Symptoms

In acute vitamin A toxicity, some or all of the following may be present:

  • Nausea
  • Vomiting
  • Anorexia
  • Irritability
  • Drowsiness
  • Altered mental status
  • Abdominal pain
  • Blurred vision
  • Headache
  • Muscle pain with weakness
  • Seizures

In chronic vitamin A toxicity, some or all of the following may be present:

  • Anorexia
  • Hair loss
  • Dryness of mucus membranes
  • Fissures of the lips
  • Pruritus
  • Fever
  • Headache
  • Insomnia
  • Fatigue
  • Irritability
  • Weight loss
  • Bone fracture [41]
  • Hyperlipidemia
  • Anemia
  • Bone and joint pains
  • Diarrhea
  • Menstrual abnormalities
  • Epistaxis

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.

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.

Isotretinoin (Accutane), a drug used for the treatment of severe forms of acne, is closely related to the chemical structure of vitamin A and therefore has similar pharmacologic and toxic attributes (see Pathophysiology and Etiology). A careful drug history to uncover possible isotretinoin use is important in patients presenting with manifestations suggestive of vitamin A intoxication.

 

Signs

Brittle nails, alopecia,

hypercalcemia, pseudotumor cerebri, bone thickening, teratogenicity

Acute toxicity

Acute vitamin A toxicity can result in the following:

  • Headache
  • Photophobia
  • Abdominal pain
  • Drowsiness
  • Irritability
  • Desquamation

Manifestations of acute toxicity also include muscle and bone tenderness, especially over the long bones of the upper and lower extremities, as well as neurologic manifestations with signs of increased intracranial pressure (eg, children may have bulging fontanelles).

Chronic toxicity

Chronic vitamin A toxicity affects the skin, the mucous membranes, and the musculoskeletal and neurologic systems. Skin and mucous membrane effects include erythema, eczema, pruritus, dry and cracked skin, angular cheilitis, conjunctivitis, palmar and plantar peeling, and alopecia.

Musculoskeletal effects include pain and tenderness, particularly in the long bones of the upper and lower extremities, which may be exacerbated by exercise. Neurologic effects include blurred vision and frontal headache, which is often the first sign of toxicity.

In addition, studies suggest that elevated levels of vitamin A may cause increased bone resorption and promote the development of osteoporosis. [543]

Manifestations of chronic vitamin A toxicity also include the following:

  • Alopecia
  • Erythematous dermatitis
  • Skin desquamation
  • Brittle nails
  • Exanthema
  • Cheilitis
  • Conjunctivitis
  • Petechiae
  • Liver cirrhosis
  • Hepatosplenomegaly
  • Peripheral neuritis
  • Benign intracranial hypertension
  • Ataxia
  • Papilledema
  • Diplopia
  • Hyperostosis
  • Edema
  • Hepatic hydrothorax [44]
  • Hepatomegaly
  • Ascites
  • Migratory arthritis
  • Craniotabes (in children)
  • Bulging fontanelle (in infants)
  • Epiphyseal capping and premature epiphyseal closure

X-Ray

Bone mineral density testing - to evaluate the effect of long-term vitamin A intoxication on reducing bone density and causing osteoporosis [45]

Laboratory Studies

Vitamin A

The reference range for vitamin A is 20-60 mcg/dL, and a toxic level is higher than 60-100 mcg/dL. Obtain a complete blood count (CBC) to rule out leukopenia. Also perform calcium, glucose, and liver function tests (LFTs). levels are affected by liver stores and dietary intake of vitamin A.

For serum carotene, the normal range is 50-300 mcg/dL. Carotene levels reflects dietary intake of vitamin A.

Laboratory studies in vitamin A toxicity include the following:

  • Serum electrolytes - If vomiting or diarrhea is present
  • Serum calcium - Hypercalcemia may be observed [42]
  • Liver function tests (LFTs)
  • Complete blood count (CBC) - For anemia, leukopenia, or thrombocytopenia
  • Vitamin A assessment by serum retinol concentrations - Vitamin A assessment by serum retinol concentrations may be helpful if the level is markedly high; in mild conditions, however, it may not be sensitive
  • High-performance liquid chromatography (HPLC)

Johnson-Davis et al reported that a modified form of HPLC they developed shortened analysis time for serum concentrations of vitamins A and E. [46] 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 found that their technique reduced run-time by 60%, mobile phase consumption by 39%, and sample injection volume by 50%.

A lumbar puncture may be indicated to rule out increased intracranial pressure in patients with vitamin A toxicity.

 

 


↑↑ PTH Effect
Moans, Groans → Pancreatitis
Bones → PTH leaching bone
Stones → Ca2+
Excess production of CSF → pseudotumor cerebri = only cause of ICP that causes no herniation
Presents with Headache and papilledema
CT → Ventricle enlargement
LP → ↑↑ pressure
Treatment:
Serial LP’s to siphon excess CSFBeing 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.

The bioavailability of retinol is generally more than 80%, whereas the bioavailability and bioconversion of carotenes (ie, provitamin A) are lower. These may be affected by species, molecular linkage, amount of carotene, nutritional 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. 

Vitamin A is highly teratogenic in pregnancy, especially in the first 8 weeks with daily intake more than 10,000 IU; however, it is also a cofactor in night vision and bone growth.

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.

Isotretinoin (Accutane), a drug used for the treatment of severe forms of acne, is closely related to the chemical structure of vitamin A, which means that the pharmacology and toxicology of these two compounds are similar. Birth defects (when taken during pregnancy), intracranial hypertension, depression, and suicidal ideation have been reported with isotretinoin.  A careful drug history to uncover this possibility of isotretinoin use is important in patients presenting with manifestations suggestive of vitamin A intoxication.

 

Supplements are typically 10,000-50,000 international units (IU) per capsule. Fish-liver oils may contain more than 180,000 IU/g.

The acute toxic dose of vitamin A is 25,000 IU/kg, and the chronic toxic dose is 4000 IU/kg every day for 6-15 months. (Beta-carotene [ie, provitamin A] is converted to retinol but not rapidly enough for acute toxicity.)

 

The body can make use of both preformed vitamin A and provitamin A carotenoids that it converts into vitamin A (retinol), and these substances have different bioactivity levels, the recommended dietary allowances (RDAs) for vitamin A are given as mcg of retinol activity equivalents (RAE).

The RDAs for vitamin A are as follows :

  • Males (>14 y) - 900 mcg RAE
  • Females (>14 y) - 700 mcg RAE
  • Pregnancy (14-18 y) - 750 mcg RAE
  • Pregnancy (19-50 y) - 770 mcg RAE
  • Lactation (14-18 y) - 1200 mcg RAE
  • Lactation (19-50 y) - 1300 mcg RAE

The RDAs for children is as follows:

  • 0-6 months - 400 mcg RAE
  • 7-12 months - 500 mcg RAE
  • 1-3 years - 300 mcg RAE
  • 4-8 years - 400 mcg RAE
  • 9-13 years - 600 mcg RAE

 

The acute toxic dose of vitamin A is 25,000 IU/kg, and the chronic toxic dose is 4000 IU/kg every day for 6-15 months. (Beta-carotene [ie, provitamin A] is converted to retinol but not rapidly enough for acute toxicity.)

Almost 60,000 instances of vitamin toxicity are reported annually to US poison control centers. [12

 

 

 

 

Emergency department care

All ingestions require supportive management and an intravenous line. Serious ingestions require hydration if vomiting or diarrhea is present. Oxygen, monitoring, and ABCs are essential if potentially life-threatening manifestations are present.

If potentially lethal coingestions are present, perform gastric lavage if the patient presents within 1 hour postingestion. Always check whether the vitamin overdose included iron supplements, and manage such an overdose aggressively.

Identify other potentially lethal coingestants, such as acetaminophen, aspirin, and dangerous prescription drugs (ie, digoxin, lithium, phenothiazines). Other care is symptomatic and supportive.

Consultations

Consult a neurosurgeon if evidence of CNS hemorrhage is present. For more information on vitamin toxicity management, consult a regional poison control center or a local medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine).

Patients on isotretinoin should be evaluated by their dermatologist for consideration of stopping the drug.

Vitamin A

Symptoms of vitamin A toxicity usually resolve after stopping vitamin A and instituting supportive therapy. The pigmentation of carotenemia usually disappears with the omission of carrots from the diet.

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

Admit patients with the following conditions:

  • Risk for suicide
  • Intractable emesis
  • Altered mental status
  • Neurologic symptoms
  • Serious coingestions
  • Severe dehydration
  • Metabolic derangements - Eg, hypercalcemia, severe electrolyte abnormalities, ECG changes, renal or liver damage)

 

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