The Diagnostic Utility of Urinary 5-HIAA and Leucine-Rich Alpha-2 Glycoprotein in Acute Appendicitis: A Narrative Review

Yahiya BaigAamer MohammedAlexandra E Butler^*

• Royal College of Surgeons in Ireland (Bahrain), Al Muharraq, Bahrain

Background:Acute appendicitis (AA) remains diagnostically challenging despite its global prevalence. Current methods rely on clinical scoring systems (e.g., Alvarado Score) and imaging (US, CT, MRI). Urinary biomarkers like 5-hydroxyindoleacetic acid (5-HIAA) and leucine-rich alpha-2 glycoprotein (LRG) offer non-invasive potential, reflecting intestinal inflammation and neutrophilic activity, respectively. This review evaluates their diagnostic accuracy.Methods:A targeted literature review was conducted using PubMed, Scopus, and ScienceDirect (2004–April 2025) to identify studies investigating urinary 5-HIAA and LRG in AA. Inclusion criteria focused on peer-reviewed studies reporting diagnostic accuracy, biomarker performance, and clinical utility. Data were extracted from 13 studies (2,623 participants) for 5-HIAA and 11 studies (1,586 participants) for LRG, including meta-analyses where available. Results were synthesized narratively, with emphasis on sensitivity, specificity, and area under the curve (AUC) metrics.Results:5-HIAA demonstrated variable diagnostic performance, with pooled sensitivity of 68.6% and specificity of 82% (AUC ~0.64). While it showed higher sensitivity (82%) in perforated appendicitis, its utility in uncomplicated cases was limited by dietary interference and methodological heterogeneity. In contrast, LRG exhibited greater consistency, particularly in pediatric populations. Serum LRG achieved an AUC of 0.95, while creatinine-adjusted urinary LRG, when combined with clinical variables (e.g., Appendicitis Urine Biomarker [AuB] score), reached 97.6% sensitivity for ruling out AA. However, standalone urinary LRG had low sensitivity (17.65%), highlighting its role as an adjunct rather than an independent diagnostic tool. Both biomarkers performed optimally when integrated with clinical scoring systems (e.g., Pediatric Appendicitis Score) or imaging.Conclusions:While 5-HIAA and LRG offer non-invasive diagnostic potential, neither biomarker is sufficient as a standalone test for AA. 5-HIAA may aid in perforation risk stratification, whereas LRG excels in ruling out AA, particularly in pediatric cases. Future research should focus on standardizing assays, validating multimodal biomarker panels (e.g., 5-HIAA + LRG + CRP), and developing point-of-care applications to enhance clinical feasibility. Until then, these biomarkers should complement—not replace—existing diagnostic strategies, serving as valuable adjuncts in ambiguous or high-risk presentations.