---
title: "Admission interleukin-6 and short-term prognosis in hospitalized cirrhosis: etiology-dependent, ti"
id: "plos-one-19-admission-interleukin-6-as-a-time-limited-etiology-dependent-prognostic-signal"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-19-admission-interleukin-6-as-a-time-limited-etiology-dependent-prognostic-signal"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0360005"
published_at: "2026-10-08T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Admission interleukin-6 and short-term prognosis in hospitalized cirrhosis: etiology-dependent, ti
## Provenance & Clinical Metadata
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- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0360005)
- **Published At:** 2026-10-08T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This prospective observational cohort enrolled 489 consecutive adults with cirrhosis admitted to a tertiary hepatology centre between April 2022 and October 2023, with serum **interleukin-6** (IL-6) measured within 24 hours of admission. - Median IL-6 was 23.8 pg/mL; in-hospital mortality was 9.0% and overall mortality during follow-up was 70.6%. - In multivariable models adjusting for age, sex and disease severity, admission IL-6 independently predicted **in-hospital mortality** (adjusted odds ratio 1.34, 95% CI 1.08–1.67); Bayesian analysis supported this association (posterior probability 99.6%). - Adding IL-6 to conventional severity scores produced modest but statistically significant improvements in discrimination for in-hospital death; the model combining the CLIF-C Organ Failure score and IL-6 achieved the highest AUC (0.802). - The prognostic effect of IL-6 was markedly stronger in **alcohol-associated liver disease** (ALD) than in metabolic dysfunction-associated steatotic liver disease (MASLD). - Infection explained part of the IL-6–mortality relationship: mediation analysis estimated that infection mediated 17.3% of the association overall, 23% in ALD, and 2% in MASLD. - IL-6’s incremental value over **MELD-3.0** was limited to patients with ALD and to those with infection; MELD-3.0 remained the dominant prognostic determinant. - The IL-6 prognostic signal attenuated for longer-term outcomes (6‑month, 12‑month, and overall mortality), indicating a time-limited predictive role focused on the in-hospital window. - Authors conclude routine IL-6 measurement in unselected admissions is not supported by these data; targeted prospective validation and economic evaluation are suggested for ALD patients, particularly when infected or with intermediate MELD-3.0 scores.
## Clinical Analysis & Structured Key Points
Admission interleukin-6 as a time-limited, etiology-dependent prognostic signal in hospitalized cirrhosis – A frequentist and Bayesian cohort study | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Peer Review Reader Comments Figures Figures Abstract Background and objectives Interleukin-6 is a proximal inflammatory cytokine implicated in cirrhosis decompensation, yet its incremental prognostic value over established severity scores remains unclear. Methods In this prospective, purely observational study (April 2022 to October 2023), 489 consecutive patients hospitalized with cirrhosis at a tertiary hepatology center were enrolled, and serum interleukin-6 was measured at admission. Results Median interleukin-6 was 23.8 pg/mL, in-hospital mortality was 9.0%, and overall mortality was 70.6%. Interleukin-6 independently predicted in-hospital mortality after adjustment for age, sex, and disease severity (adjusted odds ratio 1.34, 95% confidence interval 1.08–1.67), supported by Bayesian analysis (posterior probability 99.6%). Adding interleukin-6 to conventional severity scores modestly but significantly improved discrimination for in-hospital mortality, with the combined organ failure score plus interleukin-6 model achieving the highest area under the curve (0.802). The prognostic impact of interleukin-6 was substantially stronger in alcohol-associated liver disease compared with metabolic dysfunction-associated steatotic liver disease. Infection mediated 17.3% of the interleukin-6–mortality association. In sub-cohort analyses, the etiology-specific effect persisted after adjustment for infection and after exclusion of severe alcohol-associated hepatitis; infection mediated 23% of the interleukin-6–mortality association in alcohol-associated liver disease but 2% in metabolic dysfunction-associated steatotic liver disease, and the incremental value of interleukin-6 over MELD-3.0 was confined to alcohol-associated disease and to infected patients. MELD-3.0 remained the dominant prognostic determinant, and interleukin-6's independent prognostic signal attenuated for longer-term outcomes. Conclusions Admission interleukin-6 did not outperform established severity scores but provided modest, statistically significant incremental discrimination that was confined to the in-hospital window and concentrated in alcohol-associated disease. These findings do not support routine interleukin-6 measurement in unselected admissions but identify alcohol-associated cirrhosis, particularly with infection or intermediate MELD-3.0 scores, as the setting in which interleukin-6-informed risk stratification merits prospective validation and economic evaluation. Citation: Oommen TT, Philips CA, Theruvath AH, Ravindran R, Sreemohan A, Baby A, et al. (2026) Admission interleukin-6 as a time-limited, etiology-dependent prognostic signal in hospitalized cirrhosis – A frequentist and Bayesian cohort study. PLoS One 21(10): e0360005. https://doi.org/10.1371/journal.pone.0360005 Editor: Lanlan Chen, Charite Universitatsmedizin Berlin, GERMANY Received: July 5, 2026; Accepted: September 21, 2026; Published: October 8, 2026 Copyright: © 2026 Oommen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The data underlying this study are patient-level clinical records that cannot be shared publicly because the Institutional Ethics Committee of Rajagiri Hospital which granted a waiver of informed consent for the use of routinely collected data, does not permit their deposition in a public repository owing to institutional data-governance requirements under the ICMR National Ethical Guidelines (2017) and the Digital Personal Data Protection Act, 2023. A de-identified dataset with a data dictionary is available to qualified researchers on reasonable request, under a data-use agreement and subject to Ethics Committee approval where required, from Mr Rajeev Tharath, In-charge, Laboratory Services and Patient Data Management, The Liver Institute, Rajagiri Hospital, Aluva, Kerala 683112, India ( rajeev@theliverinst.in ). Funding: The author(s) received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. 1. Introduction Cirrhosis represents a major global health burden, accounting for approximately two million deaths annually and responsible for 4% of all deaths worldwide. The Global Burden of Disease Study estimates 10.6 million prevalent cases of decompensated cirrhosis and 112 million cases of compensated cirrhosis globally, with mortality rates 5- to 10-fold higher than the general population [ 1 , 2 ]. Despite advances in disease-modifying therapies, hospitalized patients with cirrhosis continue to experience high short-term mortality, particularly those who develop acute decompensation or acute-on-chronic liver failure (ACLF). Acute-on-chronic liver failure is a distinct clinical syndrome characterized by acute deterioration of liver function in patients with chronic liver disease, frequently complicated by extrahepatic organ failures and high short-term mortality reaching 50–90% in severe cases [ 3 ]. The pathophysiology of ACLF is increasingly recognized to involve a dysregulated systemic inflammatory response, wherein circulating levels of proinflammatory cytokines and chemokines are markedly elevated and correlate with the extent of organ dysfunction and mortality [ 4 , 5 ]. Among hospitalized patients with cirrhosis, the presence and severity of systemic inflammation – rather than liver dysfunction alone, may be a critical determinant of clinical outcomes. Interleukin-6 (IL-6) is a pleiotropic cytokine that occupies a central position in the inflammatory cascade and acute-phase response. Produced primarily by macrophages, hepatocytes, and Kupffer cells in response to infection and tissue injury, IL-6 stimulates hepatic synthesis of acute-phase reactants including C-reactive protein (CRP), complement components, and coagulation factors [ 6 , 7 ]. In cirrhosis, elevated IL-6 reflects both hepatic inflammation and extrahepatic sources such as bacterial translocation from the gut, and its levels increase progressively with disease severity from compensated cirrhosis to decompensated states and ACLF [ 8 , 9 ]. Unlike CRP and procalcitonin, which are downstream effectors of the inflammatory response, IL-6 is a proximal mediator that may provide earlier and more direct information about the inflammatory milieu driving clinical deterioration [ 10 ]. Several studies have examined IL-6 as a prognostic biomarker in cirrhosis. Remmler and colleagues demonstrated that elevated IL-6 independently predicted 90-day and 1-year mortality in patients with end-stage liver disease awaiting transplantation, with discriminative performance comparable to the Model for End-Stage Liver Disease (MELD) score [ 11 ]. Subsequent investigations have confirmed associations between IL-6 and mortality in acute decompensation and HBV-related ACLF [ 12 – 14 ]. A recent Japanese study specifically identified IL-6 as a prognostic factor in alcohol-related ACLF, suggesting potential etiology-specific effects [ 15 ]. However, several critical knowledge gaps remain. First, the incremental prognostic value of IL-6 over established scoring systems in real-world hospitalized populations has not been systematically quantified. Second, whether IL-6's prognostic significance varies by etiology – particularly between MASLD and ALD, has not been explored, despite evidence that inflammatory phenotypes differ across etiologies. Third, the mechanistic pathways by which IL-6 influences outcomes – whether primarily through infection, general inflammation, or direct hepatotoxicity – remain unclear. Fourth, optimal clinical cutoff thresholds for risk stratification and the subgroups in whom IL-6 measurement adds most value to routine prognostic assessment have not been defined. Recent efforts to improve conventional scores have focused on adding inflammation-related variables. In a meta-analysis of 32 cohorts comprising 13,939 patients with ACLF, followed by validation in 751 prospectively enrolled patients, Yu et al. showed that adding age, neutrophil count and hepatic encephalopathy grade to MELD (the CATCH-LIFE-MELD score) improved short-term prognostication over MELD, MELD-Na and CLIF-C ACLF scores, in derivation and in an external cohort [ 16 ]. That work was conducted in predominantly hepatitis B–related ACLF and used a cellular marker of inflammation; whether an upstream cytokine such as IL-6 adds prognostic information in hospitalized patients with non-viral cirrhosis, and in which subgroups, has not been established. Given these gaps, we conducted a comprehensive analysis of IL-6 at admission in a large cohort of hospitalized patients with cirrhosis. Specifically, we aimed to: (1) characterize the distribution of IL-6 across clinical phenotypes and disease severity strata; (2) evaluate the independent prognostic value of IL-6 for multiple mortality endpoints after adjustment for established prognostic scores; (3) quantify the incremental discriminative improvement afforded by adding IL-6 to existing risk models; (4) identify clinical subgroups in which IL-6 provides the greatest added prognostic value; (5) explore potential mediating pathways (infection, systemic inflammation) underlying the IL-6–mortality relationship; and (6) determine optimal IL-6 cutoffs for clinical risk stratification. 2. Patients 2.1. Setting and patient pathways The study enrolled consecutive patients (April 2022 to October 2023) with cirrhosis hospitalized at a tertiary hepatology center. Patient enrolment was prospective, and the consecutive design was adopted to minimize selection bias. The study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for cohort studies. This prospective observational study did not involve the assignment of any intervention by the investigators. Inclusion criteria were: (1) age ≥ 18 years; (2) a diagnosis of cirrhosis as defined in Section 2.2 ; (3) hospitalisation at the study centre between April 2022 and October 2023; and (4) measurement of serum IL-6 within 24 hours of admission as part of the standard admission laboratory panel. Exclusion criteria were (1) absence of liver disease and non-cirrhotic portal hypertension; (2) prior liver transplantation; (3) IL-6 not measured as per protocol; (4) patients admitted for elective procedures and evaluations were eligible provided they met the criteria. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and its pertinent revisions and was approved by the Institutional Ethics Committee of Rajagiri Hospital, Aluva, India (Approval No.: RAJH/2022/36; Date: 09 March 2022). The Ethics Committee approved a waiver of written informed consent on the basis that: (i) the study was purely observational and did not involve any deviation from routine clinical care; (ii) serum IL-6 was measured from blood samples collected as part of standard clinical evaluation at admission per Department protocols; (iii) no additional interventions, procedures, or blood draws were performed for research purposes; and (iv) all data were anonymized prior to analysis. The study protocol was reviewed and approved prior to enrolment of the first participant. The primary outcome was in-hospital all-cause mortality. Secondary outcomes included mortality at 6 months, 12 months, and overall mortality during the entire follow-up period. Time-to-event was calculated from the date of hospital admission to the date of death from any cause or last known follow-up, whichever occurred first. Patients alive at the end of the observation period were censored at the date of last contact. In-hospital mortality was analysed as a binary outcome; the time-to-event outcomes were analysed using both binary (logistic) and survival (Cox) approaches. 2.2. Definitions Cirrhosis was diagnosed based on a combination of clinical, biochemical, and imaging criteria, and/or histology when available. Compensated cirrhosis was defined as cirrhosis without current or prior episodes of ascites, variceal haemorrhage, hepatic encephalopathy (HE), or jaundice attributable to liver dysfunction. Decompensated cirrhosis was defined as cirrhosis with one or more of these complications, in accordance with the Baveno VII consensus. Acute-on-chronic liver failure (ACLF) was diagnosed and graded (grades 1–3) using the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) Consortium criteria, based on the presence and number of organ failures as assessed by the CLIF-C Organ Failure (CLIF-C OF) score. Disease severity was quantified using the Child–Turcotte–Pugh (CTP) classification, the Model for End-Stage Liver Disease 3.0 (MELD-3.0) incorporating sodium and sex-based coefficients, and the Chronic Liver Failure-Consortium Acute Decompensation (CLIF-C AD) score. HE was graded according to the West Haven criteria. Acute kidney injury (AKI) was defined per the International Club of Ascites (ICA) revised criteria as an increase in serum creatinine ≥0.3 mg/dL within 48 hours or ≥50% from a stable baseline within the preceding three months. Infection at admission was defined as a clinically, microbiologically and/or radiologically documented infection present at, or diagnosed within 48 hours of, admission, using the site-specific criteria – Bloodstream infection: growth of a recognised pathogen in at least one blood culture, or of a common skin commensal in at least two separately drawn cultures, with compatible clinical features; Urinary tract infection: urinary or systemic symptoms with >10 leukocytes per high-power field on urinalysis and a positive urine culture (≥10 5 colony-forming units/mL), or, in catheterised patients, a positive culture with pyuria; pneumonia and lower respiratory tract infection: a new or progressive pulmonary infiltrate on chest imaging plus at least two of fever or hypothermia, leukocytosis or leukopenia, purulent sputum and worsening oxygenation; spontaneous bacterial peritonitis: an ascitic-fluid polymorphonuclear count ≥250 cells/mm³ in the absence of a surgically treatable intra-abdominal source, irrespective of the culture result; and skin and soft-tissue infection: clinical cellulitis, erysipelas or necrotising infection (localised erythema, warmth, tenderness and swelling with or without fever), with or without a positive wound or tissue culture. Blood, urine and ascitic-fluid cultures and chest imaging were obtained before antibiotics in all patients with suspected infection. Empirical therapy followed the departmental protocol, aligned with the standard regional guidance, adapted to local antimicrobial resistance patterns: For community-acquired spontaneous bacterial peritonitis, urinary tract infection and pneumonia, a third-generation cephalosporin (ceftriaxone), with a macrolide added for pneumonia; for healthcare-associated or nosocomial infections and for septic shock, piperacillin–tazobactam or a carbapenem (meropenem), with a glycopeptide (vancomycin or teicoplanin) when methicillin-resistant Staphylococcus aureus or enterococcal infection was suspected, and an echinocandin in septic shock with risk factors for invasive candidiasis; de-escalation to pathogen-directed therapy within 48–72 hours according to culture results; for spontaneous bacterial peritonitis, intravenous albumin 1.5 g/kg on day 1 and 1 g/kg on day 3 in addition to antibiotics, followed by secondary prophylaxis with norfloxacin; for skin and soft-tissue infection, a cephalosporin or amoxicillin–clavulanate, with clindamycin or vancomycin for suspected MRSA and urgent surgical debridement for necrotising infection; for bloodstream infection, pathogen-directed therapy for 10–14 days with removal of intravascular devices; for urinary tract infection, a third-generation cephalosporin or a fluoroquinolone for 5–7 days according to susceptibility; for pneumonia, 7 days of therapy with review of oxygen requirement and ventilatory support. Alcohol-associated liver disease (ALD) was defined as liver disease attributable to significant alcohol consumption (>40 g/day for men, > 20 g/day for women for ≥5 years). Severe alcohol-associated hepatitis (sAH) was defined according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcoholic Hepatitis Consortia criteria and the 2019 AASLD practice guidance. Severe AH was diagnosed in patients with a Maddrey discriminant function ≥32. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined according to the 2023 multi-society Delphi consensus nomenclature as hepatic steatosis in the presence of at least one cardiometabolic risk factor. 3. Statistics 3.1. Basic statistics Continuous variables were summarized as median with interquartile range, and categorical variables as counts and percentages. Natural logarithm transformation was applied for use in parametric models, and patients were additionally categorized into tertiles and quartiles for stratified analyses. Between-group comparisons were performed using the Mann–Whitney U test and Kruskal–Wallis test for continuous variables, and the chi-squared or Fisher's exact test for categorical variables. Bivariate associations between IL-6 and clinical parameters were assessed using Spearman rank correlation coefficients. Receiver operating characteristic curves were constructed for each mortality endpoint, with AUCs estimated by the DeLong method; optimal cutoffs were determined by Youden's index and at prespecified specificity thresholds. No formal a priori sample-size calculation was performed; the sample comprised all consecutive eligible admissions during the study period. 3.2. Advanced statistics Univariate and multivariable binary logistic regression models estimated the association between log-transformed IL-6 and in-hospital, 6-month, 12-month, and overall mortality, with the primary adjusted model controlling for age, sex, and disease severity; model calibration was assessed by the Hosmer–Lemeshow test, and internal validation was performed using 500-iteration bootstrap resampling to derive an optimism-corrected C-statistic. Kaplan–Meier survival analysis with log-rank testing and Cox proportional hazards regression (with verification of the proportional hazards assumption via Schoenfeld residuals) were used for time-to-event outcomes, supplemented by landmark analyses at 30 and 90 days. Incremental predictive value of IL-6 over disease severity scoring system was quantified using the likelihood ratio test, ΔAUC (area under the curve analysis), and integrated discrimination improvement. Subgroup-specific discrimination and formal multiplicative interaction testing were performed across predefined clinical strata. Mediation analyses were performed using the Baron and Kenny framework. A classification and regression tree (CART) model explored non-linear hierarchical predictor relationships. The tree was used for exploratory purposes to identify clinically interpretable decision rules and to assess the relative importance of IL-6 compared with established prognostic scores in a non-parametric framework. Bayesian logistic regression with weakly informative priors [Normal (0,1)] and Hamiltonian Monte Carlo sampling provided posterior odds ratios with 95% credible intervals, posterior probabilities of association, and model comparison via Widely Applicable Information Criterion (WAIC) and leave-one-out cross-validation usin
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