Protean Manifestations of Vitamin D Deficiency, Part 1

The Epidemic of Deficiency

David S.H. Bell, MB


South Med J. 2011;104(5):331-334. 

In This Article

Physiology of Vitamin D

Vitamin D works like a hormone because it is produced primarily in one organ (the kidney) before circulating through the bloodstream to organs where it has wide-ranging effects.[1] External sources of vitamin D are foods such as cheese, butter, margarine, fortified milk, fish, fortified cereals, and vitamin supplements.[2] However, the majority of vitamin D comes not from the diet but from manufacture in the dermis when the skin is exposed to solar ultraviolet (UVB) (290–315 mm) light. Through this exposure, which has photochemical and thermal effects, cholecalciferol (vitamin D3) is manufactured from 7-dehydrocholesterol. Unlike excess oral intake overexposure to sunlight cannot cause vitamin D toxicity because UVB also converts any excess vitamin D3 to inert isomers.

Vitamin D3 is hydroxylated in the liver to 25-hydroxy-vitamin D3, and in the kidney and other tissues. 25-OH-vitamin D3 is further catalyzed by the enzyme 1α hydroxylase to its active form 1-25-OH-vitamin D3. 1-25-OH-vitamin D3 penetrates the cell membrane entering the cytoplasm of the cell from which it crosses into the nucleus to attach to its receptor.[3] Receptors for 1-25-OH-D3 are situated in the nuclei of cells of multiple organs and activation of these receptors results in an increased expression of more than 200 genes, all of which increase the expression of CYP27B1. This can also be increased by immune inputs, such as those from Toll-like receptor signaling. The result of CYP27B1 expression, whether due to 1-25-OH vitamin D or an immune input, is the production of the intracellular proteins, which are ultimately responsible for the protean actions of 1-25-OH vitamin D.[4]

The classic effect of vitamin D activity is in the gastro-intestinal tract where 1-25-OH vitamin D is a key component of calcium homeostasis through regulating calcium absorption. When serum calcium drops, the calcium receptor on the parathyroid gland is activated, which increases the production and release of parathyroid hormone (PTH). PTH has both an instantaneous and extended effect. The instantaneous effect occurs through activation of the PTH receptor in bone, which rapidly mobilizes calcium so that hypocalcemia and its manifestations are avoided. The extended effect of PTH is to replenish the calcium pool by increasing the conversion of 25 to 1-25-OH vitamin D in the kidney, which through activation of the 1-25-OH vitamin D receptor in the intestine increases calcium absorption.[1]

Defining Vitamin D Deficiency

Because of the long half-life of 25-OH vitamin D, its level is used to assess vitamin D deficiency. The active form of vitamin D, 1-25-OH vitamin D, will if renal function is normal, almost always be in the normal range even when severe vitamin D deficiency is present.[2] Normal 25-OH vitamin D levels are enjoyed by those who work outdoors; levels between 42 and 65 ng/mL have been documented.[5] Humans originated in equitorial East Africa, where in an unclothed state they received year-round sun exposure. An East African tribe, the Masai, have 25-OH-vitamin D levels in the 50–80 ng/mL range, which may be assumed to be a normal range. However, if a normal level is based on two standard deviations in a modern Western society, then an abnormal 25-OH-vitamin D level is below 10 ng/mL.

Based on its biological effects, a normal 25-OH vitamin D level is ≥30 ng/dL. Insufficiency is defined as a 25-OH vitamin D level of 20–29 ng/dL, deficiency as a 25-OH vitamin D level of 10–19 ng/dL, and severe deficiency as a 25-OH vitamin D level of <10 ng/dL (Table 1).[6] Based on PTH levels the World Health Organization (WHO) defines vitamin D deficiency as a serum 25-OH vitamin D of <20 ng/dL and insufficiency as a 25-OH vitamin D level of <30 ng/dL.[7] Unfortunately, many studies have shown large variations in PTH levels when 25-OH vitamin D levels are clearly in the deficient range as well as when intestinal calcium absorption is decreased.[8,9]

Causes of Vitamin D Deficiency

While vitamin D deficiency may occur due to decreased vitamin D intake or to malabsorption such as that which occurs with hepatic, pancreatic, and celiac diseases, the major cause of vitamin D deficiency is inadequate sun exposure. Decreased sun exposure is caused by avoiding sunlight, by covering the skin with clothes, or by utilizing sunscreens.[10] Exposure to sunlight is also governed by one's occupation or geographic location. In winter months humans, no matter how fair skinned, cannot manufacture vitamin D at latitudes above 35°N; and at any time of year the ability to manufacture vitamin D is inversely proportional to both the degree of skin pigmentation and age.[11,12] For example, African Americans tend to have lower 25-OH vitamin D levels than Americans of European origin.[13] Historically only fair-skinned people could survive at higher latitudes because of the their ability to manufacture sufficient vitamin D3. The exception to this rule is the dark-skinned Inuit people, who survived because of a high dietary intake of vitamin D from fish and animal livers. With aging the ability of skin to manufacture vitamin D declines, so that by age 65 the capacity to produce vitamin D3 is reduced by 75%.[12]

In modern times, especially in the Western world, the most common cause of vitamin D deficiency is obesity. This is because vitamin D is a fat-soluble vitamin that in obese people, even with adequate sunlight exposure and dietary intake, becomes sequestered in adipose tissue, where it is ineffective.[14,15]

Who Has Vitamin D Deficiency?

Worldwide, vitamin D deficiency is estimated to be present in more than 1 billion people. Somewhere between 40 and 100% of US and European elderly adults have also been shown to be vitamin D deficient. Even in Hawaii, where the average sun exposure is 11 hours per week, 50% of adults are deficient in vitamin D, probably due to skin pigmentation and obesity. In the National Health and Nutrition Survey between 25% and 57% of Americans were vitamin D deficient, and in a hospital survey 57% of patients and 20 to 51% of internal medicine residents were vitamin D deficient.[16–18] Vitamin D deficiency is also present in 24% of adolescents and 32% of young adults. A total of 9% of US children are vitamin D deficient and 61% have vitamin D insufficiency.[19,20] Risk factors for vitamin D deficiency in US children include being African American or Latino, being older, having a poor intake of milk, and spending more than four hours per week watching television or playing video games.[19] Vitamin D deficiency has also been shown to be present in 47.8% of lactating and 50% of postmenopausal women.[21,22]

The major reasons for the increased prevalence of vitamin D deficiency, when compared with earlier studies in the United States, are decreased milk consumption, decreased exposure to sunlight, increased numbers of non-European races, and particularly, the increase in the prevalence of obesity.[23] Vitamin D deficiency is also more prevalent when chronic diseases are present; for example, 87% of people with HIV and 86% of those with chronic kidney disease have vitamin D deficiency.[24]

Vitamin D Deficiency and Pregnancy

Worldwide prevalences of vitamin D deficiency during pregnancy range from 18% to 84%, depending upon the distance from the Equator and the percentage of skin covered by clothing.[25] In the United States the prevalence is lower (between 5% and 50%) but is much higher in African American women (54.1% versus 29.2%) and these prevalences persist even when prenatal vitamins have been utilized.[26] As would be expected with the high prevalence of vitamin D deficiency in African American mothers, their offspring at delivery have a higher prevalence of vitamin D deficiency (45.6% versus 9.7%). Gestational vitamin D deficiency has also been associated with low birth weight and reduced fetal bone mineral content[27,28] and an increased risk of preterm labor, preterm birth, infections, and severe eclampsia.[29–31] Gestational vitamin D deficiency has also been associated with increased wheezing in the offspring during the first years of life.[31] Furthermore, the presence of autoantibodies to the insulin-producing beta cell of the pancreas in newborns is inversely associated with maternal vitamin D intake, which may be why childhood vitamin D supplementation has been shown to decrease the incidence of type 1 diabetes.

In most infants vitamin D stores acquired in utero are depleted by eight weeks. Babies who are breast-fed, compared with those who are formula-fed, are at increased risk of vitamin D deficiency because human breast milk contains minimal vitamin D, and 47% of untreated lactating women become vitamin D deficient.[22,32] Because of the high risk of vitamin D, deficiency in breast-fed infants the American Academy of Pediatrics has recommended that exclusively breast-fed infants be supplemented with 200 IU of vitamin D daily beginning after birth and maintained through childhood and adolescence.[33]

Rickets, Osteomalacia and Beyond

In the 17th century both Whistler and Glisson described rickets, which was characterized by growth retardation, bending of the spine, deformities of the legs, and weak, toneless muscles, using autopsy studies that showed impaired mineralization of the epiphyseal growth plate cartilage.[34] In 1919, the cause of rickets was identified by Sir Edward Mellanby as being due to vitamin D deficiency.[35] Subsequently, decreased mineralization of newly formed bone (osteomalacia) in adults was also shown to be due to vitamin D deficiency and was classified as being a mild form of rickets.

Like bone, multiple organs have nuclear 1-25-OH vitamin D receptors, these organs can be adversely affected by vitamin D deficiency. A classic example is fractures in elderly adults. The amount of osteoporosis is increased, which corresponds to an increase in vitamin D deficiency-induced neuromuscular dysfunction and thus an increase in falls and fractures. A meta-analysis of six studies of vitamin D supplementation in the elderly showed that a daily intake of 800 IU of vitamin D per day resulted in a significant reduction in the frequency of falls.[36]

Beyond Rickets and Osteomalacia

Other important activities of 1-25-OH vitamin D through its nuclear receptors are regulation of cell growth and modulation of the immune system. 1-25-OH-vitamin D regulates the growth of both normal and neoplastic cells, and this is the probable reason for the increased incidence of cancer in vitamin D-deficient subjects.[37] By modulating the immune system, 1-25-OH vitamin D regulates the activities of both the B and T lymphocytes, macrophages, and the thymus gland, which would explain why vitamin D deficiency is associated with autoimmune diseases, infections, and allergic reactions.[38] The inflammatory effects of vitamin D deficiency also play a major role in the association of vitamin D deficiency with type 2 diabetes and cardiovascular disease.

In conclusion, an epidemic of vitamin D deficiency has developed in the last 20 years due mainly to a lack of exposure to the sun and the increase in obesity. Vitamin D deficiency in pregnancy can have devastating effects. Although historically, vitamin D deficiency is associated only with rickets and osteomalacia, its effects are much more protean.


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