Up to nearly half of all patients who develop sepsis also sustain damage to the liver, yet the organ has long remained a quiet bystander in critical care research, overshadowed by the kidneys, lungs, and heart. A new commentary published in Intensive Care Medicine by Antonios Katsounas, Emmanuel Tsochatzis, and Jordi Rello argues that sepsis-associated liver injury, or SALI, deserves far greater attention, both as a measurable bedside warning signal and as an immunological process whose biology is now coming into focus. Drawing together recent mechanistic discoveries and large clinical cohort analyses, the authors sketch a framework in which ordinary liver blood tests, interpreted intelligently, could help clinicians identify which septic patients are sliding toward the highest risk of death.
SALI is defined as an acute, secondary hepatic dysfunction that arises during sepsis and is observed in roughly 34 to 46 percent of patients. At the bedside it announces itself through abnormalities in standard liver tests, which can follow hepatocellular, cholestatic, or mixed patterns and range from modest enzyme elevations to profound liver failure. Crucially, the authors insist that SALI be treated as an operational clinical syndrome rather than the signature of a single underlying mechanism. Abnormal liver biochemistry in a septic patient may reflect inflammatory injury, cholestasis, hypoxic hepatitis caused by insufficient oxygen delivery, right-sided cardiac congestion, drug toxicity, or pre-existing conditions such as metabolic dysfunction-associated steatotic liver disease and occult fibrosis. The question, they argue, is not whether SALI has uniform biology, because it does not, but whether routinely available data can flag the patients most likely to deteriorate.
On the mechanistic side, one of the most striking recent findings concerns the gut. In a mouse model of sepsis, Murao and colleagues identified a pathway in which gut-primed neutrophils drive hepatic injury. Gut intraepithelial lymphocytes interact with neutrophils through the molecule CD112, facilitating the formation of neutrophil extracellular traps, the web-like DNA structures that neutrophils eject to ensnare pathogens. These primed neutrophils migrate through the portal vein into the liver, where they release their traps and activate Kupffer cells, the liver’s resident macrophages, triggering the secretion of interleukin-6 and tumor necrosis factor-alpha. Notably, portal vein neutrophils from septic mice produced significantly more neutrophil extracellular traps and induced greater Kupffer cell activation than systemic neutrophils, an effect that disappeared entirely in mice lacking PAD4, the enzyme essential for trap formation. The implication is provocative: the gut does not merely spill inflammatory mediators into the portal circulation, it actively educates immune cells that then inflict damage on distant organs.
Although the authors caution that translation to human disease requires care, the concept has clear clinical resonance. The liver receives most of its blood supply from the portal circulation and is therefore continuously bathed in gut-derived inflammatory signals. During sepsis, disruption of the intestinal barrier allows bacterial translocation and the spillover of pathogen-associated molecular patterns, which activate hepatic Toll-like receptors. Supporting this mechanistic bridge, human data from Czaikoski and colleagues have shown that neutrophil extracellular traps accumulate in organ tissue during experimental and clinical sepsis and correlate with damage. Together, these findings nominate trap formation and downstream Kupffer cell activation as candidate precision-medicine targets in SALI.
A second biological pillar concerns the loss of hepatic immune tolerance. In health, the liver is a strikingly tolerant organ, and Kupffer cells orchestrate that tolerance through antigen clearance and the induction of regulatory T cells. Recent work shows that during hepatic inflammation this tolerogenic phenotype collapses: Kupffer cells lose their signature tolerance markers, and antigen presentation shifts to infiltrating monocyte-derived macrophages. Activated Kupffer cells then recruit further immune cells to the liver, amplifying injury. Evidence from viral hepatitis research suggests that the transition from tolerance to inflammation involves dysregulation of inhibitory pathways, such as the Toll-like receptor pathway inhibitor SHIP, that normally restrain receptor signaling and keep Kupffer cells quiescent. Hepatic stellate cells, likewise, depend on inhibitory signals to remain dormant; when stimulated by microbial products or damage-associated molecular patterns, they produce extracellular matrix proteins and profibrogenic cytokines, and their contractile activation can raise sinusoidal resistance and portal pressure. Toll-like receptor 4-dependent crosstalk between Kupffer cells and stellate cells converts inflammatory signals into profibrogenic activation.
Within sepsis specifically, the inflammatory polarization of Kupffer cells toward the M1 phenotype has emerged as a hallmark of SALI. Extracellular cold-inducible RNA-binding protein, a damage-associated molecular pattern released during stress, promotes this M1 polarization through Toll-like receptor 4 signaling, driving overproduction of inflammatory cytokines. In mouse sepsis models the ratio of M1 to M2 Kupffer cells rises sharply, indicating a decisive shift toward proinflammatory function, and this polarization is not merely a byproduct of inflammation but an active driver of hepatocyte injury through reactive oxygen species, cytokines, and the recruitment of more neutrophils. In parallel, regulated forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, appear to contribute to hepatocyte dysfunction. These converging mechanisms point toward the restoration of hepatic immune tolerance as a promising future therapeutic strategy, though no SALI-targeted therapy has yet been established.
It is on the clinical side that the commentary delivers its most immediately practical message. In a retrospective cohort study spanning two large intensive care cohorts, Palmowski and colleagues examined how well routine biomarkers could stratify mortality risk among patients meeting operational criteria for SALI, defined as sepsis-associated liver-test abnormalities within seven days of sepsis onset, excluding pre-existing chronic liver disease. The criteria included alanine aminotransferase at five or more times the upper limit of normal, alkaline phosphatase at twice the upper limit, or elevated bilirubin combined with enzyme elevations. Their central finding was that the De Ritis ratio, the simple ratio of aspartate to alanine aminotransferase, outperformed both the conventional R-factor and alanine aminotransferase alone in predicting thirty-day mortality. A ratio of one or below indicated low risk, values between one and two indicated intermediate risk, and values of two or above flagged the highest risk, a pattern consistent across infection sources and admission types.
The authors of the commentary are careful to frame these strata correctly. The De Ritis ratio is not a liver-specific diagnostic marker or a mechanistic endotype, and elevated aspartate aminotransferase can also signal hypoxic hepatitis, shock, right-sided congestion, systemic inflammation, chronic kidney disease, alcohol-related injury, or cardiometabolic comorbidity. Its pragmatic value lies in risk enrichment among patients who already meet operational SALI criteria, complementing rather than replacing SOFA-bilirubin scoring. Interpreted alongside the SOFA score, lactate, hemodynamic status, cardiac context, and comorbidities, a rising ratio should trigger a structured reassessment: is infection control optimized, are hemodynamics adequate, is the lactate trajectory improving, is there occult congestion or biliary obstruction, are hepatotoxic drugs on board, and does the patient carry underlying fibrosis risk? In this framework, routine liver tests define the dominant biochemical injury pattern, whether hepatocellular, cholestatic, or mixed, and link prediction to the prevention of further hepatic and systemic deterioration and of iatrogenic harm.
The translational pathway forward, the authors suggest, will require prospective studies testing whether serial liver tests, the De Ritis ratio, SOFA scores, lactate, hemodynamic data, and immune readouts such as monocyte HLA-DR expression or ex vivo monocyte cytokine responses can identify reproducible SALI trajectories and clinically actionable phenotypes. Preclinical work has already nominated an unusually rich set of therapeutic targets, including neutrophil extracellular trap formation, Kupffer cell polarization, inflammasome activation, ferroptosis, necroptosis, and the restoration of hepatic immune tolerance. Until such approaches are validated, however, current clinical utility remains deliberately pragmatic: recognize SALI early, classify the dominant biochemical pattern, stratify mortality risk with the De Ritis ratio, hunt actively for reversible contributors, and intensify surveillance in high-risk patients.
For the authors, the larger significance of this work lies in adding an organ-specific decision layer to the 2026 Surviving Sepsis Campaign framework. New-onset liver-test abnormalities in septic adults, they argue, should no longer be treated as incidental laboratory noise. When detected, the humble ratio of two transaminases, a calculation older than modern critical care and available in every hospital on earth, may identify the patients who need intensified monitoring and protection from modifiable second hits, while the expanding immunobiology of the gut-liver axis steadily maps the routes toward genuine precision medicine for a complication that affects as many as one in two patients with sepsis.
Subject of Research: Sepsis-associated liver injury: immunobiology and bedside risk stratification with routine liver tests
Article Title: Sepsis-associated liver injury: from liver-test risk signals to immunobiology-guided precision medicine
Article References: Katsounas, A., Tsochatzis, E., & Rello, J. (2026). Sepsis-associated liver injury: from liver-test risk signals to immunobiology-guided precision medicine. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08593-1
Image Credits: AI Generated
DOI: 10.1007/s00134-026-08593-1
Keywords: sepsis-associated liver injury, De Ritis ratio, Kupffer cells, neutrophil extracellular traps, gut-liver crosstalk, hepatic immune tolerance, risk stratification, intensive care, Toll-like receptors, precision medicine, Sepsis-associated, liver
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Ophelia Keating. (September 12, 2026). Routine Liver Tests May Reveal Which Sepsis Patients Face the Deadliest Risk. Scienmag. https://scienmag.com/routine-liver-tests-may-reveal-which-sepsis-patients-face-the-deadliest-risk/
Ophelia Keating. “Routine Liver Tests May Reveal Which Sepsis Patients Face the Deadliest Risk.” Scienmag, 12 September 2026, https://scienmag.com/routine-liver-tests-may-reveal-which-sepsis-patients-face-the-deadliest-risk/. Accessed 12 September 2026.
Ophelia Keating. “Routine Liver Tests May Reveal Which Sepsis Patients Face the Deadliest Risk.” Scienmag. September 12, 2026. https://scienmag.com/routine-liver-tests-may-reveal-which-sepsis-patients-face-the-deadliest-risk/
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Tags: bedside liver test interpretationclinical indicators of severe sepsiscritical care liver assessmentDe Ritis ratioearly detection of sepsis complicationsgut–liver crosstalkhepatic immune toleranceimmunological mechanisms in SALIintensive careKupffer cellsliverliver biomarkers for sepsis prognosisliver dysfunction in critical illnessliver function tests in sepsisneutrophil extracellular trapsPrecision medicinerisk stratificationSALIsepsis mortality risk factorssepsis outcome predictionSepsis-associatedsepsis-associated liver damagesepsis-associated liver injurysepsis-related liver injuryToll-like receptors
