Hepatology

Prof. TSUGE Masataka

【Research Keywords】
Viral hepatitis, anti-viral therapy, liver steatosis, liver cirrhosis, hepatocellular carcinoma, portal hypertension

【Recent highlights】
Effective antiviral therapies for patients with chronic hepatitis C virus (HCV) infection are now available, and we can provide these remarkable anti-viral therapies, which can be expected to achieve more than 90% eradication, including in patients with decompensated liver cirrhosis. On the other hand, in patients with chronic hepatitis B virus (HBV) infection, viral replication can be suppressed by anti-viral therapy, but it is more difficult to eliminate the virus from infected hepatocytes completely. Currently, a large number of therapeutic candidates, such as antisense oligo targeting of viral RNA and vaccines that activate host immunity against HBV, have been identified, and several clinical trials are underway. However, no drug has yet been developed that successfully eliminates HBV. To identify novel therapeutic targets for HBV elimination, we are performing comprehensive gene expression analyses and examining changes in signaling pathways in hepatocytes that are affected by HBV infection. Furthermore, we also actively participate in clinical trials evaluating novel drugs for chronic HBV infection. Previously, we performed vaccine therapy with Ehime University and demonstrated a reduction of HBs antigen and the acquisition of HBs antibodies in a subset of HBV carriers (Hepatol Res, 2023). We are currently conducting a multicenter clinical trial with a larger number of patients to verify its antiviral effects.

Recently, the number of patients with liver steatosis has increased worldwide, and preventing progression to liver cirrhosis and liver cancer has become an urgent issue. To address this challenge, we are collecting clinical data from Hiroshima University Hospital and related hospitals and clinics and analyzing factors associated with the progression of liver fibrosis and carcinogenesis.

In the treatment of liver cancer, we now have several treatment options in the case of advanced-stage liver cancers owing to the development of molecular targeted drugs and immune checkpoint inhibitors. However, the range of available treatments varies by institution. Therefore, we are accumulating clinical data from Hiroshima University Hospital and related hospitals and clinics and conducting basic and clinical research to help guide the selection of optimal anti-cancer treatments.

Profiles of Faculty and Research Scholars

【Major Papers of the Laboratory】
・Fujiwara N, Matsushita Y, Tempaku M, Tachi Y, Kimura G, Izuoka K, Hayata Y, Kawamura S, Eguchi A, Nakatsuka T, Sato M, Ono A, Murakami E, Tsuge M, Oka S, Hayashi A, Hirokawa Y, Watanabe M, Parikh ND, Singal AG, Marrero JA, Hoshida Y, Mizuno S, Tateishi R, Koike K, Fujishiro M, Nakagawa H. AI-based phenotyping of hepatic fiber morphology to inform molecular alterations in metabolic dysfunction-associated steatotic liver disease. Hepatology. 2025. doi: 10.1097/HEP.0000000000001360.
・Nagaoki Y, Yamaoka K, Fujii Y, Uchikawa S, Fujino H, Ono A, Murakami E, Kawaoka T, Miki D, Aikata H, Hayes CN, Tsuge M, Oka S. Impact of viral eradication by direct-acting antivirals on clinical outcomes after curative treatment for hepatitis C virus-associated hepatocellular carcinoma. Therap Adv Gastroenterol. 18:17562848251324094, 2025.
・Kosaka M, Fujino H, Tsuge M, Yamaoka K, Fujii Y, Uchikawa S, Ono A, Murakami E, Kawaoka T, Miki D, Hayes CN, Kashiyama S, Mokuda S, Yamazaki S, Oka S. Usefulness of serum HBV RNA levels for predicting antiviral response to entecavir treatment in patients with chronic hepatitis B. J Gastroenterol. 60(4): 469-478, 2025.
・Bao H, Murakami S, Tsuge M, Uchida T, Uchikawa S, Fujino H, Ono A, Murakami E, Kawaoka T, Miki D, Hayes CN, Oka S. Alteration of Gene Expression After Entecavir and Pegylated Interferon Therapy in HBV-Infected Chimeric Mouse Liver. Viruses. 16(11): 1743, 2024.
・Nakahara H, Ono A, Hayes CN, Shirane Y, Miura R, Fujii Y, Murakami S, Yamaoka K, Bao H, Uchikawa S, Fujino H, Murakami E, Kawaoka T, Miki D, Tsuge M, Oka S; Hiroshima Liver Study Group; TransSCOT Consortium. Prediction of Hepatocellular Carcinoma After Hepatitis C Virus Sustained Virologic Response Using a Random Survival Forest Model. JCO Clin Cancer Inform. 8: e2400108, 2024.
・Miura R, Ono A, Nakahara H, Shirane Y, Yamaoka K, Fujii Y, Uchikawa S, Fujino H, Murakami E, Kawaoka T, Miki D, Tsuge M, Kishi T, Ohishi W, Sakamoto N, Arihiro K, Hayes CN, Oka S. Serum IL-6 concentration is a useful biomarker to predict the efficacy of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma. J Gastroenterol. 60(3): 328-339, 2025.
・Shirane, Y., Fujii, Y., Ono, A., Nakahara, H., Hayes, C.N., Miura, R., Murakami, S., Sakamoto, N., Uchikawa, S., Fujino, H., Nakahara, T., Murakami, E., Yamauchi, M., Miki, D., Kawaoka, T., Arihiro, K., Tsuge, M., and Oka, S., Peripheral T Cell Subpopulations as a Potential Surrogate Biomarker during Atezolizumab plus Bevacizumab Treatment for Hepatocellular Carcinoma. Cancers, 2024. 16(7).
・Duehren, S., Uchida, T., Tsuge, M., Hiraga, N., Uprichard, S.L., Etzion, O., Glenn, J., Koh, C., Heller, T., Cotler, S.J., Oka, S., Chayama, K., and Dahari, H., Interferon alpha induces a stronger antiviral effect than interferon lambda in HBV/HDV infected humanized mice. Virus Res 349: p. 199451, 2024.
・Hiyama, Y., Fujino, H., Namba, M., Fujii, Y., Uchikawa, S., Ono, A., Nakahara, T., Murakami, E., Kawaoka, T., Miki, D., Tsuge, M., and Oka, S., Value of autotaxin for hepatocellular carcinoma risk assessment in chronic hepatitis B patients treated with nucleos(t)ide analogs. Hepatology Research, 2024.
・Yamauchi M, Ono A, Amioka K, Fujii Y, Nakahara H, Teraoka Y, Uchikawa S, Fujino H, Nakahara T, Murakami E, Okamoto W, Miki D, Kawaoka T, Tsuge M, Imamura M, Hayes CN, Ohishi W, Kishi T, Kimura M, Suzuki N, Arihiro K, Aikata H, Chayama K, Oka S. Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma. Commun Med (Lond) 3(1): 152, 2023.
・Hailegiorgis A, Ishida Y, Collier N, Imamura M, Shi Z, Reinharz V, Tsuge M, Barash D, Hiraga N, Yokomichi H, Tateno C, Ozik J, Uprichard SL, Chayama K, Dahari H. Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics. PLoS Comput Biol 19(8): e1011309, 2023.
・Suehiro Y, Tsuge M, Kurihara M, Uchida T, Fujino H, Ono A, Yamauchi M, Naswa Makokha G, Nakahara T, Murakami E, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Aikata H, Nelson Hayes C, Fujita T and Chayama K. Hepatitis B Virus (HBV) Upregulates TRAIL-R3 Expression in Hepatocytes Resulting in Escape From Both Cell Apoptosis and Suppression of HBV Replication by TRAIL. J Infect Dis 227: 686-695, 2023.
・Murakami S, Imamura M, Uchida T, Suehiro Y, Namba M, Fujii Y, Uchikawa S, Teraoka Y, Fujino H, Ono A, Nakahara T, Murakami E, Okamoto W, Yamauchi M, Kawaoka T, Miki D, Hayes NC, Tsuge M, Aikata H, Ohira M, Ohdan H and Oka S. Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure. Hepatol Int 17: 1225-1232, 2023.
・Gad SA, Sugiyama M, Tsuge M, Wakae K, Fukano K, Oshima M, Sureau C, Watanabe N, Kato T, Murayama A, Li Y, Shoji I, Shimotohno K, Chayama K, Muramatsu M, Wakita T, Nozaki T and Aly HH. The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro. PLoS Pathog 18: e1009983, 2022.
・Tsuge M. Are humanized mouse models useful for basic research of hepatocarcinogenesis through chronic hepatitis B virus infection? Viruses, 13: 1920, 2021.
・Tsuge M. The association between hepatocarcinogenesis and intracellular alterations due to hepatitis B virus infection. Liver Int, 41(12): 2836-2848, 2021.

【Education】
We provide treatment for various liver diseases, including antiviral therapy for viral hepatitis, treatments for early and advanced liver cancers, endoscopic treatment for gastric and esophageal varices, and treatment and management of acute and chronic liver failure, sometimes extending to liver transplantation. You will be able to acquire a wide range of knowledge and techniques as a hepatologist. In particular, highly trained specialists are needed to oversee collaborations with other medical and co-medical departments and guide treatment of cases who have not responded to prior antiviral therapy, chemotherapy for patients with advanced liver cancers, and management of liver failure before transplantation.

【Research】
We perform basic and clinical research in several areas related to liver diseases.
1. Clinical research analyzing clinical outcomes of antiviral therapy for patients with chronic HCV infection and the progression of carcinogenesis and fibrosis after HCV eradication
2. Basic and clinical research on the mechanisms of HBV replication and HBV-related carcinogenesis
3. Analysis of the association between genetic polymorphisms and hepatitis virus infection or hepato-carcinogenesis
4. Analysis of the association between intestinal flora and liver diseases
5. Basic and clinical research on factors associated with clinical outcomes of anti-cancer therapies for hepatocellular carcinoma

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