VITAMIN D FACTS. BRIEF REVIEW.
The sequential metabolic processes which convert inactive pro-hormone (Vitamin D) to Active form called Vitamin D endocrine system. The key elements of this system are photo-conversion, the liver, the kidney as an endocrine gland, the vitamin D receptor (VDR) and the vitamin D binding protein (VDBP).
Vitamin D is then transported to the liver where it’s hydroxylated by an enzyme (CYP2R1) to produce 25(OH)D (25-hydroxyvitamin-D). 25(OH)D is then transported to the kidneys where it’s hydroxylated by another enzyme (CYP27B1) to produce 1,25OH2D (1,25- dihydroxyvitamin-D). Many cells outside the kidneys contain VDR and express CYP27B1 (the enzyme that catalyzes 25(OH)D to 1,25(OH)2D).
The vitamin D receptor (VDR), nuclear receptors, transduce hormonal signals from the immediate environment and transactivate genes in response to these signals .VDR has been identified in 37 different tissues throughout the body (including the nucleus of phagocytic cells of the immune system)
The most important function of 1,25(OH)2D is to bind to the VDR nuclear receptor and mediate the transcription of DNA, triggered by signaling proteins
The effects of 1,25(OH)2D are pleiotropic;
Most dividing cell types, normal and malignant, can express VDR and respond to 1,25(OH)2D.
VDR- activated genomic expression mediates many tissue-specific biological effects. Classical effects (e.g., calcium transport and bone health, etc.) and Non-classical, extra-skeletal effects (cell differentiation, central nervous system, skin/hair, immune regulation, hormone secretion, etc.).
In addition to the classical VDR-mediated genomic pathway, 1,25(OH)2D also has been shown to elicit rapid responses that occur within a few minutes after hormone treatment and are considered too rapid to be explained by a VDR-mediated genomic pathway. These rapid responses are mediated by a direct action of 1,25(OH)2D on the plasma membrane of target cells stimulating a signal transduction pathway involving the rapid opening of voltage- sensitive Ca2+ channels and activation of protein kinases.
VDR are present in most cell types of the immune system, particularly in antigen- presenting cells (APCs) such as monocyte, macrophages and dendritic cells. The influence of 1,25(OH)2D on the immune system is one of its most important roles. In general, the innate system is enhanced and the adaptive system is inhibited by 1,25(OH)2D. The innate system is suppressed by 25-OH and the adaptive system is stimulated by 1,25(OH)2D.
1,25(OH)2D activates the VDR to express antimicrobial peptides (AMPs) such as cathelicidin and beta defensins which attack pathogens. Recently, 1,25(OH)2D-induced autophagy has been reported (autophagy contributes to anti-aging, antimicrobial defense, and tumor suppression). VDR immune system regulation also involves cell proliferation, differentiation and apoptosis. The VDR is also expressed in both B and T white blood cells (lymphocytes)
In monocytes and macrophages (innate immune system), synthesis of 1,25(OH)2D from 25(OH)D promotes an antibacterial response to infection. Monocytes sense pathogen-associated molecular patterns (PAMPs) by utilizing pattern-recognition receptors (PRR), such as toll-like receptors (TLRs). Induction of CYP27B1 occurs following PAMP-sensing by TLR2/1. The inflammatory cytokine interferon γ (IFNγ) also stimulates expression of CYP27B1 by macrophages. As a result, 1,25(OH)2D production is increased in response to a pathogen immune challenge.
1,25(OH)2D modulates the adaptive immune system by inhibiting dendritic cell maturation, reducing T helper (Th) cells, and shifting Th1/Th17 cells to the Th2 and T regulatory pathways. In addition, 1,25(OH)2D inhibits Th1 cytokines that support cell-mediated immunity and promotes Th2 cytokines that support humoral immunity (antibodies circulating in bodily fluids). The immune response is heavily dependent on the vitamin D endocrine system, performing a balancing act of inflammation/anti-inflammation.
There is no consensus on the definition of vitamin D deficiency or insufficiency and authorities haven’t agreed on the significance of low 25(OH)D.
The Institute of Medicine (IOM) report emphasized that the current measurements, or cut-off points, of sufficiency and deficiency of 25(OH) D in use by laboratories have not been set using rigorous scientific studies. The IOM report emphasized that the current measurements, or cut-off points, of sufficiency and deficiency of 25(OH) D in use by laboratories have not been set using rigorous scientific studies. They suggest that since no central authority has determined which cut-off points to use, reports of deficiency and lab ranges may be skewed and numbers overestimated. Most importantly, 25(OH)D may not always reflect the level of 1,25(OH)2D (the active metabolite).
Researchers in Denmark measured the baseline serum 25(OH)D and total cholesterol levels of 182 fair-skinned and dark-skinned subjects; and studied the effect of UV radiation on their serum 25(OH)D levels. They found the amount of serum 25(OH)D produced was determined by the amount of cholesterol in the skin, not on skin pigmentation. Most importantly, skin pigmentation doesn’t negatively affect vitamin D status. Persons with dark skin compensate for low 25(OH)D by rapidly converting it to the active 1,25(OH)2D metabolite, thus allowing them to maintain adequate vitamin D status. Matsuoka et al concluded that while racial pigmentation has a photo-protective effect, it does not prevent the generation of normal levels of active vitamin D metabolites. The concern about dark skin and vitamin D deficiency appears to be misplaced. ample opportunities exist to form vitamin D (and store it in the liver and fat) from exposure to sunlight during the spring, summer, and fall months even in the far north latitudes.
Our bodies have mechanisms for preserving the vitamin D we acquire during the summer; which have evolved to stabilize and maintain serum levels of vitamin D in environments with variable vitamin D availability. The Vitamin D Binding Protein (DBR) optimizes and stores 25(OH)D for later use; it also binds 1,25(OH)2D, as well as the parental vitamin D itself. DBP sequesters vitamin D sterols in the serum, prolongs their serum half-lives, and provides a circulating store of vitamin D to meet transient periods of deficiency. In so doing, DBP helps to prevent the development of severe vitamin D deficiency.
Clothing is a barrier to ultraviolet radiation but this is an issue only for people who cover themselves from head to toe (e.g., woman who wear a burka may not be exposed to sufficient sunlight). It takes relatively little sunlight exposure to acquire adequate stores of vitamin D and few people wear enough clothes to prevent that from happening. Ten to 15 minutes of sunlight or daylight exposure to a small area of skin (e.g., the forearm or face, etc.) twice a week (without sunscreen) supplies all the vitamin D necessary for health. Evidence for a beneficial effect of vitamin D supplementation in cancer is lacking. The findings of a large prospective study in 2008 do not support the claim that vitamin D is associated with decreased risk of prostate cancer; in fact, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. The Women’s Health Initiative (WHI) Calcium plus Vitamin D Supplementation Trial, published in November 2013, concluded that after an average of 11 years, calcium and vitamin D supplementation did not decrease colorectal cancer incidence.
Adequate vitamin D is essential to prevent rickets, but adequate calcium is equally important; if either calcium or vitamin D is deficient, bone health suffers. Rickets is rare in the developed world; however, children in developing countries, who usually photosynthesize enough vitamin D from sunlight, develop rickets if poverty prevents them from eating enough calcium rich food. Studies found rickets occurs in sunny countries due to poor calcium intake and is cured with increased calcium ingestion.
Osteoporosis is a bone disease characterized by a decrease in bone mineral density and the appearance of small holes in bones due to loss of minerals. Vitamin D is an important factor in maintaining bone health to avoid osteoporosis. Precise maintenance of the physiologic levels of both extracellular and intracellular ionized calcium is essential to life; 1,25(OH)2D maintains calcium homeostasis between blood, cells and bones by stimulating calcium absorption from the intestines, reabsorption in the kidneys, and resorption in bones. 1,25(OH)2D up-regulates VDR in the small intestine, which then transcribes genes that shuttle calcium and phosphorus through the intestinal epithelium. However, mucosal response and calcium/phosphorus absorption is dependent on a competent VDR and elevated 1,25(OH)2D reduces VDR competence. Thus, calcium and phosphorus absorption may be inhibited if VDR function is impaired by elevated 1,25(OH)2D. This is illustrated by a study of Crohn’s patients with elevated 1,25(OH)2D and low bone mineral density which concluded that treatment of the underlying inflammation would improve metabolic bone disease.
Vitamin D supplementation is ill- advised above a threshold of 30ng/ml 25-D. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin-D status is reported in a wide range of disorders. It would be wiser to seek reasons underlying the low vitamin-D level, such as inflammatory processes. Elevated 1,25(OH)2D leads to bone loss. When levels are above 42 pg/ml 1,25(OH)2D stimulates bone osteoclasts. This leads to osteoporosis, dental fractures and calcium deposition into the soft tissues: lungs, breasts, muscle bundles, kidneys. An earlier study warned, “Vitamin D is a toxic compound, and excessive amounts can cause soft-tissue calcification. There is a narrow leeway between the amount required and that initiating tissue damage.” Combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health. This significant evidence regarding bone loss should motivate medical practitioners and researchers to measure both 25(OH)D and 1,25(OH)2D to determine vitamin D status.
Autoimmune diseases: An alternate hypothesis posits a bacterial etiology in which a persistent intracellular infection causes a cytokine release that induces signals to T cells and B cells, and the antibodies they produce (to the intracellular invader) include some that attack human proteins, as well as target the pathogens. In other words, when an innate immune system is forced to respond to a persistent infection, the resulting cascade of chemokines and cytokines will also stimulate an adaptive response. Vitamin D has a positive effect on autoimmune disease because it reduces symptoms via immune system suppression. For example, abnormal T cell reactivities in MS patients were reduced with vitamin D supplementation; serum 25(OH)D levels after 12 months were increased to 71.7 ng/ml ± 39 ng/ml. Vitamin D inhibits pro-inflammatory processes by suppressing the enhanced activity of immune cells that take part in the autoimmune reaction.
Exposure to ultraviolet light, especially UV-B wavelengths, can impair immune responses in animals and humans. Thus, seasonal variation can have an impact on the immune response; in the summer, when vitamin D3 is highest, 1,25(OH)2D down-regulates the immune system. Reduced immunity following exposure of skin to UV radiation may explain the positive latitude gradient measured for a number of autoimmune diseases (decreased incidence of disease with residence at lower latitudes). Unfortunately, some researchers believe immunosuppression is the best form of treatment for autoimmune disease. Vitamin D proponents have failed to recognize the immunosuppressive effect of elevated 25(OH)D and to acknowledge that immunosuppression is contraindicated in the presence of infection. As a result of vitamin D immunosuppression inflammation, clinical disease markers and symptoms of autoimmune disease are reduced but this doesn’t treat the underlying cause and relapse is common.
Verway et al. wonder, “Is a specific pathogen responsible for disease or rather is a dysregulated immune response generated against a complex microbial population? Why would immune-suppressive drugs be efficacious if the primary defect is an immune deficiency?”
The suppressed immune system enables chronic infection and inflammation. Intracellular bacteria are able to persist and proliferate in host phagocytes, successfully compete for nutritional resources and displace commensal organisms from their niche. The result is chronic illness.
There is a positive role for vitamin D in bone health but not in other health outcomes. Genetic findings in those predisposed to longevity cast doubt on whether low levels of vitamin D cause age-related diseases and mortality. A study concluded that vitamin D supplementation did not reduce knee pain or cartilage volume loss in patients with symptomatic knee osteoarthritis. Subjects supplemented with high doses of vitamin D saw no improvement in serum lipids, HbA1c, or HS-CRP. Supplementation did not significantly reduce the incidence or duration of upper respiratory tract infections. In a study of older adults, the decline in physical performance and strength was not associated with 25(OH)D.
Vitamin D deficiency or insufficiency can occur in certain situations. Genetic defects in the VDR may result in vitamin D deficiency; a number of mutations have been identified that lead to hereditary vitamin D resistance. Disorders that limit vitamin D absorption and conditions that impair conversion of vitamin D into active metabolites may cause deficiency. Sick or elderly people who rarely go outdoors and have poor diets are also at risk.
Decreases in vitamin D levels are a marker of deteriorating health. Inflammation is the common factor between most non-skeletal health disorders and low 25(OH)D concentrations.
Increases in 25(OH)D have no effect on inflammatory processes or on disorders at the origin of these processes.