Vitamin D. metabolism

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Vitamin D. metabolism

• Presented by Deena Abdel Hadi
• Attended by Dr. A. B. Hamam.

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Introduction

• Vitamin D. is a group of sterols having similar
  physiologic activity.
• Forms
• D2-calciferol is activated ergosterol
  (plant origin).
• D3 is activated 7-dehydrochelesterol in
  skin (animal origin).
• Vitamin D3 is naturally present in human skin,
  the provitamin (7-dehydrocholesterol ) is
  activated photo chemically to vitamin D3 which is
  then transferred to the liver. Both vitamin D2
  D3 are hydroxylated (activated) in the liver to
  25-OH-cholecalciferol , subsequently, in the
  renal cortex to 1,25-dihydroxycholecalciferol,
  which functions as a hormone. Receptors for
  1,25-dihydroxycholecalciferol are present in most
  tissues, but its 1ry roles are facilitation of
• - Intestinal absorption of Ca PO4.
• - Renal reabsorption of PO4.
• - A direct effect on bone deposition
  reabsorption of Ca PO4.
• - with parathormone calcitonin,
  1,25-dihydroxycholecalciferol plays a major role
  in Ca PO4 homeostasis of both body fluids body
  tissues.

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Characteristics

• Fat soluble.
• Stable to heat, acid, alkali oxidation.
• Bile necessary for absorption.

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Biochemical Action

• Regulates absorption deposition of Ca PO4 by
  affecting permeability of intestinal membrane.
• Regulates level of serum alkaline phosphatase,
  which is believed to be concerned with calcium
  phosphate deposition in bones teeth.

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Effects of Deficiency

• Rickets.
• Infantile Tetany.
• Poor Growth.
• Osteomalacia.

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Rickets

• Rickets is a general disorder of metabolism
  affecting chiefly the growing bones due to
  deficiency of vitamin D
• Skeletal muscles sometimes the nervous system
  are also affected .
• The essential changes in bones are
• 1) Decalcification of the normal bones
  already present.
• 2) Formation of imperfectly calcified new
  bone resulting in widening enlargement of the
  epiphyseal end of the bone .

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Etiology of Rickets

• Deficiency of vitamin D (infantile Rickets).
• Defective absorption of vitamin D calcium
  (malabsorption syndromes).
• Hepatic diseases (biliary atresia).
• Use of anticonvulsants as the combination of
  phenobarbitone phenytoin (these drugs
  accelerate degradation of vitamin D by the liver).

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Etiology of Rickets

• Renal diseases
• 1) Defective 1-Alfa-hydroxylase enzyme
• (vitamin D dependant rickets type 1 ).
• 2) Glomerular ( renal osteodystrophy in CRF)
• 3) Tubular
• - Renal tubular acidosis
• - Fanconi syndrome
• End organ unresponsiveness (vitamin D dependant
  rickets type 2 ).

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Vitamin D. Deficiency Rickets

• Etiology
• The deficiency of vitamin D usually results
  from prolonged breast feeding without Vit. D
  supplement inadequate exposure to sun rays.
• Factors help in pathogenesis of infantile
  Rickets
• 1) Rapidity of bone growth in infancy.
• 2) Race (dark skin interferes with sunlight)
• 3) Season (more in winter).

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• 4) Diet
  
  
  
• Vitamin D is present in diet such as liver,
  kidney, meat, egg yolk cod liver oil.
• CHO are poor in Vit. D, Ca P.
• Some diets are rachitogenic
• - Ca/P ratio in breast milk is 21. This is
  the optimum ratio for absorption of Ca P, in
  animal milks, the ratio is 11 resulting in
  reduction of absorption.
• - Cereals (high phytic acid, which hinders
  the absorption of Ca).

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Pathology of Rickets

• The following 4 zones are encountered in the
  epiphyseal metaphyseal region of normal bones
• Zone of resting cartilage (which is formed of 1
  layer of cells).
• Zone of proliferating cartilage (which is formed
  of regular 6 layers).
• Zone of provisional calcification epiphyseal
  line (the cartilage cells in this layer become
  mature. They contain alkaline phosphatase which
  releases phosphates into the matrix that already
  contain Ca phosphates in solution. The added
  phosphate ions will increase the product of Ca X
  PO4. Once the product exceeds 40, precipitation
  of calcium phosphate occurs in the matrix around
  these cells. This results in death of the
  cartilage cells as they are deprived from their
  nutritional supply).
• Zone of bone formation (the layer of provisional
  calcification is invaded by blood capillaries
  osteoblasts. The osteoblasts deposit a layer of
  organic bone matrix (ostoid tissue) which become
  rapidly mineralized. The calcified cartilage is
  ultimately replaced by bone).

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• Changes in infantile Rickets
• Vitamin D deficiency will lead to diminished Ca
  PO4 absorption from the intestine. This will
  cause low Ca level in the blood?
  hyperparathyroidism ? mobilization of Ca PO4
  from bones decreases tubular reabsorption of
  phosphates in the kidney ? normal serum Ca low
  serum PO4.
• Decreased CA available for bones ? Ca X PO4 will
  be far below 40 ? failure of calcification of the
  intercellular substance around the mature
  cartilage cells in the zone of provisional
  calcification as well as the ostoid tissue around
  the osteoblasts.
• THIS WILL PRODUCE THE FOLLOWING

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• The mature cartilage cells will not die. The
  proliferating zone will be formed of many layers,
  it invades the adjacent zone of provisional
  calcification hence the irregularity of the
  epiphyseal line in the X-ray.
• The zone of provisional calcification fails to
  mineralize newly formed osteoid tissue is not
  calcified or calcified irregularly. As a result a
  wide irregular frayed zone of non rigid tissue
  (the rachitic metaphysis) is produced. This layer
  is responsible for many of the skeletal
  deformities of rickets because it doesnt have
  the rigidity of the normal bone cartilage
  junction so it is liable to compression
  producing flaring of the ends of the bone the
  rachitic rosary.
• In the shaft, the performed bone is resorbed but
  it is also replaced by uncalcified osteoid tissue
  from the periosteum, which forms a shell
  surrounding the shaft over its entire length. The
  result is a soft rarified cortical bone, hence
  the bone deformities green stick fractures.
  

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Clinical Manifestations

• After several months of vitamin D. deficiency,
  skeletal changes of rickets can be recognized.
  Breast fed infants whose mothers have
  osteomalacia may have rickets by 2 months of age.
  Florid rickets becomes apparent towards the end
  of the first during the second year of life. In
  later childhood, rickets is rare.
• Symptoms
• Early (between 3-6 months)
• - head sweating.
• - irritability by day sleeplessness
  by night.
• Advanced rickets
• - delayed motor development (sitting,
  standing walking).

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• Signs
• 1) Bony Changes
• Changes in the skeleton are greatest _at_
  the sites where growth is most rapid the
  deformities are the result of gravity traction
  of muscles on the affected bones.
• A. Head
• 1) Craniotabes is the earliest bony
  changes to be observed. Its greater incidence is
  from 3-6 months of age. It usually disappears
  before the end of the first year.
• other causes of Craniotabes include
• - Prematurity.
• - Osteogenesis imperfecta.
• - Hydrocephalus.
• The rachitic Craniotabes is present in
  localized areas away from the sutures, while in
  other causes it is present near the suture lines
  or is generalized.

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• 2) Anterior fontanel is wider its closure is
  delayed than normal.
• 3) Frontal and parietal bossing are due to
  deposits of osteoid tissue which are situated
  mainly around the centers of ossification of
  these bones.
• 4) Head size looks larger than normal.
• 5) Head shape the vault occiput are flattened
  this together with frontal parietal bossings
  the grooves between the bosses result in caput
  quadratum (the skull is square).
• 6) Teeth eruption is usually delayed deciduous
  teeth may show enamel defect or decay.

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• B. Thorax
• 1) Rachitic rosary beading of ribs _at_
  costochondral junctions is another early sign
  is seen as a row of nodules about the size of
  cherries extending down backwards along the
  line of costochondral junctions.
• 2) Harrison sulcus is a horizontal groove
  corresponding to the line of attachment of the
  diaphragm with flaring of the costal margin
  below.
• 3) Longitudinal grooves due to yielding of the
  chest wall _at_ its weakest point which is the
  costochondral junction giving the picture of
  pigeon chest deformity. The groove is located
  just behind the rachitic rosary is produced by
  compression of the ribs _at_ their weakest points by
  the atmospheric pressure. The sternum with its
  adjacent cartilages appear to be projected
  forwards.

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• C. Extremities
• 1) Epiphyseal enlargement is common best felt
  _at_ the wrists ankles.
• 2) Marfans sign is a transverse groove that is
  felt over the malleoli just proximal to the ankle
  join. It is due to the excess osteoid tissue
  deposited in the centers of ossification of the
  lower ends of tibia fibula the malleoli.
• 3) Deformities tibia fibula often become
  curved after the rachitic child has started to
  walk resulting in bow legs or knock knees. The
  femur tibia may show an anterior convexity. The
  humerus the bones of the forearms may show
  convexity on their extensor surfaces as the
  infant crawls.
• 4) Fractures of the green stick variety are
  often seen.

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• D. Pelvis
• The pelvis in rickets is small continue to
  be retarded in growth. The pelvis inlet is
  narrowed by a forward projection of the
  promontory of the sacrum the outlet is narrowed
  by a forward projection of the tip of the coccyx
  . In females, these changes , if they become
  permanent , add to the hazards of the childbirth
  may necessitates C/S.

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• 2) Muscle Ligaments
• Hypotonia of the muscles laxity of the
  ligaments are usually present, they lead to the
  following
• 1. Delayed motor milestones as sitting
  walking.
• 2. Flaccidity of the whole body which may
  lead to hyper extensibility of the joints.
• 3. Smooth kyphosis in the dorsolumbar region
  while sitting. It is correctable if the infant is
  suspended from the shoulder. Lordosis of the
  lumbar region may be seen in the erect position.
  Scoliosis may occur.
• 4. The abdomen is distended due to
• - Hypotonia of the abdominal muscles
  the muscles of the intestines.
• - Downward displacement of the liver
  spleen due to Hypotonia of abdominal muscles,
  laxity of their ligaments the deformity of the
  chest wall.

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Complication of Rickets

• Tetany
• (the most important complication. It is usually
  precipitated by infections).
• Recurrent chest infections due to
• 1) Chest wall deformity.
• 2) If there is associated vitamin A
  deficiency (vitamin A is essential for the
  integrity of epithelial surfaces including
  respiratory mucosa).
• 3) Defective function of the immune system
  may occur (especially T lymphocytes).
• Bone fractures.
• Bone deformities.

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Biochemical Changes in Rickets

• Serum Ca is normal (2ry to compensatory
  hyperparathyroidism).
• Serum PO4 is decreased (2ry to compensatory
  hyperparathyroidism).
• Alkaline phosphatase in blood is increased.
• Decreased 1,25-dihydroxy vitamin D in the serum.

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Radiological Findings in Rickets

• Active Rickets
• X-ray of the wrists is best for early diagnosis,
  sine a characteristic changes of radius ulna
  occur _at_ an early stage. The X-ray shows the
  following
• 1) Broading cupping (concave) frying
  (irregular) of the lower ends of radius ulna.
  This is the classic triad of rickets.
• 2) Increased distance between the distal ends of
  radius ulna the metacarpal bones.
• 3) Demineralization of the shafts.
• 4) Fractures deformities may be present.
• 5) Periosteal elevation

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• Healing Rickets
• The appearance of the line of preparatory
  calcification indicates start of healing. This
  line appears as faint narrow irregular band _at_ the
  region of metaphysis. As healing progresses the
  osteoid tissue between this line the end of
  bone becomes calcified until they become united.
  Evidence of healing will appear in the X-ray
  between the 2nd 3rd weeks.

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Prevention Of Rickets

• Exposure to U.V. rays.
• A daily oral dose of 400 IU of vitamin D in the
  form of cod liver oil or one of the concentrates
  in water miscible form. The daily prophylactic
  dose of vitamin D recommended for prematures
  twins is 1000 units.
• Vitamin D should be given to the pregnant
  lactating mother.

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Treatment of Infantile Rickets

• A daily administration of 1000-4000 units will
  produce healing in 2-4 weeks demonstrable in
  x-ray. Healing is complete in 6-8 weeks.
• An alternative method of treatment is the oral or
  IM administration of one massive dose of vitamin
  D 600,000 IU that shouldnt be repeated except if
  there is no evidence of healing by X-ray after
  one month.
• Prevention treatment of rickets (in severe
  rickets, it is better to keep the child off his
  feet until healing is well advanced. In cases of
  severe deformity, osteotomy is needed after
  complete healing of the rachitic process.
• In prematures, in addition to vitamin D give also
  Ca (equivalent to 60 mg elemental Ca/day) PO4 (
  equivalent to 30 mg elemental P/day).

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Infantile Tetany

• Tetany is hyperirritability of the nervous system
  due to lack of active Ca ions.
• Ca in the blood is present in 2 forms
• - Active ionized Ca.
• - Non-ionized protein bound Ca when
  the protein bound Ca decreases (e.g. in
  hypoproteinemia), hypocalcaemia will be present
  but without Tetany.

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Etiology

• 1) Infantile Tetany (the commonest type) usually
  occurs as a complication of infantile rickets. It
  is usually precipitated by infections due to
  failure of parathyroid compensatory mechanism.
• 2) Hypoparathyroidism occurs in Tetany of
  newborn.
• 3) Infants fed on cows milk may get
  hyperphosphatemia subsequent hypocalcaemic
  Tetany.
• 4) Excessive vomiting leading to alkalosis with
  resulting decrease in the ionized Ca.
• 5) Excess administration of alkali e.g.
  bicarbonate.
• 6) Hyperventilation leading o alkalosis e.g. in
  acute encephalitis.
• 7) Hypomagnesaemia.

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Clinical Picture

• I. Manifest Tetany
• It occurs when the level of serum Ca lt
  7mg/dl.
• Manifest Tetany may present by
• 1) Carpo-pedal spasm
• - In carpal (hand) spasm the
  interphalangeal joints extend, the
  metacarpophalangeal joints flex the thumb is
  adducted across the palm wrists flex.
• - In pedal (foot) spasm, the feet are
  inverted toes are flexed.
• 2) Laryngeal spasm where you get whooping
  sound especially on crying, its maximal
  occurrence is between 6-15 months.
• 3) Generalized convulsions.

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• II. Latent Tetany
• Occurs when serum Ca is between 7-9mg/dl.
  The nerves are hyperirritable ischemia,
  mechanical or electrical stimulation will lead to
  characteristic responses
• A) Chovosteks sign tapping lightly with a
  patellar hummer in the region of exit of the
  facial nerve from the skull, about 3-5cm below
  in front of the ear. The facial muscles twitch
  briefly with each tap.
• B) Trousseaus sign inflation of the
  sphygmomanometer cuff on the upper arm to more
  than the systolic blood pressure is followed by
  carpal spasm within four minutes.
• C) Peroneal sign tapping the Peroneal nerve on
  the neck of fibula, the muscles it supplies
  contract leading to eversion of the foot.
• D) Erbs sign applying current less than 5
  milliamperes, the stimulated muscle contract.
  Normally, a more powerful current is needed.

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Diagnosis

• Classic clinical picture of Carpo-pedal spasm
  etiological condition as rickets.
• Laboratory investigations
• - Serum total Ca is below 7mg/dl.
• - Investigation for the cause as x-ray
  both wrists for evidence of rickets.
• Cases of convulsions laryngeal spasm must be
  thoroughly investigated before diagnosing Tetany
  as an etiology.

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Management

• I.V. Ca gluconate 10 (1-2cc/kg) is given
  immediately very slowly (to avoid cardiac arrest
  in systole).
• I.V. diazepam 0.3mg/kg/dose may be needed in
  cases with generalized convulsions before Ca
  could be given.
• Oral Ca gluconate or lactate 200-500mg/kg/day.
• Treat any associated condition e.g. acute
  infections.
• Investigate the etiological factor treat the
  underlying cause e.g. administration of vitamin D
  if the patient is rachitic.

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Effects of Excess

• Wide variation in tolerance, over 500ug/day toxic
  when continued for weeks, prolonged
  administration of 45ug/day may be toxic.
• Nausea.
• Diarrhea.
• Weight loss.
• Polyuria.
• Nocturia.
• Soft tissue calcification
• (heart, renal tubules, blood vessels,
  bronchi stomach).

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Hypervitaminosis D.

• Clinical manifestation
• The patient feels weak, thirsty, anorexic loses
  weight.
• Nausea vomiting.
• Polydepsia Polyuria.
• Constipation.
• Dehydration.
• Kidneys (stone formation or nephrocalcinosis
  which may lead to renal failure.
• Deposition of Ca in soft tissues around the
  joints in the walls of blood vessels.
  Metastatic calcification may occur in the heart,
  lungs, thyroid pancreas.

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• Laboratory findings
• Serum Ca increases.
• Serum phosphorus is normal. It increases in renal
  failure.
• Urinary Ca increases.
• Radiological findings
• Increased density of bones _at_ the growing ends.
• Dense metaphyseal lines.
• Ca deposition in soft tissues.
• U/S scan for renal stones or nephrocalcinosis.

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• Treatment
• Stop administration of vitamin D.
• Correct dehydration.
• Decrease calcium in diet by stopping milk its
  products or by increasing cereals in the diet to
  decrease calcium absorption .
• Prednisone 2mg/kg/day is an effective antidote,
  it should be given until the serum Ca has fallen
  to 12mg/dl, then it should be stopped.

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Sources

• Vitamin D-fortified milk margarine.
• Liver.
• Kidney.
• Meat.
• Egg yolk.
• Fish liver oils.
• Exposure to sunlight or other U.V. sources.

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THE END

• Thank You