Swati ChaudharyM-5429

Division Veterinary PathologyIVRI

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.

fat soluble vitamin

More than 50 genes are known to be transcribed by it

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.

Two Major Forms of Vitamin D

Vitamin D3, cholecalciferol

Vitamin D2, ergo-calciferol

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)

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.

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

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

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

Excretion

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

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 hypercalciuriaassociated with chronic granulomatous disorders and hypercalcemia seen in lymphoma

(Adams, 1989; Davies et al., 1994).

Vitamin D deficiency

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

NUTRITIONAL VITAMIN D DEFICIENCY Most common cause globely

Etiology

• Poor intake - Neonate

• Inadequate cutaneous synthesis

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

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

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

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

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

RICKETS : Defective mineralization of growing bone before epiphyseal fusion

OSTEOMALACIA : Defective mineralization of bone after epiphyseal fusion

Vitamin D deficiency diseases

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

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

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

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

Normal ossification

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

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

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

DiagnosisRadiographic 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.

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.

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

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

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

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

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 ergosterolfrom yeast or mushrooms

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.

Vitamin D ToxicityCalcification of soft tissue

Lungs, heart, blood vessels

Hardening of arteries (calcification )

Excess blood calcium leads to stone formation in kidney.

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

Treatment

No practical treatment for vitaminD3 toxicity is currently available.

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

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