Faculty Profiles - ITO Takanori

Papers - ITO Takanori

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A Proposal for a Simple Subclassification of Advanced Hepatocellular Carcinoma in Systemic Treatment. Open Access

Imai N, Yamamoto T, Mizuno K, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Kawashima H

Cancers Vol. 16 ( 22 ) 2024.11

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

Objectives: This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. Methods: We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Results: Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories—patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)—revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariable analysis, including performance status, Child–Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Conclusions: Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment.

DOI： 10.3390/cancers16223797

Modified FIB-4 Index in Type 2 Diabetes Mellitus with Steatosis: A Non-Linear Predictive Model for Advanced Hepatic Fibrosis. Open Access

Kim J, Ito T, Arai T, Atsukawa M, Kawanaka M, Toyoda H, Honda T, Yu ML, Yoon EL, Jun DW, Cha K, Nguyen MH

Diagnostics (Basel, Switzerland) Vol. 14 ( 22 ) 2024.11

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

Background: The Fibrosis-4 (FIB-4) index is widely recommended as a first-tier method for screening advanced hepatic fibrosis; however, its diagnostic performance is known to be suboptimal in patients with Type 2 diabetes mellitus (T2DM). We aim to propose a modified FIB-4, using the parameters of the existing FIB-4, tailored specifically for diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A total of 1503 patients who underwent liver biopsy were divided into T2DM (n = 517) and non-T2DM (n = 986) groups. The model was developed using multiple regression analysis in the derivation cohort and validated in the validation cohort. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic (AUC) curves. Results: Among the 1503 individuals, those with T2DM were older, more likely to be male, and had a higher prevalence of advanced hepatic fibrosis (≥F3) compared to non-T2DM individuals. Independent risk factors for advanced fibrosis in T2DM included age, AST, AST/ALT ratio, albumin, triglycerides, and platelet count. The optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index) demonstrated superior diagnostic accuracy (AUC 0.771) compared to the FIB-4 (AUC 0.735, p = 0.012). The model showed a higher negative predictive value than the original FIB-4 across all age groups in the diabetic group. Conclusions: The newly optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index), incorporating a non-linear predictive model, improves diagnostic performance (AUC) and the negative predictive value in MASLD with T2DM.

DOI： 10.3390/diagnostics14222500

肝臓学会医による肝臓学会医のための肝臓爽快特別企画を終えて

由雄祥代, 鶴岡未央, 阿部珠美, 武藤芳美, 野上麻子, 伊藤隆徳, 星川恭子, 岩本英希, 村川美也子, 石川剛, 阿部和道, 藤井英樹, 土谷薫, 多田俊史, 黒田英克, 中川美奈, 田中靖人

肝臓 Vol. 65 ( 11 ) page： 541 - 550 2024.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人　日本肝臓学会

<p>第60回日本肝臓学会総会において，田中靖人会長のご支援により若手医師参加型の特別企画を実施する機会を得たのでここに報告する．第1部は講演形式で行い，工藤正俊先生は「知的エンゲル係数」をゼロにし，集中できる時間を作ることの重要性を説いた．海道利実先生は時間管理とプレゼン技術向上の方法を示し，川口巧先生はメディカルスタッフとの連携の重要性を強調した．黒田英克先生は放射線治療の普及を目指し，小玉尚宏先生は研究を楽しむ意義を強調した．伊藤隆徳先生は多施設共同研究のコツを共有し，武藤芳美先生，野上麻子先生，阿部珠美先生，鶴岡未央先生らは肝臓学会の活性化や若手医師の教育についての提案を行った．第2部では，10のラウンドテーブルで第一部演者，ファシリテーター，若手医師が交流し，意見を交換する場を設け，セッションは盛況に終わった．本報告を通じて，今後の日本肝臓学会の更なる発展を期待する．</p>

DOI： 10.2957/kanzo.65.541

A machine learning algorithm for stratification of risk of cardiovascular disease in metabolic dysfunction-associated steatotic liver disease. Open Access

Shibata N, Morita Y, Ito T, Kanzaki Y, Watanabe N, Yoshioka N, Arao Y, Yasuda S, Koshiyama Y, Toyoda H, Morishima I

European journal of internal medicine Vol. 129 page： 62 - 70 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Internal Medicine

Background: Steatotic liver disease (SLD) is associated with adverse cardiac events. Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a condition characterized by the abnormal accumulation of hepatic lipids that is closely linked to five metabolic disorders: overweight or obesity, impaired glucose regulation, hypertension, hypertriglyceridemia, and low high-density lipoprotein-cholesterol. This retrospective study aimed to stratify the risk of cardiac events in patients with MASLD. Methods: Patients diagnosed with MASLD through ultrasonography were evaluated. We implemented a machine learning-based approach using a survival classification and regression tree (CART) model to stratify patients based on age, and the number of risk scores was investigated as a predictor of adverse outcomes in the derivation cohort. The primary outcomes were major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. Results: Among 2,962 patients (median age, 62 years; men, 53.5 %), the distribution of risk factors was as follows: one (10.8 %), two (28.5 %), three (33.0 %), four (19.9 %), and five (7.8 %). Over a median follow-up period of 6.8 years, 170 (5.7 %) patients experienced MACE. In the derivation cohort of 2,073 patients, the CART model identified age ≥60 years old and risk factors ≥4 as significant predictors of MACE. These findings were corroborated in a validation cohort of 889 patients. Patients meeting both criteria exhibited the highest risk of MACE (log-rank test, p < 0.001). Conclusions: Patients aged ≥60 years old with risk factors ≥4 indicates at high risk of MACE in patients with MASLD. This risk stratification system provides a practical tool for identifying high-risk individuals in the MASLD population.

DOI： 10.1016/j.ejim.2024.07.005

Predicting early rebleeding and mortality after endoscopic hemostasis of esophagogastric varices: Diagnostic performance of aspartate aminotransferase-to-platelet ratio index and model for end-stage liver disease-Na score. Open Access

Yokoyama S, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Mizuno K, Nakamura M, Kawashima H

Journal of hepato-biliary-pancreatic sciences Vol. 31 ( 11 ) page： 830 - 839 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Hepato Biliary Pancreatic Sciences

Background: Endoscopic variceal ligation and sclerotherapy are recommended for esophagogastric variceal bleeding (EGVB) in cirrhosis but can be complicated by early rebleeding and death. This study aimed to identify noninvasive markers accurately predicting early rebleeding and mortality after endoscopic hemostasis for EGVB. Methods: Among 116 patients with endoscopically confirmed EGVB and endoscopic hemostasis, various noninvasive markers were calculated, and their predictive accuracy was compared by receiver-operating characteristic curve analysis. Endpoints included 5-day rebleeding, 5-day mortality, 6-week rebleeding, and 6-week mortality. Results: The median age was 63 years. Child-Pugh class B and C patients accounted for 40.5% and 34.5%, respectively. Only the aspartate aminotransferase-to-platelet ratio index (APRI) significantly predicted 5-day rebleeding, with an area under the curve (AUC) of 0.777 (95% confidence interval [CI]: 0.537–1). The model for end-stage liver disease-Na (MELD-Na) score showed good predictive accuracy for 5-day mortality (AUC: 0.839, 95% CI: 0.681–0.997), 6-week rebleeding (AUC: 0.797, 95% CI: 0.663–0.932), and 6-week mortality (AUC: 0.888, 95% CI: 0.797–0.979). Conclusions: Patients with cirrhosis with a high APRI and MELD-Na score were at high risk of early rebleeding and death after EGVB. Allocating appropriate monitoring and care for those patients is necessary.

DOI： 10.1002/jhbp.12057

Outcomes of immune checkpoint inhibitor-induced liver toxicity managed by hepatologists in a multidisciplinary toxicity team.

Ito T, Mizuno K, Yamamoto T, Yasuda T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Hama M, Kataoka T, Shimokata T, Ando Y, Kawashima H

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 54 ( 11 ) page： 1060 - 1069 2024.11

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

Aim: To detect immune-related adverse events (irAEs) early and treat them appropriately, our institute established an irAE-focused multidisciplinary toxicity team in cooperation with various departments. This study aimed to evaluate a consultation system involving a team of hepatologists in terms of its utility for the management of severe immune checkpoint inhibitor (ICI)-induced liver toxicity. Methods: To analyze the diagnosis and treatment of severe ICI-induced liver toxicity (Grade 2 requiring corticosteroid therapy and Grade 3 or higher), we examined patients' clinical courses before and after the hepatologist consultation system was established (pre-period, September 2014 to February 2019; post-period, March 2019 to March 2023). Results: The median follow-up period was 392 days. Of the 1247 patients with advanced malignancies treated with ICIs, 66 developed severe ICI-induced liver toxicity (n = 22 and 44 in the pre- and post-periods, respectively). In the pre-period, hepatologist consultations were sought for 15/22 patients, whereas in the post-period, 42/44 patients were referred to and treated by hepatologists. The time from the onset of liver toxicity to the consultation was significantly shorter in the post-period than in the pre-period (mean 1.9 vs. 6.5 days, respectively; p = 0.012). The number of patients with a biopsy-confirmed diagnosis of ICI-induced liver toxicity was significantly higher in the post-period than in the pre-period (n = 22 vs. n = 3, respectively; p = 0.006). Finally, there were no cases of immune-related cholangitis in the pre-period, compared to five cases in the post-period. Conclusion: A hepatologist consultation system in an irAE-focused multidisciplinary toxicity team is useful for managing severe ICI-induced liver toxicity.

DOI： 10.1111/hepr.14043

Type 2 Diabetes and Hypertension as Risk Factors for Advanced Fibrosis in Biopsy Proven Metabolic Dysfunction-Associated Steatotic Liver Disease.

Inukai Y, Ito T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Shimizu T, Hattori M, Takeyama T, Ando Y, Nishikawa T, Morita K, Toyoda H, Ishigami M, Kawashima H

Journal of digestive diseases Vol. 25 ( 11-12 ) page： 685 - 693 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Digestive Diseases

Objectives: To identify the diagnostic criteria for metabolic dysfunction–associated steatotic liver disease (MASLD) related to liver fibrosis and to characterize patients with cryptogenic steatotic liver disease (SLD) (non-MASLD) among those previously diagnosed with nonalcoholic fatty liver disease (NAFLD). Methods: This multicenter retrospective study included 511 patients diagnosed with NAFLD via liver biopsy, and the prevalence of MASLD was assessed based on the diagnostic criteria. Patients were divided into those who met the MASLD criteria and those who did not, and the characteristics of advanced fibrosis and associated cardiometabolic factors were evaluated. Results: Of the 475 patients with NAFLD, 458 (96.4%) met the criteria for MASLD, showing a high overlap between classical NAFLD and MASLD populations. Severe fibrosis was observed, regardless of the number of cardiometabolic factors. Hypertension and diabetes mellitus significantly contributed to advanced fibrosis (≥ F3), with odds ratio of 1.92 and 2.00 (95% confidence interval of 1.17–3.16 and 1.22–3.28, respectively; both p < 0.01) on multivariate analysis. The other seventeen (3.6%) patients did not meet the diagnostic criteria for MASLD. Among them, seven had significant fibrosis and a high fibrosis-4 index. Conclusions: Diabetes mellitus and hypertension are key metabolic factors associated with advanced fibrosis. Some cases, classified as cryptogenic SLD, also exhibit significant fibrosis. Consequently, identifying high-risk patients, including those undergoing noninvasive tests for fibrosis, is crucial.

DOI： 10.1111/1751-2980.13325

A 70-year-old Woman with Asymptomatic Ferroportin Disease Open Access

Ishikawa Tetsuya, Tatsumi Yasuaki, Kato Koichi, Hayashi Yumi, Imai Norihiro, Ito Takanori, Ishizu Yoji, Ishigami Masatoshi, Nihei Wataru, Kato Ayako, Hayashi Hisao

Internal Medicine Vol. 63 ( 17 ) page： 2421 - 2425 2024.9

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

<p>A 59-year-old Japanese woman presented with hyperferritinemia. We decided against iron removal treatment because there were no symptoms or signs of iron-induced organ damage. A follow-up study revealed a gradual increase in transferrin saturation. The patient underwent a second examination at 66 years old. A liver biopsy showed substantial iron deposits in hepatocytes and Kupffer cells but no inflammation or fibrosis. Serum hepcidin-25 levels were highly parallel with hyperferritinemia. A genetic analysis revealed a <i>G80S</i> mutation in <i>SLC40A1</i>. These features are compatible with those of ferroportin disease. The patient remained asymptomatic at 70 years old, suggesting that the iron-loading condition may have been benign. </p>

DOI： 10.2169/internalmedicine.2392-23

Predictability of noninvasive liver fibrosis score for cardiac events in patients with nonalcoholic fatty liver disease.

Shibata N, Ito T, Toyoda H, Tanaka A, Morita Y, Kanzaki Y, Watanabe N, Yoshioka N, Yasuda S, Morishima I

Nutrition, metabolism, and cardiovascular diseases : NMCD Vol. 34 ( 9 ) page： 2115 - 2123 2024.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Nutrition Metabolism and Cardiovascular Diseases

Background and aims: Patients with nonalcoholic fatty liver disease (NAFLD) have a higher risk of cardiac events. However, although the severity of liver fibrosis is related to worsening prognosis in patients with NAFLD, it is unclear whether the noninvasive liver fibrosis score has a predictive value for cardiac events. Methods and results: We evaluated 4071 patients with NAFLD diagnosed using ultrasonography. Liver fibrosis was assessed and divided into three groups based on the Fibrosis-4 (FIB4) index and NAFLD fibrosis score (NFS). The primary outcome of this study was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. The median age of the evaluated patients was 61 (52–69) years, and 2201 (54.1%) were male. During the median follow-up period of 6.6 years, 179 (4.4%) patients experienced MACE. Kaplan–Meier survival analysis demonstrated that MACE increased progressively with the FIB4 index (log-rank, p < 0.001) and NFS (log-rank, p < 0.001). Multivariable analysis showed that the higher the FIB4 index, the higher the risk for MACE (low group as reference vs. intermediate group, hazard ratio [HR]: 1.860 [95% confidence interval (CI), 1.326–2.610; p < 0.001]; vs. high group, HR:3.325 [95% CI, 2.017–5.479; p < 0.001]), as well as NFS (low NFS group as reference vs. intermediate group, HR: 1.938 [95% CI, 1.391–2.699; p < 0.001]; vs. high group, HR: 3.492 [95% CI, 1.997–6.105; p < 0.001]). Conclusions: The FIB4 index and NFS are associated with the probability of MACE in patients with NAFLD. Clinical trials: The study design was approved by the ethics review board of Ogaki Municipal Hospital (approval number: 20221124–12, registration date: November 28th, 2022). https://www.ogaki-mh.jp/chiken/kenkyu.html.

DOI： 10.1016/j.numecd.2024.03.025

Impact of BMI and Body Composition on First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma. Open Access

Yamamoto T, Ito T, Mizuno K, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H

Anticancer research Vol. 44 ( 9 ) page： 4101 - 4111 2024.9

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

Background/Aim: The effects of body mass index (BMI) and body composition on the outcomes of systemic treatment for unresectable hepatocellular carcinoma (uHCC) remain unclear. Patients and Methods: In this retrospective study, patients with uHCC treated with lenvatinib (LEN) or atezolizumab+bevacizumab, were classified into high- (≥25 kg/m<sup>2</sup>) and low- (<25 kg/m<sup>2</sup>) BMI groups and evaluated for prognosis. Prognostic impact of body composition was also evaluated. Results: Patients with a high BMI had lower skeletal mass index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) compared to those in the low-BMI cohort. The baseline Child-Pugh scores and Barcelona Clinic Liver Cancer stages were comparable between the two cohorts. The overall survival (OS) was better in the high BMI group compared to the low BMI group (median, 913 vs. 484 days; p=0.008). SMI had a strong influence on OS. Additionally, low BMI, VATI, SATI, and visceral-to-subcutaneous fat ratio (VSR) in the LEN treatment group were associated with shorter progression-free survival (PFS). Conclusion: Following systemic treatment for uHCC, patients with low BMI have a poor prognosis. Among anthropometric factors, low SMI is associated with poor OS. In the LEN treatment group, low VATI may impact PFS negatively.

DOI： 10.21873/anticanres.17239

Reply - Letter to the editor.

Yokoyama S, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Mizuno K, Kojima T, Kariya N, Nakamura M, Kawashima H

Clinical nutrition (Edinburgh, Scotland) Vol. 43 ( 8 ) page： 1855 - 1856 2024.8

Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real‑world practice. Open Access

Shimose S, Saeki I, Tomonari T, Ito T, Tani J, Takeuchi Y, Yoshioka N, Naito T, Takeuchi M, Kakizaki S, Hatanaka T, Sasaki K, Yasunaka T, Sakata M, Iwamoto H, Itano S, Shirono T, Tanabe N, Yamamoto T, Naganuma A, Nishina S, Otsuka M, Kawashima H, Takayama T, Takami T, Kawaguchi T

Oncology letters Vol. 28 ( 2 ) page： 397 2024.8

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

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first‑line therapy for patients with unre‑ sectable hepatocellular carcinoma (u‑HCC), its outcomes in real‑world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u‑HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression‑free survival (PFS), therapeutic response and adverse events (AEs) were assessed.

DOI： 10.3892/ol.2024.14530

Diagnostic guide for immune checkpoint inhibitor-induced liver injury. Open Access

Ito T, Takeuchi Y, Mizuno K, Imai M, Yoshimaru Y, Abe K, Abe M, Matsuura T, Yokode M, Shiokawa M, Kodama Y, Komuta M, Harada K, Tanaka A

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 54 ( 8 ) page： 719 - 726 2024.8

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

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, the most representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

DOI： 10.1111/hepr.14078

Clinical Outcomes of Use of the Porous Glass Membrane Pumping Emulsification Device During Transarterial Chemoembolization for Hepatocellular Carcinoma. Open Access

Mizuno F, Imai N, Mizuno K, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Kawashima H

Anticancer research Vol. 44 ( 7 ) page： 3185 - 3191 2024.7

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

Background/Aim: The porous glass membrane pumping emulsification device enhances local therapeutic effects of transarterial chemoembolization for hepatocellular carcinoma (HCC); however, limited clinical outcomes have been reported. This study aimed to investigate the efficacy and safety of transarterial chemoembolization using the glass membrane pumping emulsification device for HCC. Patients and Methods: Between 2019 and 2023, 58 patients (median age=73 years) with unresectable HCC underwent 73 transarterial chemoembolizations using the glass membrane pumping emulsification device at the Nagoya University Hospital. Treatment effects were assessed using contrast-enhanced computed tomography 1-3 months after therapy and every 2-3 months thereafter. Results: The median size of treated tumors was 25.5 mm (45 solitary nodules). The median dosage of ethiodized oil mixed with the epirubicin solution was 3 ml. Complete and partial response were observed in 73% and 11% of patients, respectively. Local control rates at 6 and 12 months were 82.8% and 59.8%, respectively. The median time to recurrence after treatment was 581 days. No major treatment-related complications occurred. The number of tumors and therapeutic effects of the initial transarterial chemoembolization were significantly associated with better local control. Conclusion: The glass membrane pumping emulsification device facilitated the accumulation of more concentrated ethiodized oil within the tumor and effective local control.

DOI： 10.21873/anticanres.17133

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world. International coauthorship Open Access

Kudaravalli S, Huang DQ, Yeh ML, Trinh L, Tsai PC, Hsu YC, Kam LY, Nguyen VH, Ogawa E, Lee DH, Ito T, Watanabe T, Enomoto M, Preda CM, Ko MKL, Wan-Hin Hui R, Atsukawa M, Suzuki T, Marciano S, Barreira A, Do S, Uojima H, Takahashi H, Quek SXZ, Toe Wai Khine HH, Ishigami M, Itokawa N, Go MS, Kozuka R, Marin RI, Sandra I, Li J, Zhang JQ, Wong C, Yoshimaru Y, Vo DKH, Tseng CH, Lee CJ, Inoue K, Maeda M, Hoang JK, Chau A, Chuang WL, Dai CY, Huang JF, Huang CF, Buti M, Tanaka Y, Gadano AC, Yuen MF, Cheung R, Lim SG, Trinh HN, Toyoda H, Yu ML, Nguyen MH

Journal of hepatology Vol. 81 ( 1 ) page： 33 - 41 2024.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Hepatology

Background & Aims: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. Methods: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. Results: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). Conclusions: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. Impact and implications: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

DOI： 10.1016/j.jhep.2024.02.033

Severe hepatic steatosis promotes increased liver stiffness in the early stages of metabolic dysfunction-associated steatotic liver disease.

Kumada T, Toyoda H, Ogawa S, Gotoh T, Suzuki Y, Sugimoto K, Yoshida Y, Kuroda H, Kamada Y, Sumida Y, Ito T, Akita T, Tanaka J

Liver international : official journal of the International Association for the Study of the Liver Vol. 44 ( 7 ) page： 1700 - 1714 2024.7

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

Background & Aims: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction–associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. Methods: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging–based proton density fat fraction (MRI-PDFF) examinations at least 1 year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. Results: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483–4.547) and albumin–bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284–6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584–4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF ≥5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF >−5% and <5% in patients with LSM stage 1 or 2–4 (≥2.5 kPa). Conclusions: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa).

DOI： 10.1111/liv.15920

Guide for the Diagnosis of Immune Checkpoint Inhibitor-Induced Liver Injury

Ito Takanori, Takeuchi Yasuto, Mizuno Kazuyuki, Imai Michitaka, Yoshimaru Yoko, Abe Kazumichi, Abe Masanori, Matsuura Takanori, Yokode Masataka, Shiokawa Masahiro, Kodama Yuzo, Komuta Mina, Harada Kenichi, Tanaka Atsushi

Kanzo Vol. 65 ( 6 ) page： 268 - 276 2024.6

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

<p>With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (as an immune-related adverse event [ICI-induced liver injury]) has become a major problem in clinical settings. Comprehensive evaluations comprising the clinical course, blood tests, imaging, and pathological examination by liver biopsy are essential for diagnosing ICI-induced liver injury. Similar to other drug-induced liver injuries, the liver injury type based on R-value is useful for determining treatment strategies. Acute hepatitis is a typical pathological finding in ICI-induced liver injury. It is characterized by diffuse lobular injury with CD8-positive lymphocytic infiltration. Most patients with ICI-induced cholangitis are classified as non-hepatocellular-injury type. They respond poorly to corticosteroid treatment. Gastroenterologists and physicians in other departments should collaborate to achieve early diagnosis and appropriate treatment of ICI-induced liver injury.</p>

DOI： 10.2957/kanzo.65.268

RECAM-J 2023-Validation and development of the Japanese version of RECAM for the diagnosis of drug-induced liver injury.

Tanaka A, Tsuji K, Komiyama Y, Tsuruya K, Kakisaka K, Tsutsui A, Ichimoto K, Ueno M, Okazaki Y, Kamimura H, Takai A, Yamashiki N, Ito T, Watanabe M, Abe M, Harada KI, Kagawa T

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 54 ( 6 ) page： 503 - 512 2024.6

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

Aim: The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI. Methods: After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI. Results: We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively. Conclusion: RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.

DOI： 10.1111/hepr.14046

Risk factors for decreased bone mineral density in patients with metabolic dysfunction-associated steatotic liver disease: A cross-sectional study at a health examination center. Open Access

Yokoyama S, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Mizuno K, Kojima T, Kariya N, Nakamura M, Kawashima H

Clinical nutrition (Edinburgh, Scotland) Vol. 43 ( 6 ) page： 1425 - 1432 2024.6

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

Background & aims: Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. Methods: Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below −1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. Results: A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34–0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00–1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97–1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. Conclusion: The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

DOI： 10.1016/j.clnu.2024.04.034

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey Open Access

Miyamoto T., Izawa K., Masui S., Yamazaki A., Yamasaki Y., Matsubayashi T., Shiraki M., Ohnishi H., Yasumura J., Kawabe T., Miyamae T., Matsubara T., Arakawa N., Ishige T., Takizawa T., Shimbo A., Shimizu M., Kimura N., Maeda Y., Maruyama Y., Shigemura T., Furuta J., Sato S., Tanaka H., Izumikawa M., Yamamura M., Hasegawa T., Kaneko H., Nakagishi Y., Nakano N., Iida Y., Nakamura T., Wakiguchi H., Hoshina T., Kawai T., Murakami K., Akizuki S., Morinobu A., Ohmura K., Eguchi K., Sonoda M., Ishimura M., Furuno K., Kashiwado M., Mori M., Kawahata K., Hayama K., Shimoyama K., Sasaki N., Ito T., Umebayashi H., Omori T., Nakamichi S., Dohmoto T., Hasegawa Y., Kawashima H., Watanabe S., Taguchi Y., Nakaseko H., Iwata N., Kohno H., Ando T., Ito Y., Kataoka Y., Saeki T., Kaneko U., Murase A., Hattori S., Nozawa T., Nishimura K., Nakano R., Watanabe M., Yashiro M., Nakamura T., Komai T., Kato K., Honda Y., Hiejima E., Yonezawa A., Bessho K., Okada S., Ohara O., Takita J., Yasumi T., Nishikomori R.

Arthritis and Rheumatology Vol. 76 ( 6 ) page： 949 - 962 2024.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Arthritis and Rheumatology

Objective: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Methods: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. Results: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)—unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti–tumor necrosis factor-α agents was effective for IBD– and CAPS-associated symptoms not resolved by canakinumab monotherapy. Conclusion: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti–IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment. (Figure presented.).

DOI： 10.1002/art.42808

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