜77歳)とP2bR群72例(男性23例、女性49例、年齢36〜75歳)に無作為に割り付けた。主要評価項目は、治療終了から24週後のウイルス学的持続陰性化(SVR24)とした。SVR24はP2aR群の75.3%、P2bR群の76.4%が達成し、両群間で有意差は見られなかった。HCV RNAが陰性となった患者の割合も両群間で差はなかった。有害事象により治療中止となった患者数はP2aR群9.6%、P2bR群8.3%であった。P2aRとP2bRの3剤併用療法は、C型肝炎ウイルスジェノタイプ1b感染患者において同等のSVRを達成し、忍容性および安全性も同等であることが示された。

DOI： 10.1016/j.ultras.2016.08.010

PubMed

Publishing type：Research paper (scientific journal)  

The microRNA-29 (miR-29) family is known to suppress the activation of hepatic stellate cells (HSCs) and reversibly control liver fibrosis; however, the mechanism of how miR-29a controls liver fibrosis remains largely unknown. This study was conducted to clarify the mechanism of anti-fibrotic effect of miR-29a and to explore if miR-29a is a promising candidate for nucleic acid medicine against liver fibrosis. Two liver fibrosis murine models (carbon tetrachloride or thioacetamide) were used. MiR-29a mixed with atelocollagen was systemically administered. Hepatic fibrosis was evaluated by histological analysis and the expression levels of fibrosisrelated genes. We observed that miR-29a treatment dramatically accelerated the reversion of liver fibrosis in vivo. Additionally, miR-29a regulated the mRNA expression of collagen type I alpha 1 (COL1A1) and platelet-derived growth factor C (PDGFC). We also noted that miR-29a significantly suppressed COL1A1 mRNA expression and cell viability and significantly increased caspase-9 activity (P &lt; 0.05) in LX-2 cells. Pretreatment of miR-29a inhibited activation of LX-2 cell by transforming growth factor beta treatment. MiR-29a exhibited anti-fibrotic effect without cell toxicity in vivo and directly suppressed the expression of PDGF-related genes as well as COL1A1 and induced apoptosis of LX-2 cells. MiR-29a is a promising nucleic acid inhibitor to target liver fibrosis.

DOI： 10.1038/mt.2016.127

PubMed

Publishing type：Research paper (scientific journal)  

世界保健機構(WHO)が開発した過剰飲酒を短時間で評価するための10項目の質問文からなる「アルコール使用障害特定テスト」(The Alcohol Use Disorders Identification Test;AUDIT)の、飲酒量の推定における有用性を検討することを目的に、2014年6月〜2015年3月に当院の内科外来に通院した患者334名(男性174名、女性160名)を対象に、飲酒量を正確に推定するため電子カルテ上に飲酒頻度(日、週、月)、種類(ビール、ワイン、ウイスキー等)、量(コップ、グラス等)から1日当たりの摂取エタノール量(g/日)を自動計算するテンプレート(Juso Alcohol Calculator;JAC)を作成し、これにより推定された飲酒量と、同じ患者にAUDITを施行して得られたスコアの相関を検討した。その結果、JACによる1日当たりの摂取エタノールとAUDITスコアの間に高い相関が認められた。また、10分割交差法を用いたhazardous drinking(飲酒者や他者に対する有害事象のリスクが上昇するアルコール摂取パターン、56名(16%)が該当)におけるAUDITスコアの至適カットオフ値は8.2点で、男性10.0点、女性6.1点と、男女差を認めた。

Publishing type：Research paper (scientific journal)  

Background: Currently, no system for appropriate intra-hospital collaboration regarding hepatitis virus positive individuals exists, even in medical institutions with hepatologists among their staff. The main objective of this study was to explore a simple alert system to promote the referral of patients with hepatitis B surface antigen (HBsAg)- or anti-hepatitis C virus (HCV) antibodies positivity to hepatologists through electronic medical records.
Methods: Since April 2014 at Osaka City Juso Hospital, "sticky notes" have been put on the electronic medical records of patients newly diagnosed with HBsAg- or anti-HCV- antibodies positivity to recommend intra-hospital referral of those patients to specialists. In this study, we investigated the number of referrals to hepatologists before vs. after the introduction of this system (that is, in fiscal years 2013 [Period 1] and 2014 [Period 2], respectively), and the subsequent clinical courses of the patients.
Results: The proportions of patients with HBsAg and anti-HCV antibody positivity did not show statistically significant differences between Period 1 and Period 2 (1.6 % [43/2,757] vs. 1.3 % [39/2,891], p = 0.58; and 5.8 % [156/2,674] vs. 5.3 % [147/2,790], p = 0.39, respectively). However, the referral proportions for patients with HBsAg- and anti-HCV antibody positivity were significantly higher in Period 2 (73 % [11/15] and 65 % [41/63], respectively) than in Period 1 (28 % [5/18] and 17 % [9/54]) (p = 0.009 and p &lt; 0.001, respectively). Among patients who were referred to hepatologists, 2 HBsAg- positive and 4 anti-HCV antibody positive patients initiated antiviral treatment.
Conclusion: Our simple electronic medical record based alert system effectively promoted intra-hospital referral of hepatitis virus-positive patients, who have been detected by screening tests, to hepatologists.

DOI： 10.1186/s12879-016-1765-y

PubMed

DOI： 10.1016/j.jvir.2016.03.031

PubMed

症例は72歳女性。C型慢性肝炎(Genotype 1b)に対して、過去にインターフェロン療法を受けたが無効であった。2014年9月(71歳時)に、発熱、下腿浮腫、紫斑を呈し、C型肝炎ウイルス(hepatitis C virus:HCV)関連クリオグロブリン血管炎と診断された。ダクラタスビル(daclatasvir;DCV)、アスナプレビル(asunaprevir;ASV)による抗ウイルス療法を導入したところHCV量の低下とともに血管炎は著明に改善した。患者はウイルス学的著効となり血管炎の再燃はない。近年、多くのdirect acting antiviral agentsが開発されているが、クリオグロブリン血管炎を合併したC型慢性肝炎例に対してDCV/ASVによる治療を行った報告はなく、今後のHCV関連クリオグロブリン血管炎の治療選択肢の一つになると考えるため報告する。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1200/JCO.2016.34.15_suppl.e15671

DOI： 10.1186/s12889-016-3053-6

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Cytoglobin (Cygb) was identified in hepatic stellate cells (HSCs) and pericytes of all organs; however, the effects of Cygb on cellular functions remain unclear. Here, we report spontaneous and age-dependent malformations in multiple organs of Cygb(-/-) mice. Twenty-six percent of young Cygb(-/-) mice (<1 year old) showed heart hypertrophy, cystic disease in the kidney or ovary, loss of balance, liver fibrosis and lymphoma. Furthermore, 71.3% (82/115) of aged Cygb(-/-) mice (1-2 years old) exhibited abnormalities, such as heart hypertrophy and cancer development in multiple organs; by contrast, 5.8% (4/68) of aged wild-type (WT) mice had abnormalities (p < 0.0001). Interestingly, serum and urine analysis demonstrated that the concentration of nitric oxide metabolites increased significantly in Cygb(-/-) mice, resulting in an imbalance in the oxidative stress and antioxidant defence system that was reversed by N(G)-monomethyl-L-arginine treatment. A senescent phenotype and evidence of DNA damage were found in primary HSCs and the liver of aged Cygb(-/-) mice. Moreover, compared with HSC(+/+), HSC(-/-) showed high expression of Il-6 and chemokine mRNA when cocultured with mouse Hepa 1-6 cells. Thus, the absence of Cygb in pericytes provokes organ abnormalities, possibly via derangement of the nitric oxide and antioxidant defence system and through accelerated cellular senescence.

DOI： 10.1038/srep24990

PubMed

Publishing type：Research paper (scientific journal)  

Aim: Percutaneous radiofrequency ablation (P-RFA) therapy is a widely applied treatment for small hepatocellular carcinoma (HCC); however, local recurrence is a major issue of HCC located at the surface of the liver (surface HCC). The aimof this study was to compare the outcome of laparoscopic hepatic resection (LH) and P-RFA for surface HCC in case-control patient groups using the propensity score.
Methods: Between 2011 and 2013, 40 and 52 patients underwent LH and P-RFA for surface HCC (&lt;= 3 cm, 1-3 nodules). To correct the difference in clinicopathological factors between the two groups, propensity score matching was used at a 1: 1 ratio, which resulted in a comparison of 27 patients/group. We compared outcomes between the two groups, with special reference to local recurrence.
Results: Clinicopathological variables were well balanced between the two groups. One patient in the LH group was converted to open surgery due to adhesion. The incidence of complications was 0% in the P-RFA group and 15% (four patients) in the LH group (P = 0.11); however, none of these four patients in the LH group sustained severe complications. The duration of hospitalization following treatment was longer in the LH group than in the P-RFA group (12.6 vs 7.6 days, P&lt;0.01). The incidence of local recurrence was lower in the LH group (0%) than in the P-RFA group (eight patients [30%], P = 0.004).
Conclusion: LH is an effective treatment for surface HCC with regard to control of local recurrence.

DOI： 10.1111/hepr.12592

PubMed

2011年〜2013年の間に、表面の肝細胞癌(HCC)(3cm以下、結節は1〜3個)に対して腹腔鏡下肝臓切除(LH)を行った患者40名(男26名、女14名、平均67歳)と、経皮的ラジオ波焼灼術(P-RFA)を行った患者52名(男30名、女22名、平均71歳)を対象とした。両群の臨床病理因子の差を補正するため、傾向スコアマッチングにより1:1になるように、各群27名(LH群:男16名、女11名、平均69歳、P-RFA群:男15名、女12名、平均71歳)で比較した。特に局所再発に関して、治療成績を比較した。群間で臨床病理学的変数に関しては差が見られなかった。LH群の1名は癒着により開腹手術に切り替えた。P-RFA群では合併症の発生は0%、LH群では15%(4名)であったが、4名に重篤な合併症は見られなかった。治療後の入院期間はLH群(12.6日)の方がP-RFA群(7.6日)よりも長かった。局所再発は、LH群(0名、0%)の方がP-RFA群(8名、30%)よりも少なかった。LHは表面のHCCに対して局所再発を予防する優れた治療法であると考えられた。

DOI： 10.14670/HH-11-694

PubMed

DOI： 10.1111/hepr.12518

PubMed

持続性ウイルス陰性化(SVR)患者と持続的C型肝炎ウイルス(HCV)感染患者の肝細胞癌切除標本におけるMicroRNA(miRNA)発現を比較した。肝細胞癌を切除した71例中、持続的にHCVに感染している61例(HCV-HCC群:男性52例、女性9例、平均68±6歳)と、SVRを達成した10例(SVR-HCC群、男性10例、平均68±7歳)を対象とした。また、SVR-HCC群の4例由来の非腫瘍組織(SVR-NT)と、肝細胞癌の無い4例のSVR患者の肝組織(SVR-CH)も併せて検討した。全RNAを肝組織から抽出し、miRNA発現パターンをマイクロアレイで解析した。HEK293細胞における標的遺伝子発現を、miRNA過発現後に測定した。6種の特異的miRNAの発現パターンを用いることで、75.36%の正確度でSVR-HCC群とHCV-HCC群を鑑別することができた。また37種のmiRNA発現量は、HCV-HCC群ではSVR-HCC群に比して有意に低かったが、25種のmiRNAの発現は有意に高かった。抗腫瘍miRNAであるmiR-30a-3pの発現量は、SVR-HCC群においてHCV-HCC群に比して低かったが、トロンボスポンジン1(THBS1)の発現量は高く、両者の発現は線形回帰的に逆相関していた。しかし、両者の発現の関連は有意ではなかった。非腫瘍組織においては、7種のmiRNAは87.50%の正確度でSVR-CHとSVR-NTを鑑別することができた。包括的miRNA解析は、SVR-HCC群とHCV-HCC群を鑑別できるだけでなく、SVR達成後の肝発癌を予測できることが示唆された。

感染症スクリーニング検査で判明した肝炎ウイルス感染者が適切に院内連携できているかは明らかではない。当院では2013年4月からHBs抗原またはHCV抗体陽性者に関して電子カルテ上で専門科である肝胆膵内科への紹介を促す新たなシステムを構築した。また術前診察マニュアルを変更して麻酔科外来でも肝胆膵内科への紹介を促すようにした。当院における2012年度(新システム開始前)のHBs抗原検査数は13,004件、HCV抗体検査数は12,374件であった。陽性者はそれぞれ450例、711例で、ともに肝胆膵内科が最多であったが、整形外科、眼科、耳鼻科など外科系診療科がこれに次いだ。新システム開始後、肝炎ウイルス関連の院内紹介数は、18.8±5.7例/月から28.7±4.6例/月へと増加し、耳鼻科、眼科、整形外科など陽性者が多い診療科から確実に紹介されていた。新システムによる肝炎ウイルス感染者の拾い上げは、円滑な院内連携、陽性患者の専門医によるフォローアップや治療につながることが期待される。(著者抄録)

Hepatitis C virus (HCV) infection is a major worldwide health problem. Chronic infection induces continuous inflammation in the liver, progression of hepatic fibrosis, eventual cirrhosis, and possible hepatocellular carcinoma. Eradication of the virus is one of the most important treatment aims. A number of promising new direct-acting antivirals (DAAs) have been developed over the past 10 years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs have been approved for patients with HCV, including those with cirrhosis. This review introduces the characteristics and results of recent clinical trials of several DAAs: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. DAA treatment failure and prognosis after DAA therapy are also discussed.

DOI： 10.1155/2016/6841628

PubMed

Cytoglobin (CYGB), a new member of the globin family, was discovered in 2001 as a protein associated with stellate cell activation (stellate cell activation-associated protein [STAP]). Knowledge of CYGB, including its crystal, gene, and protein structures as well as its physiological and pathological importance, has increased progressively. We investigated the roles of oxygen (O₂)-binding CYGB as STAP in hepatic stellate cells (HSCs) to understand the part played by this protein in their pathophysiological activities. Studies involving CYGB-gene-deleted mice have led us to suppose that CYGB functions as a regulator of O₂ homeostasis; when O₂ homeostasis is disrupted, HSCs are activated and play a key role(s) in hepatic fibrogenesis. In this review, we discuss the rationale for this hypothesis.

DOI： 10.2183/pjab.92.77

PubMed

CiNii Article

It remains unclear whether intra-hospital collaboration regarding hepatitis B and C virus carriers identified by infection screening testing occurs appropriately in non-hepatology departments. Our hospital developed an alert system in April 2013 to promote referral of hepatitis B surface antigen (HBsAg)-positive or anti-heptitic C virus (HCV)-positive patients to the Department of Hepatology through electronic medical records. Since the introduction of the new system, the number of intra-hospital referrals regarding hepatitis virus infections increased from 18.8±5.7 to 29.0±4.5 per month. A steady stream of referrals originated from departments in which there were more patients who tested positive for the hepatitis virus. This alert system is useful for promoting the intra-hospital referral of hepatitis virus carriers who are detected by screening tests to hepatology specialists and is thus considered to be important in the appropriate management of chronic viral hepatitis.

DOI： 10.2957/kanzo.57.7

CiNii Article

<p>A 72-year-old female was diagnosed as having chronic hepatitis C 16 years before, and her anti-viral therapies with interferon were unsuccessful. She suffered from fever, edema and purpura for two months before admission. Then, she was diagnosed with hepatitis C virus-associated mixed cryoglobulinemic vasculitis. After treatment with daclatasvir/asunaprevir, her clinical symptoms improved rapidly and she had a sustained virologic response.</p><p>Since late 2013, several novel DAAs have been approved by the FDA. Interferon-free regimens that combine such novel DAAs are highly effective for the treatment of chronic HCV infection. To our knowledge, this is the first published report documenting the efficacy of daclatasvir/asunaprevir in a patient with HCV-associated mixed cryoglobulinemic vasculitis.</p>

DOI： 10.2957/kanzo.57.328

CiNii Article

Publishing type：Research paper (scientific journal)  

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC, and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.

DOI： 10.1038/srep16294

PubMed

DOI： 10.1002/hep.28002

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.12915

Publishing type：Research paper (scientific journal)  

Antiviral therapy for chronic hepatitis B that uses nucleos(t)ide analogue is considered effective. However, most drugs of this class frequently result in viral relapse after cessation of therapy as well as the emergence of resistance, thereby limiting their clinical use. In order to increase the therapeutic efficiency of chronic hepatitis B treatments, it is important to survey novel (chemical) reagents targeting other stages of the viral replication process. The aim of this study was to identify novel capsid inhibitor candidates using in silico screening. We discovered four such candidates that decreased the levels of HBV DNA and HBsAg in vitro. These four capsid inhibitor candidates did not induce cell toxicity even at high concentrations. Results from docking simulation showed that the candidates bounded with high affinity with the capsid protein hydrophobic binding site. Identifying direct acting HBV core protein inhibitors increases the likelihood that novel medicines can be developed that allows the combination of novel anti-viral drugs and nucleos(t)ide analogue or interferon for HBV treatment. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.06.077

PubMed

DOI： 10.1089/jir.2014.0234

PubMed

DOI： 10.1089/jir.2014.0096

PubMed

Publishing type：Research paper (scientific journal)  

Oxygen (O-2) is required for cytochrome P450 (CYP)-dependent drug metabolism. Cytoglobin (CYGB) is a unique globin expressed exclusively in hepatic stellate cells (HSCs). However, its role in O-2-dependent metabolism in neighboring hepatocytes remains unknown. This study provides evidence that CYGB in HSCs is involved in acetaminophen (N-acetyl-p-aminophenol; APAP)-induced hepatotoxicity. Serum alanine aminotransferase levels were higher in wild-type mice than in Cygb-null mice. Wild-type mice exhibited more severe hepatocyte necrosis around the central vein area compared with Cygb-null mice, thus indicating that CYGB deficiency protects against APAP-induced liver damage. Although no difference in the hepatic expression of CYP2E1, a key enzyme involved in APAP toxicity, was observed between wild-type and Cygb-null mice, the serum levels of the APAP metabolites cysteinyl-APAP and N-acetyl-cysteinyl-APAP were decreased in Cygb-null mice, suggesting reduced APAP metabolism in the livers of Cygb-null mice. In primary cultures, APAP-induced hepatocyte damage was increased by co-culturing with wild-type HSCs but not with Cygb-null HSCs. In addition, cell damage was markedly alleviated under low O-2 condition (5% O2), suggesting the requirement of O-2 for APAP toxicity. Carbon tetrachloride-induced liver injury (CYP2E1-dependent), but not lipopolysaccharide/ D-galactosamine-induced injury (CYP2E1-independent), was similarly alleviated in Cygb-null mice. Considering the function of CYGB as O-2 carrier, these results strongly support the hypothesis that HSCs are involved in the CYP2E1-mediated xenobiotic activation by augmenting O-2 supply to hepatocytes. In conclusion, CYGB in HSCs contributes to the CYP-mediated metabolism of xenobiotics in hepatocytes by supplying O-2 for enzymatic oxidation.

DOI： 10.1038/labinvest.2015.29

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ajpath.2014.12.017

PubMed

Publishing type：Research paper (scientific journal)  

The treatments for chronic hepatitis B (CHB) are interferon and nucleoside analogues reverse transcriptase (RT) inhibitors. Because both treatments are less than ideal, we conducted to identify novel anti-viral agents for HBV-reverse transcriptase (HBV-RT). We determined the ligand-binding site of the HBV-RT by conducting a homological search of the amino acid sequence and then we also determined not only structural arrangement of the target protein but the target protein-binding site of the ligand using known protein-ligand complexes in registered in the protein data bank (PDB). Finally we simulated binding between the ligand candidates and the HBV-RT and evaluated the degree of binding (in silico screening). PXB cells derived from human-mouse chimeric mouse liver, infected with HBV were administrated with the candidates, and HBVDNA in the culture medium was monitored by realtime qPCR. Among compounds from the AKosSamples database, twelve candidates that can inhibit RT were also identified, two of which seem to have the potential to control HBV replication in vitro. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2014.11.024

PubMed

Publishing type：Research paper (scientific journal)  

Aim. Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. Material and methods. This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin &lt; 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups. Results. No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR-standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). Conclusions. TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.

PubMed

DOI： 10.1038/mtna.2014.71

PubMed

Publishing type：Research paper (scientific journal)  

Background & Aims
The utility of transient elastography (FibroScan) is well studied in adults but not in children. We sought to assess the feasibility of performing FibroScans and the characteristics of FibroScan-based liver profiles in Japanese obese and non-obese children.
Methods
FibroScan examinations were performed in pediatric patients (age, 1-18 yr) who visited Osaka City University Hospital. Liver steatosis measured by controlled attenuation parameter (CAP), and hepatic fibrosis evaluated as the liver stiffness measurement (LSM), were compared among obese subjects (BMI percentile &gt;= 90%), non-obese healthy controls, and non-obese patients with liver disease.
Results
Among 214 children examined, FibroScans were performed successfully in 201 children (93.9%; median, 11.5 yr; range, 1.3-17.6 yr; 115 male). CAP values (mean +/- SD) were higher in the obese group (n = 52, 285 +/- 60 dB/m) compared with the liver disease (n = 40, 202 +/- 62, P&lt;0.001) and the control (n = 107, 179 +/- 41, P&lt;0.001) group. LSM values were significantly higher in the obese group (5.5 +/- 2.3 kPa) than in the control (3.9 +/- 0.9, P&lt;0.001), but there were no significant differences in LSM between the liver disease group (5.4 +/- 4.2) and either the obese or control group. LSM was highly correlated with CAP in the obese group (rho = 0.511) but not in the control (rho = 0.129) or liver disease (rho = 0.170) groups.
Conclusions
Childhood obesity carries a high risk of hepatic steatosis associated with increased liver stiffness. FibroScan methodology provides simultaneous determination of CAP and LSM, is feasible in children of any age, and is a non-invasive and effective screening method for hepatic steatosis and liver fibrosis in Japanese obese children.

DOI： 10.1371/journal.pone.0137239

PubMed

DOI： 10.3389/fphys.2015.00329

PubMed

Publishing type：Research paper (scientific journal)  

AimWe aimed to determine whether pretreatment serum interferon--inducible protein (IP)-10 concentration can predict response to telaprevir (TVR)-based triple therapy in patients with genotype 1 chronic hepatitis C (CHC), and to examine the effects of IP-10 concentration on liver histology.
MethodsBaseline IP-10 concentrations were measured in 97 patients with genotype 1 CHC treated with TVR-based triple therapy, and the associations between baseline IP-10 and treatment outcome were assessed by univariate and multivariate analyses. Associations between baseline serum IP-10 concentration and laboratory data and liver histological findings were also investigated.
ResultsMedian IP-10 concentration in these patients was 461.83pg/mL (range, 151.35-4297.62). Multivariate analysis showed that IL28B genotype (P=0.025) and IP-10 level (P=0.004) were factors significantly predictive of rapid virological response (RVR), whereas in pretreatment factors only, IL28B genotype (P=0.001) and liver fibrosis (P=0.035) were independent predictors of sustained virological response. Using a cut-off IP-10 concentration of 460pg/mL, patients with IL28B risk allele and low IP-10 had a significantly higher RVR rate than those with high IP-10 (P=0.005). IP-10 concentration was significantly correlated with liver fibrosis (P=0.001) and inflammation activity (P=0.006) and had the highest areas under the curve for liver histological findings.
ConclusionBaseline serum IP-10 level is a useful predictor of virological response in patients with genotype 1 CHC treated with TVR-based triple therapy, especially in patients with IL28B risk allele. IP-10 was well correlated with liver fibrosis and inflammation.

DOI： 10.1111/hepr.12326

PubMed

テラプレビル三剤併用療法に対する遺伝子型1のC型慢性肝炎患者の応答の予測に、インターフェロンγ誘導性タンパク質10(IP-10)の血清中濃度が有用であるかについて検討した。以前に直接作用型抗ウイルス剤を投与されたことのない遺伝子型1のC型慢性肝炎患者のうち、テラプレビル三剤併用療法で治療された患者105人を対象とした。多変量解析から、治療前の血清IP-10濃度は早期ウイルス陰性化(RVR)の有意な予測因子であった。一方、IL28B遺伝子型及び肝線維症だけがウイルス学的著効の独立予測因子であった。IL28Bリスクアレルを有する患者ではIP-10濃度が高い場合よりも低い場合の方が有意に高いRVR率を示した。テラプレビル三剤併用療法を受けた遺伝子型1のC型慢性肝炎の患者のうち、特にIL28Bリスクアレルを有する患者におけるIP-10のベースラインレベルはウイルス学的応答を予測する上で有用であることが分かった。

Publishing type：Research paper (scientific journal)  

Erythropoietin is widely used in the USA and some other Western countries to maintain doses of ribavirin during peginterferon/ribavirin-based treatment for chronic hepatitis C virus (HCV) infection. However, the impact of erythropoietin on sustained virological response (SVR) is unclear. Here, we report the cases of three Japanese ribavirin-intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment by adding erythropoietin. Three women aged 50, 64 and 68 years with chronic HCV genotype 2 received retreatment with peginterferon-alpha and ribavirin. During their prior therapy, HCV RNA became negative according to real-time polymerase chain reaction at weeks 4-8 in all three patients; however, the total dose of ribavirin was 18.1-30.6% lower than the planned dose, and HCV RNA relapsed post-treatment. At present, epoetin-beta 24 000 IU was introduced at weeks 2 or 3 of dual-combination therapy, resulting in a less than 4.2% reduction in the total dose of ribavirin. HCV RNA became negative at weeks 4-8, and all patients achieved SVR. Until the next-generation antiviral treatments for HCV genotype 2 become available, the addition of erythropoietin to dual therapy can be a treatment of choice for ribavirin-intolerant relapsed patients.

DOI： 10.1111/hepr.12257

PubMed

エリスロポエチン(ETP)を添加した再治療により持続性ウイルス陰性化(SVR)に至った、HCV遺伝子型2を有するリバビリン(RBV)不耐性慢性C型肝炎ウイルス(HCV)感染症再発患者(全例女性、50歳、64歳、68歳)3例について報告した。再治療ではペグインターフェロン(PEG-IFN)α2aは1週間に1回90〜180μgの皮下注射を行い、リバビリン(RBV)は患者体重あたり600〜1000mgの総投与量を経口投与で行い、ヘモグロビン数値が12g/dL以下の場合にはエポエチンβを24000IUの投与量で、1週間に6回皮下注射後に隔週で3回の皮下注射を行い、24週間の投与期間で実施した。その結果、初回治療でHCV RNAは4〜8週間目に陰性化が認められたものの、RBV総投与量は予定投与量よりも18.1〜30.6%少なく、HCV RNAは治療後に再発を来したが、再治療ではRBVの投与量減少は2.3%に留まり、HCV RNAは4〜8週目に陰性化し、全例ともSVRに達することが認められた。

通院中の非アルコール性脂肪性肝疾患(NAFLD)患者92名(o-NAFLD群)と健診受診者215名を対象に、NAFLDと胃食道逆流症(GERD)との関連について検討した。健診受診者を脂肪肝を指摘されなかった136名(C群)、指摘された34名(ALF群)、飲酒歴がなく脂肪肝を指摘されNAFLDを疑われた26名(n-NAFLD群)に分け、全対象者のGDER症状をFrequency Scale for the Symptoms of GERD(FSSG)で評価した。NAFLDのFSSGスコアは合計、酸逆流、運動不全のいずれもC群と比較して有意に高く、cut-off値8点以上のGDER症状陽性者は約2倍認めた。NAFLDは肥満の有無に関わらず症状が強く、ALF群よりも強かったが、群別にみるとo-NAFLD群のみ症状が強かった。全対象者においてGERD症状はHOMA-IR、TG値、T-CHO値と正の相関を認め、NAFLDの群別ではo-NAFLD群のみがTG値、T-CHOと相関を示した。

Publishing type：Research paper (scientific journal)  

Infection with hepatitis B virus is an important health problem worldwide: it affects more than 350 million people and is a leading cause of liver-related morbidity, accounting for 1 million deaths annually. Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver. An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease. Liver biopsy has been considered the gold standard for diagnosing disease, grading necroinflammatory activity, and staging fibrosis. However, liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications, including death. Several noninvasive evaluations have been introduced for the assessment of liver fibrosis: serum biomarkers, combined indices or scores, and imaging techniques including transient elastography, acoustic radiation force impulse, real-time tissue elastography, and magnetic resonance elastography. Here, we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C, and later in those with chronic hepatitis B. The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i34.12031

PubMed

Publishing type：Research paper (scientific journal)  

Background and Aim: F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) may detect primary lesions (PLs) and extrahepatic metastases (EHMs) only in advanced hepatocellular carcinoma (HCC) patients. We investigated the requirement of PET and the optimal timing of PET scanning for accurate staging and treatment planning.
Methods: We conducted a retrospective investigation of 64 HCC patients who underwent PET (median age, 74 years; male/female, 41/23; etiology, 46 hepatitis C virus/4 hepatitis B virus/4 alcoholic/10 others). To determine the best timing for PET examinations, we analyzed PET result-based recommended treatment changes and characteristics of patients with FDG-avid PLs or EHMs.
Results: FDG-avid PLs were detected by PET in 22 patients (34%): 18 with hypervascular PL, 11 with serum alpha-fetoprotein levels &gt;= 200 ng/mL, and 11 beyond Milan criteria. EHMs were detected in 21 patients (33%: lymph nodes, 8; lung, 5; abdominal wall, 4; bone, 3; other organs, 4 [including overlapping]). Recommended treatments changed for 16 patients (25%) because of Barcelona Clinic Liver Cancer stage increases based on PET scanning. In multivariate analyses, serum alpha-fetoprotein levels &gt;= 200 ng/mL and beyond Milan criteria were independent factors for FDG-avid PLs and a maximum standardized uptake value (SUVmax) of PLs of (&gt;=) 4.0 was an independent factor for FDG-avid EHMs (P = 0.002, 0.008, and 0.045, respectively).
Conclusions: PET allows detection of HCC spread in patients with elevated serum a-fetoprotein levels or those beyond Milan criteria and detects EHMs in patients with PLs with high SUVmax values. Optimally timed PET scans can complement conventional imaging for accurate staging and treatment strategy determination.

DOI： 10.1111/jgh.12611

PubMed

Publishing type：Research paper (scientific journal)  

Background and Aim: To elucidate the clinical characteristics of hepatitis B virus reactivation (HBV-R), we performed a prospective long-term study of patients with hematologic malignancy, including both hepatitis B virus (HBV) carriers and those with resolved HBV infection.
Methods: Twenty-one patients with hematopoietic stem-cell transplants (HSCT) and 36 patients given rituximab-based chemotherapy were enrolled. Entecavir was administered prophylactically to eight patients with HBV surface antigen (HBsAg). HBV-DNA was measured every month in 49 patients with resolved HBV infection, and preemptive therapy was given to eight patients with HBV-R.
Results: HBV-R developed in five (26%) of 19 patients with HSCT and three (10%) of 30 patients given rituximab-based chemotherapy. HBV-R occurred a median of 3 months (range: 2-10) after the end of rituximab-based chemotherapy and 22 months (range: 9-36) after HSCT. HBV-R did not develop in patients with an antibodies against HBsAg (anti-HBs) titer exceeding 200 mIU/mL at baseline. Mutations in the "a" determinant region with amino acid replacement were detected in four of the eight patients with HBV-R. Preemptive therapy prevented severe hepatitis related to HBV-R. Entecavir treatment was stopped in four patients with HBV-R. Since the withdrawal of entecavir, HBV-DNA has not been detected in two patients persistently positive for anti-HBs. No patient had fatal hepatitis.
Conclusions: Proper management of patients with HBsAg or resolved HBV infection prevented fatal hepatitis related to HBV-R in patients who received immunosuppressive or cytotoxic therapy. Entecavir could be safely discontinued in patients with HBV-R who had acquired anti-HBs.

DOI： 10.1111/jgh.12604

PubMed

DOI： 10.3748/wjg.v20.i25.8048

PubMed

DOI： 10.1002/jhbp.86

PubMed

印刷工場の従業員および元従業員111名のうち17名に発症した胆管細胞癌の臨床病理所見や予後について検討した。胆管細胞癌は25〜45歳時に診断された。患者はジクロロメタンや1,2-ジクロロプロパンへの曝露歴を有していた。全患者で血清γGTP活性が上昇していた。5名に肝内胆管の拡張がみられたが、腫瘍による閉塞はなかった。胆管細胞癌は大きな胆管から発生していた。肝内胆管癌が10名、肝外胆管癌が5名で、両方を有している患者が2名であった。病理検査を行った16名全員が低分化型腺癌に合致する胆管癌であった。手術切除標本が得られた8名の全員で、胆管の様々な部位に前癌病変および早期癌病変がみられた。12名に切除術を行い、5名に再発、1名にリンパ節転移が見られた。生存期間の中央値は578日であった。

DOI： 10.1016/j.cgh.2013.08.050

PubMed

Publishing type：Research paper (scientific journal)  

Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered ("cis" effect); and (2) the HBV genome becomes altered ("trans" effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i20.6236

PubMed

Type I interferons (IFN-alpha/beta), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN-free regimen combining oral direct-acting antiviral agents (DAA) will be approved soon for genotype 1 patients. Here, we discuss the role of IFN-alpha/beta in the forthcoming "era of DAA" with consideration of limitations and concerns about IFN-free therapies. First, the therapeutic efficacy of first-generation DAA varies among the different subtypes. While the rate of sustained virological response (SVR) is 60-90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAA. Second, there is concern about the emergence of drug-resistance resulting from inappropriate use of DAA. The clinical significance of pre-existing resistant variants has not been elucidated. Drug resistance may affect the efficacy of next-generation treatments. An IFN and ribavirin backbone in combination with DAA is an effective measure to prevent the emergence of drug resistance and/or to suppress pre-existing resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN-free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first-generation DAA, low-dose IFN maintenance therapy is a treatment option until the next-generation therapy with pan-genotypic potency and high genetic barrier become available.

DOI： 10.1111/hepr.12289

PubMed

DOI： 10.19020/j01937.2014161244

DOI： 10.11477/mf.2425101581

CiNii Article

Publishing type：Research paper (scientific journal)  

Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), alpha-smooth muscle actin (alpha-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB- and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and a-SMA, whereas myofibroblasts around the portal vein expressed a-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, alpha-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB- and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express a-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become a-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human liver.

DOI： 10.1038/Iabinvest.2013.135

DOI： 10.1038/labinvest.2013.135

PubMed

DOI： 10.1186/1755-1536-7-2

PubMed

Publishing type：Research paper (scientific journal)  

Background and AimIt is not yet clear which factors are associated with the outcome of 72-week treatment with pegylated-interferon and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection.
MethodsIn 66 patients with HCV genotype 1 who had a late viral response (LVR) to 72-week treatment of pegylated-interferon and RBV, we examined the factors that determined the outcome, including single nucleotide polymorphisms of interleukin-28B and inosine triphosphatase (ITPA) genes.
ResultsThirty seven of 66 (56%) patients with LVR achieved a sustained viral response (SVR). The mean age of these 37 SVR patients was 55, compared with 61 in 29 relapsed patients (P=0.009). Twenty six of 54 (48%) patients with the CC genotype and 11 of 12 (92%) with the CA/AA genotype of ITPA rs1127354 achieved SVR (P=0.006). The SVR rates were 79%, 40%, 60%, and 33% in patients with undetectable HCV RNA on weeks 16, 20, 24, and 28 or later, respectively (P=0.014). Finally, serum RBV concentration at week 44 of treatment was significantly higher in the SVR group (2651ng/mL) than in the relapse group (1989ng/mL, P=0.002). In contrast, the rate of the interleukin-28B genotype was not different between the groups. Multiple regression analysis showed that age &lt;60 years, ITPA CA/AA genotype, and serum RBV concentration were significant independent predictive factors for SVR.
ConclusionsOur findings elucidated the association of four factors, including ITPA genotype, with the outcome of 72-week treatment in LVR patients.

DOI： 10.1111/jgh.12376

PubMed

DOI： 10.1371/journal.pone.0106314

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIM: The association between sarcopenia and nutritional status is thought to be an important problem in patients with cirrhosis. In this study, we investigated whether nutritional factors were related to sarcopenia in patients with liver cirrhosis. METHODS: The subjects were 50 patients with cirrhosis aged 41 years or older. In this study, the subjects were interviewed about their dietary habits, and their daily physical activity was surveyed using a pedometer. The skeletal muscle mass index (SMI) was calculated using the appendicular skeletal muscle mass (ASM) measured by bioelectric impedance analysis. The handgrip strength was measured using a hand dynamometer. Sarcopenia was defined by SMI and handgrip strength. The patients with cirrhosis were categorized as normal group or sarcopenia group, and the two groups were compared. Univariate and multivariate logistic regression modeling were used to identify the relevance for sarcopenia in patients with cirrhosis. RESULTS: Height (odds ratio (OR), 5.336; 95% confidence interval [CI], 1.063-26.784; P = 0.042), energy intake per ideal bodyweight (IBW) (OR, 5.882; 95% CI, 1.063-32.554; P = 0.042) and number of steps (OR, 4.767; 95% CI, 1.066-21.321; P = 0.041) were independent relevant factors for sarcopenia. Moreover, a significantly greater number of the patients in the sarcopenia group had low values for both parameters' energy intake per IBW and number of steps. CONCLUSION: Our results suggest that walking 5000 or more steps per day and maintaining a total energy intake of 30 kcal/IBW may serve as a reference for lifestyle guidelines for compensated cirrhotic patients.

DOI： 10.1111/hepr.12085

PubMed

PubMed

肝硬変患者における栄養因子と筋肉減少症に関連があるかどうか検討した。41歳以上の肝硬変患者50名を被験者とし、食事習慣について面接を受け、日々の身体活動を歩数計により測定した。生体電気インピーダンス法を用いて四肢骨格筋量(ASM)を測定し、骨格筋体積指数(SMI)を算出した。握力計を用いて握力を測定した。筋肉減少症はSMIと握力から判定した。肝硬変患者を正常群と筋肉減少症群に分類し、2群の比較を行った。単変量および多変量ロジスティック回帰モデル化法を用いて肝硬変患者における筋肉減少症の罹患率を決定した。その結果、身長、理想体重(IBW)に対するエネルギー摂取量、そして歩数が筋肉減少症の独立の関連因子であった。さらに、筋肉減少症群では有意に多い数の患者がIBWに対するエネルギー摂取量と歩数の両方の指数で低い値を示した。以上の結果から、1日に5000歩以上の歩行と30kcal/IBWの総エネルギー摂取量を維持することで代償性肝硬変患者の生活様式の指針に関する基準が充足される可能性が示された。

トランスフォーミング増殖因子(TGF)-βのI型受容体と炎症誘導性サイトカイン活性化キナーゼは異なった様式でSmad2とSmad3をリン酸化してC末端(C)、リンカー(L)、または両方(C/L)のリン酸化型(p)アイソフォームを形成する。C型肝炎ウイルス(HCV)関連慢性肝疾患の異なったステージの患者100名を対象に、リン酸化Smad2/3の陽性率を検証した。HCV除去後のリン酸化Smad2/3の変化について検証するために、持続性ウイルス陰性化応答(SVR)の達成前後に得た肝生検試料の32組を解析して、患者を2群に分割した。20名の患者はSVR達成後に肝細胞がん(HCC)を発症せず(非HCC群)、12名の患者はSVRの達成にも拘わらずHCCを発症していた(HCC群)。分析の結果、肝臓疾患の進行に伴って、肝細胞の腫瘍抑制性pSmad3Cシグナルは発がん性pSmad3Lと線維原性pSmad2L/Cシグナルに変化していた。非HCC群ではSVR後に13名(65%)の患者で線維化の退行と炎症の低下が認められた。興味深いことに、SVRは肝細胞に細胞増殖抑制性のpSmad3Cシグナルを回復させ、一方で先に発現していた発がん性のpSmad3Cシグナルと線維原性のpSmad2L/Cシグナルを抑制した。HCC群では7名(58%)の患者が炎症活性の緩和にも拘わらず線維化は維持または進行さえ認められ、この現象は肝細胞の多くが高いpSmad3LとpSmad2L/Cシグナルを保持しつつ、pSmad3Cシグナルは低い状態であることを反映していると考えられた。

通院中の脂肪肝患者213例(男性103例、女性110例、年齢55.7±14.1歳)を対象として、アルコール性肝障害(ALD)/非アルコール性肝障害(NAFLD)指数であるANIの有用性について検討した。その結果、ANIは1日飲酒量と正の相関が示され、アルコール性肝障害(ALD)患者では非アルコール性肝障害(NAFLD)患者と比べ、有意にANIが高値を示した。ANIのカットオフ値を-0.795とした場合、感度は68%、特異度は80%、陽性的中率は44%、陰性的中率は8%であった。多変量解析では、ANI以外にγ-GTPが峻別する独立した臨床検査値として抽出された。

通院中の脂肪肝患者213例(男性103例、女性110例、年齢55.7±14.1歳)を対象として、アルコール性肝障害(ALD)/非アルコール性肝障害(NAFLD)指数であるANIの有用性について検討した。その結果、ANIは1日飲酒量と正の相関が示され、アルコール性肝障害(ALD)患者では非アルコール性肝障害(NAFLD)患者と比べ、有意にANIが高値を示した。ANIのカットオフ値を-0.795とした場合、感度は68%、特異度は80%、陽性的中率は44%、陰性的中率は8%であった。多変量解析では、ANI以外にγ-GTPが峻別する独立した臨床検査値として抽出された。

B型肝炎ウイルス(HBV)再活性化による重篤な肝障害を阻止するためにはHBV DNA測定が推奨されているが、長期間に及ぶ測定を継続することは医療経済的に問題がある。そこで関節リウマチ(RA)症例とHBs抗原陽性例におけるHBV再活性化の実態を解析、更にエンテカビル(ETV)治療介入による肝炎阻止効果について検討した。研究1では2012年6月以前に生物学的製剤を導入したRA患者71例について2〜3ヵ月ごとにHBV DNAを測定し、再活性化の観察期間別頻度を調査した。研究2ではETV投与を実施したHBs抗原陽性13例(血液疾患6例、RA5例、腎移植2例)について長期効果を調べた。その結果、研究1では4年以上観察例20例、2〜4年観察23例、2年未満観察例28例であった。HBV再活性化は2年未満観察例に1例に認められたが、4年以上の長期観察例ではHBV再活性化は認めず、長期観察例に共通する臨床背景(HBs抗体価や使用薬剤など)は特定できなかった。一方、研究2ではHBs抗原陽性例の治療前HBV DNAは定量未満2例、2.3〜8.5logで、HBs抗原陽性13例中11例に対しETV0.5mg/日が投与された。尚、治療期間12〜60ヵ月において10例でHPV DNAは検出感度未満に低下した。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

AimThe aim of this study was to evaluate the efficacy and safety of combination therapy using natural human interferon- and ribavirin (IFN-/RBV) for chronic hepatitis C patients who were injection drug users (IDU) and resident in the Airin district of Osaka, containing the biggest slums in Japan.
MethodsTwenty-nine IDU with chronic hepatitis C received combination therapy of IFN-/RBV. The psychiatrist in charge evaluated the scores of the Zung Self-rating Depression Scale (SDS), a self-rating scale based on 20 questions. Univariate logistic regression analyses were used to determine the factors that significantly contributed to complete treatment and a sustained virological response (SVR).
ResultsThirteen of the 29 patients achieved SVR according to the intention to treat analysis. All patients with a rapid virological response achieved SVR. No patient required a reduced dose of RBV because of a decrease in their hemoglobin level, or of IFN- because of a low level of white blood cells and platelet count. Two patients had psychological side-effects and stopped the therapy early in the treatment; one patient had depression and the other had anxious depression. Univariate logistic regression analyses indicated that the stage of fibrosis was the only factor that contributed to SVR, and that the SDS test and past drug abuse contributed to completion of the treatment.
ConclusionIFN-/RBV combination therapy is useful for treating IDU.

DOI： 10.1111/hepr.12066

PubMed

大阪のあいりん地区に住む、針の共用を行う注射薬物使用者(IDU)である慢性C型肝炎29名を対象に、天然のヒトインターフェロン-βとリバビリン(IFN-β/RBV)の併用療法の有効性と安全性について評価した。Zungの自己診断うつ病尺度(SDS)によるスコアを評価した。Intention-to-treat分析では29名の患者のうち12名がウイルス持続陰性化応答(SVR)を達成していた。早期ウイルス陰性化を達成した全患者がSVRを達成した。ヘモグロビン濃度の減少によりRBVの減薬が必要であった患者はおらず、白血球と血小板の低下によりIFN-βの減薬が必要な患者もいなかった。2名の患者で精神学的に悪影響を認め、早期に治療を断念した。うち1名がうつ病、もう1名が不安うつ病であった。単変量ロジスティック回帰分析の結果、線維化のステージがSVRに寄与する唯一の因子であり、SDS検査と過去の薬剤濫用は治療の完遂に関連があった。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Purpose: Mac-2 binding protein (Mac-2bp) is one of the major fucosylated glycoproteins, which we identified with glycol-proteomic analyses. We previously reported that fucosylated glycoproteins are secreted into bile, but scarcely secreted into sera in normal liver and hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes due to the loss of cellular polarity. In the present study, we investigated the availability of Mac-2bp for differential diagnosis of nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD) as a biomarker. Experimental design: Serum Mac-2bp levels were determined with our developed ELISA kit. Our cohort of 127 patients with NAFLD had liver biopsy to make a histological diagnosis of NASH and simple fatty liver. Results: Mac-2bp levels were significantly elevated in NASH patients compared with non-NASH (simple steatosis) patients (2.132 ± 1.237 vs. 1.103 ± 0.500 μg/mL, p &lt
0.01). The area under the receiver-operating characteristic curve for predicting NASH by Mac-2bp was 0.816. Moreover, multivariate logistic regression analyses showed Mac-2bp levels could predict the fibrosis stage and the presence of ballooning hepatocytes in NAFLD patients. Conclusions and clinical relevance: These results support the potential usefulness of measuring Mac-2bp levels in clinical practice as a biomarker for NASH. © 2013 WILEY-VCH Verlag GmbH &amp
Co. KGaA, Weinheim.

DOI： 10.1002/prca.201200137

PubMed

CiNii Article

Several factors influence the clinical course of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, has been considered one of the most important host factors with respect to outcomes. To date, conventional genotyping studies have shown that HLA class. loci are mainly associated with spontaneous clearance of HBV and HCV. However, the specific HLA locus associated with the outcomes of hepatitis virus infection remains unclear. A recent genome-wide association study (GWAS) using a comprehensive approach for human genotyping demonstrated single nucleotide polymorphisms (SNPs) associated with the outcomes of hepatitis virus infection. Examination of large numbers of cohorts revealed that several SNPs in both HLA-DPA1 and HLA-DPB1 loci are associated with persistent HBV infection in Asian populations. To date, however, few studies have focused on HLA-DP because polymorphisms of HLA-DP haplotype do not vary greatly as compared with other loci of HLA. There are not enough studies to reveal the function of HLA-DP. GWAS additionally detected candidate SNPs within HLA loci associated with chronic HBV or HCV hepatitis, hepatic fibrosis, and the development of hepatocellular carcinoma. The results of one cohort were not always consistent with those of other cohorts. To solve several controversial issues, it is necessary to validate reported SNPs on HLA loci in global populations and to elucidate the HLA-allele-regulated molecular response to hepatitis virus infection. (C) 2013 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v19.i33.5395

PubMed

CiNii Article

Currently available antiviral treatment for chronic hepatitis B virus infection can be divided into two classes of therapeutic agents: nucleos(t)ide analogues (NAs) and interferon (IFN). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy; the advantages of IFN include a finite course of treatment, absence of drug resistance, and an opportunity to obtain a post-treatment durable response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Here, we have reviewed previous reports of either simultaneous or sequential combination therapy with NA and IFN for chronic hepatitis B patients. In previous studies comparing the lamivudine/IFN combination and lamivudine monotherapy in a finite course, combination therapy was associated with higher rates of sustained post-treatment response and lower rates of drug resistance than lamivudine monotherapy. However, NAs such as lamivudine are generally administered indefinitely because of high rates of post-treatment relapse. In addition, concern for drug resistance has decreased significantly with newer, high-potency NAs even when administered alone. In previous studies comparing the lamivudine/IFN combination and IFN monotherapy, the combination therapy showed greater on-treatment viral suppression, but no difference was observed in the post-treatment sustained response. Thus, whether combination therapy confers an additional benefit compared to monotherapy for treating chronic hepatitis B remains unclear. The efficacy of IFN in combination with a more potent NA, such as entecavir or tenofovir, remains to be comprehensively evaluated.

DOI： 10.1007/s00535-012-0742-5

PubMed

通院中のNAFLD 42名、NASH 58名、対照群として健常者57名において、生活習慣病の保健指導支援ソフトウェア"ヘルッチェ"(スズケン)や、生活習慣記録機ライフコーダ(スズケン)などを用いて、日常の生活習慣を分析した。結果、NAFLD/NASHでは健常者に比べ、体組成的に脂肪量が多く握力が低下している傾向が見られた。この傾向はNASH群においてより顕著であった。食習慣については、健常群と比して総摂取カロリーの過剰や、PFC比の偏りは見られず、食習慣改善に対するステージモデルにおいても、実行期・維持期の割合が有意に高く、意識して改善している傾向が見られた。しかし男性では健常者に比して魚介類の摂取量が少ないことなどから、摂取食品、食材にまで気を配った食事指導が望まれた。運動習慣について、身体活動量や歩数が低値を示し、生活活動強度が低い傾向が見られた。男女ともに、NAFLD/NASH群は自らの病識も明確で、食習慣は改善意識が高く改善傾向が見られたが、生活活動強度/運動習慣においては改善の余地があった。NAFLD/NASH患者には、食事指導のみならず、生活活動強度の向上、無理のないエクササイズ実施、継続など、包括的な生活改善支援が望まれる。(著者抄録)

症例は65歳男性で、56歳時に肝細胞癌(HCC)と診断され、経カテーテル動脈化学塞栓術(TACE)が行われた。その後も再発を繰り返し、経皮的エタノール注入やTACEで治療された。CTでHCCの多発性肺転移が明らかになったが、汎血球減少症を伴うChild-Pugh Bの肝硬変を有していたため、ソラフェニブの投与を400mg/日の用量で開始した。投与期間は21日に過ぎなかったが、腫瘍の完全退縮がみられた。抗癌剤の投与なしでも腫瘍の再発はなかった。短期間のソラフェニブ治療で完全緩解が達成されたのは極めて稀である。

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10620-012-2514-8

PubMed

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Publishing type：Research paper (scientific journal)  

The optimal management of acute hepatitis B in pregnant women remains to be fully evaluated. A case of hepatitis B virus (HBV) infection in a 20-year-old pregnant woman who initially presented with jaundice is reported. Serum samples were positive for anti-HBc IgM and HBe antigen. Her husband was infected with HBV genotype A and received entecavir because of prolonged hepatitis and a high viral load. The HBV DNA sequence of the wife completely matched that of her husband, indicating that he was the source of HBV infection. In accordance with guidelines for the treatment of chronic HBV carriers, the wife started to receive tenofovir disoproxil fumarate (TDF) in her third trimester. After 4 months of treatment, the HBV DNA load decreased from 7.6 to 3.5 log copies/ml. At delivery, the serum was found negative for the HBe antigen. Seven months after treatment began, the HBs antigens also disappeared. The baby, totally healthy, received passive - active immunoprophylaxis. At 3 months, the baby remained free of HBV infection. TDF thus prevented exacerbation and prolongation of acute HBV infection in a pregnant woman. Subsequent treatment also prevented mother-to-infant transmission of HBV. The clinical course of her husband, who had HBV infection and received entecavir, is also reported. © Springer 2013.

DOI： 10.1007/s12328-013-0370-5

PubMed

20歳の妊娠中の女性。黄疸のため受診した。血清標本で抗HBc IgMおよびHBe抗原が陽性であった。夫が遺伝子型AのB型肝炎ウィルス(HBV)に感染しており、持続性肝炎と高ウィルス量のためエンテカビルを投与されていた。HBV DNA配列解析の結果、夫婦の配列は完全に一致し、夫が感染源であると考えられた。妊娠第3三半期にテノフォビルディソプロキシルフマル酸(TDF)による治療を開始した。4ヵ月後、HBV DNA量は7.6から3.5logコピー/mlに減少し、出産時には血清HBe抗原は陰性であった。治療開始から7ヵ月後、HBs抗原も消失した。児は健常で、受動-能動免疫予防を受けた。6月齢の時点でHBV感染は認めなかった。夫はエンテカルビル投与を開始して7ヵ月後もHBV DNAが検出された。

DOI： 10.1007/s00535-013-0759-4

PubMed

Publishing type：Research paper (scientific journal)  

Background: Many studies support the hypothesis that specific microRNA (miRNA) expression in various human cancers including hepatocarcinogenesis is closely associated with diagnosis and prognosis. In hepatocellular carcinoma (HCC), malignancy level is related to the degree of histological differentiation. Methods: In order to establish a novel biomarker that can determine the degree of malignancy and forecast patient prognosis, we performed a microarray analysis to investigate the miRNA expression profiles in 110 HCC which were comprised of 60 moderately, 30 poorly, and 20 well differentiated HCC. Results: We found that the expression of 12 miRNAs varied significantly according to the degree of histological differentiation. Particularly, miR-18b expression in poorly differentiated HCC was significantly higher than in well differentiated HCC. Based on miRanda and Targetscan target search algorithms and Argonaute 2 immunoprecipitation study, we noted that miR-18b can control the expression of trinucleotide repeat containing 6B (TNRC6B) as a target gene. Additionally, in two hepatoma cell lines, we found that over-expression of miR-18b or down-regulation of TNRC6B accelerated cell proliferation and loss of cell adhesion ability. Finally, we observed that after surgical resection, HCC patients with high miR-18b expression had a significantly shorter relapse-free period than those with low expression. Conclusions: miR-18b expression is an important marker of cell proliferation and cell adhesion, and is predictive of clinical outcome. From a clinical point of view, our study emphasizes miR-18b as a diagnostic and prognostic marker for HCC progression. © 2013 Murakami et al
licensee BioMed Central Ltd.

DOI： 10.1186/1471-2407-13-99

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PubMed

症例は70歳代、男性。肝細胞癌に対する経カテーテル的肝動脈塞栓術施行目的で入院した。術後に腫瘍崩壊症候群を発症したが、血液透析にて軽快した。また、一時的に肝機能障害および肝予備能低下を認めたものの保存的治療にて軽快した。巨大な肝細胞癌に対する肝動脈塞栓術後には、常に腫瘍崩壊症候群や肝予備能低下がおこる可能性に留意すべきと思われたため、若干の文献的考察を加え報告する。(著者抄録)

Publishing type：Research paper (scientific journal)  

Background The outcomes of sequential therapy with lamivudine followed by interferon have been unsatisfactory in Japanese patients with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B. However, the efficacy of sequential therapy with entecavir and interferon remains unclear. Methods Twenty-four HBeAg-positive patients (23 men and 1 woman
mean age 39 ± 7 years) received entecavir 0.5 mg alone for 36-52 weeks, followed by entecavir plus interferon-α for 4 weeks, and lastly by interferon-a alone for 20 weeks. Twenty-three patients had genotype C infection, and one had genotype A infection. Results No entecavir-resistant mutant variants emerged in any patient. Hepatitis flare occurred in three patients during interferon-a treatment after the withdrawal of entecavir, but none had hepatic decompensation. Serum hepatitis B surface antigen levels did not change during or after therapy. Serum hepatitis B core-related antigen levels were significantly decreased at the start (P &lt
0.0001) and at the end of interferon-a treatment (P &lt
0.0001), but returned to baseline levels after treatment. Twenty-four weeks after the completion of the sequential therapy, a sustained biochemical, virological, and serological response was achieved in 5 (21 %) patients. The proportion of patients in whom HBeAg was lost during entecavir treatment was significantly higher among those with a sustained response than among those with no response (P = 0.015). Conclusions The rate of response to sequential therapy with entecavir and interferon-α in Japanese patients with HBeAg-positive chronic hepatitis B was not higher than the rate in previous studies of lamivudine followed by interferon. © Springer 2012.

DOI： 10.1007/s00535-012-0645-5

PubMed

B型肝炎エンベロープ抗原(HBeAg)陽性患者24名(男性23名、女性1名、平均年齢39歳)に対し、entecavir 0.5mgを36-52週間単剤投与してから、entecavir+interferon-αを4週間併用投与し、最後にinterferon-αを20週間単剤投与した。遺伝子型Cの感染が23名、遺伝子型Aの感染が1名であった。全患者でentecavir耐性突然変異体の出現はなかった。患者3名でentecavir終了後のinterferon-α投与中に肝炎が再燃したが、肝代償不全を呈した患者はいなかった。投薬中または投薬後の血清中B型肝炎表面抗原値の変化はなかった。血清中B型肝炎ウイルスコア関連抗原値は、interferon-α投与の開始時と終了時に有意に減少したが、連続療法終了後にはベースライン値に戻った。連続療法終了から24週間後に生化学的、ウイルス学的および血清学的反応が持続していた患者は5名であった。Entecavir投与中にHBeAgが消失した患者の比率は、反応が持続していた患者の方が、反応がみられなかった患者より有意に高かった。HBeAg陽性慢性B型肝炎の日本人患者におけるentecavir+interferon-α連続療法に対する反応率は、lamivudineの後にinterferonを投与した際の過去の試験における反応率より高くなかった。

Publishing type：Research paper (scientific journal)  

The response rate and overall survival after sorafenib administration in patients with advanced hepatocellular carcinoma are unsatisfactory. We herein present the case of a 65-year-old man with multiple lung metastases of hepatocellular carcinoma. Because the patient had liver cirrhosis of Child-Pugh B accompanied by pancytopenia, sorafenib administration was initiated at a dose of 400 mg daily. Although he received sorafenib for only 21 days, the patient exhibited complete regression of the tumors. There was no clinical evidence of recurrence without the administration of anticancer treatment. It is unique that short-term sorafenib treatment achieved a complete response.<br>

DOI： 10.2169/internalmedicine.52.9340

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem around the world. NAFLD patients with nonalcoholic steatohepatitis (NASH) can develop cirrhosis and hepatocellular carcinoma. The ability to distinguish NASH from simple steatosis would be of great clinical significance. Ballooning hepatocytes are characteristic of typical pathological NASH; here, the polarized secretion of proteins is disrupted due to destruction of the cytoskeleton. We previously reported that fucosylated glycoproteins are secreted into bile, but not into sera in normal liver. Therefore, we hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes, and serum fucosylated glycoproteins would increase in NASH patients. To confirm our hypothesis, we evaluated serum fucosylated haptoglobin (Fuc-Hpt) levels in biopsy-proven NAFLD patients (n = 126) using a lectin-antibody ELISA kit. Fuc-Hpt levels were significantly increased in NASH patients compared with non-NASH (NAFLD patients without NASH) patients. Interestingly, Fuc-Hpt levels showed a significant stepwise increase with increasing hepatocyte ballooning scores. Multiple logistic regression analysis showed that Fuc-Hpt levels were independent and significant determinants of the presence of ballooning hepatocytes. Moreover, Fuc-Hpt levels were useful in monitoring liver fibrosis staging. Next, to investigate the significance of serum Fuc-Hpt in a larger population, we measured Fuc-Hpt levels in ultrasound-diagnosed NAFLD subjects (n = 870) who received a medical health checkup. To evaluate NAFLD disease severity, we used the FIB-4 index (based on age, serum AST and ALT levels, and platelet counts). Fuc-Hpt levels increased stepwise with increasing FIB-4 index. CONCLUSION: Measurement of serum Fuc-Hpt levels can distinguish NASH from non-NASH patients, and predict the presence of ballooning hepatocytes in NAFLD patients with sufficient accuracy. These results support the potential usefulness of measuring Fuc-Hpt levels in clinical practice.

DOI： 10.1371/journal.pone.0066328

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Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

INTRODUCTION: To date, there have been no prospective studies examining the effect of coffee consumption on serum alanine aminotransferase (ALT) level among individuals infected with the hepatitis C virus (HCV). We conducted a hospital-based cohort study among patients with chronic HCV infection to assess an association between baseline coffee consumption and subsequent ALT levels for 12 months. MATERIALS AND METHODS: From 1 August 2005 to 31 July 2006, total 376 HCV-RNA positive patients were recruited. A baseline questionnaire elicited information on the frequency of coffee consumption and other caffeine-containing beverages. ALT level as a study outcome was followed through the patients' medical records during 12 months. The association between baseline beverage consumption and subsequent ALT levels was evaluated separately among patients with baseline ALT levels within normal range (≤45 IU/L) and among those with higher ALT levels (>45 IU/L). RESULTS: Among 229 patients with baseline ALT levels within normal range, 186 (81%) retained normal ALT levels at 12 months after recruitment. Daily drinkers of filtered coffee were three times more likely to preserve a normal ALT level than non-drinkers (OR=2.74; P=0.037). However, decaffeinated coffee drinkers had a somewhat inverse effect for sustained normal ALT levels, with marginal significance (OR=0.26; P=0.076). In addition, among 147 patients with higher baseline ALT levels, 39 patients (27%) had ALT reductions of ≥20 IU/L at 12 months after recruitment. Daily drinkers of filtered coffee had a significantly increased OR for ALT reduction (OR=3.79; P=0.034). However, in decaffeinated coffee drinkers, OR could not be calculated because no patients had ALT reduction. CONCLUSION: Among patients with chronic HCV infection, daily consumption of filtered coffee may have a beneficial effect on the stabilization of ALT levels.

DOI： 10.1371/journal.pone.0083382

PubMed

Publishing type：Research paper (scientific journal)  

Aim: Some regions associated with sensitivity to interferon-a and ribavirin have been identified in the hepatitis C virus (HCV) genome, including amino acid 70 in the core region (core a.a. 70), a.a. 22092248 (interferon sensitivity-determining region, ISDR) and a.a. 23342379 (interferon and ribavirin resistance-determining region, IRRDR).
Methods: We examined changes in the sequences of these regions in 25 patients with chronic HCV genotype 1 infection who had not had sustained virological response (SVR) to interferon-a and ribavirin for 2448 weeks and subsequently received retreatment for 4872 weeks.
Results: At baseline, the core a.a. 70 was mutant (resistant) type in seven patients. At the start of retreatment, the core a.a. 70 had changed from sensitive to resistant type in 2 patients, and SVR was not achieved by retreatment. The ISDR variations were resistant type (01 mutations) in 17 patients at baseline. After 2 weeks of treatment, amino acid change was found in two patients; in one, the substitutions returned to baseline status after treatment, and in the other, the substitution persisted. At the start of retreatment, ISDR sequences had changed from resistant to sensitive type in two patients and SVR was achieved and from sensitive to resistant type in three patients and SVR was not achieved. The IRRDR variations were resistant type (&lt;6 mutations) in 19 patients at baseline and at the start of retreatment.
Conclusion: Sequences of the core region and ISDR sometimes change during anti-HCV therapy, potentially affecting the outcomes of retreatment.

DOI： 10.1111/j.1872-034X.2012.01046.x

PubMed

C型肝炎ウイルス(HCV)ゲノムにはインターフェロン(IFN)αとリバビリンに対する感受性に関連する領域がいくつか同定されており、コア領域の70アミノ酸残基(core a.a.70)、a.a.2209-2248(INF感受性決定領域、ISDR)、a.a.2334-2379(IFNとリバビリンの抵抗性決定領域、IRRDR)等がある。今回、遺伝子型1型のHCVに感染し、24から48週間のIFNαとリバビリン療法で持続陰性化(SVR)を達成せず、48〜72週で再投与を行っている慢性C型肝炎患者25名を対象に、上述の領域の遺伝子配列を分析した。治療開始前の段階ではa.a.70の変異型(抵抗性)が7名に認められた。再治療開始後、2名の患者でa.a.70の領域に感受性型から抵抗性型への転換が生じ、再治療によるSVRは達成できなかった。また、ISDRについては治療開始前では17名の患者で抵抗性型(0から1個の変異)であった。2週間の治療後、2名の患者でアミノ酸に変異が認められた。1名は治療後に標準状態に戻り、残り1名は変異が維持されていた。再治療開始時にISDRの配列は2名の患者で抵抗性型から感受性型に転換が認められSVRが達成されたが、感受性型から抵抗性型に変わった3名の患者ではSVRが達成できなかった。IRRDR配列については治療開始前と再治療開始前の段階で19名の患者で抵抗性(6個未満の変異)が認められた。

Publishing type：Research paper (scientific journal)  

Background MicroRNAs (miRNAs) are important in hepatic pathophysiology and the development of liver cancer.
Objective To explore miRNAs that are regulated with the progression of liver fibrosis caused by chronic liver disease.
Design The regulated miRNAs in human livers infected with hepatitis C virus were identified by microarray analysis. Their expression in human livers with nonalcoholic steatohepatitis, mouse livers from two fibrosis models and cultured stellate cells was validated by realtime RT-PCR. The regulation of miR-222 expression in stellate cells by nuclear factor kappa B (NF-kappa B) was assayed. Finally, the effects of an miR-222 precursor or inhibitor on the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) and the growth of LX-2 cells were determined.
Results It was found that miR-199a-5p/199a-3p and miR-221/222 were upregulated in the human liver in a fibrosis progressionedependent manner. Among these miRNAs, miR-221/222 were upregulated in LX-2 cells and increased during the course of culture-dependent activation of mouse primary stellate cells, in a manner similar to the expression of alpha 1(I) collagen and alpha-smooth muscle actin mRNAs. The expression of miR-221/222 increased in mouse models of liver fibrosis. In contrast, an NF-kappa B inhibitor significantly suppressed the miR-222 induction that was stimulated in culture by transforming growth factor alpha or tumour necrosis factor alpha. Although overexpression or downregulation of miR-222 failed to regulate the growth of LX-2 cells, miR-222 bound to the CDKN1B 3'UTR and regulated the expression of the corresponding protein.
Conclusion miR-221/222 may be new markers for stellate cell activation and liver fibrosis progression.

DOI： 10.1136/gutjnl-2011-300717

PubMed

Publishing type：Research paper (scientific journal)  

AIM: To assess the nourishment status and lifestyle of non-hospitalized patients with compensated cirrhosis by using noninvasive methods. METHODS: The subjects for this study consisted of 27 healthy volunteers, 59 patients with chronic viral hepatitis, and 74 patients with viral cirrhosis, from urban areas. We assessed the biochemical blood tests, anthropometric parameters, diet, lifestyle and physical activity of the patients. A homeostasis model assessment-insulin resistance (HOMA-IR) value of ≥ 2.5 was considered to indicate insulin resistance. We measured height, weight, waist circumference, arm circumference, triceps skin-fold thickness, and handgrip strength, and calculated body mass index, arm muscle circumference (AMC), and arm muscle area (AMA). We interviewed the subjects about their dietary habits and lifestyle using health assessment computer software. We surveyed daily physical activity using a pedometer. Univariate and multivariate logistic regression modeling were used to identify the relevant factors for insulin resistance. RESULTS: The rate of patients with HOMA-IR ≥ 2.5 (which was considered to indicate insulin resistance) was 14 (35.9%) in the chronic hepatitis and 17 (37.8%) in the cirrhotic patients. AMC (%) (control vs chronic hepatitis, 111.9% ± 10.5% vs 104.9% ± 10.7%, P = 0.021
control vs cirrhosis, 111.9% ± 10.5% vs 102.7% ± 10.8%, P = 0.001) and AMA (%) (control vs chronic hepatitis, 128.2% ± 25.1% vs 112.2% ± 22.9%, P = 0.013
control vs cirrhosis, 128.2% ± 25.1% vs 107.5% ± 22.5%, P = 0.001) in patients with chronic hepatitis and liver cirrhosis were significantly lower than in the control subjects. Handgrip strength (%) in the cirrhosis group was significantly lower than in the controls (control vs cirrhosis, 92.1% ± 16.2% vs 66.9% ± 17.6%, P &lt
0.001). The results might reflect a decrease in muscle mass. The total nutrition intake and amounts of carbohydrates, protein and fat were not significantly different amongst the groups. Physical activity levels (kcal/d) (control vs cirrhosis, 210 ± 113 kcal/d vs 125 ± 74 kcal/d, P = 0.001), number of steps (step/d) (control vs cirrhosis, 8070 ± 3027 step/d vs 5789 ± 3368 step/d, P = 0.011), and exercise (Ex) (Ex/wk) (control vs cirrhosis, 12.4 ± 9.3 Ex/wk vs 7.0 ± 7.7 Ex/wk, P = 0.013) in the cirrhosis group was significantly lower than the control group. The results indicate that the physical activity level of the chronic hepatitis and cirrhosis groups were low. Univariate and multivariate logistic regression modeling suggested that Ex was associated with insulin resistance (odds ratio, 6.809
95% CI, 1.288-36.001
P = 0.024). The results seem to point towards decreased physical activity being a relevant factor for insulin resistance. CONCLUSION: Non-hospitalized cirrhotic patients may need to maintain an adequate dietary intake and receive lifestyle guidance to increase their physical activity levels. © 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i40.5759

PubMed

CiNii Article

DOI： 10.1111/j.1872-034X.2012.01001.x

PubMed

Publishing type：Research paper (scientific journal)  

Background: The activation of hepatic stellate cells plays a central role in the development of liver fibrosis during chronic liver trauma. The aim of the present study was to identify a compound that inhibits the activation process of stellate cells. Methods: Rat primary cultured stellate cells and a human stellate cell line (LX-2) were used. The effects of arundic acid on the expression of α-smooth muscle actin, collagen 1α1, and cytoglobin were evaluated. Results: Arundic acid (300. μM) inhibited the activation of primary rat stellate cells, as determined by morphological transformation and α-smooth muscle actin expression, after both prophylactic and therapeutic treatment. The level of α-smooth muscle actin mRNA showed a dose-dependent decrease in response to arundic acid, and 50. μM arundic acid exhibited the maximum inhibition of collagen 1α1 mRNA expression. In contrast, arundic acid triggered an unexpected increase in mRNA and protein levels of cytoglobin, the fourth globin in mammals expressed exclusively in hepatic stellate cells. The effect of arundic acid on the level of α-smooth muscle actin mRNA was abrogated in HSCs treated with cytoglobin siRNA. Arundic acid decreased the expression of collagen 1α1 mRNA in LX-2 cells. Conclusion: Arundic acid affects the activation process of hepatic stellate cells via the unexpected induction of cytoglobin. © 2012 Elsevier Inc.

DOI： 10.1016/j.bbrc.2012.07.126

PubMed

Publishing type：Research paper (scientific journal)  

Background: miRNAs are non-coding RNAs that regulate gene expression in a wide range of biological contexts, including a variety of diseases. The present study clarified the role of miR-214-5p in hepatic fibrogenesis using human clinical tissue samples, livers from rodent models, and cultured hepatic stellate cells.Methods: The expression of miR-214-5p and genes that are involved in liver fibrosis were analyzed in hepatitis C virus-infected human livers, rodent fibrotic livers, a human stellate cell line (LX-2), and the cells from intact mouse livers using real-time PCR. The effect of miR-214-5p overexpression in LX-2 cells on cell function was investigated. Twist-1 expression in the liver tissues of mouse models and primary-cultured stellate cells was also analyzed.Results: miR-214-5p was upregulated in human and mouse livers in a fibrosis progression-dependent manner. miR-214-5p expression increased during the culture-dependent activation of mouse primary stellate cells and was significantly higher in stellate cells than in hepatocytes. The overexpression of miR-214-5p in LX-2 cells increased the expression of fibrosis-related genes, such as matrix metalloproteinase (MMP)-2, MMP-9, α-smooth muscle actin, and transforming growth factor (TGF)-β1. TGF-β stimulation induced miR-214-5p in LX-2 cells. Twist-1 was increased in fibrotic mouse livers and induced during mouse stellate cell activation.Conclusion: miR-214-5p may play crucial roles in the activation of stellate cells and the progression of liver fibrosis. Twist-1 may regulate miR-214-5p expression in the liver, particularly in stellate cells. © 2012 Iizuka et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1755-1536-5-12

PubMed

CiNii Article

遺伝子型が2型のC型肝炎ウイルス(HCV)の患者に対してresponse-guided therapyを行った際の治療効果を評価した。2型のC型肝炎ウイルスに感染し、ウイルス量が5.0LogIU/mLより高く、ペグ化インターフェロンとリバビリンの併用で目標容量の75%以上を摂取している患者105名を対象とした。4週時ウイルス陰性化(RVR)を示した患者のうち14名を16週の治療期間(A群)、28名を24週の治療期間(B群)とした。非RVR患者のうち、40名は24週の治療期間(C群)、19名は48週の治療期間(D群)とした。その結果、A群とB群の全患者が持続的ウイルス陰性化(SVR)を達成した。治療開始後のより遅い週にHCV RNAが消滅した患者の割合はD群で高かった(p=0.0578)。SVR達成率はC群で73%、D群で79%であった。5週〜8週でHCV RNAが消失した患者のうちSVRを達成したのはC群34名中28名(82%)、D群11名中10名(91%)であった。9〜12週にHCV RNAが消失した患者はC群は5名中1名(20%)、D群は8名中5名(63%)であった。以上より、RVR患者に対しては16週の混合療法により適切なウイルス抑制効果が得られた。非RVR患者に対して治療を延長することではSVR達成率を有意に改善できなかった。

Publishing type：Research paper (scientific journal)  

N-Acetylglucosaminyltransferase V (GnT-V), catalyzing 1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in tumor metastasis and carcinogenesis. Although the expression of GnT-V is induced in chronic liver diseases, the biological meaning of GnT-V in the diseases remains unknown. The aim of this study was to investigate the effects of GnT-V on the progression of chronic hepatitis, using GnT-V transgenic (Tg) mice fed a high fat and high cholesterol (HFHC) diet, an experimental model of murine steatohepatitis. Although enhanced hepatic lymphocytes infiltration and fibrosis were observed in wild-type (WT) mice fed the HFHC diet, they were dramatically prevented in Tg mice. In addition, the gene expression of inflammatory Th1 cytokines in the liver was significantly decreased in Tg mice than WT mice. Inhibition of liver fibrosis was due to the dysfunction of hepatic stellate cells (HSCs), which play pivotal roles in liver fibrosis through the production of transforming growth factor (TGF)-1. Although TGF-1 signaling was enhanced in Tg mouse-derived HSCs (Tg-HSCs) compared with WT mouse-derived HSCs (WT-HSCs), collagen expression was significantly reduced in Tg-HSCs. As a result from DNA microarray, cyclooxygenase-2 (COX2) expression, known as a negative feedback signal for TGF-1, was significantly elevated in Tg-HSCs compared with WT-HSCs. Prostaglandin E2 (PGE2), the product of COX2, production was also significantly elevated in Tg-HSCs. COX2 inhibition by celecoxib decreased PGE2 and increased collagen expression in Tg-HSCs. In conclusion, GnT-V prevented steatohepatitis progression through modulating lymphocyte and HSC functions. © The Author 2012.

DOI： 10.1093/glycob/cws012

PubMed

Publishing type：Research paper (scientific journal)  

Aim: We evaluated the efficacy of response-guided therapy in patients with hepatitis C virus (HCV) genotype 2. Methods: We studied 105 patients with an HCV genotype 2 load of higher than 5.0Log IU/mL who received more than 75% of the target dose of pegylated interferon plus ribavirin. Among patients with rapid viral response (RVR
no HCV RNA detected at week 4), 14 selected 16weeks of therapy (group A), and 28 selected 24weeks of therapy (group B). Among non-RVR patients, 40 selected 24weeks of therapy (group C), and 19 selected 48weeks of therapy (group D). Results: All patients in group A and B achieved a sustained viral response (SVR). Clinical characteristics did not differ significantly between groups C and D. However, the proportion of patients in whom HCV RNA disappeared at a later week after starting treatment was higher in group D (P=0.0578). SVR rate was 73% in C, and 79% in D. Among patients in whom HCV RNA disappeared between weeks 5 and 8, SVR was achieved in 28 (82%) of 34 patients in C and 10 (91%) of 11 patients in D. Among patients whose HCV RNA disappeared between weeks 9 and 12, SVR was achieved in one (20%) of five patients in C and five (63%) of eight patients in D (not statistically significant). Conclusions: 16weeks of combination therapy could achieve an adequate antiviral effect for RVR patients. Extending therapy could not significantly improve SVR rate in non-RVR patients. © 2012 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2011.00956.x

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND AND OBJECTIVES: Gastroparesis, a gastrointestinal autonomic neuropathy, is a common adverse reaction in chronic hepatitis C (CHC) patients receiving interferon therapy. Current therapeutic options are limited. We evaluated the efficacy of mosapride for IFN-induced gastroparesis. METHODS: Twenty-four consecutive CHC patients were randomly assigned to either the control group, which received pegylated interferon α-2b at 1.5 μg/kg/week and ribavirin at 600-1,000 mg/day, depending on body weight (PegIFN/RBV), or the mosapride group, which received PegIFN/RBV plus mosapride at 15 mg/person/day. The solid-phase gastric emptying half-times (T1/2) of the total, proximal, and distal stomach (scintigraphy) and digestive symptoms (questionnaire) were measured within one week before and four weeks after initiation of the assigned therapy. The test meal comprised a 200-g pancake containing Tc-99m diethylenetriamine pentaacetic acid. RESULTS: In the control group, after PegIFN/RBV initiation, a significant increase was observed in the total T1/2 (before: 84.0 ± 22.1 min versus after: 100.8 ± 28.9 min, P = 0.03), the distal T1/2 (before: 95.3 ± 32.2 min versus after: 115.3 ± 41.4 min, P = 0.03), and digestive symptom score (before: 3.2 ± 1.4 versus after: 8.1 ± 4.8, P = 0.02); proximal T1/2 change was not significant. In the mosapride group, no significant delays were observed in the total, proximal, and distal T1/2 values; the change in symptom scores was not significant. CONCLUSIONS: Mosapride improved total and distal gastric motility in IFN-induced gastroparesis, and consequently relieved symptoms.

DOI： 10.1007/s10620-012-2085-8

PubMed