Livers, Volume 6, Issue 3 (June 2026) – 15 articles

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory/fibrotic form, metabolic-dysfunction-associated steatohepatitis (MASH), represent a growing global health burden. This progression is driven by complex mechanisms involving metabolic dysregulation, chronic inflammation, oxidative stress, and progressive fibrosis. To date, effective pharmacological therapies remain limited. Pentacyclic triterpenes have attracted increasing attention due to their broad biological activities and ability to modulate multiple molecular pathways implicated in chronic liver disease. This review aims to provide a mechanistic overview of the potential role of pentacyclic triterpenes in MASLD and MASH. Methods: A literature review was conducted using major scientific databases (PubMed and Web of Science) to identify experimental studies investigating pentacyclic triterpenes in metabolic liver diseases. Selected studies were analyzed according to triterpene structural classification, reported bioactivities, molecular targets, and experimental evidence from in vitro and in vivo models of MASLD/MASH or related pathogenic processes. Results: Pentacyclic triterpenes, especially ursolic acid, oleanolic acid, and glycyrrhizin, exhibit hepatoprotective effects including regulation of lipid metabolism, attenuation of oxidative and endoplasmic reticulum stress, suppression of pro-inflammatory signaling, inhibition of inflammasome activation, and reduction in hepatic stellate cell activation and extracellular matrix deposition. These effects involve modulation of signaling pathways, including AMPK, NF-κB, NLRP3, TGF-β, FXR, and MAPK. Preclinical evidence demonstrates improvements in steatosis, inflammation, and fibrosis in experimental models. Conclusions: Pentacyclic triterpenes emerge as multitarget modulators of MASH pathophysiology. However, translating preclinical evidence into well-designed clinical trials is necessary to validate their safety and efficacy in humans. Full article

Porcelain gallbladder (PGB) has historically been considered a premalignant condition, although recent evidence questions the strength of its association with gallbladder carcinoma. Objective: To describe the occurrence and characteristics of malignancy in patients with porcelain gallbladder, as well as clinical, imaging, and surgical characteristics reported in clinal cases. Methods: A systematic review of case reports and case series (≤5 patients) was conducted following PRISMA 2020 guidelines. PubMed/MEDLINE, ScienceDirect, and Redalyc from database inception through March 2026. Individual patient data were extracted including demographic characteristics, imaging findings, calcification pattern, surgical management, histopathology, and outcomes. Descriptive statistics were performed. Results: Fifty-four individual cases of porcelain gallbladder were identified. Patients were predominantly female (70.4%), with ages ranging from 6 to 98 years. Complete calcification was reported in 85.2% of cases. Histopathological confirmation was available in 45 cases (83.3%). Thirteen patients had gallbladder carcinoma associated with porcelain gallbladder, corresponding to 28.9% of those with pathological examinations. Incomplete calcification showed higher frequency of malignancy compared with complete calcification. Mortality was reported in three patients (5.6%), all with malignant disease. Conclusions: The proportion of malignancy observed in published case reports reflects a selected dataset and should not be interpreted as an estimate of population risk. These findings provide descriptive insights into clinical presentations and management patterns, supporting hypothesis generation rather than risk estimation. Full article

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a global health priority affecting approximately 30% of the population. It represents the hepatic manifestation of metabolic syndrome, potentially progressing from simple steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. This review aims to compare current knowledge of MASLD in mouse models and humans, focusing on pathophysiology, histological phenotypes, and the role of preclinical imaging as a non-invasive translational screening tool. Methods: A literature search was conducted in PubMed and Web of Science to identify English-language publications from January 2020 to March 2026 on murine models and imaging techniques for MASLD, using pertinent keywords. Attention was given to highlighting similarities and differences between human and murine approaches. Results: MASLD arises from complex interactions between genetics, sedentary lifestyles, and imbalanced diets. While mouse models have been refined to capture the multifactorial interplay driving disease progression and are still essential for drug development, no single model fully mirrors the human condition. Histological assessment remains an essential tool for MASLD staging, in both humans and mouse models. However, imaging is increasingly emerging as an important complementary technique to non-invasively investigate MASLD. Conclusions: Mouse models are essential to address specific mechanistic and therapeutic questions, but understanding of their limitations and strengths is crucial for translational research. Integrating phenotype-driven approaches in both humans and mice, combining traditional histology, quantitative imaging, and metabolic profiling, as well as longitudinal, combined, and humanized preclinical models, will enhance translational alignment and accelerate the development of therapies for MASLD. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, affecting approximately 25% of the global population. MAFLD represents a broad disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The availability of experimental models that faithfully reproduce human metabolic and hepatic pathology is essential for elucidating disease mechanisms and advancing therapeutic development. This review aims to critically evaluate commonly used rodent models of MAFLD and provide guidance for model selection based on specific research objectives. Methods: A narrative, semi-systematic literature search was performed using PubMed Central, Ovid MEDLINE, and Google Scholar. Rodent models were classified according to their mode of disease induction, including diet-induced, genetically engineered, chemically or pharmacologically induced, and combination models. Models were assessed based on frequency of use, relevance to different stages of MAFLD progression, metabolic fidelity, and suitability for mechanistic studies and preclinical therapeutic evaluation. Results: Diet-induced models incorporating high fat, fructose, and cholesterol most closely recapitulate human metabolic dysfunction and are highly relevant for translational research and drug screening. Nutrient-deficient diets induce rapid steatohepatitis and fibrosis but lack key features of metabolic syndrome. Genetic models enable the targeted interrogation of specific metabolic and inflammatory pathways, whereas chemical and combination models accelerate fibrosis and HCC development. No single rodent model fully reproduces the entire spectrum of human MAFLD. Conclusions: Rodent models remain indispensable tools for MAFLD research; however, their applicability depends on alignment with the defined experimental goals. Careful selection of models based on disease stage, dominant pathogenic mechanisms, and translational intent is essential for improving reproducibility and clinical relevance. This review provides a practical framework to guide investigators in choosing appropriate preclinical models for mechanistic studies and therapeutic development in MAFLD. Full article

Dysfunction-associated steatotic liver disease (MASLD) is a newly introduced term for the condition previously known as nonalcoholic fatty liver disease (NAFLD). MASLD affects 38% of the global population and is now diagnosed based on the presence of steatosis but also with cardiometabolic risk factors indicating metabolic dysfunction. Chronic hepatitis B (CHB), another significant public health issue, impacts over 296 million people worldwide, or approximately 3.2% of the global population. Studies have consistently reported a complex relationship between MASLD and CHB. Previous studies indicate that MASLD may protect against high viral loads, while other studies indicate that coexisting MASLD and CHB may lead to more advanced fibrosis and an elevated risk of HCC. Additionally, numerous studies highlight a strong association between CHB and metabolic syndrome components. This review article examines the relationship between CHB and MASLD, considering what has been previously published. Full article

Sarcoidosis is a multisystemic inflammatory disease defined by non-caseating granuloma formation in involved organs. The liver is the third most implicated organ after the lungs and lymph nodes. Due to its frequently asymptomatic presentation, the true prevalence of hepatic sarcoidosis may be understated. Increased levels of alkaline phosphatase and gamma-glutamyl transferase are the most frequent biochemical abnormalities. The liver biopsy is still the gold standard and reveals non-caseating granulomas in almost all cases. The use of corticosteroids and ursodeoxycholic acid results in a significant decrease in biochemical parameters. However, the clinical course of hepatic sarcoidosis is diverse and requires individualized management strategies, especially to prevent hepatic complications. This review aims to synthesize the current evidence on epidemiology, pathogenesis, diagnostic approaches, and therapeutic strategies for this disease. Full article

Purpose: Simultaneous liver–kidney transplantation (SLK) eligible candidates may receive SLK or liver-alone transplant (LA) with access to kidney transplant after initial LA (KAL). We aimed to characterize SLK-eligible recipient outcomes according to treatment approach. Methods: This study utilized 2017–2023 SRTR data to identify SLK-eligible deceased donor liver transplants. Recipients were placed into two groups based on whether SLK was performed; non-SLK patients were sub-stratified into LA and KAL cohorts. After baseline comparisons, 2-year patient and graft survival outcomes were characterized by univariable and multivariable Cox proportional hazard regression and Kaplan–Meier analysis. Results: Among 4879 candidates identified, 3746 (76.8%) underwent SLK, 1023 (21.0%) LA, and 110 (2.3%) KAL. SLK recipients maintained the highest eGFRs at 6 months, 1 year, and 2 years post-transplant (p < 0.01). Compared to SLK recipients, non-SLK recipients had a higher 2-year risk of mortality (aHR 2.46, p < 0.01), all-cause events (aHR 1.91, p < 0.01), and liver graft failure (HR 1.55, p = 0.02). LA conferred a higher 2-year mortality risk (aHR 2.98, p < 0.01) and all-cause event risk (aHR 2.25, p < 0.01), while KAL had comparable mortality risk to SLK (aHR 0.43, p = 0.40). Conclusions: When SLK-eligible candidates undergo transplants, SLK remains the optimal path forward, even when a safety net kidney can be performed. Full article

Background: Neuroendocrine neoplasms are frequently diagnosed after the detection of liver metastases, often when the primary tumor remains occult. Accurate non-invasive differentiation of neuroendocrine liver metastases (NELMs) from other focal hepatic lesions is therefore crucial. This study aimed to characterize the magnetic resonance imaging (MRI) features of NELMs using hepatocyte-specific contrast agents and to identify a potential radiologic “signature” that may suggest a neuroendocrine origin. Methods: This retrospective study included three cohorts: patients with histologically confirmed NELMs (n = 51; 146 lesions), patients with colorectal cancer liver metastases (n = 18; 46 lesions), and patients with benign hepatic hemangiomas (n = 28; 51 lesions). All subjects underwent standardized liver MRI with Gd-EOB-DTPA. Lesions were evaluated for size, diffusion-weighted imaging characteristics, apparent diffusion coefficient values, arterial-phase enhancement, T2-weighted signal, hepatobiliary-phase appearance, and hemorrhagic components. Statistical analyses included univariate and multivariate testing and receiver operating characteristic curve analysis. Results: NELMs commonly demonstrated arterial hyperenhancement, diffusion restriction, and variable T2 and hepatobiliary-phase signal heterogeneity. Compared with colorectal metastases and hemangiomas, NELMs showed distinctive patterns, particularly higher rates of hepatobiliary-phase heterogeneity and arterial enhancement. Lesion size, ADC metrics, T2 heterogeneity, and hemorrhage were significant discriminators. Conclusions: Hepatocyte-specific MRI enables identification of characteristic imaging features of NELMs. An integrated assessment of morphologic, diffusion, and hepatobiliary-phase findings may facilitate early recognition of neuroendocrine metastases, even when the primary tumor is unknown, improving diagnostic confidence and clinical management. Full article

Background: Advanced cirrhosis induces profound CD4⁺ T-cell depletion through splenic sequestration and immune dysregulation. Pneumocystis jirovecii pneumonia risk thresholds remain undefined in non-HIV immunocompromised populations, necessitating investigation in cirrhotic patients. Objectives: To investigate the potential association between peripheral CD4⁺ T-cell counts and opportunistic infections (OI)—specifically Pneumocystis jirovecii (PJ)—in hospitalized patients with liver disease, and to characterize clinical outcomes across immunological risk strata. Methods: We retrospectively analyzed 455 adults hospitalized in a single institution with hepatic disorders. CD4⁺ T-cell counts were available in 227/455 patients. Among these, 22 patients met predefined immunological risk criteria (CD4⁺ < 500/µL and/or HIV positivity) and were classified into three immunological risk clusters (IRCs): IRC-A (HIV−, CD4⁺ < 200/µL; n = 9), IRC-B (HIV+, CD4⁺ < 200/µL; n = 7), and IRC-C (HIV−, CD4⁺ 200–499/µL; n = 6). PJ PCR testing was evaluated when available. Results: Among 455 patients, in-hospital mortality was 103/455 (22.6%). Of the 22 immunologically at risk patients, 15/22 had cirrhosis. PJ PCR was performed in 8/22 patients (IRC-A: 2; IRC-B: 4; IRC-C: 2), with 3/8 positive (37.5%): IRC-A (1/2), IRC-B (1/4), IRC-C (1/2). Ct values ranged from 27.0 to 31.7. Two PJ-PCR–positive cirrhotic patients (IRC-A: n = 1; IRC-C: n = 1) survived without specific anti-PJ therapy; one HIV-positive patient (IRC-B) received trimethoprim-sulfamethoxazole and survived. In-hospital mortality was 5/9 (55.6%) in IRC-A, 2/7 (28.6%) in IRC-B, and 3/6 (50.0%) in IRC-C; none of the deaths were attributable to PJ pneumonia. Conclusions: Severe CD4⁺ T-cell depletion (<200/µL) was common among cirrhotic patients and associated with PJ detection (3/8 tested), but not with PJ-related mortality (0/3). Mortality was primarily driven by hepatic decompensation and bacterial infections. CD4⁺ assessment may improve risk stratification in cirrhosis; however, prospective, multicenter studies are warranted to validate these findings and to evaluate CD4-guided strategies for the prevention of opportunistic infections. Full article

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and accounts for over 800,000 deaths worldwide, making it a major global health concern. Unfortunately, despite major advances in systemic treatments, such as the introduction of atezolizumab and bevacizumab, patient objective response rates fall below 30%. HCC most commonly develops against a background of chronic liver disease and cirrhosis, although single gene mutations can also drive HCC development, progression, and metastasis. Around 25% of HCC patient tumours carry mutations in TP53, the gene encoding the tumour-suppressor protein p53. p53 is a central regulator of genomic stability, cell-cycle arrest, apoptosis, senescence, and metabolic homeostasis, and its dysfunction is a frequent event in hepatocarcinogenesis. Accumulating evidence highlights the critical role of p53 in liver fibrosis, inflammation, and shaping of the HCC tumour microenvironment (TME). This review summarizes the role of p53 and its negative regulators Mdm2 and MdmX in HCC development and progression, with an emphasis on how p53 shapes the TME in favour of tumour progression. We also evaluate current and emerging p53-targeted therapeutic strategies, including Mdm2/MdmX inhibitors, mutant p53 reactivators, and rational combinations with immunotherapies. Finally, we discuss major challenges in translating p53-based therapies to the clinic, such as tumour heterogeneity, underlying liver dysfunction, and the development of therapeutic resistance. A deeper understanding of p53 biology in chronic liver disease may unlock new avenues for effective HCC prevention and treatment. Full article

Background: Emerging evidence indicates that the liver plays a key role in spinal cord injury (SCI) pathophysiology. Method: This study reanalysed published proteomic datasets from rat models and patients with SCI using bioinformatics and literature/database searches. The aim was to identify liver-specific molecular signatures in SCI blood samples and to link these to severity and neurological recovery at various time points (acute/sub-acute and chronic). Results: Across species, a high proportion of injury severity and neurological recovery-associated proteins were linked to liver function. Notably, non-improvers exhibited prolonged sub-acute proinflammatory responses. These changes were not restricted to classical acute-phase reactants but reflected coordinated alterations in hepatic metabolic and synthetic pathways. Pathway analysis consistently highlighted Liver X Receptor /Retinoic X Receptor (LXR/RXR), complement system/cascade and DHCR24 signalling pathways, with predicted directional changes linked to recovery status. Several proteins were identified and categorised as markers of liver dysfunction, metabolic function, complement/coagulation factors and/or acute-phase proteins. Alpha-2-HS-glycoprotein (AHSG) and afamin (AFM) were commonly dysregulated across species datasets, suggesting conserved roles in inflammation and lipid metabolism. Further associations with liver pathologies such as fibrosis and cirrhosis, particularly in non-improvers, were identified. Conclusion This work builds on emerging evidence of hepatic involvement in SCI by providing cross-species, time-resolved proteomic support for altered liver-associated protein output following injury. Together, these findings underscore the central role of hepatic responses in SCI, highlighting liver-associated proteins and pathways as candidate biomarkers that may aid in stratifying recovery trajectories and informing clinical prognostication. Full article

Liver involvement in pediatric rheumatologic diseases is an increasingly recognized but often underappreciated clinical issue. Systemic autoimmune and autoinflammatory disorders including juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, systemic vasculitis, and mixed connective tissue disease can all affect hepatic structure and function. The mechanisms of injury are multifactorial, encompassing immune-mediated inflammation, macrophage activation, drug-induced toxicity, and metabolic alterations. Hepatic manifestations range from asymptomatic transaminase elevations to fulminant liver failure, frequently influenced by immunosuppressive therapy and comorbid infections. Early recognition through routine biochemical monitoring, imaging, and targeted autoantibody testing is essential for differentiating primary disease activity from treatment-related injury. Timely, multidisciplinary management involving pediatric rheumatology and hepatology teams can prevent progression to chronic liver disease and optimize outcomes. This review summarizes the current understanding of hepatic pathology in pediatric rheumatology, highlighting diagnostic algorithms, monitoring strategies, and emerging therapeutic considerations. Full article

Background: Liver regeneration after hepatectomy is critical for recovery, yet post-hepatectomy liver failure (PHLF) remains a significant challenge. While GLP-1 RAs have shown metabolic and hepatic benefits in conditions like metabolic dysfunction–associated steatotic liver disease, and GLP-2 is known for intestinotrophic properties, their specific roles in PHLF are not well-defined. This narrative review aims to examine the roles of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Glucagon-like peptide-2 (GLP-2) in liver regeneration following partial hepatectomy. Methods: A narrative review was conducted, involving a structured appraisal of preclinical, translational, and clinical studies. Relevant literature was identified through comprehensive searches of PubMed and EMBASE databases, limited to English-language publications available up to 1 May 2025. Results: GLP-1 RAs demonstrate therapeutic potential in chronic metabolic liver diseases, but their role in acute hepatic regeneration appears unfavorable, with animal models showing attenuated regenerative responses and impaired liver mass restoration. Conversely, preclinical studies indicate that GLP-2 administration enhances liver regeneration, and human data reveal increased circulating GLP-2 levels post-resection, particularly in PHLF patients, showing dynamics inverse to GLP-1. Conclusions: GLP-1 RAs appear to inhibit acute hepatic regeneration following hepatectomy, while GLP-2 exhibits pro-regenerative activity in preclinical models and favorable dynamics in humans post-resection. Full article

The recent redefinition of steatotic liver diseases, introducing metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), reflects a growing consensus among liver societies and marks a paradigm shift in disease classification. MASLD subsumes former categories of nonalcoholic fatty liver disease (NAFLD) and incorporates metabolic criteria alongside moderate alcohol intake, while MASH replaces nonalcoholic steatohepatitis (NASH), aligning terminology with disease mechanisms. This evolution clarifies the diagnostic criteria and minimizes stigma, facilitating more consistent epidemiological and clinical investigations. Recent advances in noninvasive diagnostics, including vibration-controlled transient elastography, magnetic resonance elastography, shear-wave elastography, and the Enhanced Liver Fibrosis test, have improved the identification and stratification of patients with advanced fibrosis. Current guidelines recommend targeted screening in populations at elevated metabolic risk, enabling earlier intervention and personalized management. Population studies indicate that MASLD affects over one-third of adults and is a major contributor to cardiovascular and metabolic morbidity. Therapeutic progress is highlighted by the approval of novel agents such as resmetirom and semaglutide for the treatment of MASH with fibrosis. Emerging dual and triple agonists, as well as sodium–glucose cotransporter inhibitors, offer additional promise, although further research is required to define their long-term efficacy and safety. As the disease prevalence escalates globally, the integration of multidisciplinary care, the ongoing refinement of diagnostic tools, and the expansion of therapeutic options will remain essential to optimizing outcomes for affected individuals. Full article

Background: Cigarette smoking exposes the human body to a complex mixture of toxic and carcinogenic compounds that can exert widespread biological effects across different organ systems. From addictive responses and consequence maladaptive neuroendocrine responses, cigarette smoke delivers a variety of reactive oxygen species, polycyclic aromatic hydrocarbons, nitrosamines, and heavy metals that collectively contribute to oxidative stress, inflammation, endothelial dysfunction, and metabolic disruption. The liver, as the primary organ responsible for xenobiotic metabolism, plays a central role in processing these harmful substances and is therefore uniquely susceptible to their effects. This narrative review will aim to provide an overview of the current evidence of cigarette smoking effects on hepatic structure and function and discuss clinical implications. Methods: This narrative review synthesizes evidence from in vitro studies, animal models, and human clinical research examining the effects of cigarette smoking on liver biology. Mechanistic pathways of injury, metabolic and vascular alterations, and clinical consequences for liver disease were considered. Results: Smoking influences hepatic function both directly—through biotransformation pathways generating reactive intermediates—and indirectly via vascular impairment, immune modulation, hormonal alterations, and changes in lipid and glucose metabolism. Emerging evidence indicates that cigarette smoking contributes to hepatic steatosis, accelerates fibrosis progression, worsens outcomes in viral and alcohol-related liver disease, and increases the risk of hepatocellular carcinoma. Conclusions: Cigarette smoking exerts multifaceted deleterious effects on the liver. Recognition of smoking as a modifiable risk factor for liver-related morbidity underscores the importance of smoking cessation in patients with or at risk for liver disease and highlights implications for research and clinical practice. Full article