Altitude hypoxia and hypoxemia: pathogenesis and management

At high altitudes, which typically exceed 2500 m, approximately 80 million people reside permanently, with over a million visitors annually. The primary effect of high altitude is hypobaric hypoxia, which leads to decreased oxygen availability and a cascade of physiological responses. However, inadequate or excessive responses can lead to malacclimatization, resulting in hypoxemia and various high-altitude illnesses, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and high-altitude pulmonary hypertension (HAPH). Acute altitude illnesses (AMS, HACE, and HAPE) stem from inadequate acclimatization, whereas chronic conditions (CMS and HAPH) reflect prolonged or excessive adaptive responses. This review briefly summarizes the current knowledge on the clinical manifestations, epidemiology, and risk factors for high-altitude diseases. Additionally, this review systematically discusses the most recent pathophysiological mechanisms underlying these conditions, with a special emphasis on genetic susceptibility and chronic altitude illness (CMS and HAPH). Furthermore, a comprehensive overview of current prevention and treatment strategies is provided, emphasizing the promising effects of natural medicines, especially traditional Tibetan medicines. Despite extensive research, the exact mechanisms underlying these illnesses remain elusive, and options for their management are still limited. This review aims to provide novel insights into the pathogenic mechanisms of these complex conditions and guide future research directions to improve the prevention and management of high-altitude illnesses.