FITSUM D.

VITAMIN D DEFICIENCY
Vitamin D:- Has two forms
Vitamin D2 (ergocalciferol, a plant steroid) & D3

(cholecalciferol)
A minimum consumption of 200 IU (5 mcgms) per day

is recommended
Fat-soluble, Bile necessary for absorption;

Stable to heat, acid, alkali, and oxidation;

Hydroxylation in the liver and kidney

2
 Vitamin D
Sources
Sunlight & ultraviolet light photoisomerize provitamin

D to Vit. D
Intestinal absorption :- Diets – fortified food, fatty

fish, cod liver oil, egg

Breast milk (12–60 IU/L) & cow milk content is low

Negligible in cereals, vegetables, & fruits

3
Vit D
Vitamin D3 is synthesized nonenzymatically in skin

from 7-dehydrocholesterol during exposure to the UV-

B rays in sunlight  liver & kidney for hydroxylation
The efficiency of this process is decreased by

melanin.
25-hydroxlase - vitamin D into 25-hydroxyvitamin D 

1α-hydroxylase 1,25-dihydroxyvitamin D (1,25-D).

1α-hydroxylase is upregulated by PTH &

hypophosphatemia;
Most 1,25-D circulates bound to vitamin D–binding

protein.
ABSORPTION AND METABOLISM 
Dietary vitamin D is absorbed by enterocytes, and is

further packaged into chylomicrons.

Chylomicrons are transported to the liver where vit D

undergoes a hydroxylation by 25-vitamin-D

hydroxylase  25-hydroxy-vitamin-D (25OHD).

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Absorption & Metabolism
25-OH vitamin D is then transferred to 1,25-dihydroxy
vitamin D /calcitriol/ in the renal cortex
Has more than 25 metabolites, each with different

biologic activities
Circulates primarily bound to vit. D binding protein

Only the free fraction is biologically active.

is catabolized to biologically inert, water-soluble

compounds and is excreted in the urine and bile.

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 Biochemical actions
Primarily 1,25-dihydroxy-cholcalciferol
Facilitates intestinal absorption of calcium &
phosphorus
Renal absorption of Ph
Bone deposition of ca & Ph,

Directly suppresses PTH secretion

Direct actions on bone, including mediating resorption

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Biochemical…
Also has antiproliferative effect on cultured tumor

cells that possessed its nuclear receptor

 Similar studies done in a human promyelocytic

leukemic cell line (HL-60).

Cell growth was inhibited by as little as 10-9 M of
1,25(OH)2D3 in a dose-dependent manner.
The effect of 1,25(OH)2D3 on leukemia cells is
reversible
Deficiency  rickets and/or osteomalacia
Rickets refers to changes caused by deficient

mineralization at the growth plate.

Osteomalacia - impaired mineralization of the bone
matrix.
Rickets and osteomalacia usually occur together as

long as the growth plates are open;

Only osteomalacia occurs after the growth plates
have fused

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Cause of Vit. D Deficiency
1. VITAMIN D DISORDERS
Nutritional vitamin D deficiency

Congenital vitamin D deficiency

Secondary vitamin D deficiency

Malabsorption, Increased degradation

Decreased liver 25-hydroxylase
Vitamin D–dependent rickets type 1 & type 2

Chronic renal failure

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Cause of Vit. D Deficiency
2. CALCIUM DEFICIENCY
Low intake

Diet

Premature infants (rickets of prematurity)

Malabsorption

Primary disease

Dietary inhibitors of calcium absorption

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Cause of Vit. D Deficiency
3. PHOSPHORUS DEFICIENCY
Inadequate intake

Premature infants (rickets of prematurity)

Aluminum-containing antacid

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Cause of Vit. D Deficiency
4. RENAL LOSSES
X-linked hypophosphatemic rickets[*]

Autosomal dominant hypophosphatemic rickets[*]

Hereditary hypophosphatemic rickets with

hypercalciuria
Fanconi syndrome

Dent disease

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Cause of Vit. D Deficiency
4. RENAL LOSSES
Overproduction of phosphatonin

Tumor-induced rickets[*]

McCune-Albright syndrome[*]

Epidermal nevus syndrome[*]

Neurofibromatosis[*]

5. DISTAL RENAL TUBULAR ACIDOSIS

*
Disorders secondary to excess phosphatonin.
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Pathophysiology
Lack of vitamin D activity leads to Reduced intestinal

absorption  Hypophosphatemia & hypocalcemia

With persistent hypovitaminosis D, hypocalcemia

causes a 20 hyperparathyroidism 
Demineralization of bones, and, if untreated, to

osteomalacia in adults and rickets in children

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Pahtophysiology
Growth plate thickness is determined by two opposing

processes:

1. Chondrocyte proliferation & hypertrophy on one hand

2. Vascular invasion of the growth plate followed by

conversion into primary bone spongiosa on the other.
Requires mineralization of the growth plate cartilage
and
Is delayed or prevented by deficiency of Ca or Ph.

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Pahtophysiology
In these circumstances, growth plate cartilage

accumulates and the growth plate thickens.

The chondrocytes of the growth plate become

disorganized, losing their regular straight-columned

orientation.
In the bone below the growth plate (metaphysis), the

mineralization defect  accumulation of osteoid

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Patho…
These abnormalities decrease the biomechanical

resistance of the involved skeletal sites 

20 increase in the diameters of the growth plate

& metaphysis /rachitic metaphysis/- an attempt

to compensate for decreased bone strength by
increased bone size.

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Patho…
Rachitic metaphysis - Wide irregular, frayed zone of

non-rigid tissue
Responsible for skeletal deformity

Compressed & bulge laterally

Producing flaring of bone end & rachitic rosary

Nonetheless, bone stability is compromised, and if the

underlying condition does not improve, bowing occurs.

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 Clinical manifestations
Usually occur towards the 1st & 2nd year of life

Hypocalcemic & hypophosphatemic rickets

manifest initially at the distal forearm, knee, and

costochondral junctions.
Are sites of rapid bone growth requiring large

quantities of calcium and phosphorus

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Skeletal manifestations
Craniotabes – soft skull bones with Ping pong ball

sensation
Rachitic rosary - Enlargement of the costochondral

junction beading
Harrison sulcus

Wide wrist & bowing of the distal radius and ulna

Thickening of ankle

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 Skeletal m/n
Progressive lateral bowing of the femur & tibia

Pigeon chest deformity

Wide anterior fontanel & delayed closure

Caput quadratum

Parietal & Frontal boosing

Retarded growth with short stature - rachitic

dwarfism
Fracture,
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Extra-skeletal m/n
Delayed dental eruption
Dental caries
Decreased muscle tone – delayed achievement of
motor milestones
Tetany
Stridor due to laryngeal spasm
Seizures

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Extra-skeletal m/n
Susceptibility to infectious disease
Increased sweating probably due to bone pain
Secondary myelofibrosis

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Laboratory findings
Normal or low serum calcium

Increased ALP – as it precipitates in the mineralization

of bone and growth plate cartilage

Low serum phosphorus

Decreased total reabsorption of phosphorus

Decreased maximal tubular reabsorption of Ph per

glomerular filtration rate (TmP/GFR)

Low 25-OH vitamin D
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 X- ray findings
The distal ulna - best demonstrates

early signs of impaired mineralization

The metaphyses above & below the

knees are more useful sites in the

older child.
Wide joint space
Fraying – unwooven
Cupping
Decreased bone density / fractures

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Treatment
Sunlight is effective but oral administration is

preferred
High-dose vitamin D, with doses ranging from

2,000–5,000 IU/day over 4–6 wk

But
A single dose of 600, 000iu IM/oral vit. D is usually

advantageous /can be give in 2-4 doses/ over one day

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Treatment
Calcium intake should be maintained at ≈1000 mg per

day tapered over 2-6 weeks i.e

30 to 75 mg/kg of elemental calcium per day in three

divided doses
Avoids "hungry bone" syndrome (worsening

hypocalcemia after the start of vitamin D therapy)

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Monitoring
Measure Serum After 4 weeks of
Calcium, initiation of treatment
Phosphorus, And repeat at the 3rd
month
Alkaline phosphatase, and
Urinary calcium/creatinine ratio

Radiographs should be obtained to document the

healing of rachitic lesions after 3 months of

treatment

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Complications
Recurrent chest infections
Fracture
Cor-pulmonale
Growth retardation

Prevetnion
Direct Sun light exposure
Oral vitamin D supplementation – forified foods…

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Other vitamin disorders  rickets
Secondary Vitamin D Deficiency
Vitamin D–Dependent Rickets, Type 1
Autosomal recessive disorder
mutations in the gene encoding renal 1α-hydroxylase,
preventing conversion of 25-D into 1,25-D
present during the 1st 2 yr of life
classic features of rickets
long-term treatment with 1,25-D (calcitriol) with
adequate intake of calcium
Other vitamin disorders  rickets
Vitamin D–Dependent Rickets, Type 2
mutations in the gene encoding the vitamin D receptor.
Levels of 1,25-D are extremely elevated
autosomal recessive disorder.
Most patients present during infancy
Approximately 50-70% of children have alopecia
associated with a more severe form of the disease
Epidermal cysts are a less common manifestation.
Rx - extremely high doses of vitamin D2, 25-D or 1,25-D
& oral calcium
 long-term intravenous calcium
Calcium Deficiency  rickets
Pathophysiology
Low dietary calcium, typically <200 mg/day.
Reliance on grains and green leafy vegetables / high in
phytate, oxalate, and phosphate/  decrease
absorption of dietary calcium.
children who receive intravenous nutrition without
adequate calcium.
Malabsorption of calcium can occur in celiac disease,
intestinal abetalipoproteinemia, and after small bowel
resection.
Calcium Deficiency  rickets
Clinical Manifestations
classic signs and symptoms of rickets.

During infancy or early childhood.

Because calcium deficiency occurs after the cessation of

breast-feeding, it tends to occur later than the

nutritional vitamin D deficiency that is associated with
breast-feeding.
Calcium deficiency  rickets
Diagnosis
increased alkaline phosphatase, PTH, & 1,25-D
Calcium levels - normal or low
Decreased urinary excretion of calcium, and
Serum phosphorus = low due to renal wasting of
phosphate from secondary hyperparathyroidism.
Coexisting nutritional vitamin D deficiency, with low
25-D levels.
Calcium deficiency  rickets
Treatment
Provide adequate calciumsupplement
700 [1-3 yr age],
1,000 [4-8 yr age],
1,300 [9-18 yr age] mg/day of elemental calcium.
Vitamin D supplementation if there is concurrent
vitamin D deficiency
Prevention strategies include
discouraging early cessation of breast-feeding and
increasing dietary sources of calcium.
Phosphorous Deficiency  rickets
Inadequate Intake - starvation or severe anorexia
Malabsorption
celiac disease, cystic fibrosis, cholestatic liver disease
long-term use of aluminum-containing antacids 
chelating phosphate
 hypophosphatemia with secondary osteomalacia in
adults and rickets in children.
 responds to discontinuation of the antacid and short-
term phosphorus supplementation.
Phosphorous Deficiency  rickets
Phosphatonin
E.g Fibroblast growth factor–23 (FGF-23)

decreases renal proximal tubular reabsorption of

phosphate  decreases serum phosphorus.

decreases the activity of renal 1α-hydroxylase 

decrease in the production of 1,25-D.

Cause many of the phosphate-wasting diseases
Phosphorous Deficiency  rickets
X-Linked Hypophosphatemic Rickets
is the most common genetic disorders causing rickets

due to hypophosphatemia
prevalence of 1/20,000.

Female carriers are affected, so it is an X-linked

dominant disorder.
Phosphorous Deficiency  rickets
X-Linked Hypophosphatemic Rickets
Pathophysiology
The defective gene is called PHEX /PHosphate-

regulating gene with homology to Endopeptidases on

the X chromosome/  increased levels of FGF-23 
phosphate excretion is increased & decreased

production of 1,25-D.
Phosphorous Deficiency  rickets
Clinical Manifestations
Rickets - abnormalities of the lower extremities and

poor growth are the dominant features.

Delayed dentition and tooth abscesses.

hypophosphatemia and short stature without

clinically evident bone disease.

Phosphorous Deficiency  rickets
Laboratory Findings
high renal excretion of phosphate,
hypophosphatemia, and
increased alkaline phosphatase;
Normal PTH and serum calcium levels are normal

Hypophosphatemia normally upregulates renal 1α-

hydroxylase and should lead to an increase in 1,25-D,

BUT these patients have low or inappropriately normal
levels of 1,25-D.
Phosphorous Deficiency  rickets
Treatment
combination of oral phosphorus and 1,25-D (calcitriol).

1-3 g of elemental phosphorus divided into 4-5 doses.

Frequent dosing helps to prevent prolonged decrements

in serum phosphorus because there is a rapid decline

after each dose.
Calcitrol is administered 30-70 ng/kg/day divided into
2 doses.
growth hormone is an effective option if signicant
stunting.
Phosphorous Deficiency  rickets
Treatment – Complications if there is no balance
between Ph & calcitriol
Excess phosphorus  decrease GI calcium absorption
 20 hyperparathyroidism, with worsening of the bone
lesions.
Excess calcitriol  hypercalciuria and
nephrocalcinosis and can even cause hypercalcemia.
Hence, laboratory monitoring of treatment includes
Serum Ca, Ph, ALP, PTH, & urinary Ca
periodic renal ultrasounds.
Phosphorous Deficiency  rickets
Prognosis
The response to therapy is usually good.

Girls generally have less severe disease than boys,

probably due to the X-linked inheritance.

Short stature can persist despite healing of the rickets.
Phosphorous Deficiency  rickets
Autosomal Dominant Hypophosphatemic Rickets
much less common than XLH.

incomplete penetrance and variable age of onset.

mutation in the gene encoding FGF-23  prevent

degradation of FGF-23 by proteases  increased

phosphatonin.
laboratory findings & Treatment - similar to the

approach used in XLH.

Phosphorous Deficiency  rickets
Autosomal Recessive Hypophosphatemic Rickets
Extremely rare disorder

mutations in the gene encoding dentin matrix

protein 1  elevated levels of FGF-23

Lab finding & treatment – similar with XLH
Phosphorous Deficiency  rickets
Hereditary Hypophosphatemic Rickets with
Hypercalciuria (HHRH)
Rare disorder.
autosomal recessive disorder
mutations in the gene for a sodium-phosphate
cotransporter in the proximal tubule  renal
phosphate leak  stimulates production of 1,25-D 
increases intestinal absorption of calcium, suppressing
PTH 
Hypercalciuria ensues due to the high absorption of
calcium and the low level of PTH
Phosphorous Deficiency  rickets
Clinical Manifestations
Rachitic leg abnormalities muscle weakness
bone pain.
short stature, with a disproportionate decrease in the
length of the lower extremities
The severity of the disease varies
kidney stones secondary to hypercalciuria.
Phosphorous Deficiency  rickets
Laboratory Findings
hypophosphatemia, renal phosphate wasting,
elevated serum ALP, and 1,25-D levels.
PTH levels are low

Treatment
Oral phosphorus replacement (1-2.5 g/day of elemental
phosphorus in 5 divided oral doses).
The response to therapy is usually excellent, with
resolution of pain, weakness, and radiographic
evidence of rickets
Rickets of Prematurity
Pathogenesis
The transfer of calcium & phosphorus from mother to

fetus occurs throughout pregnancy, but 80% occurs

during the 3rd TM.
Premature birth interrupts this process
Rickets of Prematurity
Pathogenesis
Most cases occur in infants with a birthweight <1,000 g.

Breast milk and standard infant formula do not contain

enough calcium and phosphorus to supply the needs of

the premature infant.
Other risk factors include
cholestatic jaundice,
a complicated neonatal course,
prolonged use of parenteral nutrition…
… prematurity
Clinical Manifestations
Occurs 1-4 mo after birth.
Nontraumatic fractures /legs, arms, and ribs.
Fractures and softening of the ribs  decreased chest
compliance
Respiratory distress due to atelectasis and poor
ventilation.
This rachitic respiratory distress usually develops >5 wk
after birth, distinguishing it from the early-onset
respiratory disease of premature infants.
c/m …
Poor linear growth, with negative effects on growth
persisting beyond 1 yr of age.
Enamel hypoplasia.
Poor bone mineralization can contribute to
dolichocephaly.
There may be classic rachitic findings - frontal bossing,
rachitic rosary, craniotabes, and widened wrists and
ankles
Most infants with rickets of prematurity have no
clinical manifestations, and the diagnosis is based
on radiographic and laboratory findings
Laboratory Findings
Serum Ph level is low or low-normal

Low urine phosphate level; the tubular reabsorption of

phosphate is >95%.
Normal levels of 25-D

The hypophosphatemia stimulates renal 1α-

hydroxylase,  1,25-D are high or high-normal  bone

demineralization /bone resorption/.
… prematurity
Laboratory Findings
Serum levels of calcium are low, normal, or high, and
patients often have hypercalciuria.
Alkaline phosphatase levels are often elevated.

Radiologic evidence of rickets – confirmatory.

 Unfortunately, x-rays cannot show early demineralization of bone

because changes are not evident until there is >20-30% reduction

in the bone mineral content.
… prematurity
Diagnosis
Screening tests are recommended.
weekly measurements of calcium, phosphorus, and

alkaline phosphatase.

Periodic measurement of the serum bicarbonate

concentration, because metabolic acidosis causes

dissolution of bone.
At least 1 screening x-ray for rickets at 6-8 wk of age
… prematurity
Prevention
Supplement calcium, phosphorus, and vitamin D.
400 IU/day of vitamin D via formula & vitamin
supplements.
Early transition to enteral feedings.
Human milk fortified or preterm infant formula
Avoid Soy formula because there is decreased
bioavailability of calcium and phosphorus.
Increased mineral feedings until the infant weighs 3-3.5
kg.
… prematurity
Treatment
focuses on ensuring adequate delivery of calcium,
phosphorus, and vitamin D.
If mineral delivery has been good and there is no

evidence of healing,
Screen for vitamin D deficiency by measuring serum 25-D.
Measurement of PTH, 1,25-D, and urinary calcium and
phosphorus may be helpful in some cases.
References
NTP 19th
UpTodate 19.3
Ethiopian National Guidelines for Control and
Prevention of Micronutrient Deficiencies
Breast milk is a poor source of vitamin D
Vitamin D is central to calcium and bone metabolism,
& is a prodifferentiation & antiproliferative hormone.
Unlike vitamin D obtained by means of ingested
supplements, there is no potential toxicity reported for
vitamin D obtained via sunlight.
Sunlight exposure Vs skin cancer induced by sunlight-
related UV radiation exposure.
The goal is to achieve serum levels of 25(OH)D levels
above 50 nmol/L (20 ng/dL), often using
supplementation with vitamin D, but measurement of
these levels is not recommended routinely.
The main storage organs for calcium are bones & teeth.
Calcium adequacy is determined in part as a function of
bone health as measured by bone mineral content and
density, and an AI has been set for calcium intake based
on these data. Bone mineral accretion is key in the
pediatric age range, with peak bone mass being
achieved by the 2nd to 3rd decade of life.
Hematologic m/ns
Secondary myelofibrosis
Various tissues, activated B and T lymphocytes and several
cultured normal and tumor cell lines, possess high-affinity,
low-capacity 1,25(OH)2D receptor like proteins that are
quantitatively similar to the intestinal receptor
Promyeloid leukemic cells (line M-1) that had nuclear
receptors for 1,25(OH)2D3 responded to this hormone by
differentiating into macrophages
 1,25(OH)2D3 induced time- and dose-dependent
phagocytic activity and expression of cell-surface antigens
including Fc and C3 receptors and lysozyme activity
Similar studies were done in a human promyelocytic
leukemic cell line (HL-60).
Cell growth was inhibited by as little as 10-9 M of
1,25(OH)2D3 in a dose-dependent manner.
1,25(OH)2D3 was also found to be an effective
antiproliferative agent for cultured tumor cells, such
as tumor breast, colon, lung, prostate, and melanoma
cells, that possessed its nuclear receptor.
 The effect of 1,25(OH)2D3 on leukemia cells is
reversible
When clones of HL-60 cells that possessed less than 10%
of nuclear binding activity for 1,25(OH)2D3 were incubated
with 1,25(OH)2D3, little difference in their proliferative
activity was noted.
1,25(OH)2D modulates the renal production of the blood
pressure hormone renin in a negative fashion, and this may,
in part, explain the role of vitamin D sufficiency in the
prevention of hypertension
Reading assignment
Congenital rickets

Estrogen, placental growth hormone, and

prolactin role in vitamin D metabolism

70