Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A (retinyl esters, retinol, and retinal). 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 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 make a full recovery. High intake of provitamin carotenoids (such as beta-carotene) from vegetables and fruits does not cause hypervitaminosis A.
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 results from excessive intake of preformed vitamin A. Genetic variations in tolerance to vitamin A intake may occur, so the toxic dose will not be the same for everyone.[23] Children are particularly sensitive to vitamin A, with daily intakes of 1500 IU/kg body weight reportedly leading to toxicity.[21]
Types of vitamin A
It is "largely impossible" for provitamin carotenoids, such as beta-carotene, to cause toxicity, as their conversion to retinol is highly regulated.[21] No vitamin A toxicity has ever been reported from ingestion of excessive amounts.[24] Overconsumption of beta-carotene can only cause carotenosis, a harmless and reversible cosmetic condition in which the skin turns orange.
Preformed vitamin A absorption and storage in the liver occur very efficiently until a pathologic condition develops.[21] When ingested, 70–90% of preformed vitamin A is absorbed and used.[21]
Sources of toxicity
Diet – Liver is high in vitamin A. The liver of certain animals, including the polar bear, bearded seal,[25][26] fish and[27]walrus,[28] are particularly toxic (see Liver (food) § Poisoning). It has been estimated that consumption of 500 grams (18 oz) of polar bear liver would result in a toxic dose for a human.[25]
Supplements – Dietary supplements can be toxic when taken above recommended dosages.[1]
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 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.
Mechanism
Retinol is absorbed and stored in the liver very efficiently until a pathologic condition develops.[21]
Delivery to tissues
Absorption
When ingested, 70–90% of preformed vitamin A is absorbed and used.[21]
According to a 2003 review, water-miscible, emulsified, and solid forms of vitamin A supplements are more toxic than oil-based supplement and liver sources.[29]
Storage
Eighty to ninety percent of the total body reserves of preformed vitamin A are in the liver (with 80–90% of this amount being stored in hepatic stellate cells and the remaining 10–20% being stored in hepatocytes). Fat is another significant storage site, while the lungs and kidneys may also be capable of storage.[21]
Transport
Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), retinoic acid bound to albumin, water-soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids.[30]
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.[21]
Effects
Effects include increased bone turnover and altered metabolism of fat-soluble vitamins. More research is needed to fully elucidate the effects.
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,[21][24] and bone lesions.[31]
Altered fat-soluble vitamin metabolism
Preformed vitamin A is fat-soluble and high levels have been reported to affect metabolism of the other fat-soluble vitamins D,[24] E, and K.
The toxic effects of preformed 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.[24]
Mitochondrial toxicity
Preformed vitamin A and retinoids exerts several toxic effects regarding redox environment and mitochondrial function. [32]
Diagnosis
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.[21] 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.[21]
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.[21] 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.[21]
Prevention
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. Possible pregnancy, liver disease, high alcohol consumption, and smoking are indications for close monitoring and limitation of vitamin A administration.[33]
Daily tolerable upper level
Life stage group category
Upper Level
(μg/day)
Infants
0–6 months
7–12 months
600
600
Children and adolescents
1–3 years
4–8 years
9–13 years
14–18 years
600
900
1700
2800
Adults
19–70 years
3000
Treatment
Stopping high vitamin A intake is the standard treatment. Most people fully recover.
If liver damage has progressed into fibrosis, synthesizing capacity is compromised and supplementation can replenish PC. However, recovery is dependent on removing the causative agent: halting high vitamin A intake.[36][37][38][39]
History
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,[21] as observed in a fossilised leg bone of an individual of Homo erectus, which bears abnormalities similar to those observed in people suffering from an overdose of Vitamin A in the present day.[40][41]
Vitamin A toxicity has long been known to the Inuit as they will not eat the liver of polar bears or bearded seals due to them containing dangerous amounts of Vitamin A.[25] It has been known to 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.[42]
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.[43] Another study suggests, however, that exhaustion and diet change are more likely to have caused the tragedy.[44]
Other animals
Some Arctic animals demonstrate no signs of hypervitaminosis A despite having 10–20 times the level of vitamin A in their livers as other Arctic animals. These animals are top predators and include the 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.[45]
Treatment
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,[46] and prevents side effects in chicks[47]
Taurine significantly reduces toxic effects in rats.[48] Retinoids can be conjugated by taurine and other substances. Significant amounts of retinotaurine are excreted in the bile,[49] and this retinol conjugate is thought to be an excretory form, as it has little biological activity.[50]
Red yeast rice ("cholestin") – significantly reduces toxic effects in rats.[51]
^Tholen W, Paquet KJ, Rohner HG, Albrecht M (August 1980). "[Cirrhosis of the liver and esophageal bleeding after chronic vitamin A intoxication". Leber, Magen, Darm. 10 (4): 193–197. PMID6969836. (author's translation)].
^Jorens PG, Michielsen PP, Pelckmans PA, Fevery J, Desmet VJ, Geubel AP, Rahier J, Van Maercke YM (December 1992). "Vitamin A abuse: development of cirrhosis despite cessation of vitamin A. A six-year clinical and histopathologic follow-up". Liver. 12 (6): 381–386. doi:10.1111/j.1600-0676.1992.tb00592.x. PMID1470008.
^Erickson JM, Mawson AR (September 2000). "Possible role of endogenous retinoid (Vitamin A) toxicity in the pathophysiology of primary biliary cirrhosis". Journal of Theoretical Biology. 206 (1): 47–54. Bibcode:2000JThBi.206...47E. doi:10.1006/jtbi.2000.2102. PMID10968936.
^Nollevaux MC, Guiot Y, Horsmans Y, Leclercq I, Rahier J, Geubel AP, Sempoux C (March 2006). "Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption". Liver International. 26 (2): 182–186. doi:10.1111/j.1478-3231.2005.01207.x. PMID16448456. S2CID41658180.
^Cho DY, Frey RA, Guffy MM, Leipold HW (November 1975). "Hypervitaminosis A in the dog". American Journal of Veterinary Research. 36 (11): 1597–1603. PMID1190603.
^Rothenberg AB, Berdon WE, Woodard JC, Cowles RA (December 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): 1264–1267. doi:10.1007/s00247-007-0604-0. PMID17909784. S2CID34194762.
^Carpenter TO, Pettifor JM, Russell RM, Pitha J, Mobarhan S, Ossip MS, Wainer S, Anast CS (October 1987). "Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake". The Journal of Pediatrics. 111 (4): 507–512. doi:10.1016/s0022-3476(87)80109-9. PMID3655980.
^Hough S, Avioli LV, Muir H, Gelderblom D, Jenkins G, Kurasi H, Slatopolsky E, Bergfeld MA, Teitelbaum SL (June 1988). "Effects of hypervitaminosis A on the bone and mineral metabolism of the rat". Endocrinology. 122 (6): 2933–2939. doi:10.1210/endo-122-6-2933. PMID3371268.
^Cheruvattath R, Orrego M, Gautam M, Byrne T, Alam S, Voltchenok M, Edwin M, Wilkens J, Williams JW, Vargas HE (December 2006). "Vitamin A toxicity: when one a day doesn't keep the doctor away". Liver Transplantation. 12 (12): 1888–1891. doi:10.1002/lt.21007. PMID17133567. S2CID32290718.
^Gundermann KJ, Kuenker A, Kuntz E, Droździk M (2011). "Activity of essential phospholipids (EPL) from soybean in liver diseases". Pharmacological Reports. 63 (3): 643–659. doi:10.1016/S1734-1140(11)70576-X. PMID21857075. S2CID4741429.
^Navder KP, Lieber CS (March 2002). "Dilinoleoylphosphatidylcholine is responsible for the beneficial effects of polyenylphosphatidylcholine on ethanol-induced mitochondrial injury in rats". Biochemical and Biophysical Research Communications. 291 (4): 1109–1112. doi:10.1006/bbrc.2002.6557. PMID11866479.
^Lips P (January 2003). "Hypervitaminosis A and fractures". The New England Journal of Medicine. 348 (4): 347–349. doi:10.1056/NEJMe020167. PMID12540650.
^St Claire MB, Kennett MJ, Besch-Williford CL (July 2004). "Vitamin A toxicity and vitamin E deficiency in a rabbit colony". Contemporary Topics in Laboratory Animal Science. 43 (4): 26–30. PMID15264766.
^Yeh YH, Lee YT, Hsieh HS, Hwang DF (2008). "Effect of taurine on toxicity of vitamin a in rats". Food Chemistry. 106: 260–268. doi:10.1016/j.foodchem.2007.05.084.
^Skare KL, DeLuca HF (July 1983). "Biliary metabolites of all-trans-retinoic acid in the rat". Archives of Biochemistry and Biophysics. 224 (1): 13–18. doi:10.1016/0003-9861(83)90185-6. PMID6870249.
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