Vit d

Vit D: Role in various

diseases

-Dr. Nilesh Chandra

Objectives:

Introduction

Synthesis

Actions

Diseases

Supplementation

Introduction

Not strictly a vitamin.

Only when sunlight exposure is inadequate is a dietary source required.

Main function is in the regulation of calcium absorption and homeostasis.

Most of its actions are mediated by way of nuclear receptors that regulate gene expression.

Introduction

Also has a role in regulating cell proliferation and differentiation.

Intakes considerably higher than are required to maintain calcium homeostasis reduce the risk of:◦ Insulin resistance

◦ Obesity

◦ The metabolic syndrome

◦ Various cancers.

Deficiency, leading to rickets in children and osteomalacia in adults.

Vitamin D Is Synthesized in the

Skin

Vitamin D Is Activated in Liver &

Kidney

Synthesis-summary

Regulation

Calcitriol acts to reduce its own

synthesis by:

◦ inducing the 24-hydroxylase.

◦ repressing the 1-hydroxylase in the

kidney.

Other regulators are serum levels of:

◦ Phosphorus

◦ Calcium

◦ fibroblast growth factor 23 (FGF-23)

◦ parathormone (PTH)

Vit. D Receptor (VDR)

VDR: a transcription factor

Regulates expression of upto 2000

genes, directly or indirectly.

Membrane bound VDR postulated but

not yet proven.

Role in calcium homeostasis

vitamin D maintains plasma calcium

concentration in three ways:

◦ it increases intestinal absorption of

calcium.

◦ it reduces excretion of calcium (by

stimulating resorption in the distal renal

tubules).

◦ it mobilizes bone mineral.

Other actions

calcitriol is also involved in:

◦ insulin secretion.

◦ synthesis and secretion of parathyroid

and thyroid hormones.

◦ inhibition of production of interleukin by

activated T-lymphocytes and of

immunoglobulin by activated B-

lymphocytes.

◦ differentiation of monocyte precursor

cells.

◦ modulation of cell proliferation.

Normal levels

Commonly, 25 (OH)D is measured.

Analyte Conventional

Unit

SI Unit

25(OH) D 10-65 ng/ml 25-162 nmol/L

1,25 (OH) D 15-60 pg/ml 36-144 pmol/L

Causes of Vit d deficiency

Inadequate exposure to sunlight.

Inadequate dietary vit D.

Vit D malabosrption.

Severe hepatocellular disease.

Increased catabolism (e.g. drugs).

Increased loss (nephrotic syndrome).

Vit D deficiency and bone morphology

Vitamin D sufficiency leads to an

adequate calcium-phosphorus product

(Ca2+ × HPO42−) resulting in an

effective bone mineralization.

Maternal vitamin D insufficiency during

pregnancy associated with a

significant reduction in bone mineral

acquisition in infants, persisting upto 9

years of age.

In children, vitamin D deficiency with

25(OH)D levels <15 ng/mL causes:

◦ chondrocyte disorganization.

◦ hypertrophy at the mineralization front.

◦ skeletal mineralization defects.

This results in bone deformities and short

stature, the typical signs of vitamin D

deficiency rickets.


Sister (right) and

brother (left)

ages 4 years and

6.5 years,

respectively,

demonstrating

classic knock-

knees and bow

legs, growth

retardation, and

other skeletal

deformities

In adults low 25(OH)D and high PTH also lead to a low serum calcium ×phosphorus product.

Results in osteomalacia, i.e., a defective mineralization of the collagen matrix .

Causes a reduction of structural support.

Associated with an increased risk of fracture.


A decrease in 25(OH)D leads to

secondary hyperparathyroidism.

Associated with osteoclastogenesis,

which leads to:

◦ an increase in bone resorption exceeding

osteoblast-mediated bone formation.

Can precipitate and exacerbate

osteopenia and osteoporosis in adults.


Muscular health

Vitamin D deficiency is associated with:

◦ diffuse muscle pain.

◦ muscle weakness predominantly in the proximal muscle groups.

◦ a reduction in performance speed.

Vitamin D supplementation lowered the adjusted-incidence rate ratio of falls by 72% compared to those taking placebo over 5 months.

Protective role in

carcinogenesis 1,25(OH)2D inhibits carcinogenesis by

several mechanisms:

◦ promotes cyclin-dependent kinase (CDK)

inhibitor synthesis.

◦ influences several growth factors and their

signaling pathways including:

insulin-like growth factor 1 (IGF-1)

transforming growth factor β (TGFβ)

Wnt/β-catenin

MAP kinase 5 (MAPK5)

nuclear factor κB (NF-kB)

Beneficial effects on cardiovascular

risk factors and cardiovascular health

The vitamin D receptor is present in

endothelium, vascular smooth muscle, and

cardiomyocytes.

May protect against atherosclerosis

through:

◦ The inhibition of macrophage cholesterol uptake

and foam cell formation.

◦ reduced vascular smooth muscle cell

proliferation.

◦ reduced expression of adhesion molecules in

endothelial cells.

◦ inhibition of cytokine release from lymphocytes.

Protective role in Type II DM

vitamin D exerts various antidiabeticeffects.

The VDR is expressed in pancreatic beta cells and 1,25(OH)2D stimulates insulin secretion.

Improvement in vitamin D status also leads to a improvement of insulin sensitivity, mediated by upregulation of insulin receptors.

Vit D modulates inflammation, which is also thought to play a role in type 2 diabetes.

Additional benefits

Protective role has been found in:

◦ Autoimmune Disease:

Multiple Sclerosis

Type I DM

Rheumatoid Arthritis

◦ Infections, especially:

Tuberculosis

Influenza

Viral URTI

◦ Respiratory Diseases

A Schematic representation of the major causes for

vitamin D deficiency and potential health

consequences

Vit D supplementation

According to the Endocrine Society

Practice Guidelines:

Age Daily

supplementation

Safety limit

Upto 1 year 400–1000 IU up to 2000 IU

1-18 years 600–1000 IU up to 4000 IU

>18 years 1500–2000 IU up to 10,000 IU

Treatment of deficiency

According to the Endocrine Society Practice

Guidelines:

Age Initial therapy

for 6 weeks

Maintenance

Upto 1 year 2000 IU/day or 400–1000 IU/day

50,000 IU/wk

1-18 years 2000 IU/day or 600–1000 IU/day

50,000 IU/wk

>18 years ~6000 IU/day or 1500–2000

IU/day

50,000 IU/wk

(both for 8 wks)

In obese patients, patients with malabsorption syndromes,

and patients on medications affecting vitamin D

metabolism, two to three times higher doses are

recommended.

Summary

Vit D synthesis.

Actions and systems affected.

Effects of deficiency.

Treatment of deficiency.

References

Tietz Textbook of Clinical Chemistry

and Molecular Diagnosis, Fifth Edition.

Harper’s Illustrated Biochemistry, 29th

Edition.

Wacker,M and Holick, M.F . Vitamin

D—Effects on Skeletal and

Extraskeletal Health and the Need for

Supplementation. Nutrients. 2013

January; 5(1): 111–148.

THANK YOU!!

Vit d

Health & Medicine

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