Liver Function Research Articles

A Cross Sectional Study of the Prevalence of Retinopathy in Patients with Chronic Kidney Disease on Hemodialysis in a Tertiary Care Centre in Chengalpattu District, South India

Context: Many studies have reported varying proportions of retinopathy among cases with chronic kidney disease (CKD). Cases with severe grades of CKD were more likely to develop ocular complications, especially diseases which occurs due to small vessel pathology. Aim: To estimate the prevalence of various types of retinopathies in patients with CKD undergoing hemodialysis in a tertiary care centre in South India. Settings and Design: The outpatient Department of Ophthalmology and Hemodialysis unit of Nephrology, Karpaga Vinayaga Institute of Medical Sciences from January 2022 to June 2023 A cross-sectional hospital-based observational study in a low resource setting. Methods and Material: The study consists of 28 patients who were known cases of CKD on hemodialysis. Patients underwent complete ocular evaluation and findings were noted. The pre hemodialysis values of blood urea and serum creatine, hemoglobin, liver function tests and vital parameters were also noted. Data analysis was done utilising version 20 of Statistical Packages for the Social Sciences (SPSS). Results: 56 eyes of 28 patients on hemodialysis were studied. The mean age was 53 years + 10.9 with a male preponderance. 31.6% had retinopathy of which 26.3% had hypertensive retinopathy and 5.3% had diabetic retinopathy. This is contrary to the previous studies that have reported a higher incidence of diabetic retinopathy in patients with end stage CKD. Hypertension resulted in CKD earlier than diabetes. Conclusion: The results emphasize the importance of frequent eye examination in patients with CKD to identify retinopathy earlier, thus potentially averting permanent vision impairment.

Night shift-induced circadian disruption: links to initiation of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and risk of hepatic cancer.

The circadian system plays a crucial role in regulating metabolic homeostasis at both systemic and tissue levels by synchronizing the central and peripheral clocks with exogenous time cues, known as zeitgebers (such as the light/dark cycle). Our body's behavioral rhythms, including sleep-wake cycles and feeding-fasting patterns, align with these extrinsic time cues. The body cannot effectively rest and repair itself when circadian rhythms are frequently disrupted. In many shift workers, the internal rhythms fail to fully synchronize with the end and start times of their shifts. Additionally, exposure to artificial light at night (LAN), irregular eating patterns, and sleep deprivation contribute to circadian disruption and misalignment. Shift work and jet lag disrupt the normal circadian rhythm of liver activity, resulting in a condition known as "circadian disruption". This disturbance adversely affects the metabolism and homeostasis of the liver, contributing to excessive fat accumulation and abnormal liver function. Additionally, extended working hours, such as prolonged night shifts, may worsen the progression of non-alcoholic fatty liver disease (NAFLD) toward non-alcoholic steatohepatitis (NASH) and increase disease severity. Studies have demonstrated a positive correlation between night shift work (NSW) and elevated liver enzymes, indicative of hepatic metabolic dysfunction, potentially increasing the risk of hepatocellular carcinoma (HCC) related to NAFLD. This review consolidates research findings on circadian disruption caused by NSW, late chronotype, jet lag, and social jet lag, drawing insights from studies involving both humans and animal models that investigate the effects of these factors on circadian rhythms in liver metabolism.

Synergistic Effects of Fructose and Food Preservatives on Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): From Gut Microbiome Alterations to Hepatic Gene Expression.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem closely linked to dietary habits, particularly high fructose consumption. This study investigates the combined effects of fructose and common food preservatives (sodium benzoate, sodium nitrite, and potassium sorbate) on the development and progression of MASLD. Methods: We utilized a human microbiota-associated mouse model, administering 10% fructose with or without preservatives for 11 weeks. Liver histology, hepatic gene expression (microarray analysis), biochemical markers, cytokine profiles, intestinal permeability, and gut microbiome composition (16S rRNA and Internal Transcribed Spacer (ITS) sequencing) were evaluated. Results: Fructose and potassium sorbate synergistically induced liver pathology characterized by increased steatosis, inflammation and fibrosis. These histological changes were associated with elevated liver function markers and altered lipid profiles. The treatments also induced significant changes in both the bacterial and fungal communities and disrupted intestinal barrier function, leading to increased pro-inflammatory responses in the mesenteric lymph nodes. Liver gene expression analysis revealed a wide range of transcriptional changes induced by fructose and modulated by the preservative. Key genes involved in lipid metabolism, oxidative stress, and inflammatory responses were affected. Conclusions: Our findings highlight the complex interactions between dietary components, gut microbiota, and host metabolism in the development of MASLD. The study identifies potential risks associated with the combined consumption of fructose and preservatives, particularly potassium sorbate. Our data reveal new mechanisms that are involved in the development of MASLD and open up a new avenue for the prevention and treatment of MASLD through dietary interventions and the modulation of the microbiome.

Datura stramonium seed ingestion leading to unintentional poisoning in a 3-year-old Ethiopian toddler: case report

IntroductionDatura stramonium poisoning, resulting from the ingestion of seeds, leaves, or flowers of Datura stramonium, is a severe condition with significant risks, particularly for young children. Most documented cases of Datura stramonium poisoning in the literature involve teenagers who intentionally ingest the plant to induce hallucinogenic and euphoric experiences. This report presents a rare instance of unintentional Datura stramonium poisoning in a 3year-old Ethiopian toddler.Case presentationHe presented with symptoms consistent with anticholinergic toxidrome, including altered mental status, agitation, seizures, dilated pupils, and tachycardia. Laboratory tests, including complete blood count, liver function test, renal function test, electrolyte levels and cerebrospinal fluid analysis were normal. Results of blood toxicology screen were negative. Timely recognition and supportive care lead to a positive outcome.ConclusionThrough this report, we aim to add to the limited body of literature on Datura stramonium poisoning in toddlers and offer insights into its clinical course and management in paediatric patients.

Liver magnetic resonance imaging, non-alcoholic fatty liver disease and metabolic syndrome risk in pre-pubertal Mexican boys.

Rising global pediatric obesity rates, increase non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) prevalence, with MetS being a NAFLD risk factor. NAFLD can be asymptomatic, with liver function tests insensitive to mild disease, and liver biopsy, risking complications. Thus, we investigated multiparametric MRI (mpMRI) metrics of liver fat (proton density fat fraction, PDFF) and disease activity (fibro-inflammation; iron-corrected T1, cT1), in a Hispanic pre-pubertal pediatric cohort, with increased risk of NAFLD. Pre-pubertal boys (n = 81) of varying Body-Mass Index (BMI) were recruited in Mexico City. Most children (81%) had normal liver transaminase levels, 38% had high BMI, and 14% had ≥ 3 MetS risk factors. Applying mpMRI thresholds, 12%, 7% and 4% of the cohort had NAFLD, NASH and high-risk NASH respectively. Participants with ≥ 3 MetS risk factors had higher cT1 (834ms vs. 737ms, p = 0.004) and PDFF (8.7% vs. 2.2%, p < 0.001) compared to those without risk factors. Those with elevated cT1 tended to have high BMI and high insulin (p = 0.005), HOMA-IR (p = 0.005) and leptin (p < 0.001). The significant association of increased risk of MetS with abnormal mpMRI, particularly cT1, proposes the potential of using mpMRI for routine pediatric NAFLD screening of high-risk (high BMI, high MetS risk score) populations.

Icariin is a potential neurodegenerative candidate against ammonia–glutamate excitotoxicity–oxidative stress pathway

BackgroundHepatic encephalopathy (HE) is a pathological state characterized by the abrupt or chronic failure of the liver. This study intends to conduct a comparative analysis of potential benefits of icariin (ICA), a primary component of flavonoids found in the Chinese medicinal plant Epimedium, with silymarin (SLY) as a hepatic and brain support agent in a model of HE rats, focusing on assessment of the behavioral and biochemical effects. Thioacetamide (TAA) was given intraperitoneally to rats at a dosage of 200 mg/kg on three separate days to induce HE. Oral gavage of silymarin or ICA (100 mg/kg) was given daily for 14 days following HE induction. All rats underwent behavioral assessments (open field and Y maze). Estimates were made for hepatic functions and brain cortex oxidative stress indicators as well as cytochrome c and caspase-3.ResultsThe findings demonstrated that the administration of ICA to rodents with HE induced by TAA led to a recovery of hepatic enzymes activities and behavioral adjustments as shown by an improvement in locomotor and memory functions. Furthermore, Icariin demonstrated a reduction in cortex biochemical indicators through the amelioration of hyperammonemia and enhancement of antioxidant status. This was achieved by reducing malondialdehyde, calcium, nitric oxide contents and downregulating lactate dehydrogenase activities. In addition, ICA maintains alteration of glutamate and glutamine contents.ConclusionICA suggested to possess the capacity to serve as a beneficial hepatotherapeutic and neurotherapeutic adjunct in brain disorders associated with hyperammonemia–glutamate-mediated excitotoxicity.

Evaluating the involvement and mutual interaction of wbp2 and yap in embryogenesis with an emphasis on liver function in zebrafish embryos

The Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) play complex roles in liver health, influencing processes such as fibrosis, cancer development, and regeneration. WW domain binding protein-2 (WBP2) primarily enhances the co-translational activity of YAP/TAZ, which is crucial for the progression of liver diseases. Despite existing knowledge, the specific functions of WBP2 and its interactions with YAP remain inadequately understood. This study investigates the expression levels of WBP2 in zebrafish embryos and its molecular interaction with YAP. We employed morpholino-mediated knockdown of wbp2 and yap, followed by assessments of liver histology, immunofluorescence, and co-immunoprecipitation. Subsequently, RNA sequencing analyses were conducted to elucidate the signaling pathways and mechanisms underlying the interplay between YAP and WBP2 in liver injury. Our findings highlight the significant interaction between WBP2 and YAP, emphasizing their potential as therapeutic targets for liver diseases.

COMPLICATIONS AND RISKS ASSOCIATED WITH PROLONGED PARENTERAL NUTRITION IN PEDIATRIC AND NEONATAL ICU PATIENTS: A SYSTEMATIC REVIEW

Objective: The general objective of this study is to analyze the scientific literature on the complications and risks associated with prolonged parenteral nutrition in pediatric and neonatal patients in intensive care units (ICU), aiming to ensure greater knowledge about this therapeutic practice and its clinical implications. Methodology: The searches were performed through searches in the PubMed Central (PMC) databases. Three descriptors were used in combination with the Boolean term “AND”: Parenteral Nutrition, Neonatal Intensive Care Unit and Risk Factors. A total of 101 articles were found, which were subsequently submitted to the selection criteria. After applying the inclusion and exclusion criteria, 20 studies were selected, of which 10 articles were used for detailed analysis. Results: Parenteral nutrition (PN) is essential in the care of premature newborns and critically ill pediatric patients. However, it is associated with several potential complications, including hepatobiliary, infectious, mechanical and metabolic problems such as hyperglycemia and hypertriglyceridemia. Administration of PN requires careful planning and strict safety policies to minimize risks and maximize clinical benefits. Prolonged PN can lead to serious complications, such as catheter-associated bloodstream infections, cholestasis, and liver dysfunction. Conclusion: Prolonged PN in pediatric and neonatal ICU patients is associated with significant risks that require close surveillance and preventive interventions. Continuous monitoring of glucose, triglyceride levels, and liver function, as well as rigorous infection control practices, are crucial to ensure the safety and efficacy of PN. Further studies are needed to identify management strategies that can reduce these complications and improve clinical outcomes.

Nonalcoholic Fatty Liver Disease Risk and Proprotein Convertase Subtilisin Kexin 9 in Familial Hypercholesterolemia Under Statin Treatment.

Fatty acids are involved in some hepatic disorders. The proprotein convertase subtilisin kexin 9 (PCSK9) inhibits the uptake of low-density lipoproteins (LDLs), which contain lipids, into the liver and may thus be associated with nonalcoholic fatty liver disease (NAFLD), a cardiovascular disorder (CVD) risk. Statins reduce blood LDL-cholesterol (LDL-C) levels and CVD risk and can attenuate the development of NAFLD while increasing blood PCSK9 levels. We investigated the correlation between PCSK9 and liver conditions in patients with familial hypercholesterolemia (FH), a CVD risk population with elevated blood LDL-C levels, under statin treatment. Blood tests for lipids, PCSK9, and liver function (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were performed in patients with FH taking statins (n = 25, mean age = 57 years, 12% of males). The ALT:AST ratio was used as a marker of NAFLD risk. The mean LDL-C level was 3.38 mmol/L, and the median PCSK9 level was 312 ng/mL. The median ALT:AST ratio was 0.88. A significant negative correlation was observed between the PCSK9 and ALT:AST ratio (β = -0.67, p < 0.05). Their negative correlation might give a hypothetical insight into the effect of statin treatment on the development of NAFLD, in relation to PCSK9 behavior, in patients with FH.

Significant Microbial Pathogenesis Perspective of Biliary Diseases.

This review explores various biliary tract diseases caused by different organisms, in-cluding cholelithiasis, hepatolithiasis, and choledocholithiasis. The biliary tract's primary func-tions include collecting, storing, concentrating, and delivering bile juice produced by the liver. Neurohormonal systems involving the vagus and splanchnic nerves, alongside cholecystokinin, regulate gallbladder movement during fasting and digestion. Under normal conditions, bile acids play a crucial role, with approximately 95% being reabsorbed by the intestinal epithelium and returned to the liver via the portal vein system. The liver, often hailed as a miracle worker, de-toxifies, purifies, and regenerates, performing essential functions in the body. Recent research indicates that the gallbladder, akin to the intestine, harbors a diverse microbiota. Additionally, the biliary mucosa features chemical, mechanical, and immunological barriers that promote im-munological tolerance. Hepatotoxicity remains a significant global health concern and a leading cause of mortality. Providing clear and accurate information on liver toxicity is critical, especially in the context of medication safety and public health. By refining these elements, this review can effectively convey the complexity and importance of biliary tract diseases and liver function in health and disease contexts.

Efficacy and Safety of Tenofovir Amibufenamide and Tenofovir Alafenamide for First-Time HBV-Related Decompensated Cirrhosis.

Clinical studies of tenofovir amibufenamide (TMF) and tenofovir alafenamide (TAF) treatment in patients with HBV-related decompensated cirrhosis (HBV-DC) are limited. This study evaluated the efficacy and safety of TMF versus TAF in naive-treated patients with first-time HBV-DC. Based on the antiviral drug used, patients were categorised into the TMF group and the TAF group. Virological and serological responses, hepatic and renal functions and blood lipid changes in both groups were evaluated during 48 weeks of treatment. A total of 98 patients were enrolled, 45 in the TMF group and 53 in the TAF group. At 48 weeks of treatment, the proportions of patients who achieved complete virological response (CVR) were 85.7% and 90.7%, respectively (p = 0.791). Improvement of at least 2 points in Child-Turcotte-Pugh scores was observed in 64.3% versus 79.1% (p = 0.169) of the patients. There were no significant changes in serum creatinine, estimated glomerular filtration rate or total cholesterol from baseline to week 48 between the two groups. Cystatin C remained stable in the TMF group but increased over time in the TAF group (p < 0.001). Low-density lipoprotein cholesterol remained stable in the TMF group but increased significantly in the TAF group at week 48 (p = 0.015). These results suggest that both TMF and TAF can rapidly suppress HBV replication, improve hepatic function and have no negative effects on renal function among patients with HBV-DC. Regarding lipid metabolism, both showed a better safety, while regular monitoring of blood lipid levels is recommended.

Comparison of blood parameters in two genetically different groups of horses for functional longevity in show jumping.

In order to find early selection criteria to improve the longevity of show jumping horses, a specific protocol was designed. Before entering competition, young horses selected from extreme stallions for longevity were measured for many traits, including blood parameters. Blood samples were taken from 952 horses aged 2-4years old, sired by two groups of stallions: one with unfavorable (U) and the other with favorable (F) extreme estimated breeding values for functional longevity. These breeding values were previously calculated from data on 202,320 horses that participated in show jumping competitions between 1985 and 2022. Functional longevity was defined as time spent in competition, adjusted for the level of performance. The 59 measured parameters included hematology, proteins, cytokines, liver and kidney function, bone and joint health, oxidative stress and endocrinology. Heritability was estimated using a mixed model that accounted for the effect of age, sex, estimated weight, visit (place and date of collection), and animal random additive value with 10,280 horses in pedigree. A Partial Least Square logistic regression was performed to predict the sire group. Age, sex and estimated weight significantly affected 36, 19 and 16 variables, respectively. The visit had a significant effect on all variables. Heritability estimates were high, with 75% higher than 0.20% and 30% higher than 0.50. The most heritable traits included mean corpuscular volume (0.92, se 0.11), mean corpuscular hemoglobin (0.90, se 0.11), white blood cells (0.55, se 0.13), total alkaline phosphatase (0.68, se 0.12) and percentage of γ-globulin (0.57, se 0.12). The logistic regression that predicted the group of sires favorable for longevity identified 16 significant variables. Key findings included: lower mean corpuscular hemoglobin (p-value < 0.001), lower mean corpuscular volume (p-value < 0.001), lower number of white blood cells (p-value < 0.01), higher percentage of intestinal and bone alkaline phosphatase (p-value < 0.01) for a lower total alkaline phosphatase (p-value < 0.01), higher percentage of α2-globulin (p-value < 0.001) and lower percentage of β1-globulin (p-value < 0.01). Blood parameters measured at rest in young horses may be predictive of their genetic value for functional longevity in show jumping.

Ameliorative Potential of Menstrual Blood-derived Endometrial Stem Cells in Alcohol-Induced Fatty Liver Disease

Background: Alcohol-induced fatty liver disease (AFLD) begins with steatosis and may progress to a range of pathological liver changes, including fibrosis, cirrhosis, and complications. Menstrual blood-derived endometrial stem cells (MenSCs) have shown potential therapeutic effects against various types of liver damage. However, the liver-protective effects of MenSCs in AFLD are not well understood. This study aimed to evaluate the therapeutic effects of MenSCs on AFLD progression. Methods: MenSCs were sourced from women in good health (N=5, 25-34 years old). Male C57BL/6 mice were separated into three distinct groups to establish the mouse models. The AH/- MenSCs group received MenSCs (5×105 cells/mouse) transplantation through tail injection on the 7th and 13th days following the initiation of the alcohol-induced fatty liver model. The therapeutic effects of MenSCs transplantation in AFLD mouse models were subsequently explored using qPCR, Western blotting, histopathological examination, and mRNA sequencing analysis. Results: MenSCs significantly improved liver function and reduced lipid accumulation in AFLD. Treatment with MenSCs was also found to reduce the expression levels of inflammatory cytokines and profibrotic markers in the liver tissues of the mouse model. Additionally, the MenSCs- treated group demonstrated a significant reduction in endoplasmic reticulum (ER) stress and oxidative stress, along with an increase in autophagic activity. Conclusion: The findings provided preliminary evidence of the multifaced protective effects of MenSCs in AFLD.

Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases

Tolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04). A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs. 32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes.

Improvement of endorgan function following tricuspid edge-to-edge repair

Abstract Background/Introduction Subjects with severe tricuspid regurgitation (TR) often suffer from impaired endorgan function. The potential to improve endorgan function is an important goal of treatment. Purpose To assess baseline endorgan function and changes in organ function following transcatheter edge-to-edge repair with the TriClip device in subjects with severe TR from the TRILUMINATE Pivotal randomized controlled trial. Methods Right heart catheterization was required prior to enrollment; medication history was collected. Changes in biomarkers, including MELD-XI, GGT, eGFR, BUN, and TR and KCCQ overall summary score were assessed at baseline and 12-month follow-up for all enrolled subjects. A 15% improvement in biomarker levels was considered clinically relevant. The odds of achieving a 15% improvement in biomarkers between baseline and 12-month follow-up was compared between the Device and Control groups (presented as OR [95% CI]). Results A total of 572 subjects were enrolled and randomized. At baseline, subjects had elevated levels of GGT (83.0±87.7 U/L) and MELD-XI score (10.3±5.2), low eGFR (56.7±21.0 mL/min/1.73m2), and elevated BUN (29.5±16.7 mg/dL). Nearly 90% of subjects were on loop diuretics, with approximately 50% taking these in combination with a thiazide or potassium-sparing diuretic. The average diuretic dosage was 71 mg (furosemide equivalent). Most subjects had normal left ventricle ejection fraction (only 5% with LVEF &amp;lt;40%). Subjects had well-managed blood pressure (systolic: 122±13 mmHg, diastolic: 69±10), slightly elevated central venous pressures (12±6 mmHg), systolic pulmonary artery pressures (40±10 mmHg) and pulmonary capillary wedge pressures (15±4 mmHg), and normal transpulmonary gradients (11±4 mmHg). The odds of achieving a 15% improvement in liver and renal function was higher in TriClip patients compared to control: MELD-XI score (1.79 [1.22, 2.63]), GGT (1.83 [1.21, 2.77]), and eGFR (1.81 [1.18, 2.77]) - Fig 1. The favorable changes in organ function observed were also reflected when stratifying subjects by residual TR severity: The odds of a 15% biomarker improvement favored subjects with moderate or less residual TR for MELD-XI score (2.05 [1.39, 3.00]), GGT (1.91 [1.26, 2.90]), and eGFR (1.83 [1.20, 2.80]) compared with subjects who had severe or worse residual TR. Lastly, improvement in these biomarkers also favored subjects with a 15-point or greater improvement in KCCQ compared with subjects with less than a 15-point KCCQ improvement. Conclusions Use of TriClip in subjects with severe tricuspid regurgitation was associated with improvement in kidney and liver function, and this improvement was associated with reduction in the severity of TR. These data provide the first objective evidence of the physiologic impact of TR reduction obtained in a randomized clinical trial.

Combined evaluation of liver and kidney function improves prediction of clinical outcome in patients with chronic heart failure and reduced ejection fraction

Abstract Background/Introduction The liver and the kidneys are important organs for body homeostasis and are both affected by heart failure (HF) either by systemic venous congestion or hypoperfusion. Purpose We aimed to verify whether the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI), as well as a combination of cholestatic liver and kidney function tests carry prognostic value in patients with chronic HF with reduced ejection fraction (HFrEF). The liver parameters included alkaline phosphatase (ALP), gamma glutamyl-transpeptidase (GGT), and total bilirubin, while kidney parameters consisted of eGFR and the tubular damage markers urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1. Methods We categorized 250 patients with HFrEF on the basis of baseline biomarker levels. We assumed elevated NT-proBNP indicates hemodynamic congestion necessary to induce congestive liver or kidney dysfunction. Thus, in every organ damage category, NT-proBNP level above median was incorporated, next to any 2 out of 3: ALP, GGT or total bilirubin above median for liver dysfunction; any 2 out of 3 NAG or KIM-1 above median or eGFR below median for kidney dysfunction; or coexistence of liver and kidney dysfunction as defined above. Additionally, a subgroup of patients with both NT-proBNP and MELD-XI above the median was analyzed. The primary endpoint was a composite of cardiovascular death, heart transplantation, LVAD implantation, and hospitalization for acute or worsened HF, whichever occurred first. Univariable and multivariable Cox proportional hazard regression models were used. Results Median (Q1-Q3) age of the study population was 68 (58-76) years; 184 (74%) were men, 62 (25%) in NYHA class III or IV, and mean left ventricular ejection fraction (LVEF) was 31±9%. During a median (Q1-Q3) follow-up of 2.2 (1.4-2.5) years, 66 (26%) patients reached the primary endpoint. We observed that liver dysfunction, kidney dysfunction or their coexistence was associated with significantly higher risk of reaching the primary endpoint (HR 3.54, 95% CI 1.75–7.16; HR 1.85, 95% CI 1.00–3.41; HR 2.52, 95% CI 1.03–6.11 respectively) in the clinically adjusted model (Table 1). Higher MELD-XI was associated with higher risk of reaching the primary endpoint in an unadjusted model but not in a clinically adjusted model. Figure 1 presents event-free survival probability of patients falling into organ dysfunction categories. Conclusions Our results show that markers of cholestatic liver function and kidney function predict unfavorable clinical outcome and provide better prognostic value in chronic HFrEF patients than the MELD-XI alone. Thus, screening for liver and kidney damage may help identify high-risk patients in whom more careful observation and individualized therapy is warranted.Fig 1.Event-free survival probability

Clinical implications of hepatorenal function in patients undergoing percutaneous coronary intervention: insights from the SAKURA PCI2 registry

Abstract Background Hepatorenal function is a prognostic predictor for heart failure, cardiac surgery, and transcatheter intervention for structural heart disease. However, the clinical implications of hepatorenal function assessed by the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI) score is still unclear in patients undergoing percutaneous coronary intervention (PCI). Purpose This study aimed to clarify the association between clinical prognosis and the MELD-XI score. Methods We analyzed 993 patients who underwent PCI from June 2020 to July 2022 in the SAKURA PCI2 registry, a prospective multicenter registry. Patients were stratified into high (&amp;gt;10) or low (≤10) MELD-XI scores. Primary outcome was defined as 2-year major adverse cardio or cerebrovascular event (MACCE), including all-cause death, ischemic stroke, and non-fatal myocardial infarction. Secondary outcome was defined as major bleeding according to the Bleeding Academic Research Consortium 3 or 5. Results Of study participating patients, 253 patients (25.5%) were stratified into a high MELD-XI score group and had a higher prevalence of the high bleeding risk than patients with a low MELD-XI score (92.5% vs. 53.7%, p&amp;lt;0.01). Patients with a high MELD-XI score were associated with MACCE (13.1% vs. 2.7%, p&amp;lt;0.01; adjusted HR 3.78, 95%CI 1.78-8.03, p&amp;lt;0.01) and major bleeding (4.0% vs. 1.3%, p&amp;lt;0.01: unadjusted HR 3.32, 95%CI 1.35-8.18, p=0.01). Moreover, these associations remained consistent in patients with chronic and acute coronary syndrome (MACCE, p for interaction=0.89; major bleeding; p for interaction=0.64). Conclusion A high MELD-XI score was associated with an increased risk of MACCE and major bleeding within two years. Therefore, the MELD-XI score could provide information for risk stratification in patients undergoing PCI.Outcomes

Pharmacometabolomics Approach to Explore Pharmacokinetic Variation and Clinical Characteristics of a Single Dose of Desvenlafaxine in Healthy Volunteers

This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine’s therapeutic use and minimize potential adverse effects, this knowledge is essential. Methods: Thirty-five healthy volunteers were enrolled after a health trial and received a single dose of desvenlafaxine (Pristiq®, 100 mg). First, liquid chromatography coupled to tandem mass spectrometry was used to determine the main pharmacokinetic parameters. Next, ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry was used to identify plasma metabolites with different relative abundances in the metabolome at pre-dose and when the desvenlafaxine peak plasma concentration was reached (pre-dose vs. post-dose). Results: Correlations were observed between metabolomic profiles, such as tyrosine, sphingosine 1-phosphate, and pharmacokinetic parameters, as well as acetoacetic acid and uridine diphosphate glucose associated with clinical characteristics. Our findings suggest that desvenlafaxine may have a broader effect than previously thought by acting on the proteins responsible for the transport of various molecules at the cellular level, such as the solute carrier SLC and adenosine triphosphate synthase binding cassette ABC transporters. Both of these molecules have been associated with PK parameters and adverse events in our study. Conclusions: This altered transporter activity may be related to the reported side effects of desvenlafaxine, such as changes in blood pressure and liver function. This finding may be part of the explanation as to why people respond differently to the drug.

Liver function tests in patients receiving high-intensity care after hospital admission for acute heart failure: the STRONG-HF trial

Abstract Background/Introduction Episodes of acute heart failure (AHF) unfavorably affect extra-cardiac organs such as the liver due to altered hemodynamics and neurohormonal activation. In AHF, elevated levels of levels of alanine aminotransferase (ALT) and total bilirubin (tBil) may reflect congestion and impaired liver function, while lower levels of ALT (which is also produced in muscle cells) correlate with malnutrition and sarcopenia. Thus, the clinical importance of these markers in AHF and the post-discharge period is unclear. Purpose To assess circulating concentrations of ALT and tBil in patients with AHF before discharge and during high-intensity care (HIC) vs usual care follow-up in association with clinical outcomes. Methods ALT and tBil concentrations were measured 1-2 days before discharge in patients hospitalized for AHF (baseline), and again after 90 days of either HIC or usual care according to the STRONG-HF protocol. Baseline values and changes in ALT and tBil were analyzed in association with the primary outcome of all-cause death or HF readmission by day 180. Results At baseline, the median (Q1-Q3) concentrations of ALT and tBil were 21 (15-32) U/L and 14 (10-21) umol/L, respectively. Lower levels of both ALT and tBil were associated with female sex, Black race, lower BMI, higher LVEF, lower hemoglobin, lower creatinine and less frequent atrial fibrillation/flutter, while there were no significant associations with age. Patients with lower ALT, but not tBil, were more likely to have edema, elevated JVP and orthopnea, and used higher loop diuretic doses and less beta-blockers, pre-randomization (Figure, panel A). ALT was inversely associated with risk for the primary outcome (HR 0.81 [95%CI 0.65,1.00) per log increment, p=0.05), while there was no association with risk for tBil (HR 1.04 [95%Ci 0.84-1.28], p=0.73) (Figure, panel B). After 90 days, ALT and tBil concentrations were lower than at baseline, with a greater reduction in tBil in the HIC group vs usual care group (mean -1.7 [95%CI -3.0,-0.4] umol/L, p=0.01), while there was no significant between-group differences in ALT changes (mean -0.6 [95%CI -4.7,3.4] U/L, p=0.75) (Figure, panel C). The treatment effect of HIC over usual care on the primary outcome was consistent across the range of baseline ALT (P-interaction=0.30) and tBil (P-interaction=0.80) (Figure, panel D). Conclusion Contrary to our hypothesis of higher liver function tests with hepatic congestion in AHF, lower ALT was associated with more congestion and worse outcomes among patients hospitalized for AHF in STRONG-HF. There was no prognostic value from tBil levels. This suggests that ALT may be a marker of sarcopenia in these patients. Importantly, the beneficial effect of HIC on clinical outcomes is consistent irrespective of ALT and tBil levels at discharge.Figure

Early postoperative Fibrinogen-to-Albumin Ratio prognosticate 6-month procedural success in patients undergoing orthotopic heart transplantation

Abstract Background The Fibrinogen-to-Albumin ratio (FAR) has emerged as a novel biomarker, integrating liver function and inflammatory reaction with proven prognostic value in heart failure (HF) patients. This study aims to evaluate its significance in advanced HF patients treated with orthotopic heart transplantation (HTx). Methods Mean fibrinogen, albumin and FAR values were analyzed one week post-HTx. The primary endpoint of the study was 6-month all-cause mortality. Regression models incorporating parameters significantly different between survivor and deceased groups (troponin, potassium, asparagine aminotransferase [AST]) were developed to assess predictive value of FAR. Additionally, the Spearman's rank correlation between FAR and inflammatory biomarkers (C-reactive protein [CRP], procalcitonin, white blood cells (WBC)] and liver enzymes [AST, alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGTP]) were calculated. Results The analysis included 104 patients undergoing HTx with a median age of 53 years (44.5-62.5), 82% were male, 44% had ischaemic aetiology of HF. Within 6 months post-HTx 17 patients (16%) died. Mean fibrinogen in all patients was (3.18 ± 0.83), albumin (3.17 ± 0.35) and FAR (1.01 ± 0.28). Deceased patients exhibited lower 1 week post HTx mean fibrinogen (2.46 ± 1.13) compared to survivors (3.30 ± 0.70), lower albumin (2.93 ± 0.43) vs. (3.21 ± 0.32), and lower FAR median (0.73, 0.53-1.16) vs. (0.99, 0.88-1.18), all p&amp;lt;0.05. The post-HTx fibrinogen independently predicted death: (RR 0.37, p=0.003, 95% CI [0.19,0.71]), as did post-HTx albumin: (RR 0.21, p=0.05, 95% CI [0.04,1.0]). FAR was also an independent risk factor: (RR 0.08, p=0.009, 95% CI [0.01,0.54]). There were significant correlations between FAR and CRP (R=0.30, p=0.003), and GGTP (R=0.25, p=0.045). FAR was not significantly correlated with procalcitonin, WBC, AST and ALT. Conclusions Early post-HTx fibrinogen, albumin and FAR are independent predictors of an unfavorable prognosis in HF patients undergoing HTx. In contrast to chronic HF, early post-HTx FAR was inversely correlated with mortality. The calculated correlation between FAR, inflammatory markers and liver enzymes suggests limited association with inflammatory processes and liver function in this population.