Establishing Population-Specific Thyroid-Stimulating Hormone Reference Intervals for Syrians: An Age- and Sex-Stratified Analysis Using Indirect Method

<ns7:p>Background Thyroid-stimulating hormone (TSH) reference intervals used in Syrian clinical laboratories are derived predominantly from Western or manufacturer-specified populations, without local validation. Given that TSH distributions are shaped by population-specific genetic architecture, iodine sufficiency, autoimmune burden, nutritional status, and chronic psychosocial stress—factors operating with particular intensity in a conflict-affected Syrian context. This study sought to establish age- and sex-stratified, population-specific TSH reference intervals for Syria using a large indirect retrospective dataset. Methods A total of 9,735 consecutive TSH results were analysed from Alkhatib Medical Laboratory, Damascus (2020–2024), comprising 6,708 females (68.9%) and 3,027 males (31.1%). The cohort was stratified into six subgroups: children, adolescents, and adults of each sex. TSH was measured by third-generation electrochemiluminescence immunoassay (Elecsys, Roche Diagnostics; LOD 0.005 μIU/mL; calibrated to WHO IRP 80/558). Reference intervals were derived by iterative ±2SD truncation of the inlier distribution per CLSI EP28-A3c. Results Upper reference limits exceeded the manufacturer’s generic ceiling of 4.20 μIU/mL in five of six subgroups. Male adults exhibited the widest dispersion and highest upper boundary (7.01 μIU/mL; CV 117.9%), representing a 66.9% excess. Female adults yielded an upper limit of 6.34 μIU/mL (+51.0%), and paediatric subgroups ranged from 5.85 to 6.06 μIU/mL. A consistent ontogenic trajectory emerged in both sexes: HPT axis variability was greatest in childhood, contracted during adolescence (the only subgroup whose upper limit fell below 4.20 μIU/mL, with female adolescents reaching 3.05 μIU/mL, 27.4% below the manufacturer’s threshold), then re-broadened substantially in adulthood. A sex-dimorphic inversion was observed in adults, with males displaying greater TSH dispersion than females—contrary to classical Western epidemiological patterns. Conclusions Applying generic TSH intervals to the Syrian population produces systematic diagnostic misclassification: over-diagnosis of hypothyroidism in adults and potential failure to detect subclinical hypothyroidism in female adolescents. The derived intervals represent a clinically actionable foundation for improving thyroid diagnostic practice in Syria and should be considered for formal laboratory adoption, pending prospective validation in rigorously screened healthy cohorts. More broadly, these findings reinforce the imperative that diagnostic reference standards in populations defined by distinct genetic, nutritional, and environmental profiles must be locally derived rather than imported.</ns7:p>