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Hypervitaminosis A

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Title: Hypervitaminosis A  
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Subject: Far Eastern Party, Megavitamin therapy, Beta-Carotene, Retinol, Vitamin
Collection: Effects of External Causes, Hypervitaminosis
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Hypervitaminosis A

Hypervitaminosis A
Classification and external resources
ICD-10 E67.0
ICD-9-CM 278.2
DiseasesDB 13888
MedlinePlus 000350
eMedicine med/2382
Cod liver oil - a potentially toxic source of Vitamin A: Hypervitaminosis A can result from ingestion of too much vitamin A from diet, supplements, or prescription medications.

Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A. Symptoms arise as a result of altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervitaminosis A is believed to have occurred in early humans, and the problem has persisted throughout human history.

Toxicity results from ingesting too much preformed vitamin A from foods (such as fish or animal liver), supplements, or prescription medications and can be prevented by ingesting no more than the recommended daily amount.

Diagnosis can be difficult, as serum retinol is not sensitive to toxic levels of vitamin A, but there are effective tests available. Hypervitaminosis A is usually treated by stopping intake of the offending food(s), supplement(s), or medication. Most people fully recover.

High intake of provitamin carotenoids (such as beta carotene) from vegetables and fruits does not cause hypervitaminosis A, as conversion from carotenoids to the active form of vitamin A is regulated by the body to maintain an optimum level of the vitamin. Carotenoids themselves cannot produce toxicity.


  • Signs and symptoms 1
  • Causes 2
    • Types of vitamin A 2.1
    • Sources of toxicity 2.2
    • Types of toxicity 2.3
  • Mechanism 3
    • Delivery to tissues 3.1
    • Effects 3.2
  • Diagnosis 4
    • Tests 4.1
    • Relevance of blood tests 4.2
  • Prevention 5
    • Daily Tolerable Upper Level 5.1
  • Treatment 6
    • In humans 6.1
    • In animals 6.2
    • In vitro 6.3
  • History 7
  • Other animals 8
  • See also 9
  • References 10
  • External links 11

Signs and symptoms

Symptoms may include:[1]

  • Abnormal softening of the skull bone (craniotabes—infants and children)
  • Blurred vision
  • Bone pain or swelling
  • Bulging fontanelle (infants)
  • Changes in consciousness
  • Decreased appetite
  • Dizziness
  • Double vision (young children)
  • Drowsiness
  • Headache
  • Gastric mucosal calcinosis[2]
  • Heart valve calcification[3]
  • Hypercalcemia
  • Increased intracranial pressure manifesting as cerebral edema, papilledema, and headache[4] (may be referred to as Idiopathic intracranial hypertension)
  • Irritability
  • Liver damage[5][6][7][8][9][10][11][12][13]
  • Nausea
  • Poor weight gain (infants and children)
  • Skin and hair changes
  • Cracking at corners of the mouth
  • Hair loss
  • Higher sensitivity to sunlight
  • Oily skin and hair (seborrhea)
  • Premature epiphyseal closure[14][15][16][17][18]
  • Skin peeling, itching
  • Spontaneous fracture[19][20]
  • Yellow discoloration of the skin (aurantiasis cutis)
  • Uremic pruritus[21]
  • Vision changes
  • Vomiting


Hypervitaminosis A results from excessive intake of preformed vitamin A. A genetic variance in tolerance to vitamin A intake may occur.[22] Children are particularly sensitive to vitamin A, with daily intakes of 1500 IU/kg body weight reportedly leading to toxicity.[20]

Types of vitamin A

  • Provitamin carotenoids - such as beta carotene - are “largely impossible” to cause toxicity, as conversion to retinol is highly regulated.[20] No vitamin A toxicity has been reported from ingestion of excessive amounts.[23] Overconsumption of beta carotene can, however, cause carotenosis, a benign condition in which the skin turns orange.
  • Preformed vitamin A absorption and storage in the liver occur very efficiently until a pathologic condition develops.[20] When ingested, 70-90% of preformed vitamin A is absorbed and used.[20]

Sources of toxicity

  • Diet - liver is high in vitamin A. The liver of certain animals — including the polar bear, bearded seal,[24][25] walrus,[26] moose,[27] — are particularly toxic.
  • Supplements - usually when taken above recommended dosages - can be toxic. Cod liver oil is particularly high in vitamin A.
  • Medications - at high doses of vitamin A - are often used on long-term basis in numerous preventive and therapeutic medical applications, which may lead to hypervitaminosis A[28]

Types of toxicity

  • Acute toxicity occurs over a period of hours or a few days, and is less of a problem than chronic toxicity.
  • Chronic toxicity - ingestion of high amounts of preformed vitamin A for months or years - results from daily intakes greater than 25,000 IU for 6 years or longer and more than 100,000 IU for 6 months or longer - are considered toxic.


Absorption and storage in the liver of preformed vitamin A occur very efficiently until a pathologic condition develops.[20]

Delivery to tissues


When ingested, 70-90% of preformed vitamin A is absorbed and used.[20]


About 80% of the total body reserves of vitamin A are in the liver. Fat is another significant storage site, while the lung and kidneys may also be capable of storage.[20]


Once in the liver, retinol binds to retinol-binding protein (RBP) and is transported from the liver to tissues as the holo-RBP complex. The range of serum retinol concentrations under normal conditions is 1–3 μmol/l. Elevated amounts of retinyl ester (i.e., > 10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans. Candidate mechanisms for this increase include decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells.[20]


Effects include increased bone turnover and altered metabolism of fat-soluble vitamins. More research is needed to fully elucidate the effects.

Increased bone turnover

Retinoic acid suppresses osteoblast activity and stimulates osteoclast formation in vitro,[23] resulting in increased bone resorption and decreased bone formation. It is likely to exert this effect by binding to specific nuclear receptors (members of the retinoic acid receptor or retinoid X receptor nuclear transcription family) which are found in every cell (including osteoblasts and osteoclasts).

This change in bone turnover is likely to be the reason for numerous effects seen in hypervitaminosis A, such as hypercalcemia and numerous bone changes such as bone loss that potentially leads to osteoporosis, spontaneous bone fractures, altered skeletal development in children, skeletal pain, radiographic changes,[20][23] and bone lesions.[29]

Altered fat-soluble vitamin metabolism

Vitamin A is fat-soluble and high levels have been reported affect metabolism of the other fat-soluble vitamins D,[23] E, and K.

The toxic effects of vitamin A might be related to altered vitamin D metabolism, concurrent ingestion of substantial amounts of vitamin D, or binding of vitamin A to receptor heterodimers. Antagonistic and synergistic interactions between these two vitamins have been reported, as they relate to skeletal health.

Stimulation of bone resorption by vitamin A has been reported to be independent of its effects on vitamin D.[23]



Tests may include:[1]

  • bone X-rays
  • blood calcium test
  • cholesterol test
  • liver function test
  • blood test for vitamin A

Relevance of blood tests

Retinol concentrations are nonsensitive indicators

Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are not sensitive indicators in this range of liver vitamin A reserves.[20] The range of serum retinol concentrations under normal conditions is 1–3 μmol/l and, because of homeostatic regulation, that range varies little with widely disparate vitamin A intakes[20]

Retinol esters have been used as markers

Retinyl esters can be distinguished from retinol in serum and other tissues and quantified with the use of methods such as high-performance liquid chromatography.[20]

Elevated amounts of retinyl ester (i.e., > 10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans and monkeys.[20] This increased retinyl ester may be due to decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells.[20]


Hypervitaminosis A can be prevented by not ingesting more than the US Institute of Medicine Daily Tolerable Upper Level of intake for Vitamin A. This level is for synthetic and natural retinol ester forms of vitamin A. Carotene forms from dietary sources are not toxic. The dose over and above the RDA is among the narrowest of the vitamins and minerals. Possible pregnancy, liver disease, high alcohol consumption, and smoking are indications for close monitoring and limitation of vitamin A administration.

Daily Tolerable Upper Level

Life stage group category Upper Level (μg/day)

0–6 months
7–12 months


1–3 years
4–8 years


9–13 years
14–18 years
19 – >70 years


9–13 years
14–18 years
19 – >70 years


<19 years
19 – >50 years


<19 years
19 – >50 years



In humans

  • Stopping high Vitamin A intake is the standard treatment. Most people fully recover.[1]
  • Phosphatidylcholine, in the form of PPC, or DLPC.

If liver damage has progressed into fibrosis, synthesizing capacity is compromized and supplementation can replenish PC. However, recovery is dependent on removing the causative agent; stopping high Vitamin A intake.[30][31][32][33]

In animals

These treatments have been used to help treat or manage toxicity in animals. Although not considered part of standard treatment, they might be of some benefit to humans.

  • Vitamin E appears to be an effective treatment in rabbits,[36] prevents side effects in chicks[37]
  • Taurine significantly reduces toxic effects in rats.[38] Retinoids can be conjugated by taurine and other substances. Significant amounts of retinotaurine are excreted in the bile,[39] and this retinol conjugate is thought to be an excretory form, as it has little biological activity.[40]
  • Cholestin - significantly reduces toxic effects in rats.[41]
  • Vitamin K prevents hypoprothrombinemia in rats and can sometimes control the increase in plasma/cell ratios of vitamin A.[42]

In vitro

These treatments help prevent toxic effects in vitro.

  • Taurine, zinc, and vitamin E protect cells from retinol-induced injury.[43]
  • Cholesterol prevents retinol-induced Golgi apparatus fragmentation.[44]


Vitamin A toxicity is known to be an ancient phenomenon; fossilized skeletal remains of early humans suggest bone abnormalities may have been caused by hypervitaminosis A.[20]

Vitamin A toxicity has long been known to the Inuit and has been known by Europeans since at least 1597 when Gerrit de Veer wrote in his diary that, while taking refuge in the winter in Nova Zemlya, he and his men became severely ill after eating polar bear liver.[45]

In 1913, Antarctic explorers Douglas Mawson and Xavier Mertz were both poisoned (and Mertz died) from eating the livers of their sled dogs during the Far Eastern Party.[46] Another study suggests, however, that exhaustion and diet change are more likely to have caused the tragedy.[47]

Other animals

Some Arctic animals demonstrate no signs of hypervitaminosis A despite having 10-20 times the level of vitamin A in their livers than other Arctic animals. These animals are top predators and include polar bear, Arctic fox, bearded seal, and glaucous gull. This ability to efficiently store higher amounts of vitamin A may have contributed to their survival in the extreme environment of the Arctic.[48]

See also


  1. ^ a b c
  2. ^ Gorospe M, Fadare O (May 2007). "Gastric mucosal calcinosis: clinicopathologic considerations".  
  3. ^ Huk DJ, Hammond HL, Kegechika H, Lincoln J (February 2013). "Increased dietary intake of vitamin A promotes aortic valve calcification in vivo".  
  4. ^ Wall M (March 2008). "Idiopathic intracranial hypertension (pseudotumor cerebri)".  
  5. ^ Castaño G, Etchart C, Sookoian S (2006). "Vitamin A toxicity in a physical culturist patient: a case report and review of the literature".  
  6. ^ Minuk GY, Kelly JK, Hwang WS (1988). "Vitamin A hepatotoxicity in multiple family members".  
  7. ^ Levine PH, Delgado Y, Theise ND, West AB (February 2003). "Stellate-cell lipidosis in liver biopsy specimens. Recognition and significance".  
  8. ^ Tholen W, Paquet KJ, Rohner HG, Albrecht M (August 1980). "[Cirrhosis of the liver and esophageal bleeding after chronic vitamin A intoxication (author's transl)]".  
  9. ^ Jorens PG, Michielsen PP, Pelckmans PA, et al. (December 1992). "Vitamin A abuse: development of cirrhosis despite cessation of vitamin A. A six-year clinical and histopathologic follow-up".  
  10. ^ Babb RR, Kieraldo JH (March 1978). "Cirrhosis due to hypervitaminosis A".  
  11. ^ Erickson JM, Mawson AR (September 2000). "Possible role of endogenous retinoid (Vitamin A) toxicity in the pathophysiology of primary biliary cirrhosis".  
  12. ^ Singh M, Singh VN (May 1978). "Fatty liver in hypervitaminosis A: synthesis and release of hepatic triglycerides".  
  13. ^ Nollevaux MC, Guiot Y, Horsmans Y, et al. (March 2006). "Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption".  
  14. ^ Cho, DY; Frey, RA; Guffy, MM; Leipold, HW (1975). "Hypervitaminosis a in the dog". American journal of veterinary research 36 (11): 1597–1603.  
  15. ^ Kodaka, Tetsuo; Takaki, Hisashi; Soeta, Satoshi; Mori, Ryoichi; Naito, Yoshihisa (1998). "Local Disappearance of Epiphyseal Growth Plates in Rats with Hypervitaminosis A". Journal of Veterinary Medical Science 60 (7): 815–21.  
  16. ^ Soeta, Satoshi; Mori, Ryoichi; Kodaka, Tetsuo; Naito, Yoshihisa; Taniguchi, Kazuyuki (1999). "Immunohistochemical Observations on the Initial Disorders of the Epiphyseal Growth Plate in Rats Induced by High Dose of Vitamin A". Journal of Veterinary Medical Science 61 (3): 233–8.  
  17. ^ Soeta, Satoshi; Mori, Ryoichi; Kodaka, Tetsuo; Naito, Yoshihisa; Taniguchi, Kazuyuki (2000). "Histological Disorders Related to the Focal Disappearance of the Epiphyseal Growth Plate in Rats Induced by High Dose of Vitamin A". Journal of Veterinary Medical Science 62 (3): 293–9.  
  18. ^ Rothenberg, AB; Berdon, WE; Woodard, JC; Cowles, RA (2007). "Hypervitaminosis A-induced premature closure of epiphyses (physeal obliteration) in humans and calves (hyena disease): A historical review of the human and veterinary literature". Pediatric radiology 37 (12): 1264–7.  
  19. ^ Wick JY (February 2009). "Spontaneous fracture: multiple causes".  
  20. ^ a b c d e f g h i j k l m n o p Penniston KL, Tanumihardjo SA (February 2006). "The acute and chronic toxic effects of vitamin A".  
  21. ^ Corić-Martinović V, Basić-Jukić N (2008). "[Uremic pruritus]".  
  22. ^ Carpenter TO, Pettifor JM, Russell RM, et al. (October 1987). "Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake".  
  23. ^ a b c d e Barker ME, Blumsohn A (November 2003). "Is vitamin A consumption a risk factor for osteoporotic fracture?".  
  24. ^ Rodahl, K.; T. Moore (July 1943). "The vitamin A content and toxicity of bear and seal liver". Biochemical Journal 37 (2): 166–168.  
  25. ^ The Phoca barbata listed on pages 167–168 of the previous reference is now known as Erignathus barbatus
  26. ^ "Walrus, liver, raw (Alaska Native)". Mealographer. Retrieved 2010-03-25. 
  27. ^ "Moose, liver, braised (Alaska Native)". Mealographer. Retrieved 2012-10-15. 
  28. ^ Rutkowski M, Grzegorczyk K (June 2012). "Adverse effects of antioxidative vitamins".  
  29. ^ Hough S, Avioli LV, Muir H, et al. (June 1988). "Effects of hypervitaminosis A on the bone and mineral metabolism of the rat".  
  30. ^
  31. ^
  32. ^
  33. ^
  34. ^ McCuaig LW, Motzok I (July 1970). "Excessive dietary vitamin E: its alleviation of hypervitaminosis A and lack of toxicity".  
  35. ^ Cheruvattath R, Orrego M, Gautam M, et al. (December 2006). "Vitamin A toxicity: when one a day doesn't keep the doctor away".  
  36. ^ St Claire MB, Kennett MJ, Besch-Williford CL (July 2004). "Vitamin A toxicity and vitamin E deficiency in a rabbit colony".  
  37. ^ Weiser H, Probst HP, Bachmann H (September 1992). "Vitamin E prevents side effects of high doses of vitamin A in chicks".  
  38. ^ Yeh, Yen-Hung; Lee, Ya-Ting; Hsieh, Hung-Sheng; Hwang, Deng-Fwu (2008). "Effect of taurine on toxicity of vitamin a in rats". Food Chemistry 106: 260.  
  39. ^ Skare, Kevin L.; Deluca, Hector F. (1983). "Biliary metabolites of all-trans-retinoic acid in the rat". Archives of Biochemistry and Biophysics 224 (1): 13–8.  
  40. ^ Skare, KL; Sietsema, WK; Deluca, HF (1982). "The biological activity of retinotaurine". The Journal of nutrition 112 (8): 1626–30.  
  41. ^ Yeh, Yen-Hung; Lee, Ya-Ting; Hsieh, You-Liang (2012). "Effect of cholestin on toxicity of vitamin a in rats". Food Chemistry 132: 311.  
  42. ^ Walker SE, Eylenburg E, Moore T (1947). "The action of vitamin K in hypervitaminosis A" (PDF).  
  43. ^ Pasantes-Morales H, Wright CE, Gaull GE (December 1984). "Protective effect of taurine, zinc and tocopherol on retinol-induced damage in human lymphoblastoid cells". The Journal of Nutrition 114 (12): 2256–61.  
  44. ^ Sarkanen, Jertta-Riina; Nykky, Jonna; Siikanen, Jutta; Selinummi, Jyrki; Ylikomi, Timo; Jalonen, Tuula O. (2007). "Cholesterol supports the retinoic acid-induced synaptic vesicle formation in differentiating human SH-SY5Y neuroblastoma cells". Journal of Neurochemistry 102 (6): 1941–52.  
  45. ^ Lips, Paul (2003). "Hypervitaminosis a and Fractures". New England Journal of Medicine 348 (4): 347–9.  
  46. ^ Nataraja, Anjali (2002). "Man's best friend?". Student BMJ 10: 131–70.  
  47. ^ Carrington-Smith, Denise (2005). "Mawson and Mertz: A re-evaluation of their ill-fated mapping journey during the 1911-1914 Australasian Antarctic Expedition". The Medical journal of Australia 183 (11–12): 638–41.  
  48. ^ Senoo H, Imai K, Mezaki Y, et al. (October 2012). "Accumulation of vitamin A in the hepatic stellate cell of arctic top predators".  

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