Millions of people travel to high-altitude regions annually, and over 80 million people live permanently above 2,500 m (Tremblay and Ainslie, 2021). Chronic exposure to high-altitude hypoxia can cause chronic mountain sickness (CMS), clinically characterised by excessive erythrocytosis, hypoxic pulmonary hypertension and multisystem dysfunction (Gatterer et al., 2024). The prevalence of CMS ranges from 5% to 33% across populations, with the highest rates documented in the Andean region (León-Velarde et al., 2005), and varies with altitude, age and genetic factors. Patients with CMS experience impaired quality of life and increased morbidity and mortality, attributable to marked arterial hypoxaemia and haemodynamic abnormalities. These haemodynamic abnormalities may drive the progression of pulmonary hypertension, cor pulmonale, left ventricular dysfunction, and thromboembolic complications (Swenson, 2022). Despite having evolved unique hypoxic adaptation mechanisms through genetic selection (Liu et al., 2020; Buroker et al., 2012) (e.g., variants in EPAS1 and EGLN1), Tibetan populations exhibit inter-individual susceptibility to CMS, reflecting a complex balance between adaptive compensation and pathophysiological dysregulation (Hsieh et al., 2016).

The pathological mechanisms of CMS are fundamentally linked to hypoxia-induced multisystem maladaptation. Studies demonstrate that both acute and chronic hypoxia elevate levels of oxidative stress biomarkers (Jefferson et al., 2004). Comparative analyses of high-altitude populations show significantly elevated levels of markers of oxidative stress (e.g., ascorbate free radicals) in CMS patients compared with non-CMS high-altitude residents (Bailey et al., 2013). Bailey et al. have further elucidated systemic oxidative stress (OS) characteristics in high-altitude populations, manifested through an imbalance between free radical generation and antioxidant defense mechanisms that sustains chronic oxidative stress. This pathological state interacts synergistically with inflammatory mediators, potentially accelerating cognitive deterioration and elevating depression susceptibility (Shanjun et al., 2020; Kong et al., 2011). In addition, high-altitude populations exhibit a significantly higher prevalence of sleep-disordered breathing (SDB) compared to sea-level populations. Recent studies have demonstrated that Andean high-altitude residents show a two-fold higher in the apnea-hypopnea index (AHI) compared to sea-level counterparts, primarily manifested by increased central sleep apnea events (Pham et al., 2017). Notably, the study by Ana Sanchez-Azofra’s team revealed no significant association between the progression of CMS and alterations in sleep architecture or the severity of SDB (Sanchez-Azofra et al., 2022). While these findings have significantly advanced our understanding of hypoxia-driven oxidative stress and sleep-related pathophysiology in CMS, the complex interplay remains underexplored.

Current research predominantly focuses on traditional domains including hypoxic erythrocytosis (Haase, 2013; Yang et al., 2024), pulmonary hypertension (Ye et al., 2023; El Alam et al., 2022; Naeije, 2019), and cardiovascular complications (Savina et al., 2024; Abondio et al., 2024), whereas systematic investigations into multidimensional characteristics of CMS patients - particularly oxidative stress regulatory mechanisms, sleep disorder phenotypes, fatigue severity, and quality of life - remain substantially understudied. There is an imperative need for enhanced clinical evidence to advance the pathophysiological understanding framework.

Therefore, we conducted a study screening Tibetan permanent residents living at 4,500 m for chronic mountain sickness (CMS). We systematically collected data on haematological parameters, blood biochemical profiles, oxidative stress biomarkers, and multidimensional clinical phenotypes (including sleep quality, fatigue level, and quality of life scores). By assessing correlations between these parameters, we aimed to elucidate the pathophysiological features of CMS and to establish a scientific basis for developing prevention and treatment strategies.

CMS remains a significant health challenge for permanent residents at high altitudes. Current research on CMS at extreme altitudes (>4500 m) remains limited, predominantly focusing on migrant populations and males cohorts (Jiang et al., 2014; Champigneulle et al., 2022; Oberholzer et al., 2020). This study assessed long-term Tibetan residents (both sexes) living at 4500 m, analysing their oxidative stress, sleep quality, fatigue and quality of life. Key findings revealed that male CMS patients exhibited significantly higher RBC, HGB, HCT, UA and T-AOC compared with females. Analysis of the total population demonstrated significant positive correlations between RBC, HGB, HCT and T-AOC. Notably, 91.67% of CMS patients with HAPC were male and presented with severe CMS. Multivariate analysis identified two independent factors associated with HAPC comorbidity: decreased MCHC (OR = 0.80) and increased T-AOC (OR = 1.47). Furthermore, better sleep quality was significantly associated with higher 8-OHdG (OR = 0.95), and better scores on the bodily pain (BP) (OR = 0.91) and general health (GH) (OR = 0.90) domains.

Oxidative stress is implicated in the pathogenesis of several human diseases, while antioxidants regulate redox homeostasis and signalling pathways. OS occurs when endogenous antioxidant defences are overwhelmed, leading to molecular, tissue and cellular damage (Silvestrini and Mancini, 2024). T-AOC is a biomarker measuring the antioxidant potential of body fluids (Manafikhi et al., 2017). In this study, we observed positive correlations between HGB, UA, and T-AOC in CMS patients, with HGB, UA and T-AOC levels being higher in males than in females. Epidemiological studies indicated that humans at high altitudes, characterised by low pressure and low oxygen, experience elevated HGB and UA levels (Pu et al., 2024). Previous experimental studies demonstrated that uric acid influences T-AOC measurements by direct scavenging of free radicals, synergistic enhancing other antioxidant systems, and elevating of humoral antioxidant reserves (Cao and Prior, 1998). Consequently, the endogenous antioxidant system may exhibit responsiveness to oxidative stress during hypoxia. Uric acid, as an endogenous antioxidant, may play an important protective role against oxidative stress in the context of systemic hypoxia during high-altitude exposure, particularly when blood viscosity is increased (Baillie et al., 2007).

In patients with CMS complicated by HAPC, elevated levels of antioxidants (including T-AOC and GSH) were observed compared to those with CMS alone. This paradoxical phenomenon, characterized by an enhanced antioxidant response correlating with greater disease severity, contrasts with previous reports. For example, a study using chronic hypobaric hypoxia-induced CMS rat models (simulated 5,000 m altitude for 30 days) showed that the CMS group had significantly elevated MDA levels and decreased SOD and GSH levels compared to the normal control group (Ma et al., 2014). Additionally, Bailey et al. reported that CMS patients at high altitude had lower levels of GSH and higher levels of oxidised glutathione (GSSG) than non-CMS individuals, and that these oxidative and inflammatory responses were associated with cognitive decline and depressive symptoms (Bailey et al., 2019). In this study, HGB influenced CMS disease severity and was positively correlated with UA and T-AOC, which may account for the observed higher antioxidant levels in more severe CMS. Future studies could investigate the relationship between CMS disease severity and antioxidant levels after controlling for HGB.

The present study observed that CMS patients with good sleep quality exhibited lower levels of bodily pain, improved general health perceptions and reduced fatigue indices, suggesting a potentially optimal adaptive state. Notably, however, patients with good sleep quality predominated in males and had significantly higher levels of HGB and the oxidative stress marker 8-OHdG. Both the greater propensity of males to self-report favourable health status compared to females (Meyer et al., 2014) and a possible association between HGB concentrations and sleep quality parameters may explain the observed males predominance and elevated HGB levels. Sanchez-Azofra et al. demonstrated that isovolemic hemodilution in patients with CMS resulted in decreased HGB levels, but acutely exacerbated nocturnal oxygen saturation and aggravated the severity of sleep apnea (Sanchez-Azofra et al., 2022). 8-OHdG, a biomarker of RNA or DNA oxidation, is widely used in disease mechanism research, environmental exposure assessment and drug efficacy monitoring. Its levels are influenced by gender, age, smoking and physical activity (Peres et al., 2020). On the one hand, studies have shown that 8-OHdG is associated with a variety of disease risks. Specifically, higher 8-OHdG levels show a positive association with cardiovascular disease (CVD) incidence in females, but a U-shaped association in males (Nagao et al., 2020). Elevated plasma 8-OHdG is associated with increased motor cognitive risk (MCR) in older adults, and Alzheimer’s disease patients exhibit higher urinary 8-OHdG levels than healthy elderly controls (Dai et al., 2024; Zengi et al., 2012). On the other hand, previous studies have postulated that this phenomenon may be related to inter-individual variations in DNA damage repair capacity. When exposed to comparable levels of oxidative damage, individuals with enhanced repair functionality may demonstrate more efficient excision and subsequent repair of 8-OHdG adducts on DNA strands, thereby exhibiting relatively elevated urinary excretion levels of this oxidative damage biomarker (Il’yasova et al., 2012). However, a prospective epidemiological study by Loft et al. found no significant association between lung cancer risk and urinary 8-OHdG excretion (Loft et al., 2006). Similarly, Peres et al. showed in their cross-sectional study that the severity of obstructive sleep apnoea (OSA) was not significantly associated with 8-OHdG biomarkers (Peres et al., 2020). Therefore, whether the higher blood 8-OHdG levels observed in CMS patients with good sleep quality reflect more severe DNA oxidative damage or enhanced DNA repair capacity needs to be further investigated in prospective studies.

Although this study has strengths, the findings should be interpreted considering several limitations. First, the absence of a representative control group (e.g., individuals without CMS matched for gender and age) limits the ability to directly compare biomarker levels between CMS and non-CMS populations. Second, convenience sampling method used in these high-altitude areas, characterised by low population density and dispersed distribution, may introduce selection bias, potentially limiting the generalizability of the findings. Third, the assessment of sleep quality using the PSQI questionnaire in CMS patients may be subject to participants’ subjective perceptions and cognitive biases. Fourth, as a small-scale cross-sectional study, this research can only provide evidence of associations rather than establish causal relationships. Further validation through prospective studies with larger sample sizes is warranted.

In summary, this study reveals sex-specific characteristics in CMS patients, with males demonstrating elevated hematological indices (RBC, HGB, HCT) and T-AOC compared to females. Notably, HAPC comorbidity occurred primarily in severe male CMS cases and was associated with lower MCHC and higher AOC levels. Paradoxically, male sex and elevated oxidative stress markers (8-OHdG) coexisted with improved sleep quality, suggesting complex compensatory mechanisms in chronic hypoxic adaptation. These findings provide a scientific basis for understanding the haematological, oxidative stress and patient-reported characteristics of CMS patients at extreme altitudes.