Novel Challenges and Therapeutic Options for Liver Diseases

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Clinical Medicine, Cell, and Organism Physiology".

Deadline for manuscript submissions: closed (1 February 2024) | Viewed by 11730

Special Issue Editor

1. Professor Emeritus, Department of Gastroenterology and Hepatology, University Hospital, University of Duisburg-Essen, D-45122 Essen, Germany
2. Senior Consultant, Helios Klinikum Niederberg, 42549 Velbert, Germany
Interests: gastroenterology; hepatology; oncology; hepatitis; autoimmunity; transplantation; endoscopy; liver cirrhosis; hepatocellular carcinoma (HCC); cholangiocellular carcinoma (CCC)

Special Issue Information

Dear Colleagues,

Hepatic diseases rank among the biggest health concerns worldwide and are related to some of the most common causes of death. In Europe, acute and chronic hepatic diseases and their consequences are responsible for the second most common medical supply problem overall. The importance of early diagnosis and early treatment of different hepatic diseases, and their primary as well as secondary prevention, should be of first priority in Europe and across the world.

Thanks to scientific advances in the last three decades, there has been ground-breaking development in the diagnosis and therapy of hepatic diseases. Therefore, it is a great honour and pleasure for me to take the role of guest editor of this Special Issue, dedicated to new developments in the field of clinical and translational hepatology.

This Special Issue focuses on cutting-edge developments, from viral diseases via autoimmune, vascular, metabolic, and genetic disorders, through to liver cirrhosis and its consequent complications, such as acute and chronic hepatic failure and development of primary liver carcinoma.

In recent hepatology, it is becoming more and more important to integrate the advances afforded by digitalisation and translational research in the field.

Hepatology is characterised by excellent research outputs, both translational and on a basic level, in conjunction with prominent transversal competence and interdisciplinarity.

As such, topics such as therapeutic immunisation, cell-based tumour therapy, liver–gut interaction based on the microbiome, and precision medicine using the example of molecular profiling of tumours will be discussed.

Cutting-edge topics, such as artificial intelligence in medical technology and digitalisation in the development of the smart hospital, will be presented as well.

Primary and secondary prevention in hepatology is particularly important for early detection and early therapy, including examples such as check-up programmes, lifestyle changes, and the acquisition and processing of big data in order to generate new, globalised prevention studies. Especially important for the future of hepatology is the promotion, integration, and training of our young colleagues for clinical and basic research in the field.

As the guest editor of this Special Issue in clinical and translational hepatology, I hope that all interested readers will benefit from its insightful collegial discussions.

Finally, I would like to thank all our distinguished authors for their excellent contributions.

Prof. Dr. Guido Gerken
Guest Editor

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Keywords

  • hepatology
  • hepatitis
  • liver cancer
  • liver transplantation
  • liver cirrhosis
  • hepatocellular carcinoma (HCC)
  • autoimmune hepatitis
  • portal hypertension
  • metabolic syndrome
  • vaccination
  • digitalization
  • prevention

Published Papers (10 papers)

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Research

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12 pages, 643 KiB  
Article
Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrioR) of Chronically HBV Infected Patients
by Hedwig Roggendorf, Daniel Shouval, Michael Roggendorf and Guido Gerken
J. Pers. Med. 2024, 14(4), 364; https://doi.org/10.3390/jpm14040364 (registering DOI) - 29 Mar 2024
Abstract
Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) [...] Read more.
Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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14 pages, 3610 KiB  
Article
Influence of the Bile Acid Transporter Genes ABCB4, ABCB8, and ABCB11 and the Farnesoid X Receptor on the Response to Ursodeoxycholic Acid in Patients with Nonalcoholic Steatohepatitis
by Henriette Kreimeyer, Katharina Vogt, Tobias Götze, Jan Best, Oliver Götze, Jochen Weigt, Alisan Kahraman, Mustafa Özçürümez, Julia Kälsch, Wing-Kin Syn, Svenja Sydor, Ali Canbay and Paul Manka
J. Pers. Med. 2023, 13(7), 1180; https://doi.org/10.3390/jpm13071180 - 24 Jul 2023
Viewed by 1049
Abstract
The prevalence of NAFLD and NASH is increasing worldwide, and there is no approved medical treatment until now. Evidence has emerged that interfering with bile acid metabolism may lead to improvement in NASH. In this study, 28 patients with elevated cholestatic liver function [...] Read more.
The prevalence of NAFLD and NASH is increasing worldwide, and there is no approved medical treatment until now. Evidence has emerged that interfering with bile acid metabolism may lead to improvement in NASH. In this study, 28 patients with elevated cholestatic liver function tests (especially GGT) were screened for bile acid gene polymorphisms and treated with UDCA. All patients had a bile acid gene polymorphism in ABCB4 or ABCB11. Treatment with UDCA for 12 months significantly reduced GGT in all patients and ALT in homozygous patients. No difference in fibrosis was observed using FIb-4, NFS, and transient elastography (TE). PNPLA3 and TM6SF2 were the most common NASH-associated polymorphisms, and patients with TM6SF2 showed a significant reduction in GGT and ALT with the administration of UDCA. In conclusion, NASH patients with elevated GGT should be screened for bile acid gene polymorphisms, as UDCA therapy may improve liver function tests. However, no difference in clinical outcomes, such as progression to cirrhosis, has been observed using non-invasive tests (NITs). Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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19 pages, 7124 KiB  
Article
Higher pNRF2, SOCS3, IRF3, and RIG1 Tissue Protein Expression in NASH Patients versus NAFL Patients: pNRF2 Expression Is Concomitantly Associated with Elevated Fasting Glucose Levels
by Suzan Schwertheim, Malek Alhardan, Paul P. Manka, Jan-Peter Sowa, Ali Canbay, Hartmut H.-J. Schmidt, Hideo A. Baba and Julia Kälsch
J. Pers. Med. 2023, 13(7), 1152; https://doi.org/10.3390/jpm13071152 - 18 Jul 2023
Viewed by 1044
Abstract
Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify which proteins play a role in the progression of NAFL to NASH. The study investigates paraffin-embedded samples of 22 NAFL and 33 NASH patients. To detect potential candidates, samples were analyzed by immunohistochemistry for the proteins involved in innate immune regulation, autophagy, apoptosis, and antioxidant defense: IRF3, RIG-1, SOCS3, pSTAT3, STX17, SGLT2, Ki67, M30, Caspase 3, and pNRF2. The expression of pNRF2 immunopositive nuclei and SOCS3 cytoplasmic staining were higher in NASH than in NAFL (p = 0.001); pNRF2 was associated with elevated fasting glucose levels. SOCS3 immunopositivity correlated positively with RIG1 (r = 0.765; p = 0.001). Further, in NASH bile ducts showed stronger IRF3 immunostaining than in NAFL (p = 0.002); immunopositive RIG1 tissue was higher in NASH than in NAFL (p = 0.01). Our results indicate that pNRF2, SOCS3, IRF3, and RIG1 are involved in hepatic lipid metabolism. We suggest that they may be suitable for further studies to assess their potential as therapeutics. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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9 pages, 620 KiB  
Article
No Differences in Rotational Thromboelastometry Measurements between Portal and Peripheral Circulation in Cirrhotic Patients Undergoing TIPS
by Sotiria Bedreli, Paul Manka, Matthias Buechter, Michael Jahn, Jens M. Theysohn, Ali Canbay and Antonios Katsounas
J. Pers. Med. 2023, 13(3), 424; https://doi.org/10.3390/jpm13030424 - 26 Feb 2023
Viewed by 1040
Abstract
Background: In patients with liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) is considered a standardized treatment of refractory ascites or variceal bleeding. TIPS thrombosis (TT) and/or portal vein thrombosis (PVT) are possible complications during/after TIPS placement. Previous studies suggested increased clotting activity in [...] Read more.
Background: In patients with liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) is considered a standardized treatment of refractory ascites or variceal bleeding. TIPS thrombosis (TT) and/or portal vein thrombosis (PVT) are possible complications during/after TIPS placement. Previous studies suggested increased clotting activity in portal circulation (PORC). This pilot study aimed to evaluate alterations and differences of coagulation function in PORC and in peripheral circulation (PERC) via rotational thromboelastometry during TIPS. Methods: Blood samples were collected from cirrhotic patients (n = 13; median Model of End Stage Liver Disease, MELD Score: 12; median age: 60 years) undergoing TIPS (10/13 TIPSs were elective procedures due to refractory ascites) as follows: median cubital vein (MCV; PERC)—confluence of the three hepatic veins to the inferior cava vein (HV/ICV; PORC)—portal vein (PV; PORC)—TIPS (PORC). This research utilized four variables of the extrinsic test EXTEM, i.e., clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and maximum lysis (ML). Results: EXTEM results [mean, M (range) ± standard deviation, SD (range)] showed no significant differences for CT [M (70–73) ± SD (9–13); p = 0.93] or CFT [M (137–155) ± SD (75–112); p = 0.97] or MCF [M (51–54) ± SD (9–10); p = 0.90] or ML [M (9–10) ± SD (4–5); p = 0.89] between the compartments, i.e., MCV vs. HV/ICV vs. PV vs. TIPS. Overall, we detected no differences in coagulation function between PERC and PORC. Conclusion: These results are in contrast to previous reports suggesting increased clotting activity in PORC vs. PERC in association with liver cirrhosis. Rotational thromboelastometry-based evaluation of coagulation function in PERC appears to reliably reflect coagulation function in PORC with respect to risk estimation for TT and/or PVT in cirrhotic patients undergoing TIPS. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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Review

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14 pages, 1724 KiB  
Review
Telemedicine as an Option for Monitoring Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Patients Facing the COVID-19 Pandemic: A Systematic Review and Meta-Analysis
by Femmy Nurul Akbar, Safira Rosiana Choirida, Ahmad Zaqi Muttaqin, Fika Ekayanti, Hoirun Nisa and Hari Hendarto
J. Pers. Med. 2024, 14(3), 281; https://doi.org/10.3390/jpm14030281 - 02 Mar 2024
Viewed by 581
Abstract
Healthcare visits were reduced during the COVID-19 pandemic, causing disturbances in sustainable MAFLD monitoring. Telemedicine acts to maintain connectivity between patients and healthcare professionals. This review aimed to assess the role of telemedicine in monitoring MAFLD during the pandemic. Databases searched included l [...] Read more.
Healthcare visits were reduced during the COVID-19 pandemic, causing disturbances in sustainable MAFLD monitoring. Telemedicine acts to maintain connectivity between patients and healthcare professionals. This review aimed to assess the role of telemedicine in monitoring MAFLD during the pandemic. Databases searched included l PubMed Central and ScienceDirect from 2020 to 2023. Assessment with The Cochrane Risk of Bias for randomized controlled trials (RCTs) and the Newcastle-Ottawa scale for non-RCTs systematic reviews. Meta-analyses employing a random-effect model were performed to determine the pooled mean difference (MD) and p-value. The results showed three RCT and two non-RCT (n = 239) with 56.9% males and a mean age of 51.3 years. The median intervention duration was 5.5 months. The parameters assessed included body weight (BW), body mass index (BMI), waist circumference, liver function (AST/ALT), lipid profile, HbA1c, and others. Meta-analysis revealed that telemedicine had a significant effect on improving outcomes for BW (MD −2.81: 95% CI, −4.11, −1.51, p < 0.0001) and BMI (MD −1.01: 95% CI, −1.47, −0.55, p < 0.0001) compared to standard care, while the AST/ALT levels were not significantly reduced. Some biochemical markers decreased based on the systematic reviews. In conclusion, telemedicine using mobile-based applications could be an option for monitoring lifestyle modification in MAFLD patients facing the COVID-19 pandemic. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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14 pages, 303 KiB  
Review
Prevention in Hepatology
by Ana-Maria Muñoz-Restrepo, Maria-Cristina Navas, Jimmy Daza, Marcos Girala, Ezequiel Ridruejo, Guido Gerken and Andreas Teufel
J. Pers. Med. 2024, 14(2), 132; https://doi.org/10.3390/jpm14020132 - 23 Jan 2024
Viewed by 840
Abstract
The prevention of liver disease has improved significantly in the last few decades, to the point that it can now be considered a true success story. The wide variety of interventions, including comprehensive vaccination strategies, novel medications, lifestyle changes, and even preventive surgeries, [...] Read more.
The prevention of liver disease has improved significantly in the last few decades, to the point that it can now be considered a true success story. The wide variety of interventions, including comprehensive vaccination strategies, novel medications, lifestyle changes, and even preventive surgeries, have reduced the morbidity and mortality of chronic liver diseases. However, the prevalence of chronic liver diseases is increasing worldwide. Currently, fatty liver disease alone is estimated to be present in as much as 30% of the adult population. Furthermore, there is a trend towards increasing incidences of chronic hepatitis B, and a global lack of success in efforts to eliminate chronic hepatitis C. Thus, improving and efficiently rolling out existing and successful prevention strategies for chronic liver diseases will play an essential role in healthcare throughout the upcoming decades. In this review, we summarize the current options and concepts for preventing chronic liver diseases, highlight their limitations, and provide an outlook on probable future developments to improve awareness, integrated care, and the analysis of big data. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
14 pages, 478 KiB  
Review
Acute-On-Chronic Liver Failure: Current Interventional Treatment Options and Future Challenges
by Markus Kimmann and Jonel Trebicka
J. Pers. Med. 2023, 13(7), 1052; https://doi.org/10.3390/jpm13071052 - 26 Jun 2023
Viewed by 1722
Abstract
Acute-on-chronic liver failure (ACLF) is a frequent complication in patients with liver cirrhosis that has high short-term mortality. It is characterized by acute decompensation (AD) of liver cirrhosis, intra- and extrahepatic organ failure, and severe systemic inflammation (SI). In the recent past, several [...] Read more.
Acute-on-chronic liver failure (ACLF) is a frequent complication in patients with liver cirrhosis that has high short-term mortality. It is characterized by acute decompensation (AD) of liver cirrhosis, intra- and extrahepatic organ failure, and severe systemic inflammation (SI). In the recent past, several studies have investigated the management of this group of patients. Identification and treatment of precipitants of decompensation and ACLF play an important role, and management of the respective intra- and extrahepatic organ failures is essential. However, no specific treatment for ACLF has been established to date, and the only curative treatment option currently available for these patients is liver transplantation (LT). It has been shown that ACLF patients are at severe risk of waitlist mortality, and post-LT survival rates are high, making ACLF patients suitable candidates for LT. However, only a limited number of patients are eligible for LT due to related contraindications such as uncontrolled infections. In this case, bridging strategies (e.g., extracorporeal organ support systems) are required. Further therapeutic approaches have recently been developed and evaluated. Thus, this review focuses on current management and potential future treatment options. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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15 pages, 536 KiB  
Review
Current Therapy of Chronic Viral Hepatitis B, C and D
by Jörg F. Schlaak
J. Pers. Med. 2023, 13(6), 964; https://doi.org/10.3390/jpm13060964 - 07 Jun 2023
Cited by 2 | Viewed by 2197
Abstract
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular [...] Read more.
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a “functional cure”, i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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Other

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12 pages, 594 KiB  
Systematic Review
Long-Term Outcomes of Liver Transplantation for the Management of Neuroendocrine Neoplasms: A Systematic Review
by Varun Palaniappan, Chun Hei Li, Andrea Frilling and Ashley Kieran Clift
J. Pers. Med. 2023, 13(10), 1428; https://doi.org/10.3390/jpm13101428 - 23 Sep 2023
Viewed by 861
Abstract
Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review [...] Read more.
Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review of studies published in PubMed, Scopus and OVID until 1 July 2021, we summarise and critically appraise the existing literature regarding this modality, with a special focus on long-term outcomes data where possible. Fourteen studies were identified that reported outcomes from the use of liver transplantation for metastatic neuroendocrine neoplasms. No randomised trials were identified. Generally, indications and selection criteria were poorly articulated, with the notable exception of studies using the Milan criteria. The median 5-year overall survival was 65% (ranging from 36% to 97.2%, 11 studies), and the median 10-year overall survival was 50% (ranging from 46.1% to 88.8%, 3 studies). One additional study focussed on treatments and outcomes following post-transplant recurrence. No studies reported outcomes past 10 years. Further follow-up of the largest series with explicit selection criteria will deepen our understanding of the role that transplantation has to play in this setting. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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7 pages, 218 KiB  
Perspective
Liver-Gut-Interaction: Role of Microbiome Transplantation in the Future Treatment of Metabolic Disease
by Vanessa Stadlbauer
J. Pers. Med. 2023, 13(2), 220; https://doi.org/10.3390/jpm13020220 - 27 Jan 2023
Cited by 3 | Viewed by 1312
Abstract
The association between shifts in gut microbiome composition and metabolic disorders is a well-recognized phenomenon. Clinical studies and experimental data suggest a causal relationship, making the gut microbiome an attractive therapeutic goal. Fecal microbiome transplantation (FMT) is a method to alter a person’s [...] Read more.
The association between shifts in gut microbiome composition and metabolic disorders is a well-recognized phenomenon. Clinical studies and experimental data suggest a causal relationship, making the gut microbiome an attractive therapeutic goal. Fecal microbiome transplantation (FMT) is a method to alter a person’s microbiome composition. Although this method allowed for the establishment of proof of concept for using microbiome modulation to treat metabolic disorders, the method is not yet ready for broad application. It is a resource-intensive method that also carries some procedural risks and whose effects are not always reproducible. This review summarizes the current knowledge on FMT to treat metabolic diseases and gives an outlook on open research questions. Further research is undoubtedly required to find applications that are less resource-intensive, such as oral encapsulated formulations, and have strong and predictable results. Furthermore, a clear commitment from all stakeholders is necessary to move forward in the direction of developing live microbial agents, next-generation probiotics, and targeted dietary interventions. Full article
(This article belongs to the Special Issue Novel Challenges and Therapeutic Options for Liver Diseases)
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