Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIM: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan. METHODS: This study initially included 410,061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Subjects consuming > 20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS). RESULTS: A total of 71,254 subjects were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, 2-fold difference in NAFLD prevalence between males (37.4%) and females (18.1%). NAFLD prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to FIB-4 and NFS, respectively. CONCLUSIONS: The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese subjects. The prevalence of NAFLD with advanced fibrosis was estimated to be 1% to 2%. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13947

PubMed

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

AIM: The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3-4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra-/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra-/extrahepatic events in Asian patients with biopsy-proven NAFLD. METHODS: We undertook a retrospective multicenter cohort study to investigate associations between intra-/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography. RESULTS: Among 403 enrolled patients, 11 had liver-related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3-4), Agile 3+ rule-in (F3-4, highly suspected), and Agile 4 rule-in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule-in, and Agile 4 rule-in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer. CONCLUSIONS: Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment.

DOI： 10.1111/hepr.13938

PubMed

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

BACKGROUND AND AIMS: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. METHODS: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. RESULTS: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3-4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2 ). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. CONCLUSIONS: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

DOI： 10.1111/jgh.16326

PubMed

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

DOI： 10.1016/j.jhepr.2023.100752

PubMed

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

OBJECTIVE: Liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs) obtained using vibration-controlled transient elastography (VCTE) are recognized non-invasive methods of assessing liver histology. The usefulness of CAP for predicting liver-related events (LREs: hepatocellular carcinoma, decompensation, bleeding varices) is not well understood worldwide. Our aim was to re-evaluate the cutoff values of LSM/CAP in Japan and to examine whether LSM/CAP can predict LRE. METHODS: Japanese NAFLD patients (n = 403) who underwent both liver biopsy and VCTE were enrolled. We determined optimal cutoff values of LSM/CAP diagnoses for fibrosis stage and steatosis grade and investigated their clinical outcome based on LSM/CAP values. RESULTS: The LSM cutoff values for F1 to F4 are 7.1, 7.9, 10.0 and 20.2 kPa, and the CAP cutoff values for S1 to S3 are 230, 282 and 320 dB/m. During a median follow-up of 2.7 y (range: 0.0-12.5 y), 11 patients developed LREs. The incidence of LREs in the LSM Hi (≥8.7) group was significantly higher than that in the LSM Lo (<8.7) group (p = 0.003), and the incidence in the CAP Lo (<295) group was higher than that in CAP Hi (≥295) group (p = 0.018). Considering LSM and CAP together, the risk of LRE was higher in the LSM Hi CAP Lo group than in the LSM Hi CAP Hi group (p = 0.03). CONCLUSION: We set LSM/CAP cutoff values to diagnose liver fibrosis and steatosis in Japan. Our study determined that NAFLD patients with high LSM and low CAP values are at high risk for LREs.

DOI： 10.1016/j.ultrasmedbio.2023.03.023

PubMed

DOI： 10.19020/cg.0000002673

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

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

BACKGROUND & AIMS: Noninvasive tests (NITs) have prognostic potential, but whether NITs are comparable with liver biopsy is unclear. This study aimed to examine the prognostic accuracy of NITs for liver-related mortality (LRM) and events (LREs) in patients with biopsy-proven NAFLD. METHODS: We investigated 1,313 patients with NAFLD. Patients were assigned to low-, indeterminate-, and high-risk groups using conventional cutoff values of each FIB-4 and NAFLD fibrosis score (NFS), and to stage 0-2 and stage 3-4 groups using the fibrosis stage. Survival and Cox regression analyses of the prognostic potential of NITs for LRM/LREs were conducted. RESULTS: During a median follow-up of 4.5 years, regarding to FIB-4, the incidence rate (/1000 person-years) in the low-risk was zero for LRM, and 0.5 for LREs. In contrast, the rate in stage 0-2 was 1.3 for LRM, 2.8 for LRE. The adjusted hazard ratios (aHRs) for LREs in the high-risk compared with the low-risk were 32.85 (p<0.01). The aHRs in stage 3-4 compared with stage 0-2 were 2.68 (p=0.02) for LREs, and 2.26 (p=0.582) for LRM. In the same fibrosis stage, the incidence of LRM/LREs was more frequent with a higher risk stratification. The same trend was observed for NFS. CONCLUSIONS: NITs accurately predict LRM and LREs as well as a liver biopsy in Japanese patients with NAFLD. Patients in the low-risk may not require close follow-up for at least 5 years. The simple NITs could be an acceptable alternative method to performing a liver biopsy for the prognosis of NAFLD.

DOI： 10.1111/jgh.16144

PubMed

非アルコール性脂肪性肝疾患(NAFLD)の日本人患者において、進行性線維化および肝硬変の特定にAgile 3+とAgile 4スコアが有用かどうか検討した。2012～2021年に肝生検と肝硬度測定を受け、NAFLDが証明された患者を後ろ向きに調べた。ROC曲線解析でAgile 3+とAgile 4スコアの診断能を評価し、除外診断(rule-out)の低カットオフ値、診断(rule-in)の高カットオフ値の感度、特異度、予測値を算出した。診断能を既存のFIB-4 indexとELF(Enhanced Liver Fibrosis)スコアと比較した。患者641例(年齢17～86歳、女性56.2%)を解析した。Agile 3+による線維化ステージ3以上の診断のROC曲線下面積(AUROC)は0.886、低カットオフ値の感度は95.3%、高カットオフ値の特異度は73.4%であった。Agile 4による線維化ステージ4の診断のAUROC、低カットオフ値の感度、高カットオフ値の特異度はそれぞれ0.930、100%、86.5%であった。両スコアは、FIB-4 indexおよびELFスコアより診断能が高かった。以上より、NAFLD日本人患者においてAgile 3+とAgile 4スコアは進行性線維化および肝硬変の診断に用いることが可能と考えられた。

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。

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

AIM: Agile 3+ and Agile 4 scores, based on liver stiffness measurement (LSM) by transient elastography and clinical parameters, were recently reported to be effective in identifying advanced fibrosis and cirrhosis in nonalcoholic fatty liver disease (NAFLD). This study aimed to validate the utility of these scores in Japanese patients with NAFLD. METHODS: Six hundred forty-one patients with biopsy-proven NAFLD were analyzed. The severity of liver fibrosis was pathologically evaluated by one expert pathologist. LSM, age, sex, diabetes status, platelet count, and aspartate aminotransferase and alanine aminotransferase levels were used to calculate Agile 3+ scores, and the parameters above excluding age were used for Agile 4 scores. The diagnostic performance of the two scores was evaluated using receiver operating characteristic (ROC) curve analysis. Sensitivity, specificity, and predictive values of the original low cut-off (for rule-out) value and high cut-off (for rule-in) value were tested. RESULTS: For diagnosis of fibrosis stage ≥ 3, the area under the ROC (AUROC) was 0.886, and the sensitivity of the low cut-off value and the specificity of the high cut-off value were 95.3% and 73.4%, respectively. For diagnosis of fibrosis stage 4, AUROC, the sensitivity of the low cut-off value, and the specificity of the high cut-off value were 0.930, 100% and 86.5%, respectively. Both scores had higher diagnostic performance than the FIB-4 index and the enhanced liver fibrosis score. CONCLUSIONS: Agile 3+ and Agile 4 are reliable noninvasive tests to identify advanced fibrosis and cirrhosis in Japanese NAFLD patients with adequate diagnostic performance. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13890

PubMed

DOI： 10.3390/nu15092014

Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIM: Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. METHODS: 1398 patients were included in this sub-analysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. RESULTS: During a median follow-up period of 4.6 years (range, 0.3-21.6 years), which corresponds to 8,874 person-years, 37 patients developed HCC. Using a cutoff baseline platelet count of 192×109 /L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; P<0.001). This cutoff value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192×109 /L, patients with platelet counts of 100×109 /L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81-14.2) and an adjusted HR of 11.2 (95% CI, 3.81-32.7; P<0.001), adjusting for age, sex, and advanced fibrosis (Stage 3-4). CONCLUSIONS: Baseline platelet counts less than 192×109 /L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13884

PubMed

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。

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

DOI： 10.1111/hepr.13871

PubMed

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

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。

慢性肝障害(CLD)の原因は多岐にわたるが,肝線維化の程度が予後に寄与することはあらゆる疾患において共通である.肝線維化の診断方法は肝生検による病理診断がゴールドスタンダードであるが,肝生検は出血,コスト,サンプリングエラー,観察者間のvariabilityなど課題があり,さらに肝線維化の評価のために繰り返して肝生検を施行することは実際には不可能である.そこで非侵襲的診断法(NIT)への期待が膨らみ,さまざまなスコアリングシステムやエラストグラフィが確立されつつある.ELF(enhanced liver fibrosis)testや肝線維化マーカー(Mac-2結合タンパク糖鎖異性体,4型コラーゲン7S,オートタキシンなど)については他稿に譲り,本稿では日常的な検査法から算出可能なスコアリングシステムに言及し,その現状,課題,展望について概説する.(著者抄録)

Other URL： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00060&link_issn=&doc_id=20230329010008&doc_link_id=issn%3D0039-2359%26volume%3D284%26issue%3D12%26spage%3D951&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D284%26issue%3D12%26spage%3D951&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Authorship：Corresponding author   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：International journal  

BACKGROUND & AIMS: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage. METHODS: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients. RESULTS: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality. CONCLUSIONS: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.

DOI： 10.1016/j.cgh.2022.01.002

PubMed

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

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.

DOI： 10.1007/s00535-022-01932-1

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.gastha.2023.07.018

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

The prognosis of nonalcoholic fatty liver disease (NAFLD) patients depends on liver-related events (LREs), extrahepatic cancers, and major adverse cardiovascular events (MACEs). The fibrosis-4 (FIB-4) index is one of the most reliable and useful predictors of the degree of liver fibrosis. Recent studies have reported that the FIB-4 index is also useful for predicting LREs and MACEs in NAFLD patients. In the present study, we investigated the prognostic value of the FIB-4 index in NAFLD patients. A total of 506 biopsy-confirmed NAFLD patients from six hepatology centers in Japan from 2002 to 2013 were enrolled in this study. Of these NAFLD patients, 353 were available for more than 100 days of follow-up and did not exhibit events (LREs, extrahepatic cancers, MACEs) at the time of entry. The mean follow-up duration of all the subjects was 2716 ± 1621 days (102-7483 days). New LREs (hepatocellular carcinoma (HCC) (n = 8), decompensation (n = 11), bleeding varices (n = 8)) developed in 18 patients. Twenty-four and twelve patients developed extrahepatic cancers and MACEs, respectively. The median FIB-4 index was 1.255; we divided our cohort into two groups according to this (FIB4 Low, FIB4 Hi). The incidence of HCC tended to be higher in FIB4 Hi (n = 7) than in FIB4 Low (n = 1). The incidence of LREs was significantly higher in FIB4 Hi (n = 17) than in FIB4 Low (n = 1). The incidence of extrahepatic cancers was significantly higher in FIB4 Hi (n = 20) than in FIB4 Low (n = 4); the incidence of MACEs was also significantly higher in FIB4 Hi (n = 10) than in FIB4 Low (n = 2). The FIB-4 index is a useful biomarker for predicting not only LREs but also extrahepatic cancers and MACEs.

DOI： 10.3390/nu15010066

PubMed

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

BACKGROUND& AIMS: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LRE). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1,395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years. RESULTS: The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, p < 0.001) and T2DM (HR 3.37, p = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, p < 0.001) and T2DM (HR 2.51, p = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, p = 0.010) and obesity (HR 4.60, p = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, p = 0.002) and obesity (HR 4.22, p = 0.002) were LRE risk factors. CONCLUSION: T2DM and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD.

DOI： 10.1111/jgh.16019

PubMed

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

Cholangiocarcinoma (CC) has a poor prognosis and different driver genes depending on the site of onset. Intrahepatic CC is the second-most common liver cancer after hepatocellular carcinoma, and novel therapeutic targets are urgently needed. The present study was conducted to identify novel therapeutic targets by exploring differentially regulated genes in human CC. MicroRNA (miRNA) and mRNA microarrays were performed using tissue and serum samples obtained from 24 surgically resected hepatobiliary tumor cases, including 10 CC cases. We conducted principal component analysis to identify differentially expressed miRNA, leading to the identification of miRNA-3648 as a differentially expressed miRNA. We used an in silico screening approach to identify its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). SKI protein expression was decreased in human CC cells overexpressing miRNA-3648, endogenous SKI protein expression was decreased in human CC tumor tissues, and endogenous SKI mRNA expression was suppressed in human CC cells characterized by rapid growth. SKI-overexpressing OZ cells (human intrahepatic CC cells) showed upregulation of cyclin-dependent kinase inhibitor p21 mRNA and protein expression and suppressed cell proliferation. Nuclear expression of CDT1 (chromatin licensing and DNA replication factor 1), which is required for the G1/S transition, was suppressed in SKI-overexpressing OZ cells. SKI knockdown resulted in the opposite effects. Transgenic p21-luciferase was activated in SKI-overexpressing OZ cells. These data indicate SKI involvement in p21 transcription and that SKI-p21 signaling causes cell cycle arrest in G1, suppressing intrahepatic CC cell growth. Therefore, SKI may be a potential therapeutic target for intrahepatic CC.

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

DOI： 10.1002/hep4.1954

PubMed

DOI： 10.19020/cg.0000002265

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

We previously demonstrated that Mac-2 binding protein (M2BP) is a useful biomarker for nonalcoholic fatty liver disease (NAFLD), particularly NAFLD fibrosis prediction. In the present study, we investigated the prognostic value of M2BP in patients with NAFLD. A total of 506 patients with biopsy-confirmed NAFLD from 2002 to 2013 were enrolled in this study in Japan. Three hundred fifty-three of these patients with NAFLD were available for follow-up for more than 100 days and showed no liver-related events at the time of entry. Liver-related events were defined as hepatocellular carcinoma (HCC), decompensation, and gastroesophageal varices with variceal treatment. The mean follow-up duration of all the subjects was 2716 ± 1621 days (102-7483 days). Eighteen patients developed new liver-related events (HCC, 8; decompensation, 11; varices, 8). Nine patients developed cardiovascular disease (CVD), and 24 patients developed new cancers in other organs. The median serum M2BP level was 1.603 μg/mL, and we divided our cohort into two groups according to the serum M2BP level: M2BP low group (M2BP Low) and M2BP high group (M2BP Hi). The incidence of HCC was significantly higher in M2BP Hi (n = 8) than in M2BP Low (n = 0). The incidence of liver-related events was significantly higher in M2BP Hi (n = 16) than in M2BP Low (n = 2). The incidences of death, CVD events, and cancer in other organs were not different between the groups. Interestingly, the incidence of colorectal cancer was significantly higher in M2BP Hi (n = 5) than in M2BP Low (n = 0). Conclusion: M2BP is a useful biomarker to predict liver-related events, particularly HCC. Additionally, M2BP is a potential predictive biomarker of colorectal cancer development.

DOI： 10.1002/hep4.1934

PubMed

＜文献概要＞国内では成人の25%がNAFLDに罹患し,東アジアはPNPLA3 Gアレルの頻度が高く,非肥満例を含めNAFLDは増加傾向にある.NASHの頻度は肝生検による選択バイアスのため正確に評価できないが,全人口の2～3%と推定される.国内の約1,400例を対象とした多施設共同試験(CLIONE試験)の結果によると,高度肝線維化(F3/4)では年率1.5%程度の発癌リスクがある.糖尿病患者では半数以上がNAFLDに罹患し,そのうち高度肝線維化例は17%程度と推定され,FIB-4 index高値例では肝発癌リスクが高い.2030年には国内で高度肝線維化例が約100万人に達すると推定され,NASHが肝癌・肝不全の主因となることが懸念される.

<p>Prior to the project related to the Career Support and Diversity Promotion at the 44^th meeting of the Western Branch of the Japan Society of Hepatology, we conducted a questionnaire survey among the conference participants pertaining to academic societies, housework, and social networking services. A total of 244 males and 38 females aged 2080 years filled the questionnaire. A total of 22% of the respondents in ≤39-years-old group and 11% in ≥60-years-old group answered that "the Japan Society of Hepatology is more active than before. " In addition, the participation rate in housekeeping was high among the younger group. Furthermore, with regard to the use of social networking sites, the percentage of members who did not use either Facebook or Twitter was 28% and 66% in the ≤39-year-old group ≥60-year-old group, respectively.</p>

DOI： 10.2957/kanzo.63.259

第44回日本肝臓学会西部会のキャリア支援・ダイバーシティ推進委員関連企画に先立ち,学会参加者を対象に学会,家事,SNS(Social Networking Service)に関するアンケート調査を施行し,285名から回答を得た.回答者は20歳代から80歳代までの男性244名,女性38名(不明3名)であった.「肝臓学会が以前に比し盛り上がっている」と回答した会員の割合は,39歳以下群で22%,40～49歳で6%,50～59歳で2%,60歳以上11%であった.また,家事への参加率は,39歳以下の若年層で76%と高かった.さらに,SNSの利用に関してはFacebook,Twitterをいずれも使用しない会員の割合は39歳以下群で28%,40～49歳群で42%,50～59歳群で55%,60歳以上群で66%であった.(著者抄録)

Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND AND AIMS: The coronavirus disease 2019 (COVID-19) pandemic precipitated lifestyle changes. We aimed to clarify whether COVID-19-induced lifestyle changes affected the development of metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: This retrospective longitudinal study included 973 participants who underwent health check-ups between 2018 and 2020. We used data from the MedCity21 health examination registry. Participants' clinical characteristics and lifestyle habits were investigated. Independent lifestyle predictors of MAFLD development before the pandemic (2018-2019) and during the pandemic (2019-2020) were identified using logistic regression analysis. RESULTS: In 2018, 261 (27%) patients were diagnosed with MAFLD. Before the pandemic, 22 patients developed new MAFLD. During this time, routine late-night meals were identified as an independent lifestyle predictor of MAFLD development (hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.02-6.36, P = .046). In contrast, 44 patients developed new MAFLD during the pandemic. During this time, higher daily alcohol intake was identified as an independent lifestyle predictor of MAFLD development (HR 1.03, 95% CI 1.01-1.05, P = .008). In participants aged <60 years, daily alcohol intake and the proportion of participants who ate 2 times/day were significantly higher in patients who developed MAFLD during the pandemic than in those who did not. In participants aged ≥60 years, no lifestyle habits were associated with MAFLD development before or during the pandemic. CONCLUSIONS: New MAFLD diagnoses increased during the COVID-19 pandemic. Changes in lifestyle factors, particularly in those aged <60 years, must be monitored and addressed as the pandemic continues.

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

脂肪肝を診た際には内分泌疾患や薬物投与の有無を評価する。飲酒歴や他の慢性肝疾患がなければNAFLDと診断できる。高度線維化例を除外するにはFIB-4 indexを1st stepと活用し、2nd stepとして4型コラーゲン7Sを測定し、肝臓専門医への紹介を検討する。肝臓専門医はエラストグラフィや肝生検の施行を考慮する。治療としてはライフスタイルの改善が第一であるが、非糖尿病NAFLD患者ではビタミンEの投与を勧める。糖尿病合併例ではSGLT2阻害薬やGLP-1受容体作動薬が期待できる。脂質異常症合併例ではペマフィブラートが有効である。現在NASHに対する開発治験が進行しており、新規薬剤の登場を期待したい。(著者抄録)

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。

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

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

Sodium glucose cotransporter-2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon-like peptide-1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, -0.41%, P < 0.01; BMI, -1.06 kg/m2 , P < 0.01), whereas these did not change in the CTR group (n = 26). Liver pathology was evaluated in 21/25 participants in the IPR/CTR groups, and hepatic fibrosis was found in 17 (81%) and 18 (72%) participants in the IPR and CTR groups at baseline. This was ameliorated in 70.6% (12 of 17) of participants in the IPR group and 22.2 % (4 of 18) of those in the CTR group (P < 0.01). Nonalcoholic steatohepatitis (NASH) resolved in 66.7% of IPR-treated participants and 27.3% of CTR participants. None of the participants in the IPR group developed NASH, whereas 33.3% of the CTR group developed NASH. Conclusion: Long-term ipragliflozin treatment ameliorates hepatic fibrosis in patients with NAFLD. Thus, ipragliflozin might be effective for the treatment and prevention of NASH in patients with diabetes, as well as improving glycemic control and obesity. Therefore, SGLT2is may represent a therapeutic choice for patients with diabetes with NAFLD, but further larger studies are required to confirm these effects.

DOI： 10.1002/hep4.1696

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。

DOI： 10.11405/nisshoshi.119.39

PubMed

CiNii Article

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

Interleukin (IL)-19, a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. Nonalcoholic steatohepatitis (NASH) is a disease that has progressed from nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. We evaluated the functions of IL-19 in a NAFLD/NASH mouse model using a 60% high fat diet with 0.1% methionine, without choline, and with 2% cholesterol (CDAHFD). Wild-type (WT) and IL-19 gene-deficient (KO) mice were fed a CDAHFD or standard diet for 9 weeks. Liver injury, inflammation, and fibrosis induced by CDAHFD were significantly worse in IL-19 KO mice than in WT mice. IL-6, TNF-α, and TGF-β were significantly higher in IL-19 KO mice than in WT mice. As a mechanism using an in vitro experiment, palmitate-induced triglyceride and cholesterol contents were decreased by the addition of IL-19 in HepG2 cells. Furthermore, addition of IL-19 decreased the expression of fatty acid synthesis-related enzymes and increased ATP content in HepG2 cells. The action of IL-19 in vitro suppressed lipid metabolism. In conclusion, IL-19 may play an important role in the development of steatosis and fibrosis by directly regulating liver metabolism and may be a potential target for the treatment of liver diseases.

DOI： 10.3390/cells10123513

PubMed

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

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide, including in Japan. The Japanese Society of Gastroenterology (JSGE) and the Japanese Society of Hepatology (JSH) have established the Japanese NAFLD/NASH guidelines in 2014 and revised these guidelines in 2020. As described in these guidelines, weight reduction by diet and/or exercise therapy is important for the treatment of NAFLD patients. The I148M single nucleotide polymorphism (rs738409 C > G) of PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is widely known to be associated with the occurrence and progression of NAFLD. In the Japanese, the ratio of PNPLA3 gene polymorphisms found is approximately 20%, which is higher than that found in Westerners. In addition, the ratio of lean NAFLD patients is also higher in Japan than in Western countries. Therefore, the method for lifestyle guidance for the NAFLD patients in Japan would be different from that for the people in Western countries. The problems in the treatment of NAFLD patients include alcohol consumption and sarcopenia. Therefore, guidelines that can help clinicians treat Japanese patients with NAFLD are needed. In this expert review, we summarize evidence-based interventions for lifestyle modification (diet, exercise, alcohol, and sarcopenia) for the treatment of patients with NAFLD, especially from Japan and Asian countries.

DOI： 10.1007/s00535-021-01833-9

PubMed

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

Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.

DOI： 10.1016/j.freeradbiomed.2021.10.017

PubMed

目的:人間ドック受診者における好酸球性食道(Eosinophilic esophagitis:EoE)の臨床像を明らかにすることを目的とした。方法:2015年4月～2020年10月の人間ドック受診者延べ33,877人を対象としEoEと診断したEoE群と、年齢・性別を合わせて無作為に抽出した対照群で検討を行った。標準的な健診項目と上部消化管内視鏡所見について単変量解析し、p値が0.1未満の因子に対して多変量解析した。またEoE群でEoEに特徴的な内視鏡所見についての検討も行った。結果:20,145例の解析を行いEoEの発見率は0.47%であった。単変量解析ではEoE群に飲酒歴・つかえ感や胸やけ症状・アレルギー歴があることが有意に多く、内視鏡所見と他の健診項目については有意差を認めなかった。多変量解析の結果、飲酒歴・つかえ感や胸やけ症状・アレルギー歴があること・内視鏡所見でバレット食道がないことがEoEの独立した危険因子であることが明らかになった。EoEに特徴的な内視鏡所見のなかでは縦走溝が93%と最も多く認められた。結論:アレルギー疾患の既往、つかえ感や胸やけ症状、飲酒歴があり、内視鏡所見でバレット食道を認めない受診者には、EoEである可能性を考え特徴的な内視鏡所見を探したうえで積極的に食道粘膜の好酸球数を評価することが人間ドックでのEoEの発見率向上のために重要であると考えられた。(著者抄録)

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

Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

This study aimed to prove that the FibroScan-aspartate aminotransferase (FAST) scores can be used to stratify disease severity in a Japanese cohort with fatty liver diseases [metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease (NAFLD)]. All the participants (n = 2254) underwent liver stiffness measurements and controlled attenuation parameter assessments. We compared the clinical characteristics of the patients with MAFLD and NAFLD using the FAST scores and explored the independent determinants of FAST scores ≥ 0.35, which indicated possible progressive disease. Overall, MAFLD was diagnosed in 789 patients (35.0%), while NAFLD was diagnosed in 618 (27.4%). The proportion of patients that had a condition that suggested progressive liver disease was higher in those with MAFLD than in those with NAFLD [68 (8.6%) vs 48 (7.7%)]. The area under the receiver-operating characteristic curve of the FAST score for diagnosing advanced fibrosis was 0.969 in MAFLD and 0.965 in NAFLD. Multivariate analyses determined that diabetes mellitus, alanine aminotransferase (ALT) levels, fatty liver index, and Fibrosis-4 index independently predict FAST scores ≥ 0.35 in patients with MAFLD. ALT levels had the strongest correlation with the FAST scores (p = 0.7817). The FAST score could stratify the disease severity in the Japanese cohort with fatty liver diseases.

DOI： 10.1038/s41598-021-93435-x

PubMed

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

Liver fibrosis reflects tissue scarring in the liver due to the accumulation of excessive extracellular matrix in response to chronically persistent liver injury. Hepatocyte cell death can trigger capillarization of liver sinusoidal endothelial cells, stimulation of immune cells including macrophages and Kupffer cells, and activation of hepatic stellate cells (HSCs), resulting in progression of liver fibrosis. Liver cirrhosis is the terminal state of liver fibrosis and is associated with severe complications, such as liver failure, portal hypertension, and liver cancer. Nevertheless, effective therapy for cirrhosis has not yet been established, and liver transplantation is the only radical treatment for severe cases. Studies investigating HSC activation and regulation of collagen production in the liver have made breakthroughs in recent decades that have advanced the knowledge regarding liver fibrosis pathophysiology. In this review, we summarize molecular mechanisms of liver fibrosis and discuss the development of novel anti-fibrotic therapies.

DOI： 10.3350/cmh.2020.0187

PubMed

Authorship：Lead author,　Corresponding author   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

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

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. Conclusion: COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.

DOI： 10.1002/hep4.1637

PubMed

DOI： 10.14309/ajg.0000000000000747

PubMed

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

DOI： 10.14309/ajg.0000000000000747

PubMed

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

The prevalence of obesity or metabolic syndrome is increasing worldwide (globally metabodemic). Approximately 25% of the adult general population is suffering from nonalcoholic fatty liver disease (NAFLD), which has become a serious health problem. In 2020, global experts suggested that the nomenclature of NAFLD should be updated to metabolic-dysfunction-associated fatty liver disease (MAFLD). Hepatic fibrosis is the most significant determinant of all cause- and liver -related mortality in MAFLD. The non-invasive test (NIT) is urgently required to evaluate hepatic fibrosis in MAFLD. The fibrosis-4 (FIB-4) index is the first triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness, especially for general physicians or endocrinologists, although the FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration-controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the second step after triaging by the FIB-4 index. The leading cause of mortality in MAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. MAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation. The FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocellular carcinoma, but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, the FIB-4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of the FIB-4 index in the management of MAFLD.

DOI： 10.3390/life11020143

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41374-020-00509-x

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000510911

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/life11020143

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jgh3.12474

PubMed

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

Background and Aim: Hepatitis C virus (HCV) infection causes insulin resistance and diabetes as extrahepatic manifestations. We aimed to analyze the effect of HCV eradication by direct-acting antiviral (DAA) agents on glucose tolerance. Methods: The hemoglobin A1c (HbA1c) of 272 patients with HCV infection who achieved a sustained virologic response (SVR) was analyzed at baseline before DAA treatment, at the end of DAA therapy (ETR), and 12 weeks after therapy (Post12W). Results: There were no significant differences in HbA1c between baseline, ETR, and Post12W in the overall patients. When the data were stratified according to the presence or absence of diabetes, median HbA1c significantly decreased from baseline (7.2%) to ETR (6.8%) and Post12W (6.8%) in the 55 patients with diabetes, whereas there were no significant changes in the patients without diabetes. Basal HbA1c, fasting plasma glucose, and age were independently associated with the changes in HbA1c according to multivariate analysis, and the predictive formula for changes in HbA1c was found to be ΔHbA1c (%) = 1.449-0.4* HbA1c (%) + 0.012 × Age (year). There were no changes in body mass in diabetic or nondiabetic patients. In diabetic patients taking medication, 63.4% of patients needed less medication. Conclusions: Eradication of HCV improves glycemic control, indicated by a 0.4% decrease in HbA1c in diabetes.

DOI： 10.1002/jgh3.12474

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： 10.1177/20503121211047060

PubMed

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

<p><b>Objective:</b> This study aimed to elucidate the clinical features and endoscopic findings in patients with eosinophilic esophagitis (EoE) during a medical check-up.</p><p><b>Methods:</b> This observational study was conducted on patients diagnosed with EoE during a physical examination at the MedCity21, Osaka City University, and randomly recruited age- and sex-matched healthy controls (1:1 ratio). Clinical characteristics, gastrointestinal endoscopic findings, and standard physical examination findings were analyzed using univariate analyses and compared between the patient and control groups, using multivariate logistic regression analyses for items with a <i>p</i>-value of < 0.1. Additionally, the detection rate of unique endoscopic findings in the patient group was also examined.</p><p><b>Results:</b> A total of 94/20,145 participants were diagnosed with EoE, with a 0.47% detection rate. Longitudinal grooves were the most characteristic endoscopic findings of EoE observed in 93% of patients. Univariate analyses showed that the prevalence of alcohol consumption, dysphagia or heartburn symptoms, and serological allergy were significantly higher in the patient group than in the control group. Multivariate analyses indicated that alcohol consumption, dysphagia or heartburn symptoms, history of allergies, and the absence of Barrett’s esophagus were independent risk factors for EoE.</p><p><b>Conclusions:</b> It is critical to evaluate the eosinophil count in the esophageal mucosa of patients with a history of allergic diseases and alcohol consumption, symptoms of choking or heartburn, and the absence of Barrett’s esophagus on endoscopic examination, to improve the EoE detection rate during a medical check-up.</p>

DOI： 10.11320/ningendock.36.545

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.3350/cmh.2020.0187

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/hep4.1637

Publishing type：Research paper (scientific journal)  

<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

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

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)

Publishing type：Research paper (scientific journal)  

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)

Publishing type：Research paper (scientific journal)  

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)

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12328-020-01107-6

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jgh3.12376

PubMed

Publishing type：Research paper (scientific journal)  

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

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

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)  

DOI： 10.1016/j.jhep.2020.03.051

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jhep.2020.03.051

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/liv.14534

PubMed

Publishing type：Research paper (scientific journal)  

Background/Purpose Although ursodeoxycholic acid (UDCA) is a first-line treatment for primary biliary cholangitis (PBC), 20%-30% of patients with PBC exhibit an incomplete response to UDCA. Recently, the UDCA Response Score was proposed for predicting response to UDCA using pretreatment parameters in patients with PBC. We aimed to validate the UDCA Response Score in Japanese patients with PBC.Methods Registry data of Japanese patients (n = 873) were collected. Patients with data on all clinical parameters required for calculating the UDCA Response Score were selected. The endpoint was UDCA response, defined as alkaline phosphatase All parameters were available in 804 patients (male/female = 120/684, age 58.9 [interquartile range 51.1-66.9] years). Bezafibrate was commenced within 12 months of UDCA in 78 patients (9.7%) because of the lack of an early response. We found that the endpoint was not reached in these 78 patients, and the area under the receiver operating characteristic curve (AUROC) of the score was 0.74 (95% confidence interval [CI] 0.70-0.79). The AUROC was 0.77 (95% CI 0.70-0.83) in patients undergoing UDCA monotherapy (n = 726). Finally, the AUROC of the modified UDCA Response Score using only data from the treatment start date was 0.80 (95% CI 0.70-0.90) in patients receiving a combination therapy of UDCA and bezafibrate (n = 160).Conclusion The validity of the UDCA Response Score was acceptable in Japanese patients; this score will be informative in patients treated with a combination therapy of UDCA and bezafibrate.

DOI： 10.1111/liv.14534

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.14309/ajg.0000000000000747

PubMed

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

DOI： 10.14309/ajg.0000000000000747

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

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms21113863

PubMed

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

DOI： 10.3390/ijms21113863

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

International / domestic magazine：International journal  

Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

DOI： 10.3390/ijms21061907

PubMed

Publishing type：Research paper (scientific journal)  

A fourth of the adult population is now suffering from nonalcoholic fatty liver disease (NAFLD) worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to liver-related mortality. NAFLD/NASH is closely associated with type 2 diabetes. Although pioglitazone is now recommended as the 1st line therapy for NASH with type 2 diabetes, pioglitazone has several safety concerns such as body weight gain, heart failure, fluid retention, and bone fracture in women. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a variety of functions such as glycemic control, bodyweight reduction, and decreased body pressure. Accumulating evidence has shown that this agent has also cardioprotective and renoprotective effects in patients with or without type 2 diabetes. Recent studies that SGLT2 inhibitor can also reduce in transaminase activities or hepatic fat content in NAFLD. NAFLD patients with type 2 diabetes can be indicated for SGLT2 inhibitor, because they are obese, have insulin resistance, and at high risk of cardiovascular events. The phase 3 study of dapagliflozin for NAFLD (DEAN study) is now ongoing. It remains unknown whether this agent can ameliorate hepatic fibrosis in NASH, leading to improved over-all or liver-related survival. Since the leading cause of NAFLD mortality is cardiovascular events, SGLT2 inhibitors will become the 1st line treatment for NAFLD/NASH.

DOI： 10.36502/2020/droa.6159

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms21061907

PubMed

Publishing type：Research paper (scientific journal)  

症例は39歳女性で、免疫グロブリンA腎症を有し、1年前に維持血液透析を開始していた。来院時、妊娠希望であったため薬物治療は拒否された。食事コントロールが不良であり、透析セッション間の体重増加が10%超で、高リン血症と重度副甲状腺機能亢進症も認めた。3ヵ月後、自然妊娠した。透析時間を延長し、透析膜のサイズを拡大し、血流量を増加した。妊娠22週時に羊水量が過剰となり、超音波検査で副甲状腺腫脹が判明した。適切な食事コントロールと透析療法の強化を行ったところ、血清リンと血清intact副甲状腺ホルモン(PTH)が改善した。リン吸着薬は、妊婦に対する安全性が確立している炭酸カルシウムのみを用いた。加えて、血清カルシウムと1,25-ジヒドロキシビタミンD3を定期的にモニタリングし、アルファカルシドールを注意して処方した。妊娠27週時、血清intact PTHとカルシウムが目標範囲の上限に上昇したため、アルファカルシドールをマキサカルシトール静注に変更した。妊娠32週に全身麻酔下の帝王切開を行い、健康児を出産した。

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-020-60440-5

PubMed

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

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.aohep.2020.04.002

PubMed

Publishing type：Research paper (scientific journal)  

<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

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

In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.

DOI： 10.1002/hep.30552

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.13190

PubMed

Publishing type：Research paper (scientific journal)  

<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)  

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)

Publishing type：Research paper (scientific journal)  

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)

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)

Publishing type：Research paper (scientific journal)  

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)

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.13190

PubMed

DOI： 10.1111/jgh.14608

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12328-019-00983-x

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.3892/br.2019.1224

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.14595

PubMed

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

BACKGROUND AND AIM: Although non-alcoholic fatty liver disease (NAFLD) is common in the general population, identifying patients with advanced fibrosis remains a challenge. We investigated whether the homeostasis model assessment parameter of insulin resistance (HOMA-IR), an index of IR and one of the most important metabolic factors, is an independent predictive factor for advanced fibrosis in nondiabetic patients with NAFLD. METHODS: This was a retrospective, cross-sectional multicenter study. We included 361 patients with biopsy-proven NAFLD who had not been diagnosed with type 2 diabetes mellitus: 175 (48%) were women and 48 (13%) had advanced fibrosis. We used simple random sampling; the sampling ratio of the estimation and validation groups was 7:3. A logistic model was constructed for both the estimation and validation groups. The explanatory variables were age ≥ 49 years, sex (women), body mass index ≥ 26.7 kg/m2 , the presence of hypertension, presence of dyslipidemia, fasting plasma glucose level ≥ 98 mg/dL, fasting immune reactive insulin level ≥ 12.0 μU/mL, and HOMA-IR ≥ 2.90. The median HOMA-IR of the patients was 2.88 (interquartile range: 2.1-4.8). RESULTS: In the estimation group, univariate and multivariate analyses showed that age, dyslipidemia, and HOMA-IR were independent predictors of advanced fibrosis. In the validation group, only age and HOMA-IR were found to be independent predictors of advanced fibrosis. CONCLUSIONS: Homeostasis model assessment parameter of insulin resistance was an independent predictor of advanced liver fibrosis in nondiabetic patients with NAFLD. Given that most patients with NAFLD are nondiabetic, it is important to set goals with respect to improving IR to subsequently reduce liver fibrosis.

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)   International / domestic magazine：International journal  

Pruritus is a common pathogenesis in liver diseases, including chronic hepatitis B (CHB). The phases of hepatitis B virus (HBV) infection are defined in the American Association for the Study of Liver Diseases guidelines. However, it still remains unclear whether the phase independently affects pruritus. The aim of this study was to clarify the effect of HBV infection phase on pruritus in patients with HBV. Of the 1,631 patients that attended the joint research facilities and were interviewed regarding their pruritus between January and June 2016, 196 patients with HBV infection were selected for the present analysis. One-to-one propensity score-matching using 13 variables was performed between participants in the hepatitis B e antigen (HBe-Ag)-positive/negative immune-active phase group and the inactive CHB phase group. Data from 47 patients per group were included in the final analysis. The prevalence of pruritus in the inactive CHB phase was significantly lower than in the HBe-Ag-positive/negative immune-active phase (23 vs. 47%; P=0.031). Being in the inactive CHB phase was determined to be an independent risk factor for pruritus (odds ratio, 0.35; 95% confidence interval, 0.143-0.842; P=0.019). The progression to inactive CHB phase may contribute to the amelioration of pruritus in patients with HBV infection.

DOI： 10.3892/br.2019.1224

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.14454

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S2468-1253(19)30039-1

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  

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Asia is a large, heterogeneous area with substantial variation in socioeconomic status and prevalence of obesity. We estimated the prevalence, incidence, and outcomes of NAFLD in the Asian population to assist stakeholders in understanding NAFLD disease burden. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from database inception to Jan 17, 2019, for studies reporting NAFLD prevalence, incidence, or outcome in Asia. We included only cross-sectional and longitudinal observational studies of patients with NAFLD diagnosed by imaging, serum-based indices, or liver biopsy. Studies that included patients with overlapping liver disease or that did not screen for excess alcohol consumption were excluded. Two investigators independently screened and extracted data. The main outcomes were pooled NAFLD prevalence, incidence, and hepatocellular carcinoma incidence and overall mortality in patients with NAFLD. Summary estimates were calculated using a random-effects model. This study is registered with PROSPERO, number CRD42018088468. FINDINGS: Of 4995 records identified, 237 studies (13 044 518 participants) were included for analysis. The overall prevalence of NAFLD regardless of diagnostic method was 29·62% (95% CI 28·13-31·15). NAFLD prevalence increased significantly over time (25·28% [22·42-28·37] between 1999 and 2005, 28·46% [26·70-30·29] between 2006 and 2011, and 33·90% [31·74-36·12] between 2012 and 2017; p<0·0001). The pooled annual NAFLD incidence rate was 50·9 cases per 1000 person-years (95% CI 44·8-57·4). In patients with NAFLD, the annual incidence of hepatocellular carcinoma was 1·8 cases per 1000 person-years (0·8-3·1) and overall mortality rate was 5·3 deaths per 1000 person-years (1·5-11·4). INTERPRETATION: NAFLD prevalence in Asia is increasing and is associated with poor outcomes including hepatocellular carcinoma and death. Targeted public health strategies must be developed in Asia to target the drivers of this rising epidemic and its associated complications, especially in high-risk groups, such as older obese men. FUNDING: None.

DOI： 10.1016/S2468-1253(19)30039-1

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1744-9987.12808

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/hep.30552

PubMed

Publishing type：Research paper (scientific journal)  

<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

DOI： 10.19020/cg.0000000593

Publishing type：Research paper (scientific journal)  

従来の肝線維化指標であるFIB4 indexのカットオフ値を、非アルコール性脂肪性肝疾患(NAFLD)の年齢層別に最適化した。対象はNAFLD患者1050例で、年齢層別に49歳以下395例、50〜59歳217例、60〜69歳270例、70歳以上168例に分けた。非アルコール性脂肪性肝炎有病率、進行肝線維化率は年齢依存的に増加した。年齢とFIB4 indexに正の相関があった。FIB4 indexの受信者動作特性曲線下面積(AUC)は、49歳以下が0.917、50〜59歳が0.849、60〜69歳が0.855、70歳以上が0.779であった。AUCから各年齢層のカットオフ値の上・下限値を決定した。至適カットオフ値は、49歳以下が1.05と1.21、50〜59歳が1.24と1.96、60〜69歳が1.88と3.24、70歳以上が1.95と4.56とした。

Publishing type：Research paper (scientific journal)  

従来の肝線維化指標であるFIB4 indexのカットオフ値を、非アルコール性脂肪性肝疾患(NAFLD)の年齢層別に最適化した。対象はNAFLD患者1050例で、年齢層別に49歳以下395例、50〜59歳217例、60〜69歳270例、70歳以上168例に分けた。非アルコール性脂肪性肝炎有病率、進行肝線維化率は年齢依存的に増加した。年齢とFIB4 indexに正の相関があった。FIB4 indexの受信者動作特性曲線下面積(AUC)は、49歳以下が0.917、50〜59歳が0.849、60〜69歳が0.855、70歳以上が0.779であった。AUCから各年齢層のカットオフ値の上・下限値を決定した。至適カットオフ値は、49歳以下が1.05と1.21、50〜59歳が1.24と1.96、60〜69歳が1.88と3.24、70歳以上が1.95と4.56とした。

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-018-1478-7

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-018-1474-y

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1177/2050640618791053

PubMed

DOI： 10.1007/s00280-018-3681-x

PubMed

Publishing type：Research paper (scientific journal)  

The coauthor Masashi Yoneda’s affiliation has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.

DOI： 10.1007/s00535-018-1478-7

PubMed

従来の肝線維化指標であるFIB4 indexのカットオフ値を、非アルコール性脂肪性肝疾患(NAFLD)の年齢層別に最適化した。対象はNAFLD患者1050例で、年齢層別に49歳以下395例、50～59歳217例、60～69歳270例、70歳以上168例に分けた。非アルコール性脂肪性肝炎有病率、進行肝線維化率は年齢依存的に増加した。年齢とFIB4 indexに正の相関があった。FIB4 indexの受信者動作特性曲線下面積(AUC)は、49歳以下が0.917、50～59歳が0.849、60～69歳が0.855、70歳以上が0.779であった。AUCから各年齢層のカットオフ値の上・下限値を決定した。至適カットオフ値は、49歳以下が1.05と1.21、50～59歳が1.24と1.96、60～69歳が1.88と3.24、70歳以上が1.95と4.56とした。

Publishing type：Research paper (scientific journal)  

従来の肝線維化指標であるFIB4 indexのカットオフ値を、非アルコール性脂肪性肝疾患(NAFLD)の年齢層別に最適化した。対象はNAFLD患者1050例で、年齢層別に49歳以下395例、50〜59歳217例、60〜69歳270例、70歳以上168例に分けた。非アルコール性脂肪性肝炎有病率、進行肝線維化率は年齢依存的に増加した。年齢とFIB4 indexに正の相関があった。FIB4 indexの受信者動作特性曲線下面積(AUC)は、49歳以下が0.917、50〜59歳が0.849、60〜69歳が0.855、70歳以上が0.779であった。AUCから各年齢層のカットオフ値の上・下限値を決定した。至適カットオフ値は、49歳以下が1.05と1.21、50〜59歳が1.24と1.96、60〜69歳が1.88と3.24、70歳以上が1.95と4.56とした。

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

Background: Interferon-free, direct-acting antiviral treatments can result in a sustained virologic response in nearly 100% of patients with chronic hepatitis C virus infection. Aims: The purpose of this study was to evaluate histological improvement after achieving a sustained virologic response to direct-acting antiviral treatments in patients with chronic hepatitis C. Methods: Among 691 patients with chronic hepatitis C who achieved a sustained virologic response to direct-acting antivirals, 51 underwent liver biopsy 41 ± 20 weeks after the end of treatment despite normal transaminase levels. In 20 patients, liver biopsy specimens obtained a median of 1.2 years before the start of treatment were available. Results: Among the 51 patients who underwent post-sustained virologic response biopsies, the grade of inflammation was A0 in 18 patients, A1 in 24, A2 in eight, and A3 in one; the stage of fibrosis was F0 in three patients, F1 in 20, F2 in 15, F3 in nine, and F4 in four. Among the nine post-sustained virologic response biopsy specimens with moderate-to-severe inflammation (≥A2), four showed S1-to-S3 steatosis (>5% of hepatocytes affected). In the 20 paired biopsy specimens, the inflammation grade significantly regressed (p = 0.0043), but the fibrosis stage did not (p = 0.45). Histological improvement, defined as a ≥ 2-point decrease in the Knodell inflammatory score and no worsening of the fibrosis, was found in 11 (55%) patients. The iron accumulation had significantly regressed (p = 0.0093), but the steatosis had not (p = 0.10). Conclusions: Even if transaminases become normal after obtaining a sustained virologic response, significant histological inflammation of unknown cause was found in some patients. Additionally, improvement in liver fibrosis was not evident in the short term.

DOI： 10.1177/2050640618791053

PubMed

Publishing type：Research paper (scientific journal)  

Background: The FIB4 index is clinically useful, but because its formula includes age, the appropriate cutoff point may differ by age group. Here, new FIB4 index cutoff points were validated using cohort data from 14 hepatology centers in Japan. Methods: The FIB4 index was determined in biopsy-confirmed NAFLD patients (n = 1050) who were divided into four groups: ≤ 49, 50–59, 60–69, and ≥ 70 years. ROC analysis predicted advanced fibrosis in each age group
low and high cutoff points were defined by a sensitivity and specificity of 90%. The new and conventional cutoffs were compared for detecting advanced fibrosis. Results: The modified low and high cutoff points were 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 3.24 in 60–69 years, and 1.95 and 4.56 in ≥ 70 years. In ≥ 60 years, the false-negative rate was increased using the modified high cutoff point, and the high cutoff point was better with the conventional cutoff point. The new proposed low and high cutoff points are 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 2.67 in 60–69 years, and 1.95 and 2.67 in ≥ 70 years
these cutoff points improved the accuracy of advanced fibrosis diagnosis. Conclusions: FIB4 index cutoff points for predicting advanced fibrosis in NAFLD increased with age. Cutoff points modified by age improved the diagnostic accuracy of estimations of advanced liver fibrosis using the FIB4 index.

DOI： 10.1007/s00535-018-1474-y

PubMed

DOI： 10.11477/mf.1403201505

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

＜文献概要＞患者は70歳代,男性.嘔吐,下痢,腹痛のため救急入院となった.感染性胃腸炎を疑い抗菌薬を投与したが軽快しなかった.7日後には腹痛の増強と発熱が出現し,CRPの上昇とAlbの低下を認めた.腹部造影CTにて十二指腸下行脚〜空腸の著明な壁肥厚を認めた.小腸内視鏡にて空腸上部〜十二指腸水平脚は剥離しかけの粘膜と広範な潰瘍を認め,十二指腸下行脚には島状の粘膜の残存がみられた.これらの画像所見と持続する腹痛から,紫斑はないもののIgA血管炎と診断し,ステロイド治療を行い軽快した.後日,凝固第XIII因子の低下が判明し,生検組織でIgA血管炎として矛盾しない所見と判断された.高齢者の紫斑のないIgA血管炎のまれな1例を報告し,考察を加えた.

Publishing type：Research paper (scientific journal)  

＜文献概要＞患者は70歳代,男性.嘔吐,下痢,腹痛のため救急入院となった.感染性胃腸炎を疑い抗菌薬を投与したが軽快しなかった.7日後には腹痛の増強と発熱が出現し,CRPの上昇とAlbの低下を認めた.腹部造影CTにて十二指腸下行脚〜空腸の著明な壁肥厚を認めた.小腸内視鏡にて空腸上部〜十二指腸水平脚は剥離しかけの粘膜と広範な潰瘍を認め,十二指腸下行脚には島状の粘膜の残存がみられた.これらの画像所見と持続する腹痛から,紫斑はないもののIgA血管炎と診断し,ステロイド治療を行い軽快した.後日,凝固第XIII因子の低下が判明し,生検組織でIgA血管炎として矛盾しない所見と判断された.高齢者の紫斑のないIgA血管炎のまれな1例を報告し,考察を加えた.

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

＜文献概要＞患者は70歳代,男性.嘔吐,下痢,腹痛のため救急入院となった.感染性胃腸炎を疑い抗菌薬を投与したが軽快しなかった.7日後には腹痛の増強と発熱が出現し,CRPの上昇とAlbの低下を認めた.腹部造影CTにて十二指腸下行脚〜空腸の著明な壁肥厚を認めた.小腸内視鏡にて空腸上部〜十二指腸水平脚は剥離しかけの粘膜と広範な潰瘍を認め,十二指腸下行脚には島状の粘膜の残存がみられた.これらの画像所見と持続する腹痛から,紫斑はないもののIgA血管炎と診断し,ステロイド治療を行い軽快した.後日,凝固第XIII因子の低下が判明し,生検組織でIgA血管炎として矛盾しない所見と判断された.高齢者の紫斑のないIgA血管炎のまれな1例を報告し,考察を加えた.

＜文献概要＞患者は70歳代,男性.嘔吐,下痢,腹痛のため救急入院となった.感染性胃腸炎を疑い抗菌薬を投与したが軽快しなかった.7日後には腹痛の増強と発熱が出現し,CRPの上昇とAlbの低下を認めた.腹部造影CTにて十二指腸下行脚～空腸の著明な壁肥厚を認めた.小腸内視鏡にて空腸上部～十二指腸水平脚は剥離しかけの粘膜と広範な潰瘍を認め,十二指腸下行脚には島状の粘膜の残存がみられた.これらの画像所見と持続する腹痛から,紫斑はないもののIgA血管炎と診断し,ステロイド治療を行い軽快した.後日,凝固第XIII因子の低下が判明し,生検組織でIgA血管炎として矛盾しない所見と判断された.高齢者の紫斑のないIgA血管炎のまれな1例を報告し,考察を加えた.

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-018-28650-0

PubMed

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

The prognosis of patients with nonalcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) is intricately associated with various factors. We aimed to investigate the prognostic algorithm of NAFLD-HCC patients using a data-mining analysis. A total of 247 NAFLD-HCC patients diagnosed from 2000 to 2014 were registered from 17 medical institutions in Japan. Of these, 136 patients remained alive (Alive group) and 111 patients had died at the censor time point (Deceased group). The random forest analysis demonstrated that treatment for HCC and the serum albumin level were the first and second distinguishing factors between the Alive and Deceased groups. A decision-tree algorithm revealed that the best profile comprised treatment with hepatectomy or radiofrequency ablation and a serum albumin level ≥3.7 g/dL (Group 1). The second-best profile comprised treatment with hepatectomy or radiofrequency ablation and serum albumin levels <3.7 g/dL (Group 2). The 5-year overall survival rate was significantly higher in the Group 1 than in the Group 2. Thus, we demonstrated that curative treatment for HCC and serum albumin level >3.7 g/dL was the best prognostic profile for NAFLD-HCC patients. This novel prognostic algorithm for patients with NAFLD-HCC could be used for clinical management.

DOI： 10.1038/s41598-018-28650-0

PubMed

DOI： 10.15106/j_naika121_1283

Publishing type：Research paper (scientific 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

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.12850

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.13050

PubMed

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

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： 10.1111/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。

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)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12978

PubMed

Publishing type：Research paper (scientific journal)  

慢性肝疾患患者1631例(男性741例、女性890例、中央値60歳)を対象に、そう痒の有病率とその特徴について検討した。9施設においてそう痒の有病率、発症部位、罹病期間、日々のそう痒の変動、季節による増悪の有無、治療薬、治療効果を評価した。その結果、そう痒を発症していたのは658例(40.3%)であった。肝硬変はそう痒患者に多く、脂質異常症はそう痒患者で低率、糖尿病と高尿酸血症に関してそう痒群と非そう痒群との間に有意差はなく、高血圧はそう痒群で少ない傾向にあった。肝疾患別のそう痒の有病率をみると、オーバーラップ症候群が60.0%、原発性胆汁性肝硬変(PBC)が51.4%、HBVキャリアが22.2%、自己免疫性肝炎が24.3%、非アルコール性脂肪性肝疾患が44.7%、アルコール性肝疾患が34.2%であった。そう痒部位では背部が最も多く、以下、腹部、下腿部、上腕部の順であった。そう痒が6ヵ月以上持続していたのが38.3%であり、日中の方が夜間より症状が激しく、季節による増悪ありとの申

Publishing type：Research paper (scientific journal)  

慢性肝疾患患者1631例(男性741例、女性890例、中央値60歳)を対象に、そう痒の有病率とその特徴について検討した。9施設においてそう痒の有病率、発症部位、罹病期間、日々のそう痒の変動、季節による増悪の有無、治療薬、治療効果を評価した。その結果、そう痒を発症していたのは658例(40.3%)であった。肝硬変はそう痒患者に多く、脂質異常症はそう痒患者で低率、糖尿病と高尿酸血症に関してそう痒群と非そう痒群との間に有意差はなく、高血圧はそう痒群で少ない傾向にあった。肝疾患別のそう痒の有病率をみると、オーバーラップ症候群が60.0%、原発性胆汁性肝硬変(PBC)が51.4%、HBVキャリアが22.2%、自己免疫性肝炎が24.3%、非アルコール性脂肪性肝疾患が44.7%、アルコール性肝疾患が34.2%であった。そう痒部位では背部が最も多く、以下、腹部、下腿部、上腕部の順であった。そう痒が6ヵ月以上持続していたのが38.3%であり、日中の方が夜間より症状が激しく、季節による増悪ありとの申告が45%、冬期での増悪例が最も多かった。そう痒患者のうち301例が止痒薬を投与されており、著効が36.5%、効果ありが41.2%、無効が16.6%であった。また、そう痒と関連する因子として、活動性HBV感染症、PBC、糖尿病、AST 60U/L以上が同定された。

DOI： 10.1111/hepr.12978

PubMed

慢性肝疾患患者1631例(男性741例、女性890例、中央値60歳)を対象に、そう痒の有病率とその特徴について検討した。9施設においてそう痒の有病率、発症部位、罹病期間、日々のそう痒の変動、季節による増悪の有無、治療薬、治療効果を評価した。その結果、そう痒を発症していたのは658例(40.3%)であった。肝硬変はそう痒患者に多く、脂質異常症はそう痒患者で低率、糖尿病と高尿酸血症に関してそう痒群と非そう痒群との間に有意差はなく、高血圧はそう痒群で少ない傾向にあった。肝疾患別のそう痒の有病率をみると、オーバーラップ症候群が60.0%、原発性胆汁性肝硬変(PBC)が51.4%、HBVキャリアが22.2%、自己免疫性肝炎が24.3%、非アルコール性脂肪性肝疾患が44.7%、アルコール性肝疾患が34.2%であった。そう痒部位では背部が最も多く、以下、腹部、下腿部、上腕部の順であった。そう痒が6ヵ月以上持続していたのが38.3%であり、日中の方が夜間より症状が激しく、季節による増悪ありとの申告が45%、冬期での増悪例が最も多かった。そう痒患者のうち301例が止痒薬を投与されており、著効が36.5%、効果ありが41.2%、無効が16.6%であった。また、そう痒と関連する因子として、活動性HBV感染症、PBC、糖尿病、AST 60U/L以上が同定された。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/hep4.1080

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)  

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

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

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms18020434

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

肉芽腫を認める感染性腸炎について述べた.腸結核とエルシニア腸炎の自験例について,臨床像と内視鏡像を検討し,チフス性疾患については症例を提示した.生検組織で疾患特異的な肉芽腫がみられることは少なく,臨床像,内視鏡像による鑑別診断が重要である.腸結核では無症状例が最も多い.特徴的な内視鏡像は,輪状潰瘍あるいは輪状配列する潰瘍,多発潰瘍瘢痕と活動性潰瘍の併存,発赤を伴う樹枝状不整形潰瘍,敷石像様所見である.エルシニア腸炎の臨床症状は腹痛と発熱が主である.特徴的な内視鏡像は終末回腸の小びらんを伴う腫大したPeyer板,腫大した回盲弁,終末回腸〜上行結腸のアフタである.(著者抄録)

Publishing type：Research paper (scientific journal)  

潰瘍性大腸炎(ulcerative colitis:UC)患者に合併するサイトメガロウイルス(cytomegalovirus:CMV)感染症の大部分は、ステロイドや免疫抑制薬の治療歴がある。今回ステロイド投与歴がないにも関わらずCMV再活性化を生じ、治療経過でCMV感染症を発症したため抗ウイルス治療を要したUC患者2例を経験した。1例目は66歳で、再燃時大腸内視鏡検査では発赤、浮腫、びらんのみだが、既にCMVの再活性化を呈していた。ステロイド治療で一旦軽快したが、その後CMV感染症を合併し抗ウイルス治療を要した。2例目は75歳で、再燃時大腸内視鏡検査で浮腫、びらん、小潰瘍のみであったが既にCMV再活性化を生じていた。ステロイドとタクロリムスで一旦軽快したが、CMV感染症を合併し抗ウイルス療法を要した。ステロイド投与歴にとらわれず、高齢者UC患者の再燃時には典型的な内視鏡画像を欠いてもCMVの再活性化を疑いステロイド以外の治療を考慮すべきである。(著者抄録)

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)  

肉芽腫を認める感染性腸炎について述べた.腸結核とエルシニア腸炎の自験例について,臨床像と内視鏡像を検討し,チフス性疾患については症例を提示した.生検組織で疾患特異的な肉芽腫がみられることは少なく,臨床像,内視鏡像による鑑別診断が重要である.腸結核では無症状例が最も多い.特徴的な内視鏡像は,輪状潰瘍あるいは輪状配列する潰瘍,多発潰瘍瘢痕と活動性潰瘍の併存,発赤を伴う樹枝状不整形潰瘍,敷石像様所見である.エルシニア腸炎の臨床症状は腹痛と発熱が主である.特徴的な内視鏡像は終末回腸の小びらんを伴う腫大したPeyer板,腫大した回盲弁,終末回腸〜上行結腸のアフタである.(著者抄録)

Publishing type：Research paper (scientific journal)  

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

潰瘍性大腸炎(ulcerative colitis:UC)患者に合併するサイトメガロウイルス(cytomegalovirus:CMV)感染症の大部分は、ステロイドや免疫抑制薬の治療歴がある。今回ステロイド投与歴がないにも関わらずCMV再活性化を生じ、治療経過でCMV感染症を発症したため抗ウイルス治療を要したUC患者2例を経験した。1例目は66歳で、再燃時大腸内視鏡検査では発赤、浮腫、びらんのみだが、既にCMVの再活性化を呈していた。ステロイド治療で一旦軽快したが、その後CMV感染症を合併し抗ウイルス治療を要した。2例目は75歳で、再燃時大腸内視鏡検査で浮腫、びらん、小潰瘍のみであったが既にCMV再活性化を生じていた。ステロイドとタクロリムスで一旦軽快したが、CMV感染症を合併し抗ウイルス療法を要した。ステロイド投与歴にとらわれず、高齢者UC患者の再燃時には典型的な内視鏡画像を欠いてもCMVの再活性化を疑いステロイド以外の治療を考慮すべきである。(著者抄録)

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

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

潰瘍性大腸炎(ulcerative colitis:UC)患者に合併するサイトメガロウイルス(cytomegalovirus:CMV)感染症の大部分は、ステロイドや免疫抑制薬の治療歴がある。今回ステロイド投与歴がないにも関わらずCMV再活性化を生じ、治療経過でCMV感染症を発症したため抗ウイルス治療を要したUC患者2例を経験した。1例目は66歳で、再燃時大腸内視鏡検査では発赤、浮腫、びらんのみだが、既にCMVの再活性化を呈していた。ステロイド治療で一旦軽快したが、その後CMV感染症を合併し抗ウイルス治療を要した。2例目は75歳で、再燃時大腸内視鏡検査で浮腫、びらん、小潰瘍のみであったが既にCMV再活性化を生じていた。ステロイドとタクロリムスで一旦軽快したが、CMV感染症を合併し抗ウイルス療法を要した。ステロイド投与歴にとらわれず、高齢者UC患者の再燃時には典型的な内視鏡画像を欠いてもCMVの再活性化を疑いステロイド以外の治療を考慮すべきである。(著者抄録)

DOI： 10.11280/gee.58.2161

CiNii Article

潰瘍性大腸炎(ulcerative colitis:UC)患者に合併するサイトメガロウイルス(cytomegalovirus:CMV)感染症の大部分は、ステロイドや免疫抑制薬の治療歴がある。今回ステロイド投与歴がないにも関わらずCMV再活性化を生じ、治療経過でCMV感染症を発症したため抗ウイルス治療を要したUC患者2例を経験した。1例目は66歳で、再燃時大腸内視鏡検査では発赤、浮腫、びらんのみだが、既にCMVの再活性化を呈していた。ステロイド治療で一旦軽快したが、その後CMV感染症を合併し抗ウイルス治療を要した。2例目は75歳で、再燃時大腸内視鏡検査で浮腫、びらん、小潰瘍のみであったが既にCMV再活性化を生じていた。ステロイドとタクロリムスで一旦軽快したが、CMV感染症を合併し抗ウイルス療法を要した。ステロイド投与歴にとらわれず、高齢者UC患者の再燃時には典型的な内視鏡画像を欠いてもCMVの再活性化を疑いステロイド以外の治療を考慮すべきである。(著者抄録)

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)  

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

肉芽腫を認める感染性腸炎について述べた.腸結核とエルシニア腸炎の自験例について,臨床像と内視鏡像を検討し,チフス性疾患については症例を提示した.生検組織で疾患特異的な肉芽腫がみられることは少なく,臨床像,内視鏡像による鑑別診断が重要である.腸結核では無症状例が最も多い.特徴的な内視鏡像は,輪状潰瘍あるいは輪状配列する潰瘍,多発潰瘍瘢痕と活動性潰瘍の併存,発赤を伴う樹枝状不整形潰瘍,敷石像様所見である.エルシニア腸炎の臨床症状は腹痛と発熱が主である.特徴的な内視鏡像は終末回腸の小びらんを伴う腫大したPeyer板,腫大した回盲弁,終末回腸～上行結腸のアフタである.(著者抄録)

Publishing type：Research paper (scientific journal)  

肉芽腫を認める感染性腸炎について述べた.腸結核とエルシニア腸炎の自験例について,臨床像と内視鏡像を検討し,チフス性疾患については症例を提示した.生検組織で疾患特異的な肉芽腫がみられることは少なく,臨床像,内視鏡像による鑑別診断が重要である.腸結核では無症状例が最も多い.特徴的な内視鏡像は,輪状潰瘍あるいは輪状配列する潰瘍,多発潰瘍瘢痕と活動性潰瘍の併存,発赤を伴う樹枝状不整形潰瘍,敷石像様所見である.エルシニア腸炎の臨床症状は腹痛と発熱が主である.特徴的な内視鏡像は終末回腸の小びらんを伴う腫大したPeyer板,腫大した回盲弁,終末回腸〜上行結腸のアフタである.(著者抄録)

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

It is important to screen for alcohol consumption and drinking customs by using a stan- dardized method. The aim of this study was to investigate whether standardized questionnaire was useful for predicting alcohol consumption. A cross-sectional study using the Alcohol Use Disorders Identification Test (AUDIT) was conducted in 334 outpatients who consulted the Internal Medicine Department of Osaka City Juso Hospital. The patients completed self-reported questionnaires and underwent a diagnostic interview, physical examination, and laboratory testing. Forty (23%) male patients reported daily alcohol consumption 40 g, and 16 (10%) female patients reported consumption 20 g. The optimal cutoff values of hazardous drinking (all patients)/ drinker (male)/ drinker (female) were calculated using a 10-fold cross validation, resulting in an optimal AUDIT score cutoff of 8.2/ 7.2/ 6.1, with sensitivity of 95.5%/ 96.3%/ 88.9%, specificity of 87.0%/ 96.3%/ 88.9%, false positive rate of 13.0%/ 9.4%/6.6%, false negative rate of 4.5%/ 3.'%/ 11.1%, and area under the receiver operating characteristic curve of 0.97/ 0.98/ 0.99. In conclusion, this study showed that the AUDIT score was useful for predicting alcohol consumption.

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12879-016-1765-y

PubMed

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

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-015-1129-1

PubMed

Publishing type：Research paper (scientific journal)  

非アルコール性脂肪性肝疾患(NAFLD-HCC)およびアルコール性肝疾患(ALD-HCC)に伴う肝細胞癌(HCC)の臨床経過を明確にするため、大規模レトロスペクティブ多施設共同調査を行った。ALD-HCC患者532例(男性96%、年齢中央値68歳)およびNAFLD-HCC患者209例(男性70%、年齢中央値72歳)を対象に、臨床所見、生存および再発を調査した。ALD-HCC患者は、大部分が男性であり、NAFLD-HCC患者よりも年齢が低かった。NAFLD-HCC群では特に生活習慣病が多くみられたが、ALD-HCC群では肝硬変の有病率が著しく高かった。NAFLD-HCCの組織学的診断で性差が認められた(F4:女性72.7%対男性37.6%)。組織型、生存率および再発率などのHCCの特性は、NAFLD-HCC群とALD-HCC群で類似していた。しかし、再発のリスク因子は両群で異なっていた。NAFLD-HCCのリスク因子はdes-gamma-carboxy prothrombinであり、ALD-HCCのリスク因子はα-fetoproteinであった。

Publishing type：Research paper (scientific journal)  

非アルコール性脂肪性肝疾患(NAFLD-HCC)およびアルコール性肝疾患(ALD-HCC)に伴う肝細胞癌(HCC)の臨床経過を明確にするため、大規模レトロスペクティブ多施設共同調査を行った。ALD-HCC患者532例(男性96%、年齢中央値68歳)およびNAFLD-HCC患者209例(男性70%、年齢中央値72歳)を対象に、臨床所見、生存および再発を調査した。ALD-HCC患者は、大部分が男性であり、NAFLD-HCC患者よりも年齢が低かった。NAFLD-HCC群では特に生活習慣病が多くみられたが、ALD-HCC群では肝硬変の有病率が著しく高かった。NAFLD-HCCの組織学的診断で性差が認められた(F4:女性72.7%対男性37.6%)。組織型、生存率および再発率などのHCCの特性は、NAFLD-HCC群とALD-HCC群で類似していた。しかし、再発のリスク因子は両群で異なっていた。NAFLD-HCCのリスク因子はdes-gamma-carboxy prothrombinであり、ALD-HCCのリスク因子はα-fetoproteinであった。

Publishing type：Research paper (scientific journal)  

In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC.
Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013.
The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and alpha-fetoprotein was a risk factor in ALD-HCC.
Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

DOI： 10.1007/s00535-015-1129-1

PubMed

非アルコール性脂肪性肝疾患(NAFLD-HCC)およびアルコール性肝疾患(ALD-HCC)に伴う肝細胞癌(HCC)の臨床経過を明確にするため、大規模レトロスペクティブ多施設共同調査を行った。ALD-HCC患者532例(男性96%、年齢中央値68歳)およびNAFLD-HCC患者209例(男性70%、年齢中央値72歳)を対象に、臨床所見、生存および再発を調査した。ALD-HCC患者は、大部分が男性であり、NAFLD-HCC患者よりも年齢が低かった。NAFLD-HCC群では特に生活習慣病が多くみられたが、ALD-HCC群では肝硬変の有病率が著しく高かった。NAFLD-HCCの組織学的診断で性差が認められた(F4:女性72.7%対男性37.6%)。組織型、生存率および再発率などのHCCの特性は、NAFLD-HCC群とALD-HCC群で類似していた。しかし、再発のリスク因子は両群で異なっていた。NAFLD-HCCのリスク因子はdes-gamma-carboxy prothrombinであり、ALD-HCCのリスク因子はα-fetoproteinであった。

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12889-016-3053-6

PubMed

Publishing type：Research paper (scientific journal)  

Background: It is important to screen for alcohol consumption and drinking customs in a standardized manner. The aim of this study was 1) to investigate whether the AUDIT score is useful for predicting hazardous drinking using optimal cutoff scores and 2) to use multivariate analysis to evaluate whether the AUDIT score was more useful than pre-existing laboratory tests for predicting hazardous drinking.
Methods: A cross-sectional study using the Alcohol Use Disorders Identification Test (AUDIT) was conducted in 334 outpatients who consulted our internal medicine department. The patients completed self-reported questionnaires and underwent a diagnostic interview, physical examination, and laboratory testing.
Results: Forty (23 %) male patients reported daily alcohol consumption &gt;= 40 g, and 16 (10 %) female patients reported consumption &gt;= 20 g. The optimal cutoff values of hazardous drinking were calculated using a 10-fold cross validation, resulting in an optimal AUDIT score cutoff of 8.2, with a sensitivity of 95.5 %, specificity of 87.0 %, false positive rate of 13.0 %, false negative rate of 4.5 %, and area under the receiver operating characteristic curve of 0.97. Multivariate analysis revealed that the most popular short version of the AUDIT consisting solely of its three consumption items (AUDIT-C) and patient sex were significantly associated with hazardous drinking. The aspartate transaminase (AST)/alanine transaminase (ALT) ratio and mean corpuscular volume (MCV) were weakly significant.
Conclusions: This study showed that the AUDIT score and particularly the AUDIT-C score were more useful than the AST/ALT ratio and MCV for predicting hazardous drinking.

DOI： 10.1186/s12889-016-3053-6

PubMed

Publishing type：Research paper (scientific journal)  

最近の13年間に便毒素検査や便培養により,Clostridium difficile感染症(CDI)と診断され,大腸内視鏡検査を施行した39例について後方視的に内視鏡像,臨床像,診断方法,治療などについて検討した.CDIは内視鏡像から偽膜型,アフタ型,非特異型,正常型に分類することが可能であり,それぞれの割合は,36%,28%,15%,20%であった.臨床像と炎症反応の検討により,偽膜型はCDIの重症型であり,他の3型は軽症型であると考えられた.内視鏡像の検討より,アフタは偽膜の初期像の可能性が高いと推察された.また,非偽膜型の内視鏡像からもCDIを疑うことはある程度可能であると考えられた.CDIの診断はまずCD抗原とCD毒素の検査を行うことで迅速に判定を行う.それにCD培養,内視鏡検査などを組み合わせることで効率的で確実な診断が可能となる.偽膜型では薬物投与が必須であるが,それ以外では抗菌薬の中止のみで軽快する症例がみられる.(著者抄録)

Publishing type：Research paper (scientific journal)  

最近の13年間に便毒素検査や便培養により,Clostridium difficile感染症(CDI)と診断され,大腸内視鏡検査を施行した39例について後方視的に内視鏡像,臨床像,診断方法,治療などについて検討した.CDIは内視鏡像から偽膜型,アフタ型,非特異型,正常型に分類することが可能であり,それぞれの割合は,36%,28%,15%,20%であった.臨床像と炎症反応の検討により,偽膜型はCDIの重症型であり,他の3型は軽症型であると考えられた.内視鏡像の検討より,アフタは偽膜の初期像の可能性が高いと推察された.また,非偽膜型の内視鏡像からもCDIを疑うことはある程度可能であると考えられた.CDIの診断はまずCD抗原とCD毒素の検査を行うことで迅速に判定を行う.それにCD培養,内視鏡検査などを組み合わせることで効率的で確実な診断が可能となる.偽膜型では薬物投与が必須であるが,それ以外では抗菌薬の中止のみで軽快する症例がみられる.(著者抄録)

Publishing type：Research paper (scientific journal)  

患者は70歳代,女性.Mycobacterium aviumによる肺非結核性抗酸菌症で5年前から治療中も難治であった.腹痛,下痢を主訴に入院し,大腸内視鏡検査を施行した.終末回腸に輪状傾向の浅い潰瘍が多発し,同部には微細顆粒状粘膜がみられた.一方,大腸では直腸粘膜はほぼ正常であるが,上行結腸から下行結腸には顆粒状粘膜がみられた.生検組織にて,回腸では粘膜固有層深層を中心に多量に,大腸では主に粘膜上皮直下にアミロイドA蛋白質が沈着していた.部位による内視鏡像の差は組織学的なアミロイドの沈着形式と沈着量の差によるものと考えられた.なお本邦での非結核性抗酸菌症に続発するAAアミロイドーシスは,自験例を含め6例の報告しかみられなかった.6例の平均生存期間が3.6ヵ月と短く予後不良であり,早期発見,早期治療の重要性が示唆された.(著者抄録)

Publishing type：Research paper (scientific journal)  

患者は70歳代,女性.Mycobacterium aviumによる肺非結核性抗酸菌症で5年前から治療中も難治であった.腹痛,下痢を主訴に入院し,大腸内視鏡検査を施行した.終末回腸に輪状傾向の浅い潰瘍が多発し,同部には微細顆粒状粘膜がみられた.一方,大腸では直腸粘膜はほぼ正常であるが,上行結腸から下行結腸には顆粒状粘膜がみられた.生検組織にて,回腸では粘膜固有層深層を中心に多量に,大腸では主に粘膜上皮直下にアミロイドA蛋白質が沈着していた.部位による内視鏡像の差は組織学的なアミロイドの沈着形式と沈着量の差によるものと考えられた.なお本邦での非結核性抗酸菌症に続発するAAアミロイドーシスは,自験例を含め6例の報告しかみられなかった.6例の平均生存期間が3.6ヵ月と短く予後不良であり,早期発見,早期治療の重要性が示唆された.(著者抄録)

Publishing type：Research paper (scientific journal)  

最近の13年間に便毒素検査や便培養により,Clostridium difficile感染症(CDI)と診断され,大腸内視鏡検査を施行した39例について後方視的に内視鏡像,臨床像,診断方法,治療などについて検討した.CDIは内視鏡像から偽膜型,アフタ型,非特異型,正常型に分類することが可能であり,それぞれの割合は,36%,28%,15%,20%であった.臨床像と炎症反応の検討により,偽膜型はCDIの重症型であり,他の3型は軽症型であると考えられた.内視鏡像の検討より,アフタは偽膜の初期像の可能性が高いと推察された.また,非偽膜型の内視鏡像からもCDIを疑うことはある程度可能であると考えられた.CDIの診断はまずCD抗原とCD毒素の検査を行うことで迅速に判定を行う.それにCD培養,内視鏡検査などを組み合わせることで効率的で確実な診断が可能となる.偽膜型では薬物投与が必須であるが,それ以外では抗菌薬の中止のみで軽快する症例がみられる.(著者抄録)

患者は70歳代,女性.Mycobacterium aviumによる肺非結核性抗酸菌症で5年前から治療中も難治であった.腹痛,下痢を主訴に入院し,大腸内視鏡検査を施行した.終末回腸に輪状傾向の浅い潰瘍が多発し,同部には微細顆粒状粘膜がみられた.一方,大腸では直腸粘膜はほぼ正常であるが,上行結腸から下行結腸には顆粒状粘膜がみられた.生検組織にて,回腸では粘膜固有層深層を中心に多量に,大腸では主に粘膜上皮直下にアミロイドA蛋白質が沈着していた.部位による内視鏡像の差は組織学的なアミロイドの沈着形式と沈着量の差によるものと考えられた.なお本邦での非結核性抗酸菌症に続発するAAアミロイドーシスは,自験例を含め6例の報告しかみられなかった.6例の平均生存期間が3.6ヵ月と短く予後不良であり,早期発見,早期治療の重要性が示唆された.(著者抄録)

Publishing type：Research paper (scientific journal)  

患者は70歳代,女性.Mycobacterium aviumによる肺非結核性抗酸菌症で5年前から治療中も難治であった.腹痛,下痢を主訴に入院し,大腸内視鏡検査を施行した.終末回腸に輪状傾向の浅い潰瘍が多発し,同部には微細顆粒状粘膜がみられた.一方,大腸では直腸粘膜はほぼ正常であるが,上行結腸から下行結腸には顆粒状粘膜がみられた.生検組織にて,回腸では粘膜固有層深層を中心に多量に,大腸では主に粘膜上皮直下にアミロイドA蛋白質が沈着していた.部位による内視鏡像の差は組織学的なアミロイドの沈着形式と沈着量の差によるものと考えられた.なお本邦での非結核性抗酸菌症に続発するAAアミロイドーシスは,自験例を含め6例の報告しかみられなかった.6例の平均生存期間が3.6ヵ月と短く予後不良であり,早期発見,早期治療の重要性が示唆された.(著者抄録)

最近の13年間に便毒素検査や便培養により,Clostridium difficile感染症(CDI)と診断され,大腸内視鏡検査を施行した39例について後方視的に内視鏡像,臨床像,診断方法,治療などについて検討した.CDIは内視鏡像から偽膜型,アフタ型,非特異型,正常型に分類することが可能であり,それぞれの割合は,36%,28%,15%,20%であった.臨床像と炎症反応の検討により,偽膜型はCDIの重症型であり,他の3型は軽症型であると考えられた.内視鏡像の検討より,アフタは偽膜の初期像の可能性が高いと推察された.また,非偽膜型の内視鏡像からもCDIを疑うことはある程度可能であると考えられた.CDIの診断はまずCD抗原とCD毒素の検査を行うことで迅速に判定を行う.それにCD培養,内視鏡検査などを組み合わせることで効率的で確実な診断が可能となる.偽膜型では薬物投与が必須であるが,それ以外では抗菌薬の中止のみで軽快する症例がみられる.(著者抄録)

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

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)

Publishing type：Research paper (scientific journal)  

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

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)

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem; thus, discriminating nonalcoholic steatohepatitis (NASH) from NAFLD is of great clinical significance. For the diagnosis of NASH, liver biopsy-proven histological examination is the current gold standard, and noninvasive and reliable biomarkers are greatly needed. Recently, we found that two glycobiomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), are useful independently for NASH diagnosis. In this study, we confirmed that serum Fuc-Hpt is suitable for the prediction of ballooning hepatocytes and that serum Mac2bp is suitable for the prediction of liver fibrosis severity in 124 biopsy-proven NAFLD patients (training cohort). In addition, we found that the combination of serum Fuc-Hpt and Mac2bp levels was an excellent tool for NASH diagnosis. Using receiver operating characteristic analyses, the area under the receiver operating characteristic curve, sensitivity, and specificity of the combination of these two glycobiomarkers were 0.854, 81.1%, and 79.3%, respectively. We established a prediction model for NASH diagnosis using logistic regression analysis: logit (p)=-2.700+0.00242 x Fuc-Hpt+1.225 x Mac2bp. To validate the prediction model, another 382 biopsy-proven NAFLD patients were enrolled (validation cohort). In the validation cohort, the area under the receiver operating characteristic curve of this model for NASH diagnosis was 0.844, with 71.4% and 82.3% sensitivity and specificity, respectively. In addition, we investigated the significance of our developed NASH diagnosis model in ultrasound-diagnosed NAFLD subjects who received medical health checkups (n=803). Our model also could predict NAFLD disease severity in this larger population. Conclusion: The combination of serum Fuc-Hpt and Mac2bp can distinguish NASH from NAFLD patients. Our noninvasive model using two serum glycobiomarkers contributes to a novel NASH diagnostic methodology that could replace liver biopsy. (Hepatology 2015;62:1433-1443)

DOI： 10.1002/hep.28002

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

56歳男。軽度脳性麻痺によるてんかんの既往があった。2005年にはC型慢性肝炎と診断されてバルプロ酸ナトリウムを処方され、2006年にはペグインターフェロン(IFN)-α-2bとリバビリン(RBV)を72週間処方されたが、持続性ウイルス学的著効(SVR)には達しなかった。ウルソデオキシコール酸で治療し、血清アスパラギン酸アミノ基転移酵素(AST)/アラニンアミノトランスフェラーゼ(ALT)値は2007〜2012年の間ほぼ正常値であった。2012年にテラプレビル、ペグIFN-α-2b、RBVの3剤併用療法を行った。皮疹のために5日でテラプレビルを中止し、ペグIFN-α-2bとRBVを60週間継続した。早期ウイルス学的著効に達したが、SVRには達しなかった。シメプレビル、ペグIFN-α-2b、RBVの3剤併用療法を行った。7週後の血液検査で肝機能障害が認められ、入院した。AST、ALTが上昇していた。肝生検では、門脈域に局所壊死のびまん性領域と軽度線維症を伴った好酸小体が認められた。病理学的所見から薬物誘発性肝炎と診断した。ペグIFN-α-2b、RBV、シメプレビルを中止して保存的治療を行ったところ、ASTとALTは正常値に戻った。最終的にシメプレビル誘発性肝炎と診断した。入院から10日後に退院した。

Publishing type：Research paper (scientific journal)  

患者は40歳代,男性.腹痛を主訴に受診し,炎症反応高値と尿蛋白・尿潜血陽性を認め入院となった.腹部CT検査で終末回腸に限局した腸管壁の肥厚がみられた.大腸内視鏡検査では,終末回腸に限局して輪状病変の多発と浮腫がみられた.輪状病変は潰瘍とうろこ模様で構成されていた.小腸の生検組織では血管炎に合致する所見であった.急速進行性糸球体腎炎の合併があり,顕微鏡的多発血管炎(MPA)と診断した.プレドニゾロン(PSL)40mg/dayに加えて,シクロホスファミド(CPA)50mgの隔日投与にて軽快した.MPAは多くの臓器を冒し,消化器症状もみられるが,小腸病変を内視鏡的に観察された報告は自験例を含めて3例と少なく,いまだ内視鏡診断は確立していない.小腸に輪状病変や帯状潰瘍を認めた場合,頻度は低いがMPAを含む抗好中球細胞質抗体(ANCA)関連血管炎を鑑別に入れる必要がある.(著者抄録)

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

患者は40歳代,男性.腹痛を主訴に受診し,炎症反応高値と尿蛋白・尿潜血陽性を認め入院となった.腹部CT検査で終末回腸に限局した腸管壁の肥厚がみられた.大腸内視鏡検査では,終末回腸に限局して輪状病変の多発と浮腫がみられた.輪状病変は潰瘍とうろこ模様で構成されていた.小腸の生検組織では血管炎に合致する所見であった.急速進行性糸球体腎炎の合併があり,顕微鏡的多発血管炎(MPA)と診断した.プレドニゾロン(PSL)40mg/dayに加えて,シクロホスファミド(CPA)50mgの隔日投与にて軽快した.MPAは多くの臓器を冒し,消化器症状もみられるが,小腸病変を内視鏡的に観察された報告は自験例を含めて3例と少なく,いまだ内視鏡診断は確立していない.小腸に輪状病変や帯状潰瘍を認めた場合,頻度は低いがMPAを含む抗好中球細胞質抗体(ANCA)関連血管炎を鑑別に入れる必要がある.(著者抄録)

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

患者は40歳代,男性.腹痛を主訴に受診し,炎症反応高値と尿蛋白・尿潜血陽性を認め入院となった.腹部CT検査で終末回腸に限局した腸管壁の肥厚がみられた.大腸内視鏡検査では,終末回腸に限局して輪状病変の多発と浮腫がみられた.輪状病変は潰瘍とうろこ模様で構成されていた.小腸の生検組織では血管炎に合致する所見であった.急速進行性糸球体腎炎の合併があり,顕微鏡的多発血管炎(MPA)と診断した.プレドニゾロン(PSL)40mg/dayに加えて,シクロホスファミド(CPA)50mgの隔日投与にて軽快した.MPAは多くの臓器を冒し,消化器症状もみられるが,小腸病変を内視鏡的に観察された報告は自験例を含めて3例と少なく,いまだ内視鏡診断は確立していない.小腸に輪状病変や帯状潰瘍を認めた場合,頻度は低いがMPAを含む抗好中球細胞質抗体(ANCA)関連血管炎を鑑別に入れる必要がある.(著者抄録)

患者は40歳代,男性.腹痛を主訴に受診し,炎症反応高値と尿蛋白・尿潜血陽性を認め入院となった.腹部CT検査で終末回腸に限局した腸管壁の肥厚がみられた.大腸内視鏡検査では,終末回腸に限局して輪状病変の多発と浮腫がみられた.輪状病変は潰瘍とうろこ模様で構成されていた.小腸の生検組織では血管炎に合致する所見であった.急速進行性糸球体腎炎の合併があり,顕微鏡的多発血管炎(MPA)と診断した.プレドニゾロン(PSL)40mg/dayに加えて,シクロホスファミド(CPA)50mgの隔日投与にて軽快した.MPAは多くの臓器を冒し,消化器症状もみられるが,小腸病変を内視鏡的に観察された報告は自験例を含めて3例と少なく,いまだ内視鏡診断は確立していない.小腸に輪状病変や帯状潰瘍を認めた場合,頻度は低いがMPAを含む抗好中球細胞質抗体(ANCA)関連血管炎を鑑別に入れる必要がある.(著者抄録)

慢性B型肝炎(CHB)患者での肝線維症病期診断のための磁気共鳴弾性率計測(MRE)の精度と信頼性を、MREと血清線維症マーカー間の診断能比較によって評価した。2010年1月～2014年5月に著者等の施設でMREを実施した患者1516名のうちCHBで、6ヵ月以内の病理学的肝線維症病期診断、1週間以内の臨床検査結果が入手可能な73名(男性57名、女性16名、平均年齢62.8±9.6歳)の患者を用いた。診断は2名の放射線科医が別途に行った。受診者動作特性分析は、両診断者で血清線維症マーカーよりMREの方が肝線維症病期診断に対して識別能が有意(P<0.0004)に優れていることを明らかにした。また、両診断者間のクラス内相関係数は高く(p=0.971)、肝硬化度の測定も0.1-kPa以内の差で統計的に同等であった(P=0.0157)。

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ajpath.2014.12.017

PubMed

Publishing type：Research paper (scientific journal)  

This study was conducted to clarify the role of cytoglobin (Cygb), a globin expressed in hepatic stellate cells (HSCs), in the development of Liver fibrosis and cancer in nonalcoholic steatohepatitis (NASH). Cygb expression was assessed in patients with NASH and hepatocellular carcinoma. Mouse NASH model was generated in Cygb-deficient (Cygb(-/-)) or wild-type (WT) mice by giving a choline-deficient amino acid defined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCsCygb-wild) or Cygb(-/-) (HSCsCygb-null) mice were characterized. As results, the expression of CYGB was reduced in patients with NASH and hepatocellular carcinoma. Choline-deficient amino acid treatment for 8 weeks induced prominent inflammation and fibrosis in Cygb(-/-) mice, which was inhibited by macrophage deletion. Surprisingly, at 32 weeks, despite no tumor formation in the WT mice, all Cygb(-/-) mice developed liver cancer, which was ameliorated by N-acetyl cysteine treatment. Altered expression of 31 genes involved in the metabolism of reactive oxygen species was notable in Cygb(-/-) mice. Both HSCsCygb-null and Cygb siRNA-transfected-HSCsCYgb-wild exhibited the preactivation condition. Our findings provide important insights into the role that Cygb, expressed in HSCs during liver fibrosis, plays in cancer development with NASH.

DOI： 10.1016/j.ajpath.2014.12.017

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MCG.0000000000000186

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MCG.0000000000000186

PubMed

Publishing type：Research paper (scientific journal)  

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

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

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12327

PubMed

Publishing type：Research paper (scientific journal)  

非アルコール性脂肪肝(NAFLD)患者における肝線維症の検出に血清フェリチンを使用することの臨床的意義を、大規模なJapanese Society Group(JSG)-NAFLDデータベースを用いて検討した。2001〜2013年に観察された生検で検証済のNAFLD患者1201名(男性641名、女性560名、平均50.8±15.0歳)のデータをレトロスペクティブに分析した。血清フェリチンは脂肪変性、小葉炎症、膨潤肝細胞の等級が上昇すると共に上昇した。線維症に関してはステージ0,1,2,3,4が各々228,389,315,222,47名で、対応する血清フェリチンの平均値は各々180.6,238.0,332.1,290.1,205.6ng/mLであった。多変量解析からは、性差、脂肪変性等級、線維症ステージが血清フェリチンと独立に関連した。線維症の検出に関する血清フェリチンの診断性能を評価するためにAUROCを算出したところ、ステージ1〜4に対して0.617であり、ステージ2〜4の重度線維症に関しては0.573であり、ステージ3〜4の進行した線維症に関しては0.554であった。以上の結果より、血清フェリチン単独の診断精度は、AUROCが0.6以下で低いことが再確認された。

Publishing type：Research paper (scientific journal)  

非アルコール性脂肪肝(NAFLD)患者における肝線維症の検出に血清フェリチンを使用することの臨床的意義を、大規模なJapanese Society Group(JSG)-NAFLDデータベースを用いて検討した。2001〜2013年に観察された生検で検証済のNAFLD患者1201名(男性641名、女性560名、平均50.8±15.0歳)のデータをレトロスペクティブに分析した。血清フェリチンは脂肪変性、小葉炎症、膨潤肝細胞の等級が上昇すると共に上昇した。線維症に関してはステージ0,1,2,3,4が各々228,389,315,222,47名で、対応する血清フェリチンの平均値は各々180.6,238.0,332.1,290.1,205.6ng/mLであった。多変量解析からは、性差、脂肪変性等級、線維症ステージが血清フェリチンと独立に関連した。線維症の検出に関する血清フェリチンの診断性能を評価するためにAUROCを算出したところ、ステージ1〜4に対して0.617であり、ステージ2〜4の重度線維症に関しては0.573であり、ステージ3〜4の進行した線維症に関しては0.554であった。以上の結果より、血清フェリチ

Publishing type：Research paper (scientific journal)  

Serum ferritin was recently reported to have low diagnostic accuracy for the detection of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). To corroborate these findings, we investigated the diagnostic accuracy of serum ferritin levels for detecting liver fibrosis in NAFLD patients utilizing a large Japanese cohort database. A total 1201 biopsy-proven NAFLD patients, seen between 2001 and 2013, were enrolled into the Japan Study Group of NAFLD. Analysis was performed on data from this cohort comparing between serum ferritin levels and hepatic histology. Serum ferritin increased with increasing histological grade of steatosis, lobular inflammation and ballooning. Multivariate analyses revealed that sex differences, steatotic grade and fibrotic stage were independently associated with serum ferritin levels (P&lt;0.0001, &lt;0.0001, 0.0248, respectively). However, statistical analyses performed using serum ferritin levels demonstrated that the area under the receiver-operator curve for detecting fibrosis was not adequate for rigorous prediction. Several factors including sex differences, steatosis and fibrosis were found to correlate with serum ferritin levels. Therefore, serum ferritin may have low diagnostic accuracy for specifically detecting liver fibrosis in NAFLD patients due to the involvement of multiple hepatocellular processes.

DOI： 10.1111/hepr.12327

PubMed

非アルコール性脂肪肝(NAFLD)患者における肝線維症の検出に血清フェリチンを使用することの臨床的意義を、大規模なJapanese Society Group(JSG)-NAFLDデータベースを用いて検討した。2001～2013年に観察された生検で検証済のNAFLD患者1201名(男性641名、女性560名、平均50.8±15.0歳)のデータをレトロスペクティブに分析した。血清フェリチンは脂肪変性、小葉炎症、膨潤肝細胞の等級が上昇すると共に上昇した。線維症に関してはステージ0,1,2,3,4が各々228,389,315,222,47名で、対応する血清フェリチンの平均値は各々180.6,238.0,332.1,290.1,205.6ng/mLであった。多変量解析からは、性差、脂肪変性等級、線維症ステージが血清フェリチンと独立に関連した。線維症の検出に関する血清フェリチンの診断性能を評価するためにAUROCを算出したところ、ステージ1～4に対して0.617であり、ステージ2～4の重度線維症に関しては0.573であり、ステージ3～4の進行した線維症に関しては0.554であった。以上の結果より、血清フェリチン単独の診断精度は、AUROCが0.6以下で低いことが再確認された。

Publishing type：Research paper (scientific journal)  

Aim: Serum alanine aminotransferase (ALT) is important for screening, diagnosis and management of chronic liver diseases. The incidence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), which is considered a hepatic manifestation of lifestyle-related diseases, is increasing worldwide. However, the upper limit of the normal ALT level has not yet been established because of not excluding many lifestyle-related diseases. The aim of this study was to evaluate the upper limit of normal serum ALT levels in Japanese subjects. Methods: We analyzed the serum ALT levels of 11 404 Japanese subjects negative for hepatitis B surface antigen and hepatitis C virus antibody, and who received health checkups. Lifestyle factors related to ALT levels were determined by multivariate analysis. Subjects with all factors identified by multivariate analysis within the normal range were defined as "healthy" subjects. The 90th percentile of ALT levels in healthy subjects was defined as the upper limit of normal ALT. Results: Whereas alcohol intake was not a significant factor, the following were independently associated with ALT concentration by multivariate analysis: sex
age
body mass index
waist circumference
concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides and fasting blood glucose
and fatty liver on ultrasonography. Healthy subjects consisted of 1462 (21.2%) men and 2046 (45.4%) women, and the 90th percentiles of the ALT levels in the two groups were 29 and 23 IU/L, respectively. Conclusion: The upper limits of normal ALT when considering lifestyle factors in Japanese subjects were 29 IU/L in men and 23 IU/L in women.

DOI： 10.1111/hepr.12293

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-013-0911-1

PubMed

Publishing type：Research paper (scientific journal)  

横断的多施設研究で、生検で診断された非アルコール性脂肪性肝疾患(NAFLD)患者1365例を対象とし、NAFLDの組織学的所見と生活習慣病の関係を検討した。肝線維化ステージ(0/1/2/3/4)の割合は男性がそれぞれ22.6/34.1/26.7/14.5/2.1%、女性がそれぞれ16.2/31.7/23.9/21.6/6.6%であった。脂質異常症が65.7%(高中性脂肪血症45.3%、LDLコレステロール高値37.5%、HDL-コレステロール低値19.5%)に認められた。高血圧は30.2%、糖尿病(DM)は47.3%に認められた。線維化ステージは年齢と相関して上昇し、特に閉経後女性でその傾向が認められた。肥満指数と線維化ステージとの間に相関が認められた。血糖コントロール不良は線維化ステージと相関し、特に女性で顕著であった。多変量解析の結果、年齢とDMが線維化進行と相関する独立した因子であった。高血圧と線維化ステージとの間には相関は認められなかった。血清中性脂肪値と線維化ステージは逆相関した。

Publishing type：Research paper (scientific journal)  

横断的多施設研究で、生検で診断された非アルコール性脂肪性肝疾患(NAFLD)患者1365例を対象とし、NAFLDの組織学的所見と生活習慣病の関係を検討した。肝線維化ステージ(0/1/2/3/4)の割合は男性がそれぞれ22.6/34.1/26.7/14.5/2.1%、女性がそれぞれ16.2/31.7/23.9/21.6/6.6%であった。脂質異常症が65.7%(高中性脂肪血症45.3%、LDLコレステロール高値37.5%、HDL-コレステロール低値19.5%)に認められた。高血圧は30.2%、糖尿病(DM)は47.3%に認められた。線維化ステージは年齢と相関して上昇し、特に閉経後女性でその傾向が認められた。肥満指数と線維化ステージとの間に相関が認められた。血糖コントロール不良は線維化ステージと相関し、特に女性で顕著であった。多変量解析の結果、年齢とDMが線維化進行と相関する独立した因子であった。高血圧と線維化ステージとの間には相関は認められなかった。血清中性脂肪値と線維化ステージは逆相関した。

Publishing type：Research paper (scientific journal)  

The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD.
In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated.
The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7 % (hypertriglyceridemia, 45.3 %; increased low-density lipoprotein cholesterol, 37.5 %; decreased high density lipoprotein cholesterol, 19.5 %) of patients. Hypertension was present in 30.2 %, and diabetes mellitus (DM) in 47.3 %. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage.
DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

DOI： 10.1007/s00535-013-0911-1

PubMed

横断的多施設研究で、生検で診断された非アルコール性脂肪性肝疾患(NAFLD)患者1365例を対象とし、NAFLDの組織学的所見と生活習慣病の関係を検討した。肝線維化ステージ(0/1/2/3/4)の割合は男性がそれぞれ22.6/34.1/26.7/14.5/2.1%、女性がそれぞれ16.2/31.7/23.9/21.6/6.6%であった。脂質異常症が65.7%(高中性脂肪血症45.3%、LDLコレステロール高値37.5%、HDL-コレステロール低値19.5%)に認められた。高血圧は30.2%、糖尿病(DM)は47.3%に認められた。線維化ステージは年齢と相関して上昇し、特に閉経後女性でその傾向が認められた。肥満指数と線維化ステージとの間に相関が認められた。血糖コントロール不良は線維化ステージと相関し、特に女性で顕著であった。多変量解析の結果、年齢とDMが線維化進行と相関する独立した因子であった。高血圧と線維化ステージとの間には相関は認められなかった。血清中性脂肪値と線維化ステージは逆相関した。

Publishing type：Research paper (scientific journal)  

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)  

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。

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。

CiNii Article

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)  

DOI： 10.1111/jgh.12611

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.12604

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

Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v20.i29.10108

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.clinbiochem.2014.04.026

PubMed

Publishing type：Research paper (scientific journal)  

AIM: To investigate a simple noninvasive scoring system for predicting liver cirrhosis in nonalcoholic fatty liver disease (NAFLD) patients.
METHODS: A total of 1048 patients with liver-biopsy-confirmed NAFLD were enrolled from nine hepatology centers in Japan (stage 0, 216; stage 1, 334; stage 2, 270; stage 3, 190; stage 4, 38). The weight and height of the patients were measured using a calibrated scale after requesting the patients to remove their shoes and any heavy clothing. Venous blood samples were obtained in the morning after the patients had fasted overnight for 12 h. Laboratory evaluation was performed in all patients. Statistical analysis was conducted using SPSS version 12.0. Continuous variables were expressed as mean +/- SD.
RESULTS: The optimal cutoff value of platelet count, serum albumin, and amino-transferase/alanine aminotransferase ratio (AAR) was set at &lt; 15.3 10(4)/mu L, &lt; 4.0 g/dL, and &gt; 0.9, respectively, by the receiver operating characteristic curve. These three variables were combined in an unweighted sum (platelet count = 1 point, serum albumin = 1 point, AAR = 1 point) to form an easily calculated composite score for predicting cirrhosis in NAFLD patients, called the PLALA (platelet, albumin, AAR) score. The diagnosis of PLALA &gt;= 2 had sufficient accuracy for detecting liver cirrhosis in NAFLD patients.
CONCLUSION: The PLALA score may be an ideal scoring system for detecting cirrhosis in NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i29.10108

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.clinbiochem.2014.04.026

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v20.i25.8048

PubMed

Publishing type：Research paper (scientific journal)  

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol abstinence is the most effective therapy for ALD. However, targeted therapies are urgently needed for patients with severe ALD (i.e., alcoholic hepatitis) or those who do not abstain from alcohol. The lack of studies and the availability of animal models that do not reflect all the features of this disease in humans inhibit the development of new drugs for ALD. In ALD-associated fibrosis, hepatic stellate cells are the principal cell type responsible for extracellular matrix production. Although the mechanisms underlying fibrosis in ALD are largely similar to those observed in other chronic liver diseases, oxidative stress, methionine metabolism abnormalities, hepatocyte apoptosis, and endotoxin lipopolysaccharides that activate Kupffer cells may play unique roles in disease-related fibrogenesis. Lipogenesis during the early stages of ALD has recently been implicated as a risk factor for the progression of cirrhosis. Other topics include osteopontin, interleukin-1 signaling, and genetic polymorphism. In this review, we discuss the basic pathogenesis of ALD and focus on liver fibrogenesis. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i25.8048

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-013-0871-5

PubMed

Publishing type：Research paper (scientific journal)  

It is suggested that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), can be associated with insomnia and gastro-esophageal reflux disease (GERD). The relationship between GERD and insomnia in subjects with biopsy-proven NAFLD was investigated.
This study enrolled 123 patients with biopsy-proven NAFLD. Insomnia was assessed by the Athens Insomnia Scale (AIS), a self-assessment psychometric instrument designed to quantify sleep difficulty based on ICD-10 criteria; AIS scores a parts per thousand yen 6 were considered positive for insomnia. GERD symptoms were evaluated using a frequency scale for the symptoms of GERD (FSSG); FSSG scores a parts per thousand yen 8 were considered positive. Logistic regression models were used to evaluate the association of insomnia with GERD, after adjusting for potential confounders. Thirteen patients with GERD were treated with the proton pump inhibitor rabeprazole (RPZ; 10 mg/day), for 12 weeks.
Of the 123 patients, 76 (62 %) were female and 87 (71 %) were obese, with 34 (28 %) having AIS scores a parts per thousand yen 6 and 31 (25 %) having FSSG scores a parts per thousand yen 8. Liver biopsy revealed that 40 patients (33 %) had NAFL and 83 (67 %) had NASH. FSSG and AIS scores were similar in the two groups. HOMA-IR, FSSG scores and gamma GT (GGT) concentrations were significantly higher in insomniacs than in non-insomniacs. Logistic regression analysis demonstrated that FSSG score and GGT concentration were independently associated with insomnia. RPZ treatment resulted in significantly reductions in both AIS and FSSG scores.
Nearly 30 % of patients with biopsy-proven NAFLD had insomnia, which was related to GGT and GERD and could be relieved by RPZ treatment.

DOI： 10.1007/s00535-013-0871-5

PubMed

非アルコール性脂肪性肝疾患(NAFLD)の123名(男47名、女76名、平均59歳)を対象に、不眠症と胃食道逆流症(GERD)の有無を調査した。アテネ不眠尺度でAIS≧6を不眠症とし、FSSGスコア≧8をGERDとした。123名中87名が肥満で、不眠症は34名、GERDは31名であった。肝生検では40名が単純性脂肪肝(NAFL)、83名が非アルコール性脂肪肝炎(NASH)と判定され、両群でAISとFSSGスコアは同等であった。HOMA-IR、FSSGスコアおよびγGT(GGT)濃度は非不眠症群に比べ不眠症群で有意に高く、ロジスティック回帰分析の結果、FSSGスコアとGGT濃度は独立して不眠症と関連があった。GERD患者13名をプロトン阻害薬ラベプラゾール(RPZ)10mg/日で12週間治療した結果、AISとFSSGスコアの両方に有意な低下を認めた。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/labinvest.2013.135

PubMed

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

PubMed

DOI： 10.1038/labinvest.2013.135

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.12376

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

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

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。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

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。

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

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。

Publishing type：Research paper (scientific journal)  

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。

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。

CiNii Article

Publishing type：Research paper (scientific 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 30kcal/IBW may serve as a reference for lifestyle guidelines for compensated cirrhotic patients. © 2013 The Japan Society of Hepatology.

DOI： 10.1111/hepr.12085

PubMed

Publishing type：Research paper (scientific journal)  

Aims/IntroductionWe reinvestigated the clinical usefulness of the modified NAFIC scoring system, modified by changing the weightage assigned to the fasting serum insulin level based on the importance of hyperinsulinemia in the pathogenesis of non-alcoholic steatohepatitis (NASH), in Japanese patients with non-alcoholic fatty liver disease (NAFLD) who had undergone liver biopsy.
Materials and MethodsThe NAFIC score is conventionally calculated as follows: serum ferritin 200ng/mL (female) or 300ng/mL (male), 1point; serum fasting insulin 10U/mL, 1point; and serum type IV collagen 7s 5.0ng/mL, 2points. A total of 147 patients with NAFLD who had undergone liver biopsies were included in the estimation group. To validate the modified scoring system, 355 patients from nine hepatology centers in Japan were also enrolled.
ResultsIn the estimation group, 74 (50.3%) patients were histologically diagnosed as having NASH, whereas the remaining 73 (49.7%) were diagnosed as not having NASH. As the percentage of NASH patients increased not only among participants with serum insulin levels greater than 10U/mL, but also in those with serum levels greater than 15U/mL, we advocated use of the modified NAFIC score, as follows: serum fasting insulin 10-15U/mL, 1point and 15U/mL, 2points. The modified NAFIC score showed improved sensitivity and negative predictive value for the diagnosis of NASH. This finding was also confirmed in the validation group.
ConclusionsThe modified NAFIC scoring system could be a clinically useful diagnostic screening tool for NASH.

DOI： 10.1111/jdi.12101

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jdi.12101

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12066

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)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/prca.201200137

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

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)  

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)  

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

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12066

PubMed

Publishing type：Research paper (scientific journal)  

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)  

Publishing type：Research paper (scientific journal)  

PurposeMac-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 designSerum 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.
ResultsMac-2bp levels were significantly elevated in NASH patients compared with non-NASH (simple steatosis) patients (2.132 1.237 vs. 1.103 +/- 0.500 g/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 relevanceThese results support the potential usefulness of measuring Mac-2bp levels in clinical practice as a biomarker for NASH.

DOI： 10.1002/prca.201200137

PubMed

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

CiNii Article

CiNii Article

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-012-0704-y

PubMed

Publishing type：Research paper (scientific journal)  

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&quot;ヘルッチェ&quot;(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

Publishing type：Research paper (scientific journal)  

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)

Publishing type：Research paper (scientific journal)  

The severity of liver fibrosis must be estimated to determine the prognosis, for surveillance, and for optimal treatment of nonalcoholic fatty liver disease (NAFLD). However, the severity of hepatic fibrosis tends to be underestimated in patients with normal ALT.
We investigated histological data and scoring systems (FIB-4 index, NAFLD fibrosis score, BARD score, and AST/ALT ratio) of 1,102 liver-biopsy-confirmed NAFLD patients.
A total of 235 NAFLD patients with normal ALT were estimated to exist. The ratio of advanced fibrosis (stage 3-4) was seen in 16.1 % of subjects with normal ALT. Scoring systems, especially the FIB-4 index and NAFLD fibrosis score, were clinically very useful (AUROC &gt; 0.8), even in patients with normal ALT. Furthermore, with resetting of the cutoff values, the FIB-4 index (&gt; 1.659) and NAFLD fibrosis score (&gt; 0.735) were found to have a higher sensitivity and higher specificity for the prediction of advanced fibrosis, and all of these scoring systems (FIB-4 index, NAFLD fibrosis score, BARD score, and AST/ALT ratio) had higher negative predictive values (&gt; 90.3 %). By using the resetting cutoff value, liver biopsy could have been avoided in 60.4 % (FIB-4), 66.4 % (NAFLD fibrosis score), 51.9 % (BARD score), and 62.1 % (AST/ALT ratio).
We reset the cutoff values of numerous non-invasive scoring systems to improve their clinical usefulness in the prediction of liver fibrosis in NAFLD patients with normal ALT, and these non-invasive scoring systems with the reset cutoff values could be of substantial benefit to reduce the number of liver biopsies performed.

DOI： 10.1007/s00535-012-0704-y

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)

Publishing type：Research paper (scientific journal)  

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&quot;ヘルッチェ&quot;(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

1102例の肝生検で確定診断された非アルコール性脂肪肝(NAFLD)症例を対象として、組織学的所見と各種スコアリング法(FIB-4指数、NAFLD線維化スコア、BARDスコア、AST/ALT比)を比較し、その有用性を検討した。235例は、ALT値が正常のNAFLDで、線維化が進んだ症例を16.1%に認めた。スコアリング法、特にFIB-4指数とNAFLD線維化スコアは、ALT正常例においても臨床的に有用であった(受信者操作特性曲線下領域>0.8)。カットオフ値をFIB-指数で>1.659、NAFLD線維化スコアで>0.735とすることで、高度線維化に対する感度および特異度が上昇した。また、全てのスコアリング法で陰性的中率が向上した。カットオフ値の変更により、60.4%(FIB-4)、66.4%(NAFLD線維化スコア)、51.9%(BARDスコア)、62.1% (AST/ALT比)の症例で肝生検が避けられると考えられた。

Publishing type：Research paper (scientific journal)  

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。

Publishing type：Research paper (scientific journal)  

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。

Publishing type：Research paper (scientific journal)  

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。

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。

Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0066328

PubMed

正常血清ALT濃度を維持し続ける(PNALT)C型肝炎ウイルス(HCV)保因者における初回受診時のアラニンアミノトランスフェラーゼ(ALT)濃度と長期の正常血清ALT濃度との関連性について検証した。PNALTのHCV保因者の判定は血清HCV RNAの陽性、12ヵ月以上の少なくとも三つの異なった時点でALT濃度が30IU/L以下、血小板数が15×10^4μl/mL以上、および肥満度指数(BMI)が30kg/m2以下を基準に行った。PNALTを伴うHCV保因者49名を対象に治療成績について後ろ向きに評価し、10年以上経過観察を行った。平均14.7±2.5年の経過観察期間中に30IU/L以下のALT濃度を維持したのは僅か8名(8/49、16.3%)の患者のみであった。初期のALT濃度が19IU/L以下であった17名の患者のうち9名(9/17、52.9%)は10年後にALT濃度が30IU/L以下であった。これらのPNALT患者がALT濃度30IU/L以下を維持する可能性は初期のALT濃度が20IU/L以上であった患者(n=32)と比較すると有意に高かった。異常なALT濃度は45～55歳の女性PNALT患者でより多く認められ、この時期は一般的な閉経の開始時期と重なっていた。

Publishing type：Research paper (scientific journal)  

PubMed

Publishing type：Research paper (scientific journal)  

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)  

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)

PubMed

Publishing type：Research paper (scientific journal)  

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)

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)  

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)  

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

DOI： 10.1371/journal.pone.0083382

PubMed

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

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1872-034X.2012.01046.x

PubMed

Publishing type：Research paper (scientific journal)  

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)  

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

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

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)  

DOI： 10.1136/gutjnl-2011-300717

PubMed

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)  

DOI： 10.3748/wjg.v18.i40.5759

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 &gt;= 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 &gt;= 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. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i40.5759

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

完全な早期陰性化(cEVR)を達成した慢性C型肝炎(CHC)患者150名のうちpeginterferon(PEG IFN)-α-2bとリバビリン(RBV)の併用療法を48週間(n=104)または52-64週間(n=46)行った患者を対象に、後向き研究を行い、治療期間の延長が有効性について検討した。48週の治療群では持続陰性化(SVR)しなかった患者は女性に多く、SVRを達成した患者と比べて総RBV処方量は有意に少なかった。これらの女性患者におけるSVR率は治療8週目でC型肝炎ウイルス(HCV)のRNAが陰性の男性と同等であった。治療12週目のSVR率はHCV RNAが陰性の男性と比べると低い値であった。52-64週の治療群では48週以降の総RBV投与量(mg/kg)は男性に比べて女性で少なかったが、SVR率は男性と女性で同等であった。遺伝子型1型のCHC患者でPEG IFN-α-2bとRBVの併用療法を受けた患者のうちSVRを達成できなかった割合は男性に比べて女性で少ない総RBVの処方を受けている場合が多いことが示された。cEVRを達成した女性患者では男性と比べるとSVR率が低いという状況は、たとえ貧血によりRBVの処方量が少なくなる恐れがあっても治療を継続することにより改善できる可能性が考えられた。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

CiNii Article

CiNii Article

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1872-034X.2011.00956.x

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10620-012-2085-8

PubMed

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

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)  

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.
Twenty-four consecutive CHC patients were randomly assigned to either the control group, which received pegylated interferon alpha-2b at 1.5 mu g/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.
In the control group, after PegIFN/RBV initiation, a significant increase was observed in the total T1/2 (before: 84.0 +/- A 22.1 min versus after: 100.8 +/- A 28.9 min, P = 0.03), the distal T1/2 (before: 95.3 +/- A 32.2 min versus after: 115.3 +/- A 41.4 min, P = 0.03), and digestive symptom score (before: 3.2 +/- A 1.4 versus after: 8.1 +/- A 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.
Mosapride improved total and distal gastric motility in IFN-induced gastroparesis, and consequently relieved symptoms.

DOI： 10.1007/s10620-012-2085-8

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 5.0 Log 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 16 weeks of therapy (group A), and 28 selected 24 weeks of therapy (group B). Among non-RVR patients, 40 selected 24 weeks of therapy (group C), and 19 selected 48 weeks 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: 16 weeks of combination therapy could achieve an adequate antiviral effect for RVR patients. Extending therapy could not significantly improve SVR rate in non-RVR patients.

DOI： 10.1111/j.1872-034X.2011.00956.x

PubMed