Biomarkers and potential subtypes of acute mountain sickness: A state-of-the-science review

Exposure to high altitude can cause acute mountain sickness (AMS) characterized by headache, gastrointestinal symptoms, dizziness and fatigue, which may progress to life-threatening conditions like high-altitude cerebral edema (HACE). Although the pathophysiology and development of AMS have been intensely investigated, the risk factors and underlying mechanisms remain incompletely understood. In addition, objective criteria for the diagnosis of AMS and reliable biomarkers are missing. Here we provide an overview of the molecular and pathophysiological foundations of AMS and review which potential biomarkers have been suggested and in combination with which physiological and psychological correlates of AMS they could improve diagnosis. Moreover, we point out current knowledge gaps and discuss which future research is required to enable AMS diagnosis based on more objective biomedical and psychophysical criteria. Emphasizing the apparent heterogeneity in AMS pathogenesis, we support the classification of different AMS subtypes according to etiological parameters. We propose the hypothesis that both insufficient and excessive hypoxia responses can cause AMS and that the differentiation according to these divergent mechanisms might allow the identification of AMS subtypes that can be characterized better using biomarkers and correlates of AMS.