Vitamin k and its Disorders Learning Objectives

Vitamin K and its Disorders
Learning Objectives
The students should be able to :

• 
  Define vitamins.
  
• 
  Enlist the different types of vitamins.
  
• 
  Define fat soluble vitamin
  
• 
  Justify that the vitamins k acts as coenzymes with examples.
  
• 
  Give the clinical conditions associated with the deficiency of vitamin k.
  

LECTURE OUTLINE :

Vitamins:
Definition:
Vitamins are a group of organic nutrients, required in small quantities for a variety of biochemical functions.

• 
  The discovery of the first vitamin was published in 1911 by a Polish biochemist, Casimir Funk.
  

• 
  The term vitamine is derived from the words vita (meaning life giving) and amine (were originally thought to be amines).
  

• 
  Usually only a few milligrams (mg) or micrograms (μg) are needed per day, but these amounts are essential for health.
  

Types of vitamins:

1. 
   Water soluble :
   

1. 
   Vitamin B1(thiamine)
   
2. 
   Vitamin B2(Riboflavin)
   
3. 
   Niacin
   
4. 
   Vitamin B6(pyridoxine)
   
5. 
   Vitamin B12 (cobalamin)
   

6. 
   Pantothenic Acid.
   
7. 
   Vitamin C
   
8. 
   Biotin and folic acid
   

2. 
   Lipid soluble:
   

1. 
   Vitamin A
   
2. 
   Vitamin D
   
3. 
   Vitamin E
   
4. 
   Vitamin K
   

Most vitamins cannot be synthesized by the body, so have to be provided by the diet.

• 
  An exception is vitamin D which can be obtained from cholesterol by the action of sunlight on the skin.
  

• 
  
  
  • 
    Small amounts of a B vitamin (niacin) can be made from the essential amino acid, tryptophan.
    

• 
  Vitamin K is formed by bacterial action in the large intestine.
  

Vitamin K (phylloquinone) :

• 
  Vitamin K is named anti hemorrhagic vitamin.
  

• 
  Vitamin K is found in foods from both plant and animal sources and is also made by bacteria in the gut.
  

• 
  RDA: 80 µg for men, 65 µg for women.
  

Vitamin K – Sources :

• 
  Bacteria in the large intestine (10-15%)
  

• 
  Plant sources
  

• 
  Green leafy vegetables
  
• 
  Some oils
  
• 
  Cauliflower
  
• 
  Broccoli
  
• 
  tomatoes
  

• 
  Animal sources
  

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  Liver
  
• 
  Milk.
  

Transport:__Absorption_depends_on_form'>Absorption, Transport:
Absorption depends on form:

• 
  Phylloquinone (K1)
  

• 
  Plant sources.
  

• 
  Menaquinone (K2)
  

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  Bacteria.
  

• 
  Menadione (K3)
  

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  Synthetic.
  

• 
  Absorption occurs as part of micelles thus enhanced by fat, bile salt, pancreatic juice.
  

Transport:

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  In the intestinal cell → chylomicron → lymph → blood → tissue.
  

Vitamin K:

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  The coagulation vitamin
  

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  Exists in 2 forms:
  

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  plant origin: phylloquinone or vitamin K1
  
• 
  bacterial origin: menaquinones or vitamin K2
  

• 
  Also certain synthetic quinones have vitamin K activity
  

• 
  Menadione (vitamin K3)
  
• 
  Menadiol sodium phosphate (vitamin K4).
  

Forms of Vitamin K:

• 
  K1, phylloquinone
  

• 
  Chloroplasts in plants
  

• 
  K2, menaquinone
  

• 
  Bacterial synthesis
  

• 
  K3, menadione
  

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  Synthetic, water soluble form
  
• 
  Complexed to improve stability.
  

Vitamin K1:

• 
  Phylloquinone: found in dairy products, green vegetables, and vegetable oils, are an aqueous, colloidal solution of vitamin K1.
  

• 
  Phytomenadione.
  
• 
  Phytonadione.
  
• 
  Phytylmenadione.
  
• 
  3-Phytylmenadione.
  
• 
  Phytylmenaquinone.
  

Vitamine K2:

• 
  Menaquinone, which is synthesized by gut flora.
  

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  Menatetrenone
  
• 
  MK4
  
• 
  Vitamin K2(20)
  
• 
  Vitamin MK4.
  

Vitamin K 3:

• 
  Menadione: It is a synthetic, water soluble form that is no longer used medically because of its ability to produce hemolytic anemia.
  

• 
  Menadione
  
• 
  Menadione sodium bisulfite
  
• 
  Menadiol
  
• 
  Menadiol sodium phosphate
  
• 
  Menadiol sodium phosphate hexahydrate .
  

Vitamin K 4:

• 
  Acetomenaphthone.
  

Functions:

• 
  Synthesis of proteins involved in hemostasis.
  

• 
  Coenzyme for gamma glutamyl carboxylase
  

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  Post translationally modifies specific precursor proteins.
  

• 
  Clotting factor VII,IX,X and Prothrombin.
  

• 
  Vitamin K dependent proteins.
  

• 
  Osteocalcin (Role In Bone Metabolism)
  

• 
  Protein C,S,Z
  

• 
  CHD prevention
  

• 
  Vitamin K is the only fat soluble vitamin which acts as coenzyme.
  

Role of Vitamin K in coagulation:



Vitamin K:

• 
  Clotting factors VII, IX, and X and prothrombin (II) all require carboxylation of glutamate residues for functional activity
  

• 
  Anticoagulant coumadin is a Vitamin K antagonist.
  

• 
  Activation of anticoagulant proteins C and S also requires glutamate carboxylation.
  

Role of Vitamin K in Homeostasis:

• 
  Clotting factors are synthesized in the liver as inactive precursors - vitamin K converts them to their active forms
  

• 
  Conversion of prothrombin to thrombin, an active enzyme
  
• 
  Formation of fibrinogen to fibrin, leading to clot formation
  

• 
  Stimulates bone formation and decreases bone resorption.
  

Role of Vitamin K & Ca++ in Coagulation :

• 
  Posttranslational modification requires carboxylation of glutamate residues for functional activity.
  

• 
  Gamma Carboxylation residues enhance Ca++ binding by clotting factor.
  

• 
  This Ca++ binds with Phospholipids in plasma membrane.
  

Blood-Clotting Process:

Vitamin K Calcium & thromboplastin Fibrinogen

(a phospholipid) from (a soluble protein)

blood platelets

Several precursors Prothrombin Thrombin

earlier in the series (an inactive protein) (an active enzyme)

depend on vitamin

K
Fibrin

(A solid clot)

Function and Mechanism :
Blood Clotting:
A deficiency of vitamin K results in an increase in prothrombin time. The usual clinical manifestation is a tendency to hemorrhage.

Vascular Disease:
Vascular smooth-muscle cells and arterial intima synthesize a matrix protein that undergoes a vitamin K-dependent carboxylation to become matrix gammacarboxyglutamic acid protein (MGP).
Glucose Control:

The pancreas, which makes insulin, is a site of synthesis

for certain vitamin K-dependent proteins.

Bone Activity:

Higher vitamin K status has been associated with lower fracture risks.

Cancer:

Anticarcinogenic activities of vitamin K have been observed in various cancer cell lines, including prostate cancer cells.

Vitamin K Cycle:
- Vitamin KH2 is active form and K epoxide inactive form.

• 
  Dicoumarol and warfarin are antagonists of vitamin K.
  

• 
  
  

• 
  Dicoumarol found in moldy sweet clover
  

• 
  Sweet clover disease
  
• 
  
  
• 
  Warfarin
  
• 
  
  
  • 
    Rat poison.
    

Why is newborn Vitamin K deficient ?

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  Maternal: cord blood ratio—30:1
  
• 
  Hepatic content in neonate-25% of adult.
  
• 
  Human milk content (2-15ug/l)-25% cow milk.
  
• 
  Colostrum rich in Vitamin K not given.
  
• 
  Sterile gut.
  
• 
  Plasma half-life-72 hrs.
  

Vitamin K:
Who are at great risk of vitamin k deficiency?

• 
  
  
  • 
    Infants
    

Deficiency symptoms are:

• 
  Easy bruising
  
• 
  Increase Clotting time
  
• 
  Bleeding gums and nose bleed.
  

Vitamin K – Deficiency:

• 
  Primary deficiency rare;
  
• 
  secondary deficiency occurs when fat absorption is impaired (e.g., cystic fibrosis, Crohn’s disease) or following long-term or high-dose administration of antibiotics (they kill the bacteria in large intestine)
  

• 
  Newborn babies with sterile GI tract;
  
• 
  single vitamin K dose given to prevent hemorrhage
  

• 
  Prolonged clotting time
  

• 
  Generalized hemorrhages.
  

Causes of Vitamin K Deficiency:

• 
  Fat malabsorption.
  

• 
  Reduced gut bacterial flora.
  

• 
  Administration of wide spectrum antibiotics.
  

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  neonatal period before gut is colonized
  

• 
  Liver disease with reduced recycling of vitamin K.
  

Effects of vitamin K deficiency:

• 
  Bleeding diathesis.
  

• 
  Estimated 3% prevalence of vitamin K-dependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapy for all newborns.
  

Vitamin K – Toxicity:

• 
  Not common except with over-supplementation
  

• 
  
  
  • 
    Phylloquinone and menaquinone are relatively nontoxic
    

• 
  Jaundice; brain damage.
  

• 
  
  
• 
  Menadione toxic to skin and respiratory tract in high doses.
  

• 
  Menadione Toxicity :
  
• 
  
  
  • 
    Liver damage.
    

• 
  Infants supplemented.
  

• 
  Hemolytic anemia.
  

• 
  Hyperbilirubinemia.
  

• 
  Severe jaundice.
  

Dose of Vitamin K1 :
PAEDIATRIC:

Hypoprothrombinemia:

• 
  Infants: 1 to 2 mg q4-8 hours as required.
  
• 
  Children: 2.5 to 10mg q6-8 hours as required.
  

NEONATE:

Treatment of severe hemorrhage disease:

• 
  1 to 2 mg.