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Vitamin D

Scientific Name(s): Cholecalciferol, Ergocalciferol, Vitamin D2, Vitamin D3
Common Name(s): Sunshine vitamin, Vitamin D

Clinical Overview

Use

Vitamin D, long recognized as playing a role in bone and calcium homeostasis, is being investigated for use in cardiovascular disease, cancer, diabetes, infections, multiple sclerosis, osteoporosis, psoriasis, respiratory health, and other conditions. More clinical trials are needed.

Dosing

The American Academy of Pediatrics recommends 400 units/day of vitamin D in infants and adolescents. Clinical data are not yet sufficiently robust to make definitive recommendations for therapeutic dosages of vitamin D; however, in the elderly, 700 to 1,000 units/day have been shown to reduce the risk of falls.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Routine use of supplemental vitamin D during pregnancy is not supported by safety evidence. However, adequate maternal intake of vitamin D-containing foods during lactation ensures that breast-fed infants receive sufficient vitamin D.

Interactions

The use of statins has been shown to increase serum vitamin D levels. Corticosteriods decrease the metabolism of vitamin D and orlistat reduces its absorption; phenobarbital and phenytoin increase the hepatic metabolism of vitamin D.

Adverse Reactions

High doses of vitamin D have rarely produced adverse events in clinical trials.

Toxicology

Toxicity due to vitamin D is considered to manifest at serum levels greater than 150 ng/mL of 25-hydroxyvitamin D. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and weakness associated with hypercalcemia.

Source

Vitamin D3 (cholecalciferol) is synthesized in the skin by transformation of 7-dehydrocholesterol exposed to ultraviolet B rays of the midday sun. Vitamin D binding protein transports D3 to the liver, where it is hydroxylated to the inactive 25-hydroxyvitamin D form (calcidiol). In the kidneys, it is further hydroxylated by the enzyme 1-alpha-hydroxylase to active 1, 25-dihydroxyvitamin D (calcitriol).1

Vitamin D as ergocalciferol (vitamin D2) is found in some plants and in salmon, sardines, mackerel, tuna, cod liver oil, shiitake mushrooms, egg yolk, and fortified foods.1, 2, 3 Deficiency may result from decreased absorption (such as in cystic fibrosis, celiac and Crohn diseases, and drug interactions), increased catabolism (caused by anticonvulsant and antiretroviral therapy and some immunosuppressant drugs), and hepatic and renal failure, as well as from inadequate intake.1

Chemistry

Vitamin D is a hormone precursor and acts to control calcium absorption in the small intestine. It affects parathyroid hormone, which in turn affects the metabolism of skeletal mineralization and calcium homeostasis in the blood. Additionally, effects on cytokines and immune-modulating effects are reported.1

The accepted biomarker is 25-hydroxyvitamin D (or calcidiol). Only in advanced renal disease are measurements of 1, 25-dihydroxyvitamin D (calcitriol) relevant.4 Concern over standardization of assays exists.1

Uses and Pharmacology

Alopecia

The role of vitamin D and its receptors is not well understood, but the potential for topical calcitriol to upregulate the receptors has been evaluated in animal models of chemotherapy-induced alopecia. Hair loss is not prevented; however, hair regrowth over the entire animal has been demonstrated.31 Limited clinical studies have produced varying results, possibly dependent on the chemotherapeutic agent.31

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)

No significant difference was found in musculoskeletal symptom scores, pain, stiffness, physical function, steady-state concentrations of anastrozole or letrozole, reproductive hormones, or adverse events between women taking an aromatase inhibitor for stage I to II breast cancer who were given 1,000 mg/day calcium carbonate plus the usual care dose of 600 units vitamin D3 compared to 1,000 mg/day calcium carbonate plus 4,000 units vitamin D3 .65

Atopic eczema/Dermatitis/Pruritus

A 2012 Cochrane review identified 2 randomized clinical trials evaluating vitamin D for atopic eczema/dermatitis that met criteria for analysis. Vitamin D supplementation alone did not provide significant benefit over placebo in any of the primary, secondary, or tertiary outcomes. However, vitamin D (cholecalciferol 1,600 units) and E (600 units alpha-tocopherol) combination therapy resulted in a significant difference in severity scores at the end of 60-day treatment, as well as improvement in dryness, pruritis, and erythema compared with placebo in 52 adults and children older than 13 years of age.46

A double-blind, randomized, placebo-controlled trial that assessed the use of ergocalciferol in patients with uremic pruritus was 1 of 10 new studies added to the 2016 updated Cochrane systematic review of pharmacological interventions for pruritus in adult palliative care. After 12 weeks of receiving 50,000 units orally each week, no significant differences were found between groups in pruritus values.68

Cancer

Animal data

Preclinical studies have shown an effect of vitamin D on a variety of cancer cell lines. Cell cycle interruption, apoptosis, and other mechanisms have been demonstrated.1, 5, 6

Clinical data

Meta-analyses of observational studies suggest a lower incidence of cancer with higher vitamin D serum levels.1, 7, 8 Particular attention has focused on breast, colon, and prostate cancer. In the Women's Health Initiative study, no association was found between vitamin D and breast cancer9 while the Health Professionals Follow-Up Study suggested a decreased risk of cancer with increasing 25-hydroxyvitamin D levels.1, 5 In a meta-analysis evaluating the effects of vitamin D supplementation on overall mortality risk, a subgroup analysis (n = 13 in studies) of long-term vitamin D supplementation for at least 3 years revealed a significant reduction in cancer mortality (relative risk [RR] = 0.88; 95% confidence interval [CI], 0.79 to 0.98).55

The American Society of Clinical Oncology clinical practice guideline adaptation for the screening, assessment, and management of fatigue in adult survivors of cancer (2014) notes that results from small pilot studies on the effectiveness of supplements, such as vitamin D, for managing cancer-related fatigue are equivocal (inconclusive).49

Cardiovascular

Vitamin D is thought to exert cardiovascular effects by a number of mechanisms, including effects on the renin-angiotensin-aldosterone system, homeostasis of calcium, and secondary effects on hyperparathyroidism and insulin resistance.10

Clinical data

No clinically important effect on coronary or cerebrovascular risk or outcomes was found with vitamin D and calcium supplementation over 7 years in the Women's Health Initiative randomized trial.11, 12 Other systematic reviews of clinical trials have largely found no effect of vitamin D supplementation on cardiovascular outcomes and hypertension.13, 14, 58 Based on limited trial data in populations with vitamin D insufficiency, moderate to high doses of vitamin D increase the serum vitamin D metabolite status and may reduce cardiovascular risk; however, further studies are required before a definitive place in therapy can be established.15, 16 In a meta-analysis evaluating the effects of vitamin D supplementation on overall mortality risk, a subgroup analysis (n = 13 in studies) of long-term vitamin D supplementation for at least 3 years revealed no reduction in cardiovascular mortality.55

Dementia/Depression

Observational studies and animal models suggest a role for vitamin D in treating dementia. Vitamin D exerts antioxidant effects, and receptors are found in the human cortex and hippocampus. Correlations between the Mini-Mental State Examination scores and vitamin D serum levels, as well as global cognitive function, have been shown.1, 32, 33 One clinical trial demonstrated an improvement in mild depression with vitamin D supplementation.34

The American Psychiatric Association (APA) guideline watch for the treatment of patients with Alzheimer disease and other dementias (2014) did not find enough definitive new evidence to change the 2007 guideline recommendations for alternative agents, including vitamin D.

Diabetes

Animal data

Animal studies suggest vitamin D exerts effects on the homeostasis of glucose metabolism, as supplementation in animals has led to decreases in plasma glucose.1, 17 A direct effect on insulin secretion has been suggested, as well as effects on insulin receptor expression, insulin sensitivity, and direct action on insulin itself.1, 18, 19

Clinical data

Epidemiological data support a role of vitamin D in reducing the incidence of diabetes. Vitamin D supplementation in infants has been associated with a decreased risk of type 1 diabetes, and a meta-analysis has demonstrated an association between low vitamin D status and the prevalence of type 2 diabetes or metabolic syndrome.1, 14 However, limited, small studies have shown equivocal results on the impact of vitamin D on serum glucose.17, 48 A 12-month, double-blind, randomized controlled trial (n = 86) in adults with type 2 diabetes mellitus and vitamin D deficiency (median, 11.9 ng/mL), found that vitamin D supplementation (1,904 units/day) for 6 months did not significantly affect blood glucose, insulin levels, HbA1c, systolic blood pressure, or body weight. However, a significant correlation was observed between vitamin D levels and HbA1c with the lowest HbA1c occurring at less than 20 ng/mL.51 Similar results were seen in another double-blind randomized clinical trial conducted in 158 Koreans with type 2 diabetes and vitamin D deficiency or insufficiency who supplemented their diet with 2,000 units/day of vitamin D3 plus calcium for 24 weeks. Neither glycemic control nor HbA1c were significantly different in patients treated with vitamin D plus calcium compared with those treated with only calcium supplementation.54 Interestingly, in a meta-analysis evaluating the effects of vitamin D supplementation on overall mortality risk, a subgroup analysis (n = 13 in studies) of long-term vitamin D supplementation for at least 3 years revealed a reduction in mortality only when vitamin D plus calcium was compared with placebo but not when compared with calcium, and not when vitamin D alone was compared with placebo. Other long-term subgroup benefits appeared in patients younger than 80 years, with a dose of 800 units or less, and in patients with a baseline 25-hydroxyvitamin D level less than 50 nmol/L. The meta-analysis primary outcome (n = 42 intervention randomized clinical trials; N = 85,466 patients) identified a decrease in all-cause mortality when vitamin D supplementation was continued for 3 years or longer (P = 0.001); heterogeneity was insignificant.55 A systematic review and meta-analysis of 12 randomized controlled trials that assessed the effect of vitamin D supplementation with or without calcium in 1,181 overweight and obese (body mass index range, 23 to 47 kg/m2) participants (10 trials in adults, 2 in children and adolescents) found no significant effect of vitamin D on mean fasting insulin levels, blood glucose levels, or insulin resistance. These results held true for subanalyses to determine the effect of vitamin D dose, duration of therapy, and baseline 25(OH)D levels. Doses of vitamin D alone ranged from 1,000 to 12,000 units/day given for a duration ranging from 12 to 52 weeks; 5 of the studies administered vitamin D (125 to 12,000 units/day) with calcium (500 to 1,200 mg/day).63

A prospective, double-blind, randomized placebo-controlled trial in 60 Iranian women with gestational diabetes mellitus investigated the effect of vitamin D3 (1,000 units) plus evening primrose oil (EPO) (1,000 mg) on insulin resistance and lipid parameters. When compared to changes seen with placebo, supplementation with vitamin D and EPO for 6 weeks produced significant improvements in vitamin D levels (−0.1 vs +6.9 ng/mL; P<0.001), fasting plasma glucose (−3.6 vs +1.5 mg/dL; P=0.04), serum insulin concentrations (−2 vs +4.6 microunits/mL; P=0.004), homeostasis model of assessment-insulin resistance (HOMA-IR, −0.5 vs +1.1; P=0.003), HOMA-beta-cell function (−7.7 vs +17.4; P=0.007), triacylgycerol (−20 vs +34.3 mg/dL; P<0.001), very low-density lipoprotein (vLDL) (−4 vs +6.9 mg/dL; P<0.001), LDL (−18 vs +1.8 mg/dL; P=0.001), and total cholesterol (−22.1 vs +5.3 mg/dL; P<0.001), as well as the ratio of total to high-density lipoprotein-cholesterol (HDL-C) (−0.3 vs +0.3 mg/dL; P<0.001). Changes in mean weight, body mass index, HDL-C, and Quantitative Insulin Check Index were not found to be significantly different between groups.66

As a component of medical nutrition therapy for patients with type 1 or type 2 diabetes, the American Diabetes Association Standards of Care (2014 and 2015) does not support routine supplementation with micronutrients such as vitamin D to improve glycemic control (low-quality evidence).50, 59

Falls in the elderly

Systematic reviews have been conducted on the effects of supplemental vitamin D and the risk of falls in the elderly.1, 35 Low doses (200 to 600 units/day) showed no effect, while higher doses (700 to 1,000 units/day) reduced the risk of falling in the elderly by 19% to 22%.1 Intermittent, high doses (annual dose greater than 100,000 international units or intervals longer than 1 month) were not shown to reduce falls or fractures in adults 65 and older in a meta-analysis of 9 randomized clinical trials (N = 22,012).61

GI effects

A 2 × 2 factorial randomized, placebo-controlled study conducted in 100 adult women with irritable bowel syndrome (IBS) observed significant improvements in adjusted mean symptom severity scores (P=0.047) in women who received vitamin D (50,000 units of cholecalciferol) once biweekly for 6 weeks compared to those who did not. Additionally, severity of abdominal pain (P=0.012), duration of abdominal pain (P=0.009), and life disruption (P<0.005) were all significantly improved with vitamin D compared to placebo, with some data suggesting a synergistic effect with coadministration of vitamin D as seen in total IBS scores and satisfaction with bowel habits. The soy isoflavone supplements contained diadzein 10 mg, genstein 8.5 mg, and glycerin 1.5 mg and were taken twice daily.71

Infectious disease

Vitamin D receptors are ubiquitous in the body and are found in immune system-related cells, such as B and T lymphocytes, neutrophils, and macrophages. An emerging role is being described for vitamin D in immune response.7, 20, 21

The Randomized Evaluation of Calcium or Vitamin D (RECORD) trial investigated the effect of vitamin D supplementation (800 units/day) on self-reported infections and antibiotic use but did not find a statistically significant association.22 A single dose of vitamin D demonstrated an enhanced immune response in a randomized clinical trial in tuberculosis patients23 while a systematic review of clinical trials evaluating the effect of vitamin D supplementation (largely in tuberculosis, influenza, and other viral infections) concluded that further studies are warranted.24

Despite a significant increase in serum 25-hydroxyvitamin D, the recurrence of bacterial vaginosis in women being treated at an urban sexually-transmitted disease clinic was not significantly reduced by vitamin D supplementation (50,000 units × 9 doses) over 24 weeks. The trial was a randomized, placebo-controlled, double-blind study (N = 118).57

Mortality

A meta-analysis of 32 studies published and indexed between 1966 and 2013 evaluated the relationship between vitamin D (25-hydroxyvitamin D) and all-cause mortality in healthy participants as well as patients in clinic cohorts. The age-adjusted death rate in individuals with vitamin D levels in the lowest quantile (0 to 9 ng/mL) was almost twice that of those in the highest quantile (more than 35 ng/mL). The pooled dose-response curve declined steeply between 0 and 30 to 39 ng/mL and flattened at greater than 50 ng/mL, with all-cause mortality being significantly higher when levels were up to 30 ng/mL (P < 0.01).53 Intermittent, high doses (annual dose greater than 100,000 international units or intervals longer than 1 month) were not shown to reduce falls or fractures in adults 65 and older in a meta-analysis of 9 randomized clinical trials (N = 22,012).61

Multiple sclerosis

Theoretical and epidemiological models support a place in therapy for vitamin D in multiple sclerosis. An inverse relationship has been demonstrated between vitamin D levels and multiple sclerosis, especially in patients younger than 20 years of age, while the development of multiple sclerosis in women has been associated with low 25-hydroxyvitamin D levels. Lower serum vitamin D and severity of multiple sclerosis, as well as incidence of relapses, has also been demonstrated.1, 25, 26, 27 In a double-blind, randomized, controlled trial, high-dose vitamin D supplementation (50,000 units every 5 days for 3 months) produced a significant improvement in mental and health change quality of life measures (P=0.041 and P=0.036, respectively) in adults diagnosed with relapsing-remitting multiple sclerosis.67

Little prospective data exist; however, a small clinical study (N = 12) showed a decrease in the number of lesions with magnetic resonance imaging with administration of 1 mg (40,000 units) daily over 28 weeks.1 No serious adverse events were reported at this dosage, and no hypercalcemia or hypercalciuria was reported.

Osteoporosis

Clinical data

An updated meta-analysis from the National Osteoporosis Foundation reviewed randomized controlled trials published between July 1, 2011 and July 31, 2015 that investigated supplementation of calcium plus vitamin D and associated fracture prevention compared to placebo in adults. Results were based on subanalyses of 30,970 participants, most of whom were community dwellers, 195 total hip fractures, and 2,231 total fracture events. Calcium doses ranged from 1,000 to 1,200 mg/day (except for 500 mg/day in 1 study), vitamin D was dosed at 700 to 800 units/day (except for 400 units/day in 1 study), and the follow up ranged from about 1 to 7 years. Findings corroborated previous reports. Subanalysis of 8 trials identified a significant reduction in the incidence of total fractures (15%) with a summary relative risk estimate (SSRE) of 0.85 (95% CI, 0.73 to 0.98). Similarly, a significant 30% reduction in risk of hip fractures was found in the subanalysis of 6 trials (SSRE 0.7; 95% CI, 0.56 to 0.87). Risk reduction in hip fractures was significant for institutionalized participants (n=2 studies) and "borderline statistically significant" (38%) in community-dwelling programs. Statistical significance held true after the one study removed influence analysis with SSREs ranging from 0.64 to 0.73.64

Polycystic ovary syndrome

A systematic review identified 6 studies (N=183), mostly of low quality, that investigated the effect of vitamin D supplementation on the androgenic profile of women with polycystic ovary syndrome (PCOS). Meta-analysis revealed that vitamin D supplementation reduced total testosterone levels significantly in before-after studies (P=0.02) but not randomized controlled trials. In contrast, no significant effect was seen on serum free testosterone levels or sex hormone binding globulin.69 Similarly, a 2017 meta-analysis of 16 studies found no significant effect of vitamin D supplementation on serum free or total testosterone, insulin resistance, LDL cholesterol, or serum dehydroepiandrosterone sulfate. However, 6 studies with no heterogeneity revealed a significant reduction in triglycerides (P=0.002) but when analyzed by subgroup significance held true only in the low-dose (<50,000 units) subgroup (P=0.03). Also, 5 studies showed that vitamin D supplementation resulted in a significant decrease in serum parathyroid hormone (P=0.003); however, heterogeneity was significant. Publication bias was not evident.72 Use of vitamin D supplementation in the treatment of PCOS was assessed in another systematic review and meta-analysis (9 randomized controlled trials; 502 PCOS patients). Doses ranged from 400 to 12,000 units/day. Pooled data from studies exhibiting no significant heterogeneity showed that vitamin D supplementation significantly increased the number of dominant follicles compared to no vitamin D (P=0.001); however, this result was not seen when vitamin D + metformin was compared to metformin alone. In contrast, the latter regimen led to a higher incidence of regular menstrual cycles (P=0.05), whereas vitamin D supplementation alone did not. In studies with higher heterogeneity, vitamin D supplementation significantly improved 25-hydroxy vitamin D levels (P<0.001) and PTH levels (P=0.01). No significant differences were found on glucose or lipid parameters.70 Another systematic review and meta-analysis of nutritional supplements and herbal medicines for polycystic ovary syndrome identified 2 randomized controlled trials that investigated vitamin D in 78 women with PCOS. Effects on menstrual regulation were not reported, and results of secondary outcomes were not found to be significant (ie, metabolic hormones, lipid parameters, C-reactive protein). Dosages ranged from 3 treatments of 50,000 units per 20 days for 2 months, to 12,000 units/day for 12 weeks. Incongruencies throughout this systematic review between the reference numbers in the table of studies vs reference numbers in the text led to conflicting data for many of the meta-analyses and/or interventions summarized.74

Psoriasis

Topical synthetic vitamin D (eg, tacalcitol) may be an alternative to topical steroids and may inhibit keratinocyte proliferation, as well as influence immune modulation.36, 37, 38

Renal

Clinical data

As kidney function is impaired, the inability to maintain adequate phosphorus and calcium levels results in compensatory mechanisms involving parathyroid hormone. Resultant increases in bone metabolism to release calcium to the system cause bone deformation, pain, and an increased risk of fractures. Supplementation of vitamin D suppresses parathyroid hormone, but it may also slow the progression of chronic kidney disease via novel pathways. Vitamin D analogs, such as paricalcitol, may exert anti-inflammatory effects, as well as affect the renin-angiotensin systems and decrease morbidity and mortality. However, studies are limited.28, 29, 30 A randomized, double-blind trial in chronic dialysis patients (n = 50) observed no improvement in cardiac function as measured by 24-hour blood pressure, arterial stiffness, and cardiac function in patients treated for 6 months with 75 mcg (3,000 units) or placebo. Although, left ventricular end-diastolic function was increased significantly in the treatment group (P = 0.024).52

Because impaired vitamin D metabolism may underlie pruritus in patients undergoing hemodialysis, administration of ergocalciferol (vitamin D2) was explored in 50 patients with uremic pruritus. This double-blind, randomized, placebo-controlled trial was 1 of 10 new studies added to the 2016 updated Cochrane systematic review of pharmacological interventions for pruritus in adult palliative care. After 12 weeks of receiving 50,000 units orally each week, no significant differences were found between groups in pruritus values.68

Respiratory health

Vitamin D appears to be capable of inhibiting the pulmonary inflammatory response and enhancing pulmonary defense against pathogens. Population-based studies support an association between circulating vitamin D levels and lung function.39 The use of vitamin D in cystic fibrosis is based on knowledge of vitamin insufficiency due to pancreatic insufficiency; however, evidence of benefit is lacking for vitamin D supplementation despite routine use.40 Addition of high-dose vitamin D3 (100,000 units for 1 dose, then 4,000 units/day x 28 weeks) to inhaled corticosteroid therapy (ciclesonide 320 mcg/day) in adults with symptomatic asthma and low vitamin D3 levels who failed previous treatment, did not significantly alter the rate of first treatment failure or overall treatment failure.47 These results were also supported by the randomized, placebo-controlled ViDiAs trial (N = 250) in which adults with asthma managed with inhaled corticosteroids and who were at high risk of upper respiratory tract infection experienced similar rates of asthma exacerbation and upper respiratory tract infection regardless of vitamin D3 intervention (a bolus of 3 mg vitamin D3 [120,000 units] every 2 months × 12 months).60 Supplementation of a vitamin D 10 mcg/fish oil (DHA 550 mg, EPA 550 mg) per 8 g whey protein drink twice daily for 16 weeks in young athletes did not provide a significant difference in the incidence, severity, or duration of upper respiratory tract infection; number of practitioner visits; or number of times medication was taken compared with placebo. However the total number of symptom days reported was significantly shorter with the intervention than placebo (1.72 ± 1.67 vs 2.79 ± 1.76; P < 0.05).62

Dosing

Clinical response to vitamin D does not always correspond with serum levels of the markers.1 Generally a serum level of less than 20 ng/mL of 25-hydroxyvitamin D constitutes a deficiency in adults and children.1, 2, 41

The American Academy of Pediatrics recommends 400 units/day vitamin of D in infants and adolescents.41, 42

To maintain a serum 25-hydroxyvitamin D level of 25 ng/mL, independently living elderly adults required vitamin D 7.9 to 42.8 mcg daily in a clinical study43 (20 mcg is equivalent to 800 units).22 Data from clinical studies are not yet sufficiently robust to make definitive recommendations for therapeutic dosages of vitamin D; however, in the elderly, 700 to 1,000 units/day have been shown to reduce the risk of falls.35

Vitamin D3 (1,000 units/day) in combination with evening primrose oil (1 g/day) has been used to improve glycemic and lipid profiles in women with gestational diabetes.66

Pregnancy / Lactation

The safety and efficacy of vitamin D in pregnancy has not been confirmed. Clinical trials have evaluated the excretion of vitamin D in breast milk by mothers given supplementation. Adequate levels of vitamin D are achieved in breast-fed infants from mothers with a vitamin D intake of 400 units/day. All milk formulas sold in the United States contain at least 400 units/L of vitamin D.1

Interactions

The use of statins has been shown to increase serum vitamin D levels.44 Corticosteriods decrease the metabolism and orlistat reduces absorption of vitamin D, while phenobarbital and phenytoin increase the hepatic metabolism of vitamin D.2

Adverse Reactions

High doses of vitamin D have rarely produced adverse events in clinical trials.1

Apart from the obvious hazards, prolonged sun exposure alone cannot cause vitamin D overdose because sunlight destroys excess vitamin D3.1

Toxicology

Toxicity due to vitamin D is considered to manifest at levels greater than 150 ng/mL of serum 25-hydroxyvitamin D. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and weakness associated with hypercalcemia.1, 2 Reports of toxicity exist for children administered high-dose vitamin D after World War II in Europe. Hypercalcemia, nephrocalcinosis, adverse cardiovascular effects, early aging, and premature death were reported.45

Hypervitaminosis D in 2 young brothers was reported subsequent to an overdose of an OTC vitamin D supplement that resulted from 2 simultaneous dosing errors; the OTC product (Merluzzovis cod liver oil-based capsules) contained approximately 1,000 times the labeled vitamin D content per capsule, and the mother administered twice the dose as recommended on the label. After 1 month of supplementation, the 12-year-old had received a total of 7,632,000 units (254,490 units/day instead of the recommended 400 units/day) and was hospitalized for abdominal pain, constipation, vomiting, hypercalcemia, suppressed parathyroid, and acute renal failure. The 15-year-old brother had received a total of 3,180,000 units over the previous 2 weeks, was asymptomatic, normocalcemic, and had normal renal function. Their vitamin D levels were well over the toxic lower limit (150 ng/mL) and were 535 ng/mL and 484.9 ng/mL, respectively. The 12-year-old was normocalcemic and had normal renal function within 1 month of discharge.56

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