ATP-binding cassette (ABC) transporters are transmembrane proteins involved in the translocation of bilirubin, bile acids, phospholipids, and cholesterol into bile canaliculi. Mutations in particular genes encoding these transporters—including BSEP (ABCB11 gene), MDR3 (ABCB4 gene), sterolin-1 and sterolin-2 (ABCG5/8 genes), and MRP2 (ABCC2 gene)—result in a wide spectrum of liver diseases, ranging from benign conditions such as Dubin-Johnson syndrome to more severe presentations like progressive familial intrahepatic cholestasis. The severity of disease is influenced by many factors, including zygosity, mutation type, and environmental modifiers such as hormones, consanguinity, and founder effects. Homozygous and compound heterozygous mutations typically result in severe and early-onset diseases, while heterozygous single-allelic mutants generally result in milder diseases. Next-generation genetic testing has proven to have high diagnostic value and is important for prognostication. With knowledge of the underlying specific mutations, there is also potential for future targeted therapy for many severe diseases. The aim of this review is to update and discuss the hepatic diseases associated with ABC transporter mutations, the genetic and environmental effects that influence the severity of disease, typical presentations of these cholestatic hepatic diseases, diagnostic considerations, and treatment options.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic disorder caused by mutations in the SERPINA1 gene. It results in reduced circulating levels of alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (PI) primarily produced by hepatocytes. The most common deficient alleles are PI*S and PI*Z, with PI*ZZ homozygotes having the most severe deficiency and highest risk for lung and liver disease. While AATD is well established as a cause of early-onset emphysema and liver cirrhosis, emerging evidence suggests a potential association with the formation of arterial aneurysms. The pathophysiological rationale for this association centers on protease-antiprotease imbalance and potential extracellular matrix degradation of elastin in arterial vessel walls. Several studies have reported increased frequencies of AATD alleles in patients with abdominal aortic aneurysms and intracranial aneurysms compared to the general population, with some demonstrating statistically significant associations. Additionally, patients with the PI*ZZ genotype have been shown to have larger aortic diameters, greater aortic stiffness, and reduced distensibility compared to controls. However, the evidence is inconsistent, as several large studies have failed to demonstrate significant associations between AATD and aneurysm formation. Overall, current evidence suggests an association of AATD with the development of arterial aneurysms. However, it is also clear that the presence of AATD alone is not sufficient to increase the risk of developing new-onset arterial aneurysms.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 32% of the US adult population. The present study aimed to utilize the All of Us electronic health record-linked large cohort to assess seven metabolic risk factors (MRFs) simultaneously, the impact by ethnicity and age, and clinical presentations of MASLD.

This study included a MASLD group (n = 15,060) and a frequency-matched control group (n = 75,300). Multivariable analyses were performed to compare the frequencies of MRFs and clinical outcomes between the two groups. Type 1 diabetes was not included in the multivariable analysis. Subgroup analyses were conducted according to race and ethnicity, as well as age.

The overall frequency of MASLD was 6.0%. Compared with the control group, individuals with MASLD had significantly higher independent frequencies of obesity (66.1% vs. 41.3%), type 2 diabetes (39.5% vs. 16.9%), hypertension (64.3% vs. 38.6%), hyperlipidemia (59.8% vs. 37.3%), obstructive sleep apnea (28.9% vs. 13.4%), and hypothyroidism (21.2% vs. 13.4%). Obesity was identified as the strongest independent MRF among Asians, Whites, and Hispanics, particularly in individuals younger than 50 years, whereas hypertension was the strongest independent MRF in Blacks. MASLD was also associated with significantly higher frequencies of cardiac events, including coronary artery disease (17.1% vs. 9.4%) and myocardial infarction (7.1% vs. 4.2%); hepatic events, including cirrhosis (7.5% vs. 1.1%) and hepatocellular carcinoma (0.5% vs. 0.1%); and elevated liver enzymes, including alanine aminotransferase (27.7% vs. 10.1%), aspartate aminotransferase (18.0% vs. 6.4%), and alkaline phosphatase (19.8% vs. 13.1%), compared with the control group.

Our study demonstrated that obesity, hypertension, hyperlipidemia, type 2 diabetes, obstructive sleep apnea, and hypothyroidism were independent MRFs for MASLD overall, but the ranking of these MRFs by odds ratios could vary by ethnicity and age. MASLD presents with significantly higher rates of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase elevation, as well as cardiac and hepatic events.

Acute-on-chronic liver failure (ACLF) lacks a universally accepted definition, and recent efforts have proposed consensus organ failure criteria. In this study, we aimed to compare the clinical validity of a recently proposed consensus ACLF framework with the outcome-calibrated A-TANGO classification.

We performed a multinational cohort study including 2,398 patients from the TIH cohort (India) and 2,568 from the CATCH-LIFE cohort (China) who were hospitalized with acute decompensation of cirrhosis. ACLF was defined using A-TANGO and an operationalized version of the 2025 consensus framework. Outcomes were 28- and 90-day mortality. Analyses assessed case capture, overlap, mortality risk, sensitivity, specificity, and net reclassification improvement (NRI).

ACLF prevalence differed substantially by definition. In TIH, A-TANGO classified 79.2% as ACLF versus 42.3% by the consensus definition; in CATCH-LIFE, the corresponding values were 31.4% versus 5.8%, respectively. Most consensus ACLF cases were captured by A-TANGO, which additionally classified 26%–37% of patients as having ACLF. These patients had substantial mortality (28-day: 18.1%–26.9%; 90-day: 33.2%–37.9%), significantly higher than those negative by both frameworks and comparable to established ACLF risk thresholds. A-TANGO showed higher sensitivity for 28-day mortality (TIH: 94.1% vs. 67.8%; CATCH-LIFE: 76.1% vs. 25.6%), whereas consensus criteria were more specific. Reclassification analyses showed improved discrimination with A-TANGO (NRI: 17.1% in TIH; 27.4% in CATCH-LIFE). Within the consensus non-ACLF group, A-TANGO further stratified patients into distinct risk groups with stepwise increase in mortality.

In conclusion, the two frameworks identify fundamentally different populations. The consensus definition significantly reduces sensitivity and under-recognizes high-risk patients. Compared with consensus definitions, the outcome-calibrated framework better supports diagnosis, clinical decision-making, risk stratification, and trial design in ACLF.

Hepatocellular carcinoma (HCC) remains one of the most fatal cancers, primarily due to late diagnosis and the lack of effective early biomarkers. Recent advances in multi-omics and liquid biopsy technologies hold promise for improving early detection, prognostication, and monitoring of HCC. Understanding the immune landscape of HCC through genetic and epigenetic signatures is essential for identifying therapeutic targets and improving immunotherapy outcomes. This review aims to present current findings on immune-related biomarkers, multi-omics strategies, and biomarker validation in HCC. It also aims to evaluate the role of liquid biopsy and gene signatures in predicting treatment responses, with a specific focus on their applications in immunotherapy. The goal is to provide a comprehensive framework for integrating these emerging tools into clinical practice. The integration of multi-omics approaches has led to the identification of robust gene signatures that predict HCC prognosis and response to immune checkpoint inhibitors. Liquid biopsy technologies, including circulating tumor DNA, provide non-invasive alternatives for monitoring tumor evolution and therapeutic responses. Despite promising results, challenges remain in clinical validation, particularly in cross-platform reproducibility and the interpretation of complex multi-omics data. While genetic biomarkers are rapidly advancing, their clinical application in personalized medicine remains hindered by technical and ethical challenges, such as data privacy, informed consent, and method standardization. The integration of multi-omics data and liquid biopsies offers a promising path toward real-time, personalized treatment and the development of universal prognostic signatures for HCC. However, successful clinical adoption depends on cross-disciplinary collaboration to standardize data protocols and overcome challenges regarding accuracy, reproducibility, and patient privacy.

Mediastinal germ cell tumors (GCTs) are rare malignant neoplasms that occasionally develop somatic-type malignancies (SMs), such as sarcomas, carcinomas, and hematologic malignancies.

We report a unique case of a 16-year-old male patient with a mediastinal GCT that simultaneously developed two different SMs: well-differentiated angiosarcoma and acute megakaryoblastic leukemia (AML). The patient initially presented with left shoulder pain and intermittent shortness of breath. The imaging study demonstrated a 12.5 × 9.0 × 8.5 cm heterogeneous mass in the left anterior mediastinum. The mediastinal mass was resected and showed a cystic mature teratoma with somatic transformation into well-differentiated angiosarcoma and AML. A subsequent bone marrow biopsy confirmed the diagnosis of AML, and next-generation sequencing demonstrated the presence of PTEN and TP53 gene mutations in the AML. Despite aggressive chemotherapy and allogeneic stem cell transplantation, the patient died 10 months after diagnosis.

Our report demonstrates the unique capability of mediastinal GCTs to simultaneously develop two different SMs. The presence of two different SMs in mediastinal GCTs is associated with extremely aggressive behavior and a poor prognosis.

Accurate identification of invasive fungal pathogens is crucial for appropriate antifungal therapy. The Department of Clinical Laboratory at Indus Hospital & Health Network, Karachi, Pakistan, reported two cases of invasive fungal infections between 1st January and 31st March 2024 in which conventional identification methods and automated systems produced discordant results, highlighting critical diagnostic challenges.

Two invasive yeast isolates initially showing budding yeast cells without pseudohyphae on Gram stain were subjected to conventional identification using cornmeal-Tween 80 agar, chrome agar, and BiGGY agar, followed by automated identification using the VITEK 2 ID-YST system and confirmatory API 20C AUX testing. Both isolates demonstrated typical soft, wrinkled, cream-colored colonies on Sabouraud dextrose agar, which on chrome agar appeared as dry, blue colonies and on BiGGY agar as dry, brown colonies. Characteristic arthroconidia and blastoconidia formation on cornmeal-Tween 80 agar were observed, consistent with Trichosporon species. However, the VITEK 2 ID-YST system identified both isolates as Cryptococcus laurentii with good confidence levels. India ink staining was negative for both isolates. Confirmatory API 20C AUX testing correctly identified both isolates as Trichosporon asahii (identification profile 3740734).

This discordance between automated and conventional methods underscores the continued importance of conventional identification techniques and highlights potential limitations of automated systems for certain uncommon yeasts. Laboratories should maintain proficiency in conventional methods and consider confirmatory testing when automated results conflict with morphological findings. The clinical implications of misidentification include inappropriate antifungal selection, given the different susceptibility patterns between these species.

Gliomas remain a major challenge in brain cancer treatment. Although genetic mutations have been widely studied, recent research indicates that epigenetic changes, which alter gene activity without changing the DNA sequence, also contribute significantly to tumor growth and treatment resistance. This review seeks to elucidate the principal drivers and modulators of brain tumor development, emphasizing the complex interaction between tumor metabolism and epigenetic regulation. It highlights how metabolic intermediates influence chromatin structure and transcriptional events driving glioma progression. Metabolic intermediates, such as acetyl-CoA and S-adenosylmethionine, serve as essential epigenetic cofactors, directly impacting chromatin structure and gene expression. Additionally, metabolic disorders like diabetes not only frequently coexist with gliomas but also exacerbate tumor progression through mechanisms such as inflammation, oxidative stress, and epigenetic reprogramming. Tumors located near brain regions controlling heart function may also increase the risk of sudden death, particularly in diabetic patients. The review proposes a comprehensive framework to understand glioma development by linking metabolism, epigenetics, and overall health. This integrated perspective leads to novel personalized treatment approaches, targeting both the tumor and the patient’s broader metabolic health, with the potential to improve survival rates and quality of life for glioma patients.

Cirrhotic ascites develops when portal hypertension and arterial under-filling chronically activate neuro-hormonal pathways that drive renal sodium-water retention. Augmented proximal tubular sodium reabsorption, predominantly mediated by the apical sodium/hydrogen exchanger 3 (NHE3), plays a fundamental role in this process. Given the spatial coupling of NHE3 and the sodium-glucose cotransporter 2 (SGLT2), selective SGLT2 inhibition reduces NHE3 activity via functional suppression within the apical microdomain. The increased sodium chloride delivery to the macula densa augments tubuloglomerular feedback and modulates the renin–angiotensin–aldosterone system. Early clinical investigations, ranging from case reports and retrospective analyses to pilot randomized trials, indicated potential benefits in controlling ascites and reducing decompensation events. However, their limited sample size, heterogeneous endpoints, and predominantly observational design constrain the generalizability of the findings. This review concentrates on the molecular mechanisms and emerging clinical evidence supporting the therapeutic potential of SGLT2 inhibitors in the management of cirrhotic ascites.