Health consequences of vitamin D deficiency in the human body

Studies regarding the pleiotropic activity of vitamin D carried out in recent years have confirmed the relationship of its deficiency with the occurrence of cardiovascular diseases. It has been observed that in patients with low vitamin D levels in the blood, ischemic heart disease, myocardial infarction, stroke, arrhythmias, and arterial hypertension were more common. Moreover, the mortality from these diseases was much higher. These studies also proved that the occurrence of risk factors for cardiovascular diseases, such as hypertriglyceridemia, hypercholesterolemia, diabetes, and high body mass index (BMI) was much more frequent [4].

Cardiovascular diseases are caused by, among other factors, high levels of fibrinogen (blood coagulation factor), homocysteine, asymmetric dimethylarginine C-reactive protein (CRP), and type B natriuretic propeptide. The role of vitamin D is to lower the blood levels of these potential risk factors for cardiovascular disease. Many studies also show that vitamin D has a positive effect on insulin secretion, inhibits the renin-angiotensin system, and inhibits cell proliferation and modulation of inflammatory processes. Through these mechanisms, vitamin D is directly involved in the processes associated with the development of cardiovascular diseases [1].

One of the cardiovascular diseases that vitamin D can prevent is atherosclerosis. Vitamin D has some antiatherogenic functions, inhibiting the transformation of macrophages into foam cells, enabling the transport of HDL (high density lipoprotein) [41].

The development of atherosclerosis is caused by an inflammatory process arising from an imbalance between free radicals and antioxidants. In the human body, free radicals and antioxidants remain in a state of equilibrium, the disturbance of which is caused by so-called oxidative stress, which is one of the factors affecting the formation of atherosclerosis and coronary artery disease. Vitamin D has antioxidant and anti-inflammatory properties, thus maintaining the balance between free radicals and antioxidants. As a result, it plays an important role in preventing the development of atherosclerosis and coronary disease [42].

The immune system is responsible for protecting the body against bacteria and viruses. It does sometimes happen, however, that this system perceives the body’s own cells as hostile and starts to attack them, causing what are known as autoimmune diseases. They include type 1 diabetes mellitus, hyperthyroidism and Hashimoto thyroiditis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, psoriasis, vitiligo, and scleroderma [23].

Vitamin D plays an important role in the proper functioning of the immune system. It can both prevent autoimmune diseases and support their treatment. The action of vitamin D is related to the presence of vitamin D receptors (VDR) in many cells. Vitamin D receptors are found on T and B lymphocytes and antigen-presenting cells (APC), which include dendritic cells, as well as monocytes and macrophages. The studies conducted so far confirm the influence of vitamin D on the transcriptional activity of approximately 290 genes involved in the functioning of immune system cells [2, 23].

There are two types of T lymphocytes. They are T helper (Th) lymphocytes, which are characterized by the CD4 antigen, and cytotoxic T cells, which are characterized by the CD8 antigen. There are many populations of Th lymphocytes (e.g., Th1, Th2, Th9, Th17, Th22). In the context of autoimmune diseases, the population of Th17 cells, which is characterized by the production of interleukin 17 (IL-17), has a particular effect. It works by enhancing antibacterial and antifungal immunity. Many studies indicate that calcitriol inhibits the Th17 lymphocyte response, reducing the excessive production of IL-17 [23].

The active form of vitamin D has a positive effect on the treatment of autoimmune diseases. These diseases are associated with an abnormal (excessive) response of the immune system [43]. Calcitriol prevents the excessive production of pro-inflammatory cytokines, while supporting the production of anti-inflammatory cytokines, thus reducing inflammatory reactions. Vitamin D deficiency increases the risk of autoimmune reactions [3].

One autoimmune disease is multiple sclerosis, which is affected by genetic factors, geographic location, and dysfunctions within the immune system [2,18]. This disease affects women much more often, as do other autoimmune diseases [43]. Vitamin D deficiency is very common in this disease, which may be caused by low food intake of vitamin D, as well as insufficient exposure to sunlight. Numerous studies have confirmed that vitamin D supplementation may reduce the risk of multiple sclerosis, alleviate its course, or limit its progress [23]. It has been shown that women taking pharmaceutical preparations of vitamin D in relatively high doses experience up to 40% lower risk of multiple sclerosis when compared to the women who did not use any supplementation. It has been established that by taking vitamin D at the level of 1000–4000 IU it is possible to lower the risk of developing multiple sclerosis up to 62% [44].

Autoimmune diseases associated with vitamin deficiency also include psoriasis, vitiligo, and scleroderma, which are skin diseases. On the other hand, vitamin D is supplied mainly from skin synthesis, which means that its deficiencies are closely related to these diseases. The role of calcitriol in the skin is both to maintain the correct barrier (by regulating the differentiation of keratinocytes) and to act as an antibacterial and regulate the immune response. Vitamin D is also important in the proper functioning of the melanocytes present in the skin. Currently, research is ongoing to determine whether vitamin D deficiency is the cause of autoimmune skin diseases or is the result of impaired skin synthesis due to disease [3,18, 23].

The frequent occurrence of vitamin D deficiencies has been confirmed in patients with Leśniowski-Crohn disease and their influence on the development and course of this disease [23]. Some studies have shown that 60% to 70% of patients may have a significant vitamin D deficiency. In the case of Leśniowski-Crohn disease, the deficiency is caused by inflammatory changes, including in the small intestine. This is due to the malabsorption of vitamin D from food by the intestinal mucosa, as well as the exclusion of certain foods from the patient’s diet. Another reason for the insufficient supply of vitamin D is the insufficient exposure of patients to sunlight due to their lifestyle [45].

The biologically active form of vitamin D maintains calcium homeostasis through its action in the intestines, bones, kidneys, and parathyroid glands [7]. The process of tumor formation begins when the balance between the cycle of cell birth and death is disturbed. Insulin is involved in the production of new cells, and vitamin D contributes to the death of cells. If the level of insulin is too high and the level of vitamin D is too low, the balance is disturbed. In such cases, cells multiply too quickly; the process of death of old cells is inhibited, which leads to the formation of neoplasms [7,19].

Calcitriol activity in neoplastic diseases results from the presence of the vitamin D receptor, including in the brain, breast, or colon cells [36]. The vitamin D receptor is present not only in cells and tissues involved in the regulation of calcium levels, but also in many others, including cancer cells [7]. Due to the participation of vitamin D in the processes of cell proliferation, differentiation, apoptosis, and angiogenesis, its importance in neoplastic diseases is emphasized [36].

Many studies have shown a relationship between vitamin D deficiency and the occurrence of certain cancers in the human body. Among them there are, for example, cancers of the colon, prostate, nipple, breast, as well as cancers of the bladder, head, neck, and lungs [10]. Epidemiological studies have reported lower incidence and mortality rates from several cancers in regions with higher solar exposure. These potential benefits of sun exposure have been attributed to vitamin D because solar radiation is necessary for the skin to synthesize vitamin D [7]. Both prospective and epidemiological studies indicate that 25-hydroxyvitamin D levels below 20 ng/mL are associated with a 30% to 50% increased risk of developing colorectal, prostate, and breast cancers and with higher mortality from these cancers [36].

Studies in breast cancer patients have shown that vitamin D levels were below normal when the disease developed. It was also found that vitamin D deficiency from food accelerated tumor growth [46]. A better prognosis in the case of neoplastic disease may result from increased expression of VDR, leading to a decrease in the invasiveness of cells and the risk of neoplastic metastases [36].

There is clear evidence that sun exposure increases the risk of developing all types of skin cancer, although it is also essential for vitamin D synthesis [47]. UV radiation has been recognized as an important carcinogenic factor causing cancer of the skin or lips. Researchers recommend avoiding prolonged exposure to the sun, leading to sunburn. It has been shown that people who get burns from short-term and intense exposure to the sun are more likely to develop skin cancer. The risk group also includes people with light-colored skin, hair, and eyes [48]. For this reason, it is necessary to protect the face and hands during prolonged exposure to the sun and use sun protection. It is also important to maintain the 25(OH)D level at about 20 ng/mL or higher. In many places around the world this is achievable even with brief periods of midday sun exposure in most seasons [47]. However, the relationship between the level of exposure to solar radiation and the development of various types of neoplasms is complex and perhaps depends more on the nature and duration of exposure than on the average exposure to this radiation [48].

Another disease related to vitamin D deficiency is obesity. There are several reasons that can lead to an insufficient level of vitamin D in obese people. The main reason for insufficient skin synthesis originates, among others, from the lifestyle of obese people. They tend to spend excessive time indoors, avoiding outdoor activity, thus limiting the possibility for the skin to synthesize vitamin D, which is the primary source of endogenous vitamin D. Exposure to the same dose of UVB radiation results in a 50% smaller increase in calcifediol concentration in obese people compared to people with a normal body weight [49,50].

Since vitamin D is stored in adipose tissue, its reduced bioavailability has been indicated as the second cause of low vitamin D levels in obese people [51]. The high amount of body fat in obese individuals serves as a storehouse of vitamin D. The increased amount of vitamin D necessary to saturate such a large store may therefore make obese individuals more likely to develop a serum 25(OH)D deficiency. Supplementation with vitamin D in obese people requires a double dose compared to what is recommended for people of the same age with a normal body weight [9].

All cells that build the skeleton (chondrocytes, osteoblasts and osteoclasts) contain both the vitamin D receptor and the enzyme CYP27B1 (1-alpha-hydroxylase) necessary for the production of the active vitamin D metabolite, 1,25-dihydroxyvitamin D [52]. Thus, bone itself is the main source of this vitamin’s active form [21].

The direct effect of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D on bone cells has been demonstrated. Calcium-phosphate homeostasis and the regulation of bone metabolism are closely related to skeletal mineralization. Maintaining this homeostasis is one of the basic functions of vitamin D [53]. Proper mineralization of bone tissue also requires an adequate supply of calcium and phosphorus, as well as undisturbed absorption of these substances in the gastrointestinal tract. In response to the decrease in serum calcium levels, its absorption in the gastrointestinal tract increases, as well as its reabsorption in the renal tubules. At the same time, calcium is mobilized from the bone through the increase in bone resorption over the coordinated function of osteoblasts and osteoclasts regulated by vitamin D [21].

In relation to the skeleton, a calcitriol deficiency can have very serious consequences early in life. Vitamin D deficiency results in abnormal bone mineralization, which in a later stage leads to the development of rickets in children, and in adults to disorders of bone metabolism, such as osteomalacia and osteoporosis [40]. The development of rickets in children associated with vitamin D deficiency is due to the low vitamin D content in breast milk and low sun exposure, especially in the first year of life. Also, deficiencies in the mother resulting from limited skin synthesis during pregnancy may result in vitamin D deficiency in the child [54]. In such children, vitamin D supplementation is recommended, including by feeding fortified milk. Formula-fed babies are less likely to develop vitamin D deficiency, and therefore are less at risk of developing rickets, as infant formula is often supplemented with vitamin D. Consumption of one liter of modified milk containing vitamin D covers the need for this vitamin [11].

Vitamin D deficiency especially affects the elderly and significantly increases the risk of falls, and therefore fractures, which are responsible for the increased morbidity and mortality of the elderly [55]. Vitamin D is credited with a significant anti-fracture effect, especially in the elderly. There is also a relationship between the level of vitamin D in the blood and physical fitness of adults [40]. A decreased level of 1,25(OH)₂D causes an increase in the concentration of parathyroid hormone in blood. PTH leads to an increase in bone turnover which results in loss of bone mass. Many epidemiological studies confirm that a higher level of vitamin D in the blood positively influences the increase of bone density. Bone health improvement also is caused by taking vitamin D supplements [56]. In order for vitamin D to have a beneficial effect on the skeletal system, minimizing the risk of falls and fractures, scientists suggest supplementation with vitamin D in the amount of 700–800 IU of cholecalciferol per day, and the concentration of 25(OH)D in the serum is best maintained at the level of 30 ng/mL [55].

Many studies confirm the relationship between vitamin D deficiency and the occurrence of mood disorders. Patients suffering from depression are in the group of people particularly vulnerable to vitamin D deficiency. This state may be caused by, among others, the diet of patients (not very diversified, poor in nutritional sources of vitamin D) or low activity, both social (avoiding leaving the house) and physical (most of the time is spent indoors) [31,57]. For example, seasonal affective disorders occur most often in winter, which is associated with lower exposure to sunlight, and thus lower levels of vitamin D in the body [58].

Those most at risk of developing depressive episodes associated with vitamin D deficiency include people with chronic somatic diseases, elderly patients, individuals with a history of depression, and pregnant patients [31]. Also, overweight and obese people are at risk of depressive disorders related to vitamin D deficiency [40].

A study conducted in 2010 on a group of 7358 people examining the relationship between the level of plasma vitamin D and the occurrence of depression showed that patients with vitamin D deficiency had a higher risk of developing depressive disorders compared to the group with normal plasma vitamin D levels [57]. Hoang at al. [6] also confirmed the positive effect of vitamin D₃ intake on reducing the risk of depression.

A number of studies have also been conducted to determine the effect of vitamin D₃ supplementation on the reduction of depression symptoms. In one of them, one group of subjects (overweight and obese) was supplemented with vitamin D₃ at a dose of 20,000 or 40,000 IU per week, while the other group took a placebo. There was a reduction in depressive symptoms in the group supplementing with vitamin D compared to the group that received a placebo. Another study conducted on a group of nine women (in good health) who took 5,000 IU per day for eight weeks also confirmed the positive effect of supplementation on the reduction of symptoms of depressive disorders [32]. The positive effect of vitamin D has also been demonstrated in studies on people who take supplementation with vitamin D₃ together with antidepressants. However, it is worth noting that the best results were obtained in patients with a significant vitamin D deficiency [31].

Vitamin D deficiencies are also associated with the risk of developing neurological diseases such as schizophrenia, Alzheimer disease, and cognitive impairment. Calcitriol acts in the brain via the VDR receptor, which is located in the hippocampus, hypothalamus, and cortex – that is, areas responsible for memory processes and cognition. The active form of vitamin D involved in the maturation and differentiation of neurons regulates the work of glial cells and stimulates the synthesis of neurotransmitters (e.g., dopamine), and has a neuroprotective effect [59].

For this reason, vitamin D may be associated with Parkinson disease, as the death of nerve cells responsible for the production of dopamine leads to this disease [12]. Vitamin D also has an antioxidant effect [60], contributing to the regulation of the toxicity of reactive oxygen species [61]. Research on the potential influence of vitamin D on Parkinson disease is carried out in the context of increased expression of the vitamin D receptor gene in the blood of patients with Parkinson disease. Reduced serum levels of the major metabolite of vitamin D, total 25-hydroxyvitamin D, in serum have been observed in several cross-sectional studies in patients with Parkinson disease and were more pronounced than in those with Alzheimer disease. However, it was not established whether vitamin D deficiency was related to the severity of the disease. It was found that 25(OH)D₃ attenuated the neurotoxicity of 6-hydroxydopamine, and many studies have shown an association between VDR gene polymorphisms and Parkinson disease [62].

Numerous studies confirm insufficient vitamin D levels in Alzheimer patients compared to the control group [10,12]. Studies on the effects of vitamin D on the development of Alzheimer disease indicate that this hormone is a neurosteroid that may be important in the aging process and in age-related cognitive decline. Vitamin D deficiency may be associated with an increased risk of Alzheimer disease and dementia, without being a causative factor [7]. Cognitive dysfunction and Alzheimer disease mainly affect the elderly, in whom vitamin D deficiency results both from a weakened ability to synthesize vitamin D from the sun and from a reduced supply from the diet. Reduced skin synthesis in the elderly is caused by skin thinning and deficiency of vitamin D precursor (7-dehydrocholesterol). Reduced food intake, caused by chewing, biting and swallowing problems, often affecting the elderly, contributes to the improper supply of vitamin D from food in the elderly [59].

Although it is not clear if vitamin D deficiency promotes the development of viral and bacterial diseases, there is no doubt that lower levels of vitamin D in the blood have been found in patients with hepatitis [63], influenza [64], tuberculosis [65], and COVID-19 [66].

Interestingly, the winter increase in influenza infections correlates with seasonal blood vitamin D levels, and supplementation of vitamin D reduced the risk of developing respiratory tract infections [67, 68]. Bergman et al. [69] demonstrated that the optimal dose of vitamin D was 1000 – 4000 IU/day, especially in those living above 40 degrees latitude. Berry et al. [8] in a cohort study analysis (n= 6789) showed that each 2.5 ng/mL increase in 25(OH)D was associated with a 7% lower risk of respiratory infections. However, a meta-analysis of 15 randomized controlled studies analyzing the effect of vitamin D supplementation on the risk of developing respiratory tract infections showed no significant risk reduction [70]. Since the heterogeneity among included studies was high in the above-mentioned meta-analysis, the obtained results should not be used to deny the potential benefits of vitamin D supplementation [53], especially since in a mouse model it has been confirmed that 25(OH)D₃ supplementation reduces influenza virus replication [71].

Since COVID-19 is a new disease, we are not sure if vitamin D can decrease the risk of this infection, so the calls for vitamin D supplementation are without support from human studies, but rather are based on speculations about presumed mechanisms [72]. What is known is that 25(OH)D suppresses the cytokine storm responsible for most COVID-19 deaths [73]. Meltzer et al. [74] achieved noteworthy results in their cohort study (n=489) showing that patients with an insufficient level of vitamin D in the blood had a 77% greater relative risk of being tested positive for COVID-19 when compared with those with sufficient vitamin D status. Moreover, vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls [75]. Furthermore, the severity of clinical outcomes from COVID-19 and mortality were reduced in patients who were vitamin D sufficient [76]. Maghbooli et al. noted that two-thirds of the 235 hospitalized patients had less than 30 ng/ mL of vitamin D in their blood and only 6.3% at least 40 ng/ mL. Besides, 9.7% and 20% who died had a 25(OH)D level above and below 30 ng/mL respectively [76].