Hepatic Medicine : Evidence and Research最新文献

Purpose: Hepatitis B virus (HBV) infection is a global health concern, linked to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV genome integration into host DNA is critical in disease progression and oncogenesis. Despite advancements in understanding HBV pathogenesis and therapies, the mechanisms and implications of HBV integration remain unclear. This study employs bibliometric analysis to evaluate research trends and collaborations in HBV integration.

Materials and methods: We utilized the Web of Science Core Collection (WOSCC) as our primary data source, meticulously screening and identifying 972 pertinent articles published between 1980 and November 30, 2024. Bibliometric tools, including VOSviewer, CiteSpace, and Bibliometrix, were employed to analyze publication trends, authorship, institutional contributions, and key research areas. Citation data and keyword clusters were examined to identify research hotspots.

Results: Publications have steadily increased from 1980 to November 30, 2024, with China and the United States contributing the most studies. While China leads in publication volume, the United States has the highest citation impact. The Institut Pasteur in Paris ranks highest in publications. Hino O is the most prolific author, and Koike K the most cited. Hepatology is the most cited journal, and the article "Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma" is the most referenced. Cluster analysis revealed five major research themes.

Conclusion: This study highlights global research trends and key contributors in HBV integration, offering insights into current hotspots and future directions. The findings provide a basis for advancing diagnostic and therapeutic strategies targeting HBV integration.

Background and aim: Several non-invasive tests are used to assess liver fibrosis and cirrhosis in patients with liver disease. However, most validation studies have not included populations in sub-Saharan Africa. This study aimed to evaluate the diagnostic performance of the APRI and FIB-4 scores in a Congolese cohort.

Patients and methods: A cohort of patients in Kinshasa underwent FibroScan and laboratory testing to calculate APRI and FIB-4 scores. Pearson correlation, sensitivity, specificity, and ROC curve analyses were used to evaluate the performance of these non-invasive scores against FibroScan. Cirrhosis was defined as liver stiffness ≥14 kPa by FibroScan. Thresholds for APRI and FIB-4 scores predicting cirrhosis were set at ≥ 1.5 and ≥ 2.67, respectively.

Results: The study included 316 patients (mean ± SD age: 48.1 ± 14.1 years; 60.8% male; 10.1% with diabetes; 37.1% obese; 14.2% with hepatitis B; 6.7% with hepatitis C; 25.6% with a history of alcohol use). The Pearson correlation between APRI and FibroScan was r = 0.210 (p < 0.001), while the correlation between FIB-4 and FibroScan was better (r = 0.478, p < 0.001). In subgroup analyses, FIB-4 correlated with FibroScan only among patients with alcohol use or hepatitis B or C, APRI only correlated with FibroScan in alcohol dependent patients. The sensitivity and specificity of APRI were 29.7% and 97.9% respectively, compared to 60.0% and 93.3% for FibroScan. The areas under the ROC curve were 0.8462 for APRI and 0.8312 for FIB-4, with thresholds lower than those reported in the literature: 0.422 for APRI and 1.285 for FIB-4, but these varied according to the subgroup.

Conclusion: APRI and FIB-4 scores demonstrate high specificity but low sensitivity for diagnosing cirrhosis in this population. Their diagnostic performance is notably better in patients with alcohol-related liver disease or viral hepatitis, but poor among those with diabetes or obesity.

[This corrects the article DOI: 10.2147/HMER.S509778.].

Purpose: Metabolic associated fatty liver disease (MAFLD) and its progressive form, Metabolic Dysfunction-Associated Steatohepatitis(MASH), are prevalent liver disorders with significant health implications. This study aims to identify differentially expressed genes (DEGs) associated with MAFLD/MASH and explore their potential link to ferroptosis, a form of regulated cell death.

Methods: We conducted differential expression analysis using two datasets from the GEO database. Genes related to ferroptosis were identified from the Genecards and FerrDb databases, and the intersection genes were obtained by intersecting the DEGs with ferroptosis-related genes. Functional enrichment was performed using GO and KEGG pathways. The clinical diagnostic value of the intersection genes was evaluated through ROC analysis. Finally, the research findings were validated using a high-fat diet (HFD) mouse model, observing the improvement in gene expression with HQHF treatment.

Results: We utilized two datasets, GSE89632 and GSE63067, from the GEO database, comprising 39 samples, including 24 healthy controls. Differential expression analysis revealed significant gene expression changes in NAFLD and NASH compared to healthy controls. These DEGs were visualized using volcano plots. Ferroptosis-related genes were identified from Genecards and FerrDb databases, resulting in 1937 unique genes. Venn analysis revealed intersections between DEGs and ferroptosis genes, highlighting potential regulatory roles. Functional enrichment analysis using GO and KEGG pathways indicated significant involvement in cellular components and signaling pathways, such as PPAR and HIF-1. The clinical diagnostic value of intersecting genes was assessed using ROC analysis, demonstrating promising diagnostic potential. In addition, a high-fat diet (HFD) mouse model was used to validate the research findings, showing that HQHF treatment can alleviate lipid deposition and inflammation in the liver. Transmission electron microscopy results indicated that HQHF prevented mitochondrial damage and significantly reduced the content of Fe2+ in the liver, alleviating iron deposition. We verified the reliable genes with diagnostic value through qPCR, and the results suggested that HQHF can lower the transcription levels of P4HA1, NR4A1, and EFEMP1, while increasing the transcription levels of ENo3, GRIA3, ME1, and FADS2, confirming our ROC results.

Conclusion: This study provides insights into the molecular mechanisms underlying MAFLD/MASH and suggests ferroptosis-related genes as potential diagnostic biomarkers and therapeutic targets. Further research is warranted to explore these findings in clinical settings.

Background: Surgical resection (SR) following transarterial chemoembolization (TACE) is a promising option for large hepatocellular carcinoma (LHCC) with HBV, and identification of these patients at high-risk of prognosis may help individualized treatment.

Purpose: To develop and validate pre- and postoperative prognostic nomograms integrating clinico-therapeutic-pathological features for predicting overall survival (OS) after TACE combined therapy.

Materials and methods: Between May 2010 and October 2021, 255 consecutive patients with LHCC receiving conversion therapy of TACE combined with Lenvatinib plus PD-1 inhibitors were included from three tertiary-care hospitals. In the derivation cohort (n=201), the Cox regression analysis for developing nomograms for OS (time from initial TACE to death). In the testing cohort (n = 54), two models' performance was compared with five major staging systems.

Results: The preoperative nomogram included alpha-fetoprotein (AFP, HR: 0.486; 95% CI: 0.266-0.886; P = 0.019) and albumin- bilirubin (ALBI) grade (HR: 0.323; 95% CI: 0.181-0.578; P < 0.001) and the postoperative nomogram, included AFP (HR: 0.501; 95% CI: 0.271-0.925; P = 0.027), ALBI grade (HR: 0.356; 95% CI: 0.192-0.659; P = 0.001), MVI (HR: 0.086; 95% CI: 0.024-0.192; P < 0.001), and response to TACE combined therapy (HR: 3.367; 95% CI: 1.479-7.721; P = 0.004). The testing dataset C-indexes of the pre- (0.715) and postoperative (0.912) nomograms were higher than all five staging systems (0.589-0.483; all P < 0.001). Two prognostically distinct risk strata were identified according to these nomograms (all P < 0.001).

Conclusion: Based on 255 patients receiving TACE combined conversion therapy for LHCC, we developed and validated two nomograms for predicting OS, with superior performances than five major staging systems and effective survival stratification.

Purpose: Thyroid-stimulating hormone (TSH) has been identified as an independent risk factor for non-alcoholic fatty liver disease (NAFLD), TSH binds to the TSH receptor (TSHR) to exert its function. However, the underlying mechanisms by which TSHR influences NAFLD development remain unclear. This study investigates the role of miR374b in NAFLD progression.

Methods: Firstly, a rat model of non-alcoholic fatty liver was constructed and divided into a normal group and a model group. The liver tissue pathology and fat accumulation were detected by Oil Red O staining and hematoxylin-eosin staining. Western blot and Real time PCR were used to detect for the impact of TSHR/miR-374b/C/EBP β/ FoxO1 pathway in the NAFLD model, and the expression of relevant inflammatory factors in each group was detected by ELISA assay. A NAFLD cell model was constructed using HepG2 cells, TSHR overexpression and interference, combined with miR-374b inhibitor and mimics, were transfected simultaneously to demonstrate TSHR/miR-374b/C/EBP β/ The mechanism of FoxO1 adipogenesis in vitro.

Results: TSHR stimulates miR374b secretion in human liver cancer cells (HepG2) and promotes lipid accumulation in the liver. Deficiency of miR374b in HepG2 cells attenuated NAFLD progression. Mechanistically, TSH increases miR374b expression, which then suppresses the transcription of its target genes, CCAAT/enhancer binding protein-b (C/EBP β) and Forkhead Box Protein O1 (FOXO1). This suppression influences the expression of downstream lipid metabolism proteins, including PPARγ, SREBP2, and SREBP1c. Additionally, miR374b directly targets the 3'UTR of C/EBP β and FOXO1, establishing a negative feedback loop in lipid metabolism.

Conclusion: These findings suggest that TSHR-induced upregulation of miR374b accelerates NAFLD progression by modulating lipid metabolism pathways through C/EBP β and FOXO1.

Background: Thyrotoxicosis is often associated with abnormal liver tests. This study aimed to characterize the clinical features and laboratory findings in thyrotoxic patients with liver abnormalities and to identify predictive factors for differentiating thyroid storm within this population.

Methods: This is a retrospective review of thyrotoxic patients with hepatic dysfunction between January 2015, and January 2021, at Siriraj Hospital, Thailand. Univariate and multivariate analyses were performed to identify the factors associated with thyroid storm.

Results: Among 771 thyrotoxic patients, 43 revealed abnormal liver tests within six months of diagnosis (5.58%). The mean age was 53.16 ± 15.10 years, with a female predominance (60.5%), and the majority (97.7%) were diagnosed with Graves' disease. The most common comorbidities were atrial fibrillation, heart failure, and dyslipidemia. Hepatic dysfunction presented as non-specific, with 46.5% showing a cholestatic pattern, 30.2% a mixed pattern, and 20.9% a hepatocellular pattern. The most possible etiologies of hepatic dysfunction were hyperthyroidism-related hepatitis (41.9%) with atrial fibrillation with congestive hepatopathy (38.9%), concomitant with chronic hepatitis C infection (14.0%), and methimazole-induced hepatic dysfunction (9.3%). The younger age, congestive heart failure, and total bilirubin levels ≥ 3.0 mg/dL were independent factors in distinguishing clinical thyroid storm among thyrotoxic patients without thyroid storm.

Conclusion: Liver abnormalities can be observed in patients with thyrotoxicosis. The possible causes are multifactorial, including hyperthyroidism-related hepatitis, atrial fibrillation with congestive hepatopathy, and chronic hepatitis C infection. Younger age, congestive heart failure, and total bilirubin ≥ 3.0 mg/dL were predictive factors for thyroid storm diagnosis among thyrotoxic patients.

Purpose: Both hepatic iron accumulation and hemolysis have been identified as independent prognostic factor in alcohol-related liver disease (ALD); however, the mechanisms still remain poorly understood. We here demonstrate that hepatocytes are able to directly ingest aged and ethanol-primed red blood cells (RBCs), a process termed efferocytosis.

Methods: Efferocytosis of RBCs was directly studied in vitro and observed by live microscopy for real-time visualization. RBCs pretreated with either CuSO₄ or ethanol following co-incubation with Huh7 cells and murine primary hepatocytes. Heme oxygenase-1 (HO-1) and other targets were measured by q-PCR.

Results: As shown by live microscopy, oxidized RBCs, but not intact RBCs, are rapidly ingested by both Huh7 cells and murine primary hepatocytes within 10 minutes. In some cases, more than 10 RBCs were seen within hepatocytes, surrounding the nucleus. RBC efferocytosis also rapidly induces HO1, its upstream regulator Nuclear factor erythroid 2-related factor 2 (Nrf2) and ferritin, indicating efficient heme degradation. Preliminary data further suggest that hepatocyte efferocytosis of oxidized RBCs is, at least in part, mediated by scavenging receptors such as ASGPR1. Of note, pretreatment of RBCs with ethanol but also heme and bilirubin also initiated efferocytosis. In a cohort of heavy human drinkers, a significant correlation of hepatic ASGPR1 with the heme degradation pathway was observed.

Conclusion: We here demonstrate that hepatocytes can directly ingest and degrade oxidized RBCs through efferocytosis, a process that can be also triggered by ethanol, heme and bilirubin. Our findings are highly suggestive for a novel mechanism of hepatic iron overload in ALD patients.

Background and aims: Real-world analyses on burden of illness in patients with alpha-1 antitrypsin deficiency (AATD) are limited. We investigated the real-world burden of liver-related clinical events among adult and pediatric patients with AATD in the USA.

Methods: This was a retrospective, observational analysis of administrative claims data from the IQVIA PharMetrics^® Plus and Ambulatory Electronic Medical Records databases from 2011 to 2022. Patients had a diagnosis of liver and/or lung disease with ≥180 days of continuous enrollment in the IQVIA PharMetrics Plus database before and ≥90 days after their first diagnosis. Follow-up time was assigned to the AATD with liver disease health state or AATD with both liver and lung disease health state (for patients aged ≥18 years only). Baseline demographic characteristics and liver-related clinical events of interest were reported.

Results: Of 5136 eligible patients, 771 adult and 123 pediatric patients contributed time to the AATD with liver disease health state; 541 adults contributed time to the AATD with both liver and lung disease health state. Among adults, patients with both liver and lung disease had higher rates of liver-related clinical events than patients with liver disease alone. Ascites was the most frequently observed clinical event among adults in both health states, and the median time to the composite of any liver-related clinical event was 26.5 days among all adults combined. Across all pediatric age groups, ascites, gastrointestinal bleed and hepatic encephalopathy were more common than spontaneous bacterial peritonitis and hepatocellular carcinoma, but median time to liver-related clinical event varied by age group at index date and type of event. No liver transplantations occurred in patients aged 6-17 years.

Conclusion: Diagnosed AATD with liver disease carries a substantial burden on adult and pediatric patients; new treatment options are warranted to avoid disease progression to decompensating events.