Fat soluble vitanine. mostafa askar

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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