1)Harmonizing ACLF definition: Why is it essential for scientific progress?
Kulkarni AV, Sarin SK, Choudhury A, Angeli P, Moreau R, Bajaj
JS. J Hepatol. 2026 Aug 27:S0168-8278(26)02864-3. doi: 10.1016/j.jhep.2026.08.021. (Online ahead of print)
2)Uncovering immune dysfunction in ACLF: Cellular mechanisms, molecular pathways, and therapeutic frontiers.
Ortega-Ribera M, Brenig R, Bernsmeier C, Szabo G.
J Hepatol. 2026 Sep;85(3):612-629. doi: 10.1016/j.jhep.2026.04.025. Epub 2026
Apr 29
Acute-on-chronic liver failure (ACLF) is a life-threatening condition
characterised by acute hepatic decompensation, multi-organ failure, and high
short-term mortality in patients with cirrhosis. A hallmark of ACLF is profound
immune dysfunction, which contributes to excessive organ-specific inflammation
and impaired host defence, predisposing patients to infection, multi-organ
failure and death. This review aims to elucidate the cellular and molecular
mechanisms implying systemic immune dysfunction in ACLF, highlighting key
pathophysiological pathways and their clinical significance. We provide an
overview of ACLF, including its global clinical impact, in the context of immune
dysfunction as a central driver of disease pathogenesis. The discussion focuses
on alterations in innate immunity, including impaired neutrophil and monocyte
phagocytosis, excessive neutrophil extracellular trap (NET) formation, and
monocyte/macrophage dysfunction, which contribute to immuneparesis and
exaggerated inflammation in an organ-specific manner. Also, dysregulation of
natural killer (NK) cell cytotoxicity and adaptive immune dysfunction, including
changes in T-cell subpopulations and B-cell antibody production in ACLF, are
adressed. We further dissect the emerging evidence of molecular pathways driving
dysfunction of immune cells and their impaired ability to control infections in
ACLF, emphasising the roles of pathogen- and damage-associated molecular
patterns (PAMPs/DAMPs), toll-like receptor (TLR) signalling, oxidative stress,
mitochondrial dysfunction, epigenetic/metabolic reprogramming and immune
checkpoint molecules. In addition, the review explores immune cell communication
within the innate and adaptive immune systems, as well as interactions with
parenchymal and non-parenchymal cells across organs affected by ACLF. Particular
attention is given to inter-organ crosstalk involving the liver, circulation,
brain, gut, and kidney. Finally, we summarise recent preclinical and clinical
advances in biomarkers of immune dysfunction and immunomodulatory therapeutic
strategies aimed at restoring immune homeostasis in patients with ACLF.
3)Empirical Antifungal Therapy Improves Survival in Patients With Acute-on-ChronicLiver Failure With Suspected Invasive Fungal Infections: A Pragmatic Randomized
Trial.
Verma N, Valsan A, Garg P, Sarabu S, Kaur P, Mohan N, De A, Premkumar M, Taneja S, Prinja S, Chakrabarti A, Shafiq N, Duseja A.
Am J Gastroenterol. 2026 Sep 1;121(9):2198-2210. doi: 10.14309/ajg.0000000000003832. Epub 2025 Nov 21.
INTRODUCTION: Invasive fungal infections (IFIs) in acute-on-chronic liver
failure (ACLF) are associated with transplant delistings, high morbidity, and
mortality. An optimal strategy of antifungal therapy in this setting remains
uncertain. We compared suspicion-based (empirical) with investigation-driven
(diagnostic/biomarker-driven-pre-emptive) antifungal therapy among patients with
ACLF in a high-burden setting.
METHODS: In this parallel-group, pragmatic, randomized trial with blinded
endpoint adjudication (NCT04157465), 216 hospitalized ACLF patients with
predefined host and clinical factors for IFI were randomized (1:1) to empirical
antifungal therapy at enrolment or diagnostic/biomarker-driven-pre-emptive
therapy on laboratory, radiological, or mycological confirmation.
Biomarker-guided and culture-guided antifungal stewardship protocols were
implemented in both groups. The primary outcome was 28-day overall survival.
Secondary outcomes included in-hospital mortality, changes in severity scores,
adverse events, and cost-effectiveness. Heterogeneous treatment effects were
explored through causal tree analysis.
RESULTS: Empirical antifungal therapy significantly improved 28-day survival
compared with diagnostic/biomarker-driven-pre-emptive therapy (35% vs 13%;
hazard ratio: 0.64, 95% confidence interval: 0.47-0.88; P = 0.005). Treatment
success (37.4% vs 16.9%; P = 0.002) and IFI resolution (45.8% vs 22.5%, P =
0.001) were higher; in-hospital and IFI-attributable mortality (55.6% vs 75.9%;
P = 0.003) was lower in the empirical group. Fewer adverse events with greater
quality-of-life years gains (29.9 vs 10.1) and an incremental cost-effectiveness
ratio of international normalized ratio 1,42,737 were observed with empirical
therapy. The survival benefit was maximum among patients aged 40 years or older
with cardiovascular failure but without respiratory failure.
DISCUSSION: Early empirical antifungal therapy within a structured stewardship
framework improves survival in patients with ACLF and IFIs. Timely recognition,
rapid diagnostics, and individualized antifungal strategies are essential to
bridge these high-risk patients toward recovery or definitive therapies.
4)Advances in the management of Hepatorenal syndrome
Jothimani D, Khan S, Devireddy S, Rela M, Kamath P.
Curr Opin Nephrol Hypertens. 2026 Sep 1;35(5):526-537. doi:
10.1097/MNH.0000000000001212. Epub 2026 Jul 16.
PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) is the extreme manifestation of
acute renal dysfunction in patients with cirrhosis, resulting from systemic
vasodilation and renal vasoconstriction, leading to a reduction in the
glomerular filtration rate.
RECENT FINDINGS: The diagnostic criteria redefined diagnostic criteria for
HRS-AKI (Hepatorenal syndrome -Acute kidney injury) as our understanding of
disease progression has improved. This understanding of the HRS disease process
guides current management, with the combination of intravascular volume
expansion and vasoconstrictor therapy being the cornerstone of treatment. In
addition to treatment selection, timing of treatment initiation, duration,
dosage, and monitoring during treatment are decisive factors in HRS outcomes.
Pathogenesis of HRS-AKImay be different in patients with acute-on-chronic liver
failure (ACLF) in comparison to decompensated cirrhosis. Unfortunately, outcomes
remain poor with medical therapies alone and a high risk of disease recurrence
exists for HRS-AKI with persistence of the cirrhotic milieu. Liver
transplantation remains the only definitive treatment of HRS-AKI. Given the
critical nature of HRS-AKI, a multidisciplinary approach involving
hepatologists, nephrologists, and intensive care physicians is essential for
optimal clinical management.
SUMMARY: Patients with HRS-AKI should be managed ideally in tertiary care
centers and referred for liver transplantation promptly when eligible.
5)Role of MALAT1 in the Progression of ACLF via the miR-141-3p/TGFB2 Axis and Its Association with Patient Prognosis.
Qiao Y, Wu D, Jiang H, Li Y, Zhang D.Tohoku J Exp Med. 2026 Aug 28;269(3):351-361. doi: 10.1620/tjem.2025.J144. Epub 2026 Jan 15.
Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1
(MALAT1) is implicated in inflammatory responses and is involved in the
progression of multiple diseases. The study aimed to investigate the prognostic
significance of MALAT1 in acute-on-chronic liver failure (ACLF) patients and
explore its potential molecular mechanisms. A total of 150 patients diagnosed
with ACLF and 140 healthy individuals were recruited for this study. MALAT1
expression was measured using RT-qPCR. Survival analysis was conducted using the
Kaplan-Meier method, while the Cox regression was applied to identify
independent risk factors. An in vitro liver injury model was established by
inducing the immortalized human hepatocyte line THLE-2 with lipopolysaccharide
(LPS). Cell proliferation was assessed using the CCK-8 assay, apoptosis was
determined by flow cytometry, and the inflammatory factors were quantified by
enzyme-linked immunosorbent assay (ELISA). The dual-luciferase reporter assay
was employed to indicate the targeted regulatory interactions. MALAT1 was
significantly elevated in ACLF patients, and those with high MALAT1 expression
exhibited decreased survival rates. In vitro experiments, LPS induction
significantly upregulates MALAT1 expression, while simultaneously downregulating
miR-141-3p and upregulating TGFB2 expression. Following MALAT1 inhibition, cell
proliferation was significantly enhanced, apoptosis was suppressed, and IL-6 and
IL-1β levels were reduced. However, these effects were partially reversed by
miR-141-3p inhibition. Moreover, dual-luciferase reporter assays and RNA
immunoprecipitation (RIP) experiments suggested that miR-141-3p may directly
target TGFB2. Mechanistically, MALAT1 negatively modulated miR-141-3p expression
by directly binding to it, thereby alleviating the suppression of its downstream
target TGFB2 and contributing to the progression of ACLF. MALAT1 may contribute
to ACLF via the MALAT1/miR-141-3p/TGFB2 signaling pathway.
6)HBV re-activation is associated with increased mortality and dysregulation of
oxidative and polyamine metabolism in pre-acute-on-chronic liver failure.
Glitscher M, Thiyagarajah K , Wei J, Sonnenberg J, Lembeck P, Gu W, Grammatikos G, Guo L, Trebicka J, Deng G, Wang X, Zheng X, Huang Y, Chen J, Meng Z, Gao Y, Qian Z,
Liu F, Lu X, Shi Y, Zheng Y, He Y, Li H, Hildt E, Peiffer KH.
Cell Commun Signal. 2026 Aug 24;24(1):460. doi: 10.1186/s12964-026-03145-y.
BACKGROUND/AIMS: Acute-on-chronic liver failure (ACLF) is one of the deadliest
complications of chronic liver disease yet treatment options are sparse. In
Asia, HBV-reactivation (HBVr) is one of the most common triggers. Recently,
HBV-associated ACLF was associated with distinct changes in the metabolome.
Here, metabolic impacts of HBVr were analysed in-depth in non-ACLF, pre-ACLF and
ACLF.
METHODS: Clinical and metabolic data of 1024 Chinese patients (CATCH-LIFE
studies) with chronic HBV mono-infection were analyzed. ACLF was diagnosed
according to COSSH criteria. Metabolites in plasma were quantified using LC-MS,
compared to non-ACLF and subjected to enrichment and pathway analyses using the
database SMPDB via MetaboAnalyst v6.
RESULTS: In 1024 patients (611: non-ACLF, 72: pre-ACLF, 341: ACLF), HBVr was
present in 20.2% (ACLF) or 33.3% (pre-ACLF) of patients. HBVr increased 28-day
mortality in pre-ACLF patients (2.1% in HBVnr vs. 25% in HBVr). Energy
metabolism generating reactive oxygen species (ROS) was highly induced in the
absence of ROS-detoxifying pathways in pre-ACLF. Urea cycle, thus nitric oxide
(NO) build-up, the polyamine metabolism and related pathways were highly
increased in both HBVr pre-ACLF and ACLF, shifting pre-ACLF close to mature
ACLF. Specific metabolites could be identified as putative markers and
key-regulators herein.
CONCLUSION: HBV reactivation induces inflammation, hepatic injury and mortality
especially in pre-ACLF patients. Metabolic disruption in the ROS/NO/polyamine
axis favors stress and hinders liver regeneration. Findings help identifying and
alleviating HBVr-driven progression towards ACLF via pharmacological or
biopharmaceutical intervention.
7)Baseline CALLY index is associated with all-cause mortality in HBV-ACLF patients
receiving ALSS therapy. Ma W, Yuan J, Chen Q, Wang X, Zhang L, Ou Y,
Jiao Y, Ding X.
Front Med (Lausanne). 2026 Aug 21;13:1827310. doi: 10.3389/fmed.2026.1827310.
eCollection 2026.
OBJECTIVE: Chronic hepatitis B virus (HBV)-associated acute-on-chronic liver
failure (HBV-ACLF) has a high mortality rate even with the use of artificial
liver support systems (ALSS). Reliable prognostic biomarkers are lacking. This
study investigates the association between the C-reactive protein
(CRP)-albumin-lymphocyte (CALLY) index, measured at diagnosis, and all-cause
mortality in HBV-ACLF patients receiving ALSS treatment.
METHODS: This single-center retrospective cohort study enrolled consecutive
adult patients with HBV-ACLF who received ALSS therapy at the General Hospital
of Ningxia Medical University between May 2022 and November 2025. Baseline CALLY
was calculated before ALSS initiation. Restricted cubic spline analysis,
Kaplan-Meier survival analysis, and Cox regression were used to evaluate the
association between CALLY and all-cause mortality. Logistic regression was used
to assess its associations with major complications. Time-dependent ROC curves,
Brier scores, calibration curves, and decision curve analysis were applied to
evaluate the predictive performance and clinical utility of CALLY alone and in
combination with conventional prognostic scores.
RESULTS: A total of 221 patients with HBV-ACLF were included, among whom 99
experienced all-cause mortality during follow-up. Patients with low CALLY had
more severe systemic inflammation, poorer nutritional and immune status, higher
proportions of hepatic encephalopathy and renal insufficiency, and more advanced
disease severity than those with high CALLY. Restricted cubic spline analysis
showed a significant nonlinear inverse association between baseline CALLY and
all-cause mortality risk. Kaplan-Meier analysis demonstrated significantly
better overall survival in the high-CALLY group than in the low-CALLY group
(log-rank P < 0.0001). In Cox regression analysis, higher CALLY was consistently
associated with a lower risk of all-cause mortality. Time-dependent ROC analysis
showed that CALLY had good discriminative ability for predicting all-cause
mortality at 3, 6, and 12 months, with AUCs of 0.822, 0.837, and 0.888,
respectively. The addition of CALLY to AARC grade, Child-Pugh score, MELD score,
and MELD-Na score significantly improved the AUCs of the corresponding models.
Brier score, calibration curve, and decision curve analyses further supported
the incremental predictive value and clinical utility of CALLY?
CONCLUSION: The baseline CALLY index was inversely associated with all-cause
mortality in HBV-ACLF patients receiving ALSS therapy and may enhance prognostic
assessment, especially when integrated with conventional prognostic scoring
systems.
8)Comparative Prognostic Performance of Pretransplant AARC, CLIF-C ACLF, and
MELD-Na Scores for 90-Day Mortality After Liver Transplantation in Patients With
EASL-CLIF Acute-on-Chronic Liver Failure.
Cuong NT, Duong LX, Tam NC, Do NV, Trung ND.
Ann Transplant. 2026 Sep 8;31:e954888. doi: 10.12659/AOT.954888.
BACKGROUND Acute-on-chronic liver failure (ACLF) is associated with multiorgan
failure and high short-term mortality. Liver transplantation (LT) can be
lifesaving, but commonly used pretransplant severity scores were not developed
to predict post-transplant mortality. This study compared AARC, CLIF-C ACLF, and
MELD-Na for 90-day mortality after LT. MATERIAL AND METHODS This single-center
observational cohort study included 78 consecutive patients aged 16 years or
older with EASL-CLIF ACLF who underwent LT at the 108 Military Central Hospital
between January 2022 and June 2025. All 3 scores were independently recalculated
from a common pretransplant assessment. The primary outcome was 90-day all-cause
mortality, and the primary score comparison was non-directional. Discrimination
was assessed using AUROCs with stratified percentile-bootstrap confidence
intervals and paired DeLong comparisons with Holm adjustment. Separate Firth
logistic and Cox models evaluated associations per 1-standard-deviation
increase. RESULTS HBV-related liver disease accounted for 62.8% of the cohort,
and 89.7% underwent living-donor LT. Fourteen patients (17.9%) died within 90
days. CLIF-C ACLF had the highest numerical AUROC (0.755; 95% CI, 0.562-0.917),
followed by MELD-Na (0.714; 0.550-0.854) and AARC (0.654; 0.491-0.799); no
pairwise difference remained significant after Holm adjustment. A
1-standard-deviation increase in CLIF-C ACLF (11.05 points) and MELD-Na (6.17
points) was associated with higher 90-day mortality, whereas AARC was not.
Sensitivity analyses produced similar findings. CONCLUSIONS CLIF-C ACLF showed
the strongest numerical prognostic performance, but statistically significant
superiority was not established. These scores should complement
multidisciplinary transplant assessment.
9)The clinical features and outcomes of acute-on-chronic liver failure in biliary
atresia patients on a waiting list for liver transplantation.
Matsuura T, Toriigahara Y, Maeda S, Takahashi Y, Fukuta A, Kawakubo N, Yoshimaru K, Nagata K, Tajiri T. Pediatr Surg Int. 2026 Sep 5;42(1):381. doi: 10.1007/s00383-026-06630-0.
PURPOSE: Acute-on-chronic liver failure (ACLF) in adults has an extremely poor
prognosis. However, reports on the epidemiology and outcomes of ACLF in biliary
atresia (ACLF-BA) are scarce.
METHODS: Among 123 BA cases deemed eligible for liver transplantation (LT), we
retrospectively evaluated them according to the Japanese ACLF diagnostic
criteria established in 2018 and categorized them into ACLF-BA and non-ACLF-BA
groups. We also retrospectively reviewed the liver and extrahepatic organ
failures during the waitlist period in both groups.
RESULTS: Fourteen patients (11.4%) were categorized as ACLF-BA. The liver
function in ACLF-BA dramatically worsened both in the Child-Pugh and MELD scores
in the short term after ACLF onset. Seven cases (50%) in ACLF-BA were
categorized as grade 3 with more than three extrahepatic organ failures. The
waitlist mortality rate for deceased donors in ACLF-BA was as high as 50%.
However, the post-LT patient survival rate in ACLF-BA was 90.9%, and not
statistically significantly different compared to non-ACLF-BA.
CONCLUSION: Although ACLF-BA awaiting LT carries an increased waitlist
mortality, the post-LT patient survival was comparable to recipients without
ACLF. The type and number of extrahepatic organ failures could correlate with
patient mortality. The prioritization of organ allocation for ACLF-BA warrants
further discussion.
10)Critical care aspects of the patient awaiting liver transplantation.
Nagendran M, Grimes E, Auzinger G.
Curr Opin Organ Transplant. 2026 Sep 9. doi: 10.1097/MOT.0000000000001311.
Online ahead of print.
PURPOSE OF REVIEW: The indications for liver transplantation have continued to
evolve and now extend beyond elective transplantation for decompensated
cirrhosis and emergency liver transplantation for acute liver failure (ALF), to
patients who present with acute-on-chronic liver failure (ACLF), including those
with severe alcoholic hepatitis. This review focuses on the pretransplant
critical care aspects of ALF patients and on recent developments, as the ACLF
syndrome was defined and early transplantation for alcohol-related hepatitis has
entered practice in some countries.
RECENT FINDINGS: ACLF severity, graded by the number of failing organs, predicts
both waiting list and posttransplant mortality. The UK has introduced a national
prioritization tier for selected critically ill patients with ACLF. High-volume
plasma exchange improves transplant-free survival in ALF, with ongoing trials in
ACLF. Artificial liver support and G-CSF have not shown survival benefit in
randomized trials. Continuous renal replacement therapy lowers ammonia and is
associated with reduced mortality in ALF. Early transplantation for
steroid-nonresponsive severe alcohol-related hepatitis produces survival
comparable to standard transplantation and is now delivered through structured
programmes in some countries.
SUMMARY: Pretransplant critical care focuses on extrahepatic organ support and
maintaining transplant candidacy. Prognostic scores identify risk but do not by
themselves determine futility, which is dynamic and selection-dependent.
11)ICAM-1 Hypomethylation Predicts Poor Prognosis in Patients With Hepatitis B
Virus-Related Acute-on-Chronic Liver Failure.
Xu MM, Yao YX, Lyu H, Qian Y, Tian ZZ, Fan YC, Wang K.
J Med Virol. 2026 Sep;98(9):e71118. doi: 10.1002/jmv.71118.
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is
associated with a high short-term mortality rate. Therefore, early and accurate
prognostic prediction is crucial for precise clinical management. This study
aims to investigate the expression patterns of intercellular adhesion molecule-1
(ICAM-1) and its predictive value for the short-term prognosis of patients with
HBV-ACLF. The Methylight method was used to quantitatively detect ICAM-1
promoter methylation level in peripheral blood mononuclear cells (PMBCs) of 286
participants. Meanwhile, the mRNA and plasma expression levels of ICAM-1 were
determined using RT-qPCR and ELISA, respectively. The ICAM-1 promoter
methylation levels in PBMCs of HBV-ACLF patients were significantly lower than
those in chronic hepatitis B (CHB) patients and healthy controls (HCs), whereas
the mRNA and plasma expression levels of ICAM-1 were markedly elevated. The
ICAM-1 methylation levels in HBV-ACLF patients correlated with specific clinical
parameters. Among HBV-ACLF patients, ICAM-1 methylation levels were
significantly lower in the non-survivor groups at both 28 and 90 days. The study
further revealed that ICAM-1 methylation level serves as an independent
influencing factor for the prognosis of HBV-ACLF patients at 28 and 90 days.
Based on ROC curve and Kaplan-Meier curves, ICAM-1 methylation levels
demonstrated excellent performance in predicting 28- and 90-day mortality in
patients with HBV-ACLF. In conclusion, patients with HBV-ACLF exhibit
hypomethylation of the ICAM-1 promoter. The combination of ICAM-1 promoter
methylation level and MELD score can effectively enhance the predictive ability
for the short-term prognosis of HBV-ACLF patients.
12)Spatial transcriptomics reveal impaired metabolic liver zonation in
acute-on-chronic liver failure.
Langer MM, Stadler H, Mannewitz M, Bauschen A, Jacobi S, Koliogiannis D, Guba M, Siemes D, Engel DR, Mogler C, Wirth J, Steiger K, Budeus B, Lange CM.
JHEP Rep. 2026 Sep 10:102035. doi: 10.1016/j.jhepr.2026.102035. Online ahead of
print.
BACKGROUND AND AIMS: Extrahepatic organ failures are key determinants of
acute-on-chronic liver failure (ACLF). While the role of systemic inflammation
and mitochondrial dysfunction in the pathogenesis of ACLF is well known, the
contribution of the liver itself is less understood. We therefore performed
transcriptome and functional analyses of the liver in order to identify hepatic
drivers of ACLF.
METHODS: Bulk-RNA sequencing and spatial transcriptomics were performed in liver
specimens from patients with compensated cirrhosis, decompensated cirrhosis or
ACLF. In addition, detailed analyses of genes involved in energy metabolism, as
well as a metabolome analysis and functional analyses were performed.
RESULTS: In total, 39 patients were included (9 compensated cirrhosis, 15
decompensated cirrhosis, 15 ACLF). ACLF was associated with changes in the
hepatic transcriptome, clearly distinct from compensated and decompensated
cirrhosis. Most strongly downregulated in ACLF were pathways involved in
substrate metabolism and mitochondrial function, including downregulation of
multiple genes of glucose and amino acid metabolism. In line, spatial
transcriptomics revealed a breakdown of the functional liver zonation in ACLF,
with decreasing proportions of hepatocytes specialized in
gluconeogenesis/β-oxidation (compensated cirrhosis 68%, decompensated cirrhosis
52%, ACLF 12%; P<0.03). Branched chain ketoacid dehydrogenase kinase (BCKDK), a
key regulator of branched-chain amino acid catabolism, was strongly
downregulated in ACLF (0,33- fold expression vs. compensated cirrhosis, P<0.05)
and may link dysregulation of branched-chain amino acid and glucose metabolism.
CONCLUSION: ACLF is characterized by distinct changes in the hepatic
transcriptome, which affect key pathways in substrate metabolism and
mitochondrial function and are associated with loss of functional liver
zonation. Downregulation of BCKDK in ACLF might be of particular interest, as it
links altered branched-chained amino acid metabolism to impaired glucose
production.
IMPACT AND IMPLICATIONS: Extrahepatic organ failures are well known features of
acute-on-chronic liver failure (ACLF), but the contribution of the liver itself
to their pathogenesis is not well understood. By RNA sequencing and spatial
transcriptomics of liver specimens, we could identify profoundly impaired
metabolic and mitochondrial hepatic programs, suggesting that the liver might
play a key role in the development of extrahepatic organ failures by
compromising the body's energy supply. These findings are important since they
provide a rationale for further studying molecular targets in the liver as
therapeutic strategies for ACLF.
13)Improving outcomes in donation after circulatory death vs. donation after brain
death liver transplantation for acute-on-chronic liver failure.
Yao YY, Wen T, Tjandra NW, Lau K, Lin YC, Chen X, Chahal D.
Transpl Int. 2026 Aug 21;39:16308. doi: 10.3389/ti.2026.16308. eCollection 2026.
Acute-on-chronic liver failure (ACLF) carries high short-term mortality, and
liver transplantation (LT) remains the curative treatment. Donation after
circulatory death (DCD) grafts expand the donor pool but carry higher risks of
dysfunction compared to donation after brain death (DBD) grafts, and data
directly comparing their outcomes in ACLF are limited. Using the Scientific
Registry of Transplant Recipients (SRTR), we conducted a retrospective cohort
study of 67,201 adult LT recipients from 2004 to 2023, stratified into three
eras (Era 1: 2004-2012, Era 2: 2013-2018, Era 3: 2019-2023). Patients with prior
LT, fulminant liver failure (status 1A), active hepatocellular carcinoma, or
multivisceral transplants (excluding liver-kidney) were excluded. Estimated ACLF
(EST-ACLF) severity was defined using EASL-CLIF criteria. One-year graft failure
and survival were assessed using multivariable Cox regression and Kaplan-Meier
analyses. Of 67,201 recipients, 62,510 received DBD and 4,691 DCD grafts. DCD
grafts did not show clinically meaningful differences in 1-year hazards of graft
failure compared to DBD grafts. One-year graft survival in EST-ACLF-2/3 improved
over time from 87.2% in Era 1%-96.0% in Era 3, approaching the 97.5% observed
with DBD grafts. DCD grafts may represent a viable and increasingly safe
strategy for expanding LT access in ACLF.
14)Discordance Between Japanese and European Definitions of Acute-on-Chronic Liver
Failure in Alcohol-Related Cirrhosis: Insights From a 10-Year Consecutive
Cohort.
Kamezaki H, Yamada N, Iwanaga T, Sakuma T, Takahashi K, Senoo J, Arai M, Kanda T, Ogasawara S, Kato J.
Hepatol Res. 2026 Aug 24. doi: 10.1111/hepr.70264. Online ahead of print.
AIM: To examine concordance between the Japanese acute-on-chronic liver failure
(ACLF) classification and the organ failure (OF)-based European association for
the study of the liver-chronic liver failure (EASL-CLIF) framework, and to
clarify the medium-term prognostic implications of discordance in
alcohol-related cirrhosis.
METHODS: Adults with alcohol-related cirrhosis were studied in a single-center
consecutive cohort. Japanese-defined ACLF episodes were classified as confirmed
(bilirubin plus coagulation criteria) or extended (either criterion alone), then
cross-classified by EASL-CLIF grade. First ACLF episodes were analyzed for
1-year mortality using Kaplan-Meier, Cox, and receiver operating characteristic
(ROC) analyses.
RESULTS: Among 158 patients, 26 developed Japanese-defined ACLF (30 episodes).
Discordance was substantial: 66.7% of extended and 22.2% of confirmed episodes
were EASL-CLIF grade 0, not meeting EASL-CLIF criteria. In the first-episode
cohort (n=26), 1-year survival was 77.8% for confirmed and 69.5% for extended
ACLF (log-rank p=0.692). Among Japanese-defined ACLF episodes classified as
EASL-CLIF grade 0, the estimated 90-day mortality was 0%, whereas the estimated
1-year mortality was 21.4%. In exploratory ROC analyses, the model for end-stage
liver disease (MELD) showed the numerically highest area under the ROC curve for
1-year mortality (AUC 0.797, 95% confidence interval [CI] 0.627-0.967); however,
pairwise AUC differences were not significant.
CONCLUSIONS: Japanese-defined ACLF, particularly extended ACLF, often
corresponds to EASL-CLIF grade 0, yet discordant patients showed non-negligible
1-year mortality. These findings suggest that acute hepatic deterioration
without overt OF may represent a clinically relevant early-risk phase in
alcohol-related cirrhosis. Hepatic- and OF-based frameworks should therefore be
interpreted as complementary.
15)Risk Prediction of Acute Kidney Injury in Patients with HBV-Related
Acute-on-Chronic Liver Failure.
Yurong Z, Caixia Z, Yimin Z, Jianhang S, Xiulan X.
Int J Gen Med. 2026 Aug 19;19:621488. doi: 10.2147/IJGM.S621488. eCollection
2026.
BACKGROUND: Acute kidney injury (AKI) is a common and severe complication in
patients with acute-on-chronic liver failure (ACLF), significantly increasing
morbidity and mortality. Although several biomarkers have been proposed for the
early detection of AKI, their routine clinical application remains limited by
accessibility, cost, and inconsistent performance. Therefore, early
identification of patients at high risk of AKI remains a major clinical
challenge.
METHODS: This retrospective single-center study included patients with
HBV-related ACLF. Clinical data were analyzed to identify independent risk
factors for AKI, and a prediction model was developed. Model performance was
assessed using ROC, calibration, and decision curve analyses, and patients were
stratified according to risk.
RESULTS: Among 162 patients with HBV-related ACLF, 32 (19.8%) developed AKI.
Patients who developed AKI had significantly higher baseline levels of blood
urea nitrogen (BUN) and C-reactive protein (CRP). Multivariate analysis
identified BUN (OR = 1.076, P = 0.022) and CRP (OR = 1.031, P = 0.010) as
independent predictors of AKI. A prediction model incorporating these variables
demonstrated acceptable discrimination (AUROC = 0.77, P < 0.001), good
calibration, and favorable clinical utility on decision curve analysis.
Restricted cubic spline analysis further demonstrated a nonlinear association
between BUN and AKI risk, whereas CRP showed a linear relationship.
CONCLUSION: We developed a simple BUN-CRP-based model for early prediction of
AKI in patients with HBV-related ACLF. The model demonstrated acceptable
discrimination and calibration and may provide a practical tool for early risk
stratification by integrating markers of renal dysfunction and systemic
inflammation. However, external validation in larger multicenter cohorts is
warranted before routine clinical application.
16)Plasma Metabolites for Identifying Bacterial Infection in Acute-on-chronic Liver
Failure: A Prospective Multicenter Study.
Yang X, Li H, Huang Y, Deng G, Li B, Wang X, Meng Z, Zheng Y, Gao Y, Qian Z, Liu
F, Lu X, Shi Y, Shang J, Liu J, Jia H, Li S, Guo L, Zheng X.
J Clin Transl Hepatol. 2026 Aug 28;14(8):771-784. doi: 10.14218/JCTH.2026.00384.
Epub 2026 Aug 3.
BACKGROUND AND AIMS: Bacterial infection is a key cause of mortality in patients
with acute-on-chronic liver failure (ACLF). In this study, we aimed to identify
metabolite biomarkers and develop a novel machine learning model for early
identification of bacterial infection in ACLF.
METHODS: Based on a prospective multicenter cohort from 14 centers, 1,314
patients with acute-on-chronic liver disease were enrolled, including those with
ACLF and non-ACLF. Plasma samples at admission were collected for metabolomics
profiling. Patients were randomly divided into discovery (n = 921) and
validation (n = 393) sets. Machine learning was used to develop diagnostic
models. The win ratio method was employed to assess the risk stratification
capability of the models.
RESULTS: Bacterial infection occurred in 198 of the 451 ACLF patients and 132 of
the 863 non-ACLF patients. Infection altered the plasma metabolome, especially
in lipid, amino acid, and xenobiotic metabolic pathways. Models for bacterial
infection in ACLF (five metabolites) and non-ACLF (six metabolites) demonstrated
superior discrimination in the discovery (AUCs: 0.881 and 0.935, respectively)
and validation sets (AUCs: 0.835 and 0.889, respectively) compared with
C-reactive protein, white blood cell count, procalcitonin, and the best
composite clinical model. Metabolic risk stratification based on the models
effectively predicted 90-day outcomes (all-cause death, organ failure, sepsis,
new-onset acute decompensation, and systemic inflammatory response syndrome).
CONCLUSIONS: Our models based on novel metabolic biomarkers enable
identification of patients at high risk of bacterial infection and support risk
stratification of 90-day outcomes.
17)Role of skin involvement in neutropenic patients with P. aeruginosa bloodstream
infection - a 20-year retrospective study.
Rauschning D, Keimburg SA, Krus F, Golletz TM, Franke B, Leuchte K, Surez I, Trebicka J, Lehmann C, Jung N, Vehreschild JJ, Fischer J.
Clin Microbiol Infect. 2026 Aug 26:S1198-743X(26)00481-7. doi: 10.1016/j.cmi.2026.08.032. Online ahead of print.
OBJECTIVES: Skin involvement in Pseudomonas aeruginosa bloodstream infection
(PA-BSI) is a clinically important but understudied manifestation in neutropenic
patients that may indicate a more severe course or distinct risk profile. We
aimed to identify factors associated with skin involvement among neutropenic
patients with PA-BSI in a retrospective cohort.
METHODS: Factors for skin involvement in PA-BSI were by using a single-centre,
retrospective cohort study including 142 patients with PA-BSI (April 2003 and
April 2023) from the Cologne Cohort of Neutropenic Patients study (CoCoNut)
database, which comprises 2794 bloodstream infection episodes.
RESULTS: Skin involvement occurred in 30/142 patients (21.1%). Patients with
skin involvement were more likely to have acute myeloid leukemia (AML) (20/30
vs. 43/112; p = 0.006), recurrent PA-BSI (7/30 vs. 7/112; p = 0.005), longer
neutropenia duration (median 27 days vs. 16 days; p = 0.022), and hospital stay
(median 47.5 days vs. 36.5 days; p = 0.017). In multivariate analysis, AML (OR
3.430, 95% CI: 1.181 - 9.961; adjusted p = 0.023) and recurrent PA-BSI (OR
6.168, 95% CI: 1.709 - 22.261; adjusted p = 0.005) remained independently
associated with skin involvement, while pre-existing cardiovascular disease was
inversely associated (OR 0,359, 95% CI: 0.147 - 0.908; adjusted p = 0.031).
CONCLUSIONS: In this cohort skin involvement was present in one-fifth of
neutropenic patients with PA-BSI and was independently associated with
underlying AML and PA-BSI recurrence. Prolonged neutropenia and hospitalization
appear to be associated with a more complicated clinical course. Increased
awareness of these factors may facilitate earlier recognition of skin lesions
and prompt targeted management of PA-BSI in high-risk populations.
18)Microbiological profile and 28-day mortality prediction model for bloodstream
infection in patients with acute-on-chronic liver failure.
Ding X, Yang G, Chen M, Dai F, Dang Y, Kang Y, Lou J, Yu Y.
Eur J Clin Microbiol Infect Dis. 2026 Sep 9. doi: 10.1007/s10096-026-05668-1.
Online ahead of print.
BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterized by systemic
immune dysfunction, which predisposes patients to severe infections. Bloodstream
infection (BSI) is a common and life-threatening complication in individuals
with ACLF; however, pathogen epidemiology and validated prognostic tools
specific to this population remain inadequately defined.
METHODS: This retrospective cohort study enrolled 106 patients with ACLF and
microbiologically confirmed BSI between January 2020 and December 2024. A
predictive nomogram was developed using multivariable logistic regression and
internally validated via bootstrap resampling.
RESULTS: The overall incidence of BSI was 11.9%, with corresponding 14-day and
28-day mortality rates of 35.8% and 49.1%, respectively. Of the 106 BSI
episodes, 59.4% (n = 63) were hospital-acquired. Gram-negative bacteria were the
predominant pathogens (60.4%), with Klebsiella pneumoniae (25.5%) and
Escherichia coli (14.2%) being the most frequently isolated species. Among
Gram-positive isolates (32.1%), Enterococcus spp. (11.3%) and coagulase-negative
staphylococci (10.9%) were the most common. Multidrug-resistant organisms
(MDROs) were identified in 32.1% of all isolates and were significantly more
prevalent among non-survivors than survivors (42.3% vs. 22.2%; p = 0.027). Four
independent predictors of 28-day mortality were identified: concurrent
pneumonia, leukocytosis (> 10.7 10⁹/L), MELD score > 20.7 and Pitt bacteremia
score≥ 2. The predictive nomogram demonstrated strong discriminative ability
(AUC = 0.872), excellent calibration, and favorable clinical net benefit.
CONCLUSIONS: BSI in ACLF patients is associated with high short-term mortality
and a challenging antimicrobial resistance landscape dominated by gram-negative
pathogens. The nomogram-based on four routinely available clinical variables-
enables individualized 28-day mortality risk stratification to guide clinical
management.
19)Multisystemic Anesthetic Management and Patient Blood Management in Urgent Liver Transplantation for Acute-on-Chronic Liver Failure: A Case Report.
Aquino RCM, Torres GG, Maciel RT, de Faria LJA, Moreira LFP,
Pitombo MB.
Transplant Proc. 2026 Sep;58(7):1391-1394. doi:
10.1016/j.transproceed.2026.07.003. Epub 2026 Jul 28.
BACKGROUND: Acute-on-chronic liver failure (ACLF) is associated with high
short-term mortality and frequently requires urgent liver transplantation.
Perioperative management is challenging due to severe hemodynamic instability,
coagulopathy, systemic inflammation, and multiorgan dysfunction. Optimized
anesthetic strategies combined with Patient Blood Management (PBM) principles
may improve outcomes and reduce transfusion-related complications.
CASE PRESENTATION: We report the case of a 42-year-old woman with chronic
cholestatic liver disease who developed ACLF with hepatic encephalopathy,
systemic infection, and hepatorenal syndrome, requiring urgent liver
transplantation with a deceased donor graft. Intermittent hemodialysis was
initiated preoperatively due to renal dysfunction. The procedure was performed
under total intravenous anesthesia with advanced multimodal monitoring,
including invasive hemodynamic assessment and cerebral oximetry.
Intraoperatively, the patient developed severe vasoplegia requiring high-dose
vasoactive support. Fluid therapy followed a restrictive strategy, and
coagulation management was guided by viscoelastic testing. Intraoperative blood
conservation strategies, including cell salvage, were applied, and no allogeneic
blood components or other blood-derived products were required. Postoperatively,
the patient was admitted to the intensive care unit under vasoactive support,
with progressive hemodynamic stabilization, recovery of renal function, and
resolution of encephalopathy. She was discharged home without major
complications.
CONCLUSION: This case highlights the importance of individualized anesthetic
management and strict application of PBM principles in urgent liver
transplantation for ACLF. Advanced monitoring, goal-directed therapy, and
restrictive transfusion strategies may contribute to improved perioperative
stability and favorable postoperative recovery. This case report complies with
the Declaration of Helsinki and the Declaration of Istanbul regarding ethical
organ donation.
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