Published online August 1, 2006
PEDIATRICS
Vol. 118
No. 2
August 2006, pp.
820-824
(doi:10.1542/peds.2006-0167)
Risk of Vitamin A Toxicity From Candy-Like Chewable Vitamin Supplements for Children
Hugh Simon Lam, MRCPCHa,
Chung Mo Chow, MRCPCHa,
Wing Tat Poon, MBChBb,
Chi Kong Lai, MScb,
Kwan Chee Allen Chan, FRCPAc,
Wai Lan Yeung, MRCPa,
Joannie Hui, MRCPa,
Albert Yan Wo Chan, MDb and
Pak Cheung Ng, MDa
a Departments of Pediatrics
c Chemical Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
b Toxicology Reference Laboratory, Princess Margaret Hospital, Hong Kong
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ABSTRACT
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Numerous vitamin supplements are available over-the-counter to the general public. Some such supplements are available as candy-like chewable preparations to encourage consumption by children. We report 3 cases of overdose of such preparations. Each patient had taken an estimated 200000 to 300000 IU of vitamin A. Their circulating vitamin A (retinol and retinyl palmitate) concentrations were monitored over a 6-month period. There were no clinical or biochemical complications noted. However, there were marked increases in both retinol and retinyl palmitate concentrations above age-related reference ranges. In particular, it took 1 to 3 weeks for the serum retinol concentrations to peak and many months for them to normalize. Parents should be warned about the dangers of excessive vitamin consumption. Clinicians should be aware of the late peak in serum retinol concentrations, which may lead to late complications of vitamin A overdose.
Key Words: acute vitamin A overdose • vitamin supplementation • vitamin A kinetics
Vitamin A, a fat-soluble vitamin, plays essential roles in vision, growth, and neurodevelopment. The US Institute of Medicine recommended dietary allowance of vitamin A is 1000 IU for children aged 1 to 3 years and 1320 IU for children aged 4 to 8 years.1 The ideal way to acquire adequate amounts of vitamin A is to consume a healthy and well-balanced diet. With the exception of sources such as polar bear or chicken liver, which contain 
18000 and 16000 to 17000 IU/g of vitamin A, respectively, it is unusual for individuals to develop hypervitaminosis A by consuming natural sources of this vitamin.2,3 Despite the fact that healthy individuals on a balanced diet rarely require vitamin A supplementation, numerous commercial vitamin A supplements are readily available over-the-counter (Table 1). 3–7 These preparations usually contain between 1000 and 25000 IU of vitamin A.3,4 To encourage consumption by children, many companies have produced candy-like chewable vitamin supplements (Table 1). We recently managed 3 young children who had ingested large numbers of Kawai Kanyu Drop S jelly vitamins (Kawai Pharmaceutical Co, Ltd, Saitama, Japan) over the course of a few days. They were monitored over a 6-month period. In this report we summarize their clinical features and laboratory findings.
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TABLE 1 Examples of Chewable Vitamin Supplements Available From Different Regions Around the World and Marketed to Children
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CASE REPORTS
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Three patients were admitted to the Prince of Wales Hospital in Hong Kong, each with a history of ingesting a large amount of the same brand of jelly vitamin (Kawai Kanyu Drop S). Two were 5-year-old boys and one was a 30-month-old boy. Each had consumed 100 to 150 jelly vitamins over the course of 3 to 5 days. The company processes cod liver oil into solid form while adding various ingredients including flavoring to produce these candy-like, chewable jelly vitamins. There were 300 jelly vitamins per can, with each piece containing 2000 IU of vitamin A and 200 IU of vitamin D2. Analysis at the toxicology laboratory found that retinyl palmitate was the sole vitamin A ingredient. In each case, the excessive vitamin consumption was discovered by the caregiver, who noted that the container had emptied too quickly. The boys were previously healthy and were asymptomatic on admission. There were no abnormal findings on physical examination; in particular, there were no signs of gastrointestinal, renal, or neurologic complications. Serial blood samples were taken on presentation and at regular intervals over a 6-month period after the overdoses for complete blood counts, liver and renal function, and fasting serum 25-hydroxyvitamin D, retinol, and retinyl palmitate concentrations. In addition, the jelly vitamins were sent to the toxicology laboratory for vitamin A determination by high-performance liquid chromatography.8
The serial concentrations of serum retinol are shown in Fig 1. The serum retinol concentrations were increased above the reference range (0.7–1.5 µmol/L in 1- to 6-year-old children9) on admission and continued to increase over the subsequent weeks. There then was a slow downward trend in serum retinol concentration over the following months. The serum retinyl palmitate concentrations (reference median concentration: <244 nmol/L10) were substantially increased on admission in patients 1 and 3 (371 and 437 nmol/L, respectively) and then progressively decreased within 2 to 3 weeks of the overdoses (293 and 279 nmol/L, respectively). Concentrations in patient 2 remained relatively unchanged after the overdose (261 nmol/L on admission and 255 nmol/L 3 weeks after the overdose). By 6 to 7 months, concentrations for patients 1, 2, and 3 were 280, 260, and 220 nmol/L, respectively.
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FIGURE 1 Serum retinol concentration trends in the 3 patients after the jelly vitamin overdoses (reference range: 0.7–1.5 µmol/L in 1- to 6-year-old children9).
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Serial serum 25-hydroxyvitamin D concentrations, blood counts, liver enzymes, electrolytes, and bone-profile results remained normal in all 3 patients throughout the study period.
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DISCUSSION
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Although none of our patients exhibited any clinical features of acute hypervitaminosis A, such as nausea, vomiting, headaches, blurred vision, ataxia, hair loss, skin peeling, or bone pain,2–4 the risk of acute or chronic hypervitaminosis A would have been substantial had the overdoses not been stopped in time.
It has been reported that a single 50000-IU dose of oil-based retinyl palmitate can increase the incidence of transient bulging of the fontanelle in infants,11 possibly because of increased intracranial pressure. Another study showed that single 100000-IU doses of oil-based retinyl palmitate administered orally were associated with headaches, fever, and gastrointestinal symptoms in young children.12 Although complications of vitamin A ingestion have been shown to develop at such low doses, the literature suggests that lethal doses are much higher. The median lethal dose of a single intramuscular injection of retinyl acetate in young monkeys was shown to be 560000 IU/kg,13 whereas an infant was reported to have died after receiving 90000 IU/day of a water-miscible preparation of retinyl palmitate orally over the course of 11 days (ie, a cumulative dose of 990000 IU).5 Our patients were each estimated to have taken 100 to 150 jelly vitamins, which equates to vitamin A doses of between 200000 and 300000 IU. There is evidence to suggest that the physical form of the vitamin A supplement has a profound effect on the potential for toxicity. Although in many studies on hypervitaminosis A the preparations were oil-based, the supplements consumed by our patients were not. Water-miscible, emulsified, or solid-based vitamin A supplements were shown in a meta-analysis to be as much as 10 times more potent than oil-based supplements.7 Thus, the adverse effects of consuming excessive amounts of solid candy-like vitamins could occur at much lower doses than expected. The reason for this difference in potency is likely related to the improved absorption of vitamin A by the gastrointestinal tract of solid, emulsified, and water-miscible preparations. This difference in potency also impacts on the risk of chronic hypervitaminosis A. In the same study,7 the lowest dose of non–oil-based vitamin A that caused chronic hypervitaminosis A was 670 IU/kg per day over a period of a few weeks. On the basis of this evidence, it is feasible for a 30-kg child taking 10 chewable vitamins (each containing 2000 IU vitamin A) per day for more than a few weeks to develop chronic hypervitaminosis A.
Under normal conditions, the serum concentration of retinol, the predominant form of circulating vitamin A, rises beyond the reference range after vitamin A consumption has been sufficient to saturate liver stores.3 Dietary vitamin A administered as retinyl esters is hydrolyzed almost completely in the gastrointestinal tract to retinol. The retinol is then absorbed via a protein carrier into the enterocytes before being re-esterified, mostly into retinyl palmitate,14,15 and incorporated into chylomicrons for transport via the lymphatic system.14 After oral administration of a single dose of vitamin A, serum retinyl ester concentrations usually peak within 12 hours. Meanwhile, the ester is normally converted to retinol by the liver within 24 hours of consumption.15,16 In our series, all 3 patients consumed large doses of vitamin A in the form of retinyl palmitate. It is possible that hepatic stores of retinyl esters and conversion of serum retinyl palmitate to retinol in patients 1 and 3 became saturated, causing a delay in clearance of the ester from circulation and elevated serum concentrations of both retinol and retinyl palmitate on admission. The subsequent increase in serum retinol over the weeks after the overdose may have represented continued conversion of excess retinyl esters to retinol by the liver. Although serum retinyl palmitate in patient 2 did not show a substantial increase, the serum retinol profile was similar in all 3 patients. It is possible that the difference in the serum retinyl palmitate profile between patient 2 (30-month-old boy) and patients 1 and 3 (5-year-old boys) was a result of age-related differences in vitamin A metabolism.3
Because serum retinol concentrations >3.5 µmol/L can be toxic in young children,3 patients with vitamin A overdose should be advised to take a vitamin A–restricted diet until concentrations normalize. Although circulating retinol concentrations did not reach toxic levels in our patients, it is likely that a delay in diagnosis with continued ingestion would have resulted in toxic effects. In this series, the serum concentrations of retinol peaked several weeks after the overdose. To our knowledge, this has not been reported previously. In contrast, previous studies show peak concentrations within 24 hours of vitamin A administration.15,16 In light of our findings, we recommend that similar cases be monitored for this late peak and its potential complications. The differences between our patients and subjects in other studies may be related to factors such as age, the subjects’ vitamin A status, and physical properties of the vitamin preparation. The dosing regime could also be an important contributory factor. Gastrointestinal absorption of vitamin A becomes less efficient as the dose gets larger.14 Therefore, in comparison with single large doses, smaller, frequent, multiple doses could increase vitamin A absorption.
The serum 25-hydroxyvitamin D and plasma calcium and phosphate levels of our patients remained normal despite consuming an estimated dose of 20000 IU of vitamin D2. Oral doses of up to 600000 IU of vitamin D3 have been tolerated well by healthy infants, with only transient increases in serum calcium levels.17 In addition, vitamin D2 is 3 to 10 times less potent than vitamin D3.18 Acute hypervitaminosis D, therefore, is likely only if a child takes in excess of 9000 jelly vitamins within a short period. Conservatively assuming a tolerable upper intake level of 2000 IU per day,19 a child could ingest up to 30 jelly vitamins per day indefinitely without a substantial risk of chronic hypervitaminosis D. The probability of developing hypervitaminosis D, therefore, is minimal, and as expected, our patients did not develop any clinical or biochemical evidence of vitamin D toxicity.
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CONCLUSIONS
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Similar candy-like chewable vitamin supplements (Table 1) containing substantial amounts of vitamin A must be treated with extreme care when kept at home. There is a genuine risk of children inadvertently taking large numbers of this preparation within a relatively short period of time, which can result in hypervitaminosis A. Parents must be vigilant when giving these supplements to their children. More importantly, because serum retinol concentrations may continue to rise weeks after the initial overdose, regular monitoring over the subsequent months is recommended. Although public health programs in developing regions suggest that intermittent high-dose vitamin A is safe, the circulating vitamin A profiles of our patients suggest that similar doses of non–oil-based preparations inadvertently consumed by children with adequate vitamin A reserves may not be. To prevent the occurrence of vitamin overdoses in children, the public should be educated about the dangers of excessive vitamin supplementation. It is possible that marketing these supplements as candy increases the risk of overdose in children. Measures such as child-proof containers, individually wrapped foil packaging and, as with over-the-counter analgesia,20 limitation of the number of vitamins per container may all help to decrease the possibility of overdose.
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FOOTNOTES
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Accepted Mar 2, 2006.
Address correspondence to Hugh Simon Lam, MRCPCH, Department of Pediatrics, 6/F, Clinical Sciences Building, Prince of Wales Hospital, Sha Tin, New Territories, Hong Kong. E-mail: hshslam{at}cuhk.edu.hk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES
|
|---|
- Food and Nutrition Board, Institute of Medicine.
Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001
- Fishman RA. Polar bear liver, vitamin A, aquaporins, and pseudotumor cerebri.
Ann Neurol. 2002;52
:531
–533[CrossRef][ISI][Medline]
- Allen LH, Haskell M. Estimating the potential for vitamin A toxicity in women and young children.
J Nutr. 2002;132(9 suppl)
:2907S
–2919S
- Kowalski TE, Falestiny M, Furth E, Malet PF. Vitamin A hepatotoxicity: a cautionary note regarding 25,000 IU supplements.
Am J Med. 1994;97
:523
–528[CrossRef][ISI][Medline]
- Bush ME, Dahms BB. Fatal hypervitaminosis A in a neonate.
Arch Pathol Lab Med. 1984;108
:838
–842[ISI][Medline]
- Ross DA. Recommendations for vitamin A supplementation.
J Nutr. 2002;132(9 suppl)
:2902S
–2906S
- Myhre AM, Carlsen MH, Bohn SK, Wold HL, Laake P, Blomhoff R. Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations.
Am J Clin Nutr. 2003;78
:1152
–1159[Abstract/Free Full Text]
- Hartmann S, Froescheis O, Ringenbach F, et al. Determination of retinol and retinyl esters in human plasma by high-performance liquid chromatography with automated column switching and ultraviolet detection.
J Chromatogr B Biomed Sci Appl. 2001;751
:265
–275[CrossRef][Medline]
- Lockitch G, Halstead AC, Wadsworth L, Quigley G, Reston L, Jacobson B. Age- and sex-specific pediatric reference intervals and correlations for zinc, copper, selenium, iron, vitamins A and E, and related proteins.
Clin Chem. 1988;34
:1625
–1628[Abstract/Free Full Text]
- Ballew C, Bowman BA, Russell RM, Sowell AL, Gillespie C; National Health and Nutrition Examination Survey (NHANES III). Serum retinyl esters are not associated with biochemical markers of liver dysfunction in adult participants in the third National Health and Nutrition Examination Survey (NHANES III), 1988–1994.
Am J Clin Nutr. 2001;73
:934
–940[Abstract/Free Full Text]
- de Francisco A, Chakraborty J, Chowdhury HR, et al. Acute toxicity of vitamin A given with vaccines in infancy.
Lancet. 1993;342
:526
–527[CrossRef][ISI][Medline]
- Florentino RF, Tanchoco CC, Ramos AC, et al. Tolerance of preschoolers to two dosage strengths of vitamin A preparation.
Am J Clin Nutr. 1990;52
:694
–700[Abstract/Free Full Text]
- Macapinlac MP, Olson JA. A lethal hypervitaminosis A syndrome in young monkeys (Macacus fascicularis) following a single intramuscular dose of a water-miscible preparation containing vitamins A, D2 and E.
Int J Vitam Nutr Res. 1981;51
:331
–341[ISI][Medline]
- Blomhoff R, Green MH, Green JB, Berg T, Norum KR. Vitamin A metabolism: new perspectives on absorption, transport, and storage.
Physiol Rev. 1991;71
:951
–990[Free Full Text]
- Reinersdorff DV, Bush E, Liberato DJ. Plasma kinetics of vitamin A in humans after a single oral dose of [8,9,19–13C]retinyl palmitate.
J Lipid Res. 1996;37
:1875
–1885[Abstract]
- Tang G, Qin J, Dolnikowski GG, Russell RM. Short-term (intestinal) and long-term (postintestinal) conversion of beta-carotene to retinol in adults as assessed by a stable-isotope reference method.
Am J Clin Nutr. 2003;78
:259
–266[Abstract/Free Full Text]
- Zeghoud F, Ben-Mekhbi H, Djeghri N, Garabedian M. Vitamin D prophylaxis during infancy: comparison of the long-term effects of three intermittent doses (15, 5, or 2.5 mg) on 25-hydroxyvitamin D concentrations.
Am J Clin Nutr. 1994;60
:393
–396[Abstract/Free Full Text]
- Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans.
J Clin Endocrinol Metab. 2004;89
:5387
–5391[Abstract/Free Full Text]
- Food and Nutrition Board, Institute of Medicine.
Dietary Reference Intakes for Calcium, Magnesium, Phosphorus, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997
- Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: before and after study of long term effect on poisonings [published correction appears in BMJ. 2004;329:1159].
BMJ. 2004;329
:1076[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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