Andrzej Milewicz1 and Anna Brona2
(1)
Department of Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland
(2)
Department of Sports Medicine and Nutrition, University School of Physical Education, Wroclaw, Poland
Andrzej Milewicz
Email: andrzej.milewicz@umed.wroc.pl
16.1 History of Vitamin D
Dr Adolf Otto Reinhold Windaus discovered vitamin D. He received Nobel Prize in 1928.
Merck Company synthesized vitamin D in 1937 and launched Vigantol as the first vitamin D drug.
16.2 Characteristics of Vitamin D
Vitamin D comes in two forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) [1]. Vitamin D3 is synthesized in the skin from endogenous 7-dehydrocholesterol after exposure to sunlight [1–5]. Vitamin D2 is obtained from the UV irradiation of the yeast sterol ergosterol and is found naturally in sun-exposed mushrooms [1].
Vitamins D2 and D3 are available as dietary supplements and in various food items naturally or after fortification [6].
16.3 Transport of Vitamin D, 25(OH)D and 1,25 (OH)2D to the Tissues
Being synthesized in the skin by UV, vitamin D3 enters the blood stream and is bound to vitamin D binding protein (VDBP). Vitamin D (D represents D2, or D3, or both) that is ingested in the gastrointestinal tract is incorporated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. Being transported to the liver, vitamin D is transformed to 25(OH) D, which is bound to VDBP and is secreted to the circulating blood. However, vitamin D is also transported to other tissues which, apart from 1-alpha hydroxylase, contain 25-hydroxylase converting vitamin D into 25(OH)D. This local synthesis of 1,25 (OH)2D appears to fulfill autocrine functions [7]. Independently from the abovementioned intracellular transport system, there is also megalin-dependent endocytosis system [8].
25(OH)D requires a further hydroxylation in the kidneys by the 25(OH)D-1-αOHase (CYP27B1) to form the biologically active form of vitamin D 1,25(OH)2D [9]. This system is also found in parathyroid glands and in the trophoblastic layer of placenta [7, 10].
16.4 Role of Vitamin D
Pleiotropic actions of vitamin D are presented in Table 16.1 [11, 12].
Table 16.1
Pleiotropic actions of vitamin D [11, 12]
|
Nephroprotection |
Decreased inflammation |
|
Antiproteinuric effect |
|
|
Increased nephrin expression |
|
|
Suppression of renin, RR, AT II |
|
|
Decreased NF-κB activation |
|
|
Anti EGFR signaling? |
|
|
Glucose metabolism |
Increased insulin secretion |
|
Increased insulin sensitivity |
|
|
Increased glucose uptake |
|
|
Expression of insulin receptor |
|
|
Endothelial and cardiovascular protection |
Suppression of RAAS |
|
Regulation of ANP |
|
|
Control of inflammation |
|
|
Inhibition of smooth muscle cell proliferation |
|
|
Regulation of apoptosis and antitumoral activity |
p21, p27 |
|
EGFR, TGF-α, C/EPB β |
|
|
Bcl2, Bax, caspase 3 |
|
|
Immunomodulation of lymphocytes, macrophages and dendritic cells |
Inhibition of Th1 cells |
|
Promotion of Th2 cells |
|
|
Induction of CD4 + CD25+ T cells |
|
|
Repression of γ-IFN, IL-2, GMCSF |
|
|
Promotion of Mycobacterium tuberculosis killing |
Induction of the antimicrobial peptide cathelicidin in macrophages |
|
Antiproliferation and cellular differentiation in skin cells |
p21, p27 |
|
EGFR, C/EBP β |
|
|
Sex hormones |
Control of estradiol and testosterone secretion |
|
Control of muscle and neural function |
Muscle strength |
|
Neural growth factor |
|
|
GDNF |
16.5 Vitamin D Deficiency
We can expect vitamin D deficiency in persons with frequent muscle and joint pain, osteomalation, osteoporosis with fracture, and with calcium-phosphate metabolism disturbances [3]. Patients on a wide variety of medications including anticonvulsants and medications to treat HIV/AIDS are at risk because these drugs enhance the catabolism of 25(OH)D and 25(OH)2D [13]. Patients on long-therm corticosteroid therapy (equivalent of prednisone over 7.0 mg/day) and ketoconazole are at risk for vitamin D deficiency, too [13]. Patients with chronic granuloma-forming primary disorders (tuberculosis, sarcoidosis), some lymphomas, and hyperparathyroidism who have increased metabolism of 25(OH)D to 1,25(OH)2D are also at high risk for vitamin D deficiency [14, 15].
There are several other causes for vitamin D deficiency [1, 16]. Patients with one of the fat malabsorption syndromes and bariatric patients are often unable to absorb the fat-soluble vitamin D, and in patients with cholestasis, vitamin D emulsification by bile acid is impaired. Severe hepatic parenchymal damage can results in 25(OH)D deficiency [17].
Patients with nephrotic syndrome lose 25(OH)D bound to the vitamin-D-binding protein in the urine. Impaired 1α-hydroxylation is observed in chronic kidney disease once creatinine clearance decreases to approximately 30–40 mL/min [1, 17].
Epidemiological, genetic, and basic studies indicated a potential role of vitamin D in the pathogenesis of certain systemic and organ-specific autoimmune diseases. These studies demonstrate correlation between low vitamin D and prevalence of diseases. There is a body of evidence regarding the plausible roles of vitamin D and VDR’s polymorphism in the pathogenesis of systemic (i.e., systemic lupus erythematosus, rheumatoid arthritis, psoriasis, etc.) and organ-specific (i.e., diabetes mellitus, primary biliary cirrhosis, etc.) autoimmune diseases, in which low level of vitamin D was found compared to healthy subjects [18].
Low level of vitamin D is also found in cardiovascular diseases, i.e., lower serum 25 (OH) D levels are significantly associated with impaired myocardial performance and LVMI [19]. Hypertensive patients who were exposed to a tanning bed raised their blood concentrations of 25(OH)D by >180 % in 3 months and became normotensive [20]. It was observed that in patients with low vitamin D concentrations, such disorders as ischemic heart disease, heart attack, stroke, cardiac arrhythmia, and hypertension were more frequent and mortality was significantly higher [21]. Vitamin D sufficiency may also be an important protective factor for food allergy in the first year of life [22]. There is an inverse association of serum 25(OH)D and body mass index (BMI) greater than 30 kg/m2, and thus, obesity is associated with vitamin D deficiency [23]. Low vitamin D level may be found in patients with colon cancer or prostate cancer [24, 25].
16.6 Vitamin D Deficiency: Aging
Increased use of clothing and sunscreen over sun-exposed areas and decreased consumption of vitamin-D-fortified milk increases the risk for vitamin D deficiency. In addition, age decreases the capacity of the skin to produce vitamin D3 [1]. Studies have revealed that aging does not alter the absorption of physiological or pharmacological doses of vitamin D [26].
One of the studies on age and vitamin D conducted in Poland – the POLSENIOR study – showed negative correlation between serum vitamin D concentration and biological age in elderly women (r = − 0.2863, p = 0.001) [27].
16.7 Vitamin D Deficiency: Symptoms
Vitamin D deficiency is often a silent disease. In adults, vitamin D deficiency results in osteomalacia, which presents as a poorly mineralized skeletal matrix. Adults in these cases can experience chronic muscle aches and bone pains.
Other clinical symptoms suggesting vitamin D deficiency include lack of appetite, diarrhea, insomnia, vision disturbances, bad taste, and burning sensation in the oral cavity and throat [28].
16.8 Vitamin D Deficiency: Diagnosis
Measurement of serum 25-hydroxyvitamin D (25[OH]D) is the best test to determine vitamin D status [29]. Levels of 25(OH)D are interpreted as follows [30]:
· 30–100 ng/mL (75–250 nmol/L): Vitamin D sufficiency
· 21–29 ng/mL (52.5–72.5 nmol/L): Vitamin D insufficiency
· <20 ng/mL (<50 nmol/L): Vitamin D deficiency
In Central Europe, levels of 25(OH)D are interpreted as follows [31]:
· <20 ng/ml – Vitamin D deficiency
· 20–30 ng/ml – Vitamin D insufficiency (hypovitaminosis)
· >30 ng/ml – Recommended level
Determination of PTH and calcium concentrations is recommended to establish the cause for calcium-phosphate disorders before starting vitamin D supplementation.
16.9 Treatment for Vitamin D Deficiency
Recommended treatment for vitamin D deficiency (vitamin D level below 20.0 ng/ml = 50.0 nmol/l) comprises [31] the following:
· Children and adolescent – from 3000 to 5000 IU/day
· Adult – from 7000 to 10,000 IU/day
First control of 25OHD concentration is recommended after 3–4 months and then every 6 months. Serum calcium, phosphate, and calcium in 24-h urine calcium measurement should be monitored every 1–3 months [32].
16.10 Prevention of Vitamin D Insufficiency (Hypovitaminosis)
Prevention of hypovitaminosis D (serum 25OHD lower than 30.0 ng/ml) strategies comprises the following doses [30]:
· Over 18 years old – 1500–2000 IU/day
· Obese (BMI over 30.0 kg/m2) – 4000 IU/day
· Women planning pregnancy – 1500–2000 IU/day
· Pregnant women over 18 years – from 1500 to 2000 IU/day (from at least second trimester)
· Elderly – 1500–2000 IU/day
It is very important to apply vitamin D with meal. Recommended vitamin D serum level is between 30.0 and 50.0 ng/ml (75–125 nmol/l) [33].
16.11 Polish Recommendation 2014
Polish Recommendation for optimal concentration of vitamin D for pleiotropic actions of vitamin D recommends the following levels [32]:
· Children and adolescents – 20–60 ng/ml
· Adults – 30–80 ng/ml
· Sever vitamin D deficiency is defined as vitamin D concentration below 10 ng/ml.
Treatment dose suggested for first 1–3 months is as follows:
· for newborns, 1000 IU/day; infants, 1000–3000 IU/day; children, up to 5000 IU; and adults, up to 7000 IU [32].
· Follow-up should be performed every 1–3 months and includes serum 25(OH)D concentration, alkaline phosphatase, calcium, phosphate, and 24-h urine calcium measurement with elaboration of creatinine index [32].
Useful calculations are as follows:
· Vitamin D serum concentration: 1 ng/ml = 2.5 nmol/l 25(OH)D
· Vitamin D dose: 40 IU = 1 μg vitamin D
16.12 Vitamin D Intoxication
The Drug and Therapeutics Committee of the Pediatric Endocrine Society undertook a systematic review of the safety of currently recommended high vitamin D doses as well as reported cases of intoxications in pediatrics [6].
Vitamin D hydroxylation to 25-hydroxyvitamin D (25OHD) in the liver depends on substrate availability, and therefore, 25OHD concentrations rise in circulation during excess or intoxication. In contrast, the subsequent 1 alpha-hydroxylation to 1,25-dihydrovitamin D2 in the kidney is tightly regulated by PTH and under negative feedback by calcium, phosphorus, and fibroblast growth factor 23. Consequently, in vitamin D intoxication, serum 1,25-(OH)2D concentrations are usually normal and do not correlate with serum calcium levels (JCEM 2014) [6]
Both vitamins D2 and D3 are lipophilic and rapidly removed from the circulation to various tissues such as adipose and muscle where they may remain stored for almost 2 months. Their metabolite, 25OHD, has high affinity for its transport protein, vitamin D binding protein, which results in a long half-life of 2–3 weeks. 25OHD is also lipophilic and can be stored in adipose tissue, remaining there for months. Hence, vitamin D intoxication may take weeks to resolve and require prolonged course of therapy [6].
1,25(OH)2D or Calcitriol is also available for the treatment for the hypocalcemia and secondary hyperparathyroidism of renal failure or rare conditions such as hypoparathyroidism, pseudohypoparathyroidsm, or hypophosphatemic rickets. Reports on intoxication caused by excessive Calcitriol intake are extremely rare (relatively short biological half-life) [6].
During intoxication, high concentrations of 25OHD lead to hypercalcemia by increasing intestinal calcium absorption and bone resorption. In turn, hypercalcemia increases the calcium load that is filtrated through the kidney, resulting in hypercalciuria via a mechanism that involves increased calcium excretion in the distal tubule. Persistently elevated serum calcium levels may also cause polyuria and dehydration because of inability of the kidney to appropriately concentrate urine [6].
16.13 Causes of Vitamin D Intoxication
Vitamin-D-concentrated supplements use for veterinary purpose was mistaken as cooking oil. The other cause may be excessive milk fortification (70–600 times above state limit). In adults, cases of accidental or intentional intake of excessive vitamin D caused by a variety of circumstances such as misinterpretation of prescription instruction or inappropriate prescription of excessive vitamin D doses without monitoring 25OHD levels resulted in vague musculoskeletal complaints [6].
Both in the United States and in Europe, intoxications after manufacturing errors of over-the-counter vitamin D formulations that contained substantially higher concentrations than claimed on the label (production of such supplements is not overseen be FDA ) were reported.
Over one-half of over-the counter preparations and only one-third of the compounded pills met the US Pharmacopeial Convention Reference Standards containing 90–110 % of the active ingredient, whereas the rest had either higher or lower concentrations than expected [6].
Bjelakovic et al. assessed the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. The systematic review and meta-analysis comprised 68 randomized trials with 232,606 participants (385 publications). It revealed that treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The authors concluded that the potential roles of vitamin C and selenium on mortality need further study [34].
Multivitamin preparations and dietary supplements are not recommended for vitamin D deficiency supplementation. Multivitamin preparations, e.g., cod-liver oil, include various amounts of vitamin D and large amounts of vitamin A. Ingestion of processed retinols may be toxic for the skeletal system and block vitamin D’s effects [35].
It should be remembered that vitamin D in the form of prescription drug enables strict control of the product (Table 16.2).
Table 16.2
Notification, modifies
|
Prescription medicine |
Dietary supplement |
|
|
Tests |
Necessity to carry out clinical investigations |
No obligation of investigations |
|
Registration |
Registration of medicinal product according to Pharmaceutical Law Admission to turnover by Products Registration Office subordinate to The Minister of Health |
Notification to Chief Sanitary Inspector (Electronic System of Notification Message) |
|
Safety |
Manufacturer carries out drug qualitative and quantitative control |
Manufacturer declares only quantitative amount of the component. |
|
Activity |
By definition, medicinal product: prevents, treats, or modifies organism physiological functions |
By definition, dietary supplement: facilitates, supports. Statements:“treats, prevents” are improper |
Cases of vitamin D dietary supplements intoxication reported in the literature are associated with doses other than those declared by the manufacturer. For example, a case report by Kaptein et al. described two female patients with life-threatening hypercalcemia (refractory status epilepticus) [36]. They had ingested vitamin D in dietary supplements. Vitamin D content exceeded the amount presented in the leaflet 100–1000 times. Araki T et al. presented two cases of patients with hypercalcemia after intake of vitamin D supplements including the amount of this vitamin discrepant from the information in the leaflet. Patients ingested vitamin D in doses 1000-fold exceeding daily needs [37].
In the last decade, a number of infants with suspected rickets who were prescribed high vitamin D doses without prior measurement of 25OHD presented with severe life-threatening hypercalcemia. Intoxication also occurred after intentional ingestion of products bought through the Internet for “good health” or dosing errors because of parental misinterpretation of the prescribed doses (400 IU/drop with 400 IU/ml – an infant received a 30-fold over dose) [6].
16.14 Diagnosis of Vitamin D Intoxication
Hypercalcemia, poor appetite, weight loss, abdominal pain, vomiting, constipation, polyuria, polydipsia, and – in severe cases – life-threatening dehydration are symptoms of vitamin D intoxication. Vitamin D intoxication accounts for about 10 % of all cases of nephrocalcinosis [6]. Diagnosis of vitamin D intoxication includes elevated serum 25OHD level (>150 ng/ml = 375 nmol/l), hypercalcemia, or hypercalcuria. Serum 1,25 (OH)2D level is normal. PTH is suppressed.
In contrast, hypercalcemia and hypercalcuria, with normal serum 25OHD level, elevated 1,25 (OH)2D, and suppressed PTH, raise the suspicion of idiopathic intracranial hypertension. In such cases, 24,25-dihydroxyvitamin D levels are low or undetectable [6].
16.15 Treatment of Vitamin D Intoxication
Treatment efforts in children and adolescents with symptomatic hypercalcemia target the source of vitamin D as a first step. It is removed, and the levels are allowed to decrease with time [6]. The first line therapy of hypercalcemia is iv hydration with normal saline to increase the glomerular filtration rate and calcium excretion. It can be combined with specific diuretics that increase calcium excretion, such as loop diuretics. Furosemide at 1–2 mg/kg/day, as divided doses every 4–6 h, is usually given. Thiazides, on the other hand, should be avoided because they increase calcium reabsorption at the distal tubule and, therefore, can exacerbate hypercalcemia [6]. Glucocorticoids can be added if symptomatic hypercalcemia persists despite hydration and diuretics. They prevent renal calcium reabsorption and inhibit the production and activity of 1,25(OH)2D and thus decrease intestinal calcium absorption. Prednisone at 1–2 mg/kg/day or 20–25 mg/m2/day given as divided doses every 4 h up to 2 weeks has been used in children. Onset of action can be expected within 24–72 h [6].
Bone resorption is increased in vitamin D intoxication. Therefore, antiresorptive therapy with bisphosphonates, such as Pamidronate (0.5–1.0 mg/kg/dose) or Alendronate (5–10 mg/dose), is recommended. This therapy successfully lowers serum calcium levels in intoxicated patients four time faster that steroids [6].
Steroids can be combined with subcutaneous injection of Calcitonin of 2–4 IU/kg every 6–12 h, because of the rapid effect on serum calcium. As a last resort, hemodialysis can lower serum calcium rapidly and can be used in life-threatening cases, such as acute or chronic renal failure or hypercalcemic crisis [6].
16.16 Prevention of Vitamin D Intoxication
Health care providers should be aware of the various vitamin preparations and counsel patients on both desirable doses and variability among formulations. Empirical therapy of vitamin D deficiency with high vitamin doses, such as stoss therapy, is discouraged without previous documentation of 25OHD concentrations and monitoring serum 25OHD and calcium. Health care providers should consider monitoring vitamin D levels in infants and children receiving treatment doses at the upper ranges currently recommended – the frequency, no more than every 6 months. Vitamin D excess or intoxication should be included in the differential diagnosis in children who present with hypercalcemia or hypercalcuria. Serum calcium concentrations should be monitored in children with serum 25OHD levels above 150.0 ng/ml and measured by a reliable assay such as liquid chromatography tandem mass spectrometry. For asymptomatic patients with vitamin D intoxication, monitoring of clinical symptoms, serum 25OHD, and calcium levels estimation until serum 25OHD values start declining is recommended [6].
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