Hepatocellular Carcinoma and Hepatitis: Advanced Diagnosis and Management

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 6665

Special Issue Editors


E-Mail Website
Guest Editor
Kobe Asahi Hospital, Kobe, Japan
Interests: hepatocellular carcinoma; hepatitis C virus; liver disease

E-Mail Website
Guest Editor
Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Japan
Interests: hepatitis B virus; NASH

Special Issue Information

Dear Colleagues, 

Although the universal hepatitis B virus (HBV) vaccination program has been successfully implemented for almost three decades in many countries, most HBV-related hepatocellular carcinomas (HCCs) occur in unvaccinated middle-aged and elderly adults. It has been simulated that treating 80% of eligible people could reduce HBV-related deaths by 65% in a short time. However, only 2.2% of CHB patients receive antiviral therapies globally. HBV markers related to HCC occurrence and prevention are as follows. HCC risk is highest with a baseline HBV DNA 6–7 log copies/mL and lowest with a baseline HBV DNA level > 8 log copies/mL and ≤ 4 log copies/mL. (not linear but parabolic pattern). The titer of HBV core-related antigen (HBcrAg) reflecting the amount of HBV covalently closed circular DNA (ccc DNA) in the liver is related to HCC occurrence. Sero clearance of HBs antigen (HBsAg) is more crucial than HBV DNA negativity for the prevention of HCC. In terms of secondary prevention of hepatitis B-related HCC with antiviral therapies with nucleos(t)ide analogues (NAs), there are still unsolved discussions including the definition of the immune-tolerant phase, the optimal time to start the antiviral therapies with NAs, limitations of elevated aminotransferase (ALT) level as a criterion for treatment in CHB patients, normalization of ALT with NAs and risk of HCC, and serum HBV levels and the risk of HCC. In addition, the first-line therapies with NAs such as entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) remains to be clarified. Therefore, we discuss recent findings of HBV markers related to HCC occurrence and prevention, and unsolved discussions and review the secondary current antiviral therapies for the prevention of HBV-related HCC.

Dr. Soo Ryang Kim
Dr. Soo Ki Kim
Guest Editors

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Keywords

  • hepatitis B virus
  • hepatocellular carcinoma
  • nucleos(t)ide analogues
  • secondly prevention
  • HBV DNA
  • immune-tolerant phase
  • hepatitis B virus surface antigen
  • hepatitis B virus core-related antigen
  • covalently closed circular DNA

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Published Papers (5 papers)

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Research

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13 pages, 2396 KiB  
Article
Evaluation of a Ten-Antigen Immunodot Test in Autoimmune Hepatitis and Primary Biliary Cholangitis: Lessons Learned for a Tertiary Care Academic Hospital
by Giulia Zorzi, Perrin Ngougni Pokem, Geraldine Dahlqvist, Bénédicte Délire, Nicolas Lanthier, Peter Starkel, Yves Horsmans, Cedric Aupaix, Samia Jnaoui and Damien Gruson
Diagnostics 2024, 14(17), 1882; https://doi.org/10.3390/diagnostics14171882 - 28 Aug 2024
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Abstract
Autoimmune diseases of the liver and biliary tract require timely and accurate diagnosis. This study evaluates the D-tek panel (D-Tek, Mons, Belgium) of 10 immunodot antigens for its effectiveness in diagnosing autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). We retrospectively analysed serum [...] Read more.
Autoimmune diseases of the liver and biliary tract require timely and accurate diagnosis. This study evaluates the D-tek panel (D-Tek, Mons, Belgium) of 10 immunodot antigens for its effectiveness in diagnosing autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). We retrospectively analysed serum samples from 111 patients who had undergone routine testing, including indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISA), to confirm or exclude autoimmune liver or biliary tract disease. The panel tested for M2/nPDC, M2/OGDC-E2, M2/BCOADC-E2, M2/PDC-E2, gp210, sp100, LKM1, LC1, SLA, and F-actin antigens. Results showed that all positive IIF+ELISA results were confirmed by the immunodot panel, except for two samples from patients who had never been diagnosed with AIH. The immunodot test identified over 20 additional autoantibodies in samples initially negative by IIF, corroborated by laboratory imaging and medical history. The immunodot technique proved to be a quick, sensitive, and specific method with high overall accuracy. This study suggests that the immunodot technique may be an effective screening and confirmatory method for autoimmune liver diseases, potentially improving diagnostic efficiency and accuracy in clinical practice. Full article
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9 pages, 1321 KiB  
Article
AI Digital Pathology Using qFibrosis Shows Heterogeneity of Fibrosis Regression in Patients with Chronic Hepatitis B and C with Viral Response
by Feng Liu, Yameng Sun, Dean Tai, Yayun Ren, Elaine L. K. Chng, Aileen Wee, Pierre Bedossa, Rui Huang, Jian Wang, Lai Wei, Hong You and Huiying Rao
Diagnostics 2024, 14(16), 1837; https://doi.org/10.3390/diagnostics14161837 - 22 Aug 2024
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Abstract
This study aimed to understand the dynamic changes in fibrosis and its relationship with the evaluation of post-treatment viral hepatitis using qFibrosis. A total of 158 paired pre- and post-treatment liver samples from patients with chronic hepatitis B (CHB; n = 100) and [...] Read more.
This study aimed to understand the dynamic changes in fibrosis and its relationship with the evaluation of post-treatment viral hepatitis using qFibrosis. A total of 158 paired pre- and post-treatment liver samples from patients with chronic hepatitis B (CHB; n = 100) and C (CHC; n = 58) were examined. qFibrosis was employed with artificial intelligence (AI) to analyze the fibrosis dynamics in the portal tract (PT), periportal (PP), midzonal, pericentral, and central vein (CV) regions. All patients with CHB achieved a virological response after 78 weeks of treatment, whereas patients with CHC achieved a sustained viral response after 24 weeks. For patients initially staged as F5/6 (Ishak system) at baseline, the post-treatment cases exhibited a significant reduction in the collagen proportionate area (CPA) (25–69%) and number of collagen strings (#string) (9–72%) across all regions. In contrast, those initially staged as F3/4 at baseline showed a similar CPA and #string trend at 24 weeks. For regression patients, 27 parameters (25 in the CV region) in patients staged as F3/4 and 15 parameters (three in the PT and 12 in the PP regions) in those staged as F5/6 showed significant differences between the CHB and CHC groups at baseline. Following successful antiviral treatment, the pre- and post-treatment liver samples provided quantitative evidence of the heterogeneity of fibrotic features. qFibrosis has the potential to provide new insights into the characteristics of fibrosis regression in both patients with CHB and CHC as early as 24 weeks after antiviral therapy. Full article
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12 pages, 1553 KiB  
Article
Risk Factors for Immune Checkpoint Inhibitor-Induced Liver Injury and the Significance of Liver Biopsy
by Miki Kawano, Yoshihiko Yano, Atsushi Yamamoto, Eiichiro Yasutomi, Yuta Inoue, Jun Kitadai, Ryutaro Yoshida, Takanori Matsuura, Yuuki Shiomi, Yoshihide Ueda and Yuzo Kodama
Diagnostics 2024, 14(8), 815; https://doi.org/10.3390/diagnostics14080815 - 14 Apr 2024
Viewed by 1019
Abstract
Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to [...] Read more.
Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to the classification of ICI-induced LI. In total, 254 ICI-induced LI patients among 1086 treated with ICIs between September 2014 and March 2022 were classified according to the diagnostic criteria for drug-induced LI (DILI), and their risk factors and outcomes were evaluated. Kaplan–Meier analyses showed that overall survival in patients with hepatocellular-injury-type LI was significantly longer than others (p < 0.05). Regarding pre-treatment factors, the lymphocyte count was significantly higher in patients with ICI-induced LI, especially in hepatocellular-injury-type LI. Gamma glutamyl transferase (γGTP) and alkaline phosphatase (ALP) were also significantly lower in patients with ICI-induced LI (p < 0.05). Multivariate analyses revealed that malignant melanoma, high lymphocyte count, and low ALP levels were extracted as factors contributing to hepatocellular-injury-type LI. The histological findings among 37 patients diagnosed as ICI-induced LI via liver biopsy also revealed that the spotty/focal necrosis was significantly frequent in hepatocellular-injury-type LI, whereas ductular reactions were frequently observed in cholestatic-type LI. It is suggested that the histological inflammation pattern in patients with LI is closely correlated with the type of DILI. Full article
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Review

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14 pages, 301 KiB  
Review
Clinical Significance and Remaining Issues of Anti-HBc Antibody and HBV Core-Related Antigen
by Yoshihiko Yano, Itsuko Sato, Takamitsu Imanishi, Ryutaro Yoshida, Takanori Matsuura, Yoshihide Ueda and Yuzo Kodama
Diagnostics 2024, 14(7), 728; https://doi.org/10.3390/diagnostics14070728 - 29 Mar 2024
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Abstract
Currently, hepatitis B virus (HBV) core antibody (anti-HBc antibody) and HBV core-related antigen (HBcrAg) are widely used as serum markers for diagnosis based on the HBV core region. This review focused on anti-HBc antibodies and HBcrAg and aimed to summarize the clinical significance [...] Read more.
Currently, hepatitis B virus (HBV) core antibody (anti-HBc antibody) and HBV core-related antigen (HBcrAg) are widely used as serum markers for diagnosis based on the HBV core region. This review focused on anti-HBc antibodies and HBcrAg and aimed to summarize the clinical significance of currently used assay systems and the issues involved. While anti-HBc is very significant for clinical diagnosis, the clinical significance of quantitative assay of anti-HBc antibody has been reevaluated with improvements in diagnostic performance, including its association with clinical stage and prediction of carcinogenesis and reactivation. In addition, concerning the new HBcrAg, a high-sensitivity assay method has recently been established, and its diagnostic significance, including the prediction of reactivation, is being reevaluated. On the other hand, the quantitative level of anti-HBc antibody expressed in different units among assay systems complicates the interpretation of the results. However, it is difficult to standardize assay systems as they vary in advantages, and caution is needed in interpreting the assay results. In conclusion, with the development of highly sensitive HBcrAg and anti-HBc antibody, a rapid and sensitive detection assay system has been developed and used in clinical practice. In the future, it is hoped that a global standard will be created based on the many clinical findings. Full article
14 pages, 316 KiB  
Review
Hepatocellular Carcinoma and Hepatitis: Advanced Diagnosis and Management with a Focus on the Prevention of Hepatitis B-Related Hepatocellular Carcinoma
by Soo Ryang Kim and Soo Ki Kim
Diagnostics 2023, 13(20), 3212; https://doi.org/10.3390/diagnostics13203212 - 14 Oct 2023
Cited by 1 | Viewed by 1602
Abstract
Though the world-wide hepatitis B virus (HBV) vaccination program has been well completed for almost thirty years in many nations, almost HBV-related hepatocellular carcinoma (HCC) occurs in unvaccinated middle-aged and elderly adults. Apparently, treating 80% of qualified subjects could decrease HBV-related mortality by [...] Read more.
Though the world-wide hepatitis B virus (HBV) vaccination program has been well completed for almost thirty years in many nations, almost HBV-related hepatocellular carcinoma (HCC) occurs in unvaccinated middle-aged and elderly adults. Apparently, treating 80% of qualified subjects could decrease HBV-related mortality by 65% in a short period. Nevertheless, globally, only 2.2% of CHB patients undergo antiviral therapy. The HBV markers related to HCC occurrence and prevention are as follows: the HCC risk is the highest at a baseline of HBV DNA of 6–7 log copies/mL, and it is the lowest at a baseline of an HBV DNA level of >8 log copies/mL and ≤4 log copies/mL (parabolic, and not linear pattern). The titer of an HBV core-related antigen (HBcrAg) reflecting the amount of HBV covalently closed circular DNA (ccc DNA) in the liver is related to HCC occurrence. The seroclearance of HBs antigen (HBsAg) is more crucial than HBV DNA negativity for the prevention of HCC. In terms of the secondary prevention of hepatitis B-related HCC involving antiviral therapies with nucleos(t)ide analogues (NAs), unsolved issues include the definition of the immune-tolerant phase; the optimal time for starting antiviral therapies with NAs; the limits of increased aminotransferase (ALT) levels as criteria for therapy in CHB patients; the normalization of ALT levels with NAs and the relation to the risk of HCC; and the relation between serum HBV levels and the risk of HCC. Moreover, the first-line therapy with NAs including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) remains to be clarified. Discussed here, therefore, are the recent findings of HBV markers related to HCC occurrence and prevention, unsolved issues, and the current secondary antiviral therapy for the prevention of HBV-related HCC. Full article
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