21. In the 21st century, despite all the advancing health technology and nutrition industry, vitamin D deficiency is spreading as a silent epidemic. Contrary to popular belief, vitamin D deficiency can lead not only to bone disease, but also to many systemic diseases such as cancer, autoimmune diseases, infectious diseases, rheumatic diseases, neurological diseases and heart diseases.
There are 5 known forms of vitamin D: D1 (ergocalciferol with lumisterol), D2 (ergosterol with ergocalciferol), D3 (cholecalciferol), D4 (22 dihydrocalciferol), and D5 (cytocalciferol). Among these, vitamins D2 and D3 were found in the 1930s. (1)
VITAMIN D METABOLISM
Cholecalciferol and ergocalciferol, which are biologically inactive precursors of vitamin D, are converted to their active forms in the liver and kidney. Both forms of vitamin D, which are taken with food or synthesized in the epidermis with the effect of UVB, are transported to the liver via vitamin D binding proteins after they circulate. Vitamin D is hydroxylated to form 25 hydroxyvitamin D (calcidiol) in hepatocytes. Serum 25 hydroxyvitamin D (calcidiol) level rises when plenty of sunbathing or food-borne vitamin D is taken. 25 hydroxyvitamin D (calcidiol) best reflects circulating vitamin D. In the kidney, the second major hydroxylation reaction takes place with the enzyme 25 hydroxyvitamin D 1 alpha hydroxylase and converts 25 hydroxyvitamin D to 1,25 dihydroxyvitamin D (calcitriol). The production of 1,25 dihydroxyvitamin D (calcitirol) in the kidney is regulated by numerous factors, including serum phosphorus, calcium, parathormone (PTH), fibroblast growth factor 23 (FGF-23) and calcitriol itself. Although the main source of 1 alpha hydroxylase activity is kidney, 1,25 dihydroxyvitamin D is produced extrarenally in skin, parathyroid gland, breast tissue, colon, prostate, immune system and bone cells. Most of the physiological effects of vitamin D2 in the body are related to the activity of 1,25 dihydroxyvitamin D. (2,3,4)
FORMS OF VITAMIN D
Vitamin D2 (Calciferol, Ergocalciferol): A provitamin of plant origin, ergosterol is taken in foods and collected in the skin. With the effect of UVB, it is converted to ergocalciferol in the stratum basale and stratum spinosum layer of the skin. This substance enters the hydroxylation reaction in the liver and kidneys.
Vitamin D3 (Cholecalciferol): It is partially taken with animal foods and synthesized in the body. It is a hormone analog precursor, not a true vitamin. After a two-step bioactivation, cholecalciferol is converted to calcitriol, the most active form of vitamin D, 1,25-dihydroxycholecalciferol.
Most, if not all, vitamin D activity is mediated by a nuclear transcription factor known as the VDR (vitamin D receptor). 1,25 dihydroxyvitamin D enters the cell nucleus and associates with the VDR, and another nuclear receptor called the retinoic acid X receptor (RXR) reinforces this association. In the presence of 1,25 dihydroxyvitamin D, the VDR/RXR complex binds to small sequences of DNA called vitamin D responsive elements (VDRE) and initiates molecular interaction reactions that modulate the transcription of many specific genes. Thousands of VDREs have been identified over the genomes, and VDRs activated by 1,25 dihydroxyvitamin D are thought to directly or indirectly regulate 100 to 1250 genes. (5,6)
In the past, vitamin D was known only as a vitamin that strengthens bone and muscle structure, but according to the results of recent studies, VDRs can affect brain, heart, stomach, pancreas, lymphocytes, prostate, breast, colon, It has been shown to be found in the skin and gonads, intestines and many organs. Vitamin D deficiency with or without VDR gene damage causes cell differentiation, oxidation disorders, T cell differentiation, and many diseases, including tuberculosis, infectious diseases, asthma, diabetes, cancer, rheumatic diseases, autoimmune diseases, myocardial infarction, allergic diseases and autism. constitutes a risk factor for (7)
While estrogen increases the VDRs and renal-1 hydroxylase activity of estrogen and testosterone hormones, testosterone decreases (or does not affect) causes many chronic diseases to be seen more in men and less in women. (8). On the contrary, UVA reduces the synthesis of vitamin D. Ultraviolet (UV) rays are divided into 3 main types according to their wavelengths: UVA, UVB and UVC (280 – 100 nm). (9)
Short Wavelength Rays (UVB) (315 – 280 nm): These are the rays that are easily dispersed behind the glass in cloudy weather and cannot cross the obstacle sufficiently. If you sunbathe behind a window, you’ll turn brown, but you can’t synthesize enough vitamin D because you don’t get enough UVB. In order for UVB to reach its target, it must come to the atmosphere in the open air and must not encounter any other physical factors. The best synthesis of vitamin D occurs at noon. When UVB rays come into contact with the skin, cholecalciferol (D3) is first formed from 7-dehydrocholesterol in the stratum basale and stratum spinosum layer of the skin. UVB rays do not cause much pigmentation and have an anticarcinogenic effect. (10)
Long Wavelength Rays (UVA) (400 – 315 nm): These are the rays that do not get caught in obstacles and do not scatter and reach the target easily. By stimulating the melanin cells in the skin, it increases the aging of the skin along with tanning. Tanning reduces the synthesis of vitamin D by preventing the contact of UVB rays with the skin. At the same time, UVA (unlike UVB) breaks down cholecalciferol synthesized in the skin and impairs vitamin D synthesis. In other words, when sunbathing during the hours when the sun’s rays are lying down, the tanning is mostly caused by the effect of UVA rays, but vitamin D levels remain low. UVA rays increase free radicals in the skin and cause skin cancer by causing DNA damage. These radicals also accelerate aging and skin wrinkling. (10)
EFFECTS OF CALCITRIOL
Calcium Balance: Keeping serum calcium levels within a certain and narrow range is vital for bone development and density, as well as for the normal function of the nervous system. Vitamin D is essential for the use of calcium by the body. (1) 1
Parathyroid glands are sensitive to serum calcium level and secrete parathormone (PTH) when calcium level decreases. The elevation of PTH activates the 1 alpha hydroxylase enzyme in the kidney, increasing the production of 1,25 dihydroxyvitamin D. Increased 1,25 dihydroxyvitamin D, VDR activation and increased intestinal calcium absorption; It increases the reabsorption of calcium from the kidneys and provides gene expression that will ensure the release of calcium from the bone. The aim is to keep the blood calcium level in balance. (2,3,19)
Phosphorus Balance: The regulation of calcium and phosphorus is very related to each other. PTH and 1,25 dihydroxyvitamin D control serum phosphorus. 1,25 dihydroxyvitamin D increases phosphorus absorption by sodium-phosphate cotransport from the small intestines. When PTH is increased, it increases urinary excretion by decreasing phosphorus reabsorption from the kidneys. However, it is not known exactly how 1,25 dihydroxyvitamin D directly affects renal phosphorus transport; Fibroblast growth factor (FGF-23), a phosphaturic hormone synthesized from osteoblasts, decreases the synthesis of 1,25 dihydroxyvitamin D by inhibition of 25 dihydroxyvitamin D-1 alpha hydroxylase. (20)
Cell Differentiation: Cell differentiation: Cells divide rapidly and increase their number (proliferation). The fact that cells take on special tasks is called differentiation. As the cells differentiate, the proliferation rate slows down. Thus, balance is achieved. Proliferation is a useful process, but if left unchecked, it causes diseases such as cancer. 1,25-dihydroxyvitamin D stimulates differentiation while controlling proliferation and prevents the formation of cancer (1, 9)
Immunity:1,25 dihydroxyvitamin D is a powerful immune modulator(3). The vitamin D receptor is found on most immune cells, particularly on T cells and antigen presenting cells (dendritic cells, macrophages). In some cases, macrophages can form calcitriol from calcidiol. While calcitriol strengthens the natural immunity, it also prevents the development of autoimmune diseases. (11)
Insulin Secretion: VDR is also found in insulin-secreting pancreatic cells (beta cells), and in vitro studies show that 1,25 dihydroxyvitamin D plays a role in insulin secretion against the increasing insulin demand. Vitamin D deficiency can lead to the development of type 2 diabetes by reducing insulin secretion. (12)
Heart Disease and Hypertension: 1,25 dihydroxyvitamin D, the active form of vitamin D, decreases renin activity, which raises blood pressure. 1,25 dihydroxyvitamin D found in the smooth muscle cells of the vessels reduces muscle cell growth, inflammation and thrombosis. Hypertension exacerbates the negative effects of vitamin D deficiency on the heart. The reverse is also true; Vitamin D deficiency itself causes hypertension. (13,14)
RISK FACTORS FOR VITAMIN DEFICIENCY (15)
Environmental and cultural factors play different roles in vitamin D change:
1- Climatic Factors: Less sunlight Northern countries
2- Dressing styles: Central Asian women wearing black chador
3- Sun protection methods
4- Overly protected newborns
Vitamin D There are many biological factors affecting the synthesis, absorption and metabolism of:
1- Pigmentation of the skin
2- Genetic diversity
3- Aging
4 – Chronic Kidney Disease
5- Fat Malabsorption Syndromes
6- Inflammatory Bowel Diseases
7- Obesity
8- Magnesium deficiency
VITAMIN D LEVELS
The indicating parameter is 25-hydroxy cholecalciferol (calcidiol) stored in the liver. Normal values are considered 30-110 ng/mL. The most active vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), does not show vitamin D stores. The Ministry of Health of the Republic of Turkey recommends 400 IU of vitamin D daily until the age of 1 year. However, according to the results of many studies conducted in the USA, the recommended dose is between 4000-10000 IU per day. Adults can take 5000IU (up to 40 drops of vitamin D) daily, or they can also meet their needs by drinking 1 ampoule of vitamin D of 300,0000IU. Storage vitamin D has been shown to be safe. (16)
For the prevention of vitamin D deficiency: 400IU/day for infants under 1 year old; 1-70 years old 600 IU/day; Over the age of 70, 800 IU/day of vitamin D should be given. This dose should be increased in additional diseases.
For the treatment of vitamin D deficiency: 2000IU/day in children or 50,000IU once a week (6 weeks); Adults 6000IU/day or 50,000IU once a week (8 weeks); In the presence of systemic diseases, 6000-10.000IU/day and more is recommended depending on the situation.
VITAMIN D DEFICIENCY RELATED DISEASES (15)
Osteoporosis, cancer (colorectal cancer, breast cancer and other cancers), autoimmune diseases (MS, type 1 DM, rheumatoid arthritis, SLE), cardiovascular system diseases (Hypertension, endothelial dysfunction), type 2 DM, neurodegenerative diseases (Parkinson, alzheimer’s), acute respiratory system diseases, atopic dermatitis, irritable bowel syndrome…
VITAMIN D DEFICIENCY IN TERMS OF COMPLEMENTARY MEDICINE
The fact that the deficiency of a vitamin, which has an abundant source, is both taken with food and is synthesized endogenously, the sun’s light is sufficient for its synthesis (even though there are certain conditions), and even high doses are safe, is associated with such a wide range of diseases, is another system that has been ignored. or systems should think.
Today, the common dysfunction that can develop under almost all chronic diseases for different reasons is dysbiosis. The second most common condition following dysbiosis in chronic diseases is latent acidosis. Both dysbiosis and latent acidosis cause vitamin D deficiency for different reasons. In the presence of dysbiosis, the impaired permeability of the intestinal mucosa, which hosts the intestinal flora, cannot ensure adequate absorption of vitamin D. The inability to absorb vitamin D from the intestines is one of the most important causes of deficiency. Latent acidosis, which develops due to dysbiosis or other additional reasons, causes dysfunction in the hydroxylation steps of vitamin D with the mineral imbalance that occurs during the compensation of the buffer systems. At the same time, in the presence of latent acidosis, the body provides calcium by using all its resources to bind acid metabolites and compensate for the acid load, and calcium deficiency occurs. However, the absorption of vitamin D, especially from the small intestines, depends on calcium (this is the main task of parathormone). Calcium deficiency in latent acidosis causes vitamin D deficiency in this way. (17,18, 21, 22)
For many years, many studies have been conducted and are still being conducted on multicenter and very large patient groups related to vitamin D metabolism. Another common point of these studies is that the intestinal absorption surface, intestinal flora and latent acidosis were not examined in any case. As in our approach to all chronic diseases, the aim is to re-establish the infrastructure in which the body can regulate itself. For this, it is necessary to correct the latent acidosis, clean the connective tissue and balance the intestinal flora. If there is still a deficiency at the end of this process, the replacement therapy will provide an effective treatment.
