記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan. METHODS: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis. RESULTS: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD. CONCLUSIONS: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD.

DOI： 10.1111/apt.17995

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

DOI： 10.1111/hepr.14039

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A male patient in his 70s with recurrent hepatocellular carcinoma (HCC) after surgery received atezolizumab plus bevacizumab (Atezo+Bev) therapy. Initial computed tomography (CT) revealed tumor growth along with an increase in tumor markers, and contrast-enhanced ultrasonography (CEUS) showed multiple round avascular areas within the nodules with an appearance similar to a slice of Swiss cheese. Continuation of immunotherapy with consideration of the potential for pseudoprogression produced a dramatic response. Although it is difficult to distinguish between true progression and pseudoprogression, the Swiss cheese-like appearance on CEUS may be important for the early diagnosis of pseudoprogression.

DOI： 10.2169/internalmedicine.2349-23

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. METHODS: This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. RESULTS: Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4). CONCLUSION: Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.

DOI： 10.3350/cmh.2023.0515

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本肝臓学会  

肝生検を施行されたMASLD(metabolic dysfunction-associated steatotic liver disease)における「ALT>30U/L」の有用性とその意義についてFIB-4 Index、血小板数を組み合わせて検討した。1994年12月～2020年12月に肝生検を施行されたNAFLD(Non-alcoholic fatty liver disease)1398例のうちMASLDに該当する1381例を対象とした。stage≧2は614例に認め、そのうちALT>50U/Lは470例(76%)であった。ALT>30U/LにすることによりALT30～50U/Lの症例を追加で拾い上げることができ、stage≧2は578例(94%)とより多くの線維化進展したMASLDの検出が可能となった。FIB-4 IndexでみてみるとFIB-4 Index>1.3は全体で805症例に認められたが、ALT>50U/Lから>30U/Lに基準値を変えることにより、572例(71%)から742例(92%)に検出可能症例が増加した。同様に血小板20×10^4/μL未満の557例においてもALT>50U/Lから>30U/Lにすることにより367例(66%)から509例(91%)の症例も検出可能となった。FIB-4 Indexと血小板を組み合わせることにより、治療適応になるMASLD症例の取りこぼしが少なくすることが期待された。

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00263&link_issn=&doc_id=20240419040004&doc_link_id=10.2957%2Fkanzo.65.186&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.65.186&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(株)メディカルアイ  

FNH-like noduleはFNHと似た画像を呈することが知られている。今回、我々は、造影3DSMIがFNHとの鑑別に有用であったFNH-like noduleの一例を経験したので報告する。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. Individuals 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 and NAFLD fibrosis score. RESULTS: A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease 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 the fibrosis-4 index and NAFLD fibrosis score, 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 participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.

DOI： 10.1111/hepr.13947

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: There have been several reports that some probiotics improve non-alcoholic fatty liver disease (NAFLD); however, many studies have involved cocktail therapies. We evaluated whether heat-killed Lactobacillus brevis SBL88 (L. brevis SBL88) monotherapy improves the clinical features of NAFLD. METHODS: The NAFLD model was induced in mice fed a high-fat diet (HFD) (HFD mice) or HFD + 1% heat-killed L. brevis SBL88 (SBL mice) for 16 weeks. Histopathological liver findings were analyzed. To evaluate the gut microbiota, a modified terminal restriction fragment length polymorphism analysis of the feces was performed. RNA sequencing in the liver was performed with Ion Proton™. To investigate the direct effects of heat-killed L. brevis SBL88, an in vitro study was performed. RESULTS: Histopathological findings revealed that fat droplets in the liver were significantly reduced in SBL mice; however, terminal restriction fragment length polymorphism did not show alterations in the gut microbiota between HFD mice and SBL mice. RNA sequencing and pathway analysis revealed that the regulation of lipid and insulin metabolism was affected. The mRNA expression of insulin receptor substrate 2 (IRS-2) was significantly higher in SBL mice, whereas the expression of IRS-1 was not significantly different. Phospho-IRS-2 expression was also significantly increased in SBL mice. In addition, an in vitro study revealed significant alterations in IRS-2 and forkhead box protein O1 expression levels. CONCLUSION: SBL mice exhibited partially improved selective hepatic insulin resistance. Our data suggest that heat-killed L. brevis SBL88 could attenuate the clinical features of NAFLD that are not mediated by alterations in the gut microbiota.

DOI： 10.1111/jgh.16337

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：日本語   出版者・発行元：日本消化器病学会-北海道支部  

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記述言語：日本語   出版者・発行元：(株)メディカルアイ  

造影3D超音波が病態把握に有用と考えられた若年発症の巨大肝エキノコックス症を経験したので文献的考察を加え報告する。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND 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 nonalcoholic fatty liver disease (NAFLD). METHODS: We investigated 1313 patients with NAFLD. Patients were assigned to low-risk, indeterminate-risk, 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 and 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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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: One thousand three hundred ninety-eight patients were included in this subanalysis 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 8874 person-years, 37 patients developed HCC. Using a cut-off 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 cut-off 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, NASH, and diabetes. CONCLUSIONS: Baseline platelet counts of 192 × 109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.

DOI： 10.1111/hepr.13884

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The relationship between baseline serum albumin level and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) remains unknown. This is a sub-analysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) study. The main outcomes were: death or orthotopic liver transplantation (OLT), liver-related death, and liver-related events (hepatocellular carcinoma [HCC], decompensated cirrhosis, and gastroesophageal varices/bleeding). 1383 Japanese patients with biopsy-confirmed NAFLD were analyzed. They were divided into 3 groups based on serum albumin: high (>4.0 g/dL), intermediate (3.5-4.0 g/dL), and low (<3.5 g/dL). Unadjusted hazard ratio [HR] of the intermediate albumin group, compared with the high albumin group, were 3.6 for death or OLT, 11.2 for liver-related death, 4.6 for HCC, 8.2 for decompensated cirrhosis, and 6.2 for gastroesophageal varices (all risks were statistically significant). After adjusting confounding factors, albumin remained significantly associated with death or OLT (intermediate vs. high albumin group: HR 3.06, 95% confidence interval [CI] 1.59-5.91, p < 0.001; low vs. high albumin group: HR 22.9, 95% CI 8.21-63.9, p < 0.001). Among biopsy-confirmed NAFLD patients, those with intermediate or low serum albumin had a significantly higher risk of death or OLT than those with high serum albumin.

DOI： 10.3390/nu15092014

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Capecitabine and oxaliplatin (CAPOX) plus bevacizumab (BEV) therapy (CAPOX/BEV) is a standard treatment recommended as the first-line treatment for colorectal cancer recurrence. Recently, sinusoidal obstruction syndrome (SOS) and resulting portal hypertension have been reported as important side effects of oxaliplatin. We herein report a rectal cancer patient who underwent percutaneous transhepatic stoma variceal embolization (PTO) and partial splenic artery embolization (PSE) for stomal variceal bleeding and splenomegaly due to portal hypertension caused by SOS after CAPOX therapy. A 43-year-old man who underwent robot-assisted laparoscopic abdominoperineal resection for advanced lower rectal cancer was started on CAPOX/BEV therapy for early recurrence 1 month after surgery. In the sixth course, splenomegaly rapidly worsened, stomal varices appeared, and the stoma began bleeding. At 5 months after the appearance of stomal varices, the splenomegaly worsened, the frequency of stomal bleeding increased, and PTO was performed. Five months later, PSE was performed for splenomegaly and thrombocytopenia. At 5 months since the PSE, the stoma bleeding has not recurred, and the thrombocytopenia has been corrected. The patient has been able to continue chemotherapy. We suggest that staged treatment by PTO and PSE be considered an important treatment option for stomal varices and splenomegaly associated with SOS.

DOI： 10.1007/s12328-022-01720-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spontaneous necrosis of hepatocellular carcinoma (HCC) is rare and difficult to diagnose preoperatively if it occurs before the definitive diagnosis of HCC; this is because spontaneous necrosis of HCC exhibits various patterns in imaging studies. We compared imaging and pathological findings, and examined the possibility of diagnosing spontaneous necrosis of HCC using contrast-enhanced ultrasonography (CEUS). We experienced 2 cases of spontaneous necrosis of HCC. In case 1, spontaneous necrosis occurred after HCC diagnosis, while in case 2 it occurred before the first admission. The tumor in case 2 contained internal nodules and outer fibrous tissue. CEUS revealed a vascular spot in the hypovascular area during the vascular phase and a complete defect during the Kupffer phase. These findings accorded with the pathological findings and may be important for diagnosing spontaneous necrosis of HCC.

DOI： 10.1016/j.radcr.2022.10.019

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.gastha.2023.07.018

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 63-year-old man with hepatitis C was treated with atezolizumab plus bevacizumab for unresectable diffuse hepatocellular carcinoma (HCC). After four cycles of atezolizumab plus bevacizumab, the diffuse HCC markedly shrank; however, he complained of general fatigue, loss of appetite, and slight loss of muscle strength in the lower legs. He was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD), hypothyroidism, and myopathy, suggesting multisystem immune-related adverse events (irAEs). After administration of hydrocortisone, the clinical symptoms rapidly disappeared. Patients with multisystem irAEs can have favorable outcomes; thus, to continue immune-checkpoint inhibitors therapy, a correct diagnosis and management of multisystem irAEs are important.

DOI： 10.2169/internalmedicine.9393-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 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: Type 2 diabetes mellitus 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

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocellular carcinoma (HCC) activates platelets through the action of adjacent sinusoidal cells. Activated platelets bind to tumor-associated endothelial cells and release growth factors that promote tumor progression. We hypothesized that platelets encapsulated with tumor inhibitors would function as drug carriers for tumor therapy. We propose a therapeutic strategy for HCC using autologous platelets encapsulating multiple tyrosine kinase inhibitors in a rat chemically induced HCC model. Sorafenib or lenvatinib was encapsulated in platelets isolated from tumor-bearing rats in vitro. The rats were divided into groups that received repeated intravenous injections (twice a week for 10 weeks) of the following materials: placebo, sorafenib (SOR), lenvatinib (LEN), autologous platelets, autologous platelets encapsulating sorafenib (SOR-PLT) and autologous platelets encapsulating lenvatinib (LEN-PLT). The therapeutic effect was then analyzed by ultrasonography (US) and histopathological analysis. Histopathological and US analysis demonstrated extensive tumor necrosis in the tumor tissue of SOR-PLT or LEN-PLT, but not in other experimental groups. By liquid chromatography-mass spectrometry, more abundant sorafenib was detected in tumor tissues after SOR-PLT administration than in surrounding normal tissues, but no such difference in sorafenib level was observed with SOR administration. Therefore, the use of autologous platelets encapsulating drugs might be a novel therapeutic strategy for HCC.

DOI： 10.1002/ijc.33915

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/den.14281

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

UNLABELLED: Inflammatory bowel diseases (IBDs) are chronic immune disorders of unclear etiology. Tumor necrosis factor (TNF) inhibitors are effective for IBD treatment and are cost-effective because they reduce hospital admissions and are associated with fewer surgery requirements and a better quality of life in IBD patients. A large number of clinical trials of infliximab biosimilar (CT-P13) have suggested that the administration of biosimilars provides high efficacy and safety similar to that of the originators, with a lower cost, so switching from the original to a biosimilar is considered an acceptable treatment. While several abnormalities of blood examination have been observed in patients with CT-P13 administration, no cases of drug-induced liver injury (DILI) caused by CT-P13 has been reported. A 23-year-old woman had been diagnosed with Crohn's disease and was treated with original infliximab (O-IFX) for 9 years. She developed severe jaundice 1 month after switching from O-IFX to CT-P13. Serologic tests of autoimmune and hepatitis viruses were negative, and ultrasonography, computed tomography, and magnetic resonance cholangiopancreatography revealed no abnormalities. A liver biopsy showed prominent pericentral canalicular cholestasis, without features of steatosis or sclerosing cholangitis, which was consistent with drug-induced cholestasis. The cholestasis improved 10 weeks after the discontinuation of CT-P13, and no DILI redeveloped even after re-switching from CT-P13 to O-IFX. This is the first report of DILI due to switching from O-IFX to CT-P13. While the efficacy and safety of CT-P13 are considered equal to those of O-IFX, clinicians need to be alert for certain severe DILIs when switching from O-IFX to CT-P13 with careful monitoring and appropriate treatment. PLAIN LANGUAGE SUMMARY: A case report of drug-induced liver injury due to switch from original infliximab to infliximab biosimilar Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the entire gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor (TNF) inhibitors are effective for IBD treatment and are cost-effective because they reduce hospital admissions and are associated with fewer surgery requirements and a better quality of life in IBD patients. A biological medicinal product that contains a version of the active substance of an already authorized biological medicinal product. Biosimilars of TNF inhibitors, such as CT-P13, are thought to possess equal efficacy and safety to the original with a lower cost, so switching from the original to a biosimilar considered an acceptable treatment. While several serious adverse reactions of TNF inhibitors have been reported, drug-induced liver injury (DILI) is uncommon, and liver dysfunction due to the administration of CT-P13 has not been reported in IBD patients. We herein report the first case of DILI due to CT-P13 after switching from original infliximab (O-IFX) in a patient with Crohn's disease. While the efficacy and safety of CT-P13 are considered equal to those of O-IFX, clinicians need to be alert for certain severe DILIs when switching from O-IFX to CT-P13 with careful monitoring and appropriate treatment.

DOI： 10.1177/20420986221100118

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection through unheated blood product for hemophilia caused in early 1980s has been significantly serious problem in Japan. After the development of HIV treatment in 1990s, HCV-related hepatocellular carcinoma (HCC) has been one of the most significant problem in these population. Treatment choices for HCC might be limited in hemophilia patients because of their bleeding tendency. The aim of this study was to elucidate the treatment choices and outcome of HCC in hemophilic patients coinfected with HIV/HCV due to contaminated blood products. METHODS: We asked 444 Japanese centers that specialize in treating HIV patients for participation, whether they have HIV/HCV coinfected cases with HCC, and the patient characteristics, treatments for HCC and survival after treatments were retrospectively reviewed according to each institutional medical records. RESULTS: Of 444 centers, 139 centers (31%) responded to the first query, and 8 centers (1.8%) ultimately provided 26 cases of HCC in coinfected hemophilic patients, diagnosed between December 1999 and December 2017. All 26 were male hemophilic patients, with a median age at HCC diagnosis of 49 (range, 34-73) years. Thirteen cases (50%) were HCV-RNA positive, and 14 cases (54%) had a solitary tumor. Even in the cases of Child-Pugh grade A, only 1 case underwent resection, and 18 cases (69%) did not receive the standard treatment recommended by the Japanese Society of Hepatology. CONCLUSIONS: Hemophilic HCC patients with HIV/HCV coinfection may not routinely receive standard treatment due to their bleeding tendency and several complications related to HIV/HCV coinfection.

DOI： 10.21037/jgo-21-157

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/jjco/hyab125

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.dld.2020.08.002

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記述言語：日本語   出版者・発行元：(株)メディカルアイ  

肝癌の悪性度診断における造影3D超音波のMPR画像の有用性について検討した。造影3Dを施行した5cm以下の切除肝細胞癌19症例23結節を対象とした。MPR画像にて不整欠損像を認めたものを非単純結節型(20/23)、それ以外を単純結節型(3/23)と判定し、切除標本との対比を行った。その結果、造影3Dの後血管像における肝癌肉眼型の正診率は100%(23/23)であった。輪郭不明瞭型の83%(10/12)は中分化型肝癌、残りの17%(3/12)は高分化型であり、低分化型肝癌は1例も認めなかった。それに対し、輪郭明瞭型では中分化型肝癌9%(1/11)、低分化型肝癌73%(8/11)、硬化型肝癌9%(1/11)、混合型肝癌9%(1/11)であり、高悪性度癌の占める割合が有意に高率であった。また、輪郭明瞭型は輪郭不明瞭型に比べ有意にKupffer phase ratioが低値を示した。さらに、対照群を中分化型肝癌と低分化型肝癌に分けて検討した。その結果、低分化型肝癌は中分化型肝癌に比べ有意にKupffer phase ratioが低値を示し、そのカットオフ値は0.34であった。

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

DOI： 10.3390/ijms21144939

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Because of their survival benefits, immune checkpoint inhibitors (ICIs) are widely administered to patients with various advanced-stage malignancies. During ICI treatment, drug-induced liver injury (DILI) occasionally occurs. In particular, hepatic immune-related adverse events (irAEs) are rare but serious and fatal. In patients with hepatic irAEs, immediate steroid treatment is generally recommended; however, the risk factors for ICI-associated DILI remain unknown. In the present study, we identified a risk factor for ICI-associated DILI. METHODS: We retrospectively analyzed 135 patients treated with anti-programmed cell death-1 (PD-1) antibodies, such as nivolumab and pembrolizumab, at Asahikawa Medical University Hospital. We investigated grade ≥ 2 hepatotoxic AEs during anti-PD-1 therapy, and PD-1 inhibitor-associated DILI was then diagnosed according to the Digestive Disease Week Japan (DDW-J) 2004 scale. The risk factors for PD-1 inhibitor-associated DILI were identified by Cox hazard analysis. RESULTS: Thirty-six patients developed grade ≥ 2 hepatic AEs during anti-PD-1 therapy. Among them, eight patients were diagnosed with PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. Cox hazard analysis revealed that non-alcoholic fatty liver disease (NAFLD) was a risk factor for PD-1 inhibitor-associated DILI. In addition, we revealed that the outcomes of patients with the DDW-J 2004 score = 3 were improved without steroid treatment. CONCLUSIONS: NAFLD is a potential risk factor for PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. The DDW-J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD-1 inhibitor-associated DILI.

DOI： 10.1111/jgh.14889

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 59-year-old man who was receiving lenvatinib as a third-line tyrosine kinase inhibitor to treat hepatocellular carcinoma and multiple bone metastases complained of general fatigue four months after starting lenvatinib. A blood examination showed unexpectedly elevated serum C-reactive protein (CRP) levels. Computed tomography (CT) revealed rupture of the gallbladder wall, indicating gallbladder perforation. After conservative treatment, the patient received lenvatinib again under informed consent; however, one month later, CT revealed repeated rupture of the gallbladder wall. Gallbladder perforation had again been induced by lenvatinib. For this reason, lenvatinib is strongly considered a causative drug for gallbladder perforation.

DOI： 10.2169/internalmedicine.3806-19

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記述言語：英語  

DOI： 10.1016/j.dld.2019.07.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a type of tumor that presents in the intra- or extrahepatic bile ducts. Cystic-type intrahepatic IPNB often mimics simple liver cysts, making the diagnosis difficult. Because the growth of IPNB is slow, careful follow-up and timely therapeutic intervention is recommended. There are few reports with a follow-up period longer than a decade; thus, we report the case of a patient with an IPNB that grew for over 13 years. CASE SUMMARY: A 65-year-old man was diagnosed, 13 years prior with a cystic hepatic tumor with abnormal imaging findings. The targeted tumor biopsy results showed no malignancy. Biannual follow-up examinations were performed because of the potential for malignancy. The cystic lesions showed gradual enlargement over 11 years and a 4 mm papillary proliferation appeared on the cyst wall, which is compatible with IPNB. The tumor was observed for another 2 years because of the patient's wishes. The imaging findings showed enlargement to 8 mm and a new 9 mm papillary proliferation of the cystic tumor. Contrast-enhanced ultrasonography showed hyperenhancement during the arterial phase in both cyst walls, indicating intraductal tumor progression in both tumors. Thus, liver segment 8 subsegmentectomy was performed. The pathological findings indicated that the tumors contained mucin, and high-grade atypia was observed in the papillary lesions, showing IPNB. CONCLUSION: The development of IPNB should be monitored in patients with cystic lesions and ultrasonography are useful tool for the evaluation.

DOI： 10.3748/wjg.v25.i36.5569

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Several reports have demonstrated that skeletal muscle mass influences mortality in patients with hepatocellular carcinoma (HCC) receiving sorafenib treatment; however, there is still controversy with regard to whether skeletal muscle and adipose tissue are associated with the prognosis in HCC patients. We examined the relationship between body composition and prognosis in HCC patients. METHODS: We retrospectively analyzed 82 patients with unresectable HCC receiving sorafenib treatment. The skeletal muscle area and adipose tissue area were measured by computed tomography. Patients with low skeletal muscle index (male ≤36.2 cm2/m2, female ≤29.6 cm2/m2) and high visceral to subcutaneous adipose tissue area ratio (VSR) (male ≥ 1.33, female ≥ 0.93) were diagnosed as low skeletal muscle mass (LSMM) and high VSR, respectively. RESULTS: A total of 16 and 34 patients were classified as LSMM and high VSR, respectively. LSMM patients frequently experienced serious adverse events (SAEs) and thus had a shorter duration of sorafenib treatment than non-LSMM patients. High VSR was a significant factor for progression-free survival. LSMM patients less frequently received additional/subsequent therapies combined with sorafenib than non-LSMM patients. Multivariate Cox hazard analysis demonstrated that LSMM was a significant factor for the duration of sorafenib treatment. The treatment duration and receiving of additional/subsequent therapies were significantly associated with overall survival (OS) but not with LSMM or high VSR. CONCLUSION: LSMM was associated with the frequency of SAEs, treatment tolerability, and treatment duration. LSMM patients were less likely to receive additional/subsequent therapies than non-LSMM patients. Thus, LSMM could identify a subgroup of patients with poor OS.

DOI： 10.1002/jgh3.12167

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The patient was a 76-year-old man who was treated with nivolumab due to recurrent gastric cancer. A blood examination revealed grade 3 alkaline phosphatase (ALP) elevation. A histopathological examination revealed marked portal infiltration, including eosinophils and CD4+ and CD8+ T lymphocytes, suggesting nivolumab-related cholangitis accompanied by the features of both an immune-related adverse event (irAE) and drug-induced liver injury (DILI) with allergic reaction. The patient's ALP level immediately decreased after the administration of prednisolone. Although nivolumab-related cholangitis, a rare irAE, has been reported to be refractory to steroid therapy, patients with features of irAE and allergic DILI might immediately respond to prednisolone.

DOI： 10.2169/internalmedicine.2330-18

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Some single-nucleotide polymorphisms (SNPs) are associated with the development of non-alcoholic fatty liver disease (NAFLD). As one of the genetic factors, PNPLA3 rs738409 (I148M) is important to associate with pathogenesis of NAFLD. Because other SNPs remain unclear in Japan, we performed a high-throughput sequencing that targeted more than 1000 genes to identify a novel genetic variant in Japanese patients with NAFLD. METHODS: The present study in 36 NAFLD patients and 27 healthy volunteers was performed. A high-throughput sequencer was used to detect the gene variations. Candidate genes were validated by TaqMan SNP genotyping assay in 53 NAFLD patients and 41 healthy volunteers. To investigate the function of candidate gene, we performed biochemical analyses in cultured hepatocytes and liver tissues. RESULTS: EXO1 rs1047840, PTPRD rs35929428, IFNAR2 rs2229207, CPOX rs1131857, IL23R rs1884444, IL10RA rs2228055, and FAM3B rs111988437 were identified as candidate genetic variants, and PTPRD rs35929428 was only extracted as a SNP predicting to cause protein dysfunction. In validation analysis, PTPRD rs35929428 associated with the development of NAFLD (P = 0.015, odds ratio = 5.00, 95% confidence interval: 1.33-18.70). In addition, PTPRD rs35929428 was associated with Fib-4 index and with hepatic fat droplets. Biochemical analyses indicated that PTPRD rs35929428 promoted dephosphorylation of tyrosine 705 signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes. CONCLUSION: PTPRD rs35929428 was a novel SNP in patients with NAFLD. Through exacerbation of the dephosphorylation of signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes, PTPRD rs35929428 might play a role in hepatic lipid accumulation and fibrosis, followed by the development of NAFLD.

DOI： 10.1111/jgh.13820

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tegafur-uracil has been reported to have only minor adverse effects and is associated with liver injury in 1.79% of Japanese patients. The development of tegafur-uracil-induced hepatic fibrosis with portal hypertension is rare. Here, we report a case of a 74-year-old woman with rapidly developing tegafur-uracil-induced hepatic fibrosis. The patient had no history of liver disease and had been treated with tegafur-uracil for 8 mo after breast cancer surgery. The patient was admitted to our hospital for abdominal distension and leg edema associated with liver dysfunction. Computed tomography imaging revealed massive ascites and splenomegaly, and a non-invasive assessment of liver fibrosis indicated advanced fibrosis. The histopathological findings revealed periportal fibrosis and bridging fibrosis with septation. The massive ascites resolved after discontinuing tegafur-uracil. These findings suggest that advanced hepatic fibrosis can develop from a relatively short-term administration of tegafur-uracil and that non-invasive assessment is useful for predicting hepatic fibrosis.

DOI： 10.3748/wjg.v23.i31.5823

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is frequently accompanied by iron overload. However, because of the complex hepcidin-regulating molecules, the molecular mechanism underlying iron overload remains unknown. To identify the key molecule involved in NAFLD-associated iron dysregulation, we performed whole-RNA sequencing on the livers of obese mice. METHODS: Male C57BL/6 mice were fed a regular or high-fat diet for 16 or 48 weeks. Internal iron was evaluated by plasma iron, ferritin or hepatic iron content. Whole-RNA sequencing was performed by transcriptome analysis using semiconductor high-throughput sequencer. Mouse liver tissues or isolated hepatocytes and sinusoidal endothelial cells were used to assess the expression of iron-regulating molecules. RESULTS: Mice fed a high-fat diet for 16 weeks showed excess iron accumulation. Longer exposure to a high-fat diet increased hepatic fibrosis and intrahepatic iron accumulation. A pathway analysis of the sequencing data showed that several inflammatory pathways, including bone morphogenetic protein (BMP)-SMAD signaling, were significantly affected. Sequencing analysis showed 2314 altered genes, including decreased mRNA expression of the hepcidin-coding gene Hamp. Hepcidin protein expression and SMAD phosphorylation, which induces Hamp, were found to be reduced. The expression of BMP-binding endothelial regulator (BMPER), which inhibits BMP-SMAD signaling by binding BMP extracellularly, was up-regulated in fatty livers. In addition, immunohistochemical and cell isolation analyses showed that BMPER was primarily expressed in the liver sinusoidal endothelial cells (LSECs) rather than hepatocytes. CONCLUSIONS: BMPER secretion by LSECs inhibits BMP-SMAD signaling in hepatocytes and further reduces hepcidin protein expression. These intrahepatic molecular interactions suggest a novel molecular basis of iron overload in NAFLD.

DOI： 10.1007/s00535-016-1237-6

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 52-year-old man with a 9-year history of hepatic hemangioma was treated with the anti-diabetic drug metformin, resulting in complete remission of the tumor. In 2006, a hemangioma with diameter of 20 × 25 mm was detected incidentally in the liver. The results of imaging studies including ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) were all compatible with that of hepatic hemangioma. The patient consequently underwent imaging annually from 2006 to 2015. The tumor size increased slightly, to 30 × 35 mm in 2012; however, the general tumor characteristics in imaging were not changed. Beginning May 2012, metformin (750 mg/day) was administered because of an increase in blood sugar and hemoglobin A1c levels. After the start of metformin treatment, the tumor size on US gradually decreased. Finally, in October 2015, the tumor was no longer detected. Dynamic CT study also demonstrated markedly reduced tumor size, with a decrease of 2-3 mm in diameter. These results indicate that metformin treatment strongly suppressed cell proliferation in liver hemangioma. The anti-angiogenic effect of metformin was indicated as a possible cause of the reduction in tumor size.

DOI： 10.1007/s12328-016-0705-0

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/S0168-8278(17)31651-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. By RT-PCR/agarose gel electrophoresis of hepcidin mRNA in a hepatocellular carcinoma cell line HLF, a smaller mRNA band was shown in addition to the wild-type hepcidin mRNA. From sequencing analysis, this additional band was a selective splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene, producing the transcript that encodes truncated peptide lacking 20 amino acids at the middle of preprohepcidin. In the present study, we used the digital PCR, because such a small amount of variant mRNA was difficult to quantitate by the conventional RT-PCR amplification. Among seven hepatoma-derived cell lines, six cell lines have significant copy numbers of this variant mRNA, but not in one cell line. In the transient transfection analysis of variant-type hepcidin cDNA, truncated preprohepcidin has a different character comparing with native preprohepcidin: its product is insensitive to digestion, and secreted into the medium as a whole preprohepcidin form without maturation. Loss or reduction of function of HAMP gene by aberrantly splicing may be a suitable phenomenon to obtain the proliferating advantage of hepatoma cells.

DOI： 10.1016/j.bbrc.2016.05.153

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は50歳、男性。2006年頃からB型慢性肝炎、脂質異常症、腎硬化症、高血圧、痛風で近医に通院していたが、抗ウイルス療法は施行されていなかった。2014年2月から肝機能障害の悪化を認め、2014年4月に全身倦怠感が出現し、B型慢性肝炎急性増悪と診断された。エンテカビル投与後に腎機能障害を認めたため、ラミブジン(LAM)投与に変更、15日後にaspartate aminotransferase(AST)の上昇、下肢の鈍痛、著明なcreatinine kinase(CK)、ミオグロビンの上昇を認め、横紋筋融解症と診断された。診断後、速やかなLAMの休薬と輸液療法で急性腎不全に陥ることなく救命することが可能であった。LAM誘発横紋筋融解症は極めて稀であるが、B型慢性肝炎急性増悪症例に合併した際は予後不良であるため、LAM内服開始後にも関わらずASTの上昇が見られた際には横紋筋融解症を念頭に置くことが重要であると考えられた。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J00263&link_issn=&doc_id=20150805220004&doc_link_id=10.2957%2Fkanzo.56.341&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.56.341&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は67歳男性。海外渡航後、肝機能異常を認め当科入院となった。IgM型HA抗体陽性よりA型重症急性肝炎と診断した。保存的治療によりAST、ALTは改善傾向を示したが黄疸が持続し、第32病日より急速な貧血の進行を認めた。出血の所見はなく、網状赤血球は著明に低下していたが、骨髄は明らかな異常を認めなかった。また、T-bil、LDHの再上昇、haptoglobinの著明な低下が見られたことにより、溶血性貧血と診断した。輸血のみで貧血は改善しステロイドの投与は行わなかった。また、第37病日頃より発熱が出現。サイトメガロウィルス(cytomegalovirus:CMV)抗原陽性であったためganciclovir投与開始しCMV抗原は陰性化した。入院時IgG型CMV抗体陽性であったことから、本症例はA型重症急性肝炎に溶血性貧血とCMVの再活性化を伴ったと考えられた。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J00263&link_issn=&doc_id=20150302090003&doc_link_id=10.2957%2Fkanzo.56.65&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.56.65&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: There is considerable evidence that intestinal microbiota are involved in the development of metabolic syndromes and, consequently, with the development of non-alcoholic fatty liver disease (NAFLD). Toll-like receptors (TLRs) are essential for the recognition of microbiota. However, the induction mechanism of TLR signals through the gut-liver axis for triggering the development of non-alcoholic steatohepatitis (NASH) or NAFLD remains unclear. In this study, we investigated the role of palmitic acid (PA) in triggering the development of a pro-inflammatory state of NAFLD. METHODS: Non-alcoholic fatty liver disease was induced in mice fed a high fat diet (HFD). The mice were killed and the expression of TLRs, tumor necrosis factor (TNF), interleukin (IL)-1β, and phospho-interleukin-1 receptor-associated kinase 1 in the liver and small intestine were assessed. In addition, primary hepatocytes and Kupffer cells were treated with PA, and the direct effects of PA on TLRs induction by these cells were evaluated. RESULTS: The expression of inflammatory cytokines such as TNF, IL-1β, and TLR-2, -4, -5, and -9 was increased in the liver, but decreased in the small intestine of HFD-fed mice in vivo. In addition, the expression of TLRs in primary hepatocytes and Kupffer cells was increased by treatment with PA. CONCLUSION: In the development of the pro-inflammatory state of NAFLD, PA triggers the expression of TLRs, which contribute to the induction of inflammatory cytokines through TLR signals by intestinal microbiota.

DOI： 10.1111/hepr.12199

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

70歳代女性。B型肝硬変に対しlamivudineとadefovir dipivoxil(ADV)を投与していたが、投与開始後60ヵ月目に腰背部痛と右肩痛が出現した。整形外科にて腰椎すべり症、骨粗鬆症と診断され、対症的に加療されるも改善はみられなかった。しかし、血清リンが低値であることから、ADVの副作用が疑われ、血液検査ほか、尿検査を行なったところ、尿糖、尿酸・リン排泄の亢進に加え、汎アミノ酸尿が認められた。更に血液ガス分析ではアニオンギャップ正常の代謝性アシドーシスを呈していた。以上より、近位尿細管の広汎な機能障害が考えられ、本症例はADV起因のFanconi症候群および骨軟化症と診断された。以後、治療としてADVを隔日投与に減量し、あわせて腰背部痛と右肩痛には対症療法などによって対応したところ、改善傾向は認められたが、血清リンの低値は持続し、ADV減量後2年6ヵ月目には両尺骨の病的骨折を認めた。そのためADVを週2回投与に減量し、経口リン酸製剤の内服を開始した結果、血清リン値の低下とHBV-DNAの上昇は認められなくなり、病的骨折も完治、目下も外来にて治療継続中である。

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2014&ichushi_jid=J01159&link_issn=&doc_id=20140822150019&doc_link_id=1390282681424647296&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282681424647296&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 70-year-old Japanese man was hospitalized for expanding purpura and chronic disseminated intravascular coagulation (DIC) caused by decompensated liver cirrhosis. As there are no effective treatments for chronic DIC caused by liver cirrhosis, we decided to administer recombinant human soluble thrombomodulin (rhsTM) after he provided informed consent. The DIC was rapidly improved; however, the purpura and coagulopathy recurred after two months, and repeated rhsTM treatments were required. The rhsTM treatment sufficiently controlled the coagulopathy for two years, without any complications, including bleeding. This is the first report demonstrating that rhsTM can be administered safely and repeatedly to a patient with decompensated liver cirrhosis, and that it appears to be associated with a favorable outcome.

PubMed

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/gut.2009.186650

PubMed

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.gie.2010.07.011

PubMed

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Collagenous colitis (CC) is one of the causes of undefined watery diarrhea, which is histologically accompanied by thickening of the subepithelial collagen layer. CC associated with lansoprazole normally occurs within several weeks after initial administration, but no case presenting after long-term administration of lansoprazole has yet been reported. A 77-year-old male with 6-year history of administration of lansoprazole complained of watery diarrhea and weight loss. Colonoscopy revealed disappearance of vascular networks and red spots in the sigmoid colon. Biopsy specimen showed erosion and collagen bands thickened, so the patient was diagnosed as CC. After lansoprazole discontinuation, the watery diarrhea disappeared and histological abnormalities improved.

DOI： 10.1007/s12328-009-0126-4

PubMed

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-北海道支部  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一財)日本消化器病学会  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本肝臓学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）   出版者・発行元：WILEY  

Web of Science

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記述言語：日本語   出版者・発行元：金原出版(株)  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本医事新報社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本医事新報社  

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記述言語：英語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)文光堂  

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記述言語：日本語   出版者・発行元：(一社)日本病理学会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)ヴァンメディカル  

B型慢性肝炎に用いる核酸アナログ製剤の中でアデホビル(adefovir dipivoxil:ADV)、テノホビル(tenofovir disoproxil fumarate:TDF)は長期投与することで腎機能障害・低リン血症に注意が必要である。中にはFanconi症候群を発症する例もあるため血清リン値とeGFRのモニタリングを行い、必要に応じてADV、TDFの隔日投与による減量投与を検討する。さらに減量投与で改善が認められない時には、経口リン酸製剤(ホスリボン)の投与が有効な治療となる。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：先端医学誌  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：日本語   出版者・発行元：梵天書房  

マウスに高脂肪食を16週間投与してNAFLD(非アルコール性脂肪性肝疾患)モデルを作製し、肝組織と腸管組織におけるToll-like receptors(TLRs)の発現変化を調べた(以下;検討1)。また、Kupffer細胞モデル(THP-1細胞)と腸管上皮モデル(Caco2細胞)を用いて、TLRs発現に対する脂肪酸の関与を検討した(以下;検討2)。検討1の結果、高脂肪食投与4週目・8週目にはTLRs発現に有意な変化はみられなかったが、16週目には肝組織のTLRs発現が有意に亢進し、腸管組織のTLRs発現が有意に低下した。検討2の結果、THP-1細胞にオレイン酸を添加するとTLRs発現は有意に亢進し、Caco2細胞にオレイン酸を添加するとTLRs発現は有意に低下した。

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開催年月日： 2022年12月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2022年11月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2022年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2022年6月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2022年6月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2022年3月

記述言語：日本語  

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開催年月日： 2021年11月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2021年6月

記述言語：日本語  

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開催年月日： 2020年12月

会議種別：口頭発表（一般）  

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開催年月日： 2020年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2020年11月

会議種別：ポスター発表  

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開催年月日： 2020年8月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2020年5月

会議種別：ポスター発表  

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開催年月日： 2019年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2019年5月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2018年12月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2018年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2018年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2018年4月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2018年1月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2017年11月 - 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2016年3月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2015年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2015年10月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2015年8月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2015年8月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2015年7月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2012年6月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2012年1月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2011年11月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2011年10月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2011年10月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2011年6月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2011年5月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2010年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2010年10月 - 2010年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2010年10月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2010年5月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2010年4月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2009年11月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2009年10月

記述言語：日本語   会議種別：ポスター発表  

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会議種別：口頭発表（一般）  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：口頭発表（一般）  

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会議種別：口頭発表（一般）  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：英語   会議種別：ポスター発表  

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出願人：国立大学法人旭川医科大学

出願番号：特願2015-061455  出願日：2015年3月

公開番号：特開2016-178898  公開日：2016年10月

J-GLOBAL

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出願人：国立大学法人旭川医科大学

出願番号：特願2015-061455  出願日：2015年3月

公開番号：特開2016-178898  公開日：2016年10月

特許番号/登録番号：特許第6494356号  登録日：2019年3月 

J-GLOBAL

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受賞区分：国内学会・会議・シンポジウム等の賞  受賞国：日本国

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対象： 社会人・一般

種別：講演会

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種別：講演会

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種別：対話型集会・市民会議

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種別：講演会

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種別：講演会

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種別：講演会

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対象： 社会人・一般

種別：講演会

演者

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種別：講演会

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種別：講演会

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種別：セミナー・ワークショップ

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種別：セミナー・ワークショップ

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対象： 社会人・一般

種別：対話型集会・市民会議

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対象： 社会人・一般

種別：講演会

例年学外で行った肝臓病教室を令和2年度はwebで配信した。
第1回～第6回の合計6回

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