Liver Failure Research Articles

Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health

Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol.

Serum Adiponectin Is Elevated in Critically Ill Patients with Liver Disease and Associated with Decreased Overall Survival.

Adiponectin, an adipokine with anti-inflammatory properties, has been implicated in various liver diseases. This study aimed to elucidate the prognostic value of serum adiponectin levels in critically ill patients with liver disease. This observational study included 161 critically ill patients admitted to the medical ICU of RWTH Aachen University Hospital due to acute liver failure or decompensated advanced chronic liver disease. Serum adiponectin levels were measured at ICU admission and after 48 h. Clinical parameters and outcomes, including transplant-free survival, were analyzed. Serum adiponectin concentrations were significantly elevated compared to healthy controls (p < 0.001). Levels were particularly high in patients with sepsis compared to those with gastrointestinal bleeding as the precipitating factor of acute decompensation (p = 0.045) and were higher in female patients (p = 0.023). Adiponectin concentrations correlated with the Model of End-Stage Liver Disease (MELD) score and Child-Pugh score. Multivariate analysis confirmed a significant correlation with total bilirubin (r = 0.292, p < 0.001) and serum sodium (r = -0.265, p = 0.028). Higher adiponectin concentrations were associated with a trend towards poorer 30- and 180-day survival. Cox regression analysis identified a significant association between increased adiponectin concentration and reduced transplant-free survival (p = 0.037), supported by a Kaplan-Meier analysis using a cutoff of 119 ng/mL (log-rank 5.145, p = 0.023). Elevated serum adiponectin concentrations are associated with liver dysfunction and poor outcomes in critically ill patients. Higher adiponectin levels at ICU admission may predict poorer transplant-free survival. Further research in larger, multicenter cohorts is warranted to validate these findings and explore the underlying mechanisms.

Is there a role for extracorporeal membrane oxygenation in children with acute liver failure? A retrospective analysis of the Extracorporeal Life Support Organization Registry.

Our results suggest that the use of ECMO for the management of respiratory and cardiac failure in patients with PALF should be considered with caution and that further research is needed to understand its role in this specific high-risk population. • Pediatric acute liver failure (PALF) is a clinical syndrome associated with significant morbidity and mortality. • Data on the use of extracorporeal membrane oxygenation (ECMO) in the context of PALF are scarce and controversial. • ECMO to manage acute respiratory and/or cardiac failure in the context of PALF should be considered with caution. • Bleeding and thrombotic complications in children with acute liver failure receiving ECMO are similar to the ones reported in the general pediatric population.

Experimental model of systemic inflammation during acetaminophen toxicity

Acetaminophen is one of the most toxic drugs that can cause liver damage. At the same time, acetaminophen-induced liver failure is closely associated with the development of systemic inflammatory response syndrome. However, there is no drug aimed at suppressing the systemic inflammatory response. That is, this issue needs to be studied experimentally, but a model of systemic inflammation during acetaminophen overdose has not yet been obtained. Therefore, it was decided to develop an experimental model of systemic inflammation during acetaminophen overdose. The purpose of this study was to experimentally substantiate the semi-lethal dose for acetaminophen overdose in C57Bl/6 mice and to evaluate the readings of blood tests after administration of the drug. To determine the semi-lethal dose, male C57Bl/6 mice were intraperitoneally injected with “Ifimol” (Unique Pharmaceutical Laboratories, India) or acetaminophen solution (Sigma-Aldrich, USA) with a concentration of 14 mg/ml in different doses. When introducing “Ifimol”, it was not possible to achieve a semi-lethal dose. When administering a solution of acetaminophen, 50% mortality was recorded at a dose of 600 mg/kg body weight. After establishing a semi-lethal dose, the experimental group was administered an acetaminophen solution (Sigma-Aldrich, USA) with a concentration of 14 mg/ml at a dose of 600 mg/kg. The control group was injected with saline in an equivalent volume. On the second day, liver and peripheral blood samples were taken. Subsequently, hematological and biochemical blood tests and histological analysis were performed. Histological examination revealed centrilobular necrosis and disorganization of the liver structure. According to the biochemical blood test, the activity of aspartate aminotransferase, alanine aminotransferase, creatinine concentration, and the de Ritis coefficient differed statistically significantly (p 0.05) in the experimental group compared to the control group. Among the hematological blood test parameters, there were statistically significant differences in the number of leukocytes, platelets, as well as the absolute and relative content of granulocytes and lymphocytes. Thus, 48 hours after administration of a semi-lethal dose of acetaminophen, there were signs of damage to internal organs (liver, kidneys) and changes in immune system parameters, which are similar to components of systemic inflammation in humans.

Viral etiologies of acute liver failure.

Acute liver failure (ALF) is a rare cause of liver-related mortality worldwide, with an estimated annual global incidence of more than one million cases. While drug-induced liver injury, including acetaminophen toxicity, is the leading cause of ALF in the Western world, viral infections remain a significant cause of ALF and the most common cause in many developing nations. Given the high mortality rates associated with ALF, healthcare providers should be aware of the broad range of viral infections that have been implicated to enable early diagnosis, rapid treatment initiation when possible, and optimal management, which may include liver transplantation. This review aims to provide a summary of viral causes of ALF, diagnostic approaches, treatment options, and expected outcomes.

New perspectives in the definition and classification of acute-on-chronic liver failure.

New perspectives in the definition and classification of acute-on-chronic liver failure.

Porto-sinusoidal vascular disorder in surgical candidates for liver metastases: Prevalence, noninvasive diagnosis, and burden on surgical outcomes

Chemotherapy can cause vascular and metabolic liver injury in patients with liver metastases, but scarce data are available. We aimed to (i) describe the prevalence of porto-sinusoidal vascular disorder (PSVD) among patients undergoing resection for liver metastases; and (ii) assess whether liver (LSM) and spleen stiffness measurements could diagnose PSVD and predict postoperative complications. This is a prospective single-center study enrolling consecutive patients undergoing hepatic resection for metastases at a tertiary center. For each patient, we evaluated previous exposure to chemotherapy, comorbidities, elastography, type of surgery, histological features at the resection specimen, morbidity (post-hepatectomy liver failure and major complications according to Clavien-Dindo), and 90-day survival. Sixty-eight patients were included, of whom 60 (88%) had received chemotherapy. Twenty-nine (44%) patients had PSVD. Spleen stiffness measurements &lt;21 kPa (negative predictive value 87%) and &gt;40 kPa (positive predictive value 100%) could accurately diagnose PSVD. PSVD significantly increased the risk of post-hepatectomy liver failure (22% vs. 45%) and major complications (11% vs. 31%). Preoperative LSM was associated with postoperative morbidity. The cutoff LSMs &lt;4.5 and &gt;8 kPa predicted the risk of clinically significant post-hepatectomy liver failure (0%, 11%, and 33% in LSM &lt;4.5, 4.5–8, and &gt;8 kPa, respectively) and major complications (0%, 25%, 44% in LSM &lt;4.5, 4.5–8, and &gt;8 kPa, respectively). PSVD is very common among patients undergoing liver surgery for metastases, and it is associated with increased morbidity. LSM and spleen stiffness measurements can correctly identify patients with PSVD and those at risk of clinically relevant postoperative complications.

Mesenchymal Stem Cells and Erythropoietin Therapy in Acute Liver Failure Induced by D-galactosamine in Rats

Mesenchymal Stem Cells and Erythropoietin Therapy in Acute Liver Failure Induced by D-galactosamine in Rats

Hepatic and extrahepatic metabolic modulation in hbv-related decompensated cirrhosis and acute-on-chronic liver failure

ABSTRACT Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (RatioHep/Port, RatioPeri/Hep, and RatioPort/Peri) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher RatioPeri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher RatioPort/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.

Environmentally Relevant Concentrations of S-6PPD-Quinone Caused More Serious Hepatotoxicity Than R-Enantiomer and Racemate in Oncorhynchus mykiss.

6PPD-quinone (6PPD-Q) is frequently detected in various environmental media, and the environmentally relevant concentrations can be fatal to Oncorhynchus mykiss. Notably, 6PPD-Q has two enantiomers (S-6PPD-Q and R-6PPD-Q). In this study, O. mykiss was separately exposed to each enantiomer and racemate of 6PPD-Q for 96 h at environmentally relevant concentrations, and livers were collected. Effects on the biochemical, pathological, and ultrastructural changes were assessed, and metabolomics was conducted to elucidate the potential hepatotoxicity mechanism. Compared with the control treatment, the levels of catalase (CAT, all treatments except for 0.1 μg/L rac-6PPD-Q), and glutathione-S-transferase (GST, all treatments) significantly declined. Hepatocyte space became smaller, nuclear morphology changed, and nucleolysis occurred. Mitochondrial malformation and vesicle-like structure dilation of the endoplasmic reticulum (ER) were observed in the hepatocytes, which was most serious after S-6PPD-Q exposure. Some amino acid metabolism, folate biosynthesis, taurine and hypotaurine metabolism and purine metabolism were disturbed, consistent with mitochondrial dysfunction and ER stress. The differential metabolites were in the order of S-6PPD-Q (216) > rac-6PPD-Q (88) > R-6PPD-Q (56). Thus, 6PPD-Q-induced hepatic mitochondrial dysfunction and ER stress, causing metabolic disturbance and oxidative stress might be the toxic mechanism of 6PPD-Q in O. mykiss liver, and S-6PPD-Q effects were the most serious.

Identification of four novel acute‐on‐chronic liver failure clusters with distinct clinical trajectories and mortality using machine learning methods

SummaryBackground and AimsMachine learning (ML) can identify the hidden patterns without hypothesis in heterogeneous diseases like acute‐on‐chronic live failure (ACLF). We employed ML to describe and predict yet unknown clusters in ACLF.MethodsClinical data of 1568 patients with ACLF from a tertiary care centre (2015–2023) were subjected to distance‐, density‐ and model‐based clustering algorithms. Final model was selected on best cluster separation, viz. Silhouette width and Dunn's index (for distance‐ or density‐based algorithms) and minimum BIC (for model‐based algorithms). Cluster assignments, patient trajectories and survival were analysed through inferential statistics. Supervised ML models were trained in 70% data that predicted clusters in remaining 30% data followed by an temporal validation.ResultsThe cohort was male‐predominant (87%), aged 44.3 years, with alcohol‐associated hepatitis (62.9%) and survival of 50.5%. Due to poor performance of distance‐ and density‐based algorithms and better explainability, the latent class model (LCM) was selected for exploration. LCM revealed four clusters with distinct trajectories, reversibility and survival (independent of MELD, CLIF‐C ACLF and AARC scores). Cluster1 had patients with none/one organ failure and highest reversibility. Cluster2 had females with viral hepatitis and two organ failures. More‐than‐one acute precipitant, severity, infections, organ failures and irreversibility escalated from clusters 1 to 4. Circulatory and renal failures critically influenced cluster assignments. Incorporating clusters to CLIF‐C ACLF, infection and ACLF definition improved the discriminative accuracy of CLIF‐C‐ACLF by 11%. Extreme gradient boost and decision trees could predict clusters with AUCs of 0.989 (0.979–0.995) and 0.875 (0.865–0.890). MELD, CLIF‐C‐OF, haemoglobin, lactate, CLIF‐C‐ACLF and ALT were critical variables for cluster prediction. Clusters with distinct survival were documented in a temporal validation cohort.ConclusionsML for the first time could identify clusters with distinct phenotypes, trajectories and outcomes in ACLF. Stratification into clusters can address heterogeneity, guide prognosis, recruitment in trials, resource allocation and liver transplant discussions in ACLF.

Correlation Between Clinical Assessment and Postmortem Lung Biopsy in Patients With Pulmonary Infiltrates and Respiratory Failure.

Pulmonary complications commonly cause mortality in critically ill patients with acute and chronic liver diseases in the intensive care unit. Pneumonia is the most common clinical diagnosis supported by radiological and microbiological results, which are subjective and often with poor yield. The study aimed to correlate clinical diagnosis and postmortem lung histology in patients with liver disease with respiratory failure. Records of acute and chronic liver disease patients with respiratory failure-associated mortality and postmortem lung biopsy from September 2009 to March 2020 were analyzed. Clinical diagnosis supported by radiological and/or microbiological data was compared with histology. One hundred eight patients (age 46.83±12.96 years), males 80 (74.1%), 63 (58.3%) cirrhosis of the liver, 30 (27.8%) acute-on-chronic-liver-failure, and 9 (8.3%) acute liver failure, were analyzed. Of the 76 patients (70.37 % of the total) with pneumonia, 33 (43.4 %) had histological evidence of pneumonia. Other histological diagnoses in these patients were normal or nonspecific changes in 27 (35.5 %) and alveolar hemorrhage in 13 (17.1 %). In the remaining 32 patients, histological diagnosis of pneumonia was evident in nine patients (28.1%). Using postmortem histology as the gold standard, the sensitivity, specificity, positive predictive value, and negative predictive valuefor clinical diagnosis of pneumonia were found to be 78.57%, 34.85%, 43.42%, and 71.88% respectively. The kappa statistics for agreement between the two was 0.12 (95% C.I. -0.04 to 0.27) suggesting poor agreement. Age and histological pneumonia predicted significant missed diagnosis. There is poor agreement between clinical diagnosis and postmortem histology. Postmortem lung biopsy helps with the unexplained cause of death.

Insulin‐like growth factor‐1 in cirrhosis is linked to hepatic dysfunction and fibrogenesis and predicts liver‐related mortality

SummaryBackground and AimsWe aimed to characterise insulin‐like growth factor‐1 (IGF‐1) signalling in patients with advanced chronic liver disease (ACLD).MethodsConsecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6–9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non‐bleeding hepatic decompensation and S5: further decompensation.ResultsIn total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF‐1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p &lt; 0.001). Patients with CSPH had significantly lower IGF‐1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF‐1 showed an independent negative association with body mass index (BMI; aB: −1.56; p &lt; 0.001), enhanced liver fibrosis (ELF) test (aB: −8.43; p &lt; 0.001), MELD (aB: −1.13; p = 0.042) and age (per 10 years; aB: −6.87; p &lt; 0.001). IGF‐1 exhibited an excellent AUROC (0.856) for the prediction of liver‐related death at 6 months of follow‐up. Lower IGF‐1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83–0.98; p = 0.016), acute‐on‐chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68–0.93; p = 0.004) and liver‐related death (asHR: 0.76; 95% CI: 0.63–0.91; p = 0.004).ConclusionDecreased levels of IGF‐1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF‐1 was independently linked to high BMI. Lower IGF‐1 in cirrhosis predicts decompensation, ACLF and liver‐related death.

Hepatitis B

Hepatitis B is a viral infection caused by the Hepatitis B virus (HBV), primarily affecting the liver and leading to both acute and chronic disease. With over 250 million individuals suffering from chronic Hepatitis B, it poses a significant global health challenge, being a leading cause of liver cirrhosis, liver failure, and hepatocellular carcinoma. This study aims to elucidate the transmission pathways, treatment options, and necessary public health strategies for Hepatitis B. We analyze the modes of transmission, which include contact with infectious body fluids—primarily through perinatal transmission, unprotected sexual contact, and sharing contaminated needles. Despite the availability of an effective vaccine since the 1980s, Hepatitis B remains endemic in many parts of Asia and Africa due to limited immunization coverage. The pathogenesis of HBV involves complex interactions between the virus and the host immune system, potentially leading to liver inflammation and fibrosis. Clinical presentations vary widely, ranging from asymptomatic infections to severe liver disease. Current treatment options for chronic Hepatitis B include antiviral medications such as tenofovir and entecavir, which suppress viral replication but do not cure the infection. Recent advancements in therapeutic strategies, including novel antivirals and immune modulators, show promise for more effective management and potential cures in the future. Comprehensive public health strategies—such as vaccination, screening, and education—are crucial for controlling the spread of HBV and reducing the global burden of Hepatitis B-related complications.

Shaoyao-Gancao Decoction, a famous Chinese medicine formula, protects against APAP-induced liver injury by promoting autophagy/mitophagy

BackgroundAcetaminophen (APAP)-induced hepatotoxicity is a major cause of acute liver failure (ALF), during which autophagy is triggered as a cellular defense mechanism. Shaoyao-Gancao Decoction (SGD), a traditional prescription in Chinese Medicine, is renowned for its therapeutic effects on liver diseases. However, the efficacy and mechanisms of SGD in treating APAP-induced liver injury remain underexplored. PurposeThis study aims to provide robust evidence regarding the protective effects of SGD against APAP overdose in vitro and in vivo, as well as to elucidate its hepatoprotective mechanisms and active components. Study designThe hepatoprotective mechanisms and active components of SGD were investigated through a combination of in vivo and in vitro experiments. MethodsThe protective effects of SGD on APAP-induced liver injury were assessed using a murine model and primary hepatocytes. RNA sequencing and subsequent experimental validations were conducted to uncover the underlying mechanisms of SGD's hepatoprotective actions. Comprehensive chemical profiling of SGD was performed using UHPLC-Q-Exactive Orbitrap HRMS to identify potential active ingredients. Immunohistochemistry, immunofluorescence, quantitative real-time PCR (qPCR), western blotting, enzyme-linked immunosorbent assay (ELISA), and flow cytometry were utilized to investigate the specific cellular changes in liver tissues and hepatocytes influenced by SGD. ResultsSGD was observed to mitigate APAP-induced mitochondrial damage, inflammation, and necrosis by promoting mitochondrial autophagy. The inhibition of autophagy negated the hepatoprotective effects of SGD. Additionally, a detailed characterization of SGD's chemical composition revealed that Licoisoflavone B, Liquiritin, Liquiritin apioside, Licorice saponin G2 and Paeoniflorin Sulfit were potentially critical compounds in the regulation of autophagy and mitophagy. ConclusionOur findings demonstrate that SGD promotes autophagy/mitophagy, which effectively mitigates APAP-induced hepatotoxicity, suggesting SGD's potential as a promising therapeutic agent for APAP-induced liver injury.

Metabolic Dysregulation and Metabolite Imbalances in Acute-on-chronic Liver Failure: Impact on Immune Status.

Liver failure encompasses a range of severe clinical syndromes resulting from the deterioration of liver function, triggered by factors both within and outside the liver. While the definition of acute-on-chronic liver failure (ACLF) may vary by region, it is universally recognized for its association with multiorgan failure, a robust inflammatory response, and high short-term mortality rates. Recent advances in metabolomics have provided insights into energy metabolism and metabolite alterations specific to ACLF. Additionally, immunometabolism is increasingly acknowledged as a pivotal mechanism in regulating immune cell functions. Therefore, understanding the energy metabolism pathways involved in ACLF and investigating how metabolite imbalances affect immune cell functionality are crucial for developing effective treatment strategies for ACLF. This review methodically examined the immune and metabolic states of ACLF patients and elucidated how alterations in metabolites impact immune functions, offering novel perspectives for immune regulation and therapeutic management of liver failure.

Ferroptosis Inhibition: A Key Opportunity for the Treatment of Ischemia/Reperfusion Injury in Liver Transplantation.

The outcome after liver transplantation has improved in recent years, which can be attributed to superior storage and transportation conditions of the organs, as well as better peri- and postoperative management and advancements in surgical techniques. Nevertheless, there is an increasing discrepancy between the need for organs and their availability. Consequently, the mortality rate on the waiting list is high and continues to rise. One way of counteracting this trend is to increase the use of "expanded criteria donors." This means that more and more donors will be included, especially those who are older and having additional comorbidities (eg, steatosis). A major complication of any transplantation is the occurrence of ischemia/reperfusion injury (IRI), which often leads to liver dysfunction and failure. However, there have been various promising approaches to minimize IRI in recent years, but an effective and clinically applicable method to achieve a better outcome for patients after liver transplantation is still missing. Thereby, the so-called marginal organs are predominantly affected by IRI; thus, it is crucial to develop suitable and effective treatment options for patients. Recently, regulated cell death mechanisms, particularly ferroptosis, have been implicated to play a major role in IRI, including the liver. Therefore, inhibiting this kind of cell death modality presents a promising therapeutic approach for the management of this yet untreatable condition. Thus, this review provides an overview of the role of ferroptosis in liver IRI and transplantation and discusses possible therapeutic solutions based on ferroptosis inhibition to restrain IRI in marginal organs (especially steatosis and donation after circulatory death organs).

A 4-Month-Old With Jaundice, Lethargy, and Emesis.

Acute liver failure is rare in the neonatal and infant population; however, when encountered, it requires timely diagnosis, management, and identification of the underlying etiology to provide the best clinical outcomes. Here, we present a case of new-onset liver failure in a 4-month-old infant. She had previously been diagnosed with neonatal mucocutaneous herpes simplex virus disease, but had been healthy in the interval, and was referred to our hospital for evaluation of possible need for liver transplantation because of a rapidly progressing pace of disease. In this diagnostic dilemma article, we review the case history and presentation and consider the differential diagnosis from the points of view of the primary and consultative teams. We then follow the clinical evolution of disease, identify a final diagnosis, and explore the short- and long-term management and health implications of the diagnosis. This case should be of interest to primary care providers, intensivists who care for neonates or infants, and specialists who encounter liver failure in their clinical practice.

Lymphocyte to high density lipoprotein ratio can predict the short-term prognosis of hepatitis B virus-related acute-on-chronic liver failure patients

BackgroundAcute-on-chronic liver failure (ACLF) is a syndrome characterized by systemic inflammation, leading to high short-term mortality. The lymphocyte to high-density lipoprotein ratio (LHR) has been introduced as a novel marker of inflammation. However, its role as a prognostic inflammatory biomarker in the context of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has received limited attention. MethodsWe retrospectively included 272 patients with HBV-ACLF who met the definition of APALC. Data on clinical features and laboratory tests were collected from medical records within 24 h. Logistic regression was used to identify risk factors for poor short-term prognosis, and LHR-based prediction (LHRB) models were constructed based on risk factors. Furthermore, the accuracy of the LHRB model was validated through rigorous testing. ResultsIn the survival and death groups, there were statistical differences in their CTP, MELD, MELD-Na, COSSH-ACLF II scores, and LHR. Multivariate logistic regression identified seven predictors significantly associated with 28-day mortality. Furthermore, statistically significant differences in short-term mortality and certain clinical laboratory tests for poor prognosis were observed between the high and low LHR groups. To assess the predictive performance of various models in terms of short-term mortality, the area under the receiver operating characteristic curve (AUROC) was calculated. The AUROC values for the CTP, MELD, MELD-Na, COSSH-ACLF II, and LHRB models were found to be 0.725, 0.788, 0.772, 0.871, and 0.877, respectively. The results in the validation group were similar to those in the training group, and the validation results suggested excellent performance of the LHRB model. ConclusionLHR levels have the potential to serve as indicators for the prognosis of HBV-ACLF. Additionally, the recently developed LHRB model offers an accessible risk assessment tool.

Bile duct ligation impairs visual acuity in rats by ammonia- and bilirubin-induced retinal degeneration.

Patients with hepatic failure are often accompanied by hepatic retinopathy, but the cellular and molecular mechanisms underlying the hepatic retinopathy remain unclear. In this study, we investigated how liver failure leads to hepatic retinopathy using bile duct ligation (BDL) rats as a cholestasis animal model. Light-dark box test was used to assess sensitivity to light, indexed as visual acuity. On D28 post-BDL, rats were subjected to light-dark box test and blood samples were collected for biochemical analyses. The rats then were euthanized. Liver, spleen and both side of eye were quickly harvested. We showed that BDL impaired rat sensitivity to light, significantly decreased the thickness of inner nuclear layer (INL), outer nuclear layer (ONL) and total retina, as well as the retinal cell numbers in ONL and ganglion cell layer (GCL). The expression of rhodopsin (RHO), brn-3a and GPX4 was significantly decreased in retina of BDL rats, whereas the expression of cleaved caspase 3, 8, 9, bax/bcl-2, RIP1, GFAP, and iba-1, as well as TUNEL-positive cells were significantly increased. In cultured retinal explant, we found that NH4Cl (0.2, 1, 5 mM) concentration-dependently impaired activity of retinal explant, decreased thickness of INL and ONL, downregulated expression of brn-3a, RHO and GFAP, increased expression of cl-caspase 3 and TUNEL-positive cell numbers, with NH4Cl (5 mM) almost completely disrupting the structure of the cultured retina; bilirubin (1 μM) significantly upregulated GFAP expression, whereas high level (10 μM) of bilirubin downregulated expression of GFAP. We further demonstrated in vivo that hyperammonemia impaired rat sensitivity to light, decreased thickness of INL and ONL, downregulated expression of RHO, brn-3a, GFAP and increased expression of cl-caspase 3; hyperbilirubinemia impaired rat sensitivity to light, upregulated expression of GFAP and iba-1. In conclusion, BDL impaired rat visual acuity due to the elevated levels of ammonia and bilirubin. Ammonia induced loss of retinal ganglion cells and rod photoreceptor cells via apoptosis-mediated cell death. Bilirubin impaired retinal function via activating microglia and Müller cells.