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Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 July 2020) | Viewed by 18801

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Special Issue Editor

Dr. Hirayuki Enomoto

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Guest Editor

Division of Hepatobiliary and Pancreatic Diseases, Department of Gastroenterology, Hyogo Medical University, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan
Interests: viral hepatitis; liver cirrhosis; portal hypertension; ascites; esophageal varices; liver fibrosis; hepatocellular carcinoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic liver diseases develop by a wide range of causes, including hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcoholic-related liver disease, non-alcoholic fatty liver disease (NAFLD), and autoimmune liver diseases.

Recent advances in molecular and cellular techniques have succeeded in providing new aspects in the diagnosis and treatment of chronic liver diseases.

This Special Issue aims to cover the state-of-the-art researches on chronic liver diseases. We invite authors to submit original articles, as well as review articles regarding recent findings about chronic liver diseases. We are particularly interested in molecular approaches for the diagnosis and treatment of chronic liver diseases. Potential topics include, but are not limited to:

Biomarkers for chronic liver diseases
Genomic researches for chronic liver diseases, including gene SNPs (Single Nucleotide Polymorphisms)
Molecular mechanisms of chronic liver diseases
Recent advances in the management of chronic liver diseases, including liver cirrhosis
Molecularly-targeted therapy for liver cancer

Dr. Hirayuki Enomoto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Biomarker
Genomic research
Molecular mechanisms
Viral hepatitis
Alcoholic-related liver disease
Non-alcoholic fatty liver disease
Autoimmune liver diseases
Liver cirrhosis
Hepatocellular carcinoma

Published Papers (7 papers)

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Research

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14 pages, 2798 KiB

Open AccessArticle

Inhibitory Effect of a Human MicroRNA, miR-6133-5p, on the Fibrotic Activity of Hepatic Stellate Cells in Culture

by Susumu Hamada-Tsutsumi, Masaya Onishi, Kentaro Matsuura, Masanori Isogawa, Keigo Kawashima, Yusuke Sato and Yasuhito Tanaka

Int. J. Mol. Sci. 2020, 21(19), 7251; https://doi.org/10.3390/ijms21197251 - 1 Oct 2020

Cited by 10 | Viewed by 2663

Abstract

Background: We recently identified 39 human microRNAs, which effectively suppress hepatitis B virus (HBV) replication in hepatocytes. Chronic HBV infection often results in active, hepatitis-related liver fibrosis; hence, we assessed whether any of these microRNAs have anti-fibrotic potential and predicted that miR-6133-5p may target several fibrosis-related genes. Methods: The hepatic stellate cell line LX-2 was transfected with an miR-6133-5p mimic and subsequently treated with Transforming growth factor (TGF)-β. The mRNA and protein products of the COL1A1 gene, encoding collagen, and the ACTA2 gene, an activation marker of hepatic stellate cells, were quantified. Results: The expression of COL1A1 and ACTA2 was markedly reduced in LX-2 cells treated with miR-6133-5p. Interestingly, phosphorylation of c-Jun N-terminal kinase (JNK) was also significantly decreased by miR-6133-5p treatment. The expression of several predicted target genes of miR-6133-5p, including TGFBR2 (which encodes Transforming Growth Factor Beta Receptor 2) and FGFR1 (which encodes Fibroblast Growth Factor Receptor 1), was also reduced in miR-6133-5p-treated cells. The knockdown of TGFBR2 by the corresponding small interfering RNA greatly suppressed the expression of COL1A1 and ACTA2. Treatment with the JNK inhibitor, SP600125, also suppressed COL1A1 and ACTA2 expression, indicating that TGFBR2 and JNK mediate the anti-fibrotic effect of miR-6133-5p. The downregulation of FGFR1 may result in a decrease of phosphorylated Akt, ERK (extracellular signal-regulated kinase), and JNK. Conclusion: miR-6133-5p has a strong anti-fibrotic effect, mediated by inactivation of TGFBR2, Akt, and JNK. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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13 pages, 2264 KiB

Open AccessArticle

Clusters of Circulating let-7 Family Tumor Suppressors Are Associated with Clinical Characteristics of Chronic Hepatitis C

by Yi-Shan Tsai, Ming-Lun Yeh, Pei-Chien Tsai, Ching-I Huang, Chung-Feng Huang, Meng-Hsuan Hsieh, Ta-Wei Liu, Yi-Hung Lin, Po-Cheng Liang, Zu-Yau Lin, Shinn-Cherng Chen, Jee-Fu Huang, Wan-Long Chuang, Chia-Yen Dai and Ming-Lung Yu

Int. J. Mol. Sci. 2020, 21(14), 4945; https://doi.org/10.3390/ijms21144945 - 13 Jul 2020

Cited by 9 | Viewed by 2285

Abstract

Hepatitis C virus (HCV) infections can cause permanent liver-related diseases, including hepatocellular carcinoma (HCC). Low mortality and incidence of HCC have been observed in patients with chronic hepatitis C undergoing direct-acting antiviral therapy. Tumor suppressive let-7 family members are down-regulated in HCC. The present study, therefore, aimed to investigate whether expression levels for the full spectrum of let-7 family members (let-7a, 7b, 7c, 7d, 7e, 7f, 7g, 7i, and miR-98) in the circulatory system are useful as surveillance biomarkers for liver-related diseases to monitor treatment efficacy during HCV infection. To this end, we measured the levels of mature circulating let-7 family members using quantitative reverse transcription-PCR in 236 patients with HCV infection, and 147 age- and sex-matched controls. Using hierarchical cluster analysis and principal component analysis, three clusters were obtained after measuring expression levels of let-7 family members in the patients and controls. Cluster 1 included let-7a/d/e/g, Cluster 2 comprised let-7b and let-7i, and Cluster 3 comprised let-7c/f/miR-98. Let-7b/c/g represented the three clusters and showed the best survival response to liver cancer when analyzed with respect to patient data. Therefore, considering the circulating levels of let7 b/c/g as representatives of the let-7 family may facilitate effective monitoring of liver-related disease. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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16 pages, 2300 KiB

Open AccessArticle

Post-Treatment M2BPGi Level and the Rate of Autotaxin Reduction are Predictive of Hepatocellular Carcinoma Development after Antiviral Therapy in Patients with Chronic Hepatitis C

by Kazuya Takemura, Etsuko Takizawa, Akihiro Tamori, Mika Nakamae, Hiroshi Kubota, Sawako Uchida-Kobayashi, Masaru Enomoto, Norifumi Kawada and Masayuki Hino

Int. J. Mol. Sci. 2020, 21(12), 4517; https://doi.org/10.3390/ijms21124517 - 25 Jun 2020

Cited by 3 | Viewed by 2196

Abstract

Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70–0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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11 pages, 1495 KiB

Open AccessArticle

Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein but not α-fetoprotein as a Long-Term Hepatocellular Carcinoma Predictor

by Leona Osawa, Nobuharu Tamaki, Masayuki Kurosaki, Sakura Kirino, Keiya Watakabe, Wan Wang, Mao Okada, Takao Shimizu, Mayu Higuchi, Kenta Takaura, Hitomi Takada, Shun Kaneko, Yutaka Yasui, Kaoru Tsuchiya, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Nobuyuki Enomoto and Namiki Izumi

Int. J. Mol. Sci. 2020, 21(10), 3640; https://doi.org/10.3390/ijms21103640 - 21 May 2020

Cited by 6 | Viewed by 2328

Abstract

Identification of high-risk patients for hepatocellular carcinoma (HCC) after sustained virological responses (SVR) is necessary to define candidates for long-term surveillance. In this study, we examined whether serum markers after 1 year of SVR could predict subsequent HCC development. Total 734 chronic hepatitis C patients without a history of HCC who achieved SVR with direct-acting antivirals were included. The regular surveillance for HCC started from 24 weeks after the end of treatment (SVR24). Factors at SVR24 and 1 year after SVR24 were analyzed for predicting HCC development. During the mean observation period of 19.7 ± 10 months, 24 patients developed HCC. At SVR24, Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA±M2BP) ≥ 1.85 and α-fetoprotein (AFP) ≥ 6.0 ng/mL were independent factors of HCC development. However, at 1 year after SVR24, WFA±M2BP ≥ 1.85 was associated with subsequent HCC development (hazard ratio: 23.5, 95% confidence interval: 2.68–205) but not AFP. Among patients with WFA±M2BP ≥ 1.85 at SVR24, 42% had WFA±M2BP < 1.85 at 1 year after SVR24 (WFA±M2BP declined group). Subsequent HCC development was significantly lower in the declined group than in the non-declined group (1 year HCC rate: 0% vs. 9.4%, p = 0.04). In conclusion, WFA^±M2BP but not AFP could identify high and no-risk cases of HCC at 1 year after SVR. Therefore, it was useful as a real-time monitoring tool to identify the candidates for continuous surveillance for HCC. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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13 pages, 4799 KiB

Open AccessArticle

Form-Vessel Classification of Cholangioscopy Findings to Diagnose Biliary Tract Carcinoma’s Superficial Spread

by Yoshimitsu Fukasawa, Shinichi Takano, Mitsuharu Fukasawa, Shinya Maekawa, Makoto Kadokura, Hiroko Shindo, Ei Takahashi, Sumio Hirose, Satoshi Kawakami, Hiroshi Hayakawa, Tatsuya Yamaguchi, Yasuhiro Nakayama, Taisuke Inoue, Tadashi Sato and Nobuyuki Enomoto

Int. J. Mol. Sci. 2020, 21(9), 3311; https://doi.org/10.3390/ijms21093311 - 7 May 2020

Cited by 8 | Viewed by 2247

Abstract

We aimed to evaluate a newly developed peroral cholangioscopy (POCS) classification system by comparing classified lesions with histological and genetic findings. We analyzed 30 biopsied specimens from 11 patients with biliary tract cancer (BTC) who underwent POCS. An original classification of POCS findings was made based on the biliary surface’s form (F factor, 4 grades) and vessel structure (V-factor, 3 grades). Findings were then compared with those of corresponding biopsy specimens analyzed histologically and by next-generation sequencing to identify somatic mutations. In addition, the histology of postoperative surgical stumps and preoperative POCS findings were compared. Histological malignancy rate in biopsied specimens increased with increasing F- and V-factor scores (F1, 0%; F1, 25%; F3, 50%; F4, 62.5%; p = 0.0015; V1, 0%; V2, 20%; V3, 70%; p < 0.001). Furthermore, we observed a statistically significant increase of the mutant allele frequency of mutated genes with increasing F- and V-factor scores (F factor, p = 0.0050; V-factor, p < 0.001). All surgical stumps were accurately diagnosed using POCS findings. The F–V classification of POCS findings is both histologically and genetically valid and will contribute to the methods of diagnosing the superficial spread of BTC tumors. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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13 pages, 1091 KiB

Open AccessArticle

Possible Relevance of PNPLA3 and TLL1 Gene Polymorphisms to the Efficacy of PEG-IFN Therapy for HBV-Infected Patients

by Hirayuki Enomoto, Nobuhiro Aizawa, Kunihiro Hasegawa, Naoto Ikeda, Yoshiyuki Sakai, Kazunori Yoh, Ryo Takata, Yukihisa Yuri, Kyohei Kishino, Yoshihiro Shimono, Noriko Ishii, Tomoyuki Takashima, Takashi Nishimura, Hiroki Nishikawa, Yoshinori Iwata, Hiroko Iijima and Shuhei Nishiguchi

Int. J. Mol. Sci. 2020, 21(9), 3089; https://doi.org/10.3390/ijms21093089 - 27 Apr 2020

Cited by 7 | Viewed by 2474

Abstract

Lifestyle changes have led to an increase in the number of patients with nonalcoholic fatty liver disease (NAFLD). However, the effects of NAFLD-associated single-nucleotide gene polymorphisms (SNPs) in HBV-infected patients have not been adequately investigated. Methods: We investigated the association of the NAFLD-related SNPs patatin-like phospholipase domain-containing protein 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13; rs72613567, rs6834314 and rs62305723), membrane-bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) and glucokinase regulatory protein (GCKR; rs1260326) with the presence of histologically proven hepatic steatosis (HS) in HBV-infected patients (n = 224). We also investigated tolloid-like 1 (TLL1) SNP (rs17047200), which has been reported to be involved in the disease progression in Japanese NAFLD patients, and evaluated the association of HS and various SNPs with the treatment efficacy of pegylated-interferon (PEG-IFN) monotherapy following nucleotide/nucleoside (NA) treatment (NA/PEG-IFN sequential therapy; n = 64). Among NAFLD-associated SNPs evaluated, only the PNPLA3 SNP was significantly associated with the presence of hepatic steatosis in a total of 224 HBV-infected patients (P = 1.0 × 10⁻⁴). Regarding the sequential therapy, PNPLA3 SNP and TLL1 SNP were related to the treatment efficacy, and patients without minor alleles of these SNPs showed favorable results with a high virologic response and significant reduction in their HBsAg titer. A multivariate analysis showed that HBeAg positivity (odds ratio 5.810, p = 0.016) and the absence of a risk allele in PNPLA3 and TLL1 SNPs (odds ratio 8.664, p = 0.0042) were significantly associated with treatment efficacy. The PNPLA3 SNP might be associated with the presence of HS, and the combination of the PNPLA3 and TLL1 SNPs might be related to the efficacy of PEG-IFN monotherapy following NA treatment. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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Review

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18 pages, 731 KiB

Open AccessReview

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease

by Tatsuo Kanda, Reina Sasaki, Ryota Masuzaki, Hiroshi Takahashi, Taku Mizutani, Naoki Matsumoto, Kazushige Nirei and Mitsuhiko Moriyama

Int. J. Mol. Sci. 2020, 21(17), 6384; https://doi.org/10.3390/ijms21176384 - 2 Sep 2020

Cited by 8 | Viewed by 3642

Abstract

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk. Full article

(This article belongs to the Special Issue Recent Advances in the Diagnosis and Treatment of Chronic Liver Diseases)

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