Vitamin A

Vitamin A 1.Night blindness and some eye disorders, which were well recognized in ancient Egypt, were treated by the topical application of juice squeezed from cooked liver or by prescribing liver in the diet.

 2.This

medical lore was lost over the centuries, and night blindness, called "this curious and obscure disease" by R.J. Hicks, a surgeon serving with the Confederate army in the American Civil War, plagued armies throughout the world in the nineteenth century. The active principle of liver in treating eye disease was vitamin A, which was identified as a necessary fatsoluble factor for rat growth in 19l4 and was structurally elucidated in l930.

biological conversion of β -carotene to vitamin A was shown the same year. These early studies on vitamin A are well reviewed in Moore's fine treatise.

 The

Chemistrv and Nomenclature  The

parent compound in the vitamin A group is called all-trans retinol .Its aldehyde and acid forms are retinal and retinoic acid.

 The

active form of vitamin A in vision is 11-cis retinal and a therapeutically useful form (Accutane, isotretinoin) is l3-cis retinoic acid. Retinyl palmitate is a major storage form, and retinoyl 6-glucuronide is a biologically active, water- soluble metabolite.

A

synthetic aromatic analog (etretin), which has therapeutic usefulness, is depicted. Finally, β -carotene,is a major provitamin A carotenoid.

vitamin A family  In

a nutritional sense the vitamin A family includes all naturally occurring compounds with the biological activity of retinol. Because provitamin A carotenoids are nutritionally active, they are included in the vitamin A family. Only 50 of =600 carotenoids found in nature are converted to vitamin A, but most carotenoids, including those with provitamin A activity, also can serve as singlet oxygen quenchers and as antioxidants under certain conditions.

 These

characteristics are not possessed by retinol. (Symposia that deal with various aspects of carotenoids in health and disease have re cently been published.)

 Thus,

in considering the biological actions of carotenoids, it is important to differentiate between provitamin A activity and other possible effects

Functions  The

best defined function of vitamin A is in vision.The pathway for the delivery of vitamin A to the eye involves the following steps:

 l)

interaction of plasma holo-RBP with specific cellsurface receptors on retinal pigment epithelial cells,  2) uptake of retinol by retinal pigment epithelial cells and its enzymatic isomerization to 11-cis retinol,  3) transport by IRBP to the rod outer segment,  4) enzymatic oxidation of the l l-cis retinol to 11-cis retinal, and 5) nonenzymatic association of the latter with a specific lysine group in the membrane-bound protein opsin .

 The

1l-cis retinal in the resultant,rhodopsin, when exposed to light, isomerizes to a transoid intermediate, which in turn triggers a series of conformational changes in the protein. An intermediate form,metarhodopsin ll, interacts with a complex G protein, termed transducin, which causes the α unit of the latter to replace bound GDP with GTP.

GTP- α unit complex of transducin activates phosphodiesterase, which in turn hydrolyzes cGMP to GMP cGMP is involved in keeping the sodium channels of the rod outer segment open. As cGMP decreases, sodium ion entry decreases thereby hyperpolarizing the rod cell membrane change in membrane potential is transmitted through a complex set of synapses to the brain, where the pulses received at a given time are integrated

 The

A

similar metabolic sequence seems to occur in the color-sensing cone cells of the retina.  Activated processes of temporal importance must be returned to the basal state. In the visual cascade, metarhodopsin II is converted through other conformational states to opsin and all-trans retinal, neither of which activates transducin.

 Phosphorylation

of opsin also prevents its activation of transducin. Transducin possesses a GTPase activity that converts the active GTP complex to an inactive GDP-binding form. Subsequent activated processes return as well to their basal states.

 All-trans

retinal is reduced, transported to the pigment epithelial cells, and stored as retinyl ester.

A second major function of vitamin A is in cell differentiation.  The

recent discovery of two sets of retinoic acid receptors, the RAR and RXR, has clarified in large part the molecular action of vitamin A in this process. Each set has three distinct subgroups: α ,β and γ .

 Each

receptor has six domains f an aminoterminal activation domain (A/B), a highly conserved DNA-binding domain(C), a hinge region (D), a ligand-binding domain (E), and a carboxy-terminal tail that is involved in heterodimerization.

 The

RAR receptors bind either all-trans or 9-cis retinoic acid, whereas the RXR set binds only 9-cis retinoic acid. The RXR receptors form heterodimers with themselves as well as with RAR, the vitamin D receptor, and the triiodothyronine receptor. These inteactions usually activate gene expression. RAR can also be inhibitory. For example, it interacts with Jun in a nonproductive complex. Jun normally forms a heterodimer with Fos, which binds at the AP-1 site and stimulates cell proliferation.

 In

the absence of the Jun-Fos heterodimer, the AP- l site is not activated. Thus retinoic acid isomers, in conjunction with their nuclear receptors, can both stimulate and inhibit gene expression.

A

variety of synthetic analogs of retinoic acid specificity of binding towards individual retinoic acid receptors. By their use, as well as by "knock-out",studies with transgenic mice, the functions of specific receptors and of other retinoid binding proteins are being clarified.

 Another

way in which retinoic acid may affect,cell differentiation is by the formation of retinoylated proteins. Retinoylated proteins that are the same size as nuclear receptors have been identifled in the nuclei of several differentiated cells.34 Because acylation of certain proteins with selected fatty cells or polyisoprenoids markedly affects their function, the possibility that retinoic acid may play a role in such processes is attractive. Although retinoyl β -glucuronide might serve well as a retinoyl group donor, the enzymatic steps involved have not yet been defined.

 Retinol

and retinoic acid are also essential for embryonic development. Retinoic acid has been implicated in the expression of hox genes, which determine the seguential development of various parts of an organism. The stUdy of these exciting relationships, however, is still in its infancy.

 In

addition to vision, cell differentiation, and embryonic development, vitamin A has been implicated in many other physiological processes, including spermatogenesis, immune response, taste, hearing, appetite, and growth. Most of these processes depend directly or indirectly on cellular differentiation.

Deficiency  Vitamin

A deficiency is a major public health problem in many areas of the less-industrialized world. It was eshmated that 500,000 preschool-age children become blind each year because of vitamin A deficiency.Most hlind children do not survive. Common clinical signs of vitamin A deficiency are night blindness and xerophthaimia. The most diagnostic clinical signs of vitamin.

A

deficiency in young children are Bitot's spots, whichare foamy white accumulations of sloughed cells that usually appear on the temporal quadrant of the conjunctiva. Bitot's spots are a gross manifestation of the squamous metaplasia of the conjunctival epithelia, in which keratinized cells replace goblet cells and normal epithelial cells.

 Low

concentrations (<0.35 mmol/L) of serum retinol also are closely associated with clinical signs of deficiency.

 In

addition to clinical deficiency, more than l00 mil lion children suffer from vitamin A inadequacy in the absence of clinical signs of acute deficiency.These children generally show a higher mortality rate and a higher incidence of severe infections than do vitamin A-suffcient children. With the current reduction of severe vitamin A deficiency in much of the world, inadequate vitamin A status and its consequences have become the major focus of public health programs world wide.

 An

inadequate vitamin A status is commonly associated with protein-calorie malnutrition, a low intake of fat, lipid malabsorption syndromes, and febrile diseases. Among adults, lactating women are most at risk.

 Inadequate

vitamin A status, which is also termed marginal status or precl inical deficiency, can be measured by several relatively new procedures f the relative-dose response test, the modified relativedose-response test, frequency analysis of serum retinol concentrations be fore and after supplementation, conjunctival impression cytology, and vision restoration time. Of biochemical indicators, the modified relative dose response test is proving to be a highly reliable procedure as performed by different laboratories in many different countries

 Isotope

dilution methods, which measure total body reserves of vitamin A, currently are being refined.

Requirements Recommended Intakes  The

and

average daily amount of vitamin A that should be ingested by healthy individuaIs varies with age, body mass, metabolic activity, and special conditions pregnancy and lactation. The operational endpoint also must be defined; namely, whether the objective is just to prevent deficiency or to provide as well for a suit able body reserve.

 The

heterogeneity of the population must be considered if the recommended intake is intended to meet the needs of a specified portion of the population. In general, recommended dietary intakes for population groups have tended to decrease as more informa tion has become available.

Vitamin A status can classified in five categories  deficient,

marginal,  satisfactory,  excessive,  toxic 

be

 The

deficient and marginal states were discussed earlier.  The satisfactory state implies the .absence of clinical signs,full physiological functions that are dependent either directly or indirectly on vitamin A, and an adequate total body reserve to meet stresses of various kinds and periods of low dietary intake.

 Mean

total body contents of vitamin A that fulfill all functions of the vitamin and provide a 3month reserve on a low vitamin A intake for a 76kg male and for a 62-kg female are 0. 18 mmol and 0.14 mmol, respectively. These values are derived from a satisfactory liver vitamin A concentration of 0.07 mmol vitamin A/g in both sexes.

 Three

sets of recommended dietary intakes for vitamin A are presented in Table l: the l988 recommended dietary intakes (RDI) of the Food and Agriculture Or ganization and the World Health Organization (FAO/ WHO); the l989 recommended dietary allowances (RDAs) of the Food and Nutrition Board, National Re search Council, U.S. National Academy of Sciences and the 199l dietary reference values (DRV) for the United Kingdom.

1.Xerophalmia

2.Generalized xerophthalmia

3.”Cheesy”xerophthalmia

 Bito’s

spot

Source of Vitamin A  Oil(preformed  ProvitaminA

vitamin A;

Toxin  When

ingested in large doses, vitamin A can be toxic.  There are three categories of toxicity: acute, chronic, and teratogenic.

Acute toxicity Acute toxicity is produced by one or several closely spaced very large doses of vitamin A, usually >l00 times the recommended intake (RDIor RDA) in adults and >20 times the RDI in children. Early signs of acute toxicity include nausea, vomiting,headache,vertigo,blurred vision, muscular incoordination, and, in infants, bulging of the fontanelle.

 These

signs are usually transient and disappear within a few days. When the dose is very large, a second phase, characterized by drowsiness, malaise, inappetence, physical inactivity, itching, skin exfoliation, and recurrent vomiting, follows during the next week.5o When lethal doses are given to monkeys, the terminal phase includes coma,convulsions, respiratory abnormalities, and then deathby respiratory failure or convulsions within 1--l6 d.

 For

young monkeys the LD50, value (i.e., the single intramuscular dose that killed half of the treated animals)is l68 mg retinol (560,000 IU)lkg body weight. In humans the only comparable case is that of a l-month-old male infant weighing 2.25 kg who died after receiving l,000,000 IU of vitamin A during a l1-day period, or a total dose of =440,000 IU/kg. Nonetheless, after acute dosing with sma1ler but still toxic amounts, recovery isusually complete within a few weeks.

Chronic toxicity  Chronic

toxicity, which is much more common than acute toxicity, is induced by the recurrent ingestion over a period of weeks to years of excessive doses of vitamin A that are usually S10 times the recommended intake (RDI or RDA).

 Toxic

signs commonly include headache, alopecia, cracking of the lips, dry and itchy skin, hepatomegaly, bone and joint pain, as well as many other complaints.  Most cases of chronic hypervitaminosis were reported in children with daily intakes of l2,000600,000 IU (2,000--60,000 IU/kg/d) and in adults with daily intakes of 50,000--1,000,000 IU.

Vitamin D  Vitamin

D  Parathyoid

Differential diagnosis of fat-soluble vitamin deficiency disorder          

Vitamin deficiency Differential diagnosis Vitamin A other causes of degenerative changes e.g Night blindness and infections such as syphilis,gonorrhoea , keratomalacia chlamydia in neonate(rare) Vitamin D Ca 2+ deficiency Rickets or osteomalacia renal disease-causing activity of 1-α hydroxylase liver disease:causing activity of 25- α hydroxylase

 Early

skeletal deformities of rickets can persist throughout life. Bowlegs that curves laterally indicate that the weakened bones have bent after the second year, as the result of standing. If severe rickets occurs before the child walks, it produces a combination of bowed thighs and knock-knees.

 The

rachitic rosary is, next to craniotabes, the earliest sign of rickets. Enlargement of the costochondral junctions results in beads or knobs that can sometimes be seen.

维生素 D 缺乏症  佝偻病 :

串珠。

方头、肋骨

“O” 型腿

“X” 型腿

A. Beriberi heart. This patient Was a chronic alcoholic whose diet had been poor for a long time; polyneuritis and congestive heart failure accompanied cardiac dilation. Thiamine deficiency leads to impaired function and enlargement of the heart, particularly of the right auricle and ventricle.

B. After 1 week of thiamine therapy.

C. After 3 weeks’ treatment, progressive reduction in heart size is visible.

维生素 PP 缺乏  蜀黍红斑 :

猩红舌。

急性红斑 ,

蜀黍红斑 : 急性褶烂

蜀黍红斑 : 慢性肥厚

Skin lesions in pellagra

 Pellagrous

stage

 Same

dermatitis in advanced

patient after intensive niacin therapy

Same patient after nicotinamide therapy

Casal’s necklace-advanced Pellagra. Dermatitis outlining the exposed area of the neck is pathognomonic of pellagra, as are the characteristic lesions on the backs of the hands. Either sunlight or heat from a stove may have been the precipitating factor