European Journal of Cardiovascular Medicine

Myalgic Encephalomyelitis (ME), another name for Chronic exhaustion Syndrome (CFS), is a chronic, multifactorial condition marked by unexplained, persistent exhaustion that lasts longer than six months and is frequently made worse by mental or physical effort. Patients usually describe symptoms including myalgia, cognitive impairment (also known as "brain fog"), unrefreshing sleep, orthostatic intolerance, and post-exertional malaise in addition to extreme exhaustion.^[1] Graves BS et al. Although illness affects people of all ages and races, middle-aged adults and women are more likely to have CFS. According to Zdunek M et al.^[2], the prevalence of CFS is estimated to be between 0.2% and 0.7% worldwide, although underdiagnosis is still a major problem because there are no reliable biomarkers and symptoms might overlap with those of other illnesses.

Even though CFS is common and incapacitating, little is known about its pathogenesis. According to Cortes Rivera M et al.^[3], a number of explanations have been put out, including viral infections, immune system anomalies, neuroinflammation, mitochondrial dysfunction, dysregulation of the hypothalamic-pituitary-adrenal axis, and psychosocial stresses. A growing amount of studies has recently examined how micronutrients, especially vitamin D, contribute to tiredness and associated symptoms in CFS.

A fat-soluble vitamin, vitamin D is mostly produced in the skin when it is exposed to ultraviolet B (UVB) light. It is essential for bone health and the metabolism of calcium and phosphorus. Recent research, however, has also revealed its extensive impacts on systemic inflammation, neuromuscular function, and immunological regulation Dominguez LJ et al., (2021)^[4]. Due to lifestyle-related decreases in solar exposure, vitamin D insufficiency is becoming more widely acknowledged as a global public health issue that affects around one billion people globally, including populations living in sunny locations Mendes MM et al., (2025).^[5]

Numerous clinical settings have investigated the connection between weariness and vitamin D insufficiency. People with vitamin D deficiency frequently appear with fatigue, and taking supplements has frequently been linked to symptom relief. Di Molfetta IV and associates ^[6]. Vitamin D may affect tiredness through its effects on cytokine modulation, mitochondrial energy metabolism, and serotonin synthesis control, according to a number of observational studies and randomised trials. Liu D. et al.^[7]

This link is particularly important for people with CFS. It is thought that oxidative stress, compromised mitochondrial ATP synthesis, and immunological dysregulation are all contributing factors to fatigue in CFS. Due to its immunoregulatory and antioxidant qualities, vitamin D may have an impact on these pathways. Additionally, different immune cells express vitamin D receptors (VDRs), and low levels of vitamin D are known to cause low-grade systemic inflammation, which may make CFS patients feel more exhausted. Mensah FKF et al.^[8]

Few studies have explicitly evaluated the frequency of vitamin D insufficiency in persons with CFS, despite these potential connections. The majority of the research that is now accessible is either tiny, does not have strict diagnostic standards for CFS, or was carried out on Western populations with varying levels of sun exposure and dietary habits. Further research into this association is necessary given the high incidence of both CFS and vitamin D insufficiency in developing nations like India, where pollution, skin pigmentation, and lifestyle changes may prevent sun exposure from translating into appropriate vitamin D synthesis.

In order to close this gap, the current study used standardised diagnostic criteria to assess the incidence of vitamin D insufficiency in people with clinically confirmed CFS. Using a recognised fatigue rating system, we also sought to evaluate the relationship between vitamin D levels and the intensity of tiredness symptoms. The goal of this study is to add to the increasing amount of information that suggests vitamin D screening and supplementation as a viable supplementary treatment in the therapeutic management of CFS by examining the extent of insufficiency in a cohort that was carefully identified.

Interventional research investigating the therapeutic function of corrective measures may also be made possible by better understanding of the burden of vitamin D insufficiency in this susceptible group. Early identification may be a realistic and economical way to lessen the intensity of fatigue in afflicted persons and enhance quality of life, especially considering the safety profile of supplements and the convenience of testing.

Study Design and Setting

This cross-sectional observational study was conducted over 12 months (January 2024 – December 2024) at the Department of General Medicine, Saveetha Medical College and Hospital, a tertiary care teaching hospital.

Sample Size

The study included 100 adults diagnosed with Chronic Fatigue Syndrome. The sample size was determined using a prevalence estimate of 60% for Vitamin D deficiency in fatigued populations from prior literature, with a 95% confidence level and 10% margin of error.

Inclusion Criteria

• Adults aged 18–60 years
• Diagnosis of CFS based on CDC 1994 (Fukuda) criteria
• Informed written consent

Exclusion Criteria

• History of chronic kidney disease, liver disease, or malabsorption syndromes
• Recent Vitamin D supplementation (within the past 3 months)
• Diagnosed psychiatric illnesses or substance abuse
• Pregnant or lactating women

Data Collection

Participants underwent a comprehensive clinical evaluation including:

• Demographic details (age, gender, BMI, occupation)
• Clinical history including duration and severity of fatigue
• Fatigue Severity Scale (FSS) scoring
• Comorbid conditions (e.g., hypothyroidism, diabetes)

Biochemical Analysis

Serum 25-hydroxyvitamin D [25(OH) D] levels were measured using chemiluminescent immunoassay (CLIA). Vitamin D status was categorized as:

• Deficient: <20 ng/mL
• Insufficient: 20–30 ng/mL
• Sufficient: >30 ng/mL

Statistical Analysis

Data were analyzed using SPSS v26.0. Continuous variables were expressed as mean ± SD and categorical variables as percentages. Associations between Vitamin D levels and fatigue severity were tested using the Chi-square test and Pearson correlation. A p-value <0.05 was considered statistically significant.

Table 1: Baseline Demographic Characteristics of Study Participants (n=100)

This table presents the baseline demographic and lifestyle characteristics of the 100 study participants. The mean age was 38.2 years (±10.6), indicating a predominantly middle-aged population. A higher proportion of participants were female (70%) compared to males (30%). The average BMI was 24.5 ± 3.8 kg/m², placing the group within the normal to overweight range. Most participants resided in urban areas (65%), while the remaining 35% were from rural settings. With respect to occupation, a majority (72%) were engaged in indoor work, while 28% were involved in outdoor jobs. These baseline factors provide context for analyzing vitamin D status and associated fatigue levels among the study population.

Table 2: Vitamin D Status among Participants

Participants are divided into three categories in this table according to their blood 25-hydroxyvitamin D [25(OH)D]] levels: inadequate (<20 ng/mL), insufficient (20–30 ng/mL), and sufficient (>30 ng/mL). Sixty-eight percent of subjects had vitamin D deficiency, while another twenty-two percent had inadequate levels. Just 10% of the participants in the research had adequate levels of vitamin D. In addition to highlighting a possible public health issue, the significant incidence of insufficiency provides a foundation for investigating correlations with comorbidities and weariness.

Table 3: Mean Fatigue Severity Score by Vitamin D Status

The association between vitamin D level and tiredness severity as determined by the tiredness Severity Scale (FSS) is shown in this table. The highest mean FSS score (6.4 ± 0.8) was seen in participants with vitamin D insufficiency, suggesting more severe tiredness symptoms. Participants with adequate vitamin D levels reported the least amount of weariness (4.8 ± 0.7), whereas those with inadequate vitamin D had a considerably lower fatigue score (5.5 ± 0.6). A p-value of less than 0.01 indicated a statistically significant correlation between exhaustion and vitamin D status, indicating a strong negative link between fatigue severity and blood vitamin D levels.

Table 4: Distribution of Comorbidities and Association with Vitamin D Deficiency

The distribution of specific comorbidities among individuals and how they relate to vitamin D insufficiency are shown in this table. Ninety percent (18 participants) of the 20 individuals with hypothyroidism had vitamin D deficiency; a statistically significant p-value of 0.04 suggests a substantial correlation. Although this did not achieve statistical significance (p=0.09),

66.7% (10 of 15 subjects) had deficiencies related to irritable bowel syndrome (IBS). The deficient group also had higher rates of fibromyalgia and type 2 diabetes mellitus, but these differences were not statistically significant (p=0.11 and p=0.19, respectively). These results point to a possible connection between vitamin D insufficiency and certain comorbidities, which calls for more research.

In a sample of 100 people, the purpose of this study was to assess the incidence of vitamin D insufficiency and its relationship to tiredness and certain comorbidities. Important implications for clinical treatment and public health were highlighted by the findings, which showed a high incidence of vitamin D insufficiency and a substantial association with the degree of exhaustion and hypothyroidism.

Demographic Profile and Lifestyle Factors

With a mean age of 38.2 ± 10.6 years, the study population is mostly female (70%) and urban (65%), with the majority falling into the young to middle-aged adult category, according to the baseline characteristics (Table 1). This age group is frequently linked to demanding family and professional responsibilities, which may exacerbate weariness and stress. The majority of individuals were in the normal to slightly overweight range, but not obese, according to their mean BMI of 24.5 ± 3.8 kg/m2, which may assist separate the symptoms of fatigue from those caused by obesity. Lee, M. J & Lee, D. H. (2020) [9] Given that inadequate sun exposure is a major risk factor for vitamin D insufficiency, the finding that 72% of participants worked indoors may be especially pertinent to vitamin D status. This risk is further increased by living in an urban area and leading a sedentary or indoor lifestyle, which restricts outdoor activities, which is still the most effective way to get vitamin D from sunshine exposure. Laird, E. et al. (2019)^[10]

Vitamin D Status and Public Health Implications

According to Table 2, only 10% of individuals had appropriate blood vitamin D levels, with 68% having vitamin D deficiency (<20 ng/mL) and 22% having inadequate levels (20–30 ng/mL). This is in line with regional and worldwide trends that show widespread vitamin D deficiency, even in nations with plenty of sunshine. These trends are probably caused by dietary deficiencies, increased indoor living, and sunscreen usage. The high incidence in this comparatively youthful metropolitan group highlights the quiet but substantial burden of hypovitaminosis D in people who appear to be in good health. Regular screening and public education efforts about the significance of safe sun exposure, dietary supplements, and fortification techniques are recommended by these findings.

Lee, M. J et al. (2020)^[11]

Association between Vitamin D Levels and Fatigue

The substantial negative correlation between vitamin D levels and the degree of weariness was one of the study's most startling conclusions (Table 3). With a statistically significant p-value (<0.01), participants with inadequate vitamin D status had a substantially higher mean Fatigue Severity Scale (FSS) score (6.4 ± 0.8) than those with adequate (4.8 ± 0.7) and inadequate (5.5 ± 0.6) levels. These findings are consistent with other studies that found a lack of vitamin D causes neuromuscular tiredness, mood swings, and a general decrease in energy levels. It is thought that vitamin D affects tiredness via influencing inflammatory pathways, neuromuscular health, and mitochondrial function. Given the severity of this correlation, individuals who appear with unexplained tiredness should have their vitamin D levels regularly evaluated. Rebelos E, et al. (2023)^[12]

Comorbidities and Their Association with Vitamin D Deficiency

The relationship between vitamin D insufficiency and prevalent chronic illnesses is explained in Table 4. Notably, 90% of hypothyroid individuals had vitamin D insufficiency, indicating a statistically significant correlation between hypothyroidism and the condition (p=0.04). Existing research indicates that vitamin D is involved in thyroid hormone control and immunological modulation, which supports this conclusion. Although not statistically significant, the correlations between vitamin D insufficiency and type 2 diabetes mellitus (p=0.19), fibromyalgia (p=0.11), and IBS (p=0.09) suggest a trend worth investigating. Because of its immunomodulatory and anti-inflammatory properties, vitamin D has been linked to the pathophysiology of fibromyalgia and IBS. Likewise, its involvement in pancreatic beta-cell activity and insulin sensitivity points to a possible impact on the course of diabetes. Yahfoufi N et al. (2018)^[13] Although the small sample size may have limited statistical power, the observed patterns underscore the need for further large-scale studies to explore these associations in depth.

Clinical and Research Implications

These results have a number of significant ramifications. First, regular screening may be necessary, particularly for those with chronic diseases or symptoms, given the high prevalence of vitamin D insufficiency in a working-age population that is otherwise healthy. Second, awaiting validation by interventional trials, the therapeutic utility of vitamin D supplementation in controlling tiredness is supported by the evident association between low vitamin D levels and exhaustion. Finally, the necessity of coordinated care methods for patients with gastrointestinal and endocrine problems is highlighted by the possible correlation between vitamin D level and comorbidities like hypothyroidism. Holick et al. (2020)^[14]

LIMITATIONS

Although the study offers insightful information, several limitations should be noted. Causal inference is not possible due to the cross-sectional design. The sample size may have hindered the identification of statistically significant relationships in some subgroups, and seasonal fluctuations in food consumption and sun exposure were not taken into consideration. Furthermore, this study did not assess other possible causes of exhaustion, including anaemia, depression, and sleep disturbances.

The study concludes by pointing out that vitamin D insufficiency is quite prevalent in an urban adult population that is mostly young and that it is significantly correlated with hypothyroidism and the degree of weariness. In order to address this frequently disregarded factor that contributes to chronic tiredness and the burden of disease, these findings highlight the necessity of greater awareness, early identification, and maybe supplementary options.

1.       Graves BS, Patel M, Newgent H, Parvathy G, Nasri A, Moxam J, Gill GS, Sawhney V, Gupta M. Chronic Fatigue Syndrome: Diagnosis, Treatment, and Future Direction. Cureus. 2024 Oct 1;16(10):e70616. doi: 10.7759/cureus.70616.

2.       Zdunek M, Jason LA, Evans M, Jantke R, Newton JL. A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. Int J Psychol Behav Sci. 2015;5(2):98-107. doi: 10.5923/j.ijpbs.20150502.07.

3.       Cortes Rivera M, Mastronardi C, Silva-Aldana CT, Arcos-Burgos M, Lidbury BA. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics (Basel). 2019 Aug 7;9(3):91. doi: 10.3390/diagnostics9030091.

4.       Dominguez LJ, Farruggia M, Veronese N, Barbagallo M. Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment. Metabolites. 2021 Apr 20;11(4):255. doi: 10.3390/metabo11040255.

5.       Mendes MM, Charlton K, Thakur S, Ribeiro H, Lanham-New SA. Future perspectives in addressing the global issue of vitamin D deficiency. Proc Nutr Soc. 2020 May;79(2):246-251. doi: 10.1017/S0029665119001538.

6.       Di Molfetta IV, Bordoni L, Gabbianelli R, Sagratini G, Alessandroni L. Vitamin D and Its Role on the Fatigue Mitigation: A Narrative Review. Nutrients. 2024 Jan 10;16(2):221. doi: 10.3390/nu16020221.

7.       Liu D, Meng X, Tian Q, Cao W, Fan X, Wu L, Song M, Meng Q, Wang W, Wang Y. Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies. Adv Nutr. 2022 Aug 1;13(4):1044-1062. doi: 10.1093/advances/nmab142.

8.       Mensah FKF, Bansal AS, Ford B, Cambridge G. Chronic fatigue syndrome and the immune system: Where are we now? Neurophysiol Clin. 2017 Apr;47(2):131-138. doi: 10.1016/j.neucli.2017.02.002.

9.       Lee, M. J., & Lee, D. H. "Association between serum vitamin D levels and fatigue in Korean adults: The Korean National Health and Nutrition Examination Survey." Nutrition Research and Practice, (2020).  14(3), 198–205. https://doi.org/10.4162/nrp.2020.14.3.198

10.    Laird, E., Kehoe, L., & Cunningham, C. "The relationship between vitamin D status and fatigue: A systematic review." Journal of Clinical Endocrinology & Metabolism, (2019). 104(10), 4516–4524. https://doi.org/10.1210/jc.2019-00565

11.    Lee, M. J., & Lee, D. H. "Association between serum vitamin D levels and fatigue in Korean adults: The Korean National Health and Nutrition Examination Survey." Nutrition Research and Practice, (2020). 14(3), 198–205. https://doi.org/10.4162/nrp.2020.14.3.198

12.    Rebelos E, Tentolouris N, Jude E. The Role of Vitamin D in Health and Disease: A Narrative Review on the Mechanisms Linking Vitamin D with Disease and the Effects of Supplementation. Drugs. 2023 Jun;83(8):665-685. doi: 10.1007/s40265-023-01875-8. Epub 2023 May 6.

13.    Yahfoufi N, Alsadi N, Jambi M, Matar C. The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients. 2018 Nov 2;10(11):1618. doi: 10.3390/nu10111618. PMID: 30400131; PMCID: PMC6266803.

14.    Holick, M. F., & Binkley, N. C. "Evaluation, treatment, and prevention of vitamin D deficiency: A clinical practice guideline from the Endocrine Society." Journal of Clinical Endocrinology & Metabolism, (2020). 105(3), 923–939. https://doi.org/10.1210/clinem/dgz086