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Acetylcysteine Treatment of Acetaminophen Overdose: Foundational and Clinical Development
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Comparative Analysis of the Human Proteome Profile in Visceral Adipose and Liver Tissue in Individuals with Obesity with and Without MASLD and MASH
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An Integrated Pathogenetic Model of Primary Biliary Cholangitis
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Comparison of Differentially Expressed Genes in Human Versus in Chimeric Mouse Livers Following HBV Infection
Journal Description
Livers
Livers
is an international, peer-reviewed, open access journal on liver science published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within ESCI (Web of Science), Scopus, EBSCO, and other databases.
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 27.8 days after submission; acceptance to publication is undertaken in 6.7 days (median values for papers published in this journal in the first half of 2025).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
Impact Factor:
2.4 (2024);
5-Year Impact Factor:
2.3 (2024)
Latest Articles
Hepatitis C Virus Opportunistic Screening in South-Eastern Tuscany Residents Admitted to the University Hospital in Siena
Livers 2025, 5(3), 30; https://doi.org/10.3390/livers5030030 - 30 Jun 2025
Abstract
Background. To meet the WHO’s viral hepatitis elimination goal by 2030, the Minister of Health (Italy) introduced free HCV screening among people born between 1969 and 1989 and those at greater risk (people in the care of the addiction services and detained).
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Background. To meet the WHO’s viral hepatitis elimination goal by 2030, the Minister of Health (Italy) introduced free HCV screening among people born between 1969 and 1989 and those at greater risk (people in the care of the addiction services and detained). Aims. To estimate the following: (i) the prevalence of HCV in hospitalized patients born before 1969 not included in the free HCV screening, (ii) the prevalence of transaminase values outside the range, and (iii) the HBV prevalence in a subgroup of patients. Methods. Anti-HCV antibodies and transaminase values were prospectively evaluated in patients born before 1969 and admitted to the Santa Maria alle Scotte Hospital in Siena. The first screening (October 2021–July 2022) was conducted in the Internal Medicine Division (cohort 0), and the second one (May 2024–October 2024) in Internal Medicine, Gastroenterology, and Geriatric Units (cohorts 1–3), including clinical features and HBV markers in a subgroup of patients. Results. Overall, 774 subjects underwent HCV screening. In the first screening period, 1.4% (8/567) of patients were anti-HCV+, of whom 0.7% were HCV RNA+ (4/567). In the second, 3.9% of patients (8/207) were anti-HCV+ and 0.9% were viremic (2/207). Overall, HCV prevalence was 0.8%. Of 96 patients in the gastroenterology cohort, 8 patients were at risk for occult HBV infection (8.3%). Conclusions. Our study demonstrates a chronic HCV infection prevalence of 0.8% in hospitalised patients born before 1969 and a prevalence of 8.3% of people at risk for occult HBV infection in a subgroup of patients residing in South-Eastern Tuscany, confirming that an opportunistic screening can identify the unrecognized people affected by viral hepatitis.
Full article
(This article belongs to the Special Issue The Surveillance, Prevention, and Treatment of Viral Hepatitis: Looking Forward to Global Elimination)
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Open AccessReview
Liver and Vascular Involvement in Philadelphia-Negative Chronic Myeloproliferative Neoplasms—A Narrative Review
by
Romeo G. Mihăilă, Samuel B. Todor and Marius D. Mihăilă
Livers 2025, 5(3), 29; https://doi.org/10.3390/livers5030029 - 30 Jun 2025
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Hepatosplenomegaly can occur in extrahepatic diseases such as Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), which may involve the liver and vasculature. In myelofibrosis, extramedullary hematopoiesis can be present in the liver, even within hepatic sinusoids. Liver biopsies in MPN patients have shown platelet aggregates
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Hepatosplenomegaly can occur in extrahepatic diseases such as Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), which may involve the liver and vasculature. In myelofibrosis, extramedullary hematopoiesis can be present in the liver, even within hepatic sinusoids. Liver biopsies in MPN patients have shown platelet aggregates obstructing these sinusoids. Both liver and spleen stiffness are significantly higher in myelofibrosis, correlating with the severity of bone marrow fibrosis. Spleen stiffness is also elevated in myelofibrosis and polycythemia Vera compared to essential thrombocythemia. MPNs are a leading cause of splanchnic vein thrombosis in the absence of cirrhosis or local malignancy, especially in the presence of the JAK2V617F mutation. This mutation promotes thrombosis through endothelial dysfunction and inflammation. It is found in endothelial cells, where it enhances leukocyte adhesion and upregulates thrombogenic and inflammatory genes. Hepatic sinusoidal microthromboses in MPNs may contribute to portal hypertension and liver dysfunction. MPN therapies can also affect liver function. While hepatocytolysis has been reported, agents such as Hydroxycarbamide and Ruxolitinib exhibit antifibrotic hepatic effects in experimental models. Overall, MPNs are linked to chronic inflammation, increased thrombotic risk—particularly splanchnic thrombosis—and atherogenesis.
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Open AccessReview
Liver Cirrhosis: Evolving Definitions, and Recent Advances in Diagnosis, Prevention and Management
by
Andrew Battle, Julie Mudd, Golo Ahlenstiel and Eric Kalo
Livers 2025, 5(3), 28; https://doi.org/10.3390/livers5030028 - 25 Jun 2025
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Liver cirrhosis poses major challenges for both individual health and global healthcare systems. Recent studies have challenged the traditional and predictable linear course of cirrhosis, demonstrating marked heterogeneity in the patterns of the first decompensating events. This review presents an updated epidemiology of
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Liver cirrhosis poses major challenges for both individual health and global healthcare systems. Recent studies have challenged the traditional and predictable linear course of cirrhosis, demonstrating marked heterogeneity in the patterns of the first decompensating events. This review presents an updated epidemiology of cirrhosis and its main causes, outlines an overview of the clinical features, and explores the evolving concepts of the spectrum of decompensation. It further delineates recent advancements in the diagnosis, prognostic scoring, and management of decompensated cirrhosis and the subsequent clinically challenging complications of portal hypertension. Emerging innovations in non-invasive imaging, diagnostic serum biomarkers, and etiology-specific therapies, together with the development of novel liver support systems, underscore a paradigm shift toward a multimodal approach for cirrhosis care. Furthermore, the integration of precision medicine into clinical practice holds promise for reshaping the future of liver cirrhosis management in the coming decades.
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Graphical abstract
Open AccessReview
Albumin: Bountiful Arrow in the Quiver of Liver and Its Significance in Physiology
by
Ananda Baral
Livers 2025, 5(2), 27; https://doi.org/10.3390/livers5020027 - 19 Jun 2025
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Albumin is the most abundant protein synthesized exclusively by the hepatocytes in the liver. Once secreted into plasma, it helps in the maintenance of osmotic pressure, as well as the exertion of defensive roles such as anti-oxidative and anti-inflammatory functions. Dysregulation in the
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Albumin is the most abundant protein synthesized exclusively by the hepatocytes in the liver. Once secreted into plasma, it helps in the maintenance of osmotic pressure, as well as the exertion of defensive roles such as anti-oxidative and anti-inflammatory functions. Dysregulation in the synthesis and clearance of albumin is observed in various hepatic and extra-hepatic diseases. Abnormal levels of albumin could be either a cause or an effect of various pathological ailments, including hepatic, cardiac, renal, neurological, etc. Owing to its long half-life and multiple binding sites in its heart-shaped structure, it interacts with various internal agents, such as hormones, or external substances like drugs, which is why transportation can be one of its many functions. Additionally, albumin’s drug interactions, as well as displacement of albumin–drug binding, could have serious clinical consequences, and careful considerations should be made in determining an appropriate drug regimen to achieve a desired therapeutic outcome with minimal side effects. Moreover, albumin also undergoes several post-translational modifications that can influence its physiological roles, including drug binding and antioxidant functions. Furthermore, it has a complicated role in physiology, where it can help in maintaining plasma oncotic pressure and prevent endothelial cell apoptosis but can have adverse effects on the lungs and kidneys. These adverse effects are mainly attributed to ER stress and inflammasome activation. This narrative review provides an overview of the general biology of albumin and its effects in physiology, with a focus on its beneficial and adverse effects and the underlying molecular mechanisms.
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Open AccessArticle
Potential Impact of Screening Examinations on Prognosis of De Novo Malignancies in Adult Patients After Liver Transplantation
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Sho Uemura, Yasushi Hasegawa, Hideaki Obara, Minoru Kitago, Hiroshi Yagi, Yuta Abe, Shutaro Hori, Masayuki Tanaka, Yutaka Nakano and Yuko Kitagawa
Livers 2025, 5(2), 26; https://doi.org/10.3390/livers5020026 - 16 Jun 2025
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Background: De novo malignancies (DNMs) after liver transplantation (LT) are a major cause of long-term mortality. However, no definitive screening protocol has been established due to their diversity. This study aimed to evaluate DNM diagnosis methods, screening protocols, and prognoses. Methods: This retrospective
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Background: De novo malignancies (DNMs) after liver transplantation (LT) are a major cause of long-term mortality. However, no definitive screening protocol has been established due to their diversity. This study aimed to evaluate DNM diagnosis methods, screening protocols, and prognoses. Methods: This retrospective study included 231 adult LT recipients from April 1997 to March 2021. Disease-specific survival (DSS) was analyzed to assess the impact of screening on prognosis. Most recipients underwent serum tests every three months, annual gastrointestinal endoscopy, and chest-abdominal CT as part of routine surveillance. Results: Twenty-five DNMs were diagnosed in 22 patients, with median age of 61 years (range, 23–72), of whom 13 (59.1%) were female. The duration from transplantation to DNM diagnosis of DNM was 88 months (range, 4–195). DNM was diagnosed as follows: seven patients (31.8%) through screening (screening group) and 15 patients (68.2%) by other means (non-screening group). Curative treatment was achieved in all of the patients diagnosed by screening, whereas it was possible in only 60.0% of patients diagnosed by other means (p = 0.026). DSS in the screening group was significantly longer than that in the non-screening group (p = 0.024). Conclusions: While screening was associated with earlier-stage diagnosis and improved outcomes in some patients, the overall efficacy of the protocol requires further validation in larger studies.
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Open AccessSystematic Review
From Prehabilitation to Rehabilitation: A Systematic Review of Resistance Training as a Strategy to Combat Sarcopenia in Pre- and Post-Liver Transplant Patients
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Sooraj Vellatt and Jonathan Soldera
Livers 2025, 5(2), 25; https://doi.org/10.3390/livers5020025 - 31 May 2025
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Background: Sarcopenia, defined as the progressive loss of skeletal muscle mass and strength, is a critical predictor of morbidity and mortality in patients with cirrhosis. In chronic liver disease, sarcopenia exacerbates adverse clinical outcomes and deteriorates quality of life. Physical activity, particularly resistance
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Background: Sarcopenia, defined as the progressive loss of skeletal muscle mass and strength, is a critical predictor of morbidity and mortality in patients with cirrhosis. In chronic liver disease, sarcopenia exacerbates adverse clinical outcomes and deteriorates quality of life. Physical activity, particularly resistance training, has demonstrated beneficial effects in reversing muscle depletion in various chronic conditions. Aim: This systematic review aimed to evaluate the impact of resistance training on sarcopenia among cirrhotic patients, with a focus on both pre-liver transplant and post-liver transplant populations, to improve clinical outcomes and enhance quality of life. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed/MEDLINE databases were searched for randomized controlled trials (RCTs) using a standardized search command combining MESH terms and Boolean operators. Studies meeting eligibility criteria and reporting improvements in sarcopenia following resistance training were selected for data extraction. Results: Out of 109 references identified, 12 RCTs were included—10 in pre-transplant and 2 in post-transplant populations. Across studies, resistance training led to measurable improvements in key outcomes: peak VO2 increased by up to 5.3 mL/kg/min, 6 min walk distance improved by 18–97 m, quadriceps muscle thickness increased by up to 1.05 cm, and grip strength gains ranged from 0.4 to 3.8 kg. Postoperative studies reported reductions in fatigue severity scores and length of hospital stay, along with improvements in respiratory pressures and peripheral muscle strength. Conclusions: Resistance training is effective in ameliorating sarcopenia in cirrhotic patients, thereby enhancing pre-transplant status and postoperative quality of life. Clinically, structured exercise programs should be routinely implemented.
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Open AccessReview
Liver Toxicity Induced by Exposure to Bisphenol Analogs at Environmentally Relevant Levels: Insights from a Literature Review on Multiple Species
by
Tai L. Guo, Fatma Eldefrawy and Kevin M. Guo
Livers 2025, 5(2), 24; https://doi.org/10.3390/livers5020024 - 27 May 2025
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Bisphenol analogs and their derivatives have been identified in human tissue and our living environment. There are major concerns over exposure to bisphenol analogs, especially the low-dose- and mixture-related toxicities, as they are considered potential endocrine-disrupting chemicals that may cause adverse effects in
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Bisphenol analogs and their derivatives have been identified in human tissue and our living environment. There are major concerns over exposure to bisphenol analogs, especially the low-dose- and mixture-related toxicities, as they are considered potential endocrine-disrupting chemicals that may cause adverse effects in multiple organ systems. The liver is a critical organ responsible for an array of functions, e.g., metabolism, immunity, digestion, detoxification and vitamin storage, in addition to being a leading chemical target site. In this literature review of multiple species, we discussed the metabolism of bisphenol analogs in the liver, which was followed by discussions of bisphenol analog-induced liver toxicity in various species, including humans, rodents (mice and rats) and other species (chicken, pig, sheep, etc.). Further, the mechanisms of action and markers of liver damage such as oxidative stress, apoptosis, inflammation and fibrosis were discussed. It was concluded that bisphenol analogs can produce toxic effects on the liver in different species through various mechanisms, including epigenetic modifications and disruptions of the cell signaling pathways, gene expression, microbiome and metabolome. More research should be conducted to study the toxicity of bisphenol analogs other than bisphenol A and the underlying mechanisms of action, and in particular the potential for causing dysbiosis. Understanding the mechanisms of liver injury holds promise for improving the prediction of liver toxicity from bisphenol analogs and other environmental chemicals, and their risk assessment and legislation.
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Open AccessArticle
Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences
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Razvan Cerban, Mirela Chitul, Speranta Iacob, Daria Gheorghe, Diana Georgiana Stan and Liana Gheorghe
Livers 2025, 5(2), 23; https://doi.org/10.3390/livers5020023 - 23 May 2025
Abstract
Background: Hepatitis delta virus (HDV) was recently proven to be directly carcinogenic on hepatocytes via different mechanisms compared to hepatitis B virus (HBV). Our study evaluated the differences between hepatocellular carcinoma (HCC) behaviour in both cases. Methods: A retrospective tertiary care centre study
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Background: Hepatitis delta virus (HDV) was recently proven to be directly carcinogenic on hepatocytes via different mechanisms compared to hepatitis B virus (HBV). Our study evaluated the differences between hepatocellular carcinoma (HCC) behaviour in both cases. Methods: A retrospective tertiary care centre study was conducted and included all HBsAg-positive adult patients admitted from the 1st of January 2021 to the 31st of December 2022. IBM SPSS 29.0 was used for statistics. Patients were split into a control group, HBV + HCC, and a study group, HBV + HDV + HCC. Results: A total of 679 patients were included, with an estimated prevalence of HCC in the HDV population of 20.8% versus 9.1% in the control group, p < 0.001, with an OR = 2.263 and a CI 95% of (1.536–3.333), p = 0.001. Younger patients developed HCC in the HBV monoinfection group (mean ± SD, 50.65 ± 12.302 years vs. 51.4 ± 13.708, p = 0.457). Study group patients had smaller tumours (maximum diameter: 32.66 ± 23.181 mm vs. 56.75 ± 38.09 mm, p = 0.002), lower AFP values (177.24 ± 364.8 ng/mL vs. 183.07 ± 336.77 ng/mL, p = 0.941) and predominantly loco-regional treatment. BCLC classification (p = 0.001) and the AFP-Duvoux score (p = 0.001) showed more advanced HCC in HBV monoinfection, with access to mainly systemic therapies (p < 0.001). Conclusions: HCC is more frequent in HDV-infected patients, leading to a different HCC pattern, with smaller tumours, less advanced neoplasia and less access to curative treatment compared to HBV-monoinfection-associated HCC.
Full article
(This article belongs to the Special Issue Clinical Management of Liver Cancers)
Open AccessReview
Pathophysiological Differences and Differential Diagnosis of Autoimmune and Drug-Induced Hepatitis
by
Nicola Zeni, Alessandro Cristofani, Salvatore Silvio Piano, Massimo Bolognesi and Antonietta Romano
Livers 2025, 5(2), 22; https://doi.org/10.3390/livers5020022 - 13 May 2025
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Autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) are major causes of liver inflammation with distinct pathophysiology but overlapping clinical features. Among acute cases, DILI is a key differential diagnosis for AIH, especially when drug history is unclear or the injury is non-dose-dependent.
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Autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) are major causes of liver inflammation with distinct pathophysiology but overlapping clinical features. Among acute cases, DILI is a key differential diagnosis for AIH, especially when drug history is unclear or the injury is non-dose-dependent. Mechanisms of DILI include direct toxicity, metabolic idiosyncrasies, and immune-mediated responses that can mimic AIH. Moreover, certain drugs can induce AIH-like syndromes, further complicating the diagnosis. While causality assessment tools aid initial evaluations, liver biopsy remains valuable for distinguishing AIH from DILI; given these complexities, hepatologist consultation is often essential to ensure appropriate diagnosis and treatment management.
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Open AccessReview
Exploring the Classic and Novel Pathogenetic Insights of Plastic Exposure in the Genesis and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
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Mario Romeo, Marcello Dallio, Fiammetta Di Nardo, Giuseppina Martinelli, Claudio Basile, Alessia Silvestrin, Giusy Senese, Annachiara Coppola, Carmine Napolitano, Angela Amoresano, Carlo Altucci and Alessandro Federico
Livers 2025, 5(2), 21; https://doi.org/10.3390/livers5020021 - 2 May 2025
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The term “plastics” is an umbrella term generally referring to any material containing a high level of polymer content as an essential ingredient. Micro(nano)plastics (MNPs) are derived from the degradation of plastics, representing exogenous substances whose exposure can potentially interfere with different physiological
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The term “plastics” is an umbrella term generally referring to any material containing a high level of polymer content as an essential ingredient. Micro(nano)plastics (MNPs) are derived from the degradation of plastics, representing exogenous substances whose exposure can potentially interfere with different physiological processes. In this scenario, even considering the relative paramount detoxification role, the liver emerges as a key active organ in the relationship between plastic exposure and human disease. In industrialized countries, where plastics constitute largely diffused components of objects routinely adopted in daily/social life, including food packaging, Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) represents the predominant hepatopathy and is progressively becoming the leading cause of cirrhosis and liver cancer, with an incompletely elucidated multifactorial pathogenesis. Notably, oral exposure to MNPs has been revealed to impact the gut–liver axis by influencing gut microbiota composition, gastrointestinal absorption, and, ultimately, determining hepatic accumulation. At the hepatic level, MNPs can contribute to the onset and worsening of steatosis by inducing metabolic dysfunction and inflammation. Plastics can also serve as vectors for different potentially toxic additives, with specific MNPs constituting a persistent source of release of bisphenol A (BPA), a well-recognized exogenous etiological factor contributing to MASLD genesis and worsening. Recently, exposure to MNPs and additives has demonstrated significant impacts on the immune system, oxidative stress, and metabolism. In particular, polystyrene-derived MNPs impair the mechanisms regulating hepatic lipid metabolism, simultaneously acting as antigens abnormally triggering the innate immune response. At the same time, environmental BPA exposure has been revealed to trigger trained immunity-related pathways, configuring novel pathogenetic drivers potentially promoting the progression of MASLD. The present review, after rapidly overviewing the main sources and toxicological properties of MNPs and related additives, explores plastic-related exposure’s potential implications in the genesis and progression of hepatic steatosis, highlighting the urgent need for further clarification of relative pathogenetic mechanisms.
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Open AccessFeature PaperReview
Acetylcysteine Treatment of Acetaminophen Overdose: Foundational and Clinical Development
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Barry H. Rumack
Livers 2025, 5(2), 20; https://doi.org/10.3390/livers5020020 - 25 Apr 2025
Abstract
N-acetyl para-aminophenol was suggested as a safer alternative to other drugs on the market for pain and fever in 1948. It was given the generic name “acetaminophen” in 1951 and the trade name “Tylenol” when it was put on the market in the
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N-acetyl para-aminophenol was suggested as a safer alternative to other drugs on the market for pain and fever in 1948. It was given the generic name “acetaminophen” in 1951 and the trade name “Tylenol” when it was put on the market in the USA in 1955 as a prescription drug to treat pediatric fever. It also received the generic name “paracetamol” in the UK where it was initially marketed in 1956 under the name “Panadol.” Toxicity from overdose of acetaminophen was reported in 1966. Research at the US National Institutes of Health uncovered the mechanisms of toxicity and proposed a treatment in a foundational series of papers in 1973 and 1974. A nomogram was developed in 1973 and published in 1975 to guide estimation of patient risk of hepatic toxicity. Rapid development followed utilizing acetylcysteine given both orally and intravenously. Various protocols and methods of administration have been employed over time with the primary use today of acetylcysteine intravenously as the therapeutic method. The nomogram has been revised over time to the current version, published in 2023, which allows stratification of patients to a high-risk group over 300 mg/L at 4 h and standard risk above 150 mg/L at 4 h, except in the UK where the standard risk is defined very conservatively with a line above 100 mg/L at 4 h. Adjunct therapy with fomepizole in patients with massive ingestions, delay until arrival in a health care facility or renal injury has been proposed. The mortality rate with treatment has been substantially reduced and recovery from hepatic injury is achieved in almost all patients.
Full article
(This article belongs to the Special Issue Recent Advances in Acetaminophen Hepatotoxicity)
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Open AccessCommunication
RANTES, IP-10 and MCP-1 Profiles in Patients with Autoimmune Hepatitis (AIH) at Baseline and During Immunosuppressive Treatment
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Giuseppe Colucci, Enrico Sguazzini, Sara Uceda Renteria, Riccardo Perbellini, Ferruccio Ceriotti, Clara Dibenedetto, Maria Francesca Donato and Pietro Lampertico
Livers 2025, 5(2), 19; https://doi.org/10.3390/livers5020019 - 23 Apr 2025
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Background and aims: The CC5, CXC3, and CC2 chemokines (CK) are known to play a role in the pathogenesis of autoimmune hepatitis (AIH). However, no data are available on their potential utility as markers of disease progression or response to treatment. Material and
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Background and aims: The CC5, CXC3, and CC2 chemokines (CK) are known to play a role in the pathogenesis of autoimmune hepatitis (AIH). However, no data are available on their potential utility as markers of disease progression or response to treatment. Material and methods: We analyzed their role as markers of remission in a population of patients with AIH. We retrospectively investigated the kinetics of RANTES (CCL5), IP-10 (CXCL10), and MCP-1 (CCL2) in 48 patients with AIH at the time of treatment initiation and also in 32 at biochemical, clinical and histological remission. Forty-nine healthy donors (HDs) served as controls. Results: At baseline, IP-10 and MCP-1 levels were higher in AIH patients than in HDs (261 vs. 101 pg/mL and 689 vs. 330 pg/mL, p < 0.01), and RANTES levels showed no differences. Correlations were observed between RANTES and IgG concentrations (r = 0.36 p = 0.04) and between IP-10 and Ishak’s grade (r = 0.52 p = 0.02). At remission, in 32 patients, while IP-10 and MCP-1 values showed a significant decrease from baseline reaching HD levels (261 vs. 106 pg/mL and 689 vs. 387 pg/mL, p < 0.01), RANTES did not. However, two kinetics patterns emerged, with 20 patients showing lower and 12 higher baseline RANTES values compared to HDs (29,450 pg/mL and 70,960 pg/mL vs. 52,010 pg/mL, p < 0.01). The former required longer treatment to reach remission and had higher Ishak’s grades than the latter (p < 0.01). Conclusions: RANTES, IP-10, and MCP-1 may help in predicting response to treatment and stable remission and in supporting the decision if and when to discontinue immune suppressive therapy.
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Open AccessArticle
Comparison of Differentially Expressed Genes in Human Versus in Chimeric Mouse Livers Following HBV Infection
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Huarui Bao, Masataka Tsuge, Serami Murakami, Yasutoshi Fujii, Shinsuke Uchikawa, Hatsue Fujino, Atsushi Ono, Eisuke Murakami, Tomokazu Kawaoka, Daiki Miki, Clair Nelson Hayes and Shiro Oka
Livers 2025, 5(2), 18; https://doi.org/10.3390/livers5020018 - 14 Apr 2025
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Background/Objectives: Hepatitis B virus (HBV) infection is a worldwide health problem responsible for chronic liver disease and hepatocellular carcinoma. Both innate immunity and the adaptive immune response play central roles in the development of chronic hepatitis and liver cancer. We previously performed a
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Background/Objectives: Hepatitis B virus (HBV) infection is a worldwide health problem responsible for chronic liver disease and hepatocellular carcinoma. Both innate immunity and the adaptive immune response play central roles in the development of chronic hepatitis and liver cancer. We previously performed a comprehensive analysis of gene expression in the livers of HBV-infected chimeric mice and found that several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were upregulated by HBV infection. However, due to the absence of adaptive immunity in uPA/SCID chimeric mice, we were unable to analyze the effect of the host immune response. Methods: In this study, we compared gene expression profiles in the livers obtained from HBV-infected chimeric mice with those of HBV carriers. Results: After HBV infection, the expression of genes associated with inflammation and immune response, especially involving the Th1 and Th2 activation pathways, was altered as HBV-specific intracellular immune responses both in vivo and in clinical samples. Interestingly, the proinflammatory gene IL12A was induced by HBV infection in the chimeric mouse livers but not in the human livers, and associated genes, such as SRDA5A2, AR, and CCR3, showed differential alteration by HBV infection between the chimeric mouse and human livers. Conclusions: These results suggest that hepatocarcinogenesis may be suppressed by host immunity in HBV carriers. This study highlights potential new implications for inhibiting the progression of HBV-related liver diseases, including hepatocarcinogenesis.
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Open AccessReview
The Intestinal Thread of Fate: How the Microbiota Shapes the Story of Liver Disease
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Carlo Acierno, Riccardo Nevola, Luca Rinaldi, Ferdinando Carlo Sasso, Luigi Elio Adinolfi and Alfredo Caturano
Livers 2025, 5(2), 17; https://doi.org/10.3390/livers5020017 - 10 Apr 2025
Cited by 2
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Metabolic dysfunction–associated steatotic liver disease (MASLD) is a multifactorial condition linked to liver injury, insulin resistance, and disrupted gut–liver interactions. A key aspect of MASLD pathogenesis is the dysfunction of intestinal barriers, including mechanical, immunological, and microbial alterations that amplify liver damage. The
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Metabolic dysfunction–associated steatotic liver disease (MASLD) is a multifactorial condition linked to liver injury, insulin resistance, and disrupted gut–liver interactions. A key aspect of MASLD pathogenesis is the dysfunction of intestinal barriers, including mechanical, immunological, and microbial alterations that amplify liver damage. The disruption of tight junctions and increased intestinal permeability allow microbial products, such as lipopolysaccharides, to enter the bloodstream, triggering liver inflammation via Kupffer cell activation. In MASLD, the gut vascular barrier is also compromised, marked by increased expression of PV-1. Additionally, dysbiosis, driven by high-fat, high-sugar diets, shifts the gut microbiota toward pro-inflammatory species, exacerbating systemic inflammation and intestinal permeability. This imbalance activates Toll-like receptor signaling, which promotes endotoxin-induced liver injury. Gut dysbiosis further impairs lipid metabolism, contributing to hepatic steatosis and MASLD progression. The gut–liver axis plays a critical role, with factors like altered bile acid metabolism and toxic metabolites such as hydrogen sulfide worsening intestinal barrier function and fueling chronic inflammation. This review aims to explore the complex role of the gut–liver axis in MASLD progression, highlighting the mechanisms of intestinal barrier dysfunction, dysbiosis, and microbial contributions to liver injury. It also discusses therapeutic strategies targeting intestinal barriers, including dietary and microbiota-based interventions, while acknowledging the challenges of personalized treatment approaches. Future research should focus on multi-omics technologies and the safety and efficacy of microbiota-targeted therapies in MASLD management.
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Open AccessArticle
Comparative Analysis of the Human Proteome Profile in Visceral Adipose and Liver Tissue in Individuals with Obesity with and Without MASLD and MASH
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Julie S. Pedersen, Lili Niu, Nicolai J. Wewer Albrechtsen, Viggo B. Kristiansen, Inge Marie Poulsen, Reza R. Serizawa, Torben Hansen, Lise Lotte Gluud, Sten Madsbad and Flemming Bendtsen
Livers 2025, 5(2), 16; https://doi.org/10.3390/livers5020016 - 10 Apr 2025
Abstract
Background/Objectives: Visceral adipose tissue (VAT) may play a direct role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH). In this study, we employed untargeted proteomics analyses on paired biopsies from VAT and liver
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Background/Objectives: Visceral adipose tissue (VAT) may play a direct role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH). In this study, we employed untargeted proteomics analyses on paired biopsies from VAT and liver tissues of patients with obesity, MASLD, and MASH. Our objective was to investigate tissue-specific protein expression patterns in search of a potential proteomic signature associated with MASH in both VAT and liver tissue. Methods: VAT and liver tissue were collected from 70 subjects with severe obesity (SWOs) and nine control study subjects without obesity (CON). SWOs were stratified on the basis of liver histology into LS− (no liver steatosis), LS+ (liver steatosis), and MASH. Peptides were extracted from frozen tissue and were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Raw files were analyzed with Spectronaut, proteins were searched against the human FASTA Uniprot database, and the significantly expressed proteins in the two tissues were analyzed. The p-values were false discovery rate (FDR) corrected. Results: A total of 59 VAT and 42 liver proteins were significantly differentially expressed between the four groups: LS−, LS+, MASH, and CON. The majority were upregulated, and many were related to lipid metabolism. In VAT, only one protein, the mitochondrial sulfide:quinone oxidoreductase (SQOR), was significantly downregulated in the MASH group only. In liver tissue from patients with MASH, six proteins were significantly altered compared with the three other groups. Correlation analyses between the top 10 positive VAT and liver proteins were dominated by inflammatory and detoxification proteins. Conclusions: The presence of MASH was not reflected in the VAT proteome, and both the VAT and the liver proteome were generally affected more by the presence of obesity than by MASLD severity. Several immunomodulating proteins correlated significantly between VAT and liver tissue and could reflect common pathophysiological characteristics.
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(This article belongs to the Special Issue Liver Fibrosis: Mechanisms, Targets, Assessment and Treatment)
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Open AccessReview
An Integrated Pathogenetic Model of Primary Biliary Cholangitis
by
Elias Kouroumalis, Ioannis Tsomidis and Argyro Voumvouraki
Livers 2025, 5(2), 15; https://doi.org/10.3390/livers5020015 - 28 Mar 2025
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The pathogenesis of primary biliary cholangitis (PBC) is not fully understood. Despite recent progress, many aspects require further clarification. Thus, PBC is regarded as an autoimmune disease, but immunosuppressive treatment, which is effective in other autoimmune diseases, is not working in the case
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The pathogenesis of primary biliary cholangitis (PBC) is not fully understood. Despite recent progress, many aspects require further clarification. Thus, PBC is regarded as an autoimmune disease, but immunosuppressive treatment, which is effective in other autoimmune diseases, is not working in the case of PBC. Moreover, there are controversies over the pathogenetic role of anti-mitochondrial antibodies as mitochondria are present in all cells but only cholangiocytes are damaged. In this review, all the proposed models and factors that have been involved in the pathogenesis of PBC are presented. They include mechanisms such as dysregulated autophagy, senescence, apoptosis, impairment of the protective bicarbonate umbrella, immunological abnormalities, the dysbiosis of gut microbiota, and the role of bile acids. Genetics of PBC and epigenetic transcriptional modifications are also presented. Data supporting molecular mimicry and the viral etiology of PBC are analyzed. Finally, an integrated model is proposed based on interactions of the factors that may participate in PBC pathogenesis. Therefore, the purpose of this review is to provide a unifying presentation of the various aspects of PBC pathophysiology, which will allow for a better understanding of this multifaceted disease. New treatment targets may also be identified in such a holistic model.
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Open AccessReview
AI Innovations in Liver Transplantation: From Big Data to Better Outcomes
by
Eleni Avramidou, Dominik Todorov, Georgios Katsanos, Nikolaos Antoniadis, Athanasios Kofinas, Stella Vasileiadou, Konstantina-Eleni Karakasi and Georgios Tsoulfas
Livers 2025, 5(1), 14; https://doi.org/10.3390/livers5010014 - 14 Mar 2025
Cited by 1
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Artificial intelligence (AI) has emerged as a transformative field in computational research with diverse applications in medicine, particularly in the field of liver transplantation (LT) given its ability to analyze and build upon complex and multidimensional data. This literature review investigates the application
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Artificial intelligence (AI) has emerged as a transformative field in computational research with diverse applications in medicine, particularly in the field of liver transplantation (LT) given its ability to analyze and build upon complex and multidimensional data. This literature review investigates the application of AI in LT, focusing on its role in pre-implantation biopsy evaluation, development of recipient prognosis algorithms, imaging analysis, and decision-making support systems, with the findings revealing that AI can be applied across a variety of fields within LT, including diagnosis, organ allocation, and surgery planning. As a result, algorithms are being developed to assess steatosis in pre-implantation biopsies and predict liver graft function, with AI applications displaying great accuracy across various studies included in this review. Despite its relatively recent introduction to transplantation, AI demonstrates potential in delivering cost and time-efficient outcomes. However, these tools cannot replace the role of healthcare professionals, with their widespread adoption demanding thorough clinical testing and oversight.
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Open AccessCase Report
Endogenous Alcohol and Auto-Brewery Syndrome Complicating Liver Transplantation: A Case Report and Literature Review
by
Jack C. Drda and Jill P. Smith
Livers 2025, 5(1), 13; https://doi.org/10.3390/livers5010013 - 13 Mar 2025
Abstract
Introduction: We describe the first reported case of auto-brewery syndrome complicating liver transplantation, wherein a patient was temporarily removed from a liver transplant list not due to ethanol consumption but rather spontaneous ethanolic fermentation within the gastrointestinal tract. Auto-brewery syndrome (ABS) is a
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Introduction: We describe the first reported case of auto-brewery syndrome complicating liver transplantation, wherein a patient was temporarily removed from a liver transplant list not due to ethanol consumption but rather spontaneous ethanolic fermentation within the gastrointestinal tract. Auto-brewery syndrome (ABS) is a rare metabolic condition where gastrointestinal microbiota dysbiosis leads to spontaneous microbial ethanolic fermentation under anaerobic, high carbohydrate conditions. Because no alcohol is directly consumed by the patient, this alcohol is often referred to as “endogenous”. Methods: We present a case where a patient awaiting orthotopic liver transplantation was removed from the transplant list due to significantly elevated blood alcohol levels. However, an upper endoscopy revealed Candida esophagitis, and the diagnosis of ABS was made. Results: With antifungal fluconazole treatment, the patient’s blood alcohol biomarkers decreased, and the patient underwent a successful liver transplantation. Discerning between patient exogenous alcohol consumption and endogenous alcohol production with ABS remains a significant challenge for clinicians, and this knowledge could have serious implications for a patient awaiting a life-saving liver transplant. Conclusions: This case highlights the importance of listening to the patient and carefully assessing potential liver transplant recipients who consistently deny alcohol consumption, specifically for gut dysbiosis and ABS.
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(This article belongs to the Special Issue Recent Advances in the Detection and Pathophysiology of Steatotic, Alcoholic and Drug-Induced Liver Diseases)
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Open AccessArticle
A Metabolomics-Based Approach for Diagnosing NAFLD and Identifying Its Pre-Condition Along the Potential Disease Spectrum
by
Masanori Nojima, Takeshi Kimura, Yutaka Aoki, Hirotaka Fujimoto, Kuniyoshi Hayashi, Junya Ohtake, Mariko Kimura-Asami, Kazuhiko Suzuki, Kevin Urayama, Masaaki Matsuura, Taka-Aki Sato and Katsunori Masuda
Livers 2025, 5(1), 12; https://doi.org/10.3390/livers5010012 - 12 Mar 2025
Cited by 1
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Introduction: The significant impact of nonalcoholic fatty liver disease (NAFLD) on public health, combined with the limitations of current diagnostic approaches, demands a more comprehensive and accurate method to identify NAFLD cases in large general populations. Methods: In this cross-sectional study, we recruited
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Introduction: The significant impact of nonalcoholic fatty liver disease (NAFLD) on public health, combined with the limitations of current diagnostic approaches, demands a more comprehensive and accurate method to identify NAFLD cases in large general populations. Methods: In this cross-sectional study, we recruited 3733 individuals (average age 51.8 years) who underwent health check-ups between October 2015 and October 2016. NAFLD was diagnosed using ultrasound; 114 serum metabolites were measured using gas chromatography–mass spectrometry. We adopted the least absolute shrinkage and selection operator (LASSO) method to build a metabolomic-based diagnostic model. Results: NAFLD was diagnosed in 826 participants. While each metabolite exhibited a limited diagnostic ability for NAFLD when used individually, compared with BMI, the model constructed using the LASSO demonstrated adequate diagnostic power (area under the curve [AUC] 0.866, 95% confidence interval 0.847–0.885 in test set) and even for lean (BMI < 23) populations (AUC for LASSO 0.828, for BMI 0.78). Moreover, the LASSO model-derived ‘pre-NAFLD’ condition showed a potential association with insulin resistance and elevated triglycerides. Conclusions: Our metabolomic-based approach provides a comprehensive evaluation of NAFLD or ‘pre-NAFLD’, both considered parts of a hypothetical ‘NAFLD spectrum’, independent of body type. Metabolomics could offer additional diagnostic benefits and potentially expand the disease concept.
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Open AccessReview
Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications
by
Farah Abdelhameed, Attia Mustafa, Chris Kite, Lukasz Lagojda, Alexander Dallaway, Nwe Ni Than, Eva Kassi, Ioannis Kyrou and Harpal S. Randeva
Livers 2025, 5(1), 11; https://doi.org/10.3390/livers5010011 - 4 Mar 2025
Cited by 1
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Non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of chronic liver disease worldwide. Characterized by excessive hepatic fat accumulation, this disease encompasses a spectrum from simple steatosis to more severe forms, including
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Non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of chronic liver disease worldwide. Characterized by excessive hepatic fat accumulation, this disease encompasses a spectrum from simple steatosis to more severe forms, including steatohepatitis, fibrosis, and cirrhosis. Emerging evidence highlights the pivotal role of gut dysbiosis in the pathogenesis of MASLD. Dysbiosis disrupts the gut–liver axis, an intricate communication network that regulates metabolic, immune, and barrier functions. Alterations in gut microbiota composition, increased gut permeability, and translocation of pro-inflammatory metabolites/factors have been shown to trigger liver inflammatory and fibrotic cascades, exacerbating hepatic inflammation and injury. Recent studies have identified microbiome signatures associated with MASLD, offering promise as non-invasive diagnostic biomarkers and paving the way for new potential therapeutic strategies targeting gut dysbiosis. This review explores the crucial role of the gut microbiota in MASLD pathogenesis and highlights the need for further targeted research in this field to validate microbial biomarkers and optimize therapeutic strategies. Comprehensive understanding of the gut–liver axis may enable innovative diagnostic and therapeutic approaches, transforming the clinical management of MASLD.
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