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Fassio E, Colombato L, Gualano G, Perez S, Puga-Tejada M, Landeira G. Hepatocellular Carcinoma After HCV Eradication with Direct-Acting Antivirals: A Reappraisal Based on New Parameters to Assess the Persistence of Risk. Cancers (Basel) 2025; 17:1018. [PMID: 40149352 PMCID: PMC11940336 DOI: 10.3390/cancers17061018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/12/2025] [Accepted: 03/16/2025] [Indexed: 03/29/2025] Open
Abstract
Approximately 95% of patients with chronic hepatitis C achieve viral eradication through direct-acting antiviral (DAA) treatment. Ensuing clinical benefits include halting liver fibrosis, thereby reducing the need for liver transplantation, and decreasing both liver-related and overall mortality. It is well established that, although ameliorated, the risk of developing hepatocellular carcinoma (HCC) persists, particularly among patients with pre-treatment advanced fibrosis/cirrhosis. Current guidelines recommend indefinite HCC surveillance in these patients. However, a recent Markov model evaluation shows that HCC surveillance is cost-effective only for patients with cirrhosis but not so for those with F3 fibrosis, a finding which points out the need to better define the risk of HCC in hepatitis C patients after cure and further characterize pre- and post-treatment factors that might affect the incidence of HCC in this setting. We reviewed the literature analyzing this aspect. Here we summarize the main findings: male gender and older age are independent predictors of increased risk of post-cure HCC development. Moreover, non-invasive tests for hepatic fibrosis, namely FIB4, APRI, and liver stiffness, measured before and after treatment and their post-therapy change, contribute to better stratifying the risk of HCC occurrence. Furthermore, low serum albumin, as well as an AFP above 7 ng/mL prior to and after DAA therapy, also constitute independent predictors of HCC development. Considering these findings, we propose to classify patients with HCV viral eradication and advanced fibrosis/cirrhosis into groups of low, medium, or high risk of HCC and to adopt adequate surveillance strategies for each group, including protocols for abbreviated magnetic resonance imaging (MRI) for those at the highest risk.
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Affiliation(s)
- Eduardo Fassio
- Liver Section, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires 1684, Argentina; (S.P.); (G.L.)
| | - Luis Colombato
- Hospital Británico de Buenos Aires, Buenos Aires 1280, Argentina;
| | - Gisela Gualano
- Hospital Regional Dr. Ramón Carrillo, Santiago del Estero 4200, Argentina;
| | - Soledad Perez
- Liver Section, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires 1684, Argentina; (S.P.); (G.L.)
| | - Miguel Puga-Tejada
- Instituto Ecuatoriano de Enfermedades Digestivas, Guayaquil 090505, Ecuador;
| | - Graciela Landeira
- Liver Section, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires 1684, Argentina; (S.P.); (G.L.)
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Tamaki N, Higuchi M, Keitoku T, Yamazaki Y, Uchihara N, Suzuki K, Tanaka Y, Miyamoto H, Yamada M, Okada R, Takaura K, Tanaka S, Maeyashiki C, Yasui Y, Tsuchiya K, Nakanishi H, Kanto T, Kurosaki M, Izumi N. Magnetic resonance elastography for the prediction of hepatocellular carcinoma in chronic hepatitis B. JGH Open 2024; 8:e13067. [PMID: 38665298 PMCID: PMC11044154 DOI: 10.1002/jgh3.13067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 03/07/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024]
Abstract
Background and Aim Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE-based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B. Methods A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE-based liver stiffness and HCC. Results In a cross-sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89-4.96) and 2.60 (2.22-3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC (P < 0.001). In a longitudinal analysis of patients without HCC, the 1-, 3-, and 5-year cumulative incidence of HCC in patients with liver stiffness ≥3.6 kPa and those with liver stiffness <3.6 kPa were 3.8%, 7.0%, and 22.9%, and 0%, 0.9%, and 1.5%, respectively (P < 0.001). In the multivariable analysis, MRE-based liver stiffness (per 1 kPa) or liver stiffness ≥3.6 kPa was an independent factor for HCC development with an adjusted hazard ratio (aHR) of 1.61 (95% confidence interval [CI], 1.3-2.0) or aHR of 8.22 (95% CI, 2.1-31). Conclusion MRE-based liver stiffness is associated with HCC risk in patients with chronic hepatitis B and may be used for the early prediction of HCC development and determination of indications for treatment.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Mayu Higuchi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Taisei Keitoku
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yudai Yamazaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Naoki Uchihara
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Keito Suzuki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yuki Tanaka
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Haruka Miyamoto
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Michiko Yamada
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Risa Okada
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kenta Takaura
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Shohei Tanaka
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yutaka Yasui
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Tatsuya Kanto
- Department of Liver DiseaseThe Research Center for Hepatitis and Immunology, National Center for Global Health and MedicineChibaJapan
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Namiki Izumi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
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3
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Moura Cunha G, Fan B, Navin PJ, Olivié D, Venkatesh SK, Ehman RL, Sirlin CB, Tang A. Interpretation, Reporting, and Clinical Applications of Liver MR Elastography. Radiology 2024; 310:e231220. [PMID: 38470236 PMCID: PMC10982829 DOI: 10.1148/radiol.231220] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 03/13/2024]
Abstract
Chronic liver disease is highly prevalent and often leads to fibrosis or cirrhosis and complications such as liver failure and hepatocellular carcinoma. The diagnosis and staging of liver fibrosis is crucial to determine management and mitigate complications. Liver biopsy for histologic assessment has limitations such as sampling bias and high interreader variability that reduce precision, which is particularly challenging in longitudinal monitoring. MR elastography (MRE) is considered the most accurate noninvasive technique for diagnosing and staging liver fibrosis. In MRE, low-frequency vibrations are applied to the abdomen, and the propagation of shear waves through the liver is analyzed to measure liver stiffness, a biomarker for the detection and staging of liver fibrosis. As MRE has become more widely used in clinical care and research, different contexts of use have emerged. This review focuses on the latest developments in the use of MRE for the assessment of liver fibrosis; provides guidance for image acquisition and interpretation; summarizes diagnostic performance, along with thresholds for diagnosis and staging of liver fibrosis; discusses current and emerging clinical applications; and describes the latest technical developments.
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Affiliation(s)
- Guilherme Moura Cunha
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - Boyan Fan
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - Patrick J. Navin
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - Damien Olivié
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - Sudhakar K. Venkatesh
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - Richard L. Ehman
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - Claude B. Sirlin
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
| | - An Tang
- From the Department of Radiology, University of Washington, Seattle,
Wash (G.M.C.); Department of Radiology, Université Laval, Québec,
Québec, Canada (B.F.); Department of Radiology, Mayo Clinic, Rochester,
Minn (P.J.N., S.K.V., R.L.E.); Department of Radiology, Centre Hospitalier de
l'Université de Montréal, 1058 Rue Saint-Denis,
Montréal, QC, Canada H2X 3J4 (D.O., A.T.); and Department of Radiology,
University of California San Diego, San Diego, Calif (C.B.S.)
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4
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Ishido S, Tamaki N, Kurosaki M, Mori N, Tsuji K, Hasebe C, Mashiba T, Ochi H, Yasui Y, Akahane T, Furuta K, Kobashi H, Fujii H, Ishii T, Marusawa H, Kondo M, Kusakabe A, Yoshida H, Uchida Y, Tada T, Nakamura S, Mitsuda A, Ogawa C, Arai H, Murohisa T, Uebayashi M, Izumi N. Necessity for surveillance for hepatocellualr carcinoma in older patients with chronic hepatitis C who achieved sustained virological response. JGH Open 2023; 7:424-430. [PMID: 37359109 PMCID: PMC10290273 DOI: 10.1002/jgh3.12914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/29/2023] [Accepted: 05/11/2023] [Indexed: 06/28/2023]
Abstract
Background and Aim Hepatocellular carcinoma (HCC) surveillance in low-risk patients (annual incidence <1.5%) is not recommended per the American Association for the Study of Liver Diseases guidelines. Because patients with chronic hepatitis C with non-advanced fibrosis who have achieved sustained virological response (SVR) have a low risk of HCC, HCC surveillance is not recommended for them. However, aging is a risk factor for HCC; threfore, the necessity for HCC surveillance in older patients with non-advanced fibrosis needs to be verified. Methods This multicenter, prospective study enrolled 4993 patients with SVR (1998 patients with advanced fibrosis and 2995 patients with non-advanced fibrosis). The HCC incidence was examined with particular attention to age. Results The 3-year incidence of HCC in patients with advanced and non-advanced fibrosis was 9.2% (95% CI: 7.8-10.9) and 2.9% (95% CI: 2.1-3.7), respectively. HCC incidence was significantly higher in patients with advanced fibrosis (P < 0.001). HCC incidence stratified by age and sex was investigated in patients with non-advanced fibrosis. The HCC incidence in the 18-49, 50s, 60s, 70s, and ≥80 age groups were 0.26, 1.3, 1.8, 1.7, and 2.9 per 100 person-years in men, and 0.00, 0.32, 0.58, 0.49, and 0.57 per 100 person-years in women, respectively. Conclusions Male patients with non-advanced fibrosis aged ≥60 years have a higher risk of developing HCC and, thus, require HCC surveillance.
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Affiliation(s)
- Shun Ishido
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Nobuharu Tamaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Nami Mori
- Department of GastroenterologyHiroshima Red Cross Hospital and Atomic Bomb Survivors' HospitalHiroshimaJapan
| | - Keiji Tsuji
- Department of GastroenterologyHiroshima Red Cross Hospital and Atomic Bomb Survivors' HospitalHiroshimaJapan
| | - Chitomi Hasebe
- Department of GastroenterologyAsahikawa Red Cross HospitalAsahikawaJapan
| | - Toshie Mashiba
- Center for Liver‐Biliary‐Pancreatic DiseaseMatsuyama Red Cross HospitalMatsuyamaJapan
| | - Hironori Ochi
- Center for Liver‐Biliary‐Pancreatic DiseaseMatsuyama Red Cross HospitalMatsuyamaJapan
| | - Yutaka Yasui
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Takehiro Akahane
- Department of GastroenterologyIshinomaki Red Cross HospitalIshinomakiJapan
| | - Koichiro Furuta
- Department of GastroenterologyMasuda Red Cross HospitalMasudaJapan
| | - Haruhiko Kobashi
- Department of GastroenterologyJapanese Red Cross Okayama HospitalOkayamaJapan
| | - Hideki Fujii
- Department of GastroenterologyJapanese Red Cross Kyoto Daiichi HospitalKyotoJapan
| | - Toru Ishii
- Department of GastroenterologyJapanese Red Cross Akita HospitalAkitaJapan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and HepatologyOsaka Red Cross HospitalOsakaJapan
| | - Masahiko Kondo
- Department of GastroenterologyOtsu Red Cross HospitalOtsuJapan
| | - Atsunori Kusakabe
- Department of GastroenterologyJapanese Red Cross Aichi Medical Center Nagoya Daini HospitalNagoyaJapan
| | - Hideo Yoshida
- Department of GastroenterologyJapanese Red Cross Medical CenterTokyoJapan
| | - Yasushi Uchida
- Department of GastroenterologyMatsue Red Cross HospitalMatsueJapan
| | - Toshifumi Tada
- Department of Internal MedicineHimeji Red Cross HospitalHimejiJapan
| | | | - Akari Mitsuda
- Department of GastroenterologyTottori Red Cross HospitalTottoriJapan
| | - Chikara Ogawa
- Department of GastroenterologyTakamatsu Red Cross HospitalTakamatsuJapan
| | - Hirotaka Arai
- Department of GastroenterologyMaebashi Red Cross HospitalMaebashiJapan
| | - Toshimitsu Murohisa
- Department of GastroenterologyJapanese Red Cross Ashikaga HospitalAshikagaJapan
| | - Minoru Uebayashi
- Department of GastroenterologyKitami Red Cross HospitalKitamiJapan
| | - Namiki Izumi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
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Liang J, Ampuero J, Castell J, Zhang Q, Zhang S, Chen Y, Romero-Gómez M. Clinical application of Magnetic resonance elastography in hepatocellular carcinoma: from diagnosis to prognosis. Ann Hepatol 2023; 28:100889. [PMID: 36572210 DOI: 10.1016/j.aohep.2022.100889] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/26/2022] [Accepted: 11/29/2022] [Indexed: 12/31/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major public health problem worldwide. Liver fibrosis is closely correlated with liver functional reserve and the risk of HCC development. Meanwhile, malignant tumors generally have high cellularity compared to benign tumors, which results in increased stiffness. Magnetic resonance elastography (MRE) has emerged as a new non-invasive technique for assessing tissue stiffness with excellent diagnostic accuracy, not only for assessing liver fibrosis but also for measuring tumor stiffness. Recent studies provide new evidence that MRE may play an important role in the management of patients with HCC and show several novel clinical applications, such as predicting the development of HCC, differentiating between benign/malignant liver lesions (FLL) and HCC pathological grades, assessing treatment response, and predicting recurrence after treatment, although some findings are controversial. Therefore, we conducted this review to summarize these novel applications of MRE in HCC patients and also discuss their limitations and future advancement.
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Affiliation(s)
- Jiaxu Liang
- Department of Diagnostic Radiology, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's hospital), Zhengzhou, China; Digestive Diseases Unit, CIBEREHD, Virgen del Rocío University Hospital, Seville, Spain; Institute of Biomedicine of Seville (HUVR/CSIC/US), Seville, Spain, University of Seville, Seville, Spain
| | - Javier Ampuero
- Digestive Diseases Unit, CIBEREHD, Virgen del Rocío University Hospital, Seville, Spain; Institute of Biomedicine of Seville (HUVR/CSIC/US), Seville, Spain, University of Seville, Seville, Spain
| | - Javier Castell
- Department of Radiology, Virgen del Rocío University Hospital, Seville, Spain
| | - Qiong Zhang
- Department of Diagnostic Radiology, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's hospital), Zhengzhou, China
| | - Sijia Zhang
- Department of Diagnostic Radiology, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's hospital), Zhengzhou, China
| | - Yong Chen
- Department of Diagnostic Radiology, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's hospital), Zhengzhou, China
| | - Manuel Romero-Gómez
- Digestive Diseases Unit, CIBEREHD, Virgen del Rocío University Hospital, Seville, Spain; Institute of Biomedicine of Seville (HUVR/CSIC/US), Seville, Spain, University of Seville, Seville, Spain.
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6
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Inada K, Tamaki N, Kurosaki M, Kirino S, Yamashita K, Hayakawa Y, Higuchi M, Takaura K, Kaneko S, Maeyashiki C, Yasui Y, Tsuchiya K, Nakanishi H, Izumi N. Validation of magnetic resonance elastography plus fibrosis-4 for significant fibrosis in nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2022; 37:1726-1731. [PMID: 35587726 DOI: 10.1111/jgh.15893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/25/2022] [Accepted: 05/13/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM MEFIB (the combination of magnetic resonance elastography [MRE] ≥ 3.3 kPa and fibrosis-4 (FIB-4) ≥ 1.6) is useful for detecting patients with significant fibrosis (fibrosis stage ≥ 2) having nonalcoholic fatty liver disease (NAFLD). However, age-dependent thresholds of FIB-4 have been proposed, and it remains unclear whether MEFIB could be applied with the same FIB-4 threshold in a different cohort. Therefore, in this study, we examined the best threshold of FIB-4 and validated the utility of MEFIB. METHODS This study included 105 biopsy-proven NAFLD patients with contemporaneous MRE assessment. The primary outcome was a diagnostic accuracy for significant fibrosis. RESULTS The median (interquartile range) age was 65 (58-72) years, and significant fibrosis was 76.2% (80/105). FIB-4 of 2.1 was defined as the best threshold for significant fibrosis in the cohort. The area under the receiver operating characteristics curves (AUROCs) of the combination of MRE and FIB-4 (MRE ≥ 3.3 kPa + FIB-4 ≥ 1.6: 0.80, MRE ≥ 3.3 kPa + FIB-4 ≥ 2.1: 0.84) were higher than those of each index alone (MRE ≥ 3.3 kPa: 0.76, FIB-4 ≥ 1.6: 0.72, and FIB-4 ≥ 2.1: 0.77), but AUROCs of MRE ≥ 3.3 kPa + FIB-4 ≥ 1.6 and MRE ≥ 3.3 kPa + FIB-4 ≥ 2.1 were equivalent (P = 0.3). CONCLUSIONS MEFIB is useful for detecting patients with significant fibrosis and could be utilized in a different cohort without changing the threshold of FIB-4, and it may then be used as a two-step screening strategy.
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Affiliation(s)
- Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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7
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Kawata K, Atsukawa M, Ohta K, Chida T, Noritake H, Arai T, Iwakiri K, Yasuda S, Toyoda H, Okubo T, Hiraoka A, Watanabe T, Uojima H, Nozaki A, Tani J, Morishita A, Kageyama F, Sasada Y, Nagasawa M, Matsushita M, Oyaizu T, Mikami S, Ikegami T, Abe H, Matsuura K, Tanaka Y, Tsubota A. Mac-2-binding protein glycan isomer predicts all malignancies after sustained virological response in chronic hepatitis C. Hepatol Commun 2022; 6:1855-1869. [PMID: 35344290 PMCID: PMC9315127 DOI: 10.1002/hep4.1941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/28/2022] [Accepted: 03/06/2022] [Indexed: 11/06/2022] Open
Abstract
Despite reports of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection after achieving sustained virological response (SVR), only few studies have demonstrated the incidence of other (non-HCC) malignancies. This study aimed to clarify the incidence, survival probability, and factors associated with malignancy, especially non-HCC malignancies, in patients with chronic HCV infection after achieving SVR. In this retrospective study, records of 3580 patients with chronic HCV infection who achieved SVR following direct-acting antiviral (DAA) treatment were analyzed. The cumulative post-SVR incidence of non-HCC malignancies was 0.9%, 3.1%, and 6.8% at 1, 3, and 5 years, respectively. The survival probability for patients with non-HCC malignancies was 99.1%, 78.8%, and 60.2% at 1, 3, and 5 years, respectively, and the rate was significantly lower than that for patients with HCC. The Cox proportional hazards regression model identified Mac-2-binding protein glycan isomer (M2BPGi) cutoff index (COI) ≥ 1.90 at baseline and ≥ 1.50 at 12 weeks following DAA treatment as significant and independent factors associated with the post-SVR incidence of non-HCC malignancies. Furthermore, patients with either M2BPGi COI ≥ 1.90 at baseline or M2BPGi COI ≥ 1.50 at SVR12 had a significantly higher risk of post-SVR incidence of non-HCC malignancies than of HCC. Conclusion: M2BPGi measurements at baseline and SVR12 may help predict the post-SVR incidence of non-HCC malignancies in patients with chronic HCV infection who achieved SVR following DAA treatment. Early identification of these patients is critical to prolong patient survival.
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Affiliation(s)
- Kazuhito Kawata
- Hepatology DivisionDepartment of Internal Medicine IIHamamatsu University School of MedicineHamamatsuShizuokaJapan
| | - Masanori Atsukawa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNippon Medical SchoolBunkyo‐ku, TokyoJapan
| | - Kazuyoshi Ohta
- Hepatology DivisionDepartment of Internal Medicine IIHamamatsu University School of MedicineHamamatsuShizuokaJapan
| | - Takeshi Chida
- Hepatology DivisionDepartment of Internal Medicine IIHamamatsu University School of MedicineHamamatsuShizuokaJapan
| | - Hidenao Noritake
- Hepatology DivisionDepartment of Internal Medicine IIHamamatsu University School of MedicineHamamatsuShizuokaJapan
| | - Taeang Arai
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNippon Medical SchoolBunkyo‐ku, TokyoJapan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNippon Medical SchoolBunkyo‐ku, TokyoJapan
| | - Satoshi Yasuda
- Department of Gastroenterology and HepatologyOgaki Municipal HospitalOgaki, GifuJapan
| | - Hidenori Toyoda
- Department of Gastroenterology and HepatologyOgaki Municipal HospitalOgaki, GifuJapan
| | - Tomomi Okubo
- Division of GastroenterologyNippon Medical School Chiba Hokusoh HospitalInzaiChibaJapan
| | - Atsushi Hiraoka
- Gastroenterology CenterEhime Prefectural Central HospitalMatsuyamaEhimeJapan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineSt. Marianna University School of MedicineKawasakiKanagawaJapan
| | - Haruki Uojima
- Department of Gastroenterology, Internal MedicineKitasato University School of MedicineSagamiharaKanagawaJapan
| | - Akito Nozaki
- Gastroenterological CenterYokohama City University Medical CenterYokohamaKanagawaJapan
| | - Joji Tani
- Department of Gastroenterology and NeurologyKagawa University Graduate School of MedicineKita‐gunKagawaJapan
| | - Asahiro Morishita
- Department of Gastroenterology and NeurologyKagawa University Graduate School of MedicineKita‐gunKagawaJapan
| | - Fujito Kageyama
- Department of GastroenterologyHamamatsu Medical CenterHamamatsuShizuokaJapan
| | - Yuzo Sasada
- Department of GastroenterologyIwata City HospitalIwataShizuokaJapan
| | - Masamichi Nagasawa
- Department of GastroenterologySeirei Hamamatsu General HospitalHamamatsuShizuokaJapan
| | - Masahiro Matsushita
- Department of GastroenterologyShimada Municipal HospitalShimadaShizuokaJapan
| | - Tatsuki Oyaizu
- Department of GastroenterologyShizuoka City Shizuoka HospitalShizuokaShizuokaJapan
| | - Shigeru Mikami
- Division of GastroenterologyDepartment of Internal MedicineKikkoman General HospitalNodaChibaJapan
| | - Tadashi Ikegami
- Department of GastroenterologyIbaraki Medical CenterTokyo Medical UniversityAmiIbarakiJapan
| | - Hiroshi Abe
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineShinmatusdo Central General HospitalMatsudoChibaJapan
| | - Kentaro Matsuura
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan
| | - Yasuhito Tanaka
- Department of Gastroenterology and HepatologyFaculty of Life SciencesKumamoto UniversityKumamotoKumamotoJapan
| | - Akihito Tsubota
- Core Research FacilitiesResearch Center for Medical ScienceThe Jikei University School of MedicineMinato‐ku, TokyoJapan
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8
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Reinoso-Pereira GL, Paranaguá-Vezozzo DC, Mazo DF, França JID, Ono SK, Carrilho FJ. HIGH VALUES OF LIVER STIFFNESS PLAY AN IMPORTANT ROLE IN STRATIFYING THE RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOTIC HEPATITIS C PATIENTS. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:204-211. [PMID: 35830030 DOI: 10.1590/s0004-2803.202202000-38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/23/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Evaluate the role of liver stiffness measurement (LSM) by transient elastography (TE) as a risk factor for hepatocellular carcinoma (HCC) occurrence in a prospective cohort of Brazilian hepatitis C virus (HCV) patients with cirrhosis. METHODS A cohort of 99 consecutive HCV patients was included between 2011 and 2016 with baseline LSM ≥12 kilopascals (kPa). Baseline variables were evaluated and HCC occurrence was documented. Kaplan-Meier methods with a log-rank test and the use of cox univariate and multivariate analysis assessed the association between variables and clinical results. RESULTS The mean age was 57.8±10.6 years. In a follow-up over a mean of 3.3 years, 20 (20.2%) patients developed HCC. In univariate logistic regression analysis, variables associated with HCC occurrence were: lower platelet count (P=0.0446), higher serum alpha-fetoprotein (P=0.0041) and bilirubin (P=0.0008) values, higher Model for End-Stage Liver Disease (MELD) score (P=0.0068) and higher LSM (P=0.0354). LSM evaluated by TE was independently associated with HCC development, and the best cut-off value for higher HCC risk was >21.1 kPa (HR: 5.548; 95%CI: 1.244-24.766; P=0.025). CONCLUSION A high value of liver stiffness relates substantially to an increased risk for HCC occurrence in Brazilian patients with cirrhosis due to HCV.
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Affiliation(s)
- Gleicy Luz Reinoso-Pereira
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, Divisão de Gastroenterologia Clínica e Hepatologia, São Paulo, SP, Brasil
| | - Denise Cerqueira Paranaguá-Vezozzo
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, Divisão de Gastroenterologia Clínica e Hepatologia, São Paulo, SP, Brasil
- Grupo São Paulo Clínicas de Câncer de Fígado, São Paulo, SP, Brasil
| | - Daniel F Mazo
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, Divisão de Gastroenterologia Clínica e Hepatologia, São Paulo, SP, Brasil
- Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Divisão de Gastroenterologia-Gastrocentro, Campinas, SP, Brasil
| | - João Italo Dias França
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, Divisão de Gastroenterologia Clínica e Hepatologia, São Paulo, SP, Brasil
| | - Suzane Kioko Ono
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, Divisão de Gastroenterologia Clínica e Hepatologia, São Paulo, SP, Brasil
- Grupo São Paulo Clínicas de Câncer de Fígado, São Paulo, SP, Brasil
| | - Flair José Carrilho
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, Divisão de Gastroenterologia Clínica e Hepatologia, São Paulo, SP, Brasil
- Grupo São Paulo Clínicas de Câncer de Fígado, São Paulo, SP, Brasil
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9
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Tamaki N, Kurosaki M, Yasui Y, Mori N, Tsuji K, Hasebe C, Joko K, Akahane T, Furuta K, Kobashi H, Kimura H, Yagisawa H, Marusawa H, Kondo M, Kojima Y, Yoshida H, Uchida Y, Tada T, Nakamura S, Yasuda S, Toyoda H, Loomba R, Izumi N. Hepatocellular Carcinoma Risk Assessment for Patients With Advanced Fibrosis After Eradication of Hepatitis C Virus. Hepatol Commun 2022; 6:461-472. [PMID: 34676692 PMCID: PMC8870028 DOI: 10.1002/hep4.1833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum-based risk model that could identify patients with low-risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma-glutamyl transferase < 28 IU/L, alpha-fetoprotein < 4.0 ng/mL, and Fibrosis-4 Index < 4.28) were classified as low-risk and others were classified as high-risk. When patients were stratified at the SVR24, and 1 year, and 2 years after SVR24, subsequent HCC development was significantly lower in low-risk patients (0.5-1.1 per 100 person-years in the derivation cohort and 0.9-1.1 per 100 person-years in the validation cohort) than in high-risk patients at each point. HCC risk from 1 year after SVR24 decreased in patients whose risk improved from high-risk to low-risk (HCC incidence: 0.6 per 100 person-years [hazard ratio (HR) = 0.163 in the derivation cohort] and 1.3 per 100 person-years [HR = 0.239 in the validation cohort]) than in those with sustained high risk. Conclusion: The HCC risk model based on simple serum markers at any point after SVR and its change can identify patients with advanced fibrosis who are at low HCC risk, and these patients may be able to reduce HCC surveillance.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan.,NAFLD Research CenterDivision of Gastroenterology and HepatologyDepartment of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yutaka Yasui
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Nami Mori
- Department of GastroenterologyHiroshima Red Cross Hospital and Atomic-bomb Survivors HospitalHiroshimaJapan
| | - Keiji Tsuji
- Department of GastroenterologyHiroshima Red Cross Hospital and Atomic-bomb Survivors HospitalHiroshimaJapan
| | - Chitomi Hasebe
- Department of GastroenterologyJapanese Red Cross Asahikawa HospitalAsahikawaHokkaidoJapan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic DiseaseMatsuyama Red Cross HospitalMatsuyamaEhimeJapan
| | - Takehiro Akahane
- Department of GastroenterologyJapanese Red Cross Ishinomaki HospitalIshinomakiMiyagiJapan
| | - Koichiro Furuta
- Department of GastroenterologyMasuda Red Cross HospitalMasudaShimaneJapan
| | - Haruhiko Kobashi
- Department of GastroenterologyJapanese Red Cross Okayama HospitalOkayamaOkayamaJapan
| | - Hiroyuki Kimura
- Department of GastroenterologyJapanese Red Cross Kyoto Daiichi HospitalKyotoJapan
| | - Hitoshi Yagisawa
- Department of GastroenterologyJapanese Red Cross Akita HospitalAkitaJapan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and HepatologyOsaka Red Cross HospitalOsakaJapan
| | - Masahiko Kondo
- Department of GastroenterologyJapanese Red Cross Otsu HospitalOtsuShigaJapan
| | - Yuji Kojima
- Department of HepatologyJapanese Red Cross Ise HospitalIseMieJapan
| | - Hideo Yoshida
- Department of GastroenterologyJapanese Red Cross Medical CenterTokyoJapan
| | - Yasushi Uchida
- Department of GastroenterologyMatsue Red Cross HospitalMatsueShimaneJapan
| | - Toshifumi Tada
- Department of Internal MedicineJapanese Red Cross Society Himeji HospitalHimejiJapan
| | - Shinichiro Nakamura
- Department of Internal MedicineJapanese Red Cross Society Himeji HospitalHimejiJapan
| | - Satoshi Yasuda
- Department of Gastroenterology and HepatologyOgaki Municipal HospitalOgakiJapan
| | - Hidenori Toyoda
- Department of Gastroenterology and HepatologyOgaki Municipal HospitalOgakiJapan
| | - Rohit Loomba
- NAFLD Research CenterDivision of Gastroenterology and HepatologyDepartment of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Namiki Izumi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
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10
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He HY, Hu L. Cysteine-rich intestinal protein 1 enhances the progression of hepatocellular carcinoma via Ras signaling. Kaohsiung J Med Sci 2021; 38:49-58. [PMID: 34585826 DOI: 10.1002/kjm2.12445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 06/14/2021] [Accepted: 08/08/2021] [Indexed: 11/08/2022] Open
Abstract
The present study aimed to explore the expression and clinical significance of cysteine-rich intestinal protein 1 (CRIP1) mRNA in the serum of patients with hepatocellular carcinoma (HCC). Reverse transcription polymerase chain reaction (RT-PCR) was performed to explore the level of CRIP1 mRNA in the tissues and serum of patients with HCC. Our data showed that the mRNA level of CRIP1 was significantly elevated in the serum and tissues of HCC patients. Moreover, serum CRIP1 mRNA was significantly elevated in HCC patients with larger tumor sizes and higher tumor node metastasis (TNM) stages. Receiver operating characteristic analysis showed that compared with a single marker, the combined detection of alpha-fetoprotein, carcinoembryonic antigen, and CRIP1 had the highest accuracy, sensitivity, and specificity. Further study showed that the overexpression of CRIP1 enhanced the proliferation and migration of HepG2 cells, but the inhibition of CRIP1 decreased the proliferation and migration of HepG2 cells. Microarray assays and KyotoEncyclopedia of Genes and Genomes (KEGG) pathway analysis showed that overexpression of CRIP1 induced the activation of Ras signaling. Co-immunoprecipitation (Co-IP) assays indicated that CRIP1 could interact with Ras. To further evaluate whether CRIP1 interacts with Ras, a specific siRNA targeting Ras was selected. We found that Ras knockdown reduced the activation of Ras/AKT signaling even in HepG2 cells transfected with CRIP1. Moreover, elevated expression of CRIP1 increased the proliferation of HepG2 cells, but such effects could be abolished by silencing Ras. In summary, elevated CRIP1 levels enhanced the progression of CRIP1 via Ras signaling.
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Affiliation(s)
- Hong-Yu He
- Department of Ultrasound, Tai'an Medical District, 960 Hospital of Chinese PLA, Tai'an, China
| | - Li Hu
- Physical Examination Center, Tai'an Medical District, 960 Hospital of PLA, Tai'an, China
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11
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Yamashita Y, Joshita S, Sugiura A, Yamazaki T, Kobayashi H, Wakabayashi SI, Yamada Y, Shibata S, Kunimoto H, Iwadare T, Matsumura M, Miyabayashi C, Okumura T, Ozawa S, Nozawa Y, Kobayashi N, Komatsu M, Fujimori N, Saito H, Umemura T. aMAP score prediction of hepatocellular carcinoma occurrence and incidence-free rate after a sustained virologic response in chronic hepatitis C. Hepatol Res 2021; 51:933-942. [PMID: 34216422 DOI: 10.1111/hepr.13689] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/14/2021] [Accepted: 06/25/2021] [Indexed: 02/08/2023]
Abstract
AIMS Hepatocellular carcinoma (HCC) can still occur in hepatitis C virus (HCV) patients who have achieved a sustained virologic response (SVR), which remains an important clinical issue in the direct-acting antivirals era. The current study investigated the clinical utility of the aMAP score (consisting of age, male, albumin-bilirubin, and platelets) for predicting HCC occurrence in HCV patients achieving an SVR by direct-acting antivirals. METHODS A total of 1113 HCV patients without HCC history, all of whom achieved an SVR, were enrolled for clinical comparisons. RESULTS Hepatocellular carcinoma was recorded in 50 patients during a median follow-up period of 3.7 years. The aMAP score was significantly higher in the HCC occurrence group than in the HCC-free group (53 vs. 47, p < 0.001). According to risk stratification based on aMAP score, the cumulative incidence of HCC occurrence for the low-, medium-, and high-risk groups was 0.14%, 4.49%, and 9.89%, respectively, at 1 year and 1.56%, 6.87%, and 16.17%, respectively, at 3 years (low vs. medium, low vs. high, and medium vs. high: all p < 0.01). Cox proportional hazard analysis confirmed aMAP ≥ 50 (hazard ratio [HR]: 2.78, p = 0.014), age≥ 70 years (HR: 2.41, p = 0.028), ALT ≥ 17 U/L (HR: 2.14, p < 0.001), and AFP ≥ 10 ng/mL (HR: 2.89, p = 0.005) as independent risk factors of HCC occurrence. Interestingly, all but one patient (99.5%) with aMAP less than 40 was HCC-free following an SVR. CONCLUSION The aMAP score could have clinical utility for predicting HCC occurrence in HCV patients achieving an SVR.
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Affiliation(s)
- Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shun-Ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yosuke Yamada
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Soichiro Shibata
- Department of Gastroenterology, Japanese Red Cross Society Nagano Hospital, Nagano, Japan
| | - Hideo Kunimoto
- Department of Gastroenterology, Nagano Municipal Hospital, Nagano, Japan
| | - Takanobu Iwadare
- Department of Gastroenterology, Nagano Municipal Hospital, Nagano, Japan
| | - Makiko Matsumura
- Department of Gastroenterology, Nagano Chuo Hospital, Nagano, Japan
| | | | - Taiki Okumura
- Department of Gastroenterology, NHO Matsumoto Medical Center, Matsumoto, Japan
| | - Sachie Ozawa
- Department of Internal Medicine, Nagano Prefectural Kiso Hospital, Kiso, Japan
| | - Yuichi Nozawa
- Department of Gastroenterology, Ina Central Hospital, Ina, Japan
| | | | - Michiharu Komatsu
- Department of Gastroenterology, Japanese Red Cross Society Suwa Hospital, Suwa, Japan
| | - Naoyuki Fujimori
- Department of Gastroenterology, NHO Shinshu Ueda Medical Center, Ueda, Japan
| | - Hiromi Saito
- Department of Gastroenterology, Aizawa Hospital, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
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12
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Yongpisarn T, Thimphitthaya C, Laoveeravat P, Wongjarupong N, Chaiteerakij R. Non-invasive tests for predicting liver outcomes in chronic hepatitis C patients: A systematic review and meta-analysis. World J Hepatol 2021; 13:949-968. [PMID: 34552701 PMCID: PMC8422917 DOI: 10.4254/wjh.v13.i8.949] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/14/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis leads to liver-related events in patients with chronic hepatitis C (CHC) infection. Although non-invasive tests (NITs) are critical to early detection of the development of liver fibrosis, the prognostic role of NITs remains unclear due to the limited types of NITs and liver outcomes explored in previous studies.
AIM To determine the prognostic value of NITs for risk stratification in CHC patients.
METHODS The protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42019128176). The systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search was performed using MEDLINE and EMBASE databases under a timeframe from the inception of the databases through February 25, 2020. We restricted our search to CHC cohort studies reporting an association between liver fibrosis assessed by NITs and the development of hepatocellular carcinoma, decompensation, or mortality. Pooled hazard ratios (HR) and area under the receiver operating characteristic (AUROC) for each NIT were estimated using a random effects model. Subgroup analyses were performed for NITs assessed at pre-treatment or post-treatment with sustained virologic response (SVR), treatment with either pegylated interferon and ribavirin or direct acting antiviral, Eastern or Western countries, and different cutoff points.
RESULTS The present meta-analysis included 29 cohort studies, enrolling 69339 CHC patients. Fibrosis-4 (FIB-4) index, aspartate aminotransferase to platelet ratio (APRI) score, and liver stiffness measurement (LSM) were found to have hepatocellular carcinoma predictive potential with pooled adjusted HRs of 2.48 [95% confidence interval (CI): 1.91-3.23, I2 = 96%], 4.24 (95%CI: 2.15-8.38, I2 = 20%) and 7.90 (95%CI: 3.98-15.68, I2 = 52%) and AUROCs of 0.81 (95%CI: 0.73-0.89, I2 = 77%), 0.81 (95%CI: 0.75-0.87, I2 = 68%), and 0.79 (95%CI: 0.63-0.96, I2 = 90%), respectively. Pooled adjusted HR with a pre-treatment FIB-4 cutoff of 3.25 was 3.22 (95%CI: 2.32-4.47, I2 = 80%). Pooled adjusted HRs for post-treatment with SVR FIB-4, APRI, and LSM were 3.01 (95%CI: 0.32-28.61, I2 = 89%), 9.88 (95%CI: 2.21-44.17, I2 = 24%), and 6.33 (95%CI: 2.57-15.59, I2 = 17%), respectively. Pooled adjusted HRs for LSM in patients with SVR following direct acting antiviral therapy was 5.55 (95%CI: 1.47-21.02, I2 = 36%). Pooled AUROCs for post-treatment with SVR FIB-4 and LSM were 0.75 (95%CI: 0.55-0.95, I2 = 88%) and 0.84 (95%CI: 0.66-1.03, I2 = 88%), respectively. Additionally, FIB-4 and LSM were associated with overall mortality, with pooled adjusted HRs of 2.07 (95%CI: 1.49-2.88, I2 = 27%) and 4.04 (95%CI: 2.40-6.80, I2 = 63%), respectively.
CONCLUSION FIB-4, APRI, and LSM showed potential for risk stratification in CHC patients. Cutoff levels need further validation.
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Affiliation(s)
- Tanat Yongpisarn
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Bangkok 10330, Thailand
| | - Chanattha Thimphitthaya
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Bangkok 10330, Thailand
| | - Passisd Laoveeravat
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, KY 40536, United States
| | - Nicha Wongjarupong
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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13
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Wu L, Bi J, Liu L, Zeng Y. Magnetic resonance elastography can predict the development of hepatocellular carcinoma: a meta-analysis and systematic review. J Gastrointest Oncol 2021; 12:1215-1222. [PMID: 34532081 PMCID: PMC8421890 DOI: 10.21037/jgo-21-196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 07/22/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has become the third leading cause of cancer-related death worldwide, and its incidence rate is increasing. Magnetic resonance elastography (MRE) can indirectly realize the accurate non-invasive evaluation of liver reserve function in HCC patients. In this study, we aimed to evaluate the effectiveness of MRE in the diagnosis of HCC patients. METHODS We searched globally-recognized electronic databases, such as PubMed, EMBASE, China National Knowledge Infrastructure, and Cochrane Central, for relevant literature on MRE prediction of HCC. The diagnostic performance of all studies was quantitatively summarized using a bivariate random effects model including heterogeneity analysis, receiver operating characteristic (ROC) curve, and bias determination. RESULTS The diagnostic accuracy of MRE for HCC was based on 1,735 patients. The sensitivity (31-100%) was lower than the specificity (81-94%). The overall sensitivity was 64% [95% confidence interval (CI): 46-79%; I2=92.44%], and the overall specificity was 85% (95% CI: 82-88%; I2=67.86%). Limited publication bias was observed in this study, and the sensitivity analysis showed that the study was robust. DISCUSSION The results of our meta-analysis show that MRE has moderate sensitivity and excellent specificity in the detection of HCC. MRE can be an effective diagnostic tool for HCC and can provide strong support for the selection of clinical treatment methods and prognostic judgment.
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Affiliation(s)
- Lianglong Wu
- Department of Radiology, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, China
| | - Junying Bi
- Department of Radiology, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, China
| | - Liangjin Liu
- Department of Radiology, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, China
| | - Yanni Zeng
- Department of Radiology, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, China
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14
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D’Ambrosio R, Degasperi E, Lampertico P. Predicting Hepatocellular Carcinoma Risk in Patients with Chronic HCV Infection and a Sustained Virological Response to Direct-Acting Antivirals. J Hepatocell Carcinoma 2021; 8:713-739. [PMID: 34235108 PMCID: PMC8254542 DOI: 10.2147/jhc.s292139] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 06/02/2021] [Indexed: 12/26/2022] Open
Abstract
Chronic infection with hepatitis C virus (HCV) may complicate with hepatocellular carcinoma (HCC), especially in patients with cirrhosis. Although the achievement of a sustained virological response (SVR) had been associated with a reduction in the risk of HCC already in the Interferon era, some concerns initially raised following the use of direct-acting antivirals (DAA), as their use was associated with increased risk of HCC development and aggressiveness. However, studies demonstrated that the risk of HCC was strongly influenced by pre-treatment fibrosis stage and, eventually, prior HCC history more than the type of antiviral therapy. According to published studies, rates of de-novo HCC ranged between 1.4% and 13.6% in patients with cirrhosis or advanced fibrosis vs 0.9% and 5.9% in those with chronic hepatitis C (CHC). Conversely, rates of recurrent HCC were higher, ranging between 3.2% and 49% in cirrhotics vs 0% and 40% in CHC patients. Most studies tried to identify predictors of HCC development, either de-novo or recurrent, and some authors were also able to build predictive scores for HCC risk stratification, which however still need prospective validation. Whereas some clinical features, such as age, gender, presence of comorbidities and fibrosis stage, may influence both de-novo and recurrent HCC, previous tumour burden before DAA seems to prevail over these features in recurrent HCC risk prediction.
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Affiliation(s)
- Roberta D’Ambrosio
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Elisabetta Degasperi
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
- CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Tamaki N, Kurosaki M, Yasui Y, Tsuchiya K, Izumi N. Attenuation coefficient (ATT) measurement for liver fat quantification in chronic liver disease. J Med Ultrason (2001) 2021; 48:481-487. [PMID: 34165645 DOI: 10.1007/s10396-021-01103-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/17/2021] [Indexed: 10/21/2022]
Abstract
Liver fat is one of the main clinical features in chronic liver disease, and the number of fatty liver patients is increasing as the prevalence of obesity and metabolic syndrome increases globally. Noninvasive and quantitative assessment of liver fat content was made possible by recent technological advances. Attenuation coefficient (ATT) measurement is a noninvasive and quantitative liver fat measurement method used in clinical practice. The ATT value is significantly associated with histological steatosis grade. The diagnostic accuracy of ATT for histological steatosis grade is equivalent to controlled attenuation parameter (CAP), and ATT has a lower measurement failure rate than CAP because ATT can be measured on a B-mode image with the exact location of the region of interest. Furthermore, ATT measurement has high interobserver reproducibility. Since ATT measurement and other ultrasound-based modalities for liver fat quantification are easy to perform and inexpensive, these modalities are suitable for point-of-care and screening. Although emerging data suggest that quantitative liver fat content and its changes over time may be associated with disease progression in nonalcoholic fatty liver disease, the association between ATT and disease progression has not been evaluated yet. Therefore, further investigation and validation studies are necessary to strengthen the clinical significance of ATT measurement in chronic liver disease.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.
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16
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Higuchi M, Tamaki N, Kurosaki M, Inada K, Kirino S, Yamashita K, Hayakawa Y, Sekiguchi S, Osawa L, Takaura K, Maeyashiki C, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Enomoto N, Izumi N. Changes of liver stiffness measured by magnetic resonance elastography during direct-acting antivirals treatment in patients with chronic hepatitis C. J Med Virol 2021; 93:3744-3751. [PMID: 32890408 DOI: 10.1002/jmv.26490] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/17/2020] [Accepted: 09/01/2020] [Indexed: 12/21/2022]
Abstract
Almost all patients achieved sustained virological response (SVR) by direct-acting antivirals (DAA) therapy, but it is not clear as to what extent DAA therapy affects changes in liver fibrosis after achieving SVR. In this study, we investigated the changes of liver stiffness by magnetic resonance elastogaraphy (MRE) during DAA therapy. A total of 308 patients were enrolled in the study. Liver stiffness was measured twice before and after DAA treatment using MRE and time-course change of liver stiffness was investigated. The median (interquartile range) values for liver stiffness were 4.2 (3.2-6.1) kPa at baseline and 3.3 (2.6-4.8) kPa at SVR, demonstrating a significant improvement (p < .01). A total of 44% of patients had no improvement in liver stiffness despite achieving SVR. In patients with advanced fibrosis (lower level of albumin [Alb] or histological fibrosis stage F4), it was difficult to improve liver stiffness. Except for Alb, there were no blood tests associated with nonimprovement in liver stiffness, making these cases difficult to predict. In conclusion, despite obtaining SVR, improvement in liver stiffness could not be obtained in some cases, especially in patients with advanced fibrosis. In these patients, liver stiffness must be followed even if SVR is obtained.
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Affiliation(s)
- Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shuhei Sekiguchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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17
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Abe H, Midorikawa Y, Higaki T, Yamazaki S, Aramaki O, Nakayama H, Moriguchi M, Kanda T, Moriyama M, Okada M, Nishimaki H, Sugitani M, Tsuji S, Takayama T. Magnetic resonance elastography-based prediction of hepatocellular carcinoma recurrence after curative resection. Surgery 2021; 170:167-172. [PMID: 33752906 DOI: 10.1016/j.surg.2021.02.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/11/2021] [Accepted: 02/09/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Liver stiffness measurement using magnetic resonance elastography can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection for hepatocellular carcinoma. The aim of this prospective study was to investigate whether preoperative liver stiffness measurement by magnetic resonance elastograhy can predict recurrence after curative resection for hepatocellular carcinoma. METHODS Patients who underwent preoperative liver stiffness measurement and curative resection for hepatocellular carcinoma were enrolled in this study. Potential associations between liver stiffness measurement, along with other clinical and pathologic variables, and intrahepatic hepatocellular carcinoma recurrence were analyzed. RESULTS In total, 156 patients were included in this study. During a median follow-up period of 25.1 months (range, 6.0-60.5 months), 72 (46.1%) patients with hepatocellular carcinoma had an intrahepatic recurrence. The median disease-free period after resection was 17.9 months (range, 1.0-60.5 months). In the multivariate analysis, liver stiffness measurement (hazard ratio, 1.27; 95% confidence interval, 1.11-1.43; P <.001) and vascular invasion (hazard ratio, 1.96; 95% confidence interval, 1.15-3.25; P = .013) were identified as independent predictors of recurrence. When the optimal cutoff point was set at 4.53 kPa using the minimal P value approach, the disease-free period after curative resection in 71 patients with a liver stiffness measurement value ≥4.53 kPa (11.3 months [range, 2.0-60.5 months]) was significantly shorter than that of 85 patients with a liver stiffness measurement value <4.53 kPa (22.5 months [range, 1.1-60.5 months]; P <.001). CONCLUSION Liver stiffness measurement using magnetic resonance elastography is a useful preoperative predictor of intrahepatic recurrence after curative resection for hepatocellular carcinoma.
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Affiliation(s)
- Hayato Abe
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yutaka Midorikawa
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
| | - Tokio Higaki
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Shintaro Yamazaki
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Osamu Aramaki
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Hisashi Nakayama
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Masamichi Moriguchi
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsuhiko Moriyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Masahiro Okada
- Department of Radiology, Nihon University School of Medicine, Tokyo, Japan
| | - Haruna Nishimaki
- Department of Pathology, Nihon University School of Medicine, Tokyo, Japan
| | - Masahiko Sugitani
- Department of Pathology, Nihon University School of Medicine, Tokyo, Japan
| | - Shingo Tsuji
- Research Center for Advanced Science and Technology, Genome Science Division, University of Tokyo, Japan
| | - Tadatoshi Takayama
- Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
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18
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You MW, Kim KW, Shim JJ, Pyo J. Impact of liver-stiffness measurement on hepatocellular carcinoma development in chronic hepatitis C patients treated with direct-acting antivirals: A systematic review and time-to-event meta-analysis. J Gastroenterol Hepatol 2021; 36:601-608. [PMID: 32875681 DOI: 10.1111/jgh.15243] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 08/17/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Patients with chronic hepatitis C (CHC) treated with direct-acting antivirals (DAAs) are still at risk for developing hepatocellular carcinoma (HCC) even after achieving sustained virologic response (SVR). Liver-stiffness measurement (LSM) on imaging has been investigated as a predictor of HCC occurrence. OBJECTIVES To provide systematic summary of the predictive value of LSM in predicting HCC occurrence in HCV patients treated with DAA. METHODS A comprehensive literature search of the PubMed-MEDLINE and EMBASE databases was performed to identify studies that evaluated the predictive value of LSM in CHC patients treated with DAAs. Pooled hazard ratio (HR) comparing HCC occurrence between patients with positive and negative results on LSM was calculated for all studies and various subgroups. Subgroup analyses and meta-regression were performed. RESULTS A review of 135 candidate articles identified eight eligible articles with a total of 3398patients for qualitative review and meta-analysis. The pooled HR for HCC occurrence determined by LSM was 3.43 (95% confidence interval [CI], 1.63-7.19) with heterogeneity (I2 = 81.87%, P < 0.001), thus indicating that LSM might be helpful for predicting HCC occurrence. In subgroup analyses, pooled HRs were different according to the study design (2.29; [95% CI, 0.96-5.45] for retrospective studies; 4.61 [95% CI, 2.44-8.71] for prospective studies), study population (4.00 [95% CI, 2.00-7.99] for CHC; 2.64 [0.99-7.00] for CHC with liver cirrhosis) and LSM parameter (3.17 [95% CI, 1.35-7.41] for baseline LSM; 4.19 [95% CI, 1.89-9.29] for others). In multivariate meta-regression, study design was the only influencing factor for pooled HR for HCC occurrence (P < 0.05). CONCLUSIONS Consistent evidence demonstrated the predictive value of LSM for HCC occurrence in CHC patients treated with DAA. The significant influencing factor for risk of HCC occurrence indicated by LSM was study design.
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Affiliation(s)
- Myung-Won You
- Department of Radiology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, South Korea
| | - Kyung Won Kim
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, South Korea
| | - Junhee Pyo
- WHO Collaborating Center for Pharmaceutical Policy and Regulation, Department of Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands
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19
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Tamaki N, Kurosaki M, Yasui Y, Mori N, Tsuji K, Hasebe C, Joko K, Akahane T, Furuta K, Kobashi H, Kimura H, Yagisawa H, Marusawa H, Kondo M, Kojima Y, Yoshida H, Uchida Y, Loomba R, Izumi N. Change in Fibrosis 4 Index as Predictor of High Risk of Incident Hepatocellular Carcinoma After Eradication of Hepatitis C Virus. Clin Infect Dis 2021; 73:e3349-e3354. [PMID: 33544129 DOI: 10.1093/cid/ciaa1307] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND It is unclear whether the fibrosis 4 index (FIB-4), a marker of liver fibrosis, at baseline and change in FIB-4 after sustained virological response (SVR) is associated with incident hepatocellular carcinoma (HCC) risk. In this study, we examined the association of incident HCC risk with baseline FIB-4 and sustained high FIB-4 (>3.25) at any time point after SVR. METHODS A total of 3823 patients who received direct-acting antiviral treatment and achieved SVR were enrolled. The FIB-4 was measured 24 weeks after the end of direct-acting antiviral treatment and achievement of SVR (SVR24), and 1, 2, and 3 years after SVR24, after which subsequent HCC development was investigated. RESULTS In patients with an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years after SVR24, subsequent HCC development was significantly higher than in those with an FIB-4 ≤3.25 at each point. The rates of HCC development 1, 2, 3, and 4 years after SVR24 were significantly higher in patients with sustained FIB-4 >3.25 than in those whose FIB-4 decreased to ≤3.25 (5.4%, 9.2%, 11.7%, and 16.0%, respectively, vs 2.2%, 3.1%, 3.7%, and 4.4%; P < .001). The adjusted hazard ratios (95% confidence intervals) for an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years later were 3.38 (2.4-4.8), 2.95 (1.9-4.7), 2.62 (1.3-5.1), and 3.37 (1.4-9.8), respectively. CONCLUSIONS The FIB-4 could be used to assess HCC development risk at any time after SVR, and changes in FIB-4 were associated with changes in the HCC development risk. Repeated assessments of FIB-4 could serve as a prognostic indicator of a high-risk HCC cohort that may require more intensive HCC surveillance strategy.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,NAFLD Research Center, Division of Medicine, University of California San Diego, La Jolla, California, USA
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Chitomi Hasebe
- Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Asahikawa, Japan
| | - Koji Joko
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan
| | - Koichiro Furuta
- Department of Gastroenterology, Masuda Red Cross Hospital, Masuda, Japan
| | - Haruhiko Kobashi
- Department of Gastroenterology, Japanese Red Cross Okayama Hospital, Okayama, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Hitoshi Yagisawa
- Department of Gastroenterology, Japanese Red Cross Akita Hospital, Akita, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Masahiko Kondo
- Department of Gastroenterology, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | - Yuji Kojima
- Department of Hepatology, Japanese Red Cross Ise Hospital, Ise, Japan
| | - Hideo Yoshida
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue, Japan
| | - Rohit Loomba
- NAFLD Research Center, Division of Medicine, University of California San Diego, La Jolla, California, USA
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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20
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Tamaki N, Kurosaki M, Takahashi Y, Itakura Y, Kirino S, Inada K, Yamashita K, Sekiguchi S, Hayakawa Y, Osawa L, Higuchi M, Takaura K, Maeyashiki C, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Loomba R, Izumi N. Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein as a Screening Tool for Significant Liver Fibrosis in Health Checkup. Int J Mol Sci 2020; 22:ijms22010040. [PMID: 33375190 PMCID: PMC7793131 DOI: 10.3390/ijms22010040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/09/2020] [Accepted: 12/17/2020] [Indexed: 02/08/2023] Open
Abstract
Chronic liver disease is generally widespread, and a test for screening fibrotic subjects in a large population is needed. The ability of Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA+-M2BP) to detect significant fibrosis was investigated in health checkup subjects in this research. Of 2021 health checkup subjects enrolled in this prospective cross-sectional study, those with WFA+-M2BP ≥ 1.0 were defined as high risk. Liver fibrosis was evaluated using magnetic resonance elastography (MRE) in subjects with high risk. The primary outcome was the positive predictive value (PPV) of WFA+-M2BP for significant fibrosis (liver stiffness ≥ 2.97 kPa by MRE). This trial was registered with the UMIN clinical trial registry, UMIN000036175. WFA+-M2BP ≥ 1.0 was observed in 5.3% of the 2021 subjects. The PPV for significant fibrosis with the threshold of WFA+-M2BP at ≥1.0, ≥1.1, ≥1.2, ≥1.3, ≥1.4, and ≥1.5 was 29.2%, 36.4%, 43.5%, 42.9%, 62.5%, and 71.4%, respectively. A WFA+-M2BP of 1.2 was selected as the optimal threshold for significant fibrosis among high-risk subjects, and the PPV, negative predictive value, sensitivity, and specificity for significant fibrosis were 43.5%, 84.0%, 71.4%, and 61.8%, respectively. WFA+-M2BP ≥ 1.2 was significantly associated with significant fibrosis, with an odds ratio (OR) of 4.04 (95% confidence interval (CI): 1.1–16, p = 0.04), but not FIB-4 ≥ 2.67 (OR: 2.40, 95%CI: 0.7–8.6, p-value = 0.2). In conclusion, WFA+-M2BP is associated with significant fibrosis and could narrow down potential subjects with liver fibrosis. The strategy of narrowing down fibrosis subjects using WFA+-M2BP may be used to screen for fibrotic subjects in a large population.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
- Department of Medicine, Division of Gastroenterology and Hepatology, NAFLD Research Center, University of California San Diego, La Jolla, CA 92093, USA;
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Yuka Takahashi
- Medical Examination Center, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.T.); (Y.I.)
| | - Yoshie Itakura
- Medical Examination Center, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.T.); (Y.I.)
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Shuhei Sekiguchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Rohit Loomba
- Department of Medicine, Division of Gastroenterology and Hepatology, NAFLD Research Center, University of California San Diego, La Jolla, CA 92093, USA;
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (N.T.); (M.K.); (S.K.); (K.I.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.H.); (K.T.); (C.M.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.)
- Correspondence: ; Tel.: +81-422-32-3111; Fax: +81-422-32-9551
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Tamaki N, Kurosaki M, Loomba R, Izumi N. Clinical Utility of Mac-2 Binding Protein Glycosylation Isomer in Chronic Liver Diseases. Ann Lab Med 2020; 41:16-24. [PMID: 32829576 PMCID: PMC7443525 DOI: 10.3343/alm.2021.41.1.16] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/15/2020] [Accepted: 07/29/2020] [Indexed: 12/15/2022] Open
Abstract
An accurate evaluation of liver fibrosis is clinically important in chronic liver diseases. Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel serum marker for liver fibrosis. In this review, we discuss the role of M2BPGi in diagnosing liver fibrosis in chronic hepatitis B and C, chronic hepatitis C after sustained virologic response (SVR), and nonalcoholic fatty liver disease (NAFLD). M2BPGi predicts not only liver fibrosis but also the hepatocellular carcinoma (HCC) development and prognosis in patients with chronic hepatitis B and C, chronic hepatitis C after SVR, NAFLD, and other chronic liver diseases. M2BPGi can also be used to evaluate liver function and prognosis in patients with cirrhosis. M2BPGi levels vary depending on the etiology and the presence or absence of treatment. Therefore, the threshold of M2BPGi for diagnosing liver fibrosis and predicting HCC development has to be adjusted according to the background and treatment status.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,NAFLD Research Center, Division of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Rohit Loomba
- NAFLD Research Center, Division of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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22
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Li J, Venkatesh SK, Yin M. Advances in Magnetic Resonance Elastography of Liver. Magn Reson Imaging Clin N Am 2020; 28:331-340. [PMID: 32624152 DOI: 10.1016/j.mric.2020.03.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Magnetic resonance elastography (MRE) is the most accurate noninvasive technique in diagnosing fibrosis and cirrhosis in patients with chronic liver disease (CLD). The accuracy of hepatic MRE in distinguishing the severity of disease has been validated in studies of patients with various CLDs. Advanced hepatic MRE is a reliable, comfortable, and inexpensive alternative to liver biopsy for disease diagnosing, progression monitoring, and clinical decision making in patients with CLDs. This article summarizes current knowledge of the technical advances and innovations in hepatic MRE, and the clinical applications in various hepatic diseases.
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Affiliation(s)
- Jiahui Li
- Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | | | - Meng Yin
- Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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23
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Osawa L, Tamaki N, Kurosaki M, Kirino S, Watakabe K, Wang W, Okada M, Shimizu T, Higuchi M, Takaura K, Takada H, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Enomoto N, Izumi N. Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein but not α-fetoprotein as a Long-Term Hepatocellular Carcinoma Predictor. Int J Mol Sci 2020; 21:E3640. [PMID: 32455631 PMCID: PMC7279305 DOI: 10.3390/ijms21103640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/18/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
Identification of high-risk patients for hepatocellular carcinoma (HCC) after sustained virological responses (SVR) is necessary to define candidates for long-term surveillance. In this study, we examined whether serum markers after 1 year of SVR could predict subsequent HCC development. Total 734 chronic hepatitis C patients without a history of HCC who achieved SVR with direct-acting antivirals were included. The regular surveillance for HCC started from 24 weeks after the end of treatment (SVR24). Factors at SVR24 and 1 year after SVR24 were analyzed for predicting HCC development. During the mean observation period of 19.7 ± 10 months, 24 patients developed HCC. At SVR24, Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA±M2BP) ≥ 1.85 and α-fetoprotein (AFP) ≥ 6.0 ng/mL were independent factors of HCC development. However, at 1 year after SVR24, WFA±M2BP ≥ 1.85 was associated with subsequent HCC development (hazard ratio: 23.5, 95% confidence interval: 2.68-205) but not AFP. Among patients with WFA±M2BP ≥ 1.85 at SVR24, 42% had WFA±M2BP < 1.85 at 1 year after SVR24 (WFA±M2BP declined group). Subsequent HCC development was significantly lower in the declined group than in the non-declined group (1 year HCC rate: 0% vs. 9.4%, p = 0.04). In conclusion, WFA±M2BP but not AFP could identify high and no-risk cases of HCC at 1 year after SVR. Therefore, it was useful as a real-time monitoring tool to identify the candidates for continuous surveillance for HCC.
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Affiliation(s)
- Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan;
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan;
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Takao Shimizu
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan;
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan;
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan;
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (L.O.); (N.T.); (M.K.); (S.K.); (K.W.); (W.W.); (M.O.); (T.S.); (M.H.); (K.T.); (H.T.); (S.K.); (Y.Y.); (K.T.); (H.N.); (J.I.); (Y.T.)
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