Liver Failure Research Articles

Therapeutic and Safety Promise of Mesenchymal Stem Cells for Liver Failure: From Preclinical Experiment to Clinical Application.

Liver failure (LF) is serious liver damage caused by multiple factors, resulting in severe impairment or decompensation of liver synthesis, detoxification, metabolism, and biotransformation. The general prognosis of LF is poor with high mortality in non-transplant patients. The clinical treatments for LF are mainly internal medicine comprehensive care, artificial liver support system, and liver transplantation. However, none of the above treatment strategies can solve the problems of all liver failure patients and has its own limitations. Mesenchymal stem cells (MSCs) are a kind of stem cells with multidirectional differentiation potential and paracrine function, which play an important role in immune regulation and tissue regeneration. In recent years, MSCs have shown multiple advantages in the treatment of LF in pre-clinical experiments and clinical trials. In this work, we reviewed the biological characteristics of MSCs, the possible molecular mechanisms of MSCs in the treatment of liver failure, animal experiments, and clinical application, and also discussed the existing problems of MSCs in the treatment of liver failure.

Insight to Biofabrication of Liver Microtissues for Disease Modeling: Challenges and Opportunities.

In the last decade, liver diseases with high mortality rates have become one of the most important health problems in the world. Organ transplantation is currently considered the most effective treatment for compensatory liver failure. An increasing number of patients and shortage of donors has led to the attention of reconstructive medicine methods researchers. The biggest challenge in the development of drugs effective in chronic liver disease is the lack of a suitable preclinical model that can mimic the microenvironment of liver problems. Organoid technology is a rapidly evolving field that enables researchers to reconstruct, evaluate, and manipulate intricate biological processes in vitro. These systems provide a biomimetic model for studying the intercellular interactions necessary for proper organ function and architecture in vivo. Liver organoids, formed by the self-assembly of hepatocytes, are microtissues and can exhibit specific liver characteristics for a long time in vitro. Hepatic organoids are identified as an impressive tool for evaluating potential cures and modeling liver diseases. Modeling various liver diseases, including tumors, fibrosis, non-alcoholic fatty liver, etc., allows the study of the effects of various drugs on these diseases in personalized medicine. Here, we summarize the literature relating to the hepatic stem cell microenvironment and the formation of liver Organoids.

Berberine attenuates ECM accumulation and the progression of acute liver failure through inhibition of NLRP3 inflammasome signalling

Acute liver failure (ALF) is a life-threatening disease, characterized by upregulated extracellular matrix deposition and inflammatory signalling, with no effective treatment options and targets. The present study was designed to investigate the preventive and therapeutic effects of berberine (BBR) and its underlying mechanism in thioacetamide (TAA)-induced ALF. Male SD rats were administered with TAA 300 mg/kg, i.p., thrice to induce ALF and pre- or post-treated with BBR. To decipher the effects of BBR LFT markers, histopathological analysis of key fibrotic and inflammatory proteins was performed. In addition, the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were assessed by ELISA. Our work showed TAA-induced ALF animals were associated with increased ALT, AST, bilirubin (LFT markers) and histopathological alterations with profuse infiltration of inflammatory cells in the liver tissue. Treatment with BBR has significantly inhibited LFT markers and histological alterations triggered by TAA. In addition, TAA animals demonstrated increased collagen accumulation and upregulated expression of TGF-β1, vimentin, and α-SMA compared to control. The excessive accumulation of collagen, TGF-β1, vimentin, and α-SMA were significantly modulated with BBR treatment. Further, the fluorescence intensity of ROS an activator of NLRP3 including the NLRP3 inflammasome, and its downstream signalling ASC, cleaved IL-1β, and other pro-inflammatory cytokines like TNF-α and IL-6 stimulated by TAA were attenuated by BBR treatment. The current work indicated that BBR significantly ameliorated TAA-induced ALF by inhibiting the extracellular matrix accumulation associated with the NLRP3/IL-1β signalling pathway and could be a viable therapeutic option to treat ALF and other fibroinflammatory diseases.

Outcomes of patients with acute liver failure not listed for liver transplantation: A cohort analysis.

Acute liver failure (ALF) is a rare condition leading to morbidity and mortality. Liver transplantation (LT) is often required, but patients are not always listed for LT. There is a lack of data regarding outcomes in these patients. Our aim is to describe outcomes of patients with ALF not listed for LT and to compare this with those listed for LT. Retrospective analysis of all nonlisted patients with ALF enrolled in the Acute Liver Failure Study Group (ALFSG) registry between 1998 and 2018. The primary outcome was 21-day mortality. Multivariable logistic regression was done to identify factors associated with 21-day mortality. The comparison was then made with patients with ALF listed for LT. A total of 1672 patients with ALF were not listed for LT. The median age was 41 (IQR: 30-54). Three hundred seventy-one (28.9%) patients were too sick to list. The most common etiology was acetaminophen toxicity (54.8%). Five hundred fifty-eight (35.7%) patients died at 21 days. After adjusting for relevant covariates, King's College Criteria (adjusted odds ratio: 3.17, CI 2.23-4.51), mechanical ventilation (adjusted odds ratio: 1.53, CI: 1.01-2.33), and vasopressors (adjusted odds ratio: 2.10, CI: 1.43-3.08) (p < 0.05 for all) were independently associated with 21-day mortality. Compared to listed patients, nonlisted patients had higher mortality (35.7% vs. 24.3%). Patients deemed not sick enough had greater than 95% survival, while those deemed too sick still had >30% survival. Despite no LT, the majority of patients were alive at 21 days. Survival was lower in nonlisted patients. Clinicians are more accurate in deeming patients not sick enough to require LT as opposed to deeming patients too sick to survive.

Influence of Right and Left Bundle Branch Block in Patients With Cardiogenic Shock and Cardiac Arrest.

The study investigates the prognostic impact of right bundle branch block (RBBB) and left bundle branch block (LBBB) in patients with cardiogenic shock (CS) compared with no bundle branch block (BBB). In patients with heart failure, existence of RBBB and LBBB has influence on prognosis. Prospective registry-study. ICU of a tertiary academic hospital in Germany. Adult patients with CS. None. Consecutive patients with CS were included. The prognostic impact of RBBB and LBBB on 30-day all-cause mortality was tested within the entire cohort and in the subgroup of CS patients with cardiac arrest at admission. The final study cohort comprised 248 patients. Patients with RBBB showed the highest 30-day all-cause mortality followed by LBBB and no BBB (72.5% vs. 52.9% vs. 50.0%; log-rank p = 0.015). These findings were consistent even after solely including CS patients with cardiac arrest (90.0% vs. 73.3% vs. 62.2%; log-rank p = 0.008). After adjustment for lactate, norepinephrine, troponin I, Acute Physiology Score, Society of Cardiovascular Angiography & Interventions shock stage, and heart rate in a multivariable Cox regression analysis, RBBB still revealed a negative impact on 30-day all-cause mortality (hazard ratio [HR], 1.807; 95% CI, 1.107-2.947; p = 0.018), whereas LBBB was not associated with 30-day all-cause mortality. In this multivariable Cox regression model lactate (HR, 1.065; 95% CI, 1.018-1.115; p = 0.006), troponin I (HR, 1.003; 95% CI, 1.001-1.005; p = 0.001), and Acute Physiology Score (HR, 1.033; 95% CI, 1.001-1.066; p = 0.041) were as well associated with 30-day all-cause mortality. Finally, no association of RBBB was found with the incidence of liver or severe renal failure. Besides the Acute Physiology Score, lactate, and troponin levels, RBBB was associated with an increased 30-day all-cause mortality in consecutive CS patients with and without cardiac arrest, whereas LBBB showed no prognostic impact.

Prognostic value of MELD-XI score and hemodynamic parameters in patients undergoing transcatheter tricuspid valve intervention

Abstract Background Hepatorenal dysfunction is a strong prognostic predictor in patients with tricuspid regurgitation. Patients are often hospitalized with acute heart failure due to volume overload and peripheral hypoperfusion. End-organ dysfunction is associated with the development of right ventricular failure related to hemodynamic changes such as low cardiac output and passive congestion from increased right ventricular filling pressures. Purpose This study aimed to investigate the prognostic value of hepatorenal dysfunction using the Model for End-stage Liver Disease (MELD) Score, the modified version of the score, MELD-XI, and of parameters determined during right-heart catheterization in patients undergoing transcatheter tricuspid valve intervention. Methods In this single-center prospective cohort study, data from patients undergoing edge-to-edge repair or heterotopic minimal invasive tricuspid valve repair were analyzed. Serum creatinine, INR and bilirubin were measured and the MELD score as well as the MELD XI score was calculated. All patients underwent right heart catheterization before the intervention. Receiver operator characteristics with calculation of the area under the curve (AUC) were performed to determine the predictive value of MELD (XI) score and hemodynamic parameters for the combined endpoint of rehospitalization due to decompensated heart failure and mortality within 3 months. Results Data from 36 consecutive patients were analyzed. 28 patients underwent edge-to-edge repair and 8 patients heterotopic minimal invasive tricuspid valve repair. Mean age of patients was 80.2 ± 5.9 years; 33.3% (12/36) were male. Baseline characteristics are shown in table 1. Rehospitalization due to decompensated heart failure occurred in 9/36 patients (25%). Mortality within the first 3 months was 11% (4/36). The predictive value for the composite endpoint of the modified MELD IX score was AUC 0.82 (95 % CI 0.63-0.99; p=0.009), while the conventional MELD score had an AUC of 0.77 (95 % CI 0.55-0.99; p = 0.059) (figure 1). RV pressure (AUC 0.84, 95% CI 0.66-1.00, p= 0.012) and RA pressure (AUC 0.83, 95% CI 0.67-0.98, p=0.016) showed a good predictive value for the composite endpoint (figure 2). The combination of MELD XI (at admission) and RV or PA pressure improved the AUC (MELD XI + RV: AUC 0.85; MELD XI + PA: AUC 0.84). Conclusion In this pilot-study, the modified MELD XI score, as indicator of hepatorenal dysfunction, was identified as a potential marker for short-term outcome after interventional tricuspid valve treatment.

Advances in the Treatment of Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease caused by autoimmune reactions, with an unknown etiology. If left untreated, it can progress to cirrhosis, liver failure, or even death. While most patients respond well to first-line treatments, a significant number experience poor responses or intolerance, requiring the use of second- or third-line therapies. Ongoing research into the pathogenesis of AIH is leading to the development of novel therapeutic approaches. This review summarized recent advancements in the treatment of AIH both domestically and internationally.

Comparing the anti-remodeling effect of sacubitril/valsartan and angiotensin-converting enzyme inhibition on myocardial samples of advanced heart failure patients undergoing heart transplantation

Abstract Background In decreasing heart failure (HF) hospitalization and cardiovascular death in HF patients with reduced ejection fraction, Sacubitril/Valsartan (SAC/VAL) treatment was proved to be superior to angiotensin-converting enzyme inhibition (ACEi). According to recent experimental results and clinical data based on echocardiography and circulating biomarkers, this benefit might be at least partially attributed to a greater anti-remodeling effect. However, there is a lack of direct evidence from human myocardial samples for this assumption. Purpose Therefore, we aimed to compare the anti-remodeling effect of SAC/VAL treatment to ACEi on myocardial samples of HF patients undergoing heart transplantation (HTX). Methods We studied left ventricular (LV) samples of seventy advanced HF patients who underwent HTX and received either SAC/VAL (SAC/VAL group, N=32) or ACEi treatment (ACEi group, N=38) for at least three months prior to HTX. Furthermore, all patients received beta-blockers and mineralocorticoid receptor antagonists titrated to maximally tolerated or target dose. Our groups were matched for age, sex, ejection fraction and other clinical parameters. Patients with liver or kidney failure, mechanical circulatory support, systemic inflammatory/fibrotic diseases or positive inotrope treatment were excluded. Myocardial mRNA expression of fibrotic markers and B-type natriuretic peptide (BNP) were measured with qRT-PCR and normalized to glyceraldehyde 3-phosphate dehydrogenase expression. Interstitial fibrosis area was assessed histologically. Results Preoperative plasma N-terminal pro-BNP levels were similar in the two groups (SAC/VAL: 4363±752 pg/mL vs. ACEi: 4616±1020 pg/mL; p=0.911). In contrast, the mRNA level of BNP in the myocardium was lower in patients treated with SAC/VAL (SAC/VAL: 2.2±1.05 vs. ACEi: 5.2±1.74; p=0.006). TIMP metallopeptidase inhibitor 1 (SAC/VAL: 0.07±0.01 vs. ACEi: 0.13±0.02; p=0.011), TIMP metallopeptidase inhibitor 2 (SAC/VAL: 0.06±0.01 vs. ACEi: 0.11±0.01; p&amp;lt;0.001), collagen type I alpha 1 chain (SAC/VAL: 0.02±0.00 vs. ACEi: 0.08±0.02; p&amp;lt;0.001) and collagen type III alpha 1 chain (SAC/VAL: 0.12±0.02 vs. ACEi: 0.27±0.04; p&amp;lt;0.001) relative gene expressions were also decreased in the LV of SAC/VAL-treated patients. Histology analysis confirmed reduced interstitial myocardial fibrosis area in the SAC/VAL group as well (SAC/VAL: 7.2±0.4% vs. ACEi: 8.6±0.5%; p=0.031). Conclusions SAC/VAL treatment decreased the myocardial expression of BNP and fibrosis-related genes to a greater extent compared with ACEi in LV samples of patients undergoing HTX. Histological analysis also verified the differences in fibrosis. Thus, the anti-remodeling effect of SAC/VAL might be superior to ACEi even in advanced HF.

MELD-albumin score is strongly associated with all-cause mortality in patients with acute myocardial infarction complicated by cardiogenic shock

Abstract Background Kidney and liver injury are frequent complications in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) because of hypoperfusion and venous congestion. Model of End-Stage Liver Disease replacing INR with albumin (MELD-Albumin) score quantifies liver and kidney function and has been associated with mortality in acute heart failure. Higher MELD-albumin score indicates particularly more severe hepatic dysfunction. The predictive value of MELD-albumin score has yet to be assessed in AMICS. Methods This is a retrospective, multicenter observational cohort study of 1,716 patients admitted with AMICS at two tertiary facilities in Denmark between 2010 and 2017. MELD-albumin was calculated for each patient individually from 0–72-hour peak s-albumin, s-creatinine and s-bilirubin values in patients alive beyond day 2. Patients were stratified into groups according to score (Low: 1-10, Intermediate: 11-25, High: &amp;gt;25). Using national health registries, we performed follow-up until a maximum of 5 years (median 3.4 years). The primary outcome was all-cause mortality. Results Of 1716 patients in the cohort, 1284 (75%) were alive beyond admission day 2. Albumin, creatinine, and bilirubin measurements were available in 764 patients (60%). The median MELD-albumin score was 17. In the comparison across high vs. intermediate vs. low score groups, the high score group revealed a significantly higher prevalence of hypertension (61 vs. 49 vs. 39%, p=0.038), diabetes mellitus (33 vs. 18 vs. 13%, p=0.003), and history of acute myocardial infarction (24 vs. 13 vs. 17%, p=0.026). Fewer had suffered out-of-hospital cardiac arrest (34 vs. 52 vs. 48%, p=0.014) and revascularization attempts (82 vs. 93 vs. 92%, p=0.007) in the high score group. No significant differences were observed in the initial hemodynamic pressures, lactate levels, left ventricular ejection fraction (LVEF), number of diseased vessels and culprit lesions between the three groups. Patients in the high score group had a 30-day mortality rate of 58%, which was higher compared to 40% in the medium- and 17% in the low score group (Figure 1, p&amp;lt;0.001, using the log-rank test). These findings were still significant when excluding s-creatinine from the calculations. In a Cox Regression analysis, a MELD-albumin score of &amp;gt;25 was associated with a hazard ratio (HR) of 4.34 for 5-year mortality (p &amp;lt; 0.001), whereas a score of 11-25 was associated with a HR of 2.52 (p &amp;lt; 0.001). When adjusting for age, diabetes, hypertension, dyslipidemia, peripheral arterial disease, STEMI, left ventricular ejection fraction and baseline lactate, scores of &amp;gt;25 and 11-25 were still associated with similar 4- to 2.5-fold increases in 5-year mortality risks. Conclusions This study revealed a strong association between MELD-albumin score and all-cause mortality among patients with AMICS, supporting kidney and liver function inclusion in future risk stratification models.

Late Diagnosis of Hereditary Tyrosinemia Type I: The Case of Two First Cousins

Hereditary Tyrosinemia Type I (HT1) is a rare metabolic disorder caused by a deficiency in fumarylacetoacetate hydrolase, leading to the accumulation of toxic metabolites and resulting in hepatic and renal complications. This case report details a 10-year-old patient from a consanguineous family with a significant history of hepatic failure due to hepatocellular carcinoma. The patient presented with abdominal pain, jaundice, and urinary abnormalities, which led to the diagnosis of HT1, confirmed by elevated succinylacetone levels. Despite initial treatment with nitisinone and a low-protein diet, surgical resection of the hepatic mass was impeded by vascular invasion, necessitating preoperative chemotherapy. This case underscores the importance of early detection and a multidisciplinary approach in managing HT1, highlighting ongoing research into advanced therapies and genetic interventions to improve patient outcomes.

Transition of patients with familial chylomicronaemia syndrome from volanesorsen to olezarsen: safety and pharmacokinetic results

Abstract Background Familial chylomicronaemia syndrome (FCS) is a rare genetic disorder of lipoprotein lipase deficiency resulting in severe hypertriglyceridaemia and pancreatitis risk. Volanesorsen is a weekly-injected antisense oligonucleotide (ASO) designed to degrade APOC3 mRNA that is approved as an adjunct to diet to treat FCS in the EU, UK, and Brazil. Olezarsen is an investigational monthly-injected ASO-GalNAC3 conjugate also designed to degrade APOC3 mRNA, but directed to hepatocytes, resulting in more potency and less systemic exposure and making it a potential alternative to volanesorsen for FCS. Purpose This interim analysis of an open-label phase 3 trial evaluated olezarsen safety and pharmacokinetics in patients (pts) with FCS previously treated with volanesorsen. Methods Adults with FCS with prior volanesorsen treatment, or actively participating in an expanded access programme (US and Canada), started olezarsen 80 mg by subcutaneous injection every 4 weeks after a minimum washout of 6 weeks. Historical volanesorsen laboratory and safety data were unavailable. The primary objective was to assess safety from changes vs baseline in platelet count, liver enzymes, and renal function; bleeding events; and adverse events. Pharmacokinetic measurements included plasma volanesorsen and olezarsen concentrations. Immunogenicity was assessed by measuring anti-drug antibodies (Abs). Results Of 24 pts enrolled, the majority were female (n=13; 54.2%) and White (n=21; 87.5%), with mean age of 49.1 years; 20 (83.3%) had genetically and 4 (16.7%) clinically validated FCS, all had history of acute pancreatitis (or symptoms suggestive of pancreatitis requiring hospitalisation or emergency room/urgent care visit; mean, 3.4 episodes within 5 years) and 5 (20.8%) of thrombocytopaenia. Time since last volanesorsen dose was 42—1118 days. Baseline fasting triglyceride (median [interquartile range (IQR)], 18.6 [9.6,34.0] mmol/L [1648 (852,3007) mg/dL]; mean [standard deviation (SD)], 25.5 [20.5] mmol/L [2256 (1812) mg/dL]) and apolipoprotein C-III (median [IQR], 0.2 [0.1,0.4] g/L [16.1 (12.4,39.0) mg/dL]; mean [SD], 0.3 [0.2] g/L [25.9 (19.5) mg/dL]) levels were elevated. During a mean (SD) of 329 (95) days of olezarsen 80 mg treatment, no pts experienced hepatic failure, renal impairment, major bleeding events, or platelet count below the prespecified threshold of 50,000 mm³ (Table 1). Olezarsen levels at trough were elevated during the first 3 months, mainly due to residual volanesorsen levels in pts with washout &amp;lt;90 days (Figure 1). Eleven (45.8%) pts had treatment-emergent anti-olezarsen Abs, of whom 5 (20.8%) had anti-volanesorsen Abs, with no impact on safety or efficacy; pts with vs without anti-drug Abs had higher olezarsen trough levels (mean, 4.4–7.8 ng/mL vs 1.1 ng/mL). Conclusions In this interim analysis, olezarsen was safe and well tolerated in pts with FCS previously treated with volanesorsen after a minimum washout of 6 weeks.

Preoperative chemo-CIRT in Re/BRe pancreatic cancer: Insights from a multicenter prospective phase II clinical study (NCT03822936).

There is debate about the optimal management of borderline resectable (bRe) and resectable (Re) pancreatic ductal adenocarcinoma (PDAC). Both preclinical and clinical evidence showed that carbon ion radiotherapy (CIRT) produces superior control on radioresistant histologies compared to conventional photon beam radiotherapy (RT). However, so far there is a lack of data concerning the integration of CIRT in a multimodal approach with chemotherapy and surgery for bRe/Re. We recently presented the first analysis of a multicenter prospective phase II clinical study aimed at assessing the feasibility and effectiveness of a neoadjuvant chemotherapy + short course of CIRT followed by surgery and adjuvant chemotherapy in the management of bRe/Re PDAC. The study was terminated early due to low patient enrollment.Herein, we reported a post-hoc analysis focusing on toxicity, dosimetry and translational assessment. In our experience, CIRT can be integrated into a multimodal treatment strategy for bRe/Re PDAC, alongside chemotherapy and surgery. A case of fatal liver failure occurring three months post-surgery has been documented, likely related to the combination approach. Although the treatment plans were satisfactory according to the Local Effect Model (LEM) model, recalculations using the modified Microdosimetric Kinetic Model (mMKM) revealed suboptimal target coverage. Additionally, we observed an increased expression of PD-L1 following CIRT. This multimodal approach was well tolerated; however, clinicians should carefully monitor for vascular disorders during follow-up and further investigate surgical techniques after CIRT. The increased PD-L1 expression supports the immunogenic effects of particle therapy and lays the groundwork for future studies. To enhance the therapeutic ratio of CIRT treatments, integrating dose-averaged LETd (LETd-based objectives into the plan optimization process should be considered. ClinicalTrials.gov Identifier: NCT03822936.

Fatal invasive Aspergillus infection in an elderly patient with hepatitis E: A case report and literature review.

Elderly patients with acute liver failure are highly susceptible to severe complications, such as invasive fungal infections, due to weakened immune systems and altered gut microbiota. A thorough understanding of liver failure and opportunistic infections is crucial for effective management. An 84-year-old male with acute liver failure from hepatitis E experienced worsening jaundice despite standard treatments. He also developed respiratory symptoms, including blood-streaked sputum, raising concerns about a potential fungal infection. The patient was diagnosed with acute liver failure secondary to hepatitis E and an invasive fungal infection caused by Aspergillus fumigatus. Initial treatments included artificial liver plasma exchange and antifungal prophylaxis. Further diagnostics, including bronchoscopy and next-generation sequencing of alveolar lavage fluid, confirmed the Aspergillus infection. Elderly liver failure patients are particularly prone to opportunistic infections, underscoring the need for vigilant monitoring and early intervention. Despite aggressive treatments, including antifungal therapy and artificial liver support, prognosis remains poor, highlighting the importance of prompt diagnosis and comprehensive management to enhance patient outcomes.

The rate of change in clinical indicators can predict the progression of hepatitis B virus-related acute-on-chronic preliver failure.

The objective of this study was to investigate the predictors and predictive model construction of the progression of HBV-Pre.Acute-on-chronic liver failure (ACLF), a total of 133 patients with HBV-Pre.ACLF was divided into the progressive group (52 patients) and the recovery group (81 patients) according to whether they progressed to ACLF or not. The clinical parameters N%, L%, PLT, ALT, TBiL, ALB, Cre, Na, NH3, CRP, AFP, prothrombin time (PT), international normalized ratio (INR), FIB, and their rate of change at baseline were analyzed in the 2 groups. The independent risk factors for HBV-Pre.ACLF progression was found by univariate and multivariate analyses, and a predictive model was constructed. The clinical parameters ALB, FIB, Na, combined alprostadil treatment and MELD, and MELD-Na scores at baseline were significantly different between the 2 groups (P <.05), while ALT, TBiL, Cre, CHE, NH3, N%, L%, PLT, INR, and PT were not significantly different (P >.05). The change rates of Na, CHE, PT, FIB, CRP, Cre, PLT, and the ratio after to before of N% were significantly different between the 2 groups (P <.05), while the change rates of ALT, TBIL, NH3, AFP, L%, and the ratio after to before of INR were not significantly different between the 2 groups (P >.05). Univariate and multivariate analyses showed that baseline ALB, Na, FIB, combined alprostadil therapy and the rate of change of Na and PLT were protective factors for disease progression, and the rate of change of PT, CRP, and the ratio after to before of N% were independent risk factors for disease progression. The novel model was LogitP = -6.051 + 4.049×ΔPT + 0.626×ΔCRP + 4.527×the ratio after to before N% and its area under the curve was 0.944 (95% confidence interval: 0.900-0.988) predicting progression of HBV-Pre.ACLF, and the best cutoff value was -0.22. The patients with a higher logitP score (> -0.22) had an increased risk for progression to ACLF (P <.05). The novel model logitP shows good predictive value for the disease progression of HBV-Pre.ACLF.

ACCI-HBV-ACLF: A Novel Predictive Model for Hepatitis B Virus-Related Acute-On-Chronic Liver Failure.

Early identification of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) holds crucial importance in guiding clinical management and reducing mortality. However, existing scoring systems often overlook patient's underlying clinical condition, which significantly impacts prognosis. Use the age-adjusted Charlson comorbidity index (aCCI) to evaluate the patient's complications to develop a more precise model for predicting transplant-free mortality in HBV-ACLF patients. Nine hundred and six patients were included for investigation and were segregated into a training cohort and a temporal validation cohort according to the chronological order of admission in a ratio of 7:3. In the training cohort, univariate analysis, logistic regression analysis and LASSO regression analysis were used to construct a prognostic model and it was subsequently validated in a temporal validation cohort and an external validation cohort. We found total bilirubin, neutrophils, international normalised ratio and aCCI exhibited significant associations with 28-day transplant-free mortality and established a novel prognostic model, named aCCI-HBV-ACLF. The model demonstrated strong predictive performance, with area under the receiver operating characteristic curve (ROC) values of 0.859 for 28-day mortality, 0.822 for 90-day mortality. In the temporal validation cohort, aCCI-HBV-ACLF achieved area under the ROC values of 0.869 for 28-day mortality and 0.850 for 90-day mortality. In the external validation cohort, aCCI-HBV-ACLF had area under the ROC values of 0.868 for 28-day mortality and 0.888 for 90-day mortality. This study proposes a new prognostic model, which achieved excellent predictive ability for 28-/90-day transplant-free mortality rates among patients with HBV-ACLF.

Effect of clustered nursing on liver function indexes, nutrition, and emotional status of patients with severe liver failure.

Liver failure is a metabolic disorder caused by a variety of mixed factors. For such diseases, adopting cluster care can effectively improve the relevant symptoms of patients. To explore the nursing effect of nutritional nursing combined with clustered nursing for patients with severe liver failure. A total of 129 patients with severe liver failure were selected as retrospective study subjects. Nine cases were due to an end event, such as death. The other patients were divided into control group and observation group according to different nursing methods. Among them, the control group adopted nutrition nursing, and the observation group implemented cluster nursing on this basis. The differences of liver function, anxiety and depression score, gastrointestinal recovery, nutritional status, and sleep quality were compared between the 2 groups before and after nursing. After nursing, the total bilirubin, albumin, and aspartate aminotransferase of the observation group were significantly higher than those of the control group (P < .05). The nursing staff used Self-Rating Anxiety Scale and Self-Rating Depression Scale of the observation group, which were slightly lower than those of the control group. The difference was statistically significant after testing (P < .05). After nursing, the observation group's upper arm circumference, brachial tri-scalp fold thickness, and hemoglobin were better than those of the control group. Statistics showed that the difference was statistically significant (P < .05). The depth of sleep, time to fall asleep, number of awakenings, time to fall asleep after awakening, overall sleep quality, and intensive care unit environmental noise intensity in the Richards-Campbell Sleep Questionnaire sleep scale after nursing in the 2 groups were significantly higher than those before nursing, and the scores of the observation group were significantly lower than those in the observation group. In the control group, this difference was statistically significant (P < .05). Nutritional nursing combined with clustered nursing can effectively promote the recovery of gastrointestinal function in patients with severe liver failure.

Evaluation and management of hepatic dysfunction, portal hypertension and portal/splanchnic vein thrombosis in patients with myelofibrosis undergoing allogeneic haematopoietic cell transplantation: A practice based survey on behalf of the Chronic Malignancies Working Party of the EBMT

Heterogeneous approaches exist in regard to the management of disease-related co-morbidities in potential allogeneic haematopoietic cell transplantation (allo-HCT) candidates with myelofibrosis (MF). The EBMT Chronic Malignancies Working Party launched an electronic survey to evaluate how MF-specific comorbidities are approached and whether they ultimately affect the decision to transplant. A total of 41/63 (65%) Centers, all of whom were experienced in the management of MF allo-HCT, responded. Responses were aggregated and reported in a comparative fashion. Screening for portal hypertension (PH) was routinely performed in 54% centers, never in 12% and guided by clinical manifestations in the remaining. Involvement of hepatologists/gastroenterologists was always/very often considered in patients with signs of PH prior to transplant. Centers reported that radiological evidence of PH did not routinely represent a formal contraindication for allo-HCT in most cases (78%). Of note, most centers (61%) did not perform routine screening for gastroesophageal varices; this was systematically considered or guided by clinical manifestations in only 7% and 32% centers, respectively. Presence of gastroesophageal varices was always (15%) or occasionally (19%) considered a formal contraindication to allo-HCT. A prior history of portal vein thrombosis never (78%) or occasionally (15%) represented a formal contraindication. Three Centers would not proceed to transplant in such cases. Less importance was assigned to non-portal splanchnic vein thrombosis (SVT), with all but one centre proceeding to transplant regardless of prior SVT. This survey highlights a considerable heterogeneity across responding centers in approaching MF-related comorbidities prior to transplant, suggesting that harmonisation guidelines are needed to address these issues in this patient population.

Case report: exome sequencing identified mutations in the LRP5 and LGR4 genes in a case of osteoporosis with recurrent fractures and extraskeletal manifestations

BackgroundGenetic mutations have been reported in a number of bone disorders with or without extra-skeletal manifestations. The purpose of the present study was to investigate the genetic cause in a middle-aged woman with osteoporosis, recurrent fractures and extraskeletal manifestations.MethodsA 56-year-old Indian woman presented to the clinic with complaints of difficulty in walking, recurrent fractures, limb bending, progressive skeletal deformities, and poor overall health. At the age of 37, she had experienced severe anemia with diarrhea, significant weight loss, knuckle pigmentation, and a significant loss of scalp hair. She had received multiple blood transfusions and parenteral iron supplementation with normalization of hemoglobin. Subsequently, she had premature menopause at the age of 37. She died at the age of 61 due to liver failure. Exome sequencing followed by Sanger sequencing were undertaken to identify the potential pathogenic mutations.ResultsGenetic investigation identified likely pathogenic mutations in the LRP5 and LGR4 genes. Out of the two mutations, the heterozygous mutation (c.1199C&amp;gt;T) in the LRP5 gene resulted in a non-synonymous substitution of alanine with valine at the 400th position, and the second mutation (c.1403A&amp;gt;C) in the LGR4 gene led to a non-synonymous substitution of tyrosine with serine at the 468th residue of the protein. The minor allele frequencies of the c.1199C&amp;gt;T (LRP5) substitution in the 1000 genomes and IndiGenomes databases are 0.0003 and 0.001, while the c.1403A&amp;gt;C (LGR4) substitution has not been reported in these databases. Various in silico prediction tools suggested LGR4 mutation to be pathogenic and LRP5 mutation to be likely pathogenic.ConclusionHeterozygous mutations in the LRP5 and LGR4 genes had additive deteriorative effects on BMD, resulting in recurrent fractures and bone deformities, and extended the effect to extraskeletal sites, contributing to the poor overall health in this patient.

Quercetin inhibits mitophagy-mediated apoptosis and inflammatory response by targeting the PPARγ/PGC-1α/NF-κB axis to improve acute liver failure

BackgroundReactive oxygen species (ROS) from mitochondrial dysfunction are critical in triggering apoptosis and inflammation in acute liver failure (ALF). Quercetin (QUE), an antioxidant, is renowned for its therapeutic effects onliverdiseases. There are no studies on whether QUE regulates mitophagy level in hepatocytes to inhibit ALF. ObjectiveThis study investigates QUE’s protective effects on ALF and elucidates the mechanisms involved. MethodsThe ALF and hepatocyte inflammatory injury model was established using LPS and D-Galn. To predict potential targets and mechanisms of QUE in ALF treatment, transcriptomics, network pharmacology, molecular docking techniques, and ChIP were employed. The expression level related to mitophagy, apoptosis, and signaling pathways were detected by CCK8, IHC, IF staining, TUNEL, RT-qPCR, TEM, Western blotting, ELISA, and flow cytometry. ResultsNetwork pharmacology and transcriptomics revealed common targets between QUE and ALF. Enrichment analysis showed that the anti-ALF targets of QUE were significantly associated with mitochondria and NF-κB-related pathways. Subsequent experiments showed that QUE pretreatment significantly alleviated the loss of hepatocyte viability, enhanced mitochondrial membrane potential, activated mitophagy, and promoted the clearance of damaged mitochondria, thereby reducing ROS accumulation, significantly reducing cell apoptosis and inflammatory responses, reducing ALT and AST levels, and improving liver tissue pathology. Mechanistically, molecular docking, DARTS, and CETSA analyses confirmed that QUE directly binds to the PPARγ molecule, which reduced binding to IκB and significantly inhibit the NF-κB pathway to exert its protective effects. ConclusionIn short, our results provide the first evidence that QUE improves acute liver failure by promoting mitophagy through regulating the PPARγ/PGC-1α/NF-κB axis and inhibiting apoptosis and inflammatory responses mediated by mitochondrial dysfunction, which provides evidence for the potential of QUE in the treatment of ALF.

A comprehensive organ protection strategy in total arch replacement: a propensity-weighted analysis.

To report the outcomes and determine the effectiveness of a comprehensive organ protection strategy in total arch replacement. A total of 350 patients who underwent total arch replacement were enrolled. 54 patients underwent the comprehensive organ protection strategy with bilateral antegrade cerebral perfusion (bACP) and aortic balloon occlusion (ABO) technique (comprehensive strategy group) and 296 patients underwent the standard strategy with unilateral antegrade cerebral perfusion (standard strategy group). Inverse probability of treatment weighting (IPTW) was used to balance the baseline characteristics. After IPTW, the comprehensive strategy group had lower incidences of 30-day mortality (0.9% vs 4.9%, P = 0.002), continuous renal replacement therapy (CRRT) (0.6% vs 10.3%, P < 0.001), renal failure (4.6% vs 13.7%, P < 0.001), hepatic dysfunction (11.6% vs 21.1%, P = 0.001), and shorter duration of mechanical ventilation [16 (13, 31) vs 20 (14, 48) hours, P = 0.011]. Multivariable logistic analysis showed the comprehensive strategy was an independent protective factor of 30-day mortality (odds ratio (OR): 0.242, 95% confidence interval (CI): 0.068-0.867, P = 0.029), CRRT (OR: 0.045, 95% CI: 0.008-0.264, P = 0.001), renal failure (OR: 0.351, 95% CI: 0.156-0.788, P = 0.011), and mechanical ventilation >20 hours (OR: 0.531, 95% CI: 0.319-0.883, P = 0.015). Kaplan-Meier analysis showed mid-term survival was comparable. The comprehensive organ protection strategy might improve early survival, reduce the use of CRRT, have protective effects on the kidney, and shorten mechanical ventilation time in total arch replacement. This strategy might be considered a viable alternative in total arch replacement.