Impaired Liver Function Research Articles

Novel mechanistic insights of the potential role of gasotransmitters and autophagy in the protective effect of metformin against hepatic ischemia/reperfusion injury in rats.

Metformin exerts antidiabetic and pleiotropic effects. This study investigated the function and mechanisms of gasotransmitters and autophagy in the metformin-induced protection against ischemia/reperfusion injury (I/RI). According to measurements of serum hepatic function indicators and histopathological evaluation, metformin protected against hepatic I/RI-induced impairment of liver function and structure. In addition, metformin inhibited hepatic I/RI-induced hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis. Also, it suppressed hepatic I/RI-induced decrease in hepatic heme oxygenase-1 (HO-1) and hydrogen sulfide (H2S) levels and increase in nitric oxide (NO) production. Furthermore, metformin inhibited hepatic I/RI-induced decrease in protein expressions of endothelial NO synthase (eNOS), HO-1, cystathionine γ-lyase (CSE), and Beclin-1 and increase in the protein expression of inducible NO synthase (iNOS) in the liver tissue. Co-administration of the NO biosynthesis inhibitor, L-NAME, carbon monoxide(CO)-releasing molecule-A1 (CORM-A1), the H2S donor, NaHS, or the autophagy stimulator, rapamycin (RAPA), enhanced all effects of metformin. The NO donor, L-arginine, the CO biosynthesis inhibitor, zinc protoporphyrin, the H2S biosynthesis inhibitor, DL-propargylglycine, or the autophagy inhibitor, chloroquine (CQ), antagonized the effects of metformin. These findings reveal, for the first time, that increasing CO, H2S, and autophagy levels with subsequent decreasing NO level play a critical role in metformin's protective action against hepatic I/RI. The ability of L-NAME, CORM-A1, NaHS, and RAPA to boost metformin's protective effect in hepatic I/RI may positively be attributed to their ability to lower hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis.

Metabolomic Insights into Smoking-Induced Metabolic Dysfunctions: A Comprehensive Analysis of Lipid and Amino Acid Metabolomes

Background: Cigarette smoking is a leading cause of preventable mortality, largely due to the absence of effective, non-invasive biomarkers for early disease detection. Profiling serum metabolomics to identify metabolic changes holds the potential to accelerate the detection process and identify individuals at risk of developing smoking-related diseases. Objectives: This study investigated the biochemical and metabolomic changes induced by nicotine exposure, with a focus on disruptions in amino acid, lipid, and carbohydrate metabolism. Methods: Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was employed to observe significant disruptions in lipid and amino acid metabolism, along with alterations in key metabolic pathways. A total of 400 smokers and 100 non-smokers were included to evaluate the biomarkers related to insulin resistance, blood lipid profile, inflammation, and kidney and liver function. Results: The results demonstrated significantly elevated (p < 0.05) levels of glycemic markers in smokers, including fasting blood glucose; glycated hemoglobin (HbA1c); and inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). Smokers also exhibited dyslipidemia, with increased total cholesterol (154.888 ± 35.565) and LDL levels (117.545 ± 24.138). Impaired liver and kidney function was evident, with significantly higher levels (p < 0.05) of AST, ALP, ALT, blood urea nitrogen, and creatinine in smokers. A total of 930 metabolites were identified, of which 343 exhibited significant alterations (p < 0.05) in smokers compared to non-smokers. Among these, 116 metabolites were upregulated, and 127 were downregulated. Metabolomic pathway analysis revealed eight significant pathways. The study also identified three lipid metabolites specific to smokers and seven unique to non-smokers. Through LC-MS/MS, fragments of phenylalanine, tryptophan, valine, histidine, carnitine, and sphinganine were detected. Several lipidomic changes associated with insulin resistance and cardiovascular complications were observed. Cadmium (Cd) levels were higher in smokers than non-smokers (1.264 ppb vs. 0.624 ppb) and showed a strong negative correlation (R2 = 0.8061, p-value = 0.015) with serum zinc (Zn), likely due to Cd displacing Zn in proteins and causing nephrotoxicity through accumulation. Conclusions: This study highlights the distinct metabolic disruptions caused by smoking that could serve as potential biomarkers for the early detection of metabolic diseases. It emphasizes the importance of metabolomics in identifying systemic indicators of smoking-related health issues, providing new opportunities for preventive and therapeutic interventions.

Nonalcoholic fatty liver disease and chronic kidney disease: random connections or two manifestations of metabolic syndrome?

Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are two global public health problems that affect almost 30% and up to ~10-15%, respectively, of the general adult population in many parts of the world. It is quite obvious that NAFLD is a “multisystem disease” associated not only with impaired liver function and the development of hepatocellular carcinoma, but also with an increasing risk of developing cardiovascular diseases (the main cause of death in such patients), chronic kidney disease (CKD). However, the mechanisms underlying this association remain largely unknown. The aim of this review is to report on the epidemiology and pathophysiology of the relationship between NAFLD and CKD and to describe the different methods of kidney function assessment in patients with NAFLD as well as to discuss the potential for promising pharmacotherapy with simultaneous benefit for the outcomes of both diseases.

NIR Fluorescence Strategy for the Early Diagnosis of Melanoma Liver Metastasis Based on the Cascade Reaction of Two Specific Bioenzymes.

Melanoma liver metastasis poses a serious risk to patient health, leading to deterioration of liver function accompanied by symptoms such as jaundice, abdominal pain, and weight loss. Early detection is paramount as it allows for timely intervention, potentially improving treatment efficacy and patient outcomes. Herein, a dual-target probe activated by butyrylcholinesterase (BChE) and tyrosinase (TYR) was proposed by initiating an enzyme cascade reaction, revealing NIR-emissive methylene blue (MB) as a responsive product. The cascade reaction mechanism was confirmed by enzyme activity inhibition experiments and high-resolution mass spectrometry. Intercellular imaging was carried out on the coincubation model of Hep G2 and B16 cell lines, which is the first attempt to the best of our knowledge. The results showed that BChE expressed in liver cells and TYR overexpressed in B16 cells jointly activated NIR fluorescence, which provides the possibility for the precise detection of melanoma liver metastasis. In vivo studies further proved that this method holds promise for the early diagnosis and postoperative adjunctive therapy of hepatic melanoma, ultimately enhancing survival rates.

Updated results from the phase Ib/II study of fruquintinib combined with SOX and toripalimab in patients with advanced metastatic gastric/gastroesophageal junction adenocarcinoma (GC/GEJC).

423 Background: The efficacy of first-line treatment in advanced GC/GEJC patients (pts) with negative or low PD-L1 expression still needs to be improved. This phase Ib/II, open-label study (NCT05024812) evaluating fruquintinib (a highly selective VEGFR-1, -2, -3 inhibitor) plus toripalimab (anti-PD-1), and SOX has shown preliminary antitumor activity as first-line therapy in GC/GEJC. Here we update the results with longer follow-up duration and a specific focus on PD-L1 CPS features. Methods: The study of phase Ib employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) po, d1-14, in combination with fixed dose of toripalimab (240mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and S-1 (40-60mg based on BSA, po, d1-14) every 3 weeks. It had been reported in phase Ib that fruquintinib 5mg/d was defined as the RP2D. In phase II, a further 64 pts would be treated with the same regimen. Primary endpoint of phase II was PFS per RECIST 1.1. Secondary endpoints included ORR, DCR, OS, DOR and safety. Results: As of August 15, 2024, 32 pts (9 in phase Ib; 23 in phase II) had been enrolled. Pts characteristics included: median age 62 (range 38–73); 66% male; 88% with ECOG PS 1, and 31% with liver metastasis. 31 pts had PD-L1 CPS available. 40.6% were CPS < 1 and 68.8% were CPS < 5. Of the 30 pts evaluable for tumor response, the ORR was 63.5% (95% CI 43.9–80.1) with 4 pts achieving complete responses and DCR was 96.7% (95% CI 82.8–99.9). After a median follow-up of 10.94 months, the median PFS was 9.33 (95% CI: 5.68–NA) months and OS result was not reached. Pts with CPS < 5 were more likely to achieve higher response rate (65.0 vs 55.6%) and longer PFS than CPS ≥5 (12.68 vs 8.11 months). Similar trends were observed in pts with CPS < 1 and CPS ≥1 (ORR: 75.0 vs 52.9%; PFS: 12.68 vs 8.11 months). Treatment-related adverse events (TRAEs) were mainly grade 1-2 and the most common ones were hypoalbuminemia (50%), neutrophil count decreased (34%), anemia (41%), platelet count decreased (34%) and white blood cell decreased (34%). Grade 4 TRAEs occurred in 2 pts (impaired liver function, hypertriglyceridemia). There were no treatment related deaths in the trial. Conclusions: Fruquintinib combined with SOX and toripalimab provided favorable efficacy and manageable toxicity profile as first-line therapy for pts with advanced metastatic GC/GEJC, especially in pts with negative or low PD-L1 expression. More data including the potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT05024812 .

Clinical outcomes of stereotactic body radiation therapy to the liver.

565 Background: Stereotactic body radiation therapy (SBRT) can accurately and effectively target liver lesions with an ablative dose. However, prior studies suggest that SBRT directed at tumors near the central hepatobiliary tract may lead to downstream toxicity including biliary stricture and impaired liver function. This study aims to evaluate clinical outcomes and hepatobiliary toxicities associated with SBRT to the liver. Methods: This retrospective study reviews 177 patients who received CT- or MR-guided SBRT to the liver at Dana-Farber Cancer Institute and Brigham and Women’s Hospital from 2010 to 2024. Patient demographics, treatment characteristics, and clinical outcomes were extracted from electronic medical records. Local control, regional control, and overall survival were assessed using Kaplan-Meier methods. Toxicity was evaluated by tracking the incidence of biliary stricture requiring intervention and Child-Pugh (CP) scores pre- and post-SBRT. Results: Of the 177 patients, 47 (26.6%) had primary disease and 130 (73.4%) had metastatic disease, with a median follow-up of 58.7 months. Among those with primary disease, 9 (19.1%) had post-SBRT local progression (median time to progression not reached, 95% CI: 47.3, NA) and 26 (55.3%) had regional progression (median time to progression of 20.5 months, 95% CI: 6.5, 58.1). Of patients with metastatic disease, 44 (33.8%) had local progression (median time to progression of 40.2 months, 95% CI: 23.0, NA) and 96 (73.8%) had regional progression (median time to progression of 5.9 months, 95% CI: 4.8, 9.3). Median overall survival post-SBRT was 34.6 months for primary disease (95% CI: 20.2, 57.7) and 23.6 months for metastatic disease (95% CI: 19.0, 28.8). 18 patients (10.1%) later developed biliary stricture requiring intervention (12.8% of primary disease and 9.2% of metastatic disease). Of the 119 patients with CP scores available, 59 patients (49.6%) had a maximum post-SBRT CP score increase of 2 or more (55.0% of primary disease, 46.8% of metastatic disease). Conclusions: This study demonstrates that SBRT is an effective treatment option for local control in the liver, with better survival and progression outcomes for primary disease compared to metastatic disease. Among potential post-SBRT toxicities, initial analysis indicates frequent increase in CP score and low incidence of biliary stricture requiring intervention. An ongoing analysis will explore whether the dose to central bile ducts correlates with late strictures and toxicities.

Chronic environmental exposure to polystyrene microplastics increases the risk of nonalcoholic fatty liver disease.

Microplastics (MPs), as the crucial environmental pollutants, can be easily transported into the human body and accumulate in the liver. However, current studies mainly focus on acute exposure to MPs, investigations on long-term interactions with MPs alone remain limited. Thereby, we examined noxious properties of MPs and selected the most common polystyrene (PS) MPs as the research object, including unmodified PS MPs (PS-MPs) and positive-charged PS MPs (PS-NH2) at 10 mg/L employing oral drinking water methods in mice for six consecutive months in vivo. In vitro, we treated the human hepatocyte cells with MPs at 25 μg/mL to explore involved mechanisms. The results revealed that six-month MPs exposure led to nonalcoholic fatty liver disease (NAFLD) including impaired liver functions, extensive lipid depositions accompanied by abnormal levels of metabolic genes and PS-NH2 MPs exerted a stronger effect than PS-MPs. Concurrently, mice treated with MPs revealed the accumulation of senescent hepatocytes, leading to increased secretions of senescent phenotypes in the liver. We also discovered that MPs initiated the HO-1/Nrf2 axis consequently inducing ferroptosis in vivo and in vitro, as shown by massive iron deposition, extensive lipid peroxidation along with significant protein expressions in ferroptosis-related markers. Additionally, targeting the HO-1/Nrf2 pathway to further alleviate ferroptosis with corresponding inhibitors could efficiently alleviate cell senescence. Therefore, our study reveals new evidence of the relationship between chronic exposure to MPs and NAFLD and furthers the understanding of how plastic pollution affects human health.

Clinical and prognostic insights into Chlamydia trachomatis in pediatric acute respiratory infections: evidence from targeted next-generation sequencing of 5,021 cases.

Chlamydia trachomatis (CT) is a major cause of respiratory tract infections in children. The primary objective of this research was to evaluate the infection status and clinical manifestations associated with C. trachomatis in these pediatric patients. From April 2021 to November 2023, a total of 5,021 hospitalized children with acute respiratory tract infections were collected at the Guangxi Maternal and Child Health Hospital. tNGS was used to detect pathogens in their respiratory samples. Among the 5,021 hospitalized pediatric patients with acute respiratory tract infections, targeted next-generation sequencing (tNGS) detected C. trachomatis in 138 cases, with a detection rate of 2.75%. Among the 138 cases positive for C. trachomatis, 10 were identified as single C. trachomatis infection, while 128 cases involved co-infections with other pathogens. A total of 36 additional pathogens were detected in children with mixed Chlamydia trachomatis infections, with Pneumocystis jirovecii being the most frequently detected. In children with C. trachomatis infection, pulmonary consolidation and hypoxemia were the most commonly observed respiratory complications, whereas anemia and liver function impairment were the primary complications affecting other organ systems. The median duration of hospitalization for the 138 children was 8 days. Among the 138 children with C. trachomatis infection, 108 cases (78.26%) required respiratory support, and 11 cases (7.97%) required ICU admission. The detection rate of C. trachomatis among hospitalized pediatric patients with respiratory tract infections was 2.75%. This study delineates the clinical manifestations and infection patterns of C. trachomatis in Guangxi, China.

Lactobacillus extracellular vesicles alleviate alcohol-induced liver injury in mice by regulating gut microbiota and activating the Nrf-2 signaling pathway.

Lactobacillus derived extracellular vesicles (LAB-EVs) are nanosized particles secreted from Lactobacillus during fermentation, and therefore exist universally in fermented foods such as yogurt, pickles, and fermented beverages. In this study, three LAB-EVs were prepared using a simple scalable method, and then their structures, compositions, and biosafety properties were characterized. The protective properties and potential mechanisms of action of the LAB-EVs against alcoholic liver disease were studied. All three LAB-EVs alleviated alcohol-induced liver injury. It was shown by reduction of liver index, histological damage, liver function impairment, inflammation, and liver oxidative status. The results showed that three LAB-EVs positively promoted the diversity of intestinal flora in mice. Additionally, the relative hepatic protein level of Nrf-2, HO-1, and CYP2E1 was also regulated by LAB-EVs. In summary, these facts suggest that the three LAB-EVs can alleviate alcohol-induced liver damage, by positively modulating the intestinal flora and activation of the Nrf-2 signaling pathway. These results may facilitate the understanding of the composition and function of Lactobacillus fermented food and also the development of Lactobacillus fermented functional food.

Palbociclib Is Safe for Breast Cancer Patients With Mild Hepatic Impairment: A Multicenter Retrospective Study Using Real-World Data.

The liver is crucial for metabolizing the anticancer drug palbociclib, but limited information is available on the impact of hepatic impairment on its toxicity and efficacy, with no real-world data available. This study aims to evaluate how hepatic impairment affects hematological toxicity and progression-free survival (PFS) of palbociclib in advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, using the National Cancer Institute scoring system, in a large real-world dataset. This multicenter retrospective observational study included female patients treated with palbociclib between August 2017 and February 2024. Regression analysis was used to compare the risk of developing grade 3/4 hematological toxicity and PFS between patients with normal and mild impaired liver function. In total, 478 female patients were included. Patients with mild hepatic impairment (n = 205) did not have an increased risk of developing grade 3/4 neutropenia compared with patients with normal hepatic function (n = 273) (hazard ratio (HR) = 1.11; 95% CI 0.83-1.47). In addition, the PFS was not significantly different between both groups (HR = 1.15; 95% CI 0.93-1.42). In real-world settings, patients with mild hepatic impairment do not have a higher risk of developing palbociclib-induced neutropenia or disease progression than patients with normal hepatic function. These findings can guide clinicians when treating breast cancer patients with mild hepatic impairment.

Dynamic analysis of intrahepatic T cells reveals a unique group of restorative Cxcr3+ tissue-resident CD4 T cells in acute liver injury.

Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4+ T cells post-APAP injury. Amongst these, a distinct population of restorative Cxcr3+ tissue-resident CD4+ T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the Cxcr3+ tissue-resident CD4+ T cells were tightly regulated by intrahepatic ''Lgals9-Cd45'' and 'CXCL13-Cxcr3' signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.

Su’al-Qinya: Unani Perspective on Iron Deficiency Anemia, its Pathogenesis, and Therapeutic Interventions

Anemia, a pervasive global health concern, affects millions worldwide. This study aims to provide an in-depth examination of anemia from the perspective of Unani medicine, exploring its etiology, pathogenesis, and treatment modalities. A comprehensive review of classical Unani texts and contemporary research reveals that anemia is attributed to alterations in blood composition, impaired liver function, and nutrient deficiencies. Unani practitioners employ a holistic approach, incorporating regimenal therapy, herbal remedies, and lifestyle modifications to address the underlying causes of anemia. This study highlights the significance of integrating Unani principles into modern healthcare practices, providing a complementary approach to addressing anemia and promoting overall well-being. This study aims to explore the Unani perspective on anemia, examining its etiology, pathogenesis, and treatment modalities, and highlighting the potential benefits of integrating Unani principles into modern healthcare practices. This study demonstrates the relevance of Unani medicine in understanding and addressing anemia, emphasizing the importance of a holistic approach to healthcare. By integrating Unani principles into modern healthcare practices, healthcare providers can offer a more comprehensive and patient-centred approach to managing anemia and promoting overall well-being. Keywords: Su’al-Qinya, Faqru-dam, Qillatu-dam, Anemia, Unani medicine, Iron deficiency anemia.

A hypocaloric protein-rich diet before metabolic surgery improves liver function in patients with obesity and diabetes

PurposeObesity and type 2 diabetes (T2DM) are major risk factors for hepatic steatosis. Diet or bariatric surgery can reduce liver volume, fat content, and inflammation. However, little is known about their effects on liver function, as evaluated here using the LiMAx test.MethodsIn the MetaSurg study (RCT on the effects of different Roux-en-Y gastric bypass (RYGB) limb lengths on diabetes remission in patients with BMI ≥ 27 to ≤ 60 kg/m2 and T2DM; trial registration: DRKS00007810, German Clinical Trials Register Freiburg), 24 consecutive patients underwent liver function (LiMAx) and imaging assessments (MRI, transient elastography; TE) before and after diet and surgery. Two weeks before surgery, the patients received a hypocaloric protein-rich diet.ResultsNine of 18 patients had a pathologic LiMAx value (≤ 315 µg/kg/h) at baseline. After two weeks of diet, LiMAx values improved (p = 0.01, paired t test, n = 15). LiMAx values further recovered six months after RYGB (p = 0.01, paired t test, n = 15), which was accompanied by decreased liver volumes (p = 0.005, paired t test, n = 10), proton density fat fraction (p = 0.003, paired t test, n = 12), and TE measurements (p = 0.032, paired t test, n = 14). The need for medical diabetes treatment decreased from 100 to 35%.ConclusionLiver function improved after a two-week hypocaloric protein-rich diet and metabolic surgery in patients with obesity and T2DM. These data suggest that a two-week diet for this group of patients prior to abdominal surgery could improve a presumably impaired liver function.

The supply of branched-chain amino acids and branched-chain keto acids alter lipid metabolism, oxidative stress, and apoptosis in primary bovine hepatocytes.

Fatty liver impairs liver function and reduces productivity in dairy cows. Our previous in vivo findings demonstrated that branched-chain amino acids (BCAA) or branched-chain ketoacid (BCKA) improved liver function and lactation performance in dairy cows; however, the underlying mechanisms remain unclear. This study aimed to assess the impact of BCAA or BCKA supplementation on intracellular triglyceride (TG) accumulation, lipid metabolism, antioxidant response, and apoptosis in hepatocytes. Treatments were: control (CON): customized medium with amino acids, volatile fatty acids, fatty acids (FA), glucose, choline, insulin, and albumin concentrations equal to circulating levels in cows 4d postpartum; BCAA: CON + 33% additional BCAA of plasma BCAA 4d postpartum; and BCKA: CON + 33% additional BCKA of plasma BCAA 4d postpartum. Compared to CON, BCAA and BCKA reduced intracellular TG concentration by 32% and 40%, respectively, after 72 h. BCAA and BCKA enhanced the uptake of palmitic acid, but upregulated the expression of genes regulating FA oxidation. Although mitochondrial membrane potential was reduced, oxidative protein damage (protein carbonyl levels) was decreased in BCAA- and BCKA-treated hepatocytes without changes in mitochondrial copy number. Additionally, compared to CON, BCAA and BCKA decreased the expression of executioner caspases (caspase 3 and caspase 7) and reduced the portion of hepatocytes with activated caspase 3/7, suggesting reduced apoptosis. These findings suggest that BCAA or BCKA supplementation improves hepatocyte lipid metabolism, antioxidant defenses, and apoptosis regulation, potentially mitigating the adverse effects of fatty liver. These mechanisms likely underlie the previously observed improvements in liver function and lactation performance.

Cluster Analysis of HCC Prognosis Using Preoperative AFP and DCP Levels: A Multi-Institutional Study.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, characterized by high recurrence rates post-curative resection. Tumor markers des-gamma-carboxy prothrombin (DCP) and alpha-fetoprotein (AFP) are crucial for HCC diagnosis and prognosis, yet their roles in the modern era of HCC epidemiology require reevaluation. This multi-institutional retrospective study analyzed 1,515 patients who underwent hepatectomy for primary HCC. Patients were classified into four clusters using k-means analysis based on preoperative DCP and AFP levels. Clinicopathological characteristics, overall survival (OS), and recurrence rate (RR) were evaluated using Cox proportional hazards models and AUROC comparisons. Cluster 3 (concurrent elevations of DCP and AFP) had the poorest 5-year OS (52.8%) and highest RR (79.3%), while Cluster 4 (low levels of both markers) had the most favorable outcomes, with 5-year OS at 71.5% and RR at 55.7%. Cluster 1 (elevated DCP alone) was associated with larger tumors (median 45mm) and more frequent vascular invasion (43%) compared to Cluster 2 (elevated AFP alone, median tumor size 24mm, vascular invasion 36%). DCP was a stronger predictor of 5-year OS in patients with preserved liver function (AUROC 0.63), while AFP was more effective for stratifying RR in patients with impaired liver function (AUROC 0.57). NBNC-related HCC exhibited a distinct biomarker profile, with elevated DCP correlating with a higher 5-year RR (67%) compared to other etiologies. This study introduces tumor marker clustering as a novel analytical approach, providing a nuanced understanding of AFP and DCP's combined utility in predicting prognosis and recurrence. These findings highlight the independent and complementary roles of these biomarkers, particularly in NBNC-related HCC and cases with impaired liver function. AFP and DCP remain critical tools for recurrence risk assessment, guiding personalized management strategies such as surveillance, neoadjuvant therapies, and tailored postoperative interventions.

The Association of Persistent Hyperuricemia With Liver Function and the Management of Uric Acid Levels: Insights From a Three-Year Prospective Cohort Study.

The association of long-term hyperuricemia with liver function remains less well understood. This prospective cohort study aimed to investigate the relationship between hyperuricemia and liver function as well as other metabolic and cardiovascular parameters. We enrolled 375 participants with hyperuricemia and 599 normouricemic controls. Participants were followed up for 3 years, and data on liver indicators, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver ultrasonography were collected. Additionally, we assessed other parameters, such as renal function, lipid profile, blood pressure, fasting blood-glucose (FBG), and body mass index (BMI). The highest prevalence of hyperuricemia was observed in the 20-29 age groups for the participants. Among the comorbidities of patients with hyperuricemia, the proportion of dyslipidemia is the highest (58.13%), followed by fatty liver (50.13%) and liver function impairment (33.07%). During the three-year follow-up period, compared to the baseline, patients with persistent hyperuricemia showed significant increases in BMI, triglycerides, total cholesterol, AST, and ALT levels (p < 0.05). Meanwhile, patients with improved hyperuricemia for 2 years exhibited significant decreases in FBG, total cholesterol, serum creatinine (p < 0.05), along with a significant increase in eGFR (p < 0.05). Correlation analysis revealed that levels of uric acid were positively correlated with ALT, FBG, and triglycerides in persistent hyperuricemia (p < 0.05). Hyperuricemia shows a notable trend of younger age onset. Persistent hyperuricemia, correlated with elevated ALT levels, indicates an increasing risk of liver damage that should be concerned about. Effective management of hyperuricemia could improve metabolic disorders and renal dysfunction.

Involvement of intestinal mucosal microbiota in adenine-induced liver function injury.

Adenine is frequently utilized as a model medication for chronic renal disease. Adenine can affect organs other than the kidneys, including the heart and the intestine. The liver is a vital organ involved in the in vivo metabolism of adenine. Adenine may negatively impact liver function. Research indicated that adenine caused dysbiosis of the gut microbiota in mice. Investigations into the gut-liver axis have demonstrated a substantial association between drug-induced hepatic dysfunction and gut microbiota. Consequently, we delivered distinct dosages of adenine via gavage to mice to examine the correlation between adenine-induced liver impairment and gut microbiota dysbiosis. Mice were treated with low-dose adenine suspension (NLA), medium-dose adenine suspension (NMA), high-dose adenine suspension (NHA), and sterile water (NC) as a control. The results indicated that mice in the NLA, NMA, and NHA groups had decreased body weight and a reduction in liver index. Subsequent to adenine administration, the concentrations of AST, ALT, and LDH increased, whereas SDH levels decreased. As doses increased, liver function impairment and hepatic energy metabolism abnormalities aggravated.Adenine also damaged the colonic architecture in mice. Moreover, adenine modified the makeup and structure of the gut mucosal microbiota, enhancing specific bacterial genera and influencing the microbiota's energy metabolism-related functions. The results of our research established a correlation among certain bacteria, liver function injury, and hepatic energy metabolism. The gut mucosal microbiota was involved in adenine-induced liver injury and hepatic energy metabolism. These results can offer novel insights into the role of gut microbiota in drug-induced liver injury and provide specific guidelines for the modeling and therapeutic application of adenine.

Chronic Liver Disease: An Updated Review for Healthcare Professionals

Background: Chronic liver disease (CLD) is a progressive condition characterized by the deterioration of liver function over time, leading to fibrosis, cirrhosis, and potentially hepatocellular carcinoma (HCC). The liver, a vital organ, performs essential functions such as detoxification, protein synthesis, and bile production. CLD arises from various etiologies, including viral hepatitis, alcohol abuse, non-alcoholic fatty liver disease (NAFLD), autoimmune disorders, and genetic conditions. The disease progresses through stages of inflammation, fibrosis, and cirrhosis, with complications such as portal hypertension, ascites, hepatic encephalopathy, and HCC significantly impacting patient quality of life and survival. Aim: This review aims to provide healthcare professionals with an updated understanding of the etiology, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies for CLD. It emphasizes the importance of early diagnosis, targeted treatment, and multidisciplinary care to improve patient outcomes. Also, this review investigated the main role of anesthesiologists during chronic liver diseases care. Methods: The review synthesizes current literature on CLD, focusing on its diverse etiologies, molecular mechanisms, and clinical progression. Diagnostic tools, including serological tests, imaging, and liver biopsy, are discussed. Management strategies, including pharmacological treatments, lifestyle modifications, and surgical interventions, are outlined. The role of scoring systems like Child-Pugh and MELD in assessing disease severity and prognosis is also highlighted. Results: CLD is a multifactorial condition with varying progression rates depending on the underlying cause. Early-stage fibrosis may be reversible, but advanced cirrhosis is irreversible without liver transplantation. Complications such as variceal bleeding, hepatic encephalopathy, and HCC significantly worsen prognosis. Advances in antiviral therapies, antifibrotic agents, and liver transplantation have improved outcomes, but early intervention remains critical. Conclusion: CLD is a complex and debilitating condition requiring a comprehensive approach to diagnosis and management. Early detection, tailored treatment, and patient education are essential to slow disease progression and improve survival. Multidisciplinary care, including hepatologists, anesthesiologists, and surgeons, plays a pivotal role in optimizing outcomes for patients with CLD.

From a sudden flood to a silent gut: a rare case report of paralytic ileus and pulmonary hemorrhage due to leptospirosis

Leptospirosis is a zoonotic disease that can cause serious complications such as a pulmonary hemorrhage and paralytic ileus. A 49-year-old man presented with symptoms of fever, myalgia, nausea, vomiting, and diarrhea after exposure to floods in Gorontalo, Indonesia. The diagnosis of leptospirosis was made based on Modified Faine's Criteria, thrombocytopenia, leukopenia, eosinophilia, impaired liver function, and positive RDT results for Leptospira IgM. On the fifth day of treatment, the patient’s condition deteriorated, presenting as shortness of breath and acute abdominal pain. Chest x-ray and BNO 3 position examination suggest pulmonary hemorrhage and paralytic ileus. The patient’s condition improved following the administration of Ceftriaxone and multidisciplinary management, including nasogastric decompression and oxygenation. This case emphasizes the importance of monitoring and early treatment of serious complications of leptospirosis.

S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model

ABSTRACT S-amlodipine, a commonly prescribed antihypertensive agent, is widely used in clinical settings to treat hypertension. However, the potential adverse effects of long-term S-amlodipine treatment on the liver remain uncertain, given the cautionary recommendations from clinicians regarding its administration in individuals with impaired liver function. To address this, we conducted a study using an eight-week-old male rat model and administered a daily dose of 0.6 ~ 5 mg/kg of S-amlodipine for 7 weeks. Our findings demonstrated that 1.2 ~ 5 mg/kg of S-amlodipine treatment induced liver inflammation and associated dysfunction in rats, further in vitro experiments revealed that the observed liver inflammation and dysfunction were not attributable to direct effects of S-amlodipine on the liver. Metagenome sequencing analysis revealed that S-amlodipine treatment led to alterations in the gut microbiome of rats, with the bloom of E. coli (4.5 ~ 6.6-fold increase) and a decrease in A. muciniphila (1,613.4 ~ 2,000-fold decrease) and B. uniformis (20.6 ~ 202.7-fold decrease), subsequently causing an increase in the gut bacterial lipopolysaccharide (LPS) content (1.4 ~ 1.5-fold increase in feces). S-amlodipine treatment also induced damage to the intestinal barrier and increased intestinal permeability, as confirmed by elevated levels of fecal albumin; furthermore, the flux of gut bacterial LPS into the bloodstream through the portal vein resulted in an increase in serum LPS content (3.3 ~ 4-fold increase). LPS induces liver inflammation and subsequent dysfunction in rats by activating the TLR4 pathway. This study is the first to show that S-amlodipine induces liver inflammation and dysfunction by perturbing the rat gut microbiome. These results indicate the adverse effects of S-amlodipine on the liver and provide a rich understanding of the safety of long-term S-amlodipine administration.