Hypervitaminosis A

Last updated
Hypervitaminosis A
Vitamin A synthesis.svg
Forms of preformed vitamin A in the body
Specialty Toxicology

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.

Contents

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.

Signs and symptoms

Symptoms may include:

Signs

Causes

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. Basel 2012-10-06 Batch Part 4 (16).JPG
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

Sources of toxicity

Types of toxicity

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.

Increased bone turnover

Retinoic acid suppresses osteoblast activity and stimulates osteoclast formation in vitro , [24] 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).[ citation needed ]

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]

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. [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

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]

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. [40]

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. [41] Another study suggests, however, that exhaustion and diet change are more likely to have caused the tragedy. [42]

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. [43]

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.

See also

Related Research Articles

<span class="mw-page-title-main">Carotene</span> Class of compounds

The term carotene (also carotin, from the Latin carota, "carrot") is used for many related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but in general cannot be made by animals (with the exception of some aphids and spider mites which acquired the synthesizing genes from fungi). Carotenes are photosynthetic pigments important for photosynthesis. Carotenes contain no oxygen atoms. They absorb ultraviolet, violet, and blue light and scatter orange or red light, and (in low concentrations) yellow light.

<span class="mw-page-title-main">Vitamin A</span> Essential nutrient

Vitamin A is a fat-soluble vitamin and an essential nutrient for animals. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinal, retinoic acid, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: it is essential for embryo development and growth, for maintenance of the immune system, and for vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light and color vision.

<span class="mw-page-title-main">Retinol</span> Chemical compound

Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and mucous membranes, immune function and reproductive development. Dietary sources include fish, dairy products, and meat. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. It is taken by mouth or by injection into a muscle. As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.

<span class="mw-page-title-main">Cod liver oil</span> Dietary supplement derived from liver of cod fish

Cod liver oil is a dietary supplement derived from liver of cod fish (Gadidae). As with most fish oils, it contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and also vitamin A and vitamin D. Historically, it was given to children because vitamin D had been shown to prevent rickets, a consequence of vitamin D deficiency.

β-Carotene Red-orange pigment of the terpenoids class

β-Carotene (beta-carotene) is an organic, strongly colored red-orange pigment abundant in fungi, plants, and fruits. It is a member of the carotenes, which are terpenoids (isoprenoids), synthesized biochemically from eight isoprene units and thus having 40 carbons.

<span class="mw-page-title-main">Retinal</span> Chemical compound

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

<span class="mw-page-title-main">Retinoid</span> Group of tetraterpenes

The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth.

<span class="mw-page-title-main">Retinyl palmitate</span> Vitamin A chemical compound

Retinyl palmitate, or vitamin A palmitate, is the ester of retinol (vitamin A) and palmitic acid, with formula C36H60O2. It is the most abundant form of vitamin A storage in animals.

<span class="mw-page-title-main">Retinoic acid</span> Metabolite of vitamin A

Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.

<span class="mw-page-title-main">Carotenoid oxygenase</span>

Carotenoid oxygenases are a family of enzymes involved in the cleavage of carotenoids to produce, for example, retinol, commonly known as vitamin A. This family includes an enzyme known as RPE65 which is abundantly expressed in the retinal pigment epithelium where it catalyzed the formation of 11-cis-retinol from all-trans-retinyl esters.

<span class="mw-page-title-main">Carotenosis</span> Skin discoloration caused by carotenoids

Carotenosis is a benign and reversible medical condition where an excess of dietary carotenoids results in orange discoloration of the outermost skin layer. The discoloration is most easily observed in light-skinned people and may be mistaken for jaundice. Carotenoids are lipid-soluble compounds that include alpha- and beta-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin. The primary serum carotenoids are beta-carotene, lycopene, and lutein. Serum levels of carotenoids vary between region, ethnicity, and sex in the healthy population. All are absorbed by passive diffusion from the gastrointestinal tract and are then partially metabolized in the intestinal mucosa and liver to vitamin A. From there they are transported in the plasma into the peripheral tissues. Carotenoids are eliminated via sweat, sebum, urine, and gastrointestinal secretions. Carotenoids contribute to normal-appearing human skin color, and are a significant component of physiologic ultraviolet photoprotection.

<span class="mw-page-title-main">Vitamin A deficiency</span> Disease resulting from low Vitamin A concentrations in the body

Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues. It is common in poorer countries, especially among children and women of reproductive age, but is rarely seen in more developed countries. Nyctalopia is one of the first signs of VAD, as the vitamin has a major role in phototransduction; but it is also the first symptom that is reversed when vitamin A is consumed again. Xerophthalmia, keratomalacia, and complete blindness can follow if the deficiency is more severe.

<span class="mw-page-title-main">Liver (food)</span> Liver meat used as food

The liver of mammals, fowl, and fish is commonly eaten as food by humans. Pork, lamb, veal, beef, chicken, goose, and cod livers are widely available from butchers and supermarkets while stingray and burbot livers are common in some European countries.

The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the photon is absorbed, the 11-cis retinal photoisomerizes into all-trans retinal as it is ejected from the opsin protein. Each molecule of retinal must travel from the photoreceptor cell to the RPE and back in order to be refreshed and combined with another opsin. This closed enzymatic pathway of 11-cis retinal is sometimes called Wald's visual cycle after George Wald (1906–1997), who received the Nobel Prize in 1967 for his work towards its discovery.

<span class="mw-page-title-main">Hepatic stellate cell</span>

Hepatic stellate cells (HSC), also known as perisinusoidal cells or Ito cells, are pericytes found in the perisinusoidal space of the liver, also known as the space of Disse. The stellate cell is the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage, in addition these cells store and concentrate vitamin A.

Vitamins occur in a variety of related forms known as vitamers. A vitamer of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin.

<span class="mw-page-title-main">Lecithin retinol acyltransferase</span> Mammalian protein found in Homo sapiens

Lecithin retinol acyltransferase is an enzyme that in humans is encoded by the LRAT gene.

Retinyl acetate is a natural form of vitamin A which is the acetate ester of retinol. It has potential antineoplastic and chemopreventive activities.

<span class="mw-page-title-main">Jagannath Ganguly</span>

Jagannath Ganguly (1921–2007) was an Indian biochemist known for his researches on Vitamin A and fatty acids, which assisted in the better understanding of their metabolism in humans. Born on the 1 April 1921, he authored a book, Biochemistry of Vitamin A, which details the physiological, biochemical and nutritional characteristics of the organic compound. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards, in 1963, for his contributions to biological sciences. He died on 12 December 2007.

<span class="mw-page-title-main">Retinol-binding protein</span> Family of proteins that bind retinol

Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.

References

  1. 1 2 3 4 5 6 7 Olson JM, Ameer MA, Goyal A (2023), "Vitamin A Toxicity", StatPearls, Treasure Island, Florida (US): StatPearls Publishing, PMID   30422511 , retrieved 2023-12-18
  2. ↑ Gorospe M, Fadare O (May 2007). "Gastric mucosal calcinosis: clinicopathologic considerations". Advances in Anatomic Pathology. 14 (3): 224–228. doi:10.1097/PAP.0b013e31805048ea. PMID   17452819. S2CID   45905601.
  3. ↑ Huk DJ, Hammond HL, Kegechika H, Lincoln J (February 2013). "Increased dietary intake of vitamin A promotes aortic valve calcification in vivo". Arteriosclerosis, Thrombosis, and Vascular Biology. 33 (2): 285–293. doi:10.1161/ATVBAHA.112.300388. PMC   3557503 . PMID   23202364.
  4. ↑ Libien J, Kupersmith MJ, Blaner W, McDermott MP, Gao S, Liu Y, Corbett J, Wall M, NORDIC Idiopathic Intracranial Hypertension Study Group (2017-01-15). "Role of vitamin A metabolism in IIH: Results from the idiopathic intracranial hypertension treatment trial". Journal of the Neurological Sciences. 372: 78–84. doi:10.1016/j.jns.2016.11.014. ISSN   1878-5883. PMC   5290478 . PMID   28017254.
  5. ↑ Wall M (March 2008). "Idiopathic intracranial hypertension (pseudotumor cerebri)". Current Neurology and Neuroscience Reports. 8 (2): 87–93. doi:10.1007/s11910-008-0015-0. PMID   18460275. S2CID   17285706.
  6. ↑ Castaño G, Etchart C, Sookoian S (2006). "Vitamin A toxicity in a physical culturist patient: a case report and review of the literature". Annals of Hepatology. 5 (4): 293–395. doi: 10.1016/S1665-2681(19)31992-1 . PMID   17151585.
  7. ↑ Minuk GY, Kelly JK, Hwang WS (1988). "Vitamin A hepatotoxicity in multiple family members". Hepatology. 8 (2): 272–275. doi:10.1002/hep.1840080214. PMID   3356407. S2CID   6632550.
  8. ↑ Levine PH, Delgado Y, Theise ND, West AB (February 2003). "Stellate-cell lipidosis in liver biopsy specimens. Recognition and significance". American Journal of Clinical Pathology. 119 (2): 254–258. doi: 10.1309/6DKC-03C4-GAAE-N2DK . PMID   12579996.
  9. ↑ 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. PMID   6969836. (author's translation)].
  10. ↑ 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. PMID   1470008.
  11. ↑ Babb RR, Kieraldo JH (March 1978). "Cirrhosis due to hypervitaminosis A". The Western Journal of Medicine. 128 (3): 244–246. PMC   1238074 . PMID   636413.
  12. ↑ 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. PMID   10968936.
  13. ↑ Singh M, Singh VN (May 1978). "Fatty liver in hypervitaminosis A: synthesis and release of hepatic triglycerides". The American Journal of Physiology. 234 (5): E511–514. doi:10.1152/ajpendo.1978.234.5.E511. PMID   645903.
  14. ↑ 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. PMID   16448456. S2CID   41658180.
  15. ↑ Cho DY, Frey RA, Guffy MM, Leipold HW (November 1975). "Hypervitaminosis A in the dog". American Journal of Veterinary Research. 36 (11): 1597–1603. PMID   1190603.
  16. ↑ Kodaka T, Takaki H, Soeta S, Mori R, Naito Y (July 1998). "Local disappearance of epiphyseal growth plates in rats with hypervitaminosis A". The Journal of Veterinary Medical Science. 60 (7): 815–821. doi: 10.1292/jvms.60.815 . PMID   9713809.
  17. ↑ Soeta S, Mori R, Kodaka T, Naito Y, Taniguchi K (March 1999). "Immunohistochemical observations on the initial disorders of the epiphyseal growth plate in rats induced by high dose of vitamin A". The Journal of Veterinary Medical Science. 61 (3): 233–238. doi: 10.1292/jvms.61.233 . PMID   10331194.
  18. ↑ Soeta S, Mori R, Kodaka T, Naito Y, Taniguchi K (March 2000). "Histological disorders related to the focal disappearance of the epiphyseal growth plate in rats induced by high dose of vitamin A". The Journal of Veterinary Medical Science. 62 (3): 293–299. doi: 10.1292/jvms.62.293 . PMID   10770602.
  19. ↑ 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. PMID   17909784. S2CID   34194762.
  20. ↑ Wick JY (February 2009). "Spontaneous fracture: multiple causes". The Consultant Pharmacist. 24 (2): 100–102, 105–108, 110–112. doi:10.4140/TCP.n.2009.100. PMID   19275452.
  21. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Penniston KL, Tanumihardjo SA (February 2006). "The acute and chronic toxic effects of vitamin A". The American Journal of Clinical Nutrition. 83 (2): 191–201. doi: 10.1093/ajcn/83.2.191 . PMID   16469975.
  22. ↑ Corić-Martinović V, Basić-Jukić N (2008). "[Uremic pruritus]". Acta Medica Croatica. 62 (Suppl 1): 32–36. PMID   18578330.
  23. ↑ 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. PMID   3655980.
  24. 1 2 3 4 5 Barker ME, Blumsohn A (November 2003). "Is vitamin A consumption a risk factor for osteoporotic fracture?". The Proceedings of the Nutrition Society. 62 (4): 845–850. doi: 10.1079/PNS2003306 . PMID   15018484.
  25. 1 2 3 Rodahl K, Moore T (July 1943). "The vitamin A content and toxicity of bear and seal liver". The Biochemical Journal. 37 (2): 166–168. doi:10.1042/bj0370166. PMC   1257872 . PMID   16747610.
  26. ↑ The Phoca barbata listed on pages 167–168 of the previous reference is now known as Erignathus barbatus
  27. ↑ Schmitt C, Domangé B, Torrents R, de Haro L, Simon N (December 2020). "Hypervitaminosis A Following the Ingestion of Fish Liver: Report on 3 Cases from the Poison Control Center in Marseille". Wilderness Environ Med. 31 (4): 454–456. doi: 10.1016/j.wem.2020.06.003 . PMID   32861618. S2CID   221384282.
  28. ↑ Morrison J (2006). "Walrus, liver, raw (Alaska Native)". Mealographer. Retrieved 2010-03-25.
  29. ↑ Myhre AM, Monica H Carlsen, Siv K Bøhn, Heidi L Wold, Petter Laake, Rune Blomhoff (2003-12-01). "Water-Miscible, Emulsified, and Solid Forms of Retinol Supplements Are More Toxic Than Oil-Based Preparations". The American Journal of Clinical Nutrition. 78 (6): 1152–1159. doi: 10.1093/ajcn/78.6.1152 . ISSN   0002-9165. PMID   14668278 . Retrieved 2012-04-16.
  30. ↑ Li Y, Wongsiriroj N, Blaner WS (June 2014). "The multifaceted nature of retinoid transport and metabolism". Hepatobiliary Surgery and Nutrition. 3 (3): 126–139. doi:10.3978/j.issn.2304-3881.2014.05.04. PMC   4073323 . PMID   25019074.
  31. ↑ 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. PMID   3371268.
  32. ↑ de Oliveira MR (2015). "Vitamin A and Retinoids as Mitochondrial Toxicants". Oxidative Medicine and Cellular Longevity. 2015: 1–13. doi: 10.1155/2015/140267 . PMC   4452429 . PMID   26078802.
  33. ↑
  34. ↑ McCuaig LW, Motzok I (July 1970). "Excessive dietary vitamin E: its alleviation of hypervitaminosis A and lack of toxicity". Poultry Science. 49 (4): 1050–1051. doi: 10.3382/ps.0491050 . PMID   5485475.
  35. ↑ 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. PMID   17133567. S2CID   32290718.
  36. ↑ 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. PMID   21857075. S2CID   4741429.
  37. ↑ Okiyama W, Tanaka N, Nakajima T, Tanaka E, Kiyosawa K, Gonzalez FJ, Aoyama T (June 2009). "Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress". Journal of Hepatology. 50 (6): 1236–1246. doi:10.1016/j.jhep.2009.01.025. PMC   2809859 . PMID   19398233.
  38. ↑ Wu J, Zern MA (2000). "Hepatic stellate cells: a target for the treatment of liver fibrosis". Journal of Gastroenterology. 35 (9): 665–672. doi:10.1007/s005350070045. PMID   11023037. S2CID   40851639.
  39. ↑ 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. PMID   11866479.
  40. ↑ Lips P (January 2003). "Hypervitaminosis A and fractures". The New England Journal of Medicine. 348 (4): 347–349. doi:10.1056/NEJMe020167. PMID   12540650.
  41. ↑ Nataraja A (1 May 2002). "Man's best friend?" . Student BMJ. BMJ. 324 (Suppl S5): 131–170. doi:10.1136/sbmj.0205158.
  42. ↑ Carrington-Smith D (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): 638–641. doi:10.5694/j.1326-5377.2005.tb00064.x. PMID   16336159. S2CID   8430414.
  43. ↑ Senoo H, Imai K, Mezaki Y, Miura M, Morii M, Fujiwara M, Blomhoff R (October 2012). "Accumulation of vitamin A in the hepatic stellate cell of arctic top predators". Anatomical Record. 295 (10): 1660–1668. doi: 10.1002/ar.22555 . PMID   22907891.
  44. ↑ 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. PMID   15264766.
  45. ↑ Weiser H, Probst HP, Bachmann H (September 1992). "Vitamin E prevents side effects of high doses of vitamin A in chicks". Annals of the New York Academy of Sciences. 669 (1): 396–398. Bibcode:1992NYASA.669..396W. doi:10.1111/j.1749-6632.1992.tb17134.x. PMID   1444058. S2CID   40860314.
  46. ↑ 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.
  47. ↑ 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. PMID   6870249.
  48. ↑ Skare KL, Sietsema WK, DeLuca HF (August 1982). "The biological activity of retinotaurine". The Journal of Nutrition. 112 (8): 1626–1630. doi:10.1093/jn/112.8.1626. PMID   7097369.
  49. ↑ Yeh YH, Lee YT, Hsieh YL (May 2012). "Effect of cholestin on toxicity of vitamin A in rats". Food Chemistry. 132 (1): 311–318. doi:10.1016/j.foodchem.2011.10.082. PMID   26434295.
  50. ↑ Walker SE, Eylenburg E, Moore T (1947). "The action of vitamin K in hypervitaminosis A". The Biochemical Journal. 41 (4): 575–580. doi:10.1042/bj0410575. PMC   1258540 . PMID   16748217.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.