Nuzzo et al. conducted a cross-sectional study to evaluate the accuracy of citrulline, I-FABP, and D-lactate in the diagnosis of AMI. The study showed lower median citrulline concentrations in AMI patients compared to controls (15.3 μmol/L vs. 23.3 μmol/L, p = 0.001) [3]. Kulu et al. conducted a study with 48 patients to evaluate the diagnostic and prognostic values of citrulline with those of D-dimer in patients with AMI. The study showed significantly higher citrulline levels in 23 patients with abdominal pain with AMI versus 25 patients with abdominal pain without AMI. Citrulline was also statistically significant for predicting mortality [10].

The apparent directional discrepancy between these two studies—lower citrulline in AMI [3] versus higher citrulline in AMI [10]—warrants explanation. Citrulline is synthesized by enterocytes, and its plasma level reflects functional

Figure 1. Identification of studies via databases and registers.

enterocyte mass; therefore, a decrease is the expected pathophysiological response to enterocyte loss in AMI, consistent with the findings of Nuzzo et al. and the broader literature [2]. Overall, citrulline shows modest standalone diagnostic utility for AMI.

Nuzzo et al. showed that plasma D-lactate concentrations were not statistically different between AMI and controls (0.042 mmol/L vs. 0.073 mmol/L, p = 0.28). ROC analysis showed an AUC of 0.438 (0.328 - 0.547) [3]. Thus, D-lactate fails to differentiate AMI from other causes of abdominal pain. Costello et al. conducted a scoping review to evaluate current diagnostic and management strategies, comparing endovascular and open surgical approaches. After analysis of biomarkers from 22 studies, lactate levels were substantially higher in open surgical patients (3.0 - 4.8 mmol/L) versus endovascular cases (1.6 - 2.2 mmol/L) [11].

The cross-sectional study by Nuzzo et al. (2021) showed that plasma I-FABP concentrations had no statistically significant difference between AMI and other causes of abdominal pain (278 ng/L vs. 348 ng/L, p = 0.06). ROC analysis showed an AUC of 0.401 (0.291 - 0.512) [3]. I-FABP has a short plasma half-life (approximately 11 minutes), and levels may normalize if sampling occurs after the initial release phase or if ischemia is limited to the mucosa without significant enterocyte necrosis. Sun et al. (2016) conducted a meta-analysis to evaluate the accuracy of serum I-FABP for diagnosis of AMI. The study showed pooled sensitivity of 0.80 (95% CI: 0.72 - 0.86), specificity of 0.85 (95% CI: 0.73 - 0.93), positive likelihood ratio of 5.5 (95% CI: 2.8 - 10.8), and negative likelihood ratio of 0.23 (95% CI: 0.15 - 0.35). The diagnostic odds ratio was 24 (95% CI: 9 - 65) and the AUC was 0.86 (95% CI: 0.83 - 0.89, p = 0.042), indicating high overall accuracy [12].

Matsumoto et al. conducted a study to evaluate the use of I-FABP and traditional biomarkers in the early diagnosis of acute intestinal ischemia of different causes. The study showed that levels of most biomarkers (including I-FABP) were significantly higher in the vascular ischemia group versus other groups (p < 0.01). The ROC curve showed that I-FABP had an AUC of 0.80 - 0.88 [13].

Taghiyev et al. conducted a prospective observational study of 500 patients undergoing cardiac surgery with cardiopulmonary bypass. ROC analysis showed an AUC of 0.973 at 36 hours post-ICU admission (95% CI: 0.764 - 0.997, p < 0.001) and an optimal cut-off of >1421 pg/mL. Thus, I-FABP is a highly accurate and early predictor of mesenteric ischemia after cardiac surgery [14]. Of note, this study evaluated a specific clinical context (NOMI after cardiopulmonary bypass), and results may not be directly generalizable to other AMI etiologies.

Bourcier et al. conducted the multicentric prospective observational DIAGOMI study on diagnosis and prognosis features in 61 patients with suspected mesenteric ischemia. Of the 33 patients with confirmed NOMI, 27 had intestinal necrosis. Plasma I-FABP was significantly increased in the presence of intestinal necrosis, with an AUC of 0.83 (0.70 - 0.96). At a threshold of 3114 pg/mL, sensitivity was 70%, specificity 85%, negative predictive value 58%, and positive predictive value 90% for the diagnosis of intestinal necrosis [15].

Taken together, these four studies demonstrate that I-FABP is the best-validated biomarker for diagnosing vascular intestinal ischemia and detecting intestinal necrosis, though its sensitivity may be limited in early or non-vascular forms of ischemia.

El Hamwi et al. conducted a prospective study to assess whether circulating levels of proglucagon-derived peptides differ between patients with AMI and a control group. Twenty-three patients in the ischemia group and 23 in the control group were analyzed. Both GLP-1 and GLP-2 levels were higher in the ischemia group versus the control group: GLP-1 (5.3 vs. 2.3 pmol/L, p = 0.01) and GLP-2 (2.8 vs. 0.9 pmol/L, p = 0.023), respectively [4]. These findings are promising but limited by the small sample size (n = 46) and single-center design. ROC-derived diagnostic accuracy metrics (AUC, sensitivity, specificity) were not reported, precluding direct comparison with other biomarkers.

Duivenvoorden et al. described the multicentre prospective observational TACTIC study to evaluate a panel of biomarkers and volatile organic compound profiles in exhaled air to diagnose AMI. One hundred twenty patients are being recruited and recruitment is ongoing. I-FABP, villin-1, and SM22 plasma levels over time increase as mesenteric ischemic damage increases. Thus, these markers may be used to determine the severity of AMI [6].

Kurt et al. studied whether adropin and HIF-1α may be used to aid in the early detection of AMI. The study showed higher levels of adropin and HIF-1α in 20 patients with AMI compared to both the abdominal pain group (n = 20) and the healthy control group (n = 20). ROC analysis showed that HIF-1α had an AUC of 0.705 (moderate diagnostic accuracy) while adropin had an AUC of 0.692 (weak accuracy) for AMI [7]. These results are limited by the very small sample size (n = 60 total), single-center design, and the inclusion of healthy controls in the comparator group, which may inflate diagnostic performance estimates compared to the clinically relevant comparison of AMI versus other causes of acute abdominal pain. The pathophysiological role of HIF-1α in intestinal ischemia-reperfusion injury has been further characterized in preclinical models [16].

The clinical utility of each biomarker is influenced by its temporal release pattern relative to ischemia onset. I-FABP, as a small cytosolic protein (15 kDa), is rapidly released upon enterocyte membrane disruption but has a short plasma half-life of approximately 11 minutes, meaning levels may peak early and decline if sampling is delayed. In the post-cardiac surgery setting, I-FABP levels peaked between ICU admission and 36 hours [14]. SM22 becomes elevated from 4 hours of ischemia onward, reflecting the later progression from mucosal to transmural damage [5]. HIF-1α increases significantly at 3 - 6 hours after ischemia onset. These kinetic differences suggest that a staged biomarker approach, early I-FABP for mucosal injury detection, followed by SM22 for transmural progression, may optimize diagnostic sensitivity across the time course of AMI. Prior systematic reviews and meta-analyses have similarly highlighted the complementary diagnostic value of combining multiple serological biomarkers [17].