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Vitamin D Toxicity


Vitamin D Toxicity

Article Author:
Anum Asif
Article Editor:
Nauman Farooq
Updated:
5/21/2020 10:16:02 PM
For CME on this topic:
Vitamin D Toxicity CME
PubMed Link:
Vitamin D Toxicity

Introduction

Vitamin D is a fat-soluble vitamin that is found in some animal food products and is also synthesized in our bodies via exposure to the sun.[1] It is frequently used as both prescription and over the counter formulation. The toxicity of vitamin D (hypervitaminosis D) is rare and is usually caused by taking heavy doses of vitamin D due to misuse of over the counter supplements or erroneous prescriptions. Toxicity of vitamin D leads to hypercalcemia and imbalance in the regulation of bone metabolism, and the resultant hypercalcemia leads to clinical manifestations of symptoms of toxicity.[2]

Etiology

In healthy individuals, vitamin D intoxication results from taking higher than prescribed or use of over the counter formulations.[3] Prescription errors without frequent monitoring of vitamin D levels can also result in toxicity.[4] This is frequently seen in patients requiring high doses for treatment of ailments like osteoporosis, renal osteodystrophy, psoriasis, gastric bypass surgery, celiac, or inflammatory bowel disease.[5] Excessive sun exposure does not cause vitamin D toxicity due to the regulation and conversion of Vitamin D to its inactive metabolites.[6] Vitamin D is present in fish, meat, and dairy products, and the dose is rarely enough to cause toxicity.[6] Patients who are on high doses of Vitamin D and are taking inadvertently increased amounts of highly fortified milk are at increased risk for vitamin D toxicity as well. It can also result from excessive production of 1,25(OH)2D in medical ailments like granulomatous disorders and lymphomas.[7]

Epidemiology

The United States poison control center has reported data from the years 2000 to 2014, revealing that there were 25,397 people exposed to vitamin D toxicity. The annual mean was 196 cases per year from 2000 to 2005, with a subsequent 1600% increase in exposures between 2005 and 2011 to a new mean per annum of 4535 exposures per year.[8]

Pathophysiology

Vitamin D is a fat-soluble vitamin mail stored in the liver and adipose tissue. It is available from exogenous sources and is also synthesized indigenously by the human body. The Endocrine Society clinical practice guidelines suggest that daily requirements for adults aged 19 to 50 are 600 IU/d and for age 50 to 70 and 70+ years, at least 600 and 800 IU/d, respectively, of vitamin D. The maximum suggested daily requirements are 4000 IU/d for everyone over 8 years.[9]

Exposure to UV sunlight synthesized 7 dehydrocholesterol, which is converted to cholecalciferol (vitamin D3) in serum. Vitamin D3 (from dietary sources and sunlight exposure) is converted to 25-hydroxyvitamin D3 in the liver through the activity of enzyme 25-hydroxylase which is subsequently converted to 1,25-dihydroxy vitamin D3 in the kidney, and it helps in regulation of calcium metabolism. The liver is a storage place for vitamin D. There is a negative feedback regulation of enzyme vitamin 25 hydroxylase in the liver; however, it is not sufficient to prevent toxicity. When high doses of vitamin D are ingested, they are stored in the liver and adipose tissue, which saturates the vitamin D binding receptors. This increases the concentration of many other vitamin D metabolites, especially 25(OH)D. In hypervitaminosis D, the concentrations of vitamin D metabolites, such as vitamin D, 25(OH)D, 24,25(OH)2D, 25,26(OH)2D, and 25(OH)D-26,23-lactone, increase significantly.[10] Abnormally increased concentrations of vitamin D metabolites exceed the vitamin-D binding protein (VDBP) binding capacity and cause a release of free 1,25(OH)2D. The most accepted explanation for the manifestation of toxicity is the abnormally high 25(OH)D and free 1,25(OH)2D concentrations, but even this remains unproven.[10]

History and Physical

A detailed history is very important in making a diagnosis of Vitamin D toxicity. A thorough review of medications list, including the use of over the counter supplements, is pertinent. History should also focus on getting details of chronic medical ailments requiring high doses of vitamin D supplementations osteoporosis, renal osteodystrophy, psoriasis, gastric bypass surgery, celiac, or inflammatory bowel disease. Dietary history, especially the excessive use of vitamin D fortified milk along with the use of supplementary vitamin D, is another important clue. The clinical symptoms for vitamin D toxicity are manifested from the effects of hypercalcemia. These include neurological symptoms like confusion, apathy, agitated, irritability, and in severe cases, stupor and comma. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, peptic ulcers, and pancreatitis (from malignant calcifications). Renal symptoms manifest polyuria, polydipsia, and nephrolithiasis. Severe hypercalcemia can also lead to cardiac arrhythmias.

In many cases, symptoms can be nonspecific and subtle, like weakness, fatigue, anorexia, and bone pains. Physical exam of patients with signs of toxicity sometimes shows loss of skin turgor and dry mucous membranes (due to dehydration), changes in mental status, abdominal tenderness without rebound, rigidity, or guarding. In many cases, a physical exam can be normal without any overt findings, but high clinical suspicion should be kept in mind based on historical findings.

Evaluation

Vitamin D toxicity is a clinical diagnosis that can be made with a thorough history and clinical symptoms. Laboratory evaluation includes checking serum calcium (often greater than 11 mg/dL), ionized calcium, parathyroid hormone (PTH), which is suppressed due to negative feedback loop. Serum level of 25(OH)D concentration less than 150 ng/ml (375 nmol/l), and normal or increased values of 1,25(OH)2D concentration.[5] A decreased or normal 25(OH)D concentration, and elevated 1,25(OH)2D can be found in patients with coexisting granulomatous diseases. A basic metabolic panel should be done to assess kidney dysfunction due to hypercalcemia or any electrolyte derangements due to excessive vomiting. EKG is to assess the presence of any arrhythmia. The most common EKG findings are a shortened QT interval. It can also reveal a shortened ST segment, flattened T wave, or Osborn waves (J wave), a positive deflection at the J point in precordial leads.Imaging studies are usually not required to make a diagnosis of vitamin D toxicity but can reveal incidental findings of chronic toxicity due to pathological calcifications. Skeletal radiographs usually show periosteal calcifications. CT scan of the abdomen and pelvis can reveal nephrolithiasis. If a patient is significantly altered on admission, a baseline CT scan should be done to reveal alternative intracranial pathologies.

Treatment / Management

Clinical management of vitamin D toxicity is mainly supportive and focuses on lowering the levels of calcium.

  • Discontinue all vitamin D and calcium supplements. Avoid excessive bed rest to prevent hypercalcemia of immobilization.
  • Isotonic saline should be used to correct dehydration related kidney injury.
  • In cases of severe toxicity causing severe hypercalcemia (serum calcium > 14 gm/dL), calcitonin and bisphosphonates can be used. Intravenous calcitonin at 4 U/kg can be administered, and calcium levels repeated after 6 to 12 hours. IV bisphosphonates can be administered concurrently but are more beneficial to lower hypercalcemia of malignancy.
  • It should be kept in mind that calcitonin can lead to tachyphylaxis, while the effect of bisphosphonates can persist for a longer duration. Calcium levels should be carefully monitored during the use of these medications.
  • The use of intravenous glucocorticoids is controversial and usually reserved for the treatment of vitamin D toxicity related to the granulomatous disease. It reduced plasma calcium levels by reducing intestinal absorption and increasing urinary excretion of calcium.
  • In rare cases, due to significant kidney damage, patients may need hemodialysis to get rid of excessive calcium.
  • The patient’s medication list should be reviewed to adjust the future doses of vitamin D supplements.
  • Patient education is needed overuse of supplementary vitamin replacements.
  • The Endocrine Society suggests monitoring of serum levels of 25-hydroxy vitamin D and calcium for the patients on high dose vitamin D replacement.

Differential Diagnosis

Hypervitaminosis due to vitamin D should be differentiated from other causes leading to hypercalcemia or diseases mimicking the symptoms of hypervitaminosis as follow:

  • Hypercalcemia of malignancy
  • Hypercalcemia of granulomatous diseases
  • Primary, secondary and tertiary hyperparathyroidism
  • Vitamin A toxicity
  • Thyrotoxicosis
  • Paget disease
  • Hypercalcemia caused by prolonged immobilization
  • Milk-alkali syndrome

Prognosis

Most of the cases with vitamin D toxicity recover without any serious complications or sequels. In a few cases, severe hypercalcemia is noted to lead to acute renal failure requiring hemodialysis, but it is rare to have cases of permanent renal damage due to vitamin D toxicity.

Complications

The complication of vitamin D toxicity rarely leads to renal failure requiring hemodialysis.[11]

Deterrence and Patient Education

Patient education regarding the harmful effects of overuse of vitamin D supplements is extremely important. Patients should be educated on adhering to the prescription regimen, especially those who are on high doses of vitamin D for the treatment of underlying medical conditions. They should also be made aware of the importance of follow up while being on high dose supplements to avoid the risk of vitamin D toxicity.

Enhancing Healthcare Team Outcomes

Vitamin D is widely prescribed and is also used as over the counter formulation by patients. Health care providers should be aware of close monitoring of these supplements, especially in the population at risk due to high doses requirements. A thorough history and careful review of medication lists, including over the counter supplements should be done in cases of suspected vitamin D toxicity. Patient education and close monitoring of vitamin D levels are needed to prevent toxicities. Physicians should be mindful of various high dose formulation and suggested daily requirements to prevent errors in prescriptions leading to adverse outcomes.


References

[1] Moulas AN,Vaiou M, Vitamin D fortification of foods and prospective health outcomes. Journal of biotechnology. 2018 Nov 10;     [PubMed PMID: 30176270]
[2] Ozkan B,Hatun S,Bereket A, Vitamin D intoxication. The Turkish journal of pediatrics. 2012 Mar-Apr;     [PubMed PMID: 22734293]
[3] Kaur P,Mishra SK,Mithal A, Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clinical endocrinology. 2015 Sep;     [PubMed PMID: 26053339]
[4] Taylor PN,Davies JS, A review of the growing risk of vitamin D toxicity from inappropriate practice. British journal of clinical pharmacology. 2018 Jun;     [PubMed PMID: 29498758]
[5] Marcinowska-Suchowierska E,Kupisz-Urbańska M,Łukaszkiewicz J,Płudowski P,Jones G, Vitamin D Toxicity-A Clinical Perspective. Frontiers in endocrinology. 2018;     [PubMed PMID: 30294301]
[6] Holick MF, Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective. Mayo Clinic proceedings. 2015 May;     [PubMed PMID: 25939933]
[7] Hoorn EJ,Zietse R, Disorders of calcium and magnesium balance: a physiology-based approach. Pediatric nephrology (Berlin, Germany). 2013 Aug;     [PubMed PMID: 23142866]
[8] Spiller HA,Good TF,Spiller NE,Aleguas A, Vitamin D exposures reported to US poison centers 2000-2014: Temporal trends and outcomes. Human     [PubMed PMID: 26519481]
[9] Holick MF,Binkley NC,Bischoff-Ferrari HA,Gordon CM,Hanley DA,Heaney RP,Murad MH,Weaver CM, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2011 Jul;     [PubMed PMID: 21646368]
[10] Jones G, Pharmacokinetics of vitamin D toxicity. The American journal of clinical nutrition. 2008 Aug;     [PubMed PMID: 18689406]
[11] Wani M,Wani I,Banday K,Ashraf M, The other side of vitamin D therapy: 
a case series of acute kidney injury due to malpractice-related vitamin D intoxication
. Clinical nephrology. 2016 Nov;     [PubMed PMID: 27719737]