Plasma Citrulline as a Biomarker in Critical Illness: A Structured Narrative Review

Introduction: Gastrointestinal dysfunction is common in critically ill patients and is associated with increased morbidity and mortality. Plasma citrulline, a non-proteinogenic amino acid synthesized by enterocytes, has been proposed as a biomarker of intestinal function and enterocyte mass. However, the available evidence regarding its clinical significance in critically ill patients remains heterogeneous. This structured narrative review aimed to evaluate the current evidence on plasma citrulline in critical illness, focusing on its association with gastrointestinal dysfunction, disease severity, and clinical outcomes. Methods: A structured narrative review based on a structured literature search was conducted using PubMed and Scopus. Reference lists of included studies and relevant reviews were also screened. Studies evaluating circulating citrulline in adult critically ill patients and reporting gastrointestinal dysfunction, intestinal injury, disease severity, or other relevant clinical outcomes were included. Study selection was performed by two reviewers, and data were analyzed descriptively. Results: Eleven studies met the inclusion criteria, the majority being prospective observational studies. The timing of citrulline measurement, patient populations, analytical methods, and evaluated outcomes varied considerably across studies. Lower circulating citrulline concentrations were frequently associated with gastrointestinal dysfunction or markers of intestinal impairment; however, associations with disease severity, mortality, and other clinical outcomes were inconsistent. Several factors, including renal function, systemic inflammation, and methodological variability, may influence the interpretation of circulating citrulline concentrations. Conclusions: Plasma citrulline may provide complementary information regarding enterocyte function and gastrointestinal dysfunction in critically ill patients. However, current evidence does not support its use as a standalone diagnostic or prognostic biomarker. Further prospective studies using standardized measurement protocols and serial assessment are needed to determine its potential role alongside clinical evaluation and complementary biomarkers.