Vitamins

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Vitamins

• Usha Sethuraman, MD
• Emergency Medicine
• Childrens Hospital of Michigan

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Case 1

• A 2 year old boy is brought by the mother to your
  office for a routine visit. She is worried that
  he is not walking yet. He was born at 30 weeks
  gestation and was exclusively breast fed until 10
  months of age and has been a poor feeder since
  then. On exam he is short with bow legs and has
  frontal bossing and no teeth. His height and
  weight are less than the 5th percentile. You
  confirm your clinical diagnosis with appropriate
  labs and start treatment. Mom is upset and wants
  to know the cause.

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Case 2

• A 5 year old girl is brought to your office with
  the complaint that something is wrong with her
  eyes maybe he needs glasses. The child was
  adopted from an underdeveloped country at 4years
  of age and since arrival has been noticed to
  squint a lot and bump into objects in the evening
  hours.On exam he has a triangular silvery plaque
  in the scleral area of both eyes and his vision
  appears normal. You send him to an
  ophthalmologist who makes the diagnosis and
  recommends the appropriate treatment.

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Case 3

• A 2year old boy is brought to your office with
  the history of refusing to move his legs. He has
  had no fever, no trauma and has been fussy for
  past week. On exam he is irritable and refuses to
  stand. He screams when you touch his legs. You
  send him for x-rays suspecting a fracture. You
  get the news the next day from the radiologist.
  You start appropriate treatment and on follow up
  in 2 months he is a smiling normal child.

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Background

• Vitamins are organic compounds that are required
  in small amounts for normal cellular metabolisms
  that are important for the growth of the
  organisms.
• Discovered by Hopkins in 1907
• Named by Funk in 1911
• Classified by McCollum into fat and water soluble

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Classification

• Fat soluble vitamins include A,E,D and K
• Water soluble vitamins include B and C
• Vitamins are accessory food factors that are
  essential for metabolic reactions and form
  coenzymes

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Vitamin A

• Derived from pigments called carotenoids
• In nature these are called provitamins A
• Includes 4 compounds
• The first three are hydrocarbons and the fourth
  is a ßcarotene

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Vitamin A - Properties

• Vitamin A and its provitamins are water
  insoluble and fat soluble
• They are destroyed by light exposure and
  oxidation
• Protected by the presence of vitamin E
• Destroyed by dehydration but not by canning or
  freezing

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Absorption and distribution

• Exists as esters of retinol in animal products
  and as ß-carotene in vegetables
• Esters are hydrolysed in the intestinal lumen
  and absorbed as retinol but later converted to
  retinal
• The esters are stored in the liver
• When needed they are hydrolysed to retinol and
  transported by ABP

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Absorption and metabolism

• Normal plasma has 18-60µ of vitamin A in 100ml
• Levels are maintained by release from liver
• Very small amounts are excreted normally
• Mineral oils increases excretion

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Food sources and Requirement

• Mainly animal sources
• Liver oils of fish, egg yolk, butter, milk
• Carotenes are found in green and yellow
  vegetables
• Children and infants require 300µg per day

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Functions of Vitamin A

• Related to 3 main retinoids retinol, retinal,
  and retinoic acid
• Retinol is important for growth and integrity of
  epithelial cells
• Retinal is important for physiology of vision
• Retinoic acid is essential for synthesis of
  glycoproteins

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Causes of deficiency

• Inadequate absorption as in celiac disease
• Chronic mineral oil consumption
• Poor intake of fat and protein
• Hepatic disease

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Deficiency manifestations

• Skin dry and scaly follicular hyperkeratosis
• Common on the thigh and extensor surfaces

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Clinical manifestations

• Mucus membranes atrophy resulting in
  keratinization
• Resembles epidermis
• Common in lacrimal glands, GI tract, respiratory
  tract and genitourinary tract

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Hyperkeratosis follicularis
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Deficiency manifestations

• Eyes keratinization of the conjunctiva results
  in xerophthalmia
• Bitots spots may occur
• When the cornea is involved, vision is impaired
• Severe cases result in keratomalacia and blindness

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Bitots spots
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Bitots spots
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xerophthalmia
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Keratomalacia
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Deficiency manifestation

• Walds cycle is a constant splitting and
  resynthesis of vitamin A containing pigment in
  the retina
• Deficiency results in delay in resynthesis
• Causes night blindness or nyctalopia

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Deficiency manifestations

• Bones defective endochondral formation
• Decreased osteoblastic activity
• Cancellous bones

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Effects of excess

• Drowsiness
• Painful joints
• Periosteal thickening of long bones
• Increased intracranial pressure
• Loss of hair
• carotenemia

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Treatment

• Oral vitamin A 1500µg/day for 5days
• Then 7500µ//day parenterally until recovery

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Vitamin D

• Precursors are called Provitamins-D
• 2 important provitamins
• Ergosterol (provitamin D2)
• 7dehyrdrocholesterol (provitamin D3)
• D2 occurs in fungi and yeast
• D3 occurs in animals

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Absorption and metabolism

• Irradiation by ultraviolet rays converts
  ergosterol into the active ergocalciferol
  (vitamin D2 )
• 7dehydrocholesterol is converted to
  cholecalciferol (vitamin D3 )

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Properties

• Vitamin D is fat soluble
• Resistant to oxidation and heat
• Readily absorbed from small intestine

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Absorption and metabolism

• Carried in the chylomicrons to liver
• Hydroxylated by 25 hydroxylase to
  25hydroxycholecalciferol
• Further hydroxylated in renal tubules by
  1hydroxylase to 1,25 dihydroxycholecalciferol
  which acts as a harmone

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Sources and requirement

• Vitamin D fortified milk
• Margarine, fish liver oil, egg yolk
• Infants and children require 200-400 IU/day

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Functions

• Regulates calcium and phophorus metabolisms
• Releases calcium from bones and increases
  absorption from intestines
• Hypocalcemia causes parathormone release
• Parathormone increases levels of 1,25 (OH)2 D3

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Functions

• Hypophosphatemia directly causes formation of
  1,25(OH)2 D3
• This increases absorption of phosphate from the
  intestines
• Promotes endochondral growth of long bones

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Functions

• Mineralization of zone of provisional
  calcification (antirachitic action)
• Deficiency results in defect in these areas but
  with continued cartilage growth

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Deficiency - causes

• Exclusively breast fed infants with no sunlight
  exposure or supplementation
• Dark skinned babies
• Rapid growth as in low birth weight infants and
  adolescents
• Congenital rickets can occur when maternal stores
  of D are low

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Deficiency - causes

• Celiac disease
• Pancreatitis
• Steatorrhea
• Cystic fibrosis
• Anticonvulsants
• steroids

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Clinical manifestations of deficiency

• Results in rickets in children and osteomalacia
  in adults
• Infants show seizures, hypotonia, failure to
  thrive, widened sutures, frontal bossing,
  craniotabes
• Older children show pot belly, delayed
  milestones, delayed dentition, bowlegs, kyphosis,
  pelvic abnormalities

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Clinical manifestations of deficiency

• Rachitic rosary can occur
• Harrisons groove is a depression along lower
  border of chest

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Rickets knock knees
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Rickets - wrists
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Rickety rosary
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Rickets - ankles
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Harrison groove
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Frontal bossing of rickets
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Diagnosis

• Lowered serum calcium and phosphorus
• Elevated alkaline phosphorus
• Urinary cyclic AMP is elevated
• Decreased 25 hydroxy D3
• Generalized aminoaciduria occurs

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Diagnosis of rickets

• Xrays of the wrist and knees are best
• Widened distal ends with cupping and fraying
• Uncalcified larger metaphysis and osteopenia
• A zone of preparatory calcification separated
  from the distal end by a zone of decreased
  calcification suggests healing

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Rickets xray
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Rickets - wrists
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Rickets - shoulder
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Rickets
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Vitamin D resistant rickets

• Also known as familial hypophosphatemia
• Defect in the proximal reabsorption of phosphates
• Defect in the conversion of 25 (OH)2D3 to
  1,25(OH)2 D3
• X linked dominant inheritance
• Bowing of legs appear but all else is absent

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Vitamin D resistant rickets

• Near normal calcium levels
• Lowered phosphorus levels
• Elevated alkaline phosphate
• Large urinary losses of phosphates
• No evidence of secondary hyperparathyroidism

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Vitamin D dependant rickets

• Due to reduced activity of 1 a hydroxylase
• Decreased calcium, phosphorus
• Elevated alkaline phosphatase
• Levels of 1,25 (OH)2 D3 are low

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Renal rickets

• Due to phosphaturia of uremia
• Secondary hyperparathyroidism results in renal
  osteodystrophy

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Treatment

• Calcium and phosphorus levels are corrected
• Daily oral vitamin D 150-300 µg (5000-10000 IU)
• Single dose of 10,000µg can be given parenterally
• Increase in phosphate occurs in 4 days with xray
  evidence of healing in 1-2 weeks

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Treatment

• Vitamin D dependant and resistant rickets are
  treated with high amounts of phosphates and 1,25
  (OH)2 D3

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Prevention

• AAP recommendation (April 2003, Pediatrics)
• all infants including those who are exclusively
  breast fed should have a minimum vitamin D intake
  of at least 200 IU beginning in the first 2
  months and continued through adolescence
• Higher bone density in women supplemented with
  vitamin D in infancy

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Prevention - tips

• Breast milk contains less than 25 IU/L of vitamin
  D
• Formula has a minimum of 400 IU/L
• If an infant is ingesting at least 500ml of
  formula he or she will receive the recommended
  intake of 200 IU/day

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Prognosis

• Very good provided treatment is initiated early
• Early treatment prevents developmental delay
• Orthopedic intervention may be required

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Treatment of rickets
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Excess effects

• Hypotonia, anorexia
• Polydipsia, polyuria, dehydration
• Hypertension, corneal clouding
• Xrays show calcifications and osteoporosis

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Vitamin E

• Group of compounds called tocopherols
• Possess antioxidation properties particularly of
  fats
• This is facilitated by presence of ascorbic acid

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Properties

• Esters are fat soluble
• Susceptible to oxidation leading to loss of
  vitamin activity
• Protect the less susceptible compounds by
  breaking up the chain of oxidation reactions
• Heat stable

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Food sources

• Lettuce and green vegetables
• Vegetable oils
• Milk
• eggs

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Requirement and functions

• 0.7mg/g of fat seems to be adequate
• Inhibits oxidation of LDL cholesterol
• Acts on immunomodulation
• Inhibits platelet acitivity
• Involved in biosynthesis of coenzyme Q that is
  important in electron transport

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Deficiency - causes

• Malabsorption
• Abetalipoproteinemia
• Short bowel syndrome
• Cholestatic disease
• Very low birth weight infants

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Deficiency

• Muscle weakness
• Loss of position sense
• Hemolytic anemia
• Double vision
• Reduced reflexes
• Constriction of visual fields
• Sterility in animals
• Arteriosclerosis?

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Vitamin K

• Substances with vitamin K activity are
  naphthoquinones
• Absorbed mainly from the jejunum
• Bile salts are necessary for this
• Storage is unknown
• Excreted in feces

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Sources

• Green leafy vegetables
• Cabbage
• Tomatoes
• Intestinal flora

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Function

• Essential for synthesis of prothrombin
• Coagulation factors II, IV, IX and X are vitamin
  K dependant
• Plays a role in mitochondrial oxidative
  phosphorylation

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Deficiency - causes

• Intestinal flora produces adequate amounts
• Hence dietary deficiency is rare
• Newborns are deficient because of lower
  intestinal flora content, inadequate bile flow,
  intestinal hypermotility

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Deficiency - causes

• Prolonged oral antibiotics
• Biliary obstruction, sprue, chronic diarrhea
• Hepatocellular damage

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Clinical features of deficiency

• Uncontrollable bleeding in newborns
• Exaggerated in preterms who present between 2nd
  and 7th day with bleeding
• Hemorrhage is more common with breast fed infants
• Maternal drugs like phenytoin cause early bleeding

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Clinical findings

• Bleeding from intracranial, GI, nasal,
  circumcision site
• Reports of late bleeding occuring several weeks
  later

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Diagnosis

• Prolonged PT and PTT
• Normal platelet count
• Normal bleeding time
• Normal plasma fibrinogen levels

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Treatment

• All newborns should get 1mg of vitamin K
• AAP recommendation is all newborns should get
  parenteral vitamin K to prevent delayed bleeding

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Water soluble vitamins B complex

• Include
• B1 (Thiamine)
• B2 (Riboflavin)
• Niacin (P-P factor of Goldberger)
• Pyridoxine (B6 )
• Pantothenic acid
• Biotin, folic acid, and B12
• Lipoic acid and inositol

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Thiamine (B1 )

• Water soluble
• Destroyed by heat
• Synthesis is limited in man
• Children require 0.3mg-0.9mg/day

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Sources

• Breast milk and cows milk
• Vegetables
• Rice polishings
• Meat
• Legumes
• Wheat germ

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Functions

• TPP functions as a coenzyme in decarboxylation
  and transketolation of a-ketoacids
• Helps in synthesis of fats from CHO
• Required for synthesis of acetylcholine

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Deficiency

• Results in beriberi
• Irritability, fatigue
• Decreased tendon reflexes
• Peripheral neuritis
• Loss of vibration sense
• Congestive cardiac failure
• Hoarseness of voice and ataxia

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Deficiency

• Edema present in wet beriberi but absent in dry
  beriberi
• Wernickes encephalopathy mental changes, eye
  changes, cerebral bleeds

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Diagnosis and treatment

• Clinical response to thiamine is best
• Treat mother and baby that is breast fed
• 50mg/day for an adult and 10mg/day for an infant

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Riboflavin

• Forms 2 phosphorylated derivatives
• Serve as coenzymes in oxidation reduction
  reactions and for hydrogen transfers
• Is necessary for normal metabolism of tryptophan
  and oxidation of fatty acids
• For retinal pigment

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Sources

• Eggs
• Milk
• Cheese
• Liver
• Leafy vegetables

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Requirement and deficiency

• 0.5-1.0mg/day is required
• Deficiency results in
• Cheilosis, glossitis
• Keratitis, photophobia
• Anemia
• Seborrheic dermatitis
• A urine level of lt 30µg/day is abnormal

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Cheilosis
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Treatment

• 3-10 mg/day of oral riboflavin

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Niacin

• Forms NAD and NADPH important in glycolysis and
  electron transport
• End product of metabolic pathway of tryptophan
• Daily requirement is 5-13 NE
• Liver and poultry are good sources
• Milk and eggs are antipellagra

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Deficiency

• Pellagra results
• Diarrhea, dementia, dermatitis
• Skin changes resemble sunburn
• Seen in face, neck, dorsal forearms
• Diagnosis is mainly clinical
• Treat with 50-300mg of niacin
• Supplement with other vitamins

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Pellagra
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Pellagra
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Pyridoxine (vitamin B6 )

• Found in yeast, rice polishings and cereal
• Serves as coenzyme in metabolism and transfer of
  aminoacids
• Synthesis in man is limited
• Hence dietary sources are important

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Deficiency and treatment

• Seizures, peripheral neuritis, dermatitis,
  microcytic anemia
• Large amounts of xanthurenic acid in urine
  following administration of tryptophan confirms
  diagnosis
• Administration of 100mg of pyridoxine
  intramuscularly in child with seizures
• In B6 dependant children 10-100mg of pyridoxine
  orally

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Vitamin B12

• Humans cannot make B12
• Microorganisms in animals make B12
• The vitamin combines with intrinsic factor in the
  stomach
• The complex is then absorbed in the terminal
  ileum
• Bound to transcobolamin it enters cell

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Functions

• Involved in DNA synthesis and methyl group
  transfer
• Involved in synthesis of protein in the
  microsomal system
• Important for normal maintenance of hemopoiesis
• Hence also called erythrocyte maturation factor

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Requirement and food sources

• Daily requirement is 2-4 mcg
• Content of foods is low
• Only animal sources contain vitamin
• Liver, kidney, eggs, meat and milk

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Deficiency - causes

• Occurs in pure vegetarians
• Resection of terminal ileum or stomach
• Inhibition of B12 intrinsic factor complex
• Abnormalities of receptors on ileum
• Abnormalities of transcobolamin

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Deficiency manifestations

• Glossitis , peripheral sensory problems
• Gross deficiency results in pernicious anemia
• Arrested RBC development with accumulation of
  megaloblasts and myeloblasts
• Macrocytic anemia
• Degeneration of posterior and lateral columns of
  spinal cord

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Glossitis
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Deficiency manifestations

• Pernicious anemia is autosomal recessive
• Deficiency of gastric intrinsic factor
• Symptomatic at 9 years of age
• Anorexia, irritability, painful red tongue
• Ataxia, decreased reflexes, clonus and coma

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Pernicious anemia
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Diagnosis

• Anemia- macrocytic, megaloblastic
• Hypersegmented neutrophils
• Elevated LDH
• Low serum levels of B12
• Excessive methylmalonic acid in urine
• Schillings test may be abnormal even after
  therapy

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Treatment

• Prompt hematological response is seen in 2-4 days
  after treatment with 1mg of the vitamin

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Folate

• Synthesized by intestinal bacteria
• Folinic results from reduction
• Ascorbic acid and B12 are required

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Sources

• Green leafy vegetables
• Cauliflower
• Yeast
• Liver
• kidney

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Functions

• Important in the synthesis of nucleic acids
• Helps with maturation of red blood cells
• Required for normal metabolic pathway of histidine

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Deficiency

• Occurs in very low birth weight infants
• Following intestinal resection
• Megaloblastic anemia
• Diarrhea, glossitis can occur
• Failure to gain weight, irritability

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Diagnosis

• Macrocystic, megaloblastic anemia
• Hypersegmented neutrophils
• Neutropenia, thrombocytopenia
• Levels of folate may be lt 3ng/ml

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Treatment

• 1-5 mg of folate orally or parenterally
• Treating pernicious anemia with folate may cause
  cure of anemia without change in neurological
  abnormalities

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Vitamin C

• Potent reducing agent
• Present in citrus fruits, spinach, cauliflower
• Liver, kidney, adrenals
• Requirement is 75-100mg/day

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Function

• Forms the ground substance between capillary
  walls, osteoid tissue, collagen
• Involved in oxidation reduction eractions
• Required for normal growth and maturation of cells

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Deficiency - causes

• Occurs in infants with mothers whose diets are
  deficient in the vitamin
• Infants fed with unsupplemented evaporated milk
• Fever
• Diarrhea
• Protein depletion

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Clinical findings

• Irritability
• Generalized tenderness causing pseudoparalysis
• Frog position of legs
• Peripheral edema
• Swelling of gums
• Petechial hemorrhages
• Scorbitic beads in the ribs

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Scurvy
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Scurvy
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Scurvy
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Diagnosis

• X-ray findings
• Ground glass appearance of bones
• Pencil thin cortex
• Zone of calcified cartilage at the metaphysis
  (white line of Fraenkel)
• Zone of rarefaction proximal to this
• Vitamin C level of zero in the buffy layer

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Scurvy
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Treatment

• 100-200 mg/day produces quick healing