Acute-on-chronic Liver Failure Patients Research Articles

Cytokine adsorption in patients with acute-on-chronic liver failure (CYTOHEP)-A single center, open-label, three-arm, randomized, controlled intervention pilot trial.

To investigate the efficacy of bilirubin reduction by hemoadsorption with CytoSorb® in patients with acute-on-chronic liver failure (ACLF) receiving continuous renal replacement therapy (CRRT). A prospective, randomized, single-center, open-label, controlled pilot trial. Patients with ACLF, acute kidney injury, and serum bilirubin ≥5 mg/dL were assigned 1:1:1 to one of three study groups (CRRT with or without hemoadsorption, no CRRT). In the hemoadsorption group, the CytoSorb adsorber was incorporated into the CRRT system, replaced after 12, 24, and 48 h, and removed after 72 h. The primary endpoint was the serum bilirubin level after 72 h. CYTOHEP was terminated early due to difficulties in recruiting patients and ethical concerns. Three of 9 patients (33%) were treated in each group. Comparing the three groups, mean bilirubin levels after 72 h were lower by -8.0 mg/dL in the "CRRT with hemoadsorption" group compared to "CRRT without hemoadsorption" (95% CI, -21.3 to 5.3 mg/dL; p = 0.17). The corresponding mean difference between "CRRT without hemoadsorption" and "no CRRT" was -1.4 mg/dL (95% CI, -14.2 to 11.5 mg/dL; p = 0.78). Comparing "CRRT with hemoadsorption" and "no CRRT," it was -9.4 mg/dL (95% CI, -20.8 to 2.1 mg/dL; p = 0.0854). Only 1/9 patients (11%, "no CRRT" group) survived day 30 after study inclusion but died on day 89. IL-6, liver function parameters, and clinical scores were similar between the study groups. CYTOHEP failed to demonstrate that extracorporeal hemoadsorption combined with CRRT can reduce serum bilirubin in ACLF patients with acute kidney failure.

Outcome of patients with different stages of acute-on-chronic liver failure treated with artificial liver support system

BackgroundElevated international normalized ratio of prothrombin time (PT-INR) is one of the key characteristics of acute-on-chronic liver failure (ACLF). Whether the staging of PT-INR has the ability to screen out subgroups of ACLF patients who would be more eligible for artificial liver support system (ALSS) treatment has not been studied in detail.MethodsA previous study enrolled patients receiving ALSS treatment with regional citrate anticoagulation from January 2018 to December 2019. Patients with different PT-INR intervals were retrospectively enrolled: 1.3 ≤ PT-INR < 1.5 (Pre-stage), 1.5 ≤ PT-INR < 2.0 (Early-stage), 2.0 ≤ PT-INR < 2.5 (Mid-stage), and PT-INR ≥ 2.5 (End-stage). The Cox proportional hazards models were used to estimate the association between stages of ACLF or sessions of ALSS treatment and 90 day mortality.ResultsA total of 301 ACLF patients were enrolled. The 90 day mortality risk of Early-stage ACLF patients (adjusted hazard ratio (aHR) (95% confidence interval (CI)), 3.20 (1.15–8.89), p = 0.026), Mid-stage ACLF patients (3.68 (1.34–10.12), p = 0.011), and End-stage ACLF patients (12.74 (4.52–35.91), p < 0.001) were higher than that of Pre-stage ACLF patients, respectively. The 90 day mortality risk of Mid-stage ACLF patients was similar to that of Early-stage ACLF patients (1.15 (0.69–1.94), p = 0.591). The sessions of ALSS treatment was an independent protective factor (aHR (95% CI), 0.81 (0.73–0.90), p < 0.001). The 90 day mortality risk in ACLF patients received 3–5 sessions of ALSS treatment was lower than that of patients received 1–2 sessions (aHR (95% CI), 0.34 (0.20–0.60), p < 0.001), whereas the risk in patients received ≥6 sessions of ALSS treatment was similar to that of patients received 3–5 sessions (0.69 (0.43–1.11), p = 0.128).ConclusionACLF patients in Pre-, Early-, and Mid-stages might be more eligible for ALSS treatment. Application of 3–5 sessions of ALSS treatment might be reasonable.

Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure.

CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8days (IQR: 3-13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7mg/dL to median post-treatment: 10.8mg/dL; - 47.8%; p < 0.001), procalcitonin (1.34 to 0.74pg/mL; - 44.6%; p < 0.001), interleukin-6 (385 to 131ng/mL; - 66.0%; p = 0.0182)-but also of platelets (72 to 31 G/L; - 56.9%; p = 0.0014) and fibrinogen (230 to 154mg/dL; - 33.0%; p = 0.0297) were detected. ICU survivors had a trend towards a stronger relative decrease in bilirubin (- 76.1% vs. - 48.2%), procalcitonin (- 90.6% vs. - 23.5%), and IL-6 (- 54.6% vs. - 17.8%) upon CytoSorb treatment. Moreover, no serious CytoSorb-attributed complications were detected. In conclusion, use of CytoSorb adsorber in ACLF patients results in a significant decrease in bilirubin and proinflammatory cytokines, while platelets and fibrinogen were also lowered. Prospective trials are warranted to investigate the impact of CytoSorb on clinical outcomes of ACLF patients with high proinflammatory cytokine levels.

Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and non-recovery in ACLF. Here we mapped the single-cell transcriptome of circulating immune cells from ACLF-, acute decompensated (AD) cirrhosis patients and healthy individuals. We further interrogate how these findings as well as immunometabolic- and functional profiles associate with ACLF recovery (ACLF-R) or non-recovery (ACLF-NR). Our analysis unveiled two distinct states of classical monocytes (cMon). Hereto, ACLF-R cMons were characterized by transcripts associated with immune- and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1. Additional metabolomic- and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program and blunted activation among lymphoid populations in ACLF-R patients. Conversely, ACLF-NR cMon featured elevated expression of inflammatory- and stress response genes such as VIM, LGALS2, and TREM1 along with blunted metabolic activity and increased functionality. This study identifies distinct immuno-metabolic cellular states that contribute to disease outcome in ACLF patients. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or non-recovery phenotypes which may be harnessed as potential therapeutic targets in the future.

Extracorporeal Support Strategies in Liver Failure - Focus on Albumin Dialysis and Therapeutic Plasma Exchange

Combining albumin dialysis for the removal of hydrophobic substances with classical haemodialysis in the treatment of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) has a strong theoretical rational and clinical data showed a positive effect on laboratory and partly clinical characteristics of ALF and ACLF. However, neither the MARS nor the Prometheus System has so far been able to demonstrate a mortality benefit in ALF or ACLF patients. To date, only the use of therapeutic plasma exchange (TPE) has demonstrated significant removal of pathogen-associated (PAMPs), damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. In addition, TPE also acts simultaneously by replacing protective but depleted mediators, thus improving multiple key pathophysiological principles of both ALF and ACLF. In ALF, both high-volume and standard-volume TPE showed a significant improvement in survival. The data on the use of TPE in ACLF is still sparse, with only two Chinese monocentric studies in patients with exclusively hepatitis B-associated ACLF suggesting potentially improved survival with TPE. The currently recruiting APACHE study will include patients with the modern EASL-CLIF definition of ACLF.

Accuracy of chronic liver failure consortium (CLIF-C) ACLF score compared with meld, MELD-NA and CTP as a mortality predictor in acute on chronic liver failure patients admitted to tertiary rural care hospital

Background Chronic Liver Failure Consortium (CLIF-C) ACLF score, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) are established scoring systems for predicting mortality in Acute on Chronic Liver Failure (ACLF) patients. However, their comparative accuracy, especially in rural care settings, still needs to be explored. This study aims to assess and compare the predictive performance of these scoring systems, providing a nuanced understanding of their applicability in a tertiary rural care hospital. Method This prospective observational cohort study will be conducted at Acharya Vinoba Bhave Rural Hospital, following approval from the institutional ethical committee. ACLF patients aged 18 and above, presenting within one week of onset, will be included. Data collection will involve comprehensive assessments, including scoring system calculations, clinical examinations, and relevant investigations. Statistical analyses, encompassing descriptive statistics, comparative analyses, survival analyses, and multivariate models, will elucidate the accuracy and independent predictors of 28-day mortality. Expected Outcome Anticipated outcomes include a comprehensive understanding of the strengths and limitations of the CLIF-C ACLF score, MELD, MELD-Na, and CTP in predicting mortality among ACLF patients in a rural care context. The study aims to identify potential correlations and independent predictors, offering valuable insights for risk stratification. These findings are expected to guide clinicians in optimising prognostic assessments and decision-making, thereby improving the care and outcomes of ACLF patients in rural healthcare settings.

Early Versus Standard Initiation of Terlipressin for Acute Kidney Injury in ACLF: A Randomized Controlled Trial (eTerli Study).

Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates. Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40g) were randomized to receive terlipressin at 2mg/24h plus albumin at 12h (ET, n = 35) or at 48h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7. Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7days than ET arm (149.1 ± 41.8g vs. 177.5 ± 40.3g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening. In ACLF patients, early initiation of terlipressin for AKI persisting after 12h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.

Postoperative outcomes of acute-on-chronic liver failure in infants and children with biliary atresia.

Acute-on-chronic liver failure (ACLF) is associated with increased mortality and morbidity in patients with biliary atresia (BA). Data on impact of ACLF on postoperative outcomes, however, are sparse. We performed a retrospective analysis of patients with BA aged <18 years who underwent LT between 2011 and 2021 at our institution. ACLF was defined using the pediatric ACLF criteria: ≥1 extra-hepatic organ failure in children with decompensated cirrhosis. Of 107 patients (65% female; median age 14 [9-31] months) who received a LT, 13 (12%) had ACLF during the index admission prior to LT. Two (15%) had Grade 1; 4 (30%) had Grade 2; and 7 (55%) had Grade ≥3 ACLF. ACLF cohort was younger at time of listing (5 [4-8] vs. 9 [6-24] months; p < .001) and at LT (8 [8-11] vs. 16 [10-40] months, p < .001) compared to no-ACLF group. Intraoperatively, ACLF patients had higher blood loss (40 [20-53] vs. 10 [6-19] mL/kg; p < .001) and blood transfusion requirements (33 [21-69] vs. 18 [7-25] mL/kg; p = .004). Postoperatively, they needed higher vasopressor support (31% vs. 10.6%; p = .04) and had higher total hospital length of stay (106 [45-151] vs. 13 [7-30] days; p = .023). Rate of return to the operating room, hospital readmission rates, and 1-year post-LT survival rates were comparable between the groups. Despite higher perioperative complications, survival outcomes for ACLF in BA after LT are favorable and comparable to those without ACLF. These encouraging data reiterate prioritization during organ allocation of these critically ill children for LT.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure

BackgroundThe key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis.MethodsBiobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.ResultsTHBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis.ConclusionsTHBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.Graphical

Adult-to-adult right lobe graft living donor liver transplantation for acute-on-chronic liver failure: a single-centre retrospective study in Vietnam.

Acute-on-chronic liver failure (ACLF) has a high mortality rate, and liver transplantation is considered a definite treatment for patients with this condition. This study aims to evaluate the outcomes of living donor liver transplantation (LDLT) in ACLF patients in a single centre in a lower middle-income country, Vietnam. This was a retrospective study at the 108 Military Central Hospital (Hanoi, Vietnam), enroling 51 patients diagnosed with ACLF based on Asian Pacific Association for the Study of the Liver (APASL) criteria who underwent LDLT with a right lobe graft from December 2019 to December 2022. The authors utilize the model for end-stage liver disease (MELD) and APASL ACLF Research Consortium (AARC) scores to evaluate and stratify the severity of ACLF. The average age of all patients was 47.27±13.61, with 88.24% being male. The average BMI was 22.78±2.61. The most common underlying liver disease was chronic viral hepatitis B (88.2%). The average MELD score of the patients was 34.90±5.61, with 33.3% having MELD score greater than or equal to 40. In terms of ACLF severity, five patients (9.8%) had grade I ACLF, 35 patients (68.6%) had grade II ACLF, and 11 patients (21.6%) had grade III ACLF. The average AARC score was 9.43±1.68. The duration of treatment in the ICU was 8.59±7.27 days, and the length of hospital stay was 28.02±13.45 days. The most common post-transplant complication was biliary complication (19.61%). Death occurred in 7 patients (13.7%). The survival rates at 6 months, 1 year, and 3 years were 84%, 81.7%, and 81.7%, respectively. Living donor liver transplantation for ACLF patients is safe and has a high post-transplant survival rate. Multidisciplinary care before, during, and after surgery, and the decision to do a liver transplant early, is essential in saving the lives of ACLF patients.

Development and First Clinical Use of an Extracorporeal Artificial Multiorgan System in Acute-on-Chronic Liver Failure Patients.

Multiple organ failure (MOF) is a common and deadly condition. Patients with liver cirrhosis with acute-on-chronic liver failure (AOCLF) are particularly susceptible. Excess fluid accumulation in tissues makes routine hemodialysis generally ineffective because of cardiovascular instability. Patients with three or more organ failures face a mortality rate of more than 90%. Many cannot survive liver transplantation. Extracorporeal support systems like MARS (Baxter, Deerfield, IL) and Prometheus (Bad Homburg, Germany) have shown promise but fall short in bridging patients to transplantation. A novel Artificial Multi-organ Replacement System (AMOR) was developed at the University of Washington Medical Center. AMOR removes protein-bound toxins through a combination of albumin dialysis, a charcoal sorbent column, and a novel rinsing method to prevent sorbent column saturation. It removes excess fluid through hemodialysis. Ten AOCLF patients with over three organ failures were treated by the AMOR system. All patients showed significant clinical improvement. Fifty percent of the cohort received liver transplants or recovered liver function. AMOR was successful in removing large amounts of excess body fluid, which regular hemodialysis could not. AMOR is cost-effective and user-friendly. It removes excess fluid, supporting the other vital organs such as liver, kidneys, lungs, and heart. This pilot study's results encourage further exploration of AMOR for treating MOF patients.

Evaluation of G3BP1 in the prognosis of acute and acute-on-chronic liver failure after the treatment of artificial liver support system.

The increased expression of G3BP1 was positively correlated with the prognosis of liver failure. To investigate the effect of G3BP1 on the prognosis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) after the treatment of artificial liver support system (ALSS). A total of 244 patients with ALF and ACLF were enrolled in this study. The levels of G3BP1 on admission and at discharge were detected. The validation set of 514 patients was collected to verify the predicted effect of G3BP1 and the viability of prognosis. This study was shown that lactate dehydrogenase (LDH), alpha-fetoprotein (AFP) and prothrombin time were closely related to the prognosis of patients. After the ALSS treatment, the patient' amount of decreased G3BP1 index in difference of G3BP1 between the value of discharge and admission (difG3BP1) < 0 group had a nearly 10-fold increased risk of progression compared with the amount of increased G3BP1 index. The subgroup analysis showed that the difG3BP1 < 0 group had a higher risk of progression, regardless of model for end-stage liver disease high-risk or low-risk group. At the same time, compared with the inflammatory marks [tumor necrosis factor-α, interleukin (IL)-1β and IL-18], G3BP1 had higher discrimination and was more stable in the model analysis and validation set. When combined with AFP and LDH, concordance index was respectively 0.84 and 0.8 in training and validation cohorts. This study indicated that G3BP1 could predict the prognosis of ALF or ACLF patients treated with ALSS. The combination of G3BP1, AFP and LDH could accurately evaluate the disease condition and predict the clinical endpoint of patients.

Comparison of a Novel Score “NOD−ACLF” to Other Established Prognostic Scores for Prediction of Mortality in APASL−ACLF Patients: A Cohort Study from a Tertiary Care Center of North India

Commonly used prognostic scores for acute on-chronic liver failure (ACLF) have complex calculations. We tried to compare the simple counting of numbers and types of organ dysfunction to these scores, to predict mortality in ACLF patients. In this prospective cohort study, ACLF patients diagnosed on the basis of Asia Pacific Association for Study of the Liver (APASL) definition were included. Severity scores were calculated. Prognostic factors for outcome were analysed. A new score, the Number of Organ Dysfunctions in Acute-on-Chronic Liver Failure (NOD-ACLF) score was developed. Among 80 ACLF patients, 74 (92.5%) were male, and 6 were female (7.5%). The mean age was 41.0±10.7 (18-70) years. Profile of acute insult was; alcohol 48 (60%), sepsis 30 (37.5%), variceal bleeding 22 (27.5%), viral 8 (10%), and drug-induced 3 (3.8%). Profiles of chronic insults were alcohol 61 (76.3%), viral 20 (25%), autoimmune 3 (3.8%), and non-alcoholic steatohepatitis 2 (2.5%). Thirty-eight (47.5%) were discharged, and 42 (52.5%) expired. The mean number of organ dysfunction (NOD-ACLF score) was ->4.5, simple organ failure count (SOFC) score was >2.5, APASL ACLF Research Consortium score was >11.5, Model for End-Stage Liver Disease-Lactate (MELD-LA) score was >21.5, and presence of cardiovascular and respiratory dysfunctions were significantly associated with mortality. NOD-ACLF and SOFC scores had the highest area under the receiver operating characteristic to predict mortality among all these. The NOD-ACLF score is easy to calculate bedside and is a good predictor of mortality in ACLF patients performing similar or better to other scores.

A novel prognostic model to predict mortality in patients with acute-on-chronic liver failure in intensive care unit.

Acute-on-chronic liver failure (ACLF) implies high short-term mortality rates and usually requires intensive care unit (ICU) admission. Proper prognosis for these patients is crucial for early referral for liver transplantation. The superiority of CLIF-C ACLF score in Asian patients with ACLF admitted to an ICU remains inconclusive when compared to other scoring systems. The purpose of the study is (i) to compare the predictive performance of original MELD, MELD-Lactate, CLIF-C ACLF, CLIF-C ACLF-Lactate, and APACHE-II scores for short-term mortality assessment. (ii) to build and validate a novel scoring system and to compare its predictive performance to that of the original five scores. Two hundred sixty-five consecutive cirrhotic patients with ACLF who were admitted to our ICU were enrolled. The prognostic values for mortality were assessed by ROC analysis. A novel model was developed and internally validated using fivefold cross-validation. Alcohol abuse was identified as the primary etiology of cirrhosis. The AUROC of the five prognostic scores were not significantly superior to each other in predicting 1-month and 3-month mortality. The newly developed prognostic model, incorporating age, alveolar-arterial gradient (A-a gradient), BUN, total bilirubin level, INR, and HE grades, exhibited significantly improved performance in predicting 1-month and 3-month mortality with AUROC of 0.863 and 0.829, respectively, as compared to the original five prognostic scores. The novel ACLF model seems to be superior to the original five scores in predicting short-term mortality in ACLF patients admitted to an ICU. Further rigorous validation is required.

Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients.

Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.

Liver Elastography in Acute Liver Failure: A Pilot Study.

We aimed to assess the feasibility and reliability of sequential ultrasonographic and elastographic monitoring in acute liver failure (ALF). Observational study. ALF is a rare, life-threatening disease that requires intensive care admission and often liver transplant, where the accurate selection of patients is crucial. Liver elastography is a noninvasive tool that can measure hepatic stiffness, but previous results have been inconclusive in ALF. Patients admitted between October 2021 and March 2023 to the Liver Intensive Therapy Unit at King's College Hospital with ALF were recruited, with healthy control (HC) individuals and acute-on-chronic liver failure (ACLF) used as controls. None. Average shear wave velocity was recorded with ElastPQ on the right and left liver lobes and the spleen. Portal vein flow, hepatic artery resistive index, and peak systolic velocity were also recorded. Physiologic and histologic data were used for comparison. Forty patients with ALF, 22 patients with ACLF, and 9 HC individuals were included in the study. At admission, liver stiffness measurement (LSM) of the right lobe was statistically different between HC individuals (5.6 ± 2 kPa), ALF (31.7 ± 17 kPa), and ACLF (76.3 ± 71 kPa) patients (ALF vs. ACLF, p = 0.0301). Spleen size and stiffness discriminated between ALF (10.4 ± 2 cm and 21.4 ± 16.6 kPa) and ACLF (14 ± 2.3 cm and 42.6 ± 26 kPa). At admission, LSM was not different between ALF patients who spontaneously survived versus patients who died or were transplanted in the following 90 days. However, the trend over the first 10 days of admission was different with a peak of LSM at day 5 in spontaneous survivors followed by reduction during the recovery phase. ALF patients with poor prognosis showed a persistently increased LSM. In ALF stiffness peaks at day 5 of admission with subsequent reduction in patients spontaneously surviving, showing significant difference according to the prognosis at day 7 of admission. LSM might be useful in distinguishing acute from acute-on-chronic liver failure together with spleen volume and stiffness.

Impact of Onset Time, Number, Type, and Sequence of Extrahepatic Organ Failure on Prognosis of Acute-on-chronic Liver Failure.

The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients. ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan-Meier analysis and log-rank tests. A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan-Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts. The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

Relationship between skeletal muscle index at the third lumbar vertebra with infection risk and long-term prognosis in patients with acute-on-chronic liver failure.

Infection is a major cause of increased mortality in patients with acute-on-chronic liver failure (ACLF). This study aims to examine the potential correlation of the skeletal muscle index at the third lumbar vertebra (L3-SMI) with infections among ACLF patients and to evaluate its impact on the long-term survival. This retrospective study included 126 patients who underwent abdominal computed tomography (CT) and were diagnosed with ACLF at our center between December 2017 and December 2021. L3-SMI was calculated using CT, and the clinical and biochemical data as well as MELD scores were also collected, so as to analyze the relationship between L3-SMI and infections in ACLF patients and the impact on long-term prognosis. Of the 126 ACLF patients enrolled, 50 had infections. In the multivariate logistic regression analysis, both L3-SMI [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.81 - 0.97, P = 0.011] and hepatic encephalopathy (OR = 8.20, 95% CI = 1.70 - 39.59, P = 0.009) were independently associated with the risk of infection development. The overall survival (OS) estimates were obtained using Kaplan-Meier curves, and it was found that patients in the lowest tertile of L3-SMI had significantly lower 3-month, 6-month, 1-year, and 2-year survival rates than those in the highest tertile (P = 0.014; log-rank test). Low L3-SMI is an independent risk factor for the development of infections and significantly influences the long-term survival in ACLF patients.

LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.