Vitamin D exposures reported to US poison centers 2000–2014

Abstract

There has been an increased use of vitamin D both by prescription and by the public as a widely available supplement. We evaluated 15 years of single-substance vitamin D exposures to US poison centers.

Methods:

Retrospective analysis of data from the National Poison Data System (NPDS) to evaluate clinical effects, trends, and outcomes of exposures to vitamin D over the period January 1, 2000 through June 30, 2014. Cases were limited to exposures involving vitamin D as a single substance. Multiple vitamin products that may have included vitamin D were not included in this study.

Results:

From 2000 through June 30, 2014, there were 25,397 human exposures to vitamin D reported to NPDS. There was a mean of 196 cases per year from 2000 to 2005, followed by a 1600% increase in exposures between 2005 and 2011 to a new annual mean of 4535 exposures per year. The mean and median ages were 23.4 years and 10 years, respectively. There were no fatalities, but five (0.02%) major effect outcomes. Serious medical outcomes (major or moderate outcome) were infrequent, ranging from 2 patients/year to 22 patients/year. Clinical effects were primarily gastrointestinal (0.7–1.5%) and mild neurological effects (0.2–0.4%). There was a decline in the percentage of patients treated in a health care facility and of patients with serious medical outcome.

Conclusion:

Despite the enormous increase in number of exposures, there was not a significant increase in patients with a serious medical outcome. Rare severe outcomes may occur.

Introduction

In the past decade, there has been an increased focus on the potential benefits of vitamin D in a number of areas including bone health, cancer, heart disease, mortality, and cognitive function. ^1,2 Subsequent to the increased focus on potential benefits of vitamin D has been an increase in the use of vitamin D supplementation in adults and children, both by prescription and as a widely available over-the-counter (OTC) vitamin supplement. It follows that with the increased availability and use of vitamin D there is a possibility of an increased incidence of adverse events.

Oral vitamin D, either as vitamin D₂ (ergocalciferol) or vitamin D₃ (cholecalciferol), is metabolized to 25-hydroxyvitamin D (25(OH)D) and subsequently to the active form 1,25-dihydroxyvitamin D (1,25(OH)₂D). Both 25(OH)D and 1,25(OH)₂D are bound to Vitamin D binding protein and stored in the adipose tissue. However, this binding can be saturated, possibly allowing for increased free serum 1,25(OH)₂D with larger doses. Toxicity appears to be secondary either to elevated levels of 25(OH)D and/or increased levels of unbound 1,25(OH)₂D and subsequent increases in serum calcium levels. ²

Previous studies of vitamin D overdose or adverse events from supratherapeutic doses have looked at specific populations from known dosing errors and manufacturing errors. We chose to look at reports to US poison centers concerning vitamin D to see whether these reflected an increase in adverse events or incidence of toxicity. We believe this is the first study to look at demographic trends and outcomes from vitamin D exposure over a nearly 15-year period using a large database covering the entire US population.

Methods

Data source

This study was a retrospective analysis of data from the National Poison Data System (NPDS) to evaluate clinical effects, trends, and outcomes of all exposures to vitamin D reported to NPDS over the period from January 1, 2000 through June 30, 2014. The NPDS is a comprehensive poison exposure database managed by the American Association of Poison Control Centers (AAPCC). It contains data collected from all of the Poison Control Centers in the United States on a near-real time basis.

Reported exposures from the 50 US states and the District of Columbia were included in the study. Cases were limited to exposures involving vitamin D as a single substance (AAPCC generic code 0046000 vitamin D). Inclusion criteria were exposure to vitamin D in a human. Exposure is a route neutral term used by poison centers to allow for inclusion of multiple routes of exposure, such as ingestion, dermal, parenteral, inhalation, and ocular. Exclusion criteria included exposure to more than one substance (polysubstance), animal exposures, and information calls. Multiple vitamin products that may have included vitamin D were not included in this study and would not be included using the search criteria.

Data were analyzed using Epi Info 7 (CDC) software. This was a retrospective study so statistics were limited to descriptive analysis for demographics (age and gender), year of exposure, clinical effects, reason for exposure, therapies, medical outcome, and patient management site. The χ² square analysis was used to evaluate the differences in outcome between acute and chronic ingestions. For the two graphical figures, data for 2014-estimated was extrapolated from the first 6 months of 2014 data available. This extrapolation was done for better visual annual trending. All other reports of results and tallies include only data to June 30, 2014 with no extrapolation.

Medical outcome was grouped into the following categories as defined by the NPDS: minor effect (“minimally bothersome, rapidly resolving effects that usually involve the skin or mucous membranes”); moderate effect (“more pronounced or more systemic in nature, treatment usually required but effects non-life-threatening”); major effect (“symptoms are life-threatening or resulted in significant disability”); death; not followed (“it was judged as a nontoxic exposure or the poison center was otherwise unable to follow the case”); no effect; or unrelated effect. ³ In this study, “serious medical outcome” is defined as a “moderate effect” or a “major effect” as classified by the NPDS.

Data were analyzed by category of age, gender, level of health care received, medical outcome, acuity and chronicity, management site, type of medication error, and year of exposure. Medical outcomes were classified using standard NPDS categories. In this study, serious medical outcome is defined as a moderate effect, major effect, or “death” as classified by the NPDS.

This study was reviewed by the institutional review board of the authors’ institution and judged to be exempt.

Results

Demographics and reason for exposure

From January 1, 2000 through June 30, 2014, there were 25,397 human exposures to vitamin D reported to NPDS. There was a mean of 196 cases per year from 2000 to 2005, followed by a 1600% increase in exposures between 2005 and 2011 to a new annual mean of 4535 exposures per year (see Figure 1).

Figure 1.

Number of patients who consumed vitamin D and percent with serious outcome by year.

The mean and median ages were 23.4 and 10 years, respectively. A majority of cases were children under 6 years of age (n = 15,093, 59.4%) and female (n = 14,841, 58.44%). In adult cases (age >17 years), females accounted for 77% of cases. Both mean and median age in adult cases (>17 years) was 56 years, with no difference noted between genders.

Three reasons for exposure predominated in the total patient group: unintentional general (53.4%), therapeutic error (40.7%), and adverse drug reaction (3.9%). In adult patients, the predominant reasons for exposure were therapeutic error (80.2%), unintentional general (8.6%), and adverse drug reaction (7.8%). In children <6 years of age the predominant reasons for exposure were unintentional general (86.4%), therapeutic error (13.3%), and adverse drug reaction (0.2%). The majority of exposures were acute ingestions (73%), while 16% were acute-on-chronic and 11% were chronic vitamin D ingestions.

Medical outcome and clinical effects

There were no fatalities, but five (0.02%) major effect outcomes over the 15-year period. Serious medical outcomes (major or moderate outcome) were infrequent, ranging from 2 patients/year to 22 patients/year and 0.42% of patients/year to 3.83% of patients/year, respectively (Figure 1). There were a total of 156 moderate outcomes and five major outcomes. There was a significantly increased risk of a serious outcome with chronic ingestion versus acute ingestion (p < 0.01, odds ratio 3.57, 2.61–4.89). There were 106 suicide attempts using vitamin D alone, with 6 (5%) moderate outcomes and no major outcomes. Despite the enormous increase in number of exposures, there was no significant increase in patients with a serious medical outcome. Children had similar medical outcomes to the adults and the total group, and in children <6 years there were 2 (0.01% of children) major outcomes and 47 (0.3% of children) moderate outcomes. Clinical effects were primarily gastrointestinal and mild neurological effects. Effects that were reported in more than 30 patients are listed in Table 1. The clinical effects reported in the five major effect outcomes are listed in Table 2. Specific therapeutic interventions are listed in Table 3. The route of exposure was predominantly ingestion (n = 24,863, 98%), with 226 ocular, 197 dermal, 50 parenteral, and 16 other. All major outcomes were by ingestion. Four moderate outcomes were via parenteral route and all other moderate outcomes were from ingestion.

Table 1.

Clinical effects reported in more than 30 patients.

Effect	Number of patients (%)
Nausea	383 (1.5%)
Vomiting	179 (0.7%)
Abdominal pain	176 (0.7%)
Diarrhea	165 (0.7%)
Headache	138 (0.5%)
Drowsiness	101 (0.4%)
Dizziness	90 (0.4%)
Constipation	62 (0.2%)
Muscle weakness	60 (0.2%)
Anorexia	46 (0.2%)
Rash	39 (0.2%)

HCF: health care facility.

Table 2.

Clinical effects of reported in patients with major effect outcomes.

Age and gender	Chronicity	Clinical effects reported
55 years, Male	Chronic ingestion	Agitation, confusion, electrolyte abnormalities, renal failure, and seizures
78 years, Male	Chronic ingestion	Lethargy, electrolyte abnormalities, renal failure, and respiratory depression
53 years, Female	Chronic ingestion	Increased creatinine, renal failure, electrolyte abnormality, and hypertension
2 months, Female	Acute ingestion/aspiration	Cough/choke, cyanosis, and dyspnea
2 months, Female	Acute ingestion/aspiration	Cough/choke, cyanosis, respiratory depression, and X-ray findings

Table 3.

Therapies provided in patient treated in an HCF.

Intravenous fluids	73
Antihistamines	41
Antiemetics	24
Steroids	17
Bronchodilators	5
Antihypertensive	4
Oxygen	3
Hemodialysis	2

HCF: health care facility.

The majority of patients were able to be managed on-site at a non-health care facility (HCF; n = 21,964, 86.5%), mainly at their residence, with telephone consultation by the poison center. The number of patients seen in an HCF increased from 31 patients in 2000 to 470 patients in 2011, decreasing to 419 patients in 2013. However, there was a decline in the percentage of patients treated in an HCF from a high percentage of 19.1% in 2001 to a low percentage of 9.3% in 2013 with a serious medical outcome (Figure 2).

Figure 2.

Percentage of total patients managed at an HCF and with serious medical outcome.

Discussion

Significant injury after vitamin D intoxication has been reported in individual cases and in small case series from manufacturing errors, dosing errors, and misuse of OTC vitamin D supplementation. ^{4 –13} Severe clinical effects after vitamin D intoxication have occurred in children and adults, and have included confusion, seizures, coma, renal failure, cardiac arrhythmias, and psychiatric disturbances. Severe events appear to be uncommon however, despite the massive increase in the use of vitamin D both by prescription and as a widely available OTC vitamin supplement. After a 1600% increase in vitamin D exposures reported to US poison centers the incidence of severe cases remained remarkably low, without a notable increase in morbidity and no mortality. One reason for this low incidence might be that the majority of the exposures in this study were single, acute ingestions vs. chronic ingestions. The published cases of severe clinical effects have all occurred after chronic ingestion, secondary to the effect of increased serum calcium. This is consistent with our finding that chronic exposure showed an increased risk of severe outcome. Additionally the large acute ingestions in the suicide attempts did not produce major outcomes. While the two infants with major effects reported in this study were acute ingestions, the events appeared to be secondary to an adverse drug reaction and/or aspiration of the dose, rather than with elevated calcium levels. A second reason for the low incidence may be the large range between therapeutic dose and toxic dose, allowing for significant errors before seeing severe toxicity. Finally, because the nature of follow up by poison centers is short term and the half-life of 25(OH)D is 2–3 weeks, the onset of clinical effects renal stones or renal failure may have been delayed and therefore not recorded in these cases.

A small number (<4%) of patients reported clinical effects commonly associated with vitamin D intoxication and hypercalcemia: nausea, vomiting, constipation, abdominal pain, anorexia, drowsiness, and muscle weakness. NPDS data do not record calcium levels. There may have been a larger number of patients with mild or asymptomatic hypercalcemia. Therapeutic interventions normally instituted for hypercalcemia were infrequently utilized however, again reflecting the rare incidence of serious cases over the 15-year period. The percentage of patients managed in a HCF has also decreased by half. It is possible that the decrease is HCF use is because of increased familiarity of poison center personnel with vitamin D exposures and the continued lack of severe outcomes. However there continues to be >400 patients per year seen in a HCF for vitamin D exposures.

There are a number of limitations of this study, including the inherent limitations of retrospective studies and the voluntary nature of reporting vitamin D exposures to a poison center. Another limitation is that there are no serum calcium or 25(OH)D concentrations for our study to verify that the ingestion occurred, especially in the large number of asymptomatic patients. This report likely underestimates the true prevalence of vitamin D ingestions and dosing errors, as many individuals might have made errors without recognition or sought information from online resources. Nevertheless, the enormous increases noted in NPDS suggest there is an increased incidence of vitamin D ingestion in the population, and observation of these trends helps to further illustrate the scope of the problem.

Conclusion

The NPDS provides a large, accessible database conducive to characterizing toxicity and demographic trends after vitamin D ingestion. From 2000 to 2014, the number of patients reported to US poison centers of vitamin D ingestion increased to 1600%, from a mean of 196 patients per year by >4500 patient per year. Approximately 10% of these patients were seen in an HCF. The incidence of severe cases remains remarkably low, without a notable increase in morbidity and no mortality. Rare severe outcomes may occur.