Vitamin A Toxicity

Etiology

Hypervitaminosis A is relatively uncommon and usually arises from excessive supplementation or medication usage. The primary cause of toxicity is the consumption of substantial quantities of vitamin A through dietary supplements and foods. This usually occurs when individuals consume high doses of vitamin A without proper medical supervision. Most diets contain a combination of preformed vitamin A and provitamin A carotenoids. Preformed vitamin A is derived from animal sources and is found in egg yolks, butter, chicken, beef, organ meats, fish, fish oils, and fortified foods.[1] Preformed vitamin A is readily absorbed in the small intestine and subsequently stored in the liver. Therefore, excessive intake of dietary preformed vitamin A from animal-based sources and supplements can contribute to the risk of toxicity. 

Provitamin A carotenoids, such as beta-carotene, are plant pigments that the body converts into active vitamin A. These carotenoids are plentiful in leafy greens and vibrantly colored vegetables and fruits, including carrots, sweet potatoes, and papayas.[2] The absorption of provitamin A is variable and subject to feedback regulation, making it unlikely to lead to toxicity with excessive intake.[3] Certain dermatological medications, such as isotretinoin, contain analogs of vitamin A. Prolonged or excessive usage of these medications can lead to an accumulation of vitamin A stores, resulting in hypervitaminosis A, toxicity, and teratogenic effects.

The recommended daily allowance (RDA) for vitamin A is measured in retinol activity equivalents (RAE) to account for the different bioactivities of retinol and provitamin A carotenoids. Notably, 1 RAE is equivalent to 1 mcg of retinol or 3 International units (IU).

The RDA for vitamin A is as follows:

• 700 RAE for adult women
• 900 RAE for adult men
• 750 to 770 RAE for pregnant women
• 1200 to 1300 RAE for lactating women

The tolerable upper intake levels (UL) for vitamin A have been established to prevent toxicity. The UL of vitamin A for adults is 3000 RAE per day, including preformed vitamin A from foods and supplements and the amount that can be converted from plant-based sources such as beta-carotene. The consumption of preformed vitamin A from dietary supplements in developed countries frequently surpasses the RDA.[4]

Epidemiology

Few published reports of vitamin A toxicity have been published, with fewer than 10 cases per year documented from 1976 to 1987.[5] Infants and children are at a higher risk of toxicity due to their smaller body size and reduced tolerance for high doses.[6] Accidental ingestion of vitamin A supplements by children is a common cause of acute toxicity. There is no substantial difference in the occurrence of vitamin A toxicity between males and females. However, pregnant women are at risk if they take high doses of vitamin supplements.

Excessive supplement intake typically occurs in developed countries when individuals exceed the RDA.[4] Supplementation programs have been implemented in regions where vitamin deficiency is a significant public health concern. Moreover, toxicity can arise if dosing guidelines are not carefully followed.[7][8] Populations heavily reliant on liver-based food sources rich in vitamin A, such as polar bear liver and chicken liver, face an increased risk of vitamin A toxicity. However, only rare cases of this phenomenon are reported in the published literature, and it is not considered a significant public health concern.[9][10][11]

Pathophysiology

The symptoms of systemic vitamin A toxicity vary depending on the severity and duration of excessive intake. The 3 recognized syndromes of vitamin A toxicity are acute, chronic, and teratogenic.

Acute systemic vitamin A toxicity typically arises when an individual consumes over 100,000 RAE within a short period, often from supplements or high-dose medications. The toxicity symptoms include nausea, vomiting, headache, dizziness, irritability, blurred vision, and muscular incoordination. Acute toxicity is rare and is more likely to occur after consuming synthetic forms of vitamin A, such as the retinoid medication isotretinoin. Mucocutaneous effects include cheilitis and dryness of lips and oral, ophthalmic, and nasal mucosa. The suggested mechanism involves decreased sebum production, reduced epidermal thickness, and altered barrier function. Additional cutaneous effects include dry skin, pruritus, peeling of the palms and soles, and fissuring of the fingertips. Higher doses of vitamin A may lead to telogen effluvium. Severe cases may manifest with bone pain and increased intracranial pressure.

Chronic vitamin A toxicity is associated with prolonged ingestion of excessive vitamin A, typically exceeding 8000 RAE per day. This condition can develop after consuming substantial quantities of animal-based foods rich in preformed vitamin A, such as liver, or through the prolonged use of high-dose vitamin A supplements.[12] The toxicity symptoms include dry, cracked skin, hair loss, brittle nails, fatigue, loss of appetite, bone and joint pain, and hepatomegaly. Chronic retinoid toxicity affects various organ systems. Bone-related effects include bone spurs, calcinosis, and bone resorption, leading to hypercalcemia, osteoporosis, and hip fractures.[13][14] Central nervous system effects include headache, nausea, and vomiting.

Pseudotumor cerebri syndrome has been associated with vitamin A toxicity.[15] Hypothyroidism, reversible upon discontinuation of therapy, was observed in 40% of patients during clinical trials for cutaneous T-cell lymphoma with bexarotene, a derivative of vitamin A.[16] Reversible renal dysfunction with elevated serum creatinine has been observed after etretinate use, but not after isotretinoin use.[17] Etretinate, a psoriasis medication, is no longer prescribed in most countries because of its teratogenic effects.

Hypertriglyceridemia is the most common laboratory abnormality associated with oral retinoid use. Triglyceride, low-density lipoprotein, and total cholesterol levels increase in many patients using bexarotene, isotretinoin, etretinate, and acitretin.[18][19] Elevated serum transaminases may also occur with oral retinoid usage, more often with etretinate or acitretin compared to isotretinoin and bexarotene. These levels typically show an increase within 2 to 8 weeks after the initiation of therapy, followed by normalization over the subsequent 2 to 4 weeks. Prolonged liver damage can include fibrosis and cirrhosis.[20] No definitive causal association has been established between isotretinoin and depression, psychosis, or suicide attempts, although such a link had been previously suggested.[21]

The teratogenic effects of vitamin A intake were first discovered in animal studies during the 1950s. Subsequently, extensive research has been conducted to elucidate the underlying causes of the effects.[22] Excessive vitamin A consumption during pregnancy has been associated with various congenital malformations in humans. The disabilities associated with this condition include abnormalities in the central nervous system, such as microcephaly and hydrocephalus; cardiac issues, such as transposition of the great vessels; craniofacial deformities, such as cleft lip and palate; limb abnormalities; and urinary tract disorders.[5][3] 

Vitamin A is critical for regulating gene expression and guiding cell differentiation during embryonic development. The embryo is particularly susceptible to the teratogenic effects of excessive amounts of vitamin A during the first trimester, which is a phase marked by rapid organogenesis. Teratogenic effects are primarily associated with high doses of retinoid medications such as isotretinoin rather than dietary sources of vitamin A. A minimum safe dose of oral retinoids during pregnancy has not been established. Isotretinoin is estimated to increase the risk of fetal malformations by 25-fold.[5] The mechanism is believed to be linked to 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.[23] 

Pregnant women should refrain from using oral retinoid medications and excessive vitamin A supplements to mitigate the risk of vitamin A-related malformations. They should consult healthcare professionals and prenatal care providers to ensure proper prenatal nutrition and avoid drugs or supplements that are contraindicated during pregnancy. Prescribers should only recommend oral retinoids to women of childbearing age who are not pregnant and use reliable birth control methods to prevent the potential risk of vitamin A-related teratogenic effects. 

Histopathology

Hypervitaminosis A affects multiple organ systems of the body and can damage the liver, bones, central nervous system, and skin. The specific histopathological findings differ based on the severity and duration of the toxicity, some of which are listed below.

Liver: Hepatic steatosis, hepatocellular injury, and fibrosis with collagen deposits

Bone: Osteoporosis and thickening of cortical bone

Central nervous system: Pseudotumor cerebri and cerebral edema

Skin: Exfoliative dermatitis and epidermal hyperplasia [24][25]

Toxicokinetics

The toxicokinetics of vitamin A toxicity involve its absorption, distribution, metabolism, and elimination from the body.

Absorption: Dietary vitamin A is sourced from 2 main categories: preformed vitamin A, including retinol and retinyl esters, which are found in animal-derived products and supplemented foods, and provitamin A carotenoids present in fruits and vegetables. High-fat meals enhance the absorption of vitamin A in the small intestine.

Distribution: After absorption, vitamin A is transported to the liver, where it is stored as retinyl esters. From there, it is released into the bloodstream bound to retinol-binding protein (RBP) and transthyretin. These carrier proteins help transport vitamin A to target tissues, including the eyes, skin, and other organs.

Metabolism: Retinol is converted into its active forms, retinal and retinoic acid, within target tissues. Lecithin retinol acyltransferase (LRAT) is the enzyme responsible for catalyzing retinoid esterification for storage in the liver.[26] Cellular RBP assists LRAT in regulating retinoid uptake and metabolism. These 2 proteins are essential in the metabolism of retinoids, which may be responsible for the toxic effects of vitamin A.

Elimination: Fat-soluble vitamin A and its metabolites are primarily excreted through bile and feces, with only a small portion being eliminated in the urine. 

History and Physical

The medical history will likely reveal excessive consumption of vitamin A-rich foods, supplements, or oral retinoid medications. Symptoms include blurred vision, headaches, dry skin, hair loss, fatigue, and bone pain. Typical physical examination findings may include dryness of the conjunctiva and mucous membranes, scaly skin, alopecia, papilledema, bone tenderness, and hepatomegaly. 

Patients with a history of using topical vitamin A derivatives will likely exhibit localized skin peeling and erythema, but systemic signs and symptoms are not expected. 

Evaluation

A patient's history and physical examination findings guide the selection of diagnostic studies. Patients with persistent headaches while taking vitamin A medications should be evaluated for increased intracranial pressure and pseudotumor cerebri syndrome.

Laboratory findings obtained during assessing patients with vitamin A toxicity can reveal several abnormalities, a few of which are mentioned below.

Serum vitamin A levels: The serum vitamin A levels exceed 80 mcg/dL.

Liver function tests: Elevated levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) indicate potential hepatic damage or inflammation.

Serum lipids: Increased levels of triglycerides and cholesterol are observed.

Hematological abnormalities: The identified abnormalities in the blood include leukocytosis, thrombocytopenia, and anemia.

Bone markers: Increased levels of ALP are associated with bone turnover.

Renal function: Elevations of blood urea nitrogen and creatinine occur.

Electrolyte imbalances: Alterations in electrolyte levels, such as sodium, potassium, and calcium occur.

Some patients require laboratory testing to monitor their condition. Individuals taking isotretinoin should undergo regular lipid level checks.[27] Elevations in liver enzymes are usually mild and reversible, although ALT and AST may need to be monitored based on the dosage and any comorbidities the patient may have.[28]

Women of childbearing age must have 2 negative pregnancy tests, conducted 30 days apart, before initiating isotretinoin treatment. Additional testing during and immediately after discontinuing the treatment is also necessary.[29] 

Free T4 should be monitored both before and during treatment with bexarotene.[30] In addition, baseline fasting serum lipid levels should be measured at treatment initiation and then every 1 to 2 weeks during therapy until they stabilize.

Patients with a history of kidney disease and undergoing etretinate therapy should regularly monitor their renal function throughout the treatment course.[17]

Treatment / Management

The treatment of systemic vitamin A toxicity includes discontinuing vitamin A intake, providing supportive care, and managing patient symptoms.

The management of skin irritation caused by topical retinoids involves reducing the volume and frequency of applications while increasing the use of emollients. Patients can be reassured that this adverse effect will likely improve with the continued use of the skincare products.

Acute retinoid toxicity is rare, but in documented cases, recovery is typically rapid upon discontinuation of the medication.[31] The sources of excess vitamin A intake, including dietary supplements and medications, must be identified as a primary step. Furthermore, healthcare professionals should recommend avoiding foods rich in preformed vitamin A to patients, such as liver and fortified products, until the toxicity resolves.(B3)

Supportive care involves close monitoring of the patient's condition, including vital signs and overall health status. Severe cases may necessitate hospital admission. Hypotension can be managed with fluid administration, and hypercalcemia can be treated with calcitonin and corticosteroids. When there is evidence of hepatic damage, liver function tests can assess the extent of the injury and guide further management decisions.

Patients with dry or peeling skin are advised to use moisturizers or emollients to alleviate discomfort and facilitate skin healing. For patients experiencing dry eyes, artificial tears and lubricating eye drops, including those containing methylcellulose, can be beneficial. 

The treatment of medication-induced chronic toxicity depends on the specific drug and its adverse effects. In cases where oral retinoids can lead to an elevation of the fasting triglyceride level to 800 mcg/dL or higher, options such as discontinuation, dose reduction, or the addition of lipid-lowering medication can be considered to prevent pancreatitis. Milder elevations can be monitored or treated similarly.

Patients experiencing toxicity from bexarotene can consider using a statin or fibrate concurrently to manage retinoid-induced hyperlipidemia and lower the risk of pancreatitis. Therapy may need to be discontinued if values remain elevated despite intervention and exceed 3 times the upper limit of normal.[32]

Patients diagnosed with pseudotumor cerebri syndrome should discontinue using vitamin A medications and might need acetazolamide to lower the intracranial pressure.[15](B3)

Teratogenic malformations result in permanent damage, and the necessary supportive or surgical care varies based on the affected organ system.

Differential Diagnosis

When assessing the differential diagnosis of hypervitaminosis A, it is crucial to exclude other conditions that might manifest with similar symptoms, some of which are listed below.

Acute liver injury: Viral hepatitis, alcohol use, or drug toxicity.

Hypercalcemia: Hyperparathyroidism, malignancy, or excessive calcium and vitamin D intake.

Hypothyroidism: Primary thyroid disorders or medications.

Chronic renal failure: Diabetes, hypertension, glomerulonephritis, or polycystic kidney disease.

Central nervous system: Headache, nausea, and vomiting may be symptoms of pseudotumor cerebri and are not always caused by vitamin A toxicity.

Dermatological conditions: Exfoliative dermatitis and other skin conditions.

Nonspecific symptoms: The nonspecific symptoms, including skin rashes, joint pain, fatigue, and renal and liver abnormalities, can also indicate conditions such as systemic lupus erythematosus and may not solely point to vitamin A toxicity.

Prognosis

The prognosis of hypervitaminosis A depends on the severity of the condition and the duration of exposure to high levels of vitamin A. In most patients who discontinue the source of excess vitamin A, toxicity symptoms gradually reverse, and complete recovery is expected. Symptoms such as dry skin, headache, and nausea typically improve within a few weeks or months with no long-term complications.

However, severe cases can have serious consequences. Prolonged and excessive vitamin A intake can result in significant organ damage, including the liver, bones, central nervous system, and skin. Liver fibrosis or cirrhosis may be irreversible. Bone abnormalities, such as reduced bone density or fractures, may persist even after discontinuing vitamin A intake. In cases of pseudotumor cerebri, visual impairment may be permanent. The prognosis depends on the extent of organ damage and the promptness of medical intervention.

Complications

Complications of vitamin A toxicity include those listed below. 

Acute toxicity: Nausea, vomiting, headache, dizziness, irritability, blurred vision, and intracranial hypertension

Chronic toxicity: Dry, itchy skin, hair loss, bone and joint pain, fatigue, anorexia, and weight loss

Teratogenic effects: Craniofacial abnormalities, central nervous system malformations, and cardiovascular malformations

Hepatic toxicity: Hepatomegaly, elevated liver enzymes, jaundice, fibrosis, and cirrhosis

Skeletal abnormalities: Increased bone resorption, decreased bone formation, osteoporosis, fractures, and bone pain

Hematological disturbances: Leukocytosis, anemia, and thrombocytopenia

Central nervous system: Pseudotumor cerebri, with symptoms of headache, visual disturbances, and papilledema