Faculty Profiles - ITO Takanori

Papers - ITO Takanori

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Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma. Open Access

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

Cancers Vol. 16 ( 9 ) 2024.4

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

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.

DOI： 10.3390/cancers16091675

A new criterion including the aspartate aminotransferase-to-platelet ratio index and liver and spleen stiffness to rule out varices needing treatment in children with biliary atresia: Modification of the Baveno VII criteria. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Muto H, Shirota C, Tainaka T, Sumida W, Makita S, Takada S, Nakagawa Y, Maeda T, Nakamura M, Ishigami M, Uchida H, Kawashima H

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 54 ( 4 ) page： 347 - 357 2024.4

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

Aims: Biliary atresia (BA) is a congestive biliary disease that develops in the neonatal period or early infancy. It may present with portal hypertension and varices needing treatment (VNT) even after successful Kasai portoenterostomy. This study aimed to stratify the risk of VNT in children and adolescents with BA. Methods: In this prospective cross-sectional study, we measured liver stiffness (LS) and spleen stiffness (SS) by two-dimensional shear wave elastography and checked for VNT endoscopically in 53 patients with BA who attended for follow-up between July 2018 and September 2022. Varices needing treatment were defined as large esophageal varices, esophageal varices of any size with red color signs, and/or gastric varices along the cardia. Results: Twenty-five patients (aged 0–18 years) had VNT. Eighteen patients met the Baveno VI criteria (LS <20 kPa; platelet count >150 000/L) and were deemed to be at low risk of VNT (spared endoscopies) while three had missed VNT (16.7%). Applying the Baveno VII criteria, which combines the SS cut-off value of 40 kPa with the Baveno VI criteria, resulted in five missed VNTs among 22 spared endoscopies (22.7%). A modification of the Baveno VII criteria using the aspartate aminotransferase-to-platelet ratio index (APRI) instead of the platelet count with cut-off values of 25 kPa, 30 kPa, and 1.04 for LS, SS, and APRI, respectively, missed only one VNT (5.0%) among 20 spared endoscopies. Conclusions: A novel diagnostic criterion that combines LS, SS, and APRI reduced the risk of missing VNT to 5% in children and adolescents with BA.

DOI： 10.1111/hepr.13976

Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis. International coauthorship Open Access

Le MH, Le DM, Baez TC, Dang H, Nguyen VH, Lee K, Stave CD, Ito T, Wu Y, Yeo YH, Ji F, Cheung R, Nguyen MH

Clinical and molecular hepatology Vol. 30 ( 2 ) page： 235 - 246 2024.4

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

Background/Aims: Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events. Methods: We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events. Results: 19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m<sup>2</sup>. Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC (P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia (P<0.05). No significant differences were observed by sex. Time-period analyses showed decreasing rates of cardiovascular and non-liver cancer mortality and increasing rates of decompensated cirrhosis (P<0.05). Conclusions: People with NAFLD have high incidence of liver and non-liver adverse clinical events, varying by NASH, geographic region, and time-period, but not sex.

DOI： 10.3350/cmh.2023.0485

Skill Proficiency, Efficacy, and Safety of the Transradial Approach in Transarterial Treatments for Hepatocellular Carcinoma. Reviewed

Sasaki K, Kawamura Y, Ogawa C, Yabushita K, Watanabe S, Hayashi H, Kochi T, Tomonari T, Ninomiya M, Takai K, Imajo K, Ito T, Kita R, Mawatari S, Nishina S, Toyoda H

Cureus Vol. 16 ( 4 ) page： e57800 2024.4

Identification of the Microbiome Associated with Prognosis in Patients with Chronic Liver Disease. Open Access

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

Microorganisms Vol. 12 ( 3 ) 2024.3

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

We investigated the prognostic role of the gut microbiome and clinical factors in chronic liver disease (hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]). Utilizing data from 227 patients whose stool samples were collected over the prior 3 years and a Cox proportional hazards model, we integrated clinical attributes and microbiome composition based on 16S ribosomal RNA sequencing. HCC was the primary cause of mortality, with the Barcelona Clinic Liver Cancer staging system-derived B/C significantly increasing the mortality risk (hazard ratio [HR] = 8.060; 95% confidence interval [CI]: 3.6509–17.793; p < 0.001). Cholesterol levels < 140 mg/dL were associated with higher mortality rates (HR = 4.411; 95% CI: 2.0151–9.6555; p < 0.001). Incertae sedis from Ruminococcaceae showed a protective effect, reducing mortality risk (HR = 0.289; 95% CI: 0.1282 to 0.6538; p = 0.002), whereas increased Veillonella presence was associated with a higher risk (HR = 2.733; 95% CI: 1.1922–6.2664; p = 0.017). The potential of specific bacterial taxa as independent prognostic factors suggests that integrating microbiome data could improve the prognosis and treatment of chronic liver disease. These microbiome-derived markers have prognostic significance independently and in conjunction with clinical factors, suggesting their utility in improving a patient’s prognosis.

DOI： 10.3390/microorganisms12030610

Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study. International coauthorship

Chau A, Yeh ML, Tsai PC, Huang DQ, Kim SE, Trinh H, Yoon EL, Oh H, Jeong JY, Ahn SB, An J, Tseng CH, Hsu YC, Jeong SW, Cho YK, Shim JJ, Kim HS, Ito T, Marciano S, Kawashima K, Suzuki T, Watanabe T, Nozaki A, Ishikawa T, Inoue K, Eguchi Y, Uojima H, Abe H, Takahashi H, Chuma M, Ishigami M, Hoang JK, Maeda M, Huang CF, Gadano A, Dai CY, Huang JF, Tanaka Y, Chuang WL, Lim SG, Cheung R, Yu ML, Jun DW, Nguyen MH

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Vol. 22 ( 3 ) page： 572 - 580.e5 2024.3

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

Background & Aims: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. Methods: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. Results: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17–1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03–1.31; P = .016), but VR and HCC risks were similar. Conclusions: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

DOI： 10.1016/j.cgh.2023.09.002

A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma: TACTICS-L Trial. Open Access

Kudo M, Ueshima K, Saeki I, Ishikawa T, Inaba Y, Morimoto N, Aikata H, Tanabe N, Wada Y, Kondo Y, Tsuda M, Nakao K, Ito T, Hosaka T, Kawamura Y, Kuzuya T, Nojiri S, Ogawa C, Koga H, Hino K, Ikeda M, Moriguchi M, Hisai T, Yoshimura K, Furuse J, Arai Y

Liver cancer Vol. 13 ( 1 ) page： 99 - 112 2024.2

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

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14.21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child- Pugh A liver function, 0.2 prior TACE sessions, tumor size .10 cm, number of tumors .10, and ECOG performance status 0.1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. Themedian age was 72 years, 77.4% of patientsweremen, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1.31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months. NR). LENTACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

DOI： 10.1159/000531377

Successful Treatment with Steroids in a Patient with Vanishing Bile Duct Syndrome and Acute Tubular Necrosis Open Access

Mizuno Fumitaka, Imai Norihiro, Yasuda Kazushi, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki

Internal Medicine Vol. 63 ( 1 ) page： 57 - 61 2024.1

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

<p>Vanishing bile duct syndrome (VBDS) is a rare but potentially serious cholestatic liver disease caused by various etiologies, including drugs. We herein report a complicated case of VBDS with acute tubular necrosis (ATN) that improved significantly with steroid treatment. An Asian man in his 30s was admitted with the acute onset of severe jaundice and a decline in the renal function. Although initial treatment with ursodeoxycholic acid did not reduce jaundice or renal dysfunction, steroid treatment remarkably improved the VBDS and ATN to within the respective normal ranges. Steroid treatment can be considered in cases of VBDS that appear to have an immune-mediated cause. </p>

DOI： 10.2169/internalmedicine.1826-23

Alpha-fetoprotein and des-gamma-carboxy prothrombin can predict the objective response of patients with hepatocellular carcinoma receiving durvalumab plus tremelimumab therapy. Open Access

Saeki I, Shimose S, 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, Kanayama Y, Naganuma A, Nishina S, Otsuka M, Kobara H, Kawashima H, Takayama T, Kawaguchi T, Yamasaki T, Takami T, Hepatology InVestigator Experts in Japan (HIVE-J) Study Group

PloS one Vol. 19 ( 9 ) page： e0311084 2024

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

Durvalumab plus tremelimumab (Durva/Treme) combined immunotherapy is the first-line therapy recommended for unresectable hepatocellular carcinoma (HCC). Since sequential therapy is more effective in improving prognosis, tumor markers have been used as predictive biomarkers for response to systemic therapy. This study aimed to investigate the predictive ability of objective response (OR) by tumor markers for Durva/Treme therapy against HCC. In this multicenter study, 110 patients with HCC who received Durva/Treme therapy were retrospectively enrolled. The OR rate was 15.5%. To aid early decision-making regarding OR, we evaluated the predictors contributing to OR in two steps: before (first step) and 4 weeks after (second step) treatment induction. Changes in tumor markers (alpha-fetoprotein [AFP] and des-gamma-carboxy prothrombin [DCP]) from baseline to 4 weeks after treatment (ΔAFP/ΔDCP) were included as the input factors. In the first step, multivariable analysis identified only the baseline AFP level (odds ratio 3.497, p = 0.029) as a predictor of OR. Patients with AFP ≥ 400 ng/mL had a significantly higher OR rate than those with < 400 ng/mL (28.2 vs. 8.5%, p = 0.011), and there was no significant difference in progression-free survival (PFS) between the two groups. When AFP/DCP response was defined as a ≥10% reduction from baseline, multivariable analysis showed that AFP response (odds ratio 6.023, p = 0.042) and DCP response (odds ratio 11.657, p = 0.006) were both independent predictors of OR in the second step. The PFS of patients with AFP or DCP response was significantly longer than that of patients without AFP or DCP response. The study demonstrated that the use of AFP and DCP can predict the OR of patients with HCC receiving Durva/Treme therapy.

DOI： 10.1371/journal.pone.0311084

Immunoglobulin-like transcript 2 as an impaired anti-tumor cytotoxicity marker of natural killer cells in patients with hepatocellular carcinoma. Open Access

Sakata T, Yoshio S, Yamazoe T, Mori T, Kakazu E, Aoki Y, Aoyanagi N, Okamoto T, Ito T, Toyoda H, Kawaguchi T, Ono Y, Takahashi Y, Taketomi A, Kanto T

Frontiers in immunology Vol. 15 page： 1389411 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Immunology

Introduction: Natural killer (NK) cells play a pivotal role in immune surveillance in the liver. We aimed to identify potential targets for NK cell-mediated immune intervention by revealing the functional molecules on NK cells in HCC patients. Methods: To evaluate the impact of aging on NK cell phenotypes, we examined NK cells from healthy volunteers (HVs) of various ages. Because ILT2 expression on CD56<sup>dim</sup> NK cells increased with increasing age, we enrolled age-matched HCC patients and HVs. We determined the NK cell phenotypes in blood mononuclear cells (PBMCs) and intrahepatic lymphocytes (IHLs) from cancerous and non-cancerous tissues. We evaluated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of NK cells in vitro. Results: ILT2-positive CD56<sup>dim</sup> NK cells in PBMCs were increased in HCC patients compared with HVs. In HCC patients, ILT2-positive CD56<sup>dim</sup> NK cells were increased in cancerous IHLs compared with non-cancerous IHLs and PBMCs. We examined the impact of macrophage migration inhibitory factor (MIF) on ILT2 expression in co-cultures of HCC cells and NK cells. The enhanced expression of ILT2 on CD56<sup>dim</sup> NK cells from HCC patients was inhibited by masking antibodies against MIF and CXCR4. ILT2-positive CD56<sup>dim</sup> NK cells exhibited lower capacities for cytotoxicity and ADCC than ILT2-negative cells, which were partially restored by ILT2 blockade. Conclusions: In HCC patients, ILT2 is a signature molecule for cancerous CD56<sup>dim</sup> NK cells with impaired cytolytic capacity. The MIF-CXCR4 interaction is associated with ILT2 induction on CD56<sup>dim</sup> NK cells and ILT2 serves as a target for functional NK cell restoration.

DOI： 10.3389/fimmu.2024.1389411

ICI-induced liver injury Reviewed

ITO Takanori, KAWASHIMA Hiroki

Nippon Shokakibyo Gakkai Zasshi Vol. 121 ( 12 ) page： 948 - 956 2024

特集 NASH/NAFLDアップデート:患者数急増時代の実践ガイド新しい話題と今後の展望非肥満,lean NASH/NAFLDとは

伊藤隆徳, 石上雅敏, 川嶋啓揮

診断と治療 Vol. 111 ( 12 ) page： 1649 - 1654 2023.12

Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis. Open Access

Sugiyama Y, Yamamoto K, Honda T, Kato A, Muto H, Yokoyama S, Ito T, Imai N, Ishizu Y, Nakamura M, Asano T, Enomoto A, Zaitsu K, Ishigami M, Fujishiro M, Kawashima H

Hepatology international Vol. 17 ( 6 ) page： 1378 - 1392 2023.12

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

Background: Elevated bile acid levels have been associated with liver tumors in fatty liver. Ileal bile acid transporter inhibitors may inhibit bile acid absorption in the distal ileum and increase bile acid levels in the colon, potentially decreasing the serum and hepatic bile acid levels. This study aimed to investigate the impact of these factors on liver tumor. Methods: C57BL/6J mice received a one-time intraperitoneal injection of 25-mg/kg diethylnitrosamine. They were fed a choline-deficient high-fat diet for 20 weeks starting from 8 weeks of age, with or without elobixibat (EA Pharma, Tokyo, Japan). Results: Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free, tauro-conjugated, glyco-conjugated, and tauro-α/β-muricholic acids in the liver, were noticeably reduced following elobixibat treatment. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%). Conclusion: Elobixibat suppressed tumor growth by inhibiting bile acid reabsorption, and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.

DOI： 10.1007/s12072-023-10581-2

Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

Huang DQ, Tran A, Yeh ML, Yasuda S, Tsai PC, Huang CF, Dai CY, Ogawa E, Ishigami M, Ito T, Kozuka R, Enomoto M, Suzuki T, Yoshimaru Y, Preda CM, Marin RI, Sandra I, Tran S, Quek SXZ, Khine HHTW, Itokawa N, Atsukawa M, Uojima H, Watanabe T, Takahashi H, Inoue K, Maeda M, Hoang JK, Trinh L, Barnett S, Cheung R, Lim SG, Trinh HN, Chuang WL, Tanaka Y, Toyoda H, Yu ML, Nguyen MH

Hepatology (Baltimore, Md.) Vol. 78 ( 5 ) page： 1558 - 1568 2023.11

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

Background and Aims: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase. Approach and Results: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log<inf>10</inf> IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively (p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase<upper limit of normal. In multivariable Cox proportional hazards analysis adjusted for age, sex, HBeAg, HBV DNA, alanine transaminase, diabetes, and platelets, antiviral therapy remained an independent predictor of reduced HCC risk (adjusted HR = 0.3, 95% CI: 0.1-0.6, p = 0.001). Conclusions: Antiviral therapy reduces HCC risk by 70% among patients with indeterminate-phase CHB. These data have important implications for the potential expansion of CHB treatment criteria.

DOI： 10.1097/HEP.0000000000000459

Clinical course and prognosis of patients with hepatocellular carcinoma and haemophilia. Open Access

Matsuda N, Imai N, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Kawashima H

European journal of gastroenterology & hepatology Vol. 35 ( 10 ) page： 1211 - 1215 2023.10

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

Introduction Although patients with haemophilia are known to develop hepatocellular carcinoma (HCC) at a lower age than patients without, there are few reports on the clinical course and prognosis of HCC. Aim We aimed to investigate the clinical course and prognosis of patients with HCC and haemophilia. Methods Twenty-two patients with haemophilia, who were initially diagnosed with HCC between 2003 and 2021, were included. Their clinical courses and prognoses were retrospectively analysed. The results were compared with those of the 24th Nationwide Follow-up Survey of Primary Liver Cancer. Results All 22 patients were male; of these, 20 patients had haemophilia A, and 2 had haemophilia B. The mean age of diagnosis was 63 years (range 45-78 years) which is lower than the mean of 72 years reported in the Nationwide Survey. The mean diameter of the largest tumour was 30 mm (range 11-70 mm), and 18 tumours (82%) were solitary at the initial diagnosis. Standard treatments for HCC were performed in all patients. Sixty-one transarterial chemoembolisation, 28 RFA, 10 hepatectomies, and 2 radiation treatments were performed, and molecular-targeted agents were administered to 5 patients during their clinical courses. No deaths were associated with complications of HCC treatments. The median survival time after initial treatment was 6.4 years (range 0.9-18.7 years) which did not differ much from the median survival time of 5.8 years in the Nationwide Survey. Conclusion Standard treatment for HCC could improve the prognosis of patients with HCC and haemophilia.

DOI： 10.1097/MEG.0000000000002628

Identification of clinical phenotypes associated with poor prognosis in patients with nonalcoholic fatty liver disease via unsupervised machine learning.

Ito T, Morooka H, Takahashi H, Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Kawanaka M, Morishita A, Munekage K, Kawata K, Tsutsumi T, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Ishigami M, Kamada Y, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)

Journal of gastroenterology and hepatology Vol. 38 ( 10 ) page： 1832 - 1839 2023.10

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

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/m<sup>2</sup> 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/m<sup>2</sup>). 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

Diagnostic Performance of the Fibrosis-4 Index and Nonalcoholic Fatty Liver Disease Fibrosis Score in Lean Adults With Nonalcoholic Fatty Liver Disease. International coauthorship International journal Open Access

Park H, Yoon EL, Ito T, Jo AJ, Kim M, Lee J, Kim HL, Arai T, Atsukawa M, Kawanaka M, Toyoda H, Ishigami M, Yu ML, Jun DW, Nguyen MH

JAMA network open Vol. 6 ( 8 ) page： e2329568 2023.8

Language：English Publishing type：Research paper (scientific journal) Publisher：JAMA Network Open

IMPORTANCE: The diagnostic performance of the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for advanced fibrosis in lean patients with NAFLD is limited. OBJECTIVE: To evaluate the diagnostic performance of the FIB-4 and NFS in lean individuals with NAFLD. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included adults with biopsy-proven NAFLD from 6 referral centers in Asia from 1995 to 2019. Cohorts were matched by age and sex between the lean and nonlean groups. All statistical analyses were executed from October 2022 to March 2023. MAIN OUTCOMES AND MEASURES: The diagnostic performance of the FIB-4 and NFS at the current cutoff for advanced hepatic fibrosis in lean (body mass index [BMI] below 23 [calculated as weight in kilograms divided by height in meters squared]) and nonlean (BMI above 23) patients were evaluated. RESULTS: A total of 1501 patients were included in analysis (mean [SD] age, 46.1 [16.4] years); 788 male (52.5%), 115 lean (7.7%), 472 (30.2%) Korean, 821 (48.7%) Japanese, and 341 (21.3%) Taiwanese. Among the age-and sex-matched cohort, the mean (SD) age was 52.3 (15.1) years and 41.2% (47 of 114) were male. The diagnostic performance and areas under the operating characteristic curve of the FIB-4 (lean, 0.807 vs nonlean, 0.743; P =.28) and NFS (lean, 0.790 vs nonlean, 0.755; P =.54) between the 2 groups were comparable in the age-and sex-matched cohort. The sensitivity and specificity of the NFS showed increasing and decreasing tendency according to the BMI quartiles (P for trend <.001), while those of the FIB-4 did not (P for trend =.05 and P =.20, respectively). Additionally, although the areas under the operating characteristic curve of the FIB-4 and NFS were not significantly different in the lean group (0.807 vs 0.790; P =.09), the sensitivity of the current NFS cutoff values was lower in the lean group than in that of FIB-4 (54.4% vs 81.8%; P =.03). CONCLUSIONS AND RELEVANCE: In this cohort study, the performance of the FIB-4 and NFS in diagnosing advanced fibrosis did not differ significantly between the 2 groups overall. However, in lean NAFLD, while the sensitivity for diagnosing advanced hepatic fibrosis remained reasonable at the current cutoff level, the sensitivity of NFS at the current cutoff was too low to be an adequate screening tool.

DOI： 10.1001/jamanetworkopen.2023.29568

Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons. International coauthorship

Le MH, Le DM, Baez TC, Wu Y, Ito T, Lee EY, Lee K, Stave CD, Henry L, Barnett SD, Cheung R, Nguyen MH

Journal of hepatology Vol. 79 ( 2 ) page： 287 - 295 2023.8

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

Background & Aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence. Methods: We performed a systematic review and meta-analysis of cohort studies of adults without NAFLD at baseline to evaluate the global incidence of ultrasound-diagnosed NAFLD. Results: A total of 63 eligible studies (1,201,807 persons) were analyzed. Studies were from Mainland China/Hong Kong (n = 26), South Korea (n = 22), Japan (n = 14), other (n = 2, Sri Lanka, Israel); 63.8% were clinical center studies; median study year 2000 to 2016; 87% were good quality. Among the 1,201,807 persons at risk, 242,568 persons developed NAFLD, with an incidence rate of 4,612.8 (95% CI 3,931.5-5,294.2) per 100,000 person-years and no statistically significant differences by study sample size (p = 0.90) or study setting (p = 0.055). Males had higher incidence vs. females (5,943.8 vs. 3,671.7, p = 0.0013). Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more likely to develop NAFLD (8,669.6 vs. 2,963.9 and 8,416.6 vs. 3,358.2, respectively) (both p <0.0001). Smokers had higher incidence than non-smokers (8,043.2 vs. 4,689.7, p = 0.046). By meta-regression, adjusting for study year, study setting, and study location, study period of 2010 or after and study setting were associated with increased incidence (p = 0.010 and p = 0.055, respectively). By country, China had a higher NAFLD incidence compared to non-China regions (p = 0.012) and Japan a lower incidence compared to non-Japan regions (p = 0.005). Conclusions: NAFLD incidence is increasing with a current estimate of 4,613 new cases per 100,000 person-years. Males and overweight/obese individuals had significantly higher incidence rates compared to females and those of normal weight. Public health interventions for prevention of NAFLD are needed with a special emphasis on males, overweight/obese individuals, and higher risk regions. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of people worldwide and appears to be increasing, but data to estimate the incidence rate are limited. In this meta-analytic study of over 1.2 million people, we estimated an incidence rate of NAFLD of 46.13 per 1,000 person-years with significant differences by sex, BMI, geography, and time-period. As treatment options for NAFLD remain limited, prevention of NAFLD should remain the focus of public health strategies. Studies such as these can help policy makers in determining which and whether their interventions are impactful.

DOI： 10.1016/j.jhep.2023.03.040

特集浮腫と脱水-Q＆Aで学ぶジェネラリストのための体液量異常診療浮腫をきたす疾患の診断とそのマネジメント肝硬変による浮腫のメカニズムとマネジメント

伊藤隆徳, 石上雅敏, 川嶋啓揮

medicina Vol. 60 ( 8 ) page： 1248 - 1252 2023.7

特集肝疾患-診療のチェックポイント2023 第Ⅰ部　診断のチェックポイント　第5章　肝疾患鑑別診断のチェックポイント　1.薬物性肝障害が疑われるとき

伊藤隆徳, 山本崇文, 水野和幸, 石上雅敏, 川嶋啓揮

臨床消化器内科 Vol. 38 ( 7 ) page： 799 - 806 2023.6

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