Vitamin D.

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

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 (7dehydrocholesterol ) 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 1,25dihydroxycholecalciferol, which functions as a hormone. Receptors for 1,25dihydroxycholecalciferol 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.

Characteristics

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

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.

Effects of Deficiency

Rickets.
Infantile Tetany.
Poor Growth.
Osteomalacia.

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 2:1. This is the optimum
ratio for absorption of Ca & P, in animal milks, the
ratio is 1:1 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 @ 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 @ 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 @ 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 @ 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 @ 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 @ 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 @ 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 & 3 rd 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 < 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 @ 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
o
o
o
o
o
o
o

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