Hypervitaminosis A

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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] 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.

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 that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: essential in embryo development for growth, maintaining the immune system, and healthy 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">Tretinoin</span> Medication

Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present and is taken by mouth for up to three months. Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.

<span class="mw-page-title-main">Retinal</span> Vitamin A aldehyde, a polyene chromophore

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 natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are used in medicine where they regulate skin health, immunity and bone disorders.

<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 (simplified nomenclature for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-trans-retinoic acid is required for chordate animal development, 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. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function. and male fertility. Retinoic acid administered as a drug (see tretinoin and alitretinoin) causes significant toxicity that is distinct from normal retinoid biology.

<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">Alitretinoin</span> Chemical compound

Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

<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.

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> Type of liver cell

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.

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