Hepatic–Renal Biomarker Clustering Identifies Subclinical Acclimatization Phenotypes at High Altitude

Accurate assessment of high-altitude acclimatization is essential for identifying individuals at risk of maladaptation, yet current strategies relying on single-organ biomarkers or subjective symptom scores fail to capture the multi-organ physiological response to hypoxia. This study aimed to identify distinct acclimatization phenotypes through unsupervised hierarchical clustering of five routinely available hepatic and renal biomarkers and to evaluate their association with an objective index of high-altitude acclimatization. A total of 184 healthy adults residing in Lhasa (3650 m) were recruited. Serum creatinine (CR), uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were standardized and submitted to hierarchical clustering. The altitude acclimatization/adaptation index (AAI), defined as the ratio of peripheral oxygen saturation (SpO2) to hematocrit (HCT), was used as an criterion of acclimatization status. Cluster stability was assessed through multiple sensitivity analyses, and a general linear model evaluated the association between cluster assignment and AAI. Two clusters were identified: a Relatively Healthy cluster (n = 152) and a Metabolically Abnormal cluster (n = 32), differing significantly across all five indicators and in AAI. Sensitivity analyses supported the robustness of this two-cluster structure. General linear model results showed that, after adjustment for sex, race, age, and body mass index, cluster assignment remained significantly associated with AAI (p = 0.029), with adjusted means of 1.97 versus 1.84. Both values exceeded the maladaptation threshold of 1.72, underscoring that the panel detects meaningful acclimatization differences within the conventionally well-acclimatized range. Five hepatic and renal biomarkers stratify high-altitude residents into distinct acclimatization phenotypes by capturing subclinical metabolic strain within the conventionally well-acclimatized range and identify actionable intervention targets for advancing precision management of high-altitude acclimatization.