Summary Of Exposure |
A) USES: Used as a dietary supplement and found in some topical preparations to promote wound healing. Naturally present in high concentrations in some foods.
B) PHARMACOLOGY: Essential nutrient required for bone development, vision, reproduction, and differentiation and maintenance of epithelial tissue. Required cofactor for glycosylation of glycoproteins.
C) TOXICOLOGY: High doses stimulate bone resorption and inhibit keratinization. Excessive doses are stored in hepatic Ito cells, which become hypertrophied and obstruct sinusoidal blood flow eventually causing portal hypertension.
D) EPIDEMIOLOGY: Poisoning is rare, with acute toxicity even more unusual than chronic toxicity.
E) WITH POISONING/EXPOSURE
1) ACUTE: Ingestion or parenteral overdose may produce significant increases in intracranial pressure, which may result in bulging fontanelles (in infants), nausea/vomiting, abdominal pain, headache, blurred vision, irritability and other effects associated with increased intracranial pressure. Exfoliation of the skin has also been reported. 2) CHRONIC: Signs and symptoms of toxicity include nausea/vomiting, abdominal pain, anorexia, fatigue, irritability, diplopia, headache, bone pain, alopecia, skin lesions, cheilosis, and signs of increased intracranial pressure (e.g. papilledema). a) Laboratory findings include elevated liver enzymes and bilirubin, increased INR, hypercalcemia, elevated erythrocyte sedimentation rate and periosteal calcification on radiographs. Increased opening pressure may be noted on lumbar puncture.
b) Symptoms usually begin to resolve within days to weeks after discontinuation of vitamin A use. The prognosis is usually excellent with few, if any, long term sequelae.
3) BETA CAROTENE: There are no known cases of vitamin A toxicity associated with beta-carotene ingestion, although excessive beta-carotene ingestion may result in carotenemia (yellow skin discoloration). |
Vital Signs |
3.3.3) TEMPERATURE
A) FEVER 1) WITH POISONING/EXPOSURE a) Fever has been reported following chronic use (Nagai et al, 1999).
b) A 17-year-old female with an 18-month history of using RETINOL (50,000 to 200,000 units/day) developed a fever (37.5 to 39 degrees C) of two months duration. The fever resolved after retinol therapy was discontinued and returned when she reinstituted retinol use (Muntaner et al, 1990).
c) Fever developed in a 7-year-old boy who developed vitamin A toxicity after taking 25,000 to 50,000 IU daily for one year (Wason & Lovejoy, 1982).
d) Fever developed in a 1-year-old boy who developed vitamin A toxicity after receiving 6,000 IU a day for three months (Scherl et al, 1992).
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Heent |
3.4.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Diplopia, nystagmus, tinnitus and papilledema may be noted (pseudotumor cerebri) as a result of vitamin A intoxication.
3.4.3) EYES
A) DIPLOPIA 1) WITH POISONING/EXPOSURE a) Diplopia is a common complaint in adults with chronic toxicity (Lombaert & Carton, 1976; James et al, 1982; Muenter et al, 1971).
B) PAPILLEDEMA 1) WITH POISONING/EXPOSURE a) Papilledema is a common finding and flame hemorrhages have been reported with chronic intoxication (Morrice et al, 1960; Selhorst et al, 1984; Patel et al, 1988).
C) NYSTAGMUS 1) WITH POISONING/EXPOSURE a) Nystagmus may develop with chronic intoxication (Lombaert & Carton, 1976; Katz & Tzagournis, 1972).
D) BLINDNESS 1) WITH POISONING/EXPOSURE a) Rarely, blindness may result from optic atrophy (Goldfrank et al, 1998).
3.4.4) EARS
A) TINNITUS 1) WITH POISONING/EXPOSURE a) Tinnitus may develop with chronic intoxication (Morrice et al, 1960; Lombaert & Carton, 1976).
3.4.6) THROAT
A) GINGIVITIS 1) WITH POISONING/EXPOSURE a) Hyperemia and bleeding of the gums may develop with chronic intoxication (Muenter et al, 1971; Katz & Tzagournis, 1972; Baxi & Dailey, 1982).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) PLEURAL EFFUSION 1) WITH POISONING/EXPOSURE a) Pleural effusions have been reported in a few patients with ascites from chronic intoxication (Mendoza et al, 1988; Rosenberg et al, 1982; Noseda et al, 1985).
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Neurologic |
3.7.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Fatigue, irritability, headache, lethargy, papilledema, and increased intracranial pressure may be noted. Unusual effects include seizures and cranial nerve palsy.
3.7.2) CLINICAL EFFECTS
A) BENIGN INTRACRANIAL HYPERTENSION 1) WITH POISONING/EXPOSURE a) PSEUDOTUMOR CEREBRI - Benign increased intracranial pressure (pseudotumor cerebri) is a common feature in both acute and chronic vitamin A intoxication (Bhettay & Bakst, 1988; Farris & Erdman, 1982). Effects include headache, lethargy, vomiting, papilledema, stiff neck, and in infants bulging and delayed closure of the fontanelles (James et al, 1982; Morrice et al, 1960; Pasquariello et al, 1977; Silverman & Lecks, 1982; Nagai et al, 1999; Coghlan & Cranswick, 2001).
b) Increased cerebrospinal fluid pressure may be noted on lumbar puncture (Farris & Erdman, 1982; Selhorst et al, 1984).
c) Enlarged ventricles may be noted on head CT (Scherl et al, 1992).
d) BULGING FONTANELLES or delayed closure of the fontanelles and splitting of the cranial sutures have been reported in infants with chronic poisoning (Mahoney et al, 1980; Pasquariello et al, 1977; Scherl et al, 1992). Bulging fontanelles have also been reported with acute overdose (de Francisco et al, 1993; Ng et al, 2000).
B) HYDROCEPHALUS 1) WITH POISONING/EXPOSURE a) Hydrocephalus was reported in an infant who received 25,000 IU daily for several months (Gottrand et al, 1986).
C) NYSTAGMUS 1) WITH POISONING/EXPOSURE a) Cranial nerve abnormalities may include papilledema, nystagmus and 6th nerve palsy (Morrice et al, 1960; Selhorst et al, 1984; Patel et al, 1988; Katz & Tzagournis, 1972).
D) HEADACHE 1) WITH POISONING/EXPOSURE a) Headache is a common manifestation of chronic or acute overdose (Nagai et al, 1999; Patel et al, 1988; Cleland & Southcott, 1969; Nater & Doeglas, 1970) .
E) SEIZURE 1) WITH POISONING/EXPOSURE a) Seizures have been reported in acute (Cleland & Southcott, 1969) and chronic overdose (Schurr et al, 1983), but are not common.
F) IMPAIRED COGNITION 1) WITH POISONING/EXPOSURE a) Mental status changes include lethargy, irritability, impaired attention span and emotional lability (Schurr et al, 1983; Bhettay & Bakst, 1988; Mahoney et al, 1980; Fishbane et al, 1995).
G) ATAXIA 1) WITH POISONING/EXPOSURE a) CEREBELLAR EFFECTS - Ataxia and loss of fine motor coordination have been reported (Fishbane et al, 1995).
H) NEUROPATHY 1) WITH POISONING/EXPOSURE a) CASE REPORT - A 5-month-old with feeding intolerance and failure to thrive received vitamin A 50,000 IU intramuscularly followed 2 days later by 25,000 IU for two days. He developed a bulging fontanelle after the first dose and 5 days later was noted to have a complete abduction deficit of the left eye (acute sixth nerve palsy) which resolved over the next two months (Ng et al, 2000).
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Gastrointestinal |
3.8.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Nausea, vomiting, abdominal pain and anorexia may be noted.
3.8.2) CLINICAL EFFECTS
A) VOMITING 1) WITH POISONING/EXPOSURE a) Nausea, vomiting, abdominal pain and anorexia are common after acute or chronic overdose (Howard & Willhite, 1986; Silverman et al, 1987).
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Hepatic |
3.9.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Chronic hypervitaminosis A may result in elevation of liver enzymes, hepatic fibrosis, hepatosplenomegaly and hepatitis. In severe cases, it may progress to cirrhosis, portal hypertension and ascites. Liver transplant was necessary in one patient following chronic toxicity. One report of fulminant hepatic failure was reported in an adult following acute acitretin (metabolite of vitamin A) ingestion.
3.9.2) CLINICAL EFFECTS
A) LIVER DAMAGE 1) WITH POISONING/EXPOSURE a) CHRONIC INGESTION 1) CHRONIC EXPOSURE - Hepatic toxicity is most frequently associated with excessive long term ingestion of vitamin A. The range of doses associated with hepatotoxicity are daily doses of 15,000 to 1,400,000 IU with a mean daily dose of 120,000 IU (Cheruvattath et al, 2006; Sarles et al, 1990).
2) Elevated levels of hepatic aminotransferases, alkaline phosphatase, and bilirubin and increased INR are common in chronic intoxication (Sarles et al, 1990; Geubel et al, 1991; Minuk et al, 1988; Inkeles et al, 1986; Grubb, 1990; Nagai et al, 1999).
3) Individuals with pre-existing liver disease are at a greater risk of developing or worsening hepatic pathology due to the reduced capacity to produce Retinol-Binding protein.
b) ACUTE INGESTION 1) CASE REPORT - Fulminant hepatic failure was reported in a 42-year-old healthy woman with a history of psoriasis after intentionally ingesting 600 mg of acitretin (metabolite of vitamin A). She presented with vomiting and abdominal pain two days after exposure. Signs and symptoms included scleral icterus, mild right upper quadrant tenderness, and grade II encephalopathy with a slightly altered personality. Toxicology screening was negative for other agents. Initial laboratory studies (ie, bilirubin 97 micromol/L, alanine aminotransferase 10226 Units/L, alkaline phosphatase 153 Units/L, gamma-glutamyl transferase 111 Units/L) revealed significant hepatic injury. An increase in creatinine and BUN was also observed and thought to be secondary to hepatic impairment. Following symptomatic care including acetylcysteine, laboratory parameters and clinical symptoms improved with no permanent sequelae (Leithead et al, 2009).
B) CIRRHOSIS OF LIVER 1) WITH THERAPEUTIC USE a) 4 children (ages 7 to 18) with congenital ichthyosis developed hepatic fibrosis after the chronic use of vitamin A to treat that condition. Their daily doses ranged from 30,000 to 70,000 IU/day for 6 to 12 years (Sarles et al, 1990).
b) Cirrhosis was reported in 17 of 41 cases in one study on liver damage from vitamin A (Geubel et al, 1991).
c) A 50-year-old female was diagnosed as having hepatic fibrosis while undergoing evaluation of an unrelated malady. She showed no signs of hypervitaminosis A after using vitamin A 40,000 IU/day for several years (Bioulac-Sage et al, 1988).
2) WITH POISONING/EXPOSURE a) Fibrotic changes in the liver are the most common hepatic sequelae associated with chronic toxicity and result in fluorescent vacuoles in the liver (Geubel et al, 1991).
b) Continued use of vitamin A has resulted in development of cirrhosis due to transformation of the Ito cells into fibroblasts, with production of collagen. The onset of symptoms may occur after years of excessive vitamin A intake (Guarascio et al, 1983; Rosenberg et al, 1982; Jacques et al, 1979; Muenter et al, 1971).
C) TOXIC HEPATITIS 1) WITH POISONING/EXPOSURE a) Three family members who ingested 20,000 to 45,000 IU of vitamin A daily for 7 to 10 years developed hepatitis that was confirmed via liver biopsy. Two individuals in the same household did not use vitamin A and failed to develop hepatitis (Minuk et al, 1988).
D) JAUNDICE 1) WITH POISONING/EXPOSURE a) Jaundice and pruritus developed in a 67-year-old male who used vitamin A 150,000 IU/day for several years. A liver biopsy revealed inflammatory but not fibrotic changes. Liver function returned to normal after discontinuation of vitamin A (Smith, 1989).
E) PORTAL HYPERTENSION 1) WITH POISONING/EXPOSURE a) Chronic Toxicity 1) Chronic hypervitaminosis A initially results in hypertrophy and increased numbers of liver fat storage cells "Ito cells", with subsequent development of portal hypertension (Cheruvattath et al, 2006; Braitberg et al, 1995). Hepatosplenomegaly and ascites occur secondary to portal hypertension.
F) ASCITES 1) WITH POISONING/EXPOSURE a) Ascites has been reported in a limited number of cases of chronic intoxication (Cheruvattath et al, 2006; Russell et al, 1974; Baker et al, 1990; Braitberg et al, 1995). 1) Two cases involved children who received 100,000 to 300,000 IU daily for 6 months to one year (Rosenberg et al, 1982; Noseda et al, 1985).
b) ADULT - A 60-year-old man consumed 500,000 units of vitamin A daily for 4 months, then 100,000 units monthly for 6 months and developed an elevated aminotransferase concentration, alopecia, nail dystrophy, and ascites. Fluid analysis following paracentesis was consistent with portal hypertension, and narrowing of the inferior vena cava was observed on abdominal CT. Liver biopsy indicated the presence of Ito cells and vacuolated Kuppfer cells without the presence of cirrhosis. The patient developed refractory ascites, and his clinical condition continued to decline, despite the discontinuation of vitamin A. The patient underwent orthotopic liver transplantation 5 months after symptoms developed and recovery was uneventful. The patient was able to return to an active lifestyle (Cheruvattath et al, 2006). c) TODDLER - A 3-year-old developed ascites after using 100,000 IU/day for a week followed by 50,000 IU/day for 6 months (Mendoza et al, 1988). d) TEENAGER Ascites, pleural effusion, and portal hypertension developed in a 14-year-old female who ingested 100-200,000 IU/day for 15 months. Ascites developed 2 months after vitamin A use was terminated. Portal hypertension resolved 6 months following cessation of therapy (Noseda et al, 1985). |
Genitourinary |
3.10.2) CLINICAL EFFECTS
A) ABNORMAL RENAL FUNCTION 1) WITH POISONING/EXPOSURE a) Renal insufficiency may develop in patients with hepatic failure from chronic vitamin A intoxication (Braitberg et al, 1995). Renal dysfunction (ie, elevated BUN and creatinine) without oliguria was also observed in an adult female following an acute ingestion of 600 mg of acitretin (metabolite of vitamin A) (Leithead et al, 2009).
b) CASE REPORT - A 22-year-old male athlete developed hypercalcemia and acute renal failure after starting a conditioning program and injecting himself with anabolic hormones and intramuscular injections of vitamins A, D, and E. Initial labs included: an ionized calcium of 1.99 mmol/L (range: 1.11-140 ) and total calcium 14.8 mg/dL (range: 8.6-10.3), serum creatinine of 3.0 (0.7-1.3 mg/dL), BUN 61 (10-50 mEq/L) and potassium 2.9 (3.5-4.5 mEq/L). The parathyroid hormone was completely suppressed with a 25-hydroxyvitamin D concentration of 327 ng/mL (range: 30-60 ng/mL). Hypercalcemia persisted despite saline hydration and diuretics; the patient was treated with pamidronate (a single 60 mg dose) with complete resolution of his symptoms and normalization of renal function (Titan et al, 2009). Even though vitamin A levels were not obtained, the authors concluded that both vitamin A and D lead to hypercalcemia in this patient.
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Hematologic |
3.13.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Elevated erythrocyte sedimentation rate is common. Hypoprothrombinemia may develop in patients with hepatic injury.
3.13.2) CLINICAL EFFECTS
A) COAG./BLEEDING TESTS ABNORMAL 1) WITH POISONING/EXPOSURE a) Prolonged PT and diminished levels of clotting factors may develop in patients with hepatic injury secondary to chronic intoxication (Rosenberg et al, 1982; Sarles et al, 1990; Geubel et al, 1991; Minuk et al, 1988).
B) ESR RAISED 1) WITH POISONING/EXPOSURE a) Erythrocyte sedimentation rate (ESR) is often elevated in chronic toxicity (Patel et al, 1988; Muenter et al, 1971; Wason & Lovejoy, 1982).
C) ANEMIA 1) WITH POISONING/EXPOSURE a) Hypoplastic anemia is an uncommon effect of chronic intoxication (Josephs, 1942; Silverman et al, 1987; Sarles et al, 1990).
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Dermatologic |
3.14.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) The dermal changes are frequently among the first signs of hypervitaminosis A and are likely to include cheilosis, dryness, pruritus, desquamation, seborrhea-like eruptions, skin pigmentation, brittle nails and alopecia. Facial swelling associated with palmar-plantar desquamation may be noted following overdose with isotretinoin (Accutane(R)).
3.14.2) CLINICAL EFFECTS
A) DRY SKIN 1) WITH POISONING/EXPOSURE a) Skin is often dry, scaling and pruritic. Seborrhea-like eruptions and changes in skin pigmentation may develop. Cheilosis, or fissuring of the skin around the mouth, and dry cracked lips are common (Lippe et al, 1981; Pasquariello et al, 1977; Muenter et al, 1971; Nagai et al, 1999).
B) GENERALIZED EXFOLIATIVE DERMATITIS 1) WITH POISONING/EXPOSURE a) Peeling of perioral areas may progress to loss of skin layers over most of the body. Exfoliation of the skin occurs from one to several days after ingestion and may continue for several weeks (Coghlan & Cranswick, 2001; Nater & Doeglas, 1970).
b) Facial scaling associated with palmar-plantar desquamation may be noted following overdose with ISOTRETINOIN (Accutane).
C) NAIL FINDING 1) WITH POISONING/EXPOSURE a) Nails may be brittle or may separate from nailbeds (Ruskin et al, 1992).
b) PARONYCHIA - Patients with chronic intoxication may develop chronic paronychia of the fingers and toes (Jowsey & Riggs, 1968; Muenter et al, 1971).
D) ALOPECIA 1) WITH POISONING/EXPOSURE a) Alopecia has been reported with chronic use (Coghlan & Cranswick, 2001; Ruskin et al, 1992; Nagai et al, 1999).
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Musculoskeletal |
3.15.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Subcutaneous swelling, pain in bones and joints, with tenderness over the long bones commonly occurs.
3.15.2) CLINICAL EFFECTS
A) PAIN 1) WITH POISONING/EXPOSURE a) BONE PAIN - Subcutaneous swelling, pains in bones and joints, with tenderness over the long bones has been reported following vitamin A intoxication (James et al, 1982; Nagai et al, 1999; Coghlan & Cranswick, 2001).
B) DECREASED BODY GROWTH 1) WITH POISONING/EXPOSURE a) Chronic hypervitaminosis A may cause growth retardation in children due to premature closure of the epiphyses (Anon, 1972; Patel et al, 1988).
C) DISORDER OF BONE 1) WITH POISONING/EXPOSURE a) Periosteal new bone formation has been demonstrated radiographically in children with chronic intoxication (Frame et al, 1974; Wason & Lovejoy, 1982).
b) Increased bone resorption has been reported on biopsy (Jowsey & Riggs, 1968).
c) Osteopenia has been reported on radiographic examination (Scherl et al, 1992).
3.15.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) DWARFISM a) Vitamin A intoxication in young swine resulted in dwarfism due to premature epiphyseal growth plate closure (Doige & Schoonderwoerd, 1988).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) DISORDER OF MENSTRUATION 1) WITH POISONING/EXPOSURE a) Women with chronic intoxication may develop oligomenorrhea or amenorrhea (Morrice et al, 1960; Muenter et al, 1971).
B) FINDING OF THYROID FUNCTION 1) WITH POISONING/EXPOSURE a) Vitamin A supplementation 50,000 IU per day for 21 to 71 days decreased thyroid uptake of radioactive iodine in one human study (Logan, 1957).
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Reproductive |
3.20.1) SUMMARY
A) Vitamin A is classified as FDA pregnancy category X. The safety of vitamin A exceeding 6000 units/day during pregnancy has not been established. Animal reproduction studies have demonstrated fetal abnormalities associated with vitamin A overdose in several species.
3.20.2) TERATOGENICITY
A) CONGENITAL ANOMALY 1) In one study, there was no evidence of an increased risk of major malformations in 311 infants exposed to a median daily dose of 50,000 International Units of vitamin A per day (range 10,000 to 300,000) during organogenesis compared with infants exposed later in pregnancy or unexposed infants (Mastroiacovo et al, 1999).
2) There is a well-established association between some vitamin A congeners and a teratogenic outcome in infants whose mothers were exposed during pregnancy (Kizer et al, 1990).
3) Isolated reports describe teratogenic effects following the use of greater than 25,000 International Units daily during the first trimester (Anon, 1987; Rosa et al, 1986).
4) In one case report, multiple congenital abnormalities similar to those associated with isotretinoin were observed following the maternal intake of 2000 International Units of vitamin A daily during pregnancy (Lungarotti et al, 1987).
5) Preterm neonates who developed bronchopulmonary dysplasia had lower plasma concentrations of retinol binding protein at birth and at 21 days compared with infants who did not develop this condition. In this study, 64% of preterm infants had levels less than 20 mcg/dL (Hustead et al, 1984).
6) In a prospective study of 22,755 women, high intake of vitamin A (retinol greater than 15,000 international units/day from combined sources of food and supplements or greater than 10,000 International Units/day from supplements) was associated with an increased incidence of birth defects. Incidences of malformations of tissues derived from neural crest cells (ie, craniofacial, CNS, thymus, and heart) that were only noted when high vitamin A intake occurred between 2 weeks preconception and 6 weeks post-conception demonstrated the greatest increase. The increase was less pronounced for musculoskeletal and urogenital defects. After correcting for confounding variables (ie, age, education, race, family history of birth defects, and folate, ethanol, or anticonvulsant use), the differences persisted. The study findings that vitamin A is potentially teratogenic were confined to vitamin A in the form of retinol. The study did not examine teratogenicity of vitamin A in the form of beta carotene (Rothman et al, 1995).
B) LACK OF EFFECT 1) No teratogenic effects were reported in 1203 pregnant women receiving 6000 international units/day of vitamin A, at least 1 month prior to conception and for up to the twelfth week of pregnancy (Dudas & Czeizel, 1992).
C) ANIMAL STUDIES 1) In animal reproduction studies, fetal abnormalities of the central nervous system, the eye, the palate, and the urogenital tract associated with vitamin A overdose have been reported (Prod Info AQUASOL A(R) PARENTERAL intramuscular injection, 2005)
2) Retinoic acid syndrome resulting from high vitamin A intake in animals has been characterized by central nervous system, craniofacial, cardiovascular, and thymus malformations. In humans, similar abnormalities were observed when patients receiving therapeutic treatment with retinoic acid became pregnant (Lammer et al, 1985). Vitamin A deficiency has also been shown to be detrimental to the offspring of rats, including lethal failure in lung development. Similarly, respiratory distress syndrome has been observed in premature infants whose vitamin A status was often deficient (Azais-Braesco & Pascal, 2000).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified vitamin A as FDA pregnancy category X (Prod Info AQUASOL A(R) PARENTERAL intramuscular injection, 2005).
B) SPONTANEOUS ABORTION 1) The risk of spontaneous abortion or congenital malformations may be as high as 100% in women taking vitamin A in therapeutic doses during the second month of gestation (CDC, 2002).
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