Sepsis & homocysteine: a biomarker under influence?

#Sepsis #Homocysteine #Biomarker #Mortality #PersonalizedMedicine #IntensiveCare    


Sepsis is an exacerbated systemic inflammatory response triggered by infection, leading to acute organ dysfunction. It remains one of the leading causes of death in hospital settings. Despite advancements in early diagnosis, resuscitation protocols, and antimicrobial treatments, short-term mortality remains high, reaching up to 30% in severe cases. Current treatments are primarily symptomatic and standardized, with limited ability to identify high-risk patients or tailor the immune response on an individual basis.  

In light of this therapeutic deadlock, identifying reliable prognostic biomarkers is a major lever for refining risk stratification, guiding early interventions, and potentially steering medicine towards a more personalized approach. Homocysteine (Hcy), a sulfur-containing amino acid derived from methionine metabolism, has emerged as a biomarker of interest. Known for its harmful effects on vascular endothelium, its role in oxidative stress, its promotion of a pro-thrombotic state, and its activation of systemic inflammation, Hcy exhibits a biological profile directly linked to the pathophysiological mechanisms of sepsis.  

However, available clinical data remain heterogeneous and sometimes contradictory, particularly due to methodological differences and potential ethnic variations in homocysteine metabolism. This study was initiated within that context. Its dual objective was to clarify the association between plasma Hcy levels at admission and short-term mortality in sepsis patients, and to assess whether this relationship varies based on patients' geographic or ethnic origin.  

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Homocysteine: a real alarm signal?  

Nine cohort studies, both prospective and retrospective, including 771 adult patients with sepsis, were selected and analyzed. In each study, plasma Hcy concentrations were measured within 48 hours of diagnosis — a critical window for prognostic evaluation. The analysis followed two main axes:  

• Comparison of mean Hcy levels between survivors and non-survivors;
• Calculation of mortality risk associated with a unit increase in Hcy (adjusted odds ratio).

 
On a global scale, no statistically significant association was found between Hcy levels and short-term mortality. However, a strong and significant association was observed specifically in Chinese-origin patients, in whom higher Hcy levels correlated with an increased risk of death. No such link was found in non-Asian patients. This disparity suggests a probable ethnic influence, possibly related to genetic polymorphisms and specific dietary factors. Sensitivity analyses confirmed the robustness of these results, but methodological heterogeneity between studies remained high (I² > 70%), underscoring the need for more harmonized future research.  

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Towards more targeted medicine  

Sepsis continues to be one of the greatest challenges in modern intensive care medicine, with a daunting prognosis and high mortality. The absence of reliable prognostic biomarkers still hampers the possibility of personalized care, making risk stratification often imprecise. In this context, homocysteine is garnering increasing interest due to its well-established role in oxidative stress, systemic inflammation, and endothelial dysfunction — all key mechanisms in sepsis pathophysiology.  

The results of this study suggest that homocysteine could play a discriminating role in certain subgroups, especially in patients of Asian origin. This disparity might be explained by genetic determinants (such as the MTHFR C677T polymorphism) and nutritional deficiencies (folate, vitamin B6 and B12) that affect its metabolism and clinical impact. These observations call for a reassessment of biomarker use in sepsis. Rather than aiming for a universal indicator, a more personalized approach is needed, taking into account the genetic, ethnic, and nutritional specificities of patients.  

Additional studies are necessary to confirm these results, relying on more homogeneous methods and larger populations. Future research should be multicenter, prospective, and integrate genetic, nutritional, and clinical data collected from the earliest hours of sepsis. The goal will be to better understand whether homocysteine can truly serve as a risk biomarker in certain patients. In parallel, it would be worthwhile to assess, through well-designed trials, whether supplementation with folates and B vitamins could improve survival. These directions pave the way toward a more personalized approach in intensive care, better adapted to the biological characteristics of each patient.

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