Vitamin D Toxicity-Clinical Implications [Hot Topic]

Singh
Ravinder Singh, Ph.D.

There has been significant interest in identifying those patients at risk of vitamin D deficiency. However, in this era of increased supplementation, there is growing evidence that individuals may be at risk of vitamin D toxicity as a result of overdosing. The use of multiple products that contain vitamin D supplementation can combine to potentially toxic levels.

Presenters and Credentials:
Ravinder Singh, Ph.D., Professor of Laboratory Medicine and Pathology in the Division of Clinical Biochemistry and Immunology at Mayo Clinic in Rochester, Minnesota

Transcript

PresenterWelcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.

Our speaker for this program is Dr. Ravinder Singh, Professor of Laboratory Medicine and Pathology in the Division of Clinical Biochemistry & Immunology at Mayo Clinic in Rochester, Minnesota. Dr. Singh will be discussing the toxicity of vitamin D. Thank you Dr. Singh for presenting with us today.

Objective

Thank you, Cara.  So objective today is to discuss the case of hypercalcemia due to vitamin D toxicity.

Disclosure

I have no disclosures related to this talk, and I won’t be discussing any drug, either off label or investigational, use.

Learning Points

So the learning points for the presentation today would be that vitamin D toxicity is not a myth but is a reality.  Vitamin D is a prohormone and is part of the complex endocrine system.  Vitamin D toxicity is not limited to the children.

Case of Hypercalcemia

So regarding the case this was a case which came to Mayo Clinic a 4-month-old girl was admitted to the pediatric intensive care unit.  Her calcium was very high when she was admitted (18), and then it was still up and down, and it was 15.5 and 15.4; and her phosphorus was 2, 1.8; parathyroid hormone was <6; PTHrP or parathyroid hormone-related peptide was normal.  The physician was concerned and she called the lab—what will cause PTH to be low, and are there any interferences in the PTH assays?  And the lab looked at the results and verified that there was nothing wrong with the lab assay, and the PTH was really low, which was <6.

A little more history on the baby here.  Ultrasound of the abdomen was normal, but ultrasound of the kidneys did show nephrocalcinosis, which is small stones and damage to the kidney.  Further finding more about the history of the baby:  baby was being was breastfed and, according to the mother, she was also giving some teething medicine some kind of homeopathic medicine and mom does not remember the brand of the natural vitamin D, but she did say she was giving some vitamin D to this newborn baby.

Diagnosis of Hypercalcemia-Vitamin D Toxicity?

The challenge for our physician at Mayo Clinic was—what is a diagnosis of hypercalcemia?  Could it be vitamin D toxicity?  But the physician was thinking very hard—if mom is giving excess vitamin D, then in the addition to the high calcium levels, phosphorus levels should also be high.  But if you remember in the previous slide, they were on the low end or normal.

History: 4-Month-Old Female: Vomiting/Diarrhea

Further history about this particular child is this baby was sick right from birth, failure to thrive.  Baby used to vomit frequently at home every couple of hours, baby was vomiting consisting of breast milk and partially digested breast milk, and baby had history of diarrhea of multiple loose watery stools every day.

History of 4-Month-Old Female: Weight Loss

According to the parents, baby has decreased appetite and just seems to be more tired and kind of out of it.  And the physicians and nurses also noted that she had lost 200 grams of her weight since her last visit, which was 1 month ago.

History of 4-Month-Old Female in Pediatric Intensive Care Unit

As physicians were attending this particular child, they did notice that her presentation was consistent with dehydration; and in order to correct that, she received fluid bolus fluids and repeat labs, 12 hours showed some improvement in blood urea nitrogen as well as there was a decline in her total calcium.

Case: Serum Calcium

This particular slide shows her course of calcium, which was high, which did not improve just with simple hydration.  Then physicians used a very potent drug called calcitonin, which normalized the calcium, and then the baby was discharged from the Saint Mary’s Hospital.  But as soon as the baby was discharged and the effect of the calcitonin drug was over, then calcium came back.  Baby was readmitted to the hospital again, and then baby was treated with a different bisphosphonate drug, which is called pamidronate.  And then as you can notice, the baby’s calcium was normalized during the course of the treatment.

Laboratory Results for Mother

The curiosity with the patient care team was that—is there anything in mother’s condition which could be contributing to the hypercalcemia in this particular child?
Looking at the electrolytes for the mom, it was good to find that her calcium, potassium, and creatinine were very normal.  And we also tested vitamin D levels in the mother, which was very normal; 25-hydroxyvitamin D was only 13, and 1,25-dihydroxyvitamin D was also 39.  So these labs indicate that there was nothing from the mother which was transferring to the baby in the breast milk, causing her hypercalcemia.

Vitamin D Level in the Baby was Very High

But in this slide, if you compare the lab results of the infant with the mother head-to-head, of course, we know that baby’s calcium was very high, and we already noticed baby’s phosphate was lower compared to the reference range, which goes from 2.5 to 4.5; but to everyone’s surprise in the care team was that her vitamin D level turned out to be 293 and, correspondingly, 1,25-dihydroxyvitamin D was also 138.

So vitamin D, either made in the skin or circulation through the sunlight or taken through the diet, quickly gets converted to 25-hydroxyvitamin D through an enzyme called 25-hydroxylase in the liver; but then, bioactive hormone, which is 1,25-dihydroxyvitamin D is only synthesized on an  need basis by the kidney, using an enzyme called 1-alpha-hydroxylase.  And 1,25-dihydroxyvitamin D levels are in picogram/mL vs 25-hydroxyvitamin D levels in nanogram/mL.  And 25-hydroxyvitamin D is accepted as a biomarker to determine vitamin D deficiencies or toxicity.

Vitamin D Endocrine System

This particular slide now highlights that vitamin D endocrine system is very complex.  In situations when the calcium is low, the calcium-sensing receptor will act on the calcium-sensing receptor in the parathyroid gland.  Parathyroid hormone will be secreted.  Parathyroid hormone will convert 25-hydroxyvitamin D by the kidney into 1,25-hydroxyvitamin D.  Then 1,25-dihydroxyvitamin D will help in absorbing calcium and phosphorus from the diet through the receptors in the intestine, and the PTH also helps in absorbing the calcium.  Today, we are focusing on the hypercalcemia, not the hypocalcemia or calcium deficiency or vitamin D deficiencies.  So in this case, as you can imagine, if the vitamin D levels were high, the PTH will be suppressed because it was hypercalcemia; thus, the body will try to down regulate the synthesis of 1,25-dihydroxyvitamin D.

Day 2 in PICU 4-Month-Old Female

Getting back to the baby in the intensive care unit, further talking to the mom, mom did say that she has been giving this particular baby supplemental vitamin D as mom’s friend convinced her that vitamin D is good and safe.  Mom thinks that she was giving 100 units, which was kind of accepted guidelines to use that kind of amount, and she was giving 0.25 mL.  Mom was requested to provide this supplement and was given to the lab to find out what exactly is the concentration of vitamin D in this supplement.

How Much Vitamin D was the Baby Getting?

So, lab tested the vitamin D.  This is different than the 25-hydroxyvitamin D, which is a biomarker, so we had to develop a special test, and then vitamin D was found to be 3-fold higher in a drop, like 6,000 international units/per drop, compared to what was listed in the label which was 2,000 international/drop, and also mother was giving full dropper, which was many, many more than was intended.  An overall calculation showed that, on an average, mom was giving 50,000 units to this particular baby daily for months, and that probably would have resulted in hypercalcemia and vitamin D toxicity.

Vitamin D Toxicity

So this is the 25-hydroxyvitamin D data on the Y axis on the left, and then you can see the total calcium on the right.  So this was over a period of almost 2 months now that it took almost 2 months for the baby’s vitamin D to normalize, which is the white line here.  And since the vitamin D stayed still in higher than the normal range for babies, the calcium was difficult to control with the treatment and the drugs.

2-Month Follow-up

After another 2 months, baby is now 6 months old; and, according, to the physician, there are no concerns for 6-month-old young lady, and she is doing quite well, and her development has really picked up.

Hypercalcemia-Adult: Due to Vitamin D Intoxication

So, vitamin D toxicity or hypercalcemia is not limited to children only.  It has also been reported in adults.  This particular case report was reported in the New England Journal of Medicine in 2001.  And if you notice here, calcium was also high (15); and upon treatment, which was similar to the treatment we discussed in this child, was brought into normal range.  But interestingly, again, this patient was taking a lot of vitamin D, and vitamin D level was 500, which is much, much higher than the safe zone for vitamin D levels.  And it took almost 30 months for this particular individual to bring his vitamin D levels in the safe zone.

At Mayo Clinic, we also had one case in an adult.  This particular individual was taking some kind of chocolate which was supplemented with the vitamin D.  It is called Sunny D chocolate.  And this person also developed hypercalcemia; and for the testing vitamin D, it was 350 or so.  And as you can notice, again, it took more than a year to normalize this particular vitamin, 25-hydroxyvitamin D, in this individual.  In this case, we also confirmed vitamin D storage levels in the fat biopsy, which were also reported to be high, which is, again, a very invasive procedure and is not recommended for every patient.

Vitamin D Toxicity: Myth or Reality

So this particular concern about the toxicity and the hypercalcemia was also brought up by the Institute of Medicine, which was a report published in 2010, and this particular group of experts in the committee concluded that the majority of the Americans and Canadians are receiving adequate amounts of both calcium and vitamin D, and supplementation should be considered when it is really clinically needed.  And rather, they were even further concerned about that too much of these nutrients may be harmful.

Vitamin D Metabolism

This particular slide summarizes that once you take vitamin D, either through the diet, supplements, or through the UVB light which is from the skin, that kidneys will help in clearing the excess 25-hydroxyvitamin D or excess of 1,25-hydroxyvitamin D by using another enzyme, which is called 24-hydroxylase, by converting 25-hydroxyvitamin D into 24, 25 or converting 1,25 into 1,24, 25-hydroxyvitamin D.  But when there is an excess of vitamin D, these enzymes get saturated, and patients will develop hypercalcemia due to vitamin D toxicity.

Vitamin D Endocrine System

Again, this is again, summarizing that vitamin D is a prohormone.  It’s not a benign compound.  It has multiple effects in physiology.  It will down regulate PTH; and as you noticed in our case, we still can’t explain why the phosphate is low in some of the recent cases we have observed, even though the traditional book knowledge is that both calcium and phosphorus should be high.  So we are investigating that—is it a lab methodology issue, or is it a clinical issue?  We don’t have the answer for this yet.

References

These are some of the references for your consideration, which have been used in the preparation of this particular talk.  Even though there is a lot of literature, a lot of new publications are coming every month from this area.  Thank you, Cara

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