Susceptibility to mild and severe acute mountain sickness is associated with distinct urine metabolite profiles

Rapid ascent to high altitude (HA) in unacclimatized lowlanders elicits a series of hematologic, ventilatory, metabolic, and cardiovascular adaptations to counteract the lower partial pressure of oxygen. When ascent occurs faster than the body can acclimatize, high-altitude illnesses (HAIs) can occur. The most prevalent of the HAIs is acute mountain sickness (AMS), which can range in severity from mild (minor inconvenience) to severe (total incapacitation). Symptoms of AMS include headache, fatigue, gastrointestinal distress, dizziness, and in some cases sleep disturbances. Identifying individuals at risk for severe AMS, prior to their ascent to HA, would be useful to initiate appropriate prophylaxis approaches in those individuals prior to ascent. We previously reported eight urinary metabolites, measured prior to HA exposure, that discriminated individuals susceptible to moderate or severe AMS from those resistant to AMS (NoAMS). These metabolites include creatine, acetylcarnitine, 3-methylhistidine, N-methylhistidine, hypoxanthine, 1-methylnicotinamide, taurine, and 4-hydroxyphenylpyruvate. This follow-on study examined 41 unacclimatized, physically active healthy soldiers (mean ± SD; age=26 ± 5yr) who were tested at their baseline residence (BLR, 331 m), transported to Taos, NM (2845 m), then immediately hiked (active ascent; n=21) or were driven (passive ascent; n=20) to a HA (3600 m) facility where they resided for four days. AMS was assessed using the shortened version of the Environmental Symptoms Questionnaire (ESQ) and AMS-C scores were calculated. Participants were categorized into resistant (NoAMS; AMS-C< 0.7), mild AMS (mAMS; AMS-C ≥0.7 but <1.53), and moderate to severe AMS (sAMS; AMS-C ≥1.53) groups. Urine samples collected at BLR and HA were analyzed using proton nuclear magnetic resonance (NMR) spectroscopy. BLR urinary metabolite profiles were significantly different (p ≤ 0.05) between sAMS vs. NoAMS individuals, identifying an AMS risk pattern prior to HA exposure. Differentially expressed metabolites in sAMS group included elevated levels of creatine, acetylcarnitine, 3-methylhistidine, isobutyrate, and decreased levels of N-methylhistidine, hypoxanthine, taurine and 1-methylnicotinamide. Interestingly, most of the metabolites that distinguish the different AMS groups are linked to energy production, corroborating findings from our previous study. As urinary levels of these metabolites directly or indirectly reflect the status of the metabolic pathways involved in energy production, these pathways can potentially influence physiologic outcomes to hypoxia.