Vitamin D Toxicity: Can It Be Defined?

Recently, patients have presented to the office being told by their primary care physicians to reduce their vitamin D intake due to concern of vitamin D toxicity, despite their levels falling into the standard reference range, between 55 and 80 ng/mL.

High dose vitamin D therapy has been used historically and in modern times to treat a myriad of diseases though this is either no longer recommended nor even tried by most due to fear of toxicity.

This led to researching vitamin D toxicity:

• What does vitamin D toxicity mean?
• Can it be defined?
• At what level do you become toxic?
• What does the research tell us?

Ranges of Vitamin D

Though levels used to define deficiency, insufficiency, optimal, and toxicity are not generally agreed upon, two medical societies do agree on the rarity of vitamin D toxicity:

“In statements released over the last decade, the Institute of Medicine (IOM) and the Endocrine Society have both concluded that acute vitamin D toxicity (VDT) is extremely rare in the literature, that serum 25(OH)D concentrations must exceed 150 ng/mL, and other factors, such as calcium intake, may affect the risk of developing hypercalcemia and VDT. Regardless of additional risk factors for VDT, many studies provided evidence vitamin D is probably one of the least toxic fat-soluble vitamins…”

What is the Prevalence of Vitamin D Toxicity?

Actual prevalence of vitamin D toxicity is unfounded in the literature  as there is NO agreed upon definition of toxicity.

A 2018 study concludes vitamin D toxicity is rare and the prevalence is unknown; they state the hallmark of toxicity is a level greater than 150 ng/mL.  Repeating this level as the criterion for toxicity is a 2022 study though the authors state toxicity can range from asymptomatic to life threatening due to hypercalcemia.  The question arises, how can you be toxic if you are asymptomatic without evidence of lab abnormalities other than a high Vitamin D level?

Using this criterion, they studied the levels of 105,398 subjects taking vitamin D in dosages ranging from 2,000 to 200,000 IU a day over the span of one year. Included in the final analysis were 186 subjects, concluding the prevalence of potential toxicity was extremely rare – 0.23% for adults and 1.12% for children. Note the authors use the words “potential toxicity” rather than “toxicity”.

The prevalence of vitamin D toxicity cannot be concluded as there is no unified definition or criteria of toxicity today. Though it is unknown, it is generally agreed upon toxicity from vitamin D is extremely rare. 

Clinical Toxicity

A 2018 review of vitamin D toxicity states the clinical condition is characterized by a level over 150 ng/mL with severe hypercalcemia; the first measurable manifestations of toxicity are hypercalciuria and hypercalcemia, (measured high calcium in urine and blood).

Another study states the clinical symptoms of toxicity are the result of hypercalciuria and hypercalcemia which are similar to those of hypercalcemia due to any other cause.

RMC Patients 

If we characterize vitamin D toxicity as the presence of hypercalcemia and hyperphosphatemia, this has never been seen in practice.   To date RMC patients with vitamin D levels >150 ng/mL have not demonstrated lab findings of toxicity.

High-Dose Case Studies and Toxicity

The following section highlights various case reports and studies of patients on high-dose vitamin D supplementation. 

• A seven-year study of hospitalized patients given vitamin D to correct or prevent deficiency concluded daily oral doses between 5,000-60,000 IU were safe and well-tolerated. The mean vitamin D level was 118.9 ng/mL, with a range from 74.4 to 348.8 ng/mL. There were no cases of vitamin D induced hypercalcemia, kidney stones or other health issues. Remarkable benefits and improvement were recorded in patients with asthma, skin cancer and psoriasis. The authors conclude doses as high as 60,000 IU taken daily for years are safe and well tolerated and advocate for a revision of the daily upper intake limit.
• A 2022 study of 319 patients with autoimmune disease were treated with high doses of vitamin D with a mean daily oral dose of 35,291 IU. No patients experienced hypercalcemia. The authors conclude, “…hypercalcemia does not appear to be a first line risk of high-dose vitamin D3 therapy.”

A case series summarizes the events of three adult males taking high dose vitamin D supplementation for 6 years who were assessed for evidence of toxicity. The following table summarizes the dosing protocols and serum levels of vitamin D monitored during the time period:

Of note, male 2 reported marked clinical improvement in asthma. The highest serum level reached was 225 ng/mL. There were no adverse effects nor hypercalcemia among any of these patients. This case series concludes prolonged daily use of vitamin D at dosages ranging between 10,000 IU to 60,000 IU were safely tolerated without evidence of toxicity.

A report summarizes two patients with toxicity as a result of manufacturing error of the supplements they took. One patient took 1,864,000 IU daily for 2 months resulting in hypercalcemia and a serum vitamin D level of 1220 ng/mL which normalized without sequalae after supplementation was stopped and levels fell to 400 ng/mL. The second patient took 970,000 daily for one month and resulted in hypercalcemia and a serum level of 645 ng/mL. This normalized without sequalae.

A case report of two patients following accidental ingestion of 2,000,000 IU showed a rapid increase in vitamin D levels. The patients were followed for three months with no evidence of toxicity.

Several reports show adults who ingested up to 1,000,000 IU daily for several months raised blood levels > 500 ng/mL and resulted in hypercalcemia. Removing vitamin D supplementation led to complete resolution of calcium levels in a short period of time without sequalae.

A case report of a 3-month-old who inadvertently received 14,000 IU daily for 20 days, 35 times the recommended daily amount for infants, led to a serum level of 425 ng/mL. There was no significant change noted in the infant’s calcium or phosphorus levels nor change in kidney function. Short-term high dosing with serum levels over 400 ng/mL was well tolerated without evidence of toxicity.

In all of these cases, the definition of toxicity had nothing to do with the actual serum value but whether there was resultant hypercalcemia or not. Most cases in the literature describing vitamin D toxicity were the result of inadvertent or accidental dosing without monitoring by a physician. In the rare event hypercalcemia is present, it is reported in studies, “…it is not life threatening, and is easily reversible with cessation of vitamin D supplementation.”

What Level > 150 ng/mL Causes Toxicity?

As there is conflicting information in the literature regarding toxicity simply being a level above 150 ng/mL or being the presence of hypercalcemia, the question should then be, at what vitamin D level does hypercalcemia occur? We do not have an answer to this question. This is highly variable per patient. Stated in a previously mentioned study:

“It is challenging to assign an absolute serum vitamin D concentration over which toxicity is always present. Some patients can have 25(OH)D concentrations well over 80 ng/mL without hypercalcemia or hypercalciuria…The vitamin D concentration at which an individual develops hypercalcemia or hypercalciuria is likely influenced by the amount of dietary calcium intake. As a result, serum and urine calcium concentrations may be quite variable, despite concentrations of serum 25(OH)D that might be regarded as elevated.”

High Calcium Levels Not Related to Vitamin D Levels

A 10-year population-based study evaluated 20,308 vitamin D levels of more than 50 ng/mL with the potential for toxicity, characterized by the presence of hypercalcemia. The authors found vitamin D levels were not statistically significantly related to blood calcium levels. Of all measurements, only one case had clinical toxicity demonstrated by hypercalcemia associated with a vitamin D level of 363 ng/mL. A 2017 study concluded hypercalcemia was not related to an increase in vitamin D levels nor vitamin D dose and a 2022 study found a “very weak relationship” between vitamin D dosage and calcium levels.

In the case reports, serum vitamin D levels exceeded 200, 300 and 400 ng/mL without evidence of toxicity. This tells us how variable this is and serum levels cannot be used as a definition of toxicity.

Where did the number > 150 ng/mL as toxic come from? In the research, it is unknown when or why this number was first stated and yet it is continuously repeated in studies for decades without validation.

Vitamin D Toxicity Cannot Be Defined

In the process of researching vitamin D toxicity, there is no real definition for the following reasons:

1. To date, the levels used to define deficiency, insufficiency, optimal and toxicity are not generally agreed upon.
2. There is no consistent vitamin D serum level in scientific literature that characterizes toxicity.
3. Most patients with levels over 150 ng/mL do not develop hypercalcemia.
4. Most studies do not specify how toxicity was characterized other than a level over 150 ng/mL, even in asymptomatic individuals without lab abnormalities.
5. Vitamin D levels were found to be not statistically significantly related to blood calcium levels.

Conclusion

• There is no absolute serum vitamin D level at which toxicity occurs.
• Vitamin D toxicity is accepted as extremely rare though historical decades-old reports of vitamin D toxicity continue to fuel current fears.
• Vitamin D is shown to be one of the least toxic fat-soluble vitamins in studies.
• High dose vitamin D has been used to prevent, treat and cure disease though many miss out on the potential benefits of this therapy due to uncredible scientific literature and historical fear.

Have an awesome day! Dr. D