VITAMINS Fat Soluble Vitamins
PREPARED BYMostafa A. Askar
ASSISTANT LECTURE IMMUNOLOGY& ONCOLOGY
NCRRT, EAEA, CAIRO
Vitamins are micronutrients
VITAMINS
VITAL+AMINE
Nutrients
VITAMINE
µg-mg/day
VITAMINS
Vitamins are organic nutrients that are required in small quantities for a variety of biochemical functions and which generally
cannot be synthesized in the body and must be supplied by the diet
Definition
VITAMINS
Water soluble
Fat soluble
• B complex• C or Ascorbic acid
• A or Retinol• D or Cholecalciferol• E or Tocopherol• K
Classification
Vitamin B complex
• B1 - Thiamine• B2 - Riboflavin• B3 - Niacin• B5 - Pantothenic acid• B6 - Pyridoxine• Biotin• Folic acid• B12- Cobalamine
Vitamine C or Ascorbic acid
• Water soluble vitaminsVITAMINS
Energy-releasing
Hematopoietic
Other
B1 B2
B3
BiotinPantothenic acid
Folic acidVitamin B12
Pyridoxine
• Vitamins B-complexVITAMINS
Water soluble vitamins Fat soluble vitamins
Solubility Water soluble Fat soluble
Absorption Simple Along with lipids
Storage *No storage Stored in liver
Excretion Excreted Not excreted
Excess intake Nontoxic Toxic
Deficiency Manifests rapidly Manifests slowly
Treatment Regular dietary supply Single large dose
Difference b/w water soluble & fat soluble vitaminsVITAMINS
FAT SOLUBLE VITAMINS
Vitamin A Vitamin D
Vitamin E Vitamin K
VITAMIN
VITAMIN A
Chemistry
Sources
Daily Requirements
Absorption, Transport and
storage
Functions
Deficincy Vitamin A excess
VITAMIN A CHEMISTRY• Vitamin A occurs in two forms in food
Retinoids Retinol
Retinal
Retinoic acid
Carotenes α- carotene
β- carotene
γ- carotene
RETINOIDS
RETINOLRETINAL
RETINOIC ACID
β-ionone ring
β- CAROTENE
VITAMIN A
SOURCES OF VITAMIN A
SOURCES OF VITAMIN A
Polar Bear
One ounce of polar bear liver contains enough vitamin A (retinol) to kill a person!
RECOMMENDED DAILY ALLOWANCE [RDA]
• The daily requirement of vitamin A is expressed as retinol equivalents [RE]
1000 REMEN
800 REWOMEN
1RE = 1µg of retinol = 3.3 IU of retinol
ABSORPTION TRANSPORT ANDSTORAGE
VITAMIN A
RETINA
TARGET TISSUES
ABSORPTION TRANSPORT AND
STORAGE
ABSORPTION TRANSPORT
ANDSTORAGE
FUNCTIONS OF VITAMIN A
Vision : 11-cis retinal [Wald’s visual cycle]
Reproduction: Retinol
Growth and differentiation : Retinoic acid
Epithelial Integrity : Retinol
ImmunityAntioxidants :β -carotenes
Glycoprotein synthesis
VITAMIN A AND VISION
RODS
RHODOPSIN
11-Cis retinal Opsin
Photoreceptor cells in the retina
Photosensitive pigment
WALD’S VISUAL CYCLE
Rhodopsin cycle comprises two distinct events
Bleaching of rhodopsin & generation of nerve impulse
Regeneration of rhodopsin
WALD’S VISUAL CYCLE
VITAMIN A AND COLOUR VISION
CONES
Porphyropsin
Iodopsin
Cynopsin
Photoreceptor cells in the retinaRequired for vision in daylight and colour identification
VITAMIN A DEFICIENCY
Causes Inadequate intake
Impaired absorption
Impaired storage & transport
Increased excretion [RBP]
Alcoholism
VITAMIN A DEFICIENCY
Features Nightblindness
Xerophthalmia
Bitot spots
Keratomalacia
Infections
Hyperkeratinization of skin
Growth retardation
Bitot’s spot Bitot’s spot
Keratomalacia Xerophthalmia
DIAGNOSIS OF VITAMIN A DEFICIENCY
Impaired dark adaptation time
Decreased vitamin A in plasma
Decreased RBP in plasma
Normal plasma vitamin 20 to 80 µg/100ml
VITAMIN A TOXICITYOver ingestionCauses
Bone and joint pain
Anorexia
Hair loss
Headache
Hepatomegaly
Weight loss
VITAMIN D
Chemistry Sources
Daily Requirements
Absorption, Transport and
storageFunctions
Vitamin D refers to a group of fat-soluble secosteroids responsible for enhancing intestinal
absorption of calcium, iron,magnesium, phosphate and zinc. In humans, the most important compounds in this group are vitamin D3 (also known ascholecalciferol) and vitamin
D2 (ergocalciferol)
VITAMIN D
Name Chemical composition
Vitamin D1 molecular compound of ergocalciferol with lumisterol, 1:1
Vitamin D2 ergocalciferol (made from ergosterol)
Vitamin D3 cholecalciferol (made from 7-dehydrocholesterol in the skin).
Vitamin D4 22-dihydroergocalciferol
Vitamin D5 sitocalciferol (made from 7-dehydrositosterol)
Vitamin D2 Vitamin D3Vitamin D4Vitamin D5
VITAMIN D CHEMISTRY
FUNCTION AND IMPORTANT OF VITAMIN D
Important to maintain calcium and phosphate homeostasis and bone and muscle integrity
Calcitriol stimulates absorption of calcium from GI tract and reduces loss of calcium in urine
PTH activates enzyme which converts inactive vitamin D to the active form and so can be raised in vitamin D deficiency.
Calcitriol acts on intranuclear receptors present on most body cells
Calcitriol directly stimulates bone remodelling
Activation in liver and kidneys to CALCITRIOL
Why is it important?
• Vitamin D insufficiency and deficiency common• Implications for bone and muscle health• Public health issue and raised awareness• More requests for testing and cost implications in testing
and prescribing
Sources & Metabolism of Vitamin DSolar UVB (280-310nm)
Endogenous Vitamin D3
Dietary sourceVitamin D2 & D3
Oily fish, eggs, fortified foods e.g:
Infant formulas
Cereals
Liver25-Hydroxyvitamin D (major circulating metabolite)
1,25-Dihydroxyvitamin D
Kidney
1α hydroxylase (CYP27B1)
PTH (+) ↓ P (+) FGF23 (-)
(7-dehydoxycholesterol)
DBP
25-hydroxylase (CYP2R1)
24-hydroxylase (CYP24A1)
DBP
24,25-hydroxyvitamin D
Calcitroic acid
Why do people become vitamin D deficient?
• Lack of UVB sunlight exposure (90% UK too far north to have adequate levels for 6 months of the year!)
• Small quantities in food• Sunscreen with SPF 15+ blocks 99% vitamin D synthesis• Possibility of many other health problems associated with
Vitamin D deficiency inc cardiovascular disease, infections, autoimmune diseases and cancers...
Factors which contribute to development of Vitamin D deficiency
Residence in Northern or Southern Latitudes
Pigmented skin
Sun blocking creams – Factor 8 ↓ Vit D synthesis by >95%
Sunshine avoidance for religious or cultural reasons
Cloud Cover & Atmospheric Pollution
Obesity Genetic propensity
An independent protective effect of meat consumption
Low dietary Calcium & High Fibre diets
Roles of 1,25-Dihydroxyvitamin D in Bone Mineral Homeostasis
Stimulates GI calcium absorption Promotes renal calcium re-absorption Stimulates GI phosphorous absorption Calcium homeostasis: together with PTH it mobilises calcium from skeletal
stores Mineralisation of the growth plate & osteoid
Normal Growth Plate Rachitic Growth Plate
Low CalciumorLow Phosphorous
Radiograph showingRachitic Changes
Low Calcium & High Fibre Diet and Vitamin D Status
Vitamin D Dietary Ca
High fibre & phytic acid reduce dietary Ca intake
Low Ca intake leads to secondary hyperparathyroidism & raised serum 1,25(OH)2D concentration
Raised serum 1,25(OH)2D concentration degrades 25OHD to inactive 24,25-dihydroxyvitamin D, thereby depleting body stores of vitamin D Clements et al. Nature 1987;325:62–5
DIETARY CALCIUM INTAKE
1 ml ~ 1mg
1 pot ~ 150 mg
~ 35 mg/slice
1 Bowl ~ 80 mg
1 oz ~ 200 mgRNI (mg/day) in the UKInfants up to 1 yr 525
Children 1- 3 yrs 350
Children 2-6 yrs 450
Children 7-10 yrs 550
Adolescent boys 11-18 yrs 1000
Adolescent girls 11-18 yrs 800
DIAGNOSIS: Severe vitamin D deficiency & low calcium intake
Pre Rx Post Rx
25(OH)D (ng/ml) <2 27.1
PTH (ng/ml)(10-60)
593 90
Calcium (mmol/l)(2.15 – 2.65)
1.38 2.23
Phosphate (mmol/l)(1.0 – 1.8)
1.68 1.43
Alk Phos (I/U) 1020 592
Rx: Single orally dose 180, 000 IU Vitamin D3 + 500mg/day Ca supplement
Vitamin D Deficiency & MyopathyVitamin D Deficiency & Myopathy
14 year old female
Limb pains
Difficulty walking & Climbing stairs
Life long intolerance of dairy products (Ca intake <300 mg/day)
Arrived from Saudi Arabia 8 months ago
8th April 09 5th May 09
Life threatening Cardiomyopathy in Early Infancy
Maiya S et al .Hypocalcaemia and Vitamin D deficiency: an important, but preventable cause of life threatening infant heart failure.Heart. 2007 Aug 9; [Epub]
16 infants (6 South Asian, 10 Black ethnicity) admitted to GOS with Heart Failure Median age 5.3 months (3 weeks - 8 months);12 exclusively breast-fed 12 needed inotropic support 8 ventilated & 2 needed ECMO 2 referred for cardiac transplantation 6 suffered a cardiac arrest & 3 died!
Median (range) Reference rangeCalcium (mmol/L) 1.50 (1.07 – 1.74) 2.17 – 2.44PTH (pmol/L) 34.3 (8.9 – 102) 0.7 – 5.625OHD (nmol/L) 18.5 (0.00 – 46) >50Fractional shortening (%) 10 (5-18) 28 – 45
Left ventricular end diastolicdimension Z score 4.1 (3.1-7) -2 < +2
Holick BMJ June 2008;336:1318-1319
Possible Consequences of Vitamin D Deficiency
Vitamin D & Innate Immunity
Adequate serum 25(OH)D
Innate immunity
Toll like receptors recognise pathogens
expression of VDR & CYP27B1 enzyme 25(OH)D 1,25(OH)2D
1,25(HO)2D leads to production of antimicrobial proteins (AMPs)
AMPs (e.g. Cathelcidin) important role in defence against bacterial & viral infections
Vitamin D Deficiency & Pneumonia
New RMCH July 2009
Preventing Vitamin D Deficiency in children
DOH recommendations:
• All infants and children under 5 years should take supplements – at least 280 IU daily
• All pregnant women should take 400IU vitamin D supplements daily
• All breastfeeding should take 400 IU vitamin D supplements daily
Preventing Vitamin D Deficiency in adults
• Fair skinned young person – needs 20-30min UVB exposure at midday to face and forearms 3 x /wk for healthy vitamin D levels (each exposure = 2000IU)
• Elderly and those with pigmented skin need more frequent and longer sun exposure to achieve same levels (2 to 10 fold!)
• Healthy adults at risk of deficiency – 400IU vitamin D supplement daily
• Adults at high risk of deficiency e.g. South Asians, aged over 65 years, extensive covering take 800IU vitamin D supplement daily
Recommendations
1. To treat vitamin D deficiency with 60,000IU per week for 12 weeks
2. To encourage patients to buy OTC supplements and share the approximate costs with them as they may perceive the cost to be much higher.
3. To prescribe Hux D3/Biovit D3 instead of Dekristol (cheaper as not unlicensed)
4. To prescribe vitamin D supplement by brand5. To prescribe Fultium D3 as maintenance therapy instead of
AdcalD3 in vitamin D deficiency
VITAMIN E
Chemistry Sources
Daily Requirements
Absorption, Transport and
storageFunctions
Both structures are similar except the tocotrienol structure has double bonds on the isoprenoid units.
There are many derivatives of these structures due to the different substituents possible on the aromatic ring at positions 5, 6, 7, and 8.
Position of methyl groupson aromatic ring Tocopherol structure Tocotrienol structure
5,7,8 alpha-Tocopherol alpha-Tocotrienol
5,8 beta-Tocopherol beta-Tocotrienol
7,8 tau-Tocopherol tau-Tocotrienol
8 delta-Tocopherol delta-Tocotrienol
VITAMIN E CHEMISTRY
• Vitamin A occurs in two forms in food
WHY DO WE NEED VITAMIN E?
Vitamin E, a fat-soluble vitamin, is an antioxidant vitamin involved in the metabolism of all cells. It protects vitamin A and essential fatty acids from oxidation in the body cells and prevents breakdown of body tissues.
FUNCTIONS OF VITAMIN E
• Chain-breaking antioxidant• Protects cell membranes• Enhances immune response• Regulates platelet aggregation• Regulates protein kinase C activation
SOURCES AND REQUIREMENTS OF VITAMIN E
Vegetable oils, sunflower seeds and nuts are the richest dietary sources
Average daily intake is 15 I.U. in men and 11.4 I.U in women (NHANES III)
DRI and RDA is 15 mg alpha-tocopherol (22.5 I.U.)
Optimal vitamin E intakes may be 100-400 I.U. per day
CLINICAL DEFICIENCY STATES
• Susceptible groups– Patients with malabsorption syndromes– Premature infants– Patients on TPN
• Characterized by progressive neurological syndrome– Gait disturbances– Absent or altered reflexes– Limb weakness– Sensory loss in arms and legs
• Improved neurological function with vitamin E therapy
VITAMIN E DEFICIENCY
VITAMIN E DEFICIENCY
EFFICACY OF NATURAL-SOURCE VS SYNTHETIC VITAMIN E
• Natural-source is a single isomer (d-alpha-tocopherol)• Synthetic is a mixture of eight isomers• Natural-source has twice the bioavailability of
synthetic
VITAMIN K
Chemistry Sources
Daily Requirements
Absorption, Transport and
storageFunctions
VITAMIN K• Vitamin K is a group of lipophilic, hydrophobic vitamins.
• They are needed for the postranslation modification of proteins required for blood coagulation,
• They are involved in metabolism pathways, in bone mineralisation, cell growth, metabolism of blood vessel wall.
Vitamin K1
Vitamin K2
Vitamin K
• Vitamin K1 (phylloquinon) – plant origin
• Vitamin K2 (menaquinon) – normally produced by bacteria in the large intestine
• K1 a K2 are used differently in the body – K1 – used mainly for blood clothing – K2 – important in non-coagulation
actions - as in metabolism and bone mineralization, in cell growth, metabolism of blood vessel walls cells. Synthetic derivatives of Vit.K
VITAMIN K - FUNCTION• Cofactor of liver microsomal carboxylase which carboxylates glutamate
residues to g-carboxyglutamate during synthesis of prothrombin and coagulation factors VII, IX a X (posttranslation reaction).
• Carboxylated glutamate chelates Ca2+ ions, permitting the binding of blood clotting proteins to membranes.
• Forms the binding site for Ca2+ also in other proteins – osteocalcin.
Sources of vitamin K • Green leafy vegetables • vegetable oil • broccoli• cereals
http://health.allrefer.com/health/nutrition.html
PHYSIOLOGICAL EFFECTS OF VITAMIN K
• Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K-dependent proteins. These proteins are involved in:
1) Coagulation2) Bone Mineralization3) Cell growth
Deficiencies are very rare in humans except in newborns due to:
• insufficient gut bacteria• poor placental transport of vitamin K• low prothrombin synthetic capacity
of neonatal liver
Newborns routinely receive vitamin K injection (0.5 -1 mg vitamin K) or 2 mg orally, because human milk is very low in vitamin K (2.5 μg/L).
Bleeding episodes may occur in patients
with low vitamin K status on long-term antibiotic treatment (loss of colonic bacteria).
Vitamin K Deficiency
Vitamin K - deficiency• Deficiency is caused by fat malabsorption or by the liver
failure. • Blood clotting disorders – dangerous in newborns, life-
threatening bleeding (hemorrhagic disease of the newborn).
• Osteoporosis due to failed carboxylation of osteokalcin and decreased activity of osteoblasts.
• Under normal circumstances there is not a shortage, vit. K is abundant in the diet.
Symptoms of Vitamin K Deficiency
• Bruising from bleeding into the skin• Nosebleeds• Bleeding gums• Bleeding in stomach• Blood in urine• Blood in stool• Tarry black stool• Extremely heavy menstrual bleeding• In infants, may result in intracranial hemorrhage
Vitamin K Deficiency in InfantsNewborns are prone to vitamin K deficiency because…
1. Vitamin K and lipids are not easily transported across the placental barrier2. Prothrombin synthesis in the liver is an immature process in newborns,
especially when premature.3. The neonatal gut is sterile, lacking the bacteria that is necessary in
menaquinone synthesis.4. Breast milk is not a good source of vitamin K
Results in a hemorrhagic disease called vitamin K deficiency bleeding (VKDB)
This disease is associated with breastfeeding, maladsorption of lipids, or liver disorders.
Coagulation• The transformation of
liquid blood into a solid gel
• Stops blood flow in the damaged area
• Fibrin is the final protein which produces a meshwork to trap RBC and other cells
Vitamin K Dependent Coagulation• Certain clotting factors/proteins require calcium to bind for
activation
• Calcium can only bind after gamma carboxylation of specific glutamic acid residues in these proteins
• The reduced form of vitamin K2 (vitamin KH2) acts as a cofactor for this carboxylation reaction.
• These proteins are known as “Vitamin K dependent” proteins
Vitamin K Dependent Proteins• factor II (prothrombin)• factor VII (proconvertin)• factor IX (thromboplastin component)• factor X (Stuart factor) • protein C & protein S• Protein Z
CLOTTING CASCADE
Vitamin K Cycle
Glutamic Acid
Gamma Carboxy Glutamic Acid
Vitamin K
Vitamin K Epoxide
Vitamin KH2
Vitamin K DependentCarboxylase
Reductase
EpoxideReductase
Warfarin Inhibits
Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z)
EpoxideReductase
-Carboxylase(GGCX)
Warfarin inhibits the vitamin K cycle
Warfarin
Inactivation
CYP2C9
Pharmacokinetic
Adequate Intake for Vitamin KLife Stage Age Males (mcg/day) Females (mcg/day)
Infants 0-6 months 2.0 2.0
Infants 7-12 months 2.5 2.5
Children 1-3 years 30 30
Children 4-8 years 55 55
Children 9-13 years 60 60
Adolescents 14-18 years 75 75
Adults 19 years and older 120 90
Pregnancy 18 years and younger - 75
Pregnancy 19 years and older - 90
Breast-feeding 18 years and younger - 75
Breast-feeding 19 years and older - 90
As outlined by the Food and Nutrition Board (FNB) of the Institute of Medicine in the US (January 2001)
Prevention/Treatment• Vitamin K can be given orally • In the case of someone who improperly absorbs fat or is at high risk of bleeding, Vitamin K can
be injected under the skin
• If a drug is causing Vitamin K deficiency, the dose is altered or extra Vitamin K is given
• In people who suffer from both severe liver disorders and Vitamin K deficiency, Vitamin K injections may be insufficient so blood transfusions may be necessary to replenish clotting factors
• It is recommended that all newborns are given an injection of phylloquinone (Vitamin K1) into the muscle to prevent intracranial bleeding after delivery
• Formulas for infants contain Vitamin K
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