Editor’s Choice Articles

Ascites and renal dysfunction are among the most frequent and severe complications of decompensated advanced chronic liver disease (dACLD), often representing two interrelated manifestations of a shared pathophysiological continuum. Recurrent ascites and refractory ascites pose significant therapeutic challenges and are frequently associated with kidney impairment, particularly hepatorenal syndrome. Recent advances have reshaped the understanding of the underlying mechanisms, moving beyond the classical paradigm of peripheral arterial vasodilation to encompass systemic inflammation, gut dysbiosis, and cirrhosis-associated immune dysfunction (CAID). These insights have prompted a shift from uniform treatment protocols toward personalized, multidisciplinary strategies. Therapeutic innovations such as long-term albumin infusion, a transjugular intrahepatic portosystemic shunt, and the Alfapump^® system offer promising options, though each requires careful patient selection. Emerging approaches—including fecal microbiota transplantation and peritoneal dialysis—further expand the therapeutic landscape. Ultimately, early risk stratification, the integration of non-invasive tools, and individualized care models are essential to improving outcomes in this high-risk population. This review synthesizes current evidence and highlights future directions for the tailored management of dACLD patients with ascites and renal dysfunction. Full article

Background: We have previously demonstrated that the function and expression of the Na⁺/taurocholate cotransporting polypeptide (NTCP) and the organic cation transporter 1 (OCT1) are affected by increasing free or unesterified cholesterol in the plasma membrane by an acute incubation with cholesterol for 30 min. In the current study we wanted to extend these findings to a more chronic condition to mimic what would be seen in obese patients. Methods: We incubated HEK293 cells that stably express NTCP or OCT1 for 24 h with 0.05 mM cholesterol and determined their function by measuring uptake of radioactive taurocholate or MPP⁺. Expression at the plasma membrane was quantified with a biotinylation assay combined with Western blots. Results: Incubation with cholesterol increased the cholesterol content of the cells by about 2-fold. Transport mediated by NTCP and OCT1 was decreased. Membrane expression for both transporters showed a slight decrease, and when kinetics were normalized for the membrane expression, the V_max for NTCP-mediated taurocholate uptake slightly decreased, but the V_max and the capacity (V_max/K_m) for OCT1-mediated MPP⁺ uptake increased by 2.5-fold and 3-fold, respectively. Acyl-Coenzyme A acyltransferase inhibitors enhanced the decrease in transport function, potentially due to retention of more free cholesterol in the plasma membrane. Conclusions: Chronic increases in free cholesterol in the plasma membrane can result in increased or decreased transporter function and expression. In the case of OCT1, which is involved in the uptake of the anti-diabetic drug metformin into hepatocytes, the 3-fold increase in transport capacity might affect drug therapy. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with liver metastases (CRLM) representing a common and often incurable manifestation. While surgical resection combined with chemotherapy remains the standard for resectable disease, a significant subset of patients presents with unresectable CRLM. Recent advances have positioned liver transplantation (LT) as a promising therapeutic option for select patients with unresectable CRLM. This review synthesizes current evidence from landmark studies—including the SECA and TRANSMET trials—and emerging data from North American cohorts, highlighting the evolution of patient selection criteria, prognostic indicators such as the Oslo score and metabolic tumor volume, and the role of living-donor and extended-criteria grafts. Outcomes from recent studies demonstrate that LT can achieve 5-year overall survival rates exceeding 70% in well-selected patients, rivaling those of traditional transplant indications. Ongoing trials such as SECA-III and SOULMATE aim to refine indications and address organ allocation challenges. Collectively, these findings suggest that LT can offer long-term survival benefits comparable to traditional transplant indications, marking a paradigm shift in the management of metastatic CRC. Full article

Irritable Bowel Syndrome (IBS) and Metabolic dysfunction-associated fatty liver disease (MAFLD) have traditionally been viewed as disorders of distinct organ systems. IBS is a gut–brain axis disorder characterized by abdominal pain, altered bowel habits, and psychological comorbidities. MAFLD, recently redefined to emphasize its metabolic underpinnings, is the hepatic manifestation of systemic metabolic dysfunction. Growing evidence suggests that these conditions share overlapping pathophysiological mechanisms linked through disruption of the gut–liver–brain axis (GLBA), including psychological stress, gut dysbiosis, impaired intestinal permeability, systemic inflammation, and altered neuroendocrine signaling. Neuroimaging studies further reveal functional alterations in brain regions responsible for interoception, emotional regulation, and stress responsiveness in both disorders. This narrative review explores how psychological distress influences the onset and progression of IBS and MAFLD via GLBA dysfunction and stress-induced epigenetic reprogramming. A targeted literature search of major biomedical databases, supplemented by manual screening, identified relevant observational, clinical, neuroimaging, and molecular studies. Findings indicate that chronic psychological distress activates the hypothalamic–pituitary–adrenal (HPA) axis, elevates cortisol, disrupts gut microbiota, and reduces vagal tone; amplifying intestinal permeability and microbial translocation. These changes promote hepatic inflammation and gastrointestinal symptoms. Stress-related epigenetic modifications further impair GLBA communication, while psychological and lifestyle interventions may reverse some of these molecular imprints. Recognizing the shared neuromodulation and epigenetic mechanisms that link IBS and MAFLD opens promising avenues for integrated therapeutic strategies targeting the GLBA to improve outcomes across both conditions. Full article

Herbal and dietary supplements (HDS) are used by over half of American adults and represent a multi-billion-dollar industry. More recently, they have gained popularity, in part due to promotion on multiple social media platforms. However, the Food and Drug Administration (FDA) does not regulate these products rigorously, and up to 20% of acute liver injuries are attributed to HDS. The true incidence of HDS hepatotoxicity is unknown but thought to be underreported. According to the World Health Organization (WHO), HDS-induced liver injuries are now the fifth most common cause of liver disease–associated death. The most common type of supplements associated with liver injury are bodybuilding and weight loss supplements. This study represents a comprehensive literature review of HDS-induced liver injury with a focus on the two most common culprits: bodybuilding supplements and weight loss supplements. Future strategies recommended to mitigate hepatotoxicity include strengthening regulatory oversight through mandatory product listing, enhancing post-market surveillance with standardized reporting and registries, improving product quality via ingredient verification and contaminant testing and, possibly, implementing standardized risk labeling. Full article

Background: As the growing global population continues to age, the risk of chronic metabolic diseases, including cardiovascular disease, neurodegenerative disorders, type 2 diabetes mellitus, and fatty liver disease, increases considerably. Driven largely by lifestyle factors and metabolic dysfunction, this escalating health crisis is placing mounting pressure on healthcare systems and contributing to significant economic costs. Insulin resistance and hyperinsulinaemia are major drivers of these disorders, emphasising the need for early detection and intervention. Changes in liver enzymes, such as alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), commonly assessed in routine laboratory testing, can serve as biomarkers of early-stage insulin resistance, offering a potentially underutilised window for intervention and disease prevention. Correspondingly, low-carbohydrate ketogenic diets have shown to be effective in reversing insulin resistance, metabolic disease, and liver disease. Objectives: We chose to explore the relationship between suppressing ketosis and changes in liver enzymes in the Ketosis Suppression and Ageing cohort. Methods: Ten lean (BMI 20.5 kg/m² ± 1.4), healthy young women (age 32.3 ± 8.9 years) who habitually followed a ketogenic diet maintaining nutritional ketosis (NK) for an average of 3.9 years (±2.3) were exposed to a higher carbohydrate diet, in line with standard healthy eating guidelines for a 21-day phase and then transitioned back to a ketogenic diet. Results: Carbohydrate challenge and suppression of ketosis increased insulin resistance score HOMA-IR by 2.13-fold (p = 0.0008), GKI by 22.28-fold (p = 0.0024), and liver markers ALT by 1.85-fold (p = 0.0010), GGT, 1.29-fold (p = 0.0087) and the ALT/AST, 1.30-fold (p = 0.0266), reflecting an adverse pattern suggestive of hepatic insulin resistance. Conclusions: These results support the clinical utility of liver markers as early and directional signs of hyperinsulinaemia. Full article

Background: Perihilar cholangiocarcinoma (pCCA), especially the periductal-infiltrating subtype, is notoriously difficult to diagnose due to subtle imaging findings and the absence of a mass. Case Presentation: We describe a 56-year-old man with morbid obesity and deep vein thrombosis (DVT), admitted for severe cholestatic jaundice. Initial ultrasound and two ERCPs were inconclusive, with only mild hilar duct dilation on CT. MRI was not possible due to the severe weight of the patient. Only at the 3rd ERCP with digital cholangioscopy were irregular mucosa and tumor infiltration observed, and a biopsy confirmed moderately to poorly differentiated adenocarcinoma. The patient deteriorated rapidly after discharge, returning in septic shock. Despite laparoscopy excluding cholecystitis and cirrhosis, he died from multiorgan failure. Autopsy revealed diffuse hilar tumor infiltration, nodal metastases, and fatal pulmonary tumor embolism (Bismuth IV). Conclusions: This case highlights the necessity of early escalation to cholangioscopy in unresolved cholestasis, the importance of recognizing paraneoplastic thrombosis, and the value of autopsy in clarifying cause of death. Full article

Liver cirrhosis, a progressive and often irreversible condition, exerts widespread systemic effects, with the skin frequently serving as a visible window into the extent of hepatic dysfunction. Cutaneous manifestations, such as spider angiomas, palmar erythema, jaundice, and pruritus, not only reflect underlying pathophysiologic changes but also serve as important, non-invasive diagnostic and prognostic markers of disease severity. Early detection of such cutaneous findings may allow for early treatment, optimize patient management, and improve outcomes. This review addresses the various cutaneous manifestations of liver cirrhosis, their pathogenesis, and their prognostic and diagnostic importance, emphasizing the need for heightened clinical awareness of the improvement in patient care. Full article

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. The strongly hygroscopic metformin (1-1-dimethylbiguanide), first synthesized 1922 and resuscitated as an oral antidiabetic (type 2 of the elderly) compound first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977–1997). It was then released in the USA after a short-term prospective trial in healthy overweight “young” type 2 diabetics (mean age 53 years) in 1995 for oral treatment of type 2 diabetes. It was, however, prescribed to mostly multimorbid older patients (above 60–65 years of age). Metformin is now the most used oral drug for type 2 diabetes worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase in their intestinal concentration (up to 300-fold compared to that measured in the blood), to reduced absorption of glucose from the diet, to increased excretion of glucose through the stool, and to decrease in insulin serum level through increased hepatic uptake and decreased production. Intravenously injected F18-labeled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is like that observed in patients after bowel-cleansing or chronically taking different types of laxatives, where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to “attraction” of glucose from the hepatocyte into the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Furthermore, these compounds have also a diuretic effect (loss of sodium and water in the urine) Acute gastrointestinal side effects accompanied by fluid loss often lead to the drugs’ dose reduction and strongly limit adherence to therapy. Main long-term consequences are “chronic” dehydration, deficiency of vitamin B12 and of iron, and, as observed for all the biguanides, to “chronic” increase in fasting and postprandial lactate plasma level as a laboratory marker of a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Metformin is not different from the other biguanides: synthalin B, buformin, and phenformin. The mechanism of action of the biguanides as antihyperglycemic substances and their side effects are comparable if not even stronger (abdominal pain, nausea, vomiting, diarrhea, fluid loss) to those of laxatives. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis are cardiometabolic twin disorders with shared underlying pathophysiological mechanisms such as insulin resistance and chronic inflammation. This review explores the salient role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in linking hepatic dysfunction to cardiovascular disease. Findings in mice with genetic modulation of Ceacam1 gene established a critical role for CEACAM1 protein in regulating insulin and lipid metabolism and endothelial integrity and modulating immune response. Loss of CEACAM1 in hepatocytes impairs insulin clearance, causing chronic hyperinsulinemia, a process that ultimately leads to insulin resistance and hepatic and extra-hepatic fat accumulation, which in turn causes inflammatory infiltration. This prompts a paradigm shift that positions impaired hepatic CEACAM1 function as a mechanistic underpinning of the link between insulin resistance, MASH, and atherosclerosis. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, affecting approximately 25–30% of the global adult population and highlighting the urgent need for effective therapeutics and prevention strategies. MASLD is characterized by excessive hepatic lipid accumulation and can progress, in a subset of patients, to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of liver cirrhosis and hepatocellular carcinoma. Although the molecular drivers of MASLD progression remain incompletely understood, several key metabolic pathways—such as triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy—are consistently dysregulated in MASLD livers. This narrative review summarizes primary literature and highlights insights from recent reviews on the multifaceted role of the mRNA-binding protein Human antigen R (HuR) in the post-transcriptional regulation of critical cellular processes, including nutrient metabolism, cell survival, and stress responses. Emerging evidence underscores HuR’s essential role in maintaining liver homeostasis, particularly under metabolic stress conditions characteristic of MASLD, with hepatocyte-specific HuR depletion associated with exacerbated disease severity. Moreover, comorbid conditions such as obesity, type 2 diabetes mellitus, and cardiovascular disease not only exacerbate MASLD progression but also involve HuR dysregulation in extrahepatic tissues, further contributing to liver dysfunction. A deeper understanding of HuR-regulated post-transcriptional networks across metabolic organs may enable the development of targeted therapies aimed at halting or reversing MASLD progression. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver condition. Its prevalence is estimated to further increase. The gut–liver axis, which represents both anatomical and functional connections, contributes significantly to the development of MASLD. Dysbiosis, characterized by an imbalance in gut microbiota, can exacerbate the disease by increasing intestinal permeability, which permits harmful bacteria and their components to enter the bloodstream. This review sought to explore the impact of probiotics, prebiotics, and synbiotics on the treatment of MASLD. Method: The methodology for scoping reviews in accordance with Prisma-ScR guidelines was followed. A comprehensive search was conducted in databases such as PubMed, Scopus, and Medline. Out of 1390 studies screened, 25 were selected for the final analysis. Results: The findings of this scoping review highlight the therapeutic potential of probiotics, prebiotics, and synbiotics in the management and treatment of MASLD, as showcased by the existing literature. Conclusions: This scoping review offers important insights into the advantages of probiotics, prebiotics, and synbiotics in the treatment of MASLD. The limitations identified in this study emphasize the necessity for larger, long-term, and geographically diverse studies in order to obtain more solid scientific results. Full article

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. Full article

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

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. Full article

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. Full article

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. Full article

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

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. Full article

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. Full article

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

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Background/Objectives: Transarterial chemoembolization (TACE) is the most widely used bridging treatment for hepatocellular carcinoma (HCC) before liver transplantation (LT) but may be associated with dropout and post-LT HCC recurrence. We aimed to identify a subgroup of HCC LT candidates at high risk of TACE-to-LT strategy failure (TLSF). Methods: All consecutive HCC LT candidates with French AFP-scores ≤ 2 who underwent at least one bridging TACE at Paul Brousse Hospital in 2013–2018 were included (n = 173). Dropout for HCC progression during waiting list and post-LT HCC recurrence was defined TLSF. Results: The one-year TLSF cumulative incidence was 15%. According to univariate analysis, pre-TACE AFP > 15 ng/mL was the only factor associated with decreased overall survival (OS) and TLSF-free survival (TLSF-FS) after the first TACE. The absence of complete radiological response (CRR) or pre-TACE AFP > 15 ng/mL were associated with reduced OS and TLSF-FS after a second TACE (n = 118). The cumulative incidence of TLSF reached 41% one year after the second TACE in patients with both AFP > 15 ng/mL and no CRR, while it was 7% for others (p < 0.001). Conclusions: HCC patients receiving bridging TACE, with pre-TACE AFP > 15 ng/mL and no CRR after two TACEs, are at high risk of delisting for HCC progression or of post-LT recurrence. Alternative therapeutic strategies should be proposed early for this better-defined population. Full article

Conventionally, drug-induced liver injury (DILI) exists in two types: idiosyncratic and intrinsic. Both types are classified as non-immune disorders, thereby ignoring that some iDILI cases may have an immune or autoimmune background that requires a different therapeutic approach because steroids may be helpful. The purpose of this analysis was to analyze and classify the subtypes of iDILI which, indeed, show autoimmune or immune features among four cohorts, namely idiosyncratic DILI type 1: idiosyncratic drug-induced autoimmune hepatitis (DIAIH), to be differentiated from the classic drug-unrelated idiosyncratic autoimmune hepatitis (AIH); idiosyncratic DILI type 2: human leucocyte antigen-based idiosyncratic drug-induced autoimmune hepatitis; idiosyncratic DILI type 3: anti-cytochrome P450-based idiosyncratic drug-induced autoimmune hepatitis; and idiosyncratic DILI type 4: immune-based idiosyncratic drug-induced liver injury associated with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In conclusion, the traditional non-immune and non-autoimmune iDILI, as well as the four immune or autoimmune iDILI subtypes, are now well classified and clinically characterized by the broadly applied Roussel Uclaf Causality Assessment Method (RUCAM), facilitating additional immunology and therapy studies for the four subtypes, all of which could benefit from steroid treatment. Full article

Liver transplantation (LT) in the United States is evolving in response to shifting disease patterns, innovative therapies, and technological advancements. Metabolic-associated fatty liver disease (MAFLD) and alcohol-associated liver disease (ALD) now are the most common indications for LT, reflecting the impact of the obesity epidemic and increased alcohol consumption. Advances in pharmacotherapy for MAFLD and tailored protocols for ALD management are reducing disease progression and improving outcomes. The inclusion of colorectal liver metastases (CRLM) and intrahepatic cholangiocarcinoma (iCCA) as transplant indications highlights progress in chemotherapy and patient selection. Technologies like normothermic machine perfusion (NMP) are expanding the donor pool, while xenotransplantation and organ rehabilitation offer transformative solutions to organ shortages. As the population ages, LT programs must address challenges in older patients and explore minimally invasive approaches for donors and recipients. By integrating innovation and multidisciplinary expertise, LT will continue to provide life-saving care while adapting to the needs of diverse patient populations. Full article

The global burden of liver metastases from different primary lesions is increasing, resulting in significant challenges for public health systems. Accordingly, colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with a high incidence of liver metastases. Although surgical resection is considered the standard curative treatment, it is only viable for a limited subset of patients. This review aims to describe a potential alternative nonsurgical intervention, such as electrochemotherapy (ECT), in the treatment of CRC oligometastatic liver disease. ECT has been largely used for the treatment of cutaneous and subcutaneous lesions, while its visceral use is currently a novel approach. ECT consists of the administration of intravenous anticancer drugs, followed by the application of intralesional electrode needles, which release localized electrical pulses to induce electroporation, a process that transiently increases cell membrane permeability, thereby facilitating the intracellular delivery of otherwise membrane-impermeable drugs. The main topics of this review focus on the technical and clinical applications, efficacy, safety, and possible complications of ECT for CRC liver metastases. A comparison with other locoregional treatments is also performed, highlighting possible advantages and disadvantages. Full article

Liver fibrosis is a very complicated dynamic process where several immune cells are involved. Both innate and adaptive immunity are implicated, and their interplay is always present. Multi-directional interactions between liver macrophages, hepatic stellate cells (HSCs), immune cells, and several cytokines are important for the induction and perpetuation of liver fibrosis. Detailed studies of proteomics and transcriptomics have produced new evidence for the role of individual cells in the process of liver fibrosis and cirrhosis. Most of these cells are controlled by the various immune checkpoints whose main function is to maintain the homeostasis of the implicated immune cells. Recent evidence indicates that several immune checkpoints are involved in liver fibrosis. In particular, the role of the programmed cell death protein 1 (PD-1), the programmed death-ligand 1 (PD-L1), and the role of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been investigated, particularly after the availability of checkpoint inhibitors. Their activation leads to the exhaustion of CD4+ve and CD8+ve T cells and the promotion of liver fibrosis. In this review, the current pathogenesis of liver fibrosis and the immunological abnormalities are discussed. The recent data on the involvement of immune checkpoints are identified as possible targets of future interventions. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the novel terminology encompassing liver disease associated with metabolic dysfunction, replacing the previous terminology of non-alcoholic fatty liver disease (NAFLD). This disease is strongly associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. MASLD and dyslipidemia are deeply interconnected, driven by shared pathophysiological mechanisms. Emerging evidence suggests that statins, a class of lipid-lowering medications, may have beneficial effects on MASLD beyond their primary role in reducing cholesterol levels through several mechanisms, including anti-inflammatory, antioxidant, anti-fibrosis, and immunomodulatory effects. This review aims to summarize the efficacy of statins in the management of MASLD and provide insights into their potential mechanisms of action. It discusses the pathophysiology of MASLD and the role of statins in targeting key aspects of the disease. Additionally, the review examines the clinical evidence supporting the use of different statins in MASLD treatment and highlights their specific effects on liver enzymes, inflammation, and fibrosis. Furthermore, an algorithm for statin therapy in MASLD is proposed based on the current knowledge and available evidence. Full article

Chronic liver disease poses significant challenges to healthcare systems, which frequently struggle to meet the needs of end-stage liver disease patients. Early detection and management are essential because liver damage and fibrosis are potentially reversible. However, the implementation of population-wide screenings is hindered by the asymptomatic nature of early chronic liver disease, along with the risks and costs associated with traditional diagnostics, such as liver biopsies. This study pioneers the development of innovative, minimally invasive methods capable of improving the outcomes of liver disease patients by identifying liver disease biomarkers using quantification methods with translational potential. A targeted mass spectrometry assay based on stable isotope standard protein epitope signature tags (SIS-PrESTs) was employed for the absolute quantification of 108 proteins in just two microliters of plasma. The plasma profiles were derived from patients of various liver disease stages and etiologies, including healthy controls. A set of potential biomarkers for stratifying liver fibrosis was identified through differential expression analysis and supervised machine learning. These findings offer promising alternatives for improved diagnostics and personalized treatment strategies in liver disease management. Moreover, our approach is fully compatible with existing technologies that facilitate the robust quantification of clinically relevant protein targets via minimally disruptive sampling methods. Full article

Background: This study addresses a particular aspect of the biological behavior of the Spike subunit S1 of SARS-CoV-2. Researchers observed S1 acting freely in the human organism during and after COVID-19 and vaccination. One of its properties is that it interacts one-to-one with human proteins. S1 interacts with 12 specific human proteins in the liver. Methods: We used these proteins as seeds to extract their functional relationships from the human proteome through enrichment. The interactome representing the set of metabolic activities in which they are involved shows several molecular processes (KEGG), including some linked to HBV (hepatitis B) and HCC (hepatocellular carcinoma) with many genes/proteins involved. Reports show that, in some COVID patients, HBV reactivated or progressed to cancer. Results: We analyzed the interactome with several approaches to understand whether the two pathologies have independent progressions or a common progression. All our efforts consistently showed that the molecular processes involving both HBV and HCC are significantly present in all approaches we used, making it difficult to extract any useful information about their fate. Through BioGRID, we extracted experimental data in vivo but derived it from model cell systems. The lack of patient data in STRING results prevents diagnosis or prediction of real disease progression; therefore, we can consider them “aseptic” model data. Conclusion: The interactome tells us that genes involved in HCC and HVB-related pathways have the potential to activate disease processes. We can consider them as a gold standard. It is the comparison with similar molecular interactions found in individual human phenotypes that shows us whether the phenotype favors or hinders their progression. This also suggests how to use these features. These sets of proteins constitute a molecular “toolkit”. In fact, if we compare them with similar molecular sets of the patient, they will provide us with information on the level of the phenotypic state that is driving the disease. The information derived from the composition of an entire group of proteins is broader and more detailed than a single marker. Therefore, these protein compositions can serve as a reference system with which doctors can compare specific cases for personalized molecular medicine diagnoses. Full article

Steatotic liver disease is common in the general population and is associated with higher risk for cardiovascular diseases. Early diagnosis and appropriate therapy can prevent the development of irreversible end-stage liver fibrosis and reduce liver-related and cardiovascular mortality. It is important to recognise not only the common causes of metabolic dysfunction-associated steatotic liver disease, such as type 2 diabetes mellitus or morbid obesity, but also rare conditions, because their treatment is different from conventional therapy. Here, we report a female patient with familial partial lipodystrophy, in whom the diagnosis was not confirmed until several years after the initial manifestation, which delayed the start of pathogenetic therapy. After the initiation of leptin replacement therapy, a significant improvement in liver stiffness measurement was achieved within a few months. In addition, we summarise the current treatment options for diabetes and their influence on steatosis hepatis. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally. The impact of statins on liver fibrosis severity in MASLD individuals remains uncertain, despite their known cardiovascular benefits. Methods: A cross-sectional study was performed utilizing the National Health and Nutrition Examination Survey (NHANES) database from 2017 to 2018. MASLD was defined by hepatic steatosis (controlled attenuation parameter [CAP] score ≥ 288 dB/m) without other etiologies. Using inverse probability treatment weighting to minimize confounding, we examined the association between statin use and MASLD outcomes, including at-risk steatohepatitis (FibroScan-aspartate aminotransferase [AST] [FAST] score ≥ 0.67), significant and advanced fibrosis (liver stiffness measurement [LSM] ≥ 8.8 kilopascals [kPa] and ≥ 11.7 kPa), and advanced fibrosis (AGILE 3+ score ≥ 0.68). Results: Of 1283 MASLD patients, 376 were prescribed statins within the past 30 days. After adjustment for confounders, statin use was significantly associated with reduced risks of at-risk steatohepatitis, significant fibrosis, and high AGILE 3+ scores, with odds ratios (ORs) of 0.29 (95% CI: 0.01 to 0.87), 0.54 (95% CI: 0.31 to 0.95), and 0.41 (95% CI: 0.22 to 0.75), respectively. However, a subgroup analysis showed this effect persisted only with lipophilic statins. Conclusions: Statin use was associated with reduced steatohepatitis and fibrosis in patients with MASLD, supported by robust causal inference and vibration-controlled transient elastography-derived scores. Full article

Background: Unlike other chronic liver disorders, in primary biliary cholangitis (PBC), systemic oxidative stress (SOS) worsens along with liver disease progression status (DPS), influencing muscle metabolism, muscle quantity (MQ), and itch pathways. Synergistically, cholestasis contributes to reduced vitamin D absorption, with a negative impact on MM and SOS. Despite this evidence, the prevalence of sarcopenia in PBC, and the SOS-MQ relationship comparing PBC with other CLDs, has never been investigated. Moreover, the relationship between vitamin D and MQ-SOS, and the correlation between SOS and pruritus severity, remains unexplored in PBC. Methods: A total of 40 MASLD, 52 chronic HBV infections, 50 chronic HCV infections, and 41 ursodeoxycholic acid/antioxidant-naïve PBC patients were enrolled. Biochemical, nutritional, and liver stiffness (LSM) data were collected, and sarcopenia was assessed after a normalizing 3-month dietetic–physical exercise regimen. The d-ROMs/BAP tests evaluated SOS. The validated “PBC-40 questionnaire” estimated pruritus and quality of life (QoL). Results: Unlike other CLDs, in PBC patients, sarcopenia was more prevalent in initial mild fibrosis (PBC: 57.10% vs. MASLD: 30.76%, HBV: 22.60%, HCV: 20.70%, all p < 0.0001), and SOS significantly correlated with MQ (dROMs-ASM/h², p: 0.0002; BAP-ASM/h²: p: 0.0092). PBC patients presented lower vitamin D levels and a significant correlation of these with SOS and MQ (all p < 0.0001). SOS also correlated with pruritus severity (dROMs, R: 0.835; BAP, R: −0.775, p < 0.0001). QoL impairment was significantly more represented in PBC individuals with sarcopenia, SOS imbalance, and relevant pruritus (p: 0.0228). Conclusions: In PBC, SOS correlates with MQ impairment and pruritus severity, configuring two independent relationships simultaneously impacting QoL. Full article

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors. Full article

Long regarded as illicit substances with no clinical value, N-dimethylated tryptamines—such as N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine—have been found to produce naturally in a wide variety of species, including humans. Known for their psychoactive effects through serotonin receptors (5-HTRs), N-dimethylated tryptamines are currently being reinvestigated clinically for their long-term benefits in mental disorders. Endogenous tryptamine is methylated by indolethylamine-N-methyltransferase (INMT), which can then serve as an agonist to pro-survival pathways, such as sigma non-opioid intracellular receptor 1 (SIGMAR1) signaling. Fibrogenic diseases, like metabolic-associated fatty liver disease (MAFLD), steatohepatitis (MASH), and chronic kidney disease (CKD) have shown changes in INMT and SIGMAR1 activity in the progression of disease pathogenesis. At the cellular level, endothelial cells and fibroblasts have been found to express INMT in various tissues; however, little is known about tryptamines in endothelial injury and fibrosis. In this review, I will give an overview of the biochemistry, molecular biology, and current evidence of INMT’s role in hepatic fibrogenesis. I will also discuss current pre-clinical and clinical findings of N-methylated tryptamines and highlight new and upcoming therapeutic strategies that may be adapted for mitigating fibrogenic diseases. Finally, I will mention recent findings for mutualistic gut bacteria influencing endogenous tryptamine signaling and metabolism. Full article

The liver is a common site for metastatic disease. In select patients with isolated liver metastases, surgical resection improves survival and may be potentially curative in patients with favorable “tumor biology”. However, when surgical resection is not feasible, liver-directed therapies (LDTs) can also improve outcomes, including survival, in the appropriate clinical situations. LDTs, including hepatic artery infusion, radioembolization, radiation, and ablation techniques, such as thermal ablation and histotripsy, offer local control and potential systemic effects, including the abscopal effect. The abscopal effect occurs when nontargeted, nontreated tumors regress following localized therapy to other tumors. Preclinical and clinical studies suggest that antigen-induced upregulation of key immune regulators plays a central role in this process. Unfortunately, clinical reports of the abscopal effect following LDT are exceedingly rare. However, histotripsy, a noninvasive, nonionizing, and nonthermal ablation technique, may induce an abscopal effect more frequently and robustly than other LDTs. Histotripsy enhances tumor immunogenicity through precise acoustic cavitation that better preserves the local tissue architecture while increasing antigen release, resulting in a robust local and systemic immune response. Ongoing trials are investigating these immunogenic mechanisms and the ability to generate an abscopal effect more reliably with adjuncts such as checkpoint inhibitors. This work has significant implications regarding the management of patients with liver metastasis. Full article

Infection of hepatitis B (HBV) patients with hepatitis D (HDV) can cause the most severe form of viral hepatitis, leading to liver fibrosis, liver failure, and hepatocellular carcinoma. HDV relies on simultaneous infection with HBV for the generation of infectious viral particles. The innate immune response, which is weakly induced in HBV infection, becomes strongly activated upon HDV co-infection. In HBV/HDV co-infection, the immune system comprises a cell-intrinsic strong IFN response, which leads to the induction of interferon-stimulated genes (ISGs), the local activation of liver-resident innate immune cells, and additional immune cell recruitment from the blood. Efficient innate immune responses are indispensable for successful viral control and spontaneous viral clearance. Despite this fact, innate immune cell activation can also contribute to adaptive immune cell inhibition and accelerate liver damage in HBV/HDV infection. While the intrinsic IFN response in HDV-infected cells is well characterized, far less is known about the cellular innate immune cell compartment. In this review, we summarize HBV/HDV replication characteristics and decipher the role of innate immune cell subsets in the anti-viral response in HBV/HDV infections. We further review the impact of epigenetic and metabolic changes in infected heptatocytes on the innate anti-viral response. Moreover, we discuss the potential of exploiting the innate immune response for improving vaccination strategies and treatment options, which is also discussed in this review. Full article

Hepatic steatosis is considered the hepatic manifestation of metabolic disorders. Its global prevalence is a growing public health concern, estimated to affect over 30% of the population. Steatosis is strictly linked to metabolic dysfunction, leading to the revised terminology of MASLD (metabolic dysfunction-associated steatotic liver disease). The disease often progresses in conjunction with metabolic syndrome components, significantly increasing cardiovascular and overall mortality risks. The interplay between sex hormones and metabolic dysfunction is crucial, with male hypogonadism and female hyperandrogenism exacerbating the risk and severity of hepatic steatosis. In men, testosterone deficiency is associated with increased visceral adiposity and insulin resistance, creating a vicious cycle of metabolic deterioration. Conversely, in women, hyperandrogenism, particularly in conditions like polycystic ovary syndrome, may lead to severe metabolic disturbances, including hepatic steatosis. Estrogen deficiency also contributes to central adiposity and metabolic syndrome. The aim of this paper is to discuss this complex sex-dimorphic relationship. Full article

Background: Creating a model for acute liver failure in animal models is essential for research on liver regeneration and cancer. Current surgical techniques allow for a maximum of 80% partial hepatectomy in rats, with low survival rates due to poor inflow control. The common resection technique involves ligation at the liver lobe neck, causing peri-operative blood loss and postoperative blood loss. Methods: A 90% partial hepatectomy was performed on 5 rats using a bile duct-saving portal ligation technique, involving two hilum dissections for bile duct preservation. The first dissection controlled the blood supply to the median and left lateral lobes, and the second to the right inferior and superior lobes. Before closing, all rats were given 5 mL of 10% dextrose intraperitoneally and had access to ClearH₂O DietGel Recovery and 20% dextrose. Weight and behavior were closely monitored for seven days post-operatively. Results: This method resulted in 100% survival, with a 3.1% increase in liver mass and 12.3% increase in liver-to-body mass ratio. Conclusions: This technique is the first bile duct-saving portal ligation for rodent models of acute liver failure, with long-term survival and complete hepatic regeneration. Our procedure offers a viable 90% hepatectomy model for research with improved survival and regeneration outcomes. Full article

Background/Objectives: Efforts to preoperatively risk stratify and optimize patients before liver resection allow for improvements in postoperative outcomes, with hypoalbuminemia being increasingly researched as a surrogate for nutrition, overall health and functional status. Given the paucity of studies examining the relationship between hypoalbuminemia and liver resection, this study aims to determine the impact of hypoalbuminemia on outcomes following liver resections using a large multicenter database. Methods: The American College of Surgeons–National Surgical Quality Improvement Program (2017–2021) database was used to extract the data of patients who underwent a hepatic resection. Two cohorts were defined; those with hypoalbuminemia (HA; <3.0 g/L) and those with normal albumin levels (≥3.0 g/L). Both baseline characteristics and 30-day postoperative complication rates were compared between the two cohorts. Multivariable logistic regression models were used to assess the independent effect of HA on various outcomes. Area under curve–receiver operating characteristic (AUC-ROC) curves were used to identify optimal albumin thresholds for both serious complications and mortality. Results: We evaluated 26,394 patients who underwent liver resections, with 1347 (5.1%) having preoperative HA. The HA patients were older (62.3 vs. 59.8; p < 0.001) and more likely to be of an ASA class ≥ 4 (13.0% vs. 6.5%; p < 0.001). The patients with HA had significantly more complications such as an increased length of stay, readmission, reoperation, sepsis, surgical site infection, bile leak, and need for transfusion. After controlling for demographics and comorbidities, HA remained a significant independent predictor associated with both 30-day serious complication rates (aOR 2.93 [CI 95% 2.36–3.65, p < 0.001]) and mortality (aOR 2.15 [CI 95% 1.38–3.36, p = 0.001]). The optimal cut-off for albumin with respect to predicting serious complications was 4.0 g/dL (sensitivity 59.1%, specificity 56.8%, AUC-ROC 0.61) and 3.8 g/dL (sensitivity 56.6%, specificity 68.3%, AUC-ROC 0.67) for mortality. Conclusions: In this large, retrospective database analysis, preoperative HA was significantly associated with 30-day morbidity and mortality rates following hepatic resection. Preoperative albumin may serve as a useful marker for risk stratification in conjunction with pre-existing calculators. Future studies evaluating the risk mitigation impact of nutrition and exercise prehabilitation in these patients and its capacity to modify hypoalbuminemia would be beneficial. Full article

The primary objective of modern medicine is to extend human life expectancy. Currently, the majority of hospital patients across various clinical settings are elderly or advanced-age individuals, often with multiple comorbidities and age-related alterations in peripheral tissues. One such alteration is sarcopenia, a progressive decline in muscle mass, strength, and function, which significantly increases the risk of disability and mortality in older adults. Sarcopenia is associated with numerous adverse outcomes, and its underlying mechanisms are the subject of ongoing research. This narrative review discusses the epidemiology, pathophysiology, and diagnostic criteria for sarcopenia. It also examines the connections between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting potential treatment approaches for the coexistence of these two pathologies. Full article

Intestinal mucus serves as the first line barrier within the mucosa to protect against microbiota attack due to its water-repellent properties, which are the result of the high abundance of phosphatidylcholine bound to mucins. A deficiency of mucus phosphatidylcholine predisposes it to mucosal inflammation by the attack of commensal microbiota, as it is intrinsically low in ulcerative colitis. However, for precipitation of an acute inflammatory episode, mucus phosphatidylcholine has to fall below the critical level required for mucosal protection. Bacterial ectophospholipase could be a candidate for further thinning of the mucus phosphatidylcholine shield as shown, for example, with the ectophospholipase containing Helicobacter pylori bacterium. Despite supporting evidence for this mechanism in the intestine, the responsible ectophospholipase-carrying bacteria species are still to be defined. Applying phosphatidylcholine to the lumen can serve to fill up empty mucin-binding sites in ulcerative colitis as well as provide a substrate for the ectophospholipase-carrying bacteria preventing their attacks on the mucus phosphatidylcholine layer. Evidence supporting this concept comes from clinical trials in humans with ulcerative colitis as well as from colitis mouse models where phosphatidylcholine was substituted in the lumen. An alternative strategy could involve adding non-absorbable phospholipase inhibitors to the intestinal lumen, which has been shown to be effective in a mouse model of ulcerative colitis. Bacterial phospholipase should be considered a pathogenetic factor of the intestinal microbiota and therapeutic strategies should be developed to prevent their hyperactivity for clinical improvement of intestinal inflammation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area. Full article

Liver transplantation is the most effective treatment for end-stage liver disease. Despite improvements in surgical techniques, transplant rejection remains a significant concern. The liver is considered an immune-privileged organ due to its unique microenvironment and complex interactions among various cell types. Alloimmune responses mediated by T cells and antigen-presenting cells (APCs) play crucial roles in transplant rejection. The liver’s dual blood supply and unique composition of its sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs) contribute to its immune privilege. Alloantigen recognition by T cells occurs through direct, indirect, and semidirect pathways, leading to acute cellular rejection (ACR) and chronic rejection. ACR is a T cell-mediated process that typically occurs within the first few weeks to months after transplantation. Chronic rejection, on the other hand, is a gradual process characterized by progressive fibrosis and graft dysfunction, often leading to graft loss. Acute antibody-mediated rejection (AMR) is less common following surgery compared to other solid organ transplants due to the liver’s unique anatomy and immune privilege. However, when it does occur, AMR can be aggressive and lead to rapid graft dysfunction. Despite improvements in immunosuppression, rejection remains a challenge, particularly chronic rejection. Understanding the mechanisms of rejection and immune tolerance, including the roles of regulatory T cells (Tregs) and hepatic dendritic cells (DCs), is crucial for improving transplant outcomes. Strategies to induce immune tolerance, such as modulating DC function or promoting Treg activity, hold promise for reducing rejection and improving long-term graft survival. This review focuses on the liver’s unique predisposition to rejection and tolerance, highlighting the roles of individual cell types in these processes. Continued research into the mechanisms of alloimmune responses and immune tolerance in liver transplantation is essential for developing more effective therapies and improving long-term outcomes for patients with end-stage liver disease. Full article

Cell-death-inducing DNA fragmentation factor-alpha (DFFA)-like effector b (CIDEB) was first identified as an apoptosis-inducing protein. Further research revealed a pivotal role in lipid metabolism, regulating very-low-density lipoprotein (VLDL), lipid droplets (LD), sterol response element-binding protein (SREBP), and chylomicrons. Recent studies have uncovered that rare germline variants in CIDEB protect against liver diseases, including MAFLD, cirrhosis, and viral hepatitis. Furthermore, CIDEB influences steps of the hepatitis C virus (HCV) replication cycle. This review summarizes the current knowledge about CIDEB’s roles in apoptosis, lipid metabolism, and viral hepatitis, and highlights its critical role in liver diseases. Full article