Cholesterol in critical illness – a story evolving over a century

As early as the 1920s, decreased blood cholesterol levels were observed in patients with pneumonia and genito-urinary sepsis, implicating cholesterol in the host response to critical illness.1Kipp H.A. Variation in the cholesterol content of the serum in pneumonia.J Biol Chem. 1920; 44: 215-237Summary Full Text PDF Google Scholar,2Macadam W. Shiskin C. The cholesterol content of the blood in relation to genito-urinary sepsis.Proc R Soc Med. 1924; 17: 53-55PubMed Google Scholar In 1924, MacAdam and Shiskin reported that low blood cholesterol levels may be a proxy for reduced antibody-producing capacity and could indicate poor surgical outcome in patients with genito-urinary sepsis.2Macadam W. Shiskin C. The cholesterol content of the blood in relation to genito-urinary sepsis.Proc R Soc Med. 1924; 17: 53-55PubMed Google Scholar Over the subsequent decades, studies have reported altered cholesterol homeostasis in severely ill patients, not only in patients with sepsis or septic shock, but also other disease states including trauma and burns.3Hofmaenner D.A. Kleyman A. Press A. Bauer M. Singer M. The many roles of cholesterol in sepsis: a review.Am J Respir Crit Care Med. 2022; 205: 388-396Crossref PubMed Scopus (25) Google Scholar The degree of change in serum cholesterol levels has been demonstrated to be a good outcome prognosticator, with the magnitude of decrease being associated with increased morbidity and mortality.4Hofmaenner D.A. Arina P. Kleyman A. et al.Association between hypocholesterolemia and mortality in critically ill patients with sepsis: a systematic review and meta-analysis.Crit Care Explor. 2023; 5e0860Crossref PubMed Scopus (5) Google Scholar Despite our increased understanding of the broad functions of cholesterol in mammalian physiology, many questions remain regarding the clinical importance of hypocholesterolemia in critically ill patients. In the February 2024 issue of eBioMedicine, Taylor et al. performed a systematic review and meta-analysis investigating the association between systemic levels of cholesterol (including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol) and mortality across mixed intensive care unit populations with acute severe inflammatory states such as sepsis and critical illness.5Taylor R. Zhang C. George D. et al.Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.eBioMedicine. 2024; 100104981https://doi.org/10.1016/j.ebiom.2024.104981Summary Full Text Full Text PDF Scopus (0) Google Scholar The authors confirm the inverse association between hypocholesterolemia at ICU admission and mortality. One strength of this analysis is the large population number. By incorporating data from over 2500 patients undergoing treatment in a critical care setting across 24 studies in a quantitative meta-analysis, the authors enhance the credibility of their observations, surpassing previous comparable analyses. By evaluating patients with different diagnoses, the study's findings can be interpreted as indicative of a potentially common (mal-)adaptive pathophysiological response to inflammatory challenges. Risk of biases that might confound the overall findings were assessed. Furthermore, the article delves into the biological and mechanistic interplays between cholesterol and immunometabolism, offering the readership a comprehensive understanding of the intricate biological roles played by cholesterol and its lipoproteins.5Taylor R. Zhang C. George D. et al.Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.eBioMedicine. 2024; 100104981https://doi.org/10.1016/j.ebiom.2024.104981Summary Full Text Full Text PDF Scopus (0) Google Scholar As such, the authors illustrate potential paths for future trials to expand upon current research. Limitations of the work include the inability to fully control for potential confounding factors that might affect the interpretation of the obtained results. By including observational studies with different study designs, varying treatment modalities and variably reported patient characteristics, confounding effects such as statin use, ICU treatment effects, body mass index or pre-hospital trajectories of lipid levels affecting conditions at admission to critical care can likely not be fully detected. Future studies including more detailed patient data (e.g. in the frame of an individual patient data meta-analysis) could shed more light on these biasing phenomena. While the authors suggest a potential common stress response independent of admission diagnoses, the inclusion of a rather heterogeneous patient cohort might hinder the complete crystallization of detailed host responses, given the varying triggering factors depending on the cause of critical illness.5Taylor R. Zhang C. George D. et al.Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.eBioMedicine. 2024; 100104981https://doi.org/10.1016/j.ebiom.2024.104981Summary Full Text Full Text PDF Scopus (0) Google Scholar Interestingly, many of the aspects to be addressed in future research were described a century ago in the study cited above by MacAdam and Shiskin,2Macadam W. Shiskin C. The cholesterol content of the blood in relation to genito-urinary sepsis.Proc R Soc Med. 1924; 17: 53-55PubMed Google Scholar whereby cholesterol might be utilized (i) "as a measure of the capacity for antibody formation" (i.e. cholesterol and its interactions with the immune system), (ii) "as a practical guide to the degree of surgical risk" (i.e. risk stratification, phenotyping) and (iii) "where the clinical manifestations alone may give no such information" (i.e. refinement of prognostication).2Macadam W. Shiskin C. The cholesterol content of the blood in relation to genito-urinary sepsis.Proc R Soc Med. 1924; 17: 53-55PubMed Google Scholar Apart from descriptions of cholesterol alterations during critical illness and the associated prognostic implications, challenges in future research lie in the multifaceted pathophysiologic interplays between substances released by the host in response to inflammation and infection, molecules released by microorganisms such as toxins, and cholesterol, its lipoprotein carriers, or sterols derived from the oxidation of the cholesterol molecules such as oxysterols. Each gained observation should be thoroughly scrutinized in order to determine if it plays a causal role in cholesterol changes or if it is merely coincidental, epiphenomenal or even unrelated. Furthermore, the impact of confounding factors including effects arising from critical care treatment, nutrition, the patient's body mass index or previous statin use-with known pleiotropic effects other than lipid-lowering effects–should be addressed in more detail and accounted for in the interpretation of studies. In parallel with a deeper understanding of those complex interactions, phenotyping, in-depth characterizations of lipidomics, machine learning approaches or the development of treatable traits might be refined and subsequently build the basis for future interventional trials in enriched study populations. The idea of cholesterol supplementation and/or lipoprotein treatment is appealing. However, it is often unclear what benefits derive directly from cholesterol increases or rather from the associated lipoproteins. While in animal sepsis studies, the administration of HDL has shown survival benefits, comparable human studies are more difficult to conduct, with probable biases including the use of endotoxinemia models as a proxy for sepsis or the use of preparations not containing cholesterol.6Pajkrt D. Doran J.E. Koster F. et al.Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia.J Exp Med. 1996; 184: 1601-1608Crossref PubMed Google Scholar,7Dellinger R.P. Tomayko J.F. Angus D.C. et al.Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.Crit Care Med. 2009; 37: 2929-2938Crossref PubMed Scopus (0) Google Scholar Recently, a clinical study has been performed using a fish oil-containing lipid emulsion, with the idea to provide the body with substrates for the synthesis of cholesterol.8Guirgis F.W. Black L.P. Rosenthal M.D. et al.LIPid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P): phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock.BMJ Open. 2019; 9e029348Crossref PubMed Scopus (14) Google Scholar Recent promising preclinical studies include the inhibition of cholesterol ester transfer protein or cholesterol administration using nanocarriers.9Trinder M. Wang Y. Madsen C.M. et al.Inhibition of cholesteryl ester transfer protein preserves high-density lipoprotein cholesterol and improves survival in sepsis.Circulation. 2021; 143: 921-934Crossref PubMed Scopus (52) Google Scholar,10Kammann T. Hoff J. Yildirim I. et al.Intracellularly released cholesterol from polymer-based delivery systems alters cellular responses to pneumolysin and promotes cell survival.Metabolites. 2021; 11: 821Crossref PubMed Scopus (2) Google Scholar We look forward to future molecular biological studies that aim to explore the possibilities of replenishing depleted cholesterol levels in the blood and/or different tissues. DAH is the sole author. The author declares no conflicts of interest. Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studiesSystemic cholesterol levels (TC, HDL-C and LDL-C) on admission to critical care are inversely related to mortality. This finding is consistent with the notion that inflammatory and metabolic setpoints are coupled, such that the maladaptive-setpoint changes of cholesterol in critical illness are related to underlying inflammatory processes. We highlight the potential of HDL-biomarkers as early predictors of severity of illness and emphasise that future research should consider the metabolic and functional heterogeneity of HDLs.