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Vitamin A Toxicity

Mohsen S Eledrisi, MD, FACP, FACE, Consultant, Department of Internal Medicine, Division of Endocrinology and Metabolism, King Abdulaziz National Guard Medical Center, Saudi Arabia
Kevin McKinney, MD, Assistant Professor, Department of Medicine, Division of Endocrinology and Metabolism, University of Texas Medical Branch at Galveston; Mohammad S Shanti, MD, ABEM, Chair, Department of Emergency Medicine, King Faisal Specialist Hospital and Research Center

Updated: Sep 2, 2009

Introduction

Background

Vitamin A is an important fat-soluble vitamin. Its basic molecule is a retinol, or vitamin A alcohol. After absorption, retinol is transported via chylomicrons to the liver, where it is either stored as retinol ester or re-exported into the plasma in combination with retinol-binding protein for delivery to tissue sites.

Dietary vitamin A is obtained from preformed vitamin A (or retinyl esters), which is found in animal foods (liver, milk, kidney, and fish oil), fortified foods, and drug supplements. Dietary vitamin A is also obtained from provitamin A carotenoids from plant sources, principally carrots. Dietary vitamin A is available mainly as preformed vitamin A in western countries and as provitamin A carotenoids in developing countries.

The bioavailability of retinol is generally more than 80%, whereas the bioavailability and bioconversion of carotenes are lower. These may be affected by species, molecular linkage, amount of carotene, nutrition status, genetic factors, and other interactions. While in general the body absorbs retinoids and vitamin A very efficiently, it lacks the mechanisms to destroy excessive loads. Thus, the possibility of toxicity exists unless intake is carefully regulated.1 Revision of earlier estimates of daily human requirements of vitamin A has been suggested; the suggestion is that estimates ought to be revised downwards. Concerns exist about the teratogenicity of vitamin A.2

Pathophysiology

The recommended daily allowance for vitamin A is 5000 international units (IU) for adults and 8000 IU for pregnant or lactating women. Being fat-soluble, vitamin A is stored to a variable degree in the body, making it more likely to cause toxicity when taken in excess amounts.3 In contrast, water-soluble vitamins are generally excreted in the urine and stored only to a limited extent; hence, adverse effects occur only when extremely large amounts are taken.

Frequency

United States

Nutritional surveys indicate that about 35-50% of adults regularly consume vitamin and mineral supplements. Data are not available for consumption of vitamins in children.

Mortality/Morbidity

  • Mortality is rare from vitamin A toxicity.
  • Morbidity is evident by the wide range of complications observed in this condition.

Race

The use of supplements is generally higher in whites, as well as in individuals with higher levels of education and income.

Sex

The use of vitamin supplements is more common among females.

Age

Single vitamins are consumed more often by adults, while multivitamins are administered more frequently to children.

Clinical

History

  • Carotenemia, the ingestion of excessive amounts of vitamin A precursors in food, mainly carrots, is manifested by a yellow-orange coloring of the skin, primarily the palms of the hands and the soles of the feet. It differs from jaundice in that the sclerae remain white.
  • In acute vitamin A toxicity, a history of some or all of the following may be obtained:
    • Nausea
    • Vomiting
    • Anorexia
    • Irritability
    • Drowsiness
    • Altered mental status
    • Abdominal pain
    • Blurred vision
    • Headache
    • Muscle pain with weakness
  • In chronic vitamin A toxicity, a history of some or all of the following may be obtained:
    • Anorexia
    • Hair loss
    • Dryness of mucus membranes
    • Fissures of the lips
    • Pruritus
    • Fever
    • Headache
    • Insomnia
    • Fatigue
    • Irritability
    • Weight loss
    • Bone fracture4
    • Anemia
    • Bone and joint pains
    • Diarrhea
    • Menstrual abnormalities
    • Epistaxis

Physical

  • Manifestations of acute toxicity
    • Muscle and bone tenderness, especially over the long bones of the upper and lower extremities
    • Neurologic manifestations with signs of increased intracranial pressure (eg, children may have bulging fontanelles)
  • Manifestations of chronic toxicity
    • Alopecia
    • Skin erythema
    • Skin desquamation
    • Brittle nails
    • Exanthema
    • Cheilitis
    • Conjunctivitis
    • Petechiae
    • Liver cirrhosis
    • Premature epiphysial closure in children
    • Hepatosplenomegaly
    • Peripheral neuritis
    • Benign intracranial hypertension
    • Ataxia
    • Papilledema
    • Diplopia
    • Hyperostosis
    • Edema
    • Hepatic hydrothorax5

Causes

  • Causes of carotenemia  
    • Carotenemia is the result of excessive intake of vitamin A precursors in foods, mainly carrots.
    • Other than the cosmetic effect, carotenemia has no adverse consequences because the conversion of carotenes to retinol is not sufficient to cause toxicity.
  • Causes of vitamin A toxicity are generally categorized into acute and chronic.
    • Acute toxicity occurs within a few hours or days after a very large intake as a result of accidental over-ingestion or inappropriate therapy. The estimated toxic dose is about 25,000 IU/kg.
    • Chronic toxicity appears after ingestion of 25,000 IU or more daily for prolonged periods.

Differential Diagnoses

Toxicity, Iron

Other Problems to Be Considered

Vitamin D toxicity
Skin pigmentation of carotenemia (observed with consumption of large amounts of colored fruits and vegetables)

Workup

Laboratory Studies

  • Serum electrolytes, if vomiting or diarrhea is present
  • Serum calcium (hypercalcemia may be observed6 )
  • Liver function tests
  • Complete blood count (CBC) for anemia, leukopenia, or thrombocytopenia
  • Vitamin A assessment by serum retinol concentrations (This may be helpful if the level is markedly high. However, in mild conditions, it may not be sensitive.)
  • High-performance liquid chromatography (HPLC) - Johnson-Davis et al reported on a modified form of HPLC they developed to shorten analysis time for serum concentrations of vitamins A and E.7 Using their modifications — a high-throughput analytic column and small diameter tubing — to determine pediatric reference intervals for the 2 vitamins in 1136 healthy children, the authors stated that their technique reduced run-time by 60%, mobile phase consumption by 39%, and sample injection volume by 50%.

Imaging Studies

  • Hand radiography for periosteal calcifications
  • Computed tomography (CT) scanning of the brain in the presence of neurologic abnormalities
  • Bone mineral density testing to evaluate the effect of long-term vitamin A intoxication on reducing bone density and causing osteoporosis8

Other Tests

  • Electrocardiogram (ECG) to evaluate the effects of hypercalcemia

Procedures

  • Lumbar puncture may be needed in patients with increased intracranial pressure to prevent its complications.

Treatment

Medical Care

  • Emergency department care includes the following:
    • Supportive care
    • Hydration if vomiting, diarrhea, or hypercalcemia is present
    • Oxygen
    • Monitoring
    • Stopping vitamin A supplements

Consultations

Patients with neurologic symptoms may require consultation with a neurologist.

Follow-up

Further Inpatient Care

  • Admit patients with the following symptoms to the hospital:
    • Altered mental status
    • Severe dehydration
    • Neurologic deficits
    • Metabolic derangements
    • Liver toxicity
    • Significant hypercalcemia
  • Patients with increased intracranial pressure may need therapeutic lumbar punctures or further treatment with medications such as diuretics and mannitol.
  • Patients with symptomatic hypercalcemia require the following:
    • Close monitoring
    • Treatment with intravenous fluids and diuretics
    • Additional therapy, including pamidronate, calcitonin, corticosteroids, or mithramycin
    • Discontinuation of vitamin A

Further Outpatient Care

  • Follow-up is recommended with a primary care physician.
  • The pigmentation of carotenemia usually disappears with the omission of carrots from the diet.
  • Patients on isotretinoin should be evaluated by their dermatologist for consideration of stopping the drug.

Deterrence/Prevention

Education on the proper required daily allowance dose of vitamin A should be provided to modify the individual's current use of vitamin supplements.

Prognosis

  • Prognosis is generally good.
  • Mortality is rare.

Patient Education

Patient education is an important part of management because many cases are due to long-term toxicity from dietary or drug supplements.

Miscellaneous

Medicolegal Pitfalls

  • Do not forget to evaluate for ingestion of other potentially toxic substances such as other vitamins, aspirin, and acetaminophen.
  • Inquire about the intake of other supplements and evaluate for possible overdose accordingly.

Special Concerns

  • High doses of vitamin A can be teratogenic, causing birth defects.
  • Isotretinoin (Accutane), a drug used for the treatment of severe forms of acne, is closely related to the chemical structure of vitamin A. The pharmacology and toxicology of these 2 compounds are similar. Birth defects if taken during pregnancy, intracranial hypertension, depression, and suicidal ideation have been reported with isotretinoin. A careful drug history to uncover this possibility is important in patients presenting with manifestations suggestive of vitamin A intoxication.

References

  1. Maqbool A, Stallings VA. Update on fat-soluble vitamins in cystic fibrosis. Curr Opin Pulm Med. Nov 2008;14(6):574-81. [Medline].

  2. Mawson AR. On the association between low resting heart rate and chronic aggression: retinoid toxicity hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. Mar 17 2009;33(2):205-13. [Medline].

  3. Tan KP, Kosuge K, Yang M, et al. NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity. Free Radic Biol Med. Dec 15 2008;45(12):1663-73. [Medline].

  4. Genaro Pde S, Martini LA. Vitamin A supplementation and risk of skeletal fracture. Nutr Rev. Feb 2004;62(2):65-7. [Medline].

  5. Miksad R, Ledinghen V, McDougall C, et al. Hepatic hydrothorax associated with vitamin A toxicity. J Clin Gastroenterol. 2002;34:275-279. [Medline].

  6. Bhalla K, Ennis DM, Ennis ED. Hypercalcemia caused by iatrogenic hypervitaminosis A. J Am Diet Assoc. 2005;105:119-121. [Medline].

  7. Johnson-Davis KL, Moore SJ, Owen WE, et al. A rapid HPLC method used to establish pediatric reference intervals for vitamins A and E. Clin Chim Acta. Jul 2009;405(1-2):35-8. [Medline].

  8. Barker ME, Blumsohn A. Is vitamin A consumption a risk factor for osteoporotic fracture?. Proc Nutr Soc. 2003;62:845-850. [Medline].

  9. Bates CJ. Vitamin A. Lancet. Jan 7 1995;345(8941):31-5. [Medline].

  10. Hathcock JN. Vitamins and minerals: efficacy and safety. Am J Clin Nutr. Aug 1997;66(2):427-37. [Medline].

  11. Hathcock JN, Hattan DG, Jenkins MY, et al. Evaluation of vitamin A toxicity. Am J Clin Nutr. Aug 1990;52(2):183-202. [Medline].

  12. Michaelsson K, Lithell H, Vessby B, et al. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348:287-294. [Medline].

  13. Nagai K, Hosaka H, Kubo S, et al. Vitamin A toxicity secondary to excessive intake of yellow-green vegetables, liver and laver. J Hepatol. Jul 1999;31(1):142-8. [Medline].

  14. O'Donnell J. Polar hysteria: an expression of hypervitaminosis A. Am J Ther. 2004;11:507-516. [Medline].

  15. Olson JA. Adverse effects of large doses of vitamin A and retinoids. Semin Oncol. Sep 1983;10(3):290-3. [Medline].

  16. Penniston KL, Tanumihardjo S. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191-201.

  17. Perrotta S, Nobili B, Rossi F, et al. Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. Blood. 2002;99:2017-2022. [Medline].

  18. Sharieff GQ, Hanten K. Pseudotumor cerebri and hypercalcemia resulting from vitamin A toxicity. Ann Emerg Med. Apr 1996;27(4):518-21. [Medline].

Keywords

vitamin A toxicity, vitamin A, retinol, carotene, vitamin carotene, retinoid, carotenemia, isotretinoin, Accutane, carotenes, vitamin A alcohol, retinol ester, vitamin A overdose, vitamin A poisoning, dietary vitamin A, vitamin A supplements, provitamin A carotenoids

Contributor Information and Disclosures

Author

Mohsen S Eledrisi, MD, FACP, FACE, Consultant, Department of Internal Medicine, Division of Endocrinology and Metabolism, King Abdulaziz National Guard Medical Center, Saudi Arabia
Mohsen S Eledrisi, MD, FACP, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Kevin McKinney, MD, Assistant Professor, Department of Medicine, Division of Endocrinology and Metabolism, University of Texas Medical Branch at Galveston
Kevin McKinney, MD is a member of the following medical societies: Texas Medical Association
Disclosure: Nothing to disclose.

Mohammad S Shanti, MD, ABEM, Chair, Department of Emergency Medicine, King Faisal Specialist Hospital and Research Center
Mohammad S Shanti, MD, ABEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Harris C Taylor, MD, Clinical Professor of Medicine, Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine
Harris C Taylor, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Romesh Khardori, MD, Chief, Division of Endocrinology, Metabolism and Molecular Medicine, Professor, Department of Internal Medicine, Southern Illinois University School of Medicine
Romesh Khardori, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Further Reading

Related eMedicine topics:
Avitaminosis A
Carotenemia [Dermatology]
Carotenemia [Pediatrics: General Medicine]
Toxicity, Vitamin
Vitamin A Deficiency
Vitamin E Toxicity

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