metabolism of vitamin D and its deficiency diseases

1. Swati Chaudhary
M-5429
Division Veterinary Pathology
IVRI

2. History
 In 1922, Edward Mellan and Elmer McCollum discovered Vitamin D.
 Fourth vitamin to be discovered.
 Fortification of food with vitamin D was patented.
 Complete eradication of rickets in US.

3.  fat soluble vitamin
 More than 50 genes are known to be transcribed by it

4. Vitamin D fits the definition of hormone
 It is produced by body
 Has specific tissue targets
 Does not have to be supplied by the diet.

5. Two Major Forms of Vitamin D
 Vitamin D3, cholecalciferol
 Vitamin D2, ergo-calciferol

6. Other Forms of Vitamin D
 Vitamin D1: molecular compound of ergocalciferol with lumisterol, 1:1
 Vitamin D4: 22-dihydroergocalciferol
 Vitamin D5: sitocalciferol (made from 7-dehydrosisterol)

7. Synthesis
 Vitamin D is produced in the two
innermost layers of epidermis, the
stratum basale and stratum
spinosum.
 The precursor of vitamin D3 is 7-
dehydrocholesterol
 10,000 to 20,000 IU of vitamin D are
produced in 30 minutes of whole-
body exposure
 7-Dehydrocholesterol reacts
with UVB light with peak synthesis
occurring between 295 and 297 nm.

9. Groff & Gropper, 2000
Vitamin D Affects Absorption of
Dietary Ca and P
 1,25-(OH)2 D binds to vitamin
D receptor (VDR) in nucleus
 The epithelial calcium
channel, transient receptor
potential vanilloid6
(TRPV6), transports
calcium into the cell where
it binds to calbindin and is
transported across the cell
 A Ca2+ATPase and
Na+/Ca2+ exchanger then
discharges calcium into the
bloodstream.
K.E.Dittmer and K.G.Thompson

10.  Bone remodeling. In the skeleton, 1,25(OH)2D3, in association with PTH,
promotes mobilization of calcium from bone
 RANKL, a surface ligand on osteoblasts, bind to osteoclasts via RANK
(receptor activator for NF-kB)
 When RANKL binds to RANK, it induces differentiation and maturation of
osteoclast progenitor cells to osteoclasts.
 RANKL is stimulated by 1,25(OH)2D3 via VDREs on the RANKL promoter,
thereby inducing osteoclastogenesis, resorption of bone, and mobilization
of calcium.
K.E.Dittmer and K.G.Thompson

11.  Parathyroid glands
 Active vitamin D up regulate calcium-sensing receptor expression by
binding to VDREs on the calcium-sensing receptor gene promoter, leading
to increased sensitivity of the parathyroid gland to plasma calcium
 Deficiency of vitamin D results in hypocalcemia, which leads to parathyroid
hyperplasia and secondary hyperparathyroidism
 Kidney. The main role of 1,25(OH)2D3 in the kidney is to control its own
production
 by inhibition of renal 1a-hydroxylase
 and stimulation of CYP24 (24-hydroxylase)
K.E.Dittmer and K.G.Thompson

12. Excretion

13.  The renal synthesis of calcitriol is tightly regulated by two counter-acting
hormones,
 with up-regulation via parathyroid hormone
 and down-regulation via fibroblast-like growth factor-23

14.  VDRs are expressed in several white blood cells, including monocytes and
activated T and B cells
 Activated macrophages and lymphoma cells also make 1,25(OH)2 Vitamin
D
 Excessive unregulated production of 1,25(OH)2 Vitamin D by activated
macrophages and lymphoma cells is responsible for the hypercalciuria
associated with chronic granulomatous disorders and hypercalcemia seen
in lymphoma
(Adams, 1989; Davies et al., 1994).

15. Vitamin D deficiency

16.  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
 Vitamin D–dependent rickets type 2
 Chronic renal failure

17. NUTRITIONAL VITAMIN D
DEFICIENCY
 Most common cause globely
Etiology
• Poor intake - Neonate
• Inadequate cutaneous synthesis

18. CONGENITAL VITAMIN D
DEFICIENCY.
 severe maternal vitamin D deficiency during pregnancy
 Maternal risk factors
poor dietary intake of vitamin D,
lack of adequate sun exposure
closely spaced pregnancies
 presentation
intrauterine growth retardation
decreased bone ossification,
classic rachitic changes

19. SECONDARY VITAMIN D DEFICIENCY.
 Inadequate absorption - cholestatic liver disease,
-defects in bile acid
metabolism,
- other causes of pancreatic
dysfunction, celiac disease, and
Crohn disease
-intestinal lymphangiectasia
-after intestinal resection
 Decreased hydroxylation in the liver,-insufficient enzyme activity
 Increased degradation - medications, by inducing the P450 system,
 Anticonvulsants, such as phenobarbital or phenytoin
 Antituberculosis medications- isoniazid and rifampin

20. 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.
 They have normal levels of 25-D, but low levels of 1,25-D

21. VITAMIN D–DEPENDENT RICKETS,
TYPE 2.
Mutations in the gene encoding the vitamin D receptor
 Autosomal recessive disorder
 Levels of 1,25-D are extremely elevated

22. GROUPS AT RISK
 Infants
 Elderly
 Dark skinned
 Covered women
 Kidney failure patients
 Patients with chronic liver diseases
 Fat malabsorption disorders
 Genetic types of rickets
 Patients on anticonvulsant drugs

23.  RICKETS : Defective mineralization of growing bone before epiphyseal
fusion
 OSTEOMALACIA : Defective mineralization of bone after epiphyseal fusion
Vitamin D deficiency diseases

24. Rickets
Pathogenesis
 Defective mineralization of osteoid and
cartilaginous matrix of developing bone
 Persistence and continued growth of hypertrophic
epiphyseal cartilage
 Poorly calcified spicules of diaphysis of bone
resulting in bowing of legs
 Broadening of epiphysis with apparent
enlargement of joints

25. Grossly
 Enlargement of ends of long bone and costo-chondral articulations
 Long bones become distorted and deviated
 Enlarged costo-chondral articulations appear as a string Of beads
 Flattening of ends of long bones
 Bones are soft ,easily cut and fractured

26. Microscopically
 Increased proliferating undegeraded cartilage adjacent to the metaphysis
 Disarrangement chondrocytes of proliferating cartilage
 Defective calcification of cartilage and excess un-calcified osteoid tissue in
the metaphysis
 Fibrosis of bone marrow with reduction of myloid cells

27. Abnormal growth plate due to
increased depth of the hypertrophic
cartilage zone and failure of orderly
endochondral ossification.
Normal ossification

28. Irregularity of the growth plate and
increased depth of the hypertrophic
cartilage zone occur

29. , Goldner's stain. Bone forming surface with wide osteoid seam.
Mineralized bone stains green, unmineralized bone matrix (osteoid) stains
red. IN METAPHYSIS

30. Clinical signs
 Bone pain
 Stiff gait
 Swelling in the area of the
metaphysis
 Difficulty in rising
 Bowed limbs
 Enlargement of costo-chondral
junction
 Lameness
 Arching of back
 And pathologic fractures

31. Diagnosis
Radiographic examination
 The radiopacity of rachitic bones is characteristically less than that of
normal bone.
 Growth plates appear widened and irregular.
Clinical pathology
Elevation of plasma alkaline phosphate
Concentrations of serum phosphorus and vitamin D may be altered
depending on the cause of rickets.

32. Osteomalacia
 Seen in mature bones and associated with disruption of normal bone
remodeling.
 Osteomalacia is characterized by an accumulation of excessive un-
mineralized osteoid on trabecular surfaces.

33. Pathogenesis
 Similar to rickets ,no physeal lesion in adult skeleton
 Gross lesion
 Thickening of bones which appear soft , easily cut and deformed.
 Marrow cavity enlarged and cortex is thin and spongy

34. Microscopic lesion
 Active bone resorption /increased activity of osteoclasts
 Presence of uncalcified osteoid at the margin of cortices, haversian canals
and bone trabeculae
 Expension of haversian canals

39. Clinical findings
 Unthrifty
 May exhibit pica.
 Nonspecific shifting lamenesses are common.
 Fractures can be seen especially in the ribs, pelvis, and long bones.
 Spinal deformation such as lordosis or kyphosis

40. Vitamin D - Sources
 Synthesized in body
 Plants (ergosterol)
 Sun-cured forage
 Oily fish
 Egg yolk
 Butter
 Liver
Cow’s milk 0.3-4IU/100ml
Egg yolk 25IU/average yolk
Herring 1500IU/100g

41. Industrial production
 Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-
dehydrocholesterol to UVB light, followed by purification.
 The 7-dehydrocholesterol is a natural substance in fish organs, especially
the liver, or in wool grease (lanolin) from sheep.
 Vitamin D2(ergocalciferol) is produced in a similar way using ergosterol
from yeast or mushrooms

42. Vitamin toxicity
 Hypervitaminosis D is a state of vitamin D toxicity. The normal range for
blood concentration is 30.0 to 74.0 nanograms per milliliter (ng/mL).
 Causes hypercalcemia
 which manifest as:
Nausea & vomiting
Excessive thirst & polyuria
Severe itching
Joint & muscle pains
Disorientation & coma.

43. Vitamin D Toxicity
Calcification of soft tissue
 Lungs, heart, blood vessels
 Hardening of arteries (calcification )
 Excess blood calcium leads to stone formation in kidney.

44. Plants containing 1,25-dihydroxycholecalciferol
(calcitriol) glycoside
 Cestrum diurnum (wild jasmine)
 Trisetum flavescens (golden oats or yellow oat grass)
 Nierembergia veitchii
 Solanum esuriale
 S. torvum
 and S malacoxylon

45. Treatment
 No practical treatment for vitaminD3 toxicity is currently available.

46. references
 K. E. Dittmer and K. G. Thompson ,Vitamin D Metabolism and Rickets in
Domestic Animals A Review Veterinary Pathology48(2) 389-407.
 Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D,
and Fluoride
 Ross AC, Taylor CL, Yaktine AL, et al. Dietary Reference Intakes for Calcium
and Vitamin D (2011).
 Vegad JL , A Textbook of Veterinary General Pathology

47. Thank u