Continuing Education Activity

Vitamin A toxicity can due to either topical or oral vitamin A administration. Oral vitamin A toxicity can be acute, due to the ingestion of a large amount of vitamin A over a short period of time, or chronic, due to oral ingestion over a longer duration. The most severe adverse effect of systemic retinoids is teratogenicity. The most common adverse effect of topical vitamin A is skin irritation, erythema, and peeling. This activity describes the evaluation and management of vitamin A toxicity and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

• Describe the pathophysiology of vitamin A toxicity.
• Review the presentation of a patient with vitamin A toxicity.
• Describe the typical laboratory findings of a patient with vitamin A toxicity .
• Describe the importance of coordination among the interprofessional team to ensure safe prescribing practices for vitamin A supplements, in particular in women that are or may become pregnant.

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 the 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. Each year, in the US alone over 60,000 cases of Vitamin toxicity are reported. Unlike the water-soluble vitamins, the fat-soluble vitamins tend to accumulate in the body.

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]. 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.

Mental status changes are common following Vitamin A intoxication. In addition, there is a risk for seizures, headache, and blurred vision (due to elevated intracranial pressure). Chronic toxicity can lead to alopecia, anorexia, pruritus, dryness of mucous membranes, muscle and bone pain and hyperlipidemia.

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].

Acute cases may require admission with close monitoring. The hypotension needs to be managed with fluids and the hypercalcemia may require calcitonin and/or corticosteroids.

Differential Diagnosis

• Early pregnancy loss in emergency medicine

• Exfoliative dermatitis

• Hypercalcemia in emergency medicine

• Hyperparathyroidism in emergency medicine

• Migraine headache

• Munchausen syndrome

• Munchausen syndrome by proxy

• Pediatric gastroenteritis in emergency medicine

• Postconcussion syndrome

Prognosis

For most patients who discontinue the vitamin, the symptoms gradually reverse and complete recovery is the norm. However, if vitamin A ingestion is continued, then the adverse effects on the nerves and brain are not always reversible.

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

A significant number of people regularly consume large quantities of vitamins in the belief that they are available over the counter and thus safe. In fact, close to 60,000 vitamin toxicities are reported each year in the US alone. The key is public education and this requires an interprofessional team. In most cases, the pharmacist is in the prime position to educate the public about vitamin safety. Rather than encourage the use of supplements, the pharmacist should educate the public on a healthy diet- not only is this cheaper, but it is safer. Countless cases of counterfeit vitamin products have been reported over the years.

Nurses should also encourage patients to consume a healthy diet and refrain from taking vitamins unless there is a documented deficiency.

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 the maximum recommended dosages during pregnancy. [Level I]