Vitamin A Toxicity


Article Author:
Jazmine Olson


Article Editor:
Neil Shah


Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
1/16/2019 10:34:36 AM

Introduction

Vitamin A toxicity can occur from either the topical or oral form of Vitamin A. Each has its own set of adverse effects. Oral vitamin A toxicity can be acute or chronic. In acute toxicity, ingestion occurs because of ingestion of a large amount of vitamin A over a short period of time. In chronic toxicity, intake is over a longer duration. The most common adverse effect of topical retinoids is skin irritation, notably erythema and peeling. The most severe adverse effect of systemic retinoids is teratogenicity.

Etiology

As noted above, vitamin A toxicity can occur from either topical or oral use. Oral vitamin A delivery comes in two forms: provitamin A (a prodrug that is metabolized to vitamin A) and preformed vitamin A. Pre-formed vitamin A is obtained from animal food sources, including dairy products and liver, and in most supplements. A list of other foods containing Vitamin A includes milk, cheese, margarine, butter, eggs, chicken, chicken liver, beef, beef liver, processed meats, pizza, fish, and cold breakfast cereals[1]. Provitamin A (beta-carotene and other carotenoids), found in plants such as green leafy vegetables, sweet potatoes, and carrots, must be metabolized to vitamin A. As a result, it is less likely to cause toxicity.

Many people in the United States take either isolated supplemental Vitamin A or other supplements that contain vitamin, A in addition to dietary intake. The current recommended dietary allowance of vitamin A is 800 retinol equivalents or 2700 international units (IU) for women[1].

Excessive intake of preformed vitamin A, but not precursors, has been linked to teratogenicity in both human and animals studies[1]. In women taking over 10,000 IUs of preformed vitamin A per day from supplements, it is estimated that 1 of 57 babies is born with a secondary congenital disability.

Epidemiology

Reported incidences of vitamin A toxicity are quite rare, with fewer than 10 cases per year from 1976 to 1987[2]. Epidermal irritation is the most common side effect of topical retinoids. Teratogenicity is the most severe side effect of oral retinoids, affecting 1 in 57 women ingesting over 10,000 IUs daily of preformed vitamin A [1]. Isotretinoin is estimated to increase the risk of malformation 25-fold[2].

Pathophysiology

Skin irritation in the form of peeling and erythema is the most common adverse effect from topical vitamin A use. The peeling from topical retinoids is secondary to the hyper-proliferation of the epidermis mediated by retinoic acid receptor stimulation [3]. Interestingly, the erythema may be mediated through a different mechanism.

The risk of teratogenicity from the use of topical retinoids is extremely low given that systemic absorption has been inconsequential in animal and human studies [4]. Topical retinoid application has not been proven to cause congenital disorders when used during pregnancy. Other adverse effects include transient hypopigmentation and hyperpigmentation, Koebnerization of psoriasis, allergic contact dermatitis, and ectropion.

With regards to systemic retinoid usage, teratogenicity is the most worrisome adverse effect. Teratogenic findings include craniofacial (cleft lip/palate), cardiac (transposition of the great vessels), thymic, and central nervous system (microcephaly, hydrocephalus) abnormalities [2]. Isotretinoin is estimated to increase the risk of these malformations 25-fold. The mechanism is thought to be through a toxic effect on neural crest cells, possibly affecting the regulation of axial patterning in the embryo via the expression of the homeobox gene Hoxb-1[5].

Acute retinoid toxicity has resulted in mucocutaneous and laboratory abnormalities. Mucocutaneous effects include dry lips, cheilitis, and dry oral, ophthalmic, and nasal mucosa. The putative mechanism is decreased sebum production, reduced epidermal thickness, and altered barrier function. Other cutaneous effects seen include overall skin dryness and pruritus, peeling of palms and soles, and fingertip fissuring. Telogen effluvium may be seen with higher doses.

Chronic retinoid toxicity can affect many organ systems. Bone effects include changes such as bone spurs, calcinosis, and bone resorption with resulting hypercalcemia[6]. Long-term consumption of high levels of dietary vitamin A may stimulate bone resorption and inhibit formation, contributing to osteoporosis and hip fractures[7]. Central nervous system effects include headache, nausea, and vomiting. Pseudotumor cerebri syndrome rarely has been noted secondary to vitamin A toxicity [8]. Hypothyroidism, reversible upon cessation of therapy, was seen in 40% of patients in Cutaneous T-cell lymphoma trials with bexarotene [9]. Additionally, reversible renal dysfunction characterized by elevated creatinine was seen with etretinate but not isotretinoin[10].

Hypertriglyceridemia is the most common systemic effect of retinoids. Both triglyceride and cholesterol levels have been found to be elevated in patients using bexarotene, isotretinoin, etretinate, and acitretin. Total and LDL elevations may occur[11][12][11]. Accompanying cases of acute hemorrhagic pancreatitis and eruptive xanthomas can also be seen.

Elevated serum transaminases may occur with oral retinoid usage. These elevations more often occur with etretinate or acitretin as compared to isotretinoin and bexarotene. These elevations typically occur 2-8 weeks after initiation of therapy with normalization over another 2-4 weeks. Liver damage leading to fibrosis and hepatic stellate cell activation have both been seen in patients with hypervitaminosis A[13].

No causal association exists between isotretinoin and depression, psychosis, or suicide attempts, although a link had been previously suggested[14].

Toxicokinetics

The dose used in the treatment of degenerative eye diseases is 15,000 IUs daily. This is less than the maximal dose of 25,000 IU/day and is well tolerated after 12 years of treatment[15].

No safe minimum dose of oral retinoids during pregnancy has been established.

LRAT (lecithin retinol acyltransferase) is the enzyme that catalyzes retinoid esterification and storage[16]. CRBPs (cellular retinoid binding proteins) assist LRAT in regulating retinoid uptake and metabolism. These two proteins are essential in the mechanism of retinoids and may also be responsible for their toxicity.

History and Physical

With topical retinoid use, peeling and erythema may be seen at the site of application.

With systemic use, the patient may exhibit overall xerosis of the skin, oral, ophthalmic, and nasal mucosa. Fissuring and redness of the lips (cheilitis) may also be seen, as well as peeling of the palms and soles and fissuring of the fingertips. Diffuse hair shedding may also occur.

Evaluation

Given that elevated triglyceride and cholesterol levels are the most common lab abnormality in patients taking isotretinoin, both of these levels should be checked periodically in a patient taking this medication[17]. Liver enzyme elevations are typically mild and reversible. However, alanine aminotransferase and aspartate aminotransferase monitoring are recommended based upon dosage and patient comorbidities. The patient must also have two negative urine or serum pregnancy tests (beta-hCG) 30 days apart prior to initiation of isotretinoin. Beta-hCG should be checked monthly while on therapy as well as one month after cessation of treatment. A complete blood count may be considered before initiation although abnormalities are rare and idiosyncratic. Skeletal monitoring for hyperostosis is only recommended if the patient is receiving multiple courses of isotretinoin or is on the medication long-term.

In a patient taking a vitamin A-containing medication who is complaining of a persistent headache, evaluation should be undertaken for increased intracranial pressure to rule out pseudotumor cerebri syndrome.

Free T4 should be monitored before and during treatment with bexarotene[18]. Baseline fasting serum lipids should also be monitored at initiation and every 1-2 weeks during therapy until stable.

If a patient on etretinate therapy has a history of kidney disease, monitor their renal function during treatment[10].

Treatment / Management

Management of skin irritation from topical retinoids is accomplished with reduced medication volume of application, reduced frequency, and increased emollient use. Reassurance that this side effect will improve with continued use should also be provided.

For ophthalmologic dryness, artificial tears and lubricating eye drops, such as methylcellulose containing eye drops, can be helpful.

Oral retinoid administration discontinuation, dose reduction, or addition of fish oil or a fibrate medication may be considered with a fasting triglyceride level of 800 mg/dL or higher due to an elevated risk of pancreatitis. Milder elevations may be monitored or similarly treated.

For bexarotene, concomitant use of a statin or fibrate may be considered to treat retinoid-induced hyperlipidemia and reduce pancreatitis risk[19]. Elevations higher than three times the upper limit of normal may necessitate cessation of therapy if the levels remain elevated despite intervention[19].

Acute retinoid toxicity is rare, but in the cases that have been documented, recovery is rapid upon cessation of medication[20].

In patients with pseudotumor cerebri syndrome, discontinuation of the medication containing vitamin A as well as treatment with acetazolamide has been effective in reducing intracranial pressure[8].

Pearls and Other Issues

Teratogenicity is the most significant adverse effect of vitamin A toxicity. Patients should be advised not to ingest more than the recommended maximum amount of supplemental vitamin A during pregnancy. The majority of other adverse effects, including skin irritation, dryness, and increased intracranial pressure, will resolve once ingestion or application of vitamin A is reduced or discontinued. Effects such as elevated triglycerides, cholesterol, or transaminases typically resolve despite the ongoing continuation of the medication. However, these levels should be monitored, and the medication should be discontinued if elevations persist or worsen.

Enhancing Healthcare Team Outcomes

Pregnancy is an absolute contraindication to isotretinoin therapy. However, patients may ingest other medications containing vitamin A such as isolated vitamin A, other supplements, and weight loss medications that may also have teratogenic effects. It is the responsibility of the nurses and medical aides entering medications, as well as the obstetrician or physician managing females' care, acting in concert as a coordinated health care team, to be sure that all medications, including vitamins and supplements, are included in a patient's medication-list and reviewed with the patient at each visit. The patient should be informed of the risk of vitamin A ingestion during pregnancy and maximum recommended dosages during pregnancy. [Level I]


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Vitamin A Toxicity - Questions

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Which of the following has been linked to an increase in intracranial pressure in children?



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Which of the following vitamins is not supplemented for healthy pregnant females?



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Which of the following vitamin overdoses can cause increased intracranial pressure?



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Which of the following vitamins can be teratogenic if given to pregnant women?



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A 36-year-old female presents to the clinic with decreased appetite and headache. On physical exam, the provider notices that she has diffusely dry and peeling skin. Further workup also revealed an increased intracranial pressure. An excess of which of the following may be responsible for these findings?



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Which of the following may be the result of vitamin A overdosage?



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To whom should supplemental vitamin A not be administered?



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Which of the following is seen in long term vitamin A toxicity?



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Which of the following vitamin A-containing products is teratogenic and more likely to cause toxicity when consumed in large amounts?



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Vitamin A Toxicity - References

References

Hunt JR, Teratogenicity of high vitamin A intake. The New England journal of medicine. 1996 May 2     [PubMed]
Lammer EJ,Chen DT,Hoar RM,Agnish ND,Benke PJ,Braun JT,Curry CJ,Fernhoff PM,Grix AW Jr,Lott IT, Retinoic acid embryopathy. The New England journal of medicine. 1985 Oct 3     [PubMed]
Jick H, Retinoids and teratogenicity. Journal of the American Academy of Dermatology. 1998 Aug     [PubMed]
Kang S,Duell EA,Fisher GJ,Datta SC,Wang ZQ,Reddy AP,Tavakkol A,Yi JY,Griffiths CE,Elder JT, Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. The Journal of investigative dermatology. 1995 Oct     [PubMed]
Marshall H,Studer M,Pöpperl H,Aparicio S,Kuroiwa A,Brenner S,Krumlauf R, A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1. Nature. 1994 Aug 18     [PubMed]
Scheven BA,Hamilton NJ, Retinoic acid and 1,25-dihydroxyvitamin D3 stimulate osteoclast formation by different mechanisms. Bone. 1990     [PubMed]
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Sherman SI,Gopal J,Haugen BR,Chiu AC,Whaley K,Nowlakha P,Duvic M, Central hypothyroidism associated with retinoid X receptor-selective ligands. The New England journal of medicine. 1999 Apr 8     [PubMed]
Chisholm JT,Abou-Jaoude MM,Hessler AB,Sudhakar P, Pseudotumor Cerebri Syndrome with Resolution After Discontinuing High Vitamin A Containing Dietary Supplement: Case Report and Review. Neuro-ophthalmology (Aeolus Press). 2018 Jun     [PubMed]
Cribier B,Welsch M,Heid E, Renal impairment probably induced by etretinate. Dermatology (Basel, Switzerland). 1992     [PubMed]
Koo J,Nguyen Q,Gambla C, Advances in psoriasis therapy. Advances in dermatology. 1997     [PubMed]
Duvic M,Martin AG,Kim Y,Olsen E,Wood GS,Crowley CA,Yocum RC, Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Archives of dermatology. 2001 May     [PubMed]
Nollevaux MC,Guiot Y,Horsmans Y,Leclercq I,Rahier J,Geubel AP,Sempoux C, Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption. Liver international : official journal of the International Association for the Study of the Liver. 2006 Mar     [PubMed]
Bigby M, Does isotretinoin increase the risk of depression? Archives of dermatology. 2008 Sep     [PubMed]
Sibulesky L,Hayes KC,Pronczuk A,Weigel-DiFranco C,Rosner B,Berson EL, Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. The American journal of clinical nutrition. 1999 Apr     [PubMed]
Goldsmith LA,Bolognia JL,Callen JP,Chen SC,Feldman SR,Lim HW,Lucky AW,Reed BR,Siegfried EC,Thiboutot DM,Wheeland RG, American Academy of Dermatology Consensus Conference on the safe and optimal use of isotretinoin: summary and recommendations. Journal of the American Academy of Dermatology. 2004 Jun     [PubMed]
Gniadecki R,Assaf C,Bagot M,Dummer R,Duvic M,Knobler R,Ranki A,Schwandt P,Whittaker S, The optimal use of bexarotene in cutaneous T-cell lymphoma. The British journal of dermatology. 2007 Sep     [PubMed]
Wiegand UW,Chou RC, Pharmacokinetics of acitretin and etretinate. Journal of the American Academy of Dermatology. 1998 Aug     [PubMed]
Nagai K,Hosaka H,Kubo S,Nakabayashi T,Amagasaki Y,Nakamura N, Vitamin A toxicity secondary to excessive intake of yellow-green vegetables, liver and laver. Journal of hepatology. 1999 Jul     [PubMed]
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