Clinical and Molecular Hepatology

"Biomarker"

Review Article

Clinical utility of liquid biopsy in biliary tract cancer: Diagnosis to treatment monitoring: Seonjeong Woo, Sohyun Hwang, Chan Kim, Hong Jae Chon; Received March 19, 2026 Accepted June 21, 2026 Published online June 25, 2026; DOI: https://doi.org/10.3350/cmh.2026.0337 [Accepted]

Abstract
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Biliary tract cancer (BTC) represents a formidable clinical challenge characterized by extensive genomic heterogeneity and a poor prognosis, primarily due to advanced stage diagnosis. Although systemic therapies, including chemotherapy, targeted therapies, and immune checkpoint inhibitors, have become the standard of care, their efficacy remains modest, and subsequent treatment options are limited. BTC management is further complicated by the inherent difficulty of obtaining high-quality tissue biopsies, impeding timely genomic profiling and subsequent therapeutic decision-making. Liquid biopsy has emerged as a minimally invasive alternative, facilitating comprehensive tumor characterization through circulating tumor cells, cell-free DNA, RNA, and proteins. These approaches hold promise for early detection, assessment of minimal residual disease, identification of actionable targets, and real-time monitoring of treatment response and resistance, thereby supporting precision oncology. Despite technical challenges such as limited sensitivity for structural variations, variability across platforms, and the need for standardized validation, liquid biopsy offers transformative potential in BTC. This review discusses current strategies, clinical applications, and future directions for integrating liquid biopsy into routine practice to improve survival and quality of life in patients with BTC.

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Original Article

Hepatic fibro-inflammation measured by magnetic resonance imaging iron-corrected T1 predicts extrahepatic cancer risk: a UK Biobank study: Hye Yeon Chon, Seok-Jae Heo, SungA Bae, Tae Seop Lim, Ja Kyung Kim; Clin Mol Hepatol 2026;32(3):1349-1363.
Published online June 9, 2026; DOI: https://doi.org/10.3350/cmh.2025.1372

Background/Aims
Iron-corrected T1 (cT1) is a magnetic resonance imaging (MRI)-derived biomarker of hepatic fibro-inflammation. This study aimed to investigate whether high cT1 values are associated with an increased risk of extrahepatic malignancy in a large prospective cohort.
Methods
We included 24,003 cancer-free participants from the United Kingdom (UK) Biobank with liver MRI and complete covariate data. Incident extrahepatic malignancy was assessed over a median follow-up of 4.28 years. Multivariable Fine–Gray subdistribution hazard models were used to evaluate the association between cT1 and extrahepatic cancer risk, accounting for competing risks and adjusting for demographic, metabolic, and liver-related factors.
Results
During follow-up, 1,144 participants developed extrahepatic malignancies. In the multivariable analysis, higher cT1 was independently associated with increased extrahepatic cancer risk (hazard ratio [HR] 1.116; 95% confidence interval [CI] 1.033–1.205; per standard deviation increase; P=0.005). Older age (HR 1.512; 95% CI 1.402–1.631) and male sex (HR 1.388; 95% CI 1.220–1.578) were also significant predictors (P<0.001). The fibrosis-4 score showed a modest positive association (HR 1.032; 95% CI 1.004–1.062; P=0.026), whereas MRI-proton density fat fraction demonstrated an inverse association (HR 0.906; 95% CI 0.832–0.987; P=0.024). When dichotomized at 771 ms, elevated cT1 was associated with a higher cumulative incidence of extrahepatic malignancy (6.1% vs. 4.6%, P=0.002).
Conclusions
Elevated cT1 is independently associated with an increased risk of future extrahepatic malignancy, suggesting that it may reflect systemic disease processes related to cancer risk. These findings highlight the potential relevance of cT1 beyond liver-specific outcomes; however, further validation is required before clinical implementation.

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Editorials

Precision chemotherapy in biliary tract cancer moving from empiric intensification to biomarker-guided treatment: Editorial on “Molecular determinants of outcome to gemcitabine, cisplatin, and nab-paclitaxel in patients with advanced biliary tract cancer”: Sung Hwan Lee, Ahmed O. Kaseb, Ju-Seog Lee; Clin Mol Hepatol 2026;32(3):1457-1460.
Published online February 11, 2026; DOI: https://doi.org/10.3350/cmh.2026.0179

1,179 View
58 Download

Improving the choice of liver transplant for hepatocellular carcinoma: Editorial on “Network meta-analysis and validation study of expanded liver transplantation criteria for hepatocellular carcinoma: Significant role of alpha-fetoprotein”: Jongman Kim; Clin Mol Hepatol 2026;32(3):1461-1462.
Published online February 2, 2026; DOI: https://doi.org/10.3350/cmh.2026.0111

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Research Letter

Optimized MASH treatment eligibility cutoffs for MRE-measured liver stiffness and proton density fat fraction: Nana Owusu, Kyle Kalutkiewicz, Jiahui Li, Alina M. Allen, Rohit Loomba, Richard L. Ehman, Meng Yin; Clin Mol Hepatol 2026;32(1):e47-e51.
Published online December 8, 2025; DOI: https://doi.org/10.3350/cmh.2025.1267

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Reviews

Novel biomarkers for alcohol-associated liver disease and their implications across clinical settings: Kaanthi Rama, Vinay Jahagirdar, Francisco Idalsoaga, Hanna Blaney, S. Fisher Rhoads, Luis Antonio Díaz, Marco Arrese, Juan Pablo Arab; Clin Mol Hepatol 2026;32(2):443-463.
Published online November 25, 2025; DOI: https://doi.org/10.3350/cmh.2025.0921

Abstract
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Alcohol-associated liver disease (ALD) is a leading cause of preventable cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality, yet current laboratory and imaging tools detect only late-stage disease. This narrative review synthesizes emerging evidence on novel biomarkers that capture the multidimensional pathophysiology of ALD and discusses their utility for routine clinical practice. Traditional serum-based liver fibrosis markers (e.g., cytokeratin-18 fragments, Pro-C3, the enhanced liver fibrosis test) improve non-invasive staging risk beyond aminotransferases, while elastography techniques, such as vibration-controlled transient elastography and magnetic resonance elastography, can also quantify liver stiffness with high precision. Among novel mechanistic biomarkers, genetic polymorphisms in PNPLA3, TM6SF2, MBOAT7, HSD17B13, and polygenic risk scores define lifetime risk, whereas sex-specific hormonal milieus also modify susceptibility and progression. Moreover, gut dysbiosis signatures, including reduced Faecalibacterium prausnitzii, Akkermansia muciniphila, and a lower Firmicutes/Bacteroidetes ratio, and their metabolites (short-chain fatty acids, and bile acids, trimethylamine N-oxide) correlate with liver inflammation and fibrosis. Endocrine imbalances of cortisol, testosterone, and thyroid hormones further stratify metabolic vulnerability. Ultimately, multi-omics platforms (i.e., transcriptomics, lipidomics, proteomics, metabolomics, and epigenomics) can reveal distinct molecular signatures that predict steatohepatitis, fibrogenesis, and early HCC. Integrating these biomarkers enables phase-specific enrichment strategies, earlier intervention windows, adaptive dose-finding, and mechanismbased endpoints in ALD trials. Remaining challenges include assay standardization, validation across diverse cohorts, and incorporation into regulatory frameworks. Future work could evaluate cost-effectiveness and feasibility in routine clinical practice. Widespread adoption promises earlier diagnosis, personalized risk reduction, and more efficient drug development for this globally prevalent disorder.

Citations

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Senping Xu, Zhaoshan Zhang, Zhongquan Zhou, Jiawei Guo
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Review Article on: AI-Driven Precision Medicine in Liver Disease: Microbiome and Nanotechnology Integration
Rahul Kumar, Amritesh Kumar, Aayush Kumar Tiwari, MD Nasiruddin Khan, Mohit Kumar, Moidul Islam Judder
Pan-African Journal of Health and Psychological Sciences.2026;[Epub] CrossRef
N-acetylcysteine for patients with alcohol use disorder, post-traumatic stress disorder, and their co-occurrence: a systematic review of placebo-controlled randomized trials
Mohamed Awad E. Ahmed, Mufreh Amin, Yomna Emad Abdalla, Amr Abdelghani, Nourhan Eid, Aya Samy, Omar Kassar, Khalid Radwan Alsaadany, Mohamed Ezzat M. Mansour
BMC Psychiatry.2026;[Epub] CrossRef
Correspondence to editorial on “RAB25/GCN1 signaling promotes endoplasmic reticulum stress to mediate alcohol-associated liver disease progression”
Xue-Wen Liu, Zi-Bin Zhan, Yu Gong, Ze-Hua Li, Kun-Hao Bai, Jun Weng
Clinical and Molecular Hepatology.2026; 32(3): e349. CrossRef
Biomarkers From the Microbiome to Predict ALD Progression and Its Severity: A Comprehensive Review
Suraj Mishra, Harshrajsinh Solanki, Palash Mandal, Jasbir Arora
Mediators of Inflammation.2026;[Epub] CrossRef

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Tumor-based biomarkers and circulating tumor DNA for precision medicine in advanced hepatocellular carcinoma: Sabrina Sidali, Claudia Campani, Jihyun An, Ju Hyun Shim, Jean-Charles Nault; Clin Mol Hepatol 2026;32(1):69-90.
Published online August 20, 2025; DOI: https://doi.org/10.3350/cmh.2025.0746

Abstract
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and remains a major cause of cancer-related mortality worldwide. Systemic therapies, including targeted therapies and immune checkpoint inhibitors, have revolutionized the management of advanced HCC. Although the prognosis of patients with advanced HCC remains poor, significant progress has been made with recent advances in drug development, particularly with the introduction of effective treatments such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab. Indeed, treatment response varies significantly among patients, highlighting the need for robust biomarkers. In addition, the development of molecular driver-targeted therapies remains an active research focus as most genetic alterations observed in HCC are currently undruggable. Meeting these goals will require additional efforts to obtain histological material in clinical trials, in order to enable robust translational research. This review explores the current landscape of biomarkers of response to systemic treatments in HCC, including molecular, immune-based markers as well as circulating tumor DNA and highlights potential paths of improvement.

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A novel signature of palmitoylation for predicting prognosis and therapeutic response of hepatocellular carcinoma
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Functional Interpretation of Recurrent Genetic Variants in Hepatocellular Carcinoma: Molecular Consequences and Clinical Relevance
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Review Article: Biomarkers in Liver Transplantation for Hepatocellular Carcinoma: Towards Precision Medicine
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Varices and Hemorrhagic Events during Atezolizumab-bevacizumab Treatment: Reassurance with Caveats for Prognosis
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Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi
Clinical and Molecular Hepatology.2026; 32(3): e424. CrossRef
Integrated genetic and epigenetic biomarker landscapes in hepatocellular carcinoma: From molecular mechanisms to translational precision oncology
Doaa Mamdouh Aly, Asmaa Mohamed Fteah, Mohamed A. Elrefaiy, Hani E. Seddik
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Liver Cancer.2026; : 1. CrossRef
Prognostic value of tumor microenvironment-based molecular subtypes in hepatocellular carcinoma patients undergoing surgery for spinal metastases: refining conventional scoring systems
Bing Liang, Annan Hu, Jian Zhou, Juan Li, Jian Dong
Clinical and Experimental Medicine.2025;[Epub] CrossRef

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Letters to the Editor

“Surrogates without substance?” Questioning the evidence for histologic improvement with HTD1801: Letter to the editor on “HTD1801 demonstrates promising potential for histologic improvements in metabolic dysfunction-associated steatohepatitis in both a preclinical and phase 2 study”: Zhihao Lei; Clin Mol Hepatol 2026;32(2):e158-e160.
Published online August 19, 2025; DOI: https://doi.org/10.3350/cmh.2025.0868

Citations

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Safety and metabolic effects of HTD1801 in type 2 diabetes and MASLD: a phase Ib randomized trial
Jiajia Mai, Hong Zhang, Min Wu, Meng Yu, Kui Liu, Guixia Wang, Yanhua Ding
Diabetology & Metabolic Syndrome.2026;[Epub] CrossRef

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Crossref

Letter to the editor on “HTD1801 demonstrates promising potential for histologic improvements in metabolic dysfunction-associated steatohepatitis in both a preclinical and phase 2 study”: Xi-Lin Gao; Clin Mol Hepatol 2026;32(2):e161-e162.
Published online August 19, 2025; DOI: https://doi.org/10.3350/cmh.2025.0804

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Correspondence

Correspondence to letter to the editor on “Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: A randomized double-blind phase 2a trial”: Woo Hyun Paik, Heon Se Jeong, Do Hyun Park; Clin Mol Hepatol 2026;32(2):e233-e234.
Published online July 29, 2025; DOI: https://doi.org/10.3350/cmh.2025.0816

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Reply to Correspondence

GULP1: New hope for hepatocellular carcinoma: Reply to correspondence on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”: Yuhao Xie, Lu-Qi Cao, John Wurpel, Zhe-Sheng Chen; Clin Mol Hepatol 2026;32(1):e112-e114.
Published online April 28, 2025; DOI: https://doi.org/10.3350/cmh.2025.0415

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Original Article

HTD1801 demonstrates promising potential for histologic improvements in metabolic dysfunction-associated steatohepatitis in both a preclinical and phase 2 study: Vincent Wai-Sun Wong, Guy W. Neff, Adrian M. Di Bisceglie, Ru Bai, Junwei Cheng, Meng Yu, Alexander Liberman, Liping Liu, Nadege Gunn; Clin Mol Hepatol 2025;31(3):1071-1083.
Published online April 21, 2025; DOI: https://doi.org/10.3350/cmh.2025.0145

Background/Aims
Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus. The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence.
Methods
The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRIPDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH resolution index (achieving ≥–0.67).
Results
Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (p<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH.
Conclusions
These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.

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Mapping the global research output of Traditional Chinese Medicine in the treatment of metabolic dysfunction-associated steatotic liver disease: a comprehensive bibliometric analysis based on multiple databases (2000–2025)
Da Wang, Mengwei Li, Rongting Zhao, Hui Wang, Hang Chen, Minshan Huang, Yingxue Shen, Lanqing Ma
Frontiers in Medicine.2026;[Epub] CrossRef
Comparative efficacy of phase 2–3 therapies for non-cirrhotic metabolic dysfunction-associated steatohepatitis: An updated network meta-analysis
Tsubasa Tsutsumi, Nicole Shu Ying Tang, Cheng Han Ng, Hiroyuki Suzuki, Nicholas L. Syn, N. Apoorva Sasikumar, Glenn Jun Kit Ho, Damien Chua, Jing Kai Tioh, Thanawin Pramotedham, Selvakumar Vigneshwaran, Peter Jin Sun Low, Joon Ho Moon, Dan Yock Young, Vin
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“Surrogates without substance?” Questioning the evidence for histologic improvement with HTD1801: Letter to the editor on “HTD1801 demonstrates promising potential for histologic improvements in metabolic dysfunction-associated steatohepatitis in both a p
Zhihao Lei
Clinical and Molecular Hepatology.2026; 32(2): e158. CrossRef
Letter to the editor on “HTD1801 demonstrates promising potential for histologic improvements in metabolic dysfunction-associated steatohepatitis in both a preclinical and phase 2 study”
Xi-Lin Gao
Clinical and Molecular Hepatology.2026; 32(2): e161. CrossRef
Metabolic Dysfunction‐Associated Steatotic Liver Disease and Obesity: Pathogenesis, Diagnostics, Risk Stratification, and Therapeutic Approach
Beom Kyung Kim
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Research Letter

Lipidomic analysis of alcohol use disorder patients revealed the biomarkers for alcohol-related liver disease susceptibility: Dongyao Wang, Hongwei Zhang, Yuxiao Tang; Clin Mol Hepatol 2025;31(3):e259-e262.
Published online April 2, 2025; DOI: https://doi.org/10.3350/cmh.2025.0227

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Dihydroberberine in metabolic disorders: Bioavailability, molecular mechanisms, toxicology, and future perspectives
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Editorial

GULP1, a multifaceted diagnostic biomarker and potential therapeutic target in hepatocellular carcinoma: Editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”: Yuhao Xie, Lu-Qi Cao, John Wurpel, Zhe-Sheng Chen; Clin Mol Hepatol 2026;32(1):413-415.
Published online March 24, 2025; DOI: https://doi.org/10.3350/cmh.2025.0315

Citations

Citations to this article as recorded by

GULP1: New hope for hepatocellular carcinoma: Reply to correspondence on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Yuhao Xie, Lu-Qi Cao, John Wurpel, Zhe-Sheng Chen
Clinical and Molecular Hepatology.2026; 32(1): e112. CrossRef
Correspondence to editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Soon Sun Kim, Hyung Seok Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e72. CrossRef
The role and possible mechanism of intestinal fungi in the progression of chronic liver diseases
Yirui Hu, Ye Yang, Shuyan Wang, Huikuan Chu
npj Biofilms and Microbiomes.2026;[Epub] CrossRef

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Correspondence

Correspondence to letter to the editor on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”: Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun; Clin Mol Hepatol 2026;32(1):e103-e105.
Published online March 19, 2025; DOI: https://doi.org/10.3350/cmh.2025.0287

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Editorial

Unveiling GULP1 as a hepatocyte-specific role for recurrence: Editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”: Pengde Lu, Ning Wang; Clin Mol Hepatol 2026;32(1):410-412.
Published online March 19, 2025; DOI: https://doi.org/10.3350/cmh.2025.0282

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52 Download

Letter to the Editor

Letter to the editor on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”: Juan Yang, Xinyi Li, Sheng Zheng; Clin Mol Hepatol 2026;32(1):e10-e12.
Published online March 7, 2025; DOI: https://doi.org/10.3350/cmh.2025.0216

Citations

Citations to this article as recorded by

Correspondence to letter to the editor on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e103. CrossRef
Correspondence to editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Soon Sun Kim, Hyung Seok Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e72. CrossRef

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Review

Unveiling the intratumor microbiome in liver cancer: Current insights and prospective applications: Xindi Ke, Shangze Jiang, Qiaoxin Wei, Minghao Sun, Hang Sun, Mingchang Pang, Mei Liu, Lejia Sun, Huayu Yang, Yilei Mao; Clin Mol Hepatol 2025;31(3):685-705.
Published online January 22, 2025; DOI: https://doi.org/10.3350/cmh.2024.1039

Abstract
PDF

The role of the gut microbiome in the development and progression of liver cancer has long been recognized. However, the presence of microbes in tumors that were previously considered sterile has only recently been discovered. The intratumor microbiome in liver cancer likely originates from various sources, including the gut, hematogenous spread from other mucosal locations, adjacent non-cancerous tissues, and co-metastasis with the tumor cells. As a newly discovered component of the tumor microenvironment, it regulates host immune responses, promotes chronic inflammation, modulates metabolic pathways, and exerts other influences in liver cancer. These unique features offer potential new biomarkers for liver cancer prognosis and treatment response. Exploring the complex interactions between intratumor microbiome and the host to modulate or target the intratumor microbiome may provide new avenues for liver cancer treatment. This article provides a comprehensive review of our current understanding regarding the potential origins of the intratumor microbiome in liver cancer, its unique characteristics, and the underlying mechanisms by which it affects liver cancer. Furthermore, we discuss the promising clinical implications and potential challenges that remain before this knowledge can be fully integrated into clinical practice.

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The intratumoral microbiota: Orchestrating metabolic-immune crosstalk and shaping the therapeutic landscape in cancer
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Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2026; 1872(7): 168316. CrossRef
Gut‐Liver Translocation of Bacteroides Uniformis Alleviates Advanced Metabolic Dysfunction‐Associated Steatotic Liver Disease by Suppressing Hepatocyte Ferroptosis via Propionic Acid Secretion
Haiyang Liu, Zun Fan, Zhen Liu, Lei Qin, Xin Zhao
Advanced Science.2026;[Epub] CrossRef
RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond
You-Peng Ding, Cui-Cui Liu, Ke-Da Yu
Experimental Hematology & Oncology.2025;[Epub] CrossRef
Unveiling hidden players: the role of intratumoral microbiota in gastrointestinal cancer dynamics
Wanfen Tang, Fakai Li, Hongjuan Zheng, Shishi Zhou, Chenhui Li, Xifeng Xu, Jianfei Fu
Journal of Cancer Research and Clinical Oncology.2025;[Epub] CrossRef

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Original Articles

Hepatic neoplasm

Exploring methylation signatures for high de novo recurrence risk in hepatocellular carcinoma: Da-Won Kim, Jin Hyun Park, Suk Kyun Hong, Min-Hyeok Jung, Ji-One Pyeon, Jin-Young Lee, Kyung-Suk Suh, Nam-Joon Yi, YoungRok Choi, Kwang-Woong Lee, Young-Joon Kim; Clin Mol Hepatol 2025;31(2):563-576.
Published online January 13, 2025; DOI: https://doi.org/10.3350/cmh.2024.0899

Background/Aims
Hepatocellular carcinoma (HCC) exhibits high de novo recurrence rates post-resection. Current post-surgery recurrence prediction methods are limited, emphasizing the need for reliable biomarkers to assess recurrence risk. We aimed to develop methylation-based markers for classifying HCC patients and predicting their risk of de novo recurrence post-surgery.
Methods
In this retrospective cohort study, we analyzed data from HCC patients who underwent surgical resection in Korea, excluding those with recurrence within one year post-surgery. Using the Infinium Methylation EPIC array on 140 samples in the discovery cohort, we classified patients into low- and high-risk groups based on methylation profiles. Distinctive markers were identified through random forest analysis. These markers were validated in the cancer genome atlas (n=217), Validation cohort 1 (n=63) and experimental Validation using a methylation-sensitive high-resolution melting (MS-HRM) assay in Validation cohort 1 and Validation cohort 2 (n=63).
Results
The low-risk recurrence group (methylation group 1; MG1) showed a methylation average of 0.73 (95% confidence interval [CI] 0.69–0.77) with a 23.5% recurrence rate, while the high-risk group (MG2) had an average of 0.17 (95% CI 0.14–0.20) with a 44.1% recurrence rate (P<0.03). Validation confirmed the applicability of methylation markers across diverse populations, showing high accuracy in predicting the probability of HCC recurrence risk (area under the curve 96.8%). The MS-HRM assay confirmed its effectiveness in predicting de novo recurrence with 95.5% sensitivity, 89.7% specificity, and 92.2% accuracy.
Conclusions
Methylation markers effectively classified HCC patients by de novo recurrence risk, enhancing prediction accuracy and potentially offering personalized management strategies.

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Methylation of zinc-finger protein ZNF471 regulates MIS18A expression and inhibits proliferation and metastasis of hepatocellular carcinoma via negative regulation of the Wnt/β-catenin pathway, as well as enhances sensitivity to apatinib and donafenib
Xiaofei Wang, Luyao Jia, Chao Zhang, Chunjing Bian, Chenchen Huang, Kejing Ma, Tao Luo
Cellular Signalling.2026; 145: 112608. CrossRef

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Viral hepatitis

Longitudinal profile of plasma pregenomic RNA in patients with chronic hepatitis B infection on long-term nucleoside analogues and its interaction with clinical parameters: Lung-Yi Mak, Mark Anderson, Michael Stec, Matthew Shing-Hin Chung, Danny Ka-Ho Wong, Rex Wan-Hin Hui, Wai-Kay Seto, Gavin Cloherty, Man-Fung Yuen; Clin Mol Hepatol 2025;31(2):460-473.
Published online December 26, 2024; DOI: https://doi.org/10.3350/cmh.2024.0724

Backgrounds/Aims
Plasma pregenomic hepatitis B virus RNA (pgRNA) is a novel biomarker in chronic hepatitis B infection (CHB). We aimed to describe the longitudinal profile of pgRNA and factors influencing its levels in CHB patients on nucleoside analogue (NUC).
Methods
Serial plasma samples from 1,354 CHB patients started on first-line NUC were evaluated. Time of NUC initiation was taken as baseline (year 0), followed by 1-year, 3-year and 5-year of NUC therapy. pgRNA was measured by Research Use Only RealTime HBV RNA v2.0 (0.2 mL) (Abbott Diagnostics) with lower limit of detection of 0.8 log U/mL (~20 copies/mL).
Results
Among 1,354 subjects (median age at baseline 49.8 [interquartile range, IQR 40.2–57.3]) years, 65.2% male, 16.1% hepatitis B e antigen (HBeAg)-positive, 28.6% cirrhotic), baseline median HBV RNA was 3.68 (IQR 2.42–5.19) log U/mL. Upon NUC therapy, median pgRNA levels were 2.45 (IQR 1.82–3.62), 2.23 (IQR 1.67–3.05) and 2.14 (IQR 1.48–2.86) log U/mL at 1, 3 and 5 years, respectively, with the corresponding log U/mL reductions of 0.82, 1.20 and 1.54. Undetectable/ unquantifiable pgRNA was achieved in 13.5%, 15.9% and 20.1% of patients at 1, 3 and 5 years, respectively. Older age, male sex, HBeAg-negativity and high PAGE-B score were associated with lower pgRNA.
Conclusions
Plasma pgRNA declines are modest under NUC therapy, with only 16.3% achieving RNA undetectability after 5 years of first-line NUC indicating cccDNA silencing has not been achieved in the majority of patients. Clinical characteristics should be taken into consideration when interpreting the plasma pgRNA level.

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International Journal of Infectious Diseases.2026; 162: 108162. CrossRef
Targeting the innate immune system in treating hepatitis B: prospects for functional cure
Karen Cheuk-Ying Ho, Rex Wan-Hin Hui, Wai-Kay Seto, Man-Fung Yuen, Lung-Yi Mak
Clinical and Molecular Hepatology.2026; 32(1): 184. CrossRef
Hepatitis B virus RNA and hepatitis B surface antigen kinetics predict treatment outcomes in children with chronic hepatitis B
Xiaorong Peng, Yunan Chang, Jiaying Wu, Jing Zhu, Peng Hu, Hong Ren, Hongmei Xu, Ruiqiu Zhao, Tao Qin
Frontiers in Cellular and Infection Microbiology.2026;[Epub] CrossRef
Delta Describe, the French Collaborative Project: The Profile and Management of Hepatitis Delta Patients in Metropolitan France
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Viruses.2026; 18(4): 424. CrossRef
Reconsidering the role of plasma pgRNA in NUC-treated CHB: Stratified biomarker interpretation and the limits of current assays: Letter to the editor on “Longitudinal profile of plasma pregenomic RNA in patients with chronic hepatitis B infection on long-
Xu Han, Jun Sun, Yinyan Li
Clinical and Molecular Hepatology.2026; 32(2): e131. CrossRef
Profiles and kinetics of PgRNA and clinical characteristics in pregnant, postpartum, and non-pregnant women with chronic HBV infection
Genju Wang, Yandan Wu, Ziyue Zhang, Qiuchen Wu, Juan Tang, Ying Ji, Yan Wang, Guanlun Zhou, Minmin Yu
Virology Journal.2025;[Epub] CrossRef

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Review

Hepatic neoplasm

Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications: Jaeho Park, Yi-Te Lee, Vatche G. Agopian, Jessica S Liu, Ekaterina K. Koltsova, Sungyong You, Yazhen Zhu, Hsian-Rong Tseng, Ju Dong Yang; Clin Mol Hepatol 2025;31(Suppl):S255-S284.
Published online November 28, 2024; DOI: https://doi.org/10.3350/cmh.2024.0541

Abstract
PDF

Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional’s skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.

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Clinical utilization of testing for cell-free DNA in hepatocellular cancer
Jasmine J. Wang, Yi-Te Lee, Amy K. Kim, Augusto Villanueva, Amit G. Singal, Ju Dong Yang
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Sherihan G. AbdelHamid, Esraa M. Halawa, Eman M. Ibrahim, Mahmoud ElHefnawi
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Lin Ding, Yini Li, Te Liu, Xinyi He, Ying Zhao, Baishen Pan, Wenjing Yang, Xinrong Yang, Wei Guo, Beili Wang
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Ioana Manea, Speranta Maria Iacob, Razvan Iacob, Alina-Veronica Ghionescu, Andrei Sorop, Roxana Elena Saizu, Daria-Ana-Arina Gheorghe, Delia Prisecariu, Simona Olimpia Dima, Liliana Simona Gheorghe
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Zihan Jin, Libo Tang, Yuhao Wang, Shihong Zhong, Yongyin Li
Clinical and Molecular Hepatology.2026; 32(3): e427. CrossRef
Liquid biopsy: Fundamental principles and clinical value in hepatocellular carcinoma
Anil Chandra Anand, Dibyalochan Praharaj, Preetam Nath
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Prognostic Significance of Liquid Biopsy-Detected Genetic Alterations in Hepatocellular Carcinoma
Ahmet Gökhan Sarıtaş, Burak Yavuz, İshak Aydın, Harun Ağca, Uğur Topal, Tuğsan Ballı, Atil Bisgin, Abdullah Ülkü, Atılgan Tolga Akçam
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Li Yang, Ya Zhou, Huimin Li, Yao Gao, Xiaoli Xiong, Tao Zhang, Liping Zhu, Xiurong Yang
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Ding-Fan Guo, Lin-Wei Fan, Qi Wen, Jin-Ke Wang, Yun-Hui Liang, Qi Feng, Ting Wang, Kun-He Zhang
npj Precision Oncology.2025;[Epub] CrossRef

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Reply to Correspondence

Hepatic neoplasm

Reply to correspondence on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Hiroaki Kanzaki, Yujin Hoshida; Clin Mol Hepatol 2025;31(1):e121-e122.
Published online October 11, 2024; DOI: https://doi.org/10.3350/cmh.2024.0886

5,357 View
51 Download

Correspondences

Hepatic neoplasm

Correspondence to editorial 2 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 trial”: Sun Young Yim, Sung Hwan Lee, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Ju-Seog Lee; Clin Mol Hepatol 2025;31(1):e84-e86.
Published online October 7, 2024; DOI: https://doi.org/10.3350/cmh.2024.0830

5,745 View
51 Download

Hepatic neoplasm

Correspondence to editorial 1 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial”: Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S. Lee, Ahmed O. Kaseb, Ju-Seog Lee; Clin Mol Hepatol 2025;31(1):e81-e83.
Published online October 7, 2024; DOI: https://doi.org/10.3350/cmh.2024.0829

Citations

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Reply to correspondence on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”
Hiroaki Kanzaki, Yujin Hoshida
Clinical and Molecular Hepatology.2025; 31(1): e121. CrossRef

6,139 View
48 Download
Crossref

Hepatic neoplasm

Correspondence to letter to the editor on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Peng Wei, Ju-Seog Lee; Clin Mol Hepatol 2025;31(1):e110-e112.
Published online October 2, 2024; DOI: https://doi.org/10.3350/cmh.2024.0828

5,791 View
59 Download

Letter to the Editor

Hepatic neoplasm

Comprehensive analysis of transcriptomic biomarkers for predicting response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Binghua Li, Jingyuan Wen, Zhu Xu, Peng Yan, Bing Han, Decai Yu; Clin Mol Hepatol 2025;31(1):e31-e34.
Published online September 20, 2024; DOI: https://doi.org/10.3350/cmh.2024.0628

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Intratumoral Proton Density Fat Fraction Predicts the Outcome of HAIC Combined With PD‐1 Inhibitors in Advanced Hepatocellular Carcinoma
Yujie Ye, Yunzheng Li, Yanjun Lu, Yanchao Xu, Laizhu Zhang, Yican Zhu, Huan Li, Binghua Li, Min Zhou, Decai Yu
Cancer Medicine.2026;[Epub] CrossRef
Correspondence to letter to the editor on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”
Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Peng Wei, Ju-Seog Lee
Clinical and Molecular Hepatology.2025; 31(1): e110. CrossRef
S100A9 promotes resistance to anti-PD-1 immunotherapy in hepatocellular carcinoma by degrading PARP1 and activating the STAT3/PD-L1 pathway
Xianwei Zhou, Chu Qiao, Xuehui Chu, Yajing Yang, Haoran Man, Jingxin Liu, Yunzheng Li, Zhu Xu, Huan Li, Xiaodong Shan, Zaowu Lian, Yanjun Lu, Weihong Wang, Decai Yu, Xitai Sun, Binghua Li
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Comment on “Clinical outcomes and histologic findings of patients with hepatocellular carcinoma with durable partial response or durable stable disease after receiving atezolizumab plus bevacizumab”
Binghua Li, Qiang Wang, Weiwei Hu, Huan Li, Peng Yan, Yajuan Cao, Decai Yu
iLIVER.2024; 3(4): 100130. CrossRef

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Editorials

Hepatic neoplasm

Personalized approaches to the treatment of hepatocellular carcinoma using immune checkpoint inhibitors: Editorial on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Naoshi Nishida; Clin Mol Hepatol 2025;31(1):311-315.
Published online September 3, 2024; DOI: https://doi.org/10.3350/cmh.2024.0739

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Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma
Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi
Clinical and Molecular Hepatology.2026; 32(1): e38. CrossRef
Correspondence to editorial 2 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 trial”
Sun Young Yim, Sung Hwan Lee, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Ju-Seog Lee
Clinical and Molecular Hepatology.2025; 31(1): e84. CrossRef
T lymphocyte-based immune response and therapy in hepatocellular carcinoma: focus on TILs and CAR-T cells
Thikra Majid Muhammed, Saade Abdalkareem Jasim, Ahmed Hussein Zwamel, Safia Obaidur Rab, Suhas Ballal, Abhayveer Singh, Anima Nanda, Subhashree Ray, Ahmed Hjazi, Hatif Abdulrazaq Yasin
Naunyn-Schmiedeberg's Archives of Pharmacology.2025; 398(8): 10007. CrossRef
Genetic insights into sarcomatoid hepatocellular carcinoma: Critical role of ARID2 in pathogenesis and immune feature: Editorial on “Integrated molecular characterization of sarcomatoid hepatocellular carcinoma”
Naoshi Nishida
Clinical and Molecular Hepatology.2025; 31(2): 635. CrossRef
Addressing the Complexities of Pre-Liver Transplant Immune Checkpoint Inhibitors for Hepatocellular Carcinoma: A Response to Recent Commentaries
Mohammad Saeid Rezaee-Zavareh, Zhiyong Guo, Ju Dong Yang
Journal of Hepatology.2024;[Epub] CrossRef

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4 Web of Science
Crossref

Hepatic neoplasm

Transcriptomic signature in advanced hepatocellular carcinoma tissue to predict combination immunotherapy response: Editorial on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Hiroaki Kanzaki, Yujin Hoshida; Clin Mol Hepatol 2025;31(1):308-310.
Published online August 30, 2024; DOI: https://doi.org/10.3350/cmh.2024.0726

Citations

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Correspondence to letter to the editor on “Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma”
Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi
Clinical and Molecular Hepatology.2026; 32(3): e424. CrossRef
Correspondence to editorial 1 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial”
Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S. Lee, Ahmed O. Kaseb, Ju-Seog Lee
Clinical and Molecular Hepatology.2025; 31(1): e81. CrossRef
Advances and challenges in immunotherapy and molecular imaging for hepatocellular carcinoma
Tu Haibin
Discover Oncology.2025;[Epub] CrossRef

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104 Download
1 Web of Science
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Liver fibrosis, cirrhosis, and portal hypertension

Unveiling the distinctive gut microbiota and metabolites in liver cirrhosis and its complications: Novel diagnostic biomarkers: Editorial on “Gut microbiome and metabolome signatures in liver cirrhosis-related complications”: Soon Kyu Lee, Jong Young Choi; Clin Mol Hepatol 2025;31(1):301-303.
Published online August 30, 2024; DOI: https://doi.org/10.3350/cmh.2024.0716

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Identification of potential biomarkers for Polygonum multiflorum–induced liver injury in a clinical cohort: integrating machine learning of metabolomics with transcriptomic profiling
Chao Lei, Meng Qiao, Chaoren Tan, Erjun Gao, Wenliang Lv, Yanming Xie, Zhifei Wang
Journal of Ethnopharmacology.2026; 366: 121618. CrossRef
Cirrhotic refractory ascites: Pathogenesis, current therapeutic strategies, and future directions
Linxin Zhou, Jianhui Lin
Hepatobiliary Communications.2026; 1(1): 100004. CrossRef
Correspondence to editorial on: “Gut microbiome and metabolome signatures in liver cirrhosis-related complications”
Satya Priya Sharma, Ki Tae Suk
Clinical and Molecular Hepatology.2025; 31(1): e74. CrossRef
The crosstalk between gut microbiota and microbiota-derived metabolites in hepatocellular carcinoma
Sang Jun Yoon, Seul Ki Han, Tae Suk Kim, Ki Tae Suk, Dae Hee Choi, Young Don Kim, Moon Young Kim, Gab Jin Cheon, Soon Koo Baik, Dong Joon Kim
Critical Reviews in Microbiology.2025; 51(6): 1315. CrossRef
Gut-Liver Axis: The Role of Intestinal Microbiota and Their Metabolites in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease
Chao Cui, Shuai Gao, Jingfei Shi, Kai Wang
Gut and Liver.2025; 19(4): 479. CrossRef

9,083 View
110 Download
3 Web of Science
Crossref

Original Article

Microbiome

Gut microbiome and metabolome signatures in liver cirrhosis-related complications: Satya Priya Sharma, Haripriya Gupta, Goo-Hyun Kwon, Sang Yoon Lee, Seol Hee Song, Jeoung Su Kim, Jeong Ha Park, Min Ju Kim, Dong-Hoon Yang, Hyunjoon Park, Sung-Min Won, Jin-Ju Jeong, Ki-Kwang Oh, Jung A Eom, Kyeong Jin Lee, Sang Jun Yoon, Young Lim Ham, Gwang Ho Baik, Dong Joon Kim, Ki Tae Suk; Clin Mol Hepatol 2024;30(4):845-862.
Published online July 25, 2024; DOI: https://doi.org/10.3350/cmh.2024.0349

Background/Aims
Shifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis.
Methods
Microbiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to time-of-flight mass spectrometry. Correlation analyses were performed targeting the gut-microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased).
Results
Veillonella bacteria, Ruminococcus gnavus, and Streptococcus pneumoniae are cirrhosis-related microbiotas compared with control group. Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella_uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC >0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites.
Conclusions
Cirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.

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Correspondence

Hepatic neoplasm

Correspondence to editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”: Su Bin Lim, Hyo Jung Cho; Clin Mol Hepatol 2024;30(4):1009-1011.
Published online May 20, 2024; DOI: https://doi.org/10.3350/cmh.2024.0368

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Matrisomics: Beyond the extracellular matrix for unveiling tumor microenvironment
Jiwon Hong, Hyo Joon Jin, Mi Ran Choi, Darren Wan-Teck Lim, Jong-Eun Park, You-Sun Kim, Su Bin Lim
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2024; 1879(6): 189178. CrossRef

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Editorial

Hepatic neoplasm

Unveiling etiology-specific blood biomarkers in hepatocellular carcinoma: A gateway to personalized medicine: Editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”: Joseph C. Ahn, Ju Dong Yang; Clin Mol Hepatol 2024;30(4):689-691.
Published online May 14, 2024; DOI: https://doi.org/10.3350/cmh.2024.0348

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Correspondence to letter to the editor on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e103. CrossRef
Metabolites involvement in the growth and spread of liver cancer
Anurag Kumar Gautam, Vipin Kumar, Archana Bharti Sonkar, Amita Singh, Deepankar Yadav, Nitin Rajan, Pranesh Kumar, Sanjay Singh, Sudipta Saha, Vijayakumar Mahalingam Rajamanickam
Liver Research.2025; 9(4): 286. CrossRef
Correspondence to editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”
Su Bin Lim, Hyo Jung Cho
Clinical and Molecular Hepatology.2024; 30(4): 1009. CrossRef

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Correspondence

Steatotic liver disease

Correspondence on Editorial regarding “Identification of signature gene set as highly accurate determination of MASLD progression”: Sungju Jung, Sumin Yoon, Jong Hoon Park, Yeon-Su Lee, Kyung Hyun Yoo; Clin Mol Hepatol 2024;30(2):287-290.
Published online February 23, 2024; DOI: https://doi.org/10.3350/cmh.2024.0136

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The effects of next generation probiotics on metabolic dysfunction-associated steatotic liver disease: a parallel, double-blind, randomized, placebo-controlled trial
Sung-Min Won, Hyunchae Joung, In Gyu Park, Sang Hak Han, Young Lim Ham, Ji Sook Han, Yoojin Kwon, Dong Joon Kim, Ki Tae Suk
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Yiyuan Zheng, Zhekun Xiong, Lina Zhao, Chaoyuan Huang, Qiuhong Yong, Dan Fang, Fengbin Liu, Yong Li
Clinical and Molecular Hepatology.2024; 30(4): 1019. CrossRef

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Original Articles

Steatotic liver disease

Identification of signature gene set as highly accurate determination of metabolic dysfunction-associated steatotic liver disease progression: Sumin Oh, Yang-Hyun Baek, Sungju Jung, Sumin Yoon, Byeonggeun Kang, Su-hyang Han, Gaeul Park, Je Yeong Ko, Sang-Young Han, Jin-Sook Jeong, Jin-Han Cho, Young-Hoon Roh, Sung-Wook Lee, Gi-Bok Choi, Yong Sun Lee, Won Kim, Rho Hyun Seong, Jong Hoon Park, Yeon-Su Lee, Kyung Hyun Yoo; Clin Mol Hepatol 2024;30(2):247-262.
Published online January 26, 2024; DOI: https://doi.org/10.3350/cmh.2023.0449

Background/Aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression.
Methods
Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD.
Results
After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort.
Conclusions
We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.

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Opportunities and challenges of artificial intelligence in hepatology
Sarah M. G. Morel, Shuyang Wu, Timothy J. Kendall, Indra N. Guha, Jonathan A. Fallowfield
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The application of artificial intelligence in the intersection of metabolic dysfunction-associated steatotic liver disease and cardiovascular diseases
Yu Kong, Hualei Chen, Yun Chen, Chengji Wang
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Integrated serum proteomic and liver genomic analyses identify molecular signatures associated with metabolic dysfunction-associated steatotic liver disease: a multi-cohort study
Jinjian Xu, Wanglong Gou, Xinyue Wang, Dongmei Ru, Wei Hu, Jieteng Chen, Bang-yan Li, Yue Xi, Ju-Sheng Zheng, Yu-ming Chen
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Association between advanced fibrosis and epigenetic age acceleration among individuals with MASLD
Haili Wang, Zhenqiu Liu, Hong Fan, Chengnan Guo, Xin Zhang, Yi Li, Suzhen Zhao, Luojia Dai, Ming Zhao, Tiejun Zhang
Journal of Gastroenterology.2025; 60(3): 306. CrossRef
Correspondence to editorial on “DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease”
Amal Magdy, Hee-Jin Kim, Won Kim, Mirang Kim
Clinical and Molecular Hepatology.2025; 31(1): e70. CrossRef
PNPLA3 is one of the bridges between TM6SF2 E167K variant and MASLD: Correspondence to editorial on “TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD”
Baokai Sun, Likun Zhuang
Clinical and Molecular Hepatology.2025; 31(1): e67. CrossRef
Early portal hypertension in metabolic dysfunction-associated steatotic liver disease: a concise review
Iván López-Méndez, Eva Juárez-Hernández, Juan Pablo Soriano-Márquez, Misael Uribe, Graciela Castro-Narro
Expert Review of Gastroenterology & Hepatology.2025; 19(7): 755. CrossRef
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Carlos Jose Pirola, Silvia Sookoian
Clinical and Molecular Hepatology.2024; 30(2): 174. CrossRef
Correspondence on Editorial regarding “Identification of signature gene set as highly accurate determination of MASLD progression”
Sungju Jung, Sumin Yoon, Jong Hoon Park, Yeon-Su Lee, Kyung Hyun Yoo
Clinical and Molecular Hepatology.2024; 30(2): 287. CrossRef
Correspondence to editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”
Su Bin Lim, Hyo Jung Cho
Clinical and Molecular Hepatology.2024; 30(4): 1009. CrossRef
Chitinase 1: a novel therapeutic target in metabolic dysfunction-associated steatohepatitis
Jung Hoon Cha, Na Ri Park, Sung Woo Cho, Heechul Nam, Hyun Yang, Eun Sun Jung, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon, Pil Soo Sung, Si Hyun Bae
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Metabolic dysfunction-associated steatotic liver disease: a key factor in hepatocellular carcinoma therapy response
Camilo Julio Llamoza-Torres, María Fuentes-Pardo, Bruno Ramos-Molina
Metabolism and Target Organ Damage.2024;[Epub] CrossRef
Biological and clinical role of TREM2 in liver diseases
Ke Ma, Shouliang Guo, Jin Li, Tao Wei, Tingbo Liang
Hepatology Communications.2024;[Epub] CrossRef

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Hepatic neoplasm

Prognostic value of ultra-low-pass whole-genome sequencing of circulating tumor DNA in hepatocellular carcinoma under systemic treatment: Miguel Sogbe, Idoia Bilbao, Francesco P. Marchese, Jon Zazpe, Annarosaria De Vito, Marta Pozuelo, Delia D’Avola, Mercedes Iñarrairaegui, Carmen Berasain, Maria Arechederra, Josepmaria Argemi, Bruno Sangro; Clin Mol Hepatol 2024;30(2):177-190.
Published online December 29, 2023; DOI: https://doi.org/10.3350/cmh.2023.0426

Background/Aims
New prognostic markers are needed to identify patients with hepatocellular carcinoma (HCC) who carry a worse prognosis. Ultra-low-pass whole-genome sequencing (ULP-WGS) (≤0.5× coverage) of cell-free DNA (cfDNA) has emerged as a low-cost promising tool to assess both circulating tumor DNA (ctDNA) fraction and large structural genomic alterations. Here, we studied the performance of ULP-WGS of plasma cfDNA to infer prognosis in patients with HCC.
Methods
Plasma samples were obtained from patients with HCC prior to surgery, locoregional or systemic therapy, and were analyzed by ULP-WGS of cfDNA to an average genome-wide fold coverage of 0.3x. ctDNA and copy number alterations (CNA) were estimated using the software package ichorCNA.
Results
Samples were obtained from 73 HCC patients at different BCLC stages (BCLC 0/A: n=37, 50.7%; BCLC B/C: n=36, 49.3%). ctDNA was detected in 18 out of 31 patients who received systemic treatment. Patients with detectable ctDNA showed significantly worse overall survival (median, 13.96 months vs not reached). ctDNA remained an independent predictor of prognosis after adjustment by clinical-pathologic features and type of systemic treatment (hazard ratio 7.69; 95%, CI 2.09–28.27). Among ctDNA-positive patients under systemic treatments, the loss of large genomic regions in 5q and 16q arms was associated with worse prognosis after multivariate analysis.
Conclusions
ULP-WGS of cfDNA provides clinically relevant information about the tumor biology. The presence of ctDNA and the loss of 5q and 16q arms in ctDNA-positive patients are independent predictors of worse prognosis in patients with advanced HCC receiving systemic therapy.

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Reviews

Liver fibrosis, cirrhosis, and portal hypertension

Hepatorenal syndrome: Current concepts and future perspectives: Chan-Young Jung, Jai Won Chang; Clin Mol Hepatol 2023;29(4):891-908.
Published online April 13, 2023; DOI: https://doi.org/10.3350/cmh.2023.0024

Abstract
PDF

Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major complication in patients with advanced cirrhosis, often leading to death before liver transplantation (LT). Recent updates in the pathophysiology, definition, and classification of HRS have led to a complete revision of the nomenclature and diagnostic criteria for HRS type 1, which was renamed HRS-acute kidney injury (AKI). HRS is characterized by severe impairment of kidney function due to increased splanchnic blood flow, activation of several vasoconstriction factors, severe vasoconstriction of the renal arteries in the absence of kidney histologic abnormalities, nitric oxide dysfunction, and systemic inflammation. Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The optimal treatment of HRS is LT. While awaiting LT, treatment options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by intravenous albumin infusion. In patients with HRS unresponsive to pharmacological treatment and with conventional indications for kidney replacement therapy (KRT), such as volume overload, uremia, or electrolyte imbalances, KRT may be applied as a bridging therapy to transplantation. Other interventions, such as transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Although recently developed novel therapies have potential to improve outcomes of patients with HRS, further studies are warranted to validate the efficacy of these novel agents.

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Hepatic neoplasm

Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications: Paula Fernández-Palanca, Tania Payo-Serafín, Carolina Méndez-Blanco, Beatriz San-Miguel, María J. Tuñón, Javier González-Gallego, José L. Mauriz; Clin Mol Hepatol 2023;29(2):293-319.
Published online February 1, 2023; DOI: https://doi.org/10.3350/cmh.2022.0425

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.

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Hepatic neoplasm

Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region: Do Young Kim, Bao Nguyen Toan, Chee-Kiat Tan, Irsan Hasan, Lyana Setiawan, Ming-Lung Yu, Namiki Izumi, Nguyen Nguyen Huyen, Pierce Kah-Hoe Chow, Rosmawati Mohamed, Stephen Lam Chan, Tawesak Tanwandee, Teng-Yu Lee, Thi Thanh Nguyen Hai, Tian Yang, Woo-Chang Lee, Henry Lik Yuen Chan; Clin Mol Hepatol 2023;29(2):277-292.
Published online January 30, 2023; DOI: https://doi.org/10.3350/cmh.2022.0212

Abstract
PDF

Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.

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Steatotic liver disease

Noninvasive serum biomarkers for liver steatosis in nonalcoholic fatty liver disease: Current and future developments: Sang Bong Ahn; Clin Mol Hepatol 2023;29(Suppl):S150-S156.
Published online January 25, 2023; DOI: https://doi.org/10.3350/cmh.2022.0362

Abstract
PDF

Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of the population worldwide and includes nonalcoholic fatty liver, nonalcoholic steatohepatitis (NASH), and cirrhosis. Since NAFLD-associated diseases begin with steatosis, the early diagnosis of steatosis helps to prevent the progression of NASH and fibrosis. In addition, more convenient and easily diagnosable serum biomarkers are becoming crucial in disease diagnosis. In this report, we summarize the known serum biomarkers for liver steatosis and provide guidance for their application in clinical practice.

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Steatotic liver disease

Noninvasive imaging biomarkers for liver fibrosis in nonalcoholic fatty liver disease: current and future: Jung Hwan Yu, Han Ah Lee, Seung Up Kim; Clin Mol Hepatol 2023;29(Suppl):S136-S149.
Published online December 12, 2022; DOI: https://doi.org/10.3350/cmh.2022.0436

Abstract
PDF

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide and becoming a major cause of liver disease-related morbidity and mortality. The presence of liver fibrosis in patients with NAFLD is closely related to prognosis, including the development of hepatocellular carcinoma and other complications of cirrhosis. Therefore, assessment of the presence of significant or advanced liver fibrosis is crucial. Although liver biopsy has been considered the “gold standard” method for evaluating the degree of liver fibrosis, it is not suitable for extensive use in all patients with NAFLD owing to its invasiveness and high cost. Therefore, noninvasive biochemical and imaging biomarkers have been developed to overcome the limitations of liver biopsy. Imaging biomarkers for the stratification of liver fibrosis have been evaluated in patients with NAFLD using different imaging techniques, such as transient elastography, shear wave elastography, and magnetic resonance elastography. Furthermore, artificial intelligence and deep learning methods are increasingly being applied to improve the diagnostic accuracy of imaging techniques and overcome the pitfalls of existing imaging biomarkers. In this review, we describe the usefulness and future prospects of noninvasive imaging biomarkers that have been studied and used to evaluate the degree of liver fibrosis in patients with NAFLD.

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Steatotic liver disease

Non-invasive imaging biomarkers for liver steatosis in non-alcoholic fatty liver disease: present and future: Asako Nogami, Masato Yoneda, Michihiro Iwaki, Takashi Kobayashi, Yasushi Honda, Yuji Ogawa, Kento Imajo, Satoru Saito, Atsushi Nakajima; Clin Mol Hepatol 2023;29(Suppl):S123-S135.
Published online December 12, 2022; DOI: https://doi.org/10.3350/cmh.2022.0357

Abstract
PDF

Non-alcoholic fatty liver disease is currently the most common chronic liver disease, affecting up to 25% of the global population. Simple fatty liver, in which fat is deposited in the liver without fibrosis, has been regarded as a benign disease in the past, but it is now known to be prognostic. In the future, more emphasis should be placed on the quantification of liver fat. Traditionally, fatty liver has been assessed by histological evaluation, which requires an invasive examination; however, technological innovations have made it possible to evaluate fatty liver by non-invasive imaging methods, such as ultrasonography, computed tomography, and magnetic resonance imaging. In addition, quantitative as well as qualitative measurements for the detection of fatty liver have become available. In this review, we summarize the currently used qualitative evaluations of fatty liver and discuss quantitative evaluations that are expected to further develop in the future.

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Editorial

Viral hepatitis

New biomarkers of hepatitis B virus (HBV) infection: HBV RNA and HBV core-related antigen, new kids on the block?: Young-Suk Lim; Clin Mol Hepatol 2023;29(1):118-119.
Published online November 29, 2022; DOI: https://doi.org/10.3350/cmh.2022.0413

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Correspondence

Viral hepatitis

Correspondence on Editorial regarding “HBV pgRNA and HBcrAg reductions at week 4 predict favourable HBsAg response upon long-term nucleos(t)ide analogue in CHB”: Lung-Yi Mak, Wai-Kay Seto, Man-Fung Yuen; Clin Mol Hepatol 2023;29(1):191-193.
Published online November 22, 2022; DOI: https://doi.org/10.3350/cmh.2022.0410

6,573 View
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Review

Steatotic liver disease

Noninvasive serum biomarkers for liver fibrosis in NAFLD: current and future: Tina Reinson, Ryan M. Buchanan, Christopher D. Byrne; Clin Mol Hepatol 2023;29(Suppl):S157-S170.
Published online November 22, 2022; DOI: https://doi.org/10.3350/cmh.2022.0348

In the last 20 years, noninvasive serum biomarkers to identify liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) have been developed, validated against liver biopsy (the gold standard for determining the presence of liver fibrosis) and made available for clinicians to use to identify ≥F3 liver fibrosis. The aim of this review is firstly to focus on the current use of widely available biomarkers and their performance for identifying ≥F3. Secondly, we discuss whether noninvasive biomarkers have a role in identifying F2, a stage of fibrosis that is now known to be a risk factor for cirrhosis and overall mortality. We also consider whether machine learning algorithms offer a better alternative for identifying individuals with ≥F2 fibrosis. Thirdly, we summarise the utility of noninvasive serum biomarkers for predicting liver related outcomes (e.g., ascites and hepatocellular carcinoma) and non-liver related outcomes (e.g., cardiovascular-related mortality and extra hepatic cancers). Finally, we examine whether serial measurement of biomarkers can be used to monitor liver disease, and whether the use of noninvasive biomarkers in drug trials for non-alcoholic steatohepatitis can accurately, compared to liver histology, monitor liver fibrosis progression/regression. We conclude by offering our perspective on the future of serum biomarkers for the detection and monitoring of liver fibrosis in NAFLD.

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Original Article

Decreased vitamin D-binding protein level portends poor outcome in acute-on-chronic liver failure caused by hepatitis B virus: Daxian Wu, Qunfang Rao, Zhongyang Xie, Xiaoqing Zhu, Yuanmei Che, Jian Wu, Hainv Gao, Jingyu Zhang, Zhouhua Hou, Xiaoyu Cheng, Zeyu Sun; Clin Mol Hepatol 2022;28(4):912-925.
Published online July 28, 2022; DOI: https://doi.org/10.3350/cmh.2022.0121

Background/Aims
Acute-on-chronic liver failure (ACLF) is a catastrophic illness. Few studies investigated the prognostic value of vitamin D-binding protein (VDBP) for hepatitis B virus (HBV)-related ACLF (HBV-ACLF) resulted in conflicting results.
Methods
Two prospective HBV-ACLF cohorts (n=287 and n=119) were enrolled to assess and validate the prognostic performance of VDBP.
Results
VDBP levels in the non-survivors were significantly lower than in the survivors (P<0.001). Multivariate Cox regression demonstrated that VDBP was an independent prognostic factor for HBV-ACLF. The VDBP level at admission gradually decreased as the number of failed organs increased (P<0.001), and it was closely related to coagulation failure. The areas under the receiver operating characteristic curve (AUCs) of the Child-Pugh-VDBP and chronic liver failuresequential organ failure assessment (CLIF–SOFA)-VDBP scores were significantly higher than those of Child-Pugh (P<0.001) and CLIF-SOFA (P=0.0013). The AUCs of model for end-stage liver disease (MELD)-VDBP were significantly higher than those of MELD (P= 0.0384) only in the case of cirrhotic HBV-ACLF patients. Similar results were validated using an external multicenter HBV-ACLF cohort. By longitudinal observation, the VDBP levels gradually increased in survivors (P=0.026) and gradually decreased in non-survivors (P<0.001). Additionally, the VDBP levels were found to be significantly decreased in the deterioration group (P=0.012) and tended to be decreased in the fluctuation group (P=0.055). In contrast, they showed a significant increase in the improvement group (P=0.036).
Conclusions
The VDBP was a promising prognostic biomarker for HBV-ACLF. Sequential measurement of circulating VDBP shows value for the monitoring of ACLF progression.

Citations

Citations to this article as recorded by

Vitamin D deficiency in chronic hepatitis B across the disease spectrum: association with viral activity rather than hepatocellular carcinoma
Dr Tufael, Abu Bakar Siddique, Md Haroon Or Rashid, Mohd Hasan Mujahid, Nabil Deb Nath, Asim Debnath, Most Farhana Akter, Md. Robiul Islam, Vijay Jagdish Upadhye
BMC Gastroenterology.2026;[Epub] CrossRef
Integrated routine laboratory indices for risk stratification in HBV-related cirrhosis: a real-world study
Lin Zhang, Liang Li, Xiaowei Du, Suhua Pang, Youde Yan, Zhenjiang Zhang
BMC Gastroenterology.2026;[Epub] CrossRef
Omics in acute‐on‐chronic liver failure
Peng Li, Xi Liang, Jinjin Luo, Jun Li
Liver International.2025;[Epub] CrossRef
Deficiency of vitamin D-binding protein exacerbates liver fibrosis by disrupting iron homeostasis via the activation of YAP signaling
Qing Zheng, Qingquan Tan, Dan Wang, Yanling Ma, Yanni Zhou, Yonghua Chen, Dan Long, Jiayin Yang, Li Feng
Experimental Cell Research.2025; 452(2): 114767. CrossRef
miR-223-3p predicts prognosis of hepatitis B virus-related acute-on-chronic liver failure and is involved in hepatocyte injury via HSP90B1
Feiyue Xie, Qiuping Ren, Jun He, Menghang Wu
Hereditas.2025;[Epub] CrossRef

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Editorial

A crystal ball to forecast treatment responsiveness in nonalcoholic fatty liver disease: Seonghwan Hwang, Won Kim; Clin Mol Hepatol 2022;28(3):478-480.
Published online June 16, 2022; DOI: https://doi.org/10.3350/cmh.2022.0143

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Original Article

Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial: Ju Hee Oh, Dae Won Jun, Hye Young Kim, Seung Min Lee, Eileen L. Yoon, Jungwook Hwang, Jung Hwan Park, Hanbi Lee, Wankyu Kim, Hyunsung Kim; Clin Mol Hepatol 2022;28(3):497-509.
Published online April 28, 2022; DOI: https://doi.org/10.3350/cmh.2022.0019

Background/Aims
We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD).
Methods
An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy.
Results
DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels.
Conclusions
The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

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Review

Viral hepatitis

Three heads are better than two: Hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma: Jer-Wei Wu, Jia-Horng Kao, Tai-Chung Tseng; Clin Mol Hepatol 2021;27(4):524-534.
Published online February 23, 2021; DOI: https://doi.org/10.3350/cmh.2021.0012

Abstract
PDF

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naïve HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatmentnaïve cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naïve patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients.

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Artificial intelligence, epidemiology, methodology, or others

Serum milk fat globule-EGF factor 8 protein as a potential biomarker for metabolic syndrome: Han Ah Lee, Jihwan Lim, Hyung Joon Joo, Young-Sun Lee, Young Kul Jung, Ji Hoon Kim, Hyunggin An, Hyung Joon Yim, Yoon Tae Jeen, Jong Eun Yeon, Do-Sun Lim, Kwan Soo Byun, Yeon Seok Seo; Clin Mol Hepatol 2021;27(3):463-473.
Published online February 15, 2021; DOI: https://doi.org/10.3350/cmh.2020.0351

Background/Aims
Useful biomarkers for metabolic syndrome have been insufficient. We investigated the performance of serum milk fat globule-EGF factor-8 (MFG-E8), the key mediator of inflammatory pathway, in diagnosis of metabolic syndrome.
Methods
Subjects aged between 30 and 64 years were prospectively enrolled in the Seoul Metabolic Syndrome cohort. Serum MFG-E8 levels were measured at baseline.
Results
A total of 556 subjects were included, comprising 279 women (50.2%) and 277 men (49.8%). Metabolic syndrome was diagnosed in 236 subjects (42.4%), and the mean MFG-E8 level of subjects with metabolic syndrome was significantly higher than that of subjects without metabolic syndrome (P<0.001). MFG-E8 level was significantly correlated with all metabolic syndrome components and pulse wave velocity (all P<0.05). Subjects were categorized into two groups according to the best MFG-E8 cut-off value as follows: group 1, MFG-E8 level <4,745.1 pg/mL (n=401, 72.1%); and group 2, MFG-E8 level ≥4,745.1 (n=155, 27.9%). At baseline, metabolic syndrome in group 2 was significantly more prevalent than in group 1 (63.9% vs. 34.2%, P<0.001). During median follow-up of 17 months, metabolic syndrome developed in 122 (38.1%) subjects among 320 subjects without it at baseline. The incidence of metabolic syndrome in group 2 was significantly higher than that in group 1 (55.4% vs. 34.5%, P=0.003). On multivariate analysis, MFG-E8 level ≥4,745.1 pg/mL was an independent predictor for diagnosis and development of metabolic syndrome after adjusting other factors (all P<0.05).
Conclusions
Serum MFG-E8 level is a potent biomarker for the screening and prediction of metabolic syndrome.

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Adipose tissue–derived MFG-E8 promotes hepatic inflammation and fibrosis through macrophage activation in a mouse MASH model
Masashi Kuroda, Kazuhiro Nomura, Azumi Wada, Yui Hatano, Miki Ogawa, Saya Okamoto, Etsuko Ishikawa, Yuna Izumi-Mishima, Sonoko Yasui-Yamada, Yasuo M. Tsutsumi, Nagakatsu Harada, Rie Tsutsumi, Hiroshi Sakaue
npj Metabolic Health and Disease.2026;[Epub] CrossRef
Exploring the potential of MFG-E8 in neurodegenerative diseases
Dan Li, Wang Rongchun, Weihong Lu, Ying Ma
Critical Reviews in Food Science and Nutrition.2025; 65(28): 5565. CrossRef
Signature gene expression model for quantitative evaluation of MASH-like liver injury in mice
Volodymyr P. Tryndyak, Rose A. Willett, Zhuolin Song, Kostiantyn Dreval, Jennifer M. Hughes Hanks, Mark I. Avigan, Fred A. Wright, Frederick A. Beland, Ivan Rusyn, Igor P. Pogribny
Toxicology and Applied Pharmacology.2025; 502: 117442. CrossRef
Elevated circulating HHIP levels in patients with metabolic syndrome
Jingwei Lei, Yu Yang, Yerui Lai, Dongfang Liu, Cong Wang, Weiwei Xu, Ke Li, Shengbing Li, Mengliu Yang, Ling Li
Biochemical and Biophysical Research Communications.2024; 736: 150877. CrossRef
MFGE-8 identified in fetal mesenchymal-stromal-cell-derived exosomes ameliorates acute hepatic failure pathology
Adriana Psaraki, Dimitra Zagoura, Lydia Ntari, Manousos Makridakis, Christina Nikokiraki, Ourania Trohatou, Konstantina Georgila, Christos Karakostas, Ioanna Angelioudaki, Anastasios G. Kriebardis, Roberto Gramignioli, Stratigoula Sakellariou, Maria Xilou
iScience.2023; 26(11): 108100. CrossRef
Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD
Rania Dagher, Paul Fogel, Jingya Wang, David Soussan, Chia-Chien Chiang, Jennifer Kearley, Daniel Muthas, Camille Taillé, Patrick Berger, Arnaud Bourdin, Cécile Chenivesse, Sylvie Leroy, Gary Anderson, Alison A. Humbles, Michel Aubier, Roland Kolbeck, Mar
PLOS ONE.2022; 17(12): e0277357. CrossRef

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Hepatic neoplasm

Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: Hye Soo Kim, Seung Up Kim, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Young Nyun Park, Dai Hoon Han, Kyung Sik Kim, Jin Sub Choi, Gi Hong Choi, Hyon-Suk Kim; Clin Mol Hepatol 2020;26(1):33-44.
Published online June 27, 2019; DOI: https://doi.org/10.3350/cmh.2018.0073

Background/Aims
To investigate whether serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA⁺-M2BP) can predict the recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection.
Methods
Patients with chronic hepatitis B (CHB) who underwent curative resection for HCC between 2004 and 2015 were eligible for the study. Recurrence was sub-classified as early (<2 years) or late (≥2 years).
Results
A total of 170 patients with CHB were selected. During the follow-up period (median, 22.6 months), 64 (37.6%) patients developed recurrence. In multivariate analyses, WFA⁺-M2BP level was an independent predictor of overall (hazard ratio [HR]=1.490), early (HR=1.667), and late recurrence (HR=1.416), together with male sex, des-gamma carboxyprothrombin level, maximal tumor size, portal vein invasion, and satellite nodules (all P<0.05). However, WFA⁺- M2BP level was not predictive of grade B-C posthepatectomy liver failure. The cutoff value that maximized the sum of sensitivity (30.2%) and specificity (90.6%) was 2.14 (area under receiver operating characteristic curve=0.632, P=0.010). Patients with a WFA⁺-M2BP level >2.14 experienced recurrence more frequently than those with a WFA⁺-M2BP level ≤2.14 (P=0.011 by log-rank test), and had poorer postoperative outcomes than those with a WFA⁺-M2BP level ≤2.14 in terms of overall recurrence (56.0 vs. 34.5%, P=0.047) and early recurrence (52.0 vs. 20.7%, P=0.001).
Conclusions
WFA⁺-M2BP level is an independent predictive factor of HBV-related HCC recurrence after curative resection. Further studies should investigate incorporation of WFA⁺-M2BP level into tailored postoperative surveillance strategies for patients with CHB.

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Citations to this article as recorded by

Glycomics as prognostic biomarkers of hepatocellular carcinoma: A systematic review
Nicky Somers, Emma Butaye, Lorenz Grossar, Nele Pauwels, Anja Geerts, Sarah Raevens, Sander Lefere, Lindsey Devisscher, Leander Meuris, Nico Callewaert, Hans Van Vlierberghe, Xavier Verhelst
Oncology Letters.2024;[Epub] CrossRef
Prognostic value of preoperative systemic immune-inflammation index/albumin for patients with hepatocellular carcinoma undergoing curative resection
Kun-Lin Chen, Yi-Wen Qiu, Ming Yang, Tao Wang, Yi Yang, Hai-Zhou Qiu, Ting Sun, Wen-Tao Wang
World Journal of Gastroenterology.2024; 30(48): 5130. CrossRef
Post-operative recurrence of liver cancer according to antiviral therapy for detectable hepatitis B viremia: A nationwide study
Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin-Ha Yoon, Beom Kyung Kim
European Journal of Internal Medicine.2023; 107: 66. CrossRef
Comparable Mortality Between Asian Patients with Chronic Hepatitis B Under Long-Term Antiviral Therapy vs Matched Control: A Population-Based Study
Byungyoon Yun, Juyeon Oh, Sang Hoon Ahn, Jin-Ha Yoon, Beom Kyung Kim
American Journal of Gastroenterology.2023; 118(6): 1001. CrossRef
Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis
Daniel Q. Huang, Nobuharu Tamaki, Hyung Woong Lee, Soo Young Park, Yu Rim Lee, Hye Won Lee, Seng Gee Lim, Tae Seop Lim, Masayuki Kurosaki, Hiroyuki Marusawa, Toshie Mashiba, Masahiko Kondo, Yasushi Uchida, Haruhiko Kobashi, Koichiro Furuta, Namiki Izumi,
Hepatology.2023; 77(5): 1746. CrossRef
Perioperative predictors of outcome of hepatectomy for HBV-related hepatocellular carcinoma
Ziming He, Di Tang
Frontiers in Oncology.2023;[Epub] CrossRef
Serum wisteria floribunda agglutinin-positive human Mac-2 binding protein is unsuitable as a diagnostic marker of occult hepatocellular carcinoma in end-stage liver cirrhosis
Kantoku Nagakawa, Masaaki Hidaka, Takanobu Hara, Hajime Matsushima, Hajime Imamura, Takayuki Tanaka, Tomohiko Adachi, Akihiko Soyama, Kengo Kanetaka, Susumu Eguchi, Jincheng Wang
PLOS ONE.2023; 18(11): e0293593. CrossRef
Validation of PH and Varices Risk Scores for Prediction of High-Risk Esophageal Varix and Bleeding in Patients with B-Viral Cirrhosis
Seunghwan Shin, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Beom Kyung Kim
Diagnostics.2022; 12(2): 441. CrossRef
Mac-2 binding protein glycosylation isomer (M2BPGi) to evaluate liver fibrosis and cancer in HBV-infected patients in West Africa
Jeanne Perpétue Vincent, Gibril Ndow, Shintaro Ogawa, Amie Ceesay, Ramou Njie, Bakary Sanneh, Ignatius Baldeh, Umberto D’Alessandro, Maimuna Mendy, Mark Thursz, Isabelle Chemin, Yasuhito Tanaka, Maud Lemoine, Yusuke Shimakawa
Journal of Global Health.2022;[Epub] CrossRef
A Mac-2 Binding Protein Glycosylation Isomer-Based Risk Model Predicts Hepatocellular Carcinoma in HBV-Related Cirrhotic Patients on Antiviral Therapy
Chien-Hung Chen, Tsung-Hui Hu, Jing-Houng Wang, Hsueh-Chou Lai, Chao-Hung Hung, Sheng-Nan Lu, Cheng-Yuan Peng
Cancers.2022; 14(20): 5063. CrossRef
External validation of CAGE‐B and SAGE‐B scores for Asian chronic hepatitis B patients with well‐controlled viremia by antivirals
Jung Hyun Ji, Soo Young Park, Won Jeong Son, Hye Jung Shin, Hyein Lee, Hye Won Lee, Jae Seung Lee, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Beom Kyung Kim
Journal of Viral Hepatitis.2021; 28(6): 951. CrossRef
Treatment efficacy by hepatic arterial infusion chemotherapy vs. sorafenib after liver-directed concurrent chemoradiotherapy for advanced hepatocellular carcinoma
Sojung Han, Hye Jin Choi, Seung-Hoon Beom, Hye Rim Kim, Hyein Lee, Jae Seung Lee, Hye Won Lee, Jun Yong Park, Seung Up Kim, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Jinsil Seong, Jong Yun Won, Beom Kyung Kim
Journal of Cancer Research and Clinical Oncology.2021; 147(10): 3123. CrossRef
Effect of tenofovir alafenamide vs. tenofovir disoproxil fumarate on hepatocellular carcinoma risk in chronic hepatitis B
Hye Won Lee, Young Youn Cho, Hyein Lee, Jae Seung Lee, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Beom Kyung Kim, Soo Young Park
Journal of Viral Hepatitis.2021; 28(11): 1570. CrossRef
Novel Liver Stiffness-Based Nomogram for Predicting Hepatocellular Carcinoma Risk in Patients with Chronic Hepatitis B Virus Infection Initiating Antiviral Therapy
Jae Seung Lee, Hyun Woong Lee, Tae Seop Lim, Hye Jung Shin, Hye Won Lee, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Beom Kyung Kim
Cancers.2021; 13(23): 5892. CrossRef
Usefulness of Mac-2 binding protein glycosylation isomer in non-invasive probing liver disease in the Vietnamese population
Thuy Thi Thu Pham, Dat Tan Ho, Toan Nguyen
World Journal of Hepatology.2020; 12(5): 210. CrossRef
Wisteria floribunda agglutinin-positive Mac-2-binding protein as a diagnostic biomarker in liver cirrhosis: an updated meta-analysis
Shu Feng, Zhonghao Wang, Yanhua Zhao, Chuanmin Tao
Scientific Reports.2020;[Epub] CrossRef
Novel biomarkers for the management of chronic hepatitis B
Takako Inoue, Yasuhito Tanaka
Clinical and Molecular Hepatology.2020; 26(3): 261. CrossRef

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