Professor of Biochemistry Lecture-Vit-D Metabolism Dr.Saidunnisa, M.D Professor of Biochemistry Lecture-Vit-D Metabolism

Learning Objectives At the end of the session the student shall be able to : Explain the metabolic pathway for cholecalciferol synthesis List the dietary sources and RDA Explain the role of Calcitriol on the intestine, bone and kidney Correlate with the disorders Explain hypervitaminosis

Studies suggest globally many suffer from Vitamin D deficiency All studies, in virtually all nations, irrespective of latitude, show that the majority of the world’s population has inadequate vitamin D status. “Most people are not exposing themselves to the sun during the right hours which is from 11:00am to 2:00pm and this has resulted in a major Vitamin D epidemic and various health consequences related to it. “The sun is the key source of vitamin D”.

Three Ways to Obtain Vitamin D Sun exposure obtaining 10 to 15 minutes per day, with 40% of the skin exposed without sunscreen. Consuming vitamin D rich foods such as oily fish example salmon, mackerel, sardines. Vitamin D supplementation.

Vitamin-D Metabolism Is a fat soluble Vitamin. It resembles sterols in structure and functions like a hormone. During cholesterol synthesis 7-dehydro cholesterol is formed as an intermediate. On exposure to sunlight, it is converted to cholecalciferol (vit D3) in the skin.

UV radiations UV are EMR divided into 3 components according to wavelength: UVA: 320-400nm UVB: 290-320nm UVC: 100-290nm

Advantages of UVB Absorbed by the epidermal layer where highest concentration of 7-dehydrocholesterol exists. Optimum wavelength range is 295-300nm (D-UV). UVB exposure does not result in excessive production of vitamin D risking intoxication because previtamin D3 is converted to inactive product tachysterol and lumisterol.

Dark skin Dark skin people have more melanin in epidermis which competes with 7- dehydrocholestrol for absorption of UVB photos. Dark skin people are less efficient in producing vitamin D than whites. It has been reported dark skin people require 10-50 times more exposure to sunlight to produce the same amount of vitamin D as a person with white skin.

Obesity leads to less Vit D Have lower 25,hydroxyvitamin D levels. 7-dehydrocholestrol in the skin of obese and non-obese individuals is same. In obese the subcutaneous fat, stores the vitamin D3 and results in less release in to circulation.

Sunscreens These efficiently absorb UVB radiation, dramatically prevents the interaction of UVB with 7-dehydrocholesterol, the process of previtamin D3 generation. It has been shown that SPF of 8 reduces the production of pre vitamin D3 by 95% and 99% by SPF 15.

Vitamin-D Metabolism Cholecalciferol is first hydroxylated to 25- hydroxy-cholecalciferol in liver is a major storage form. In plasma 25-HCC is bound to VDBP an α-2 globulin. It is converted to 1,25 dihydroxy cholecalciferol by the enzyme 1- hydroxylase (this is called calcitriol because it has 3- OH groups) in the kidney.

Biochemical effects of vitamin D Calcitriol acts on 3 different target tissues: Intestine Bone Kidney

Calcitriol action on intestine Calcitriol increases the intestinal absorption of calcium and phosphate. In the intestinal cells Calcitriol binds with a cytosolic receptor to form Calcitriol-receptor complex. This complex then approaches the nucleus and interacts with specific DNA leading to the synthesis of calcium binding protein. This protein increases the calcium uptake by the intestine.

Calcitriol action on bone Calcitriol stimulates the osteoblasts for calcium uptake and promotes calcification. It also stimulates osteoblasts which secrete alkaline phosphatase enzyme due to which the local concentration of phosphate is increased. The ionic product of calcium and phosphorus increases and they are deposited as hydroxyapatite which is Mineralization or remodeling

Calcitriol action on Kidney Increases the reabsorption of calcium and phosphorus by renal tubules therefore both minerals are conserved.

Regulation of calcitriol Low plasma phosphate increases the activity of 1- hydroxylase thus it is a direct action. Low plasma calcium increases the production of PTH which in turn activates 1- Hydroxylase so it is a indirect action.

Regulation of calcitriol is feed back control Hypercalcemia decreases calcitriol. Low calcium and phosphorous increase 1,25-DHCC production. Half life of 1,25- DHCC is 6-8 hours. Vitamin D deficient (low calcium and phosphorous) enhance the action of 1,α- hydroxylase. Vitamin D status adequate or calcium levels high, 24 hydroxylation is favored forming 24,25 DHCC which is less active.

Recommended Dietary Allowance Children: 400IU/day Adults: 200IU/day Pregnancy, lactation : 400IU/day >60yrs: 600IU/day Dietary Sources: Fatty fish, fish liver oils, eggs yolk,

Deficiency of vitamin D Rickets in children Osteomalacia in adults

Causes of vitamin D deficiency Not exposed to sunlight (northern latitudes in winter) Bedridden for long time People who cover the whole body Nutritional deficiency Malabsorption of vitamin (high phytates content) Abnormal activation of Vitamin D (liver and renal diseases may decrease hydroxylation)

Clinical features of rickets Pigeon chest Rickety rosary: enlargement of epiphysis at the lower end of ribs and costochondral junction. Harrison's sulcus Bone defects weight bearing bones are bent. Frontal bossing

Clinical features of rickets Insufficient mineralization of bone. Bones become soft pliable and growth is affected. Serum calcium and phosphorus are low, and Increase in ALP is characteristic feature of rickets.

Osteomalacia Osteon= bone Malakia=softness Bones are softened due to insufficient mineralization and increased osteoporosis and prone to fractures. Biochemical parameters: low serum calcium , phosphorous, Vit D Increased alkaline phosphatase.

Laboratory Assessment Universally accepted that the circulating level of 25-OH-Vitamin D should be used as an indicator of Vitamin D status due to its: Ease of measurement : Methodology: Vitamin D blood testing by HPLC or LC/MS-MS) (modified method). Recommend serum as the sample of choice. Long half-life in circulation (approx 2-3weeks) Correlation of its level with clinical conditions.

Different types of rickets Classical Vit D deficiency Hypophosphatemic rickets: due to defective renal tubular reabsorption of phosphate. Vitamin D resistant rickets: found in fanconi syndrome where the renal tubular reabsorption of bicarbonate, phosphate, glucose, and amino acids are also deficient. Renal rickets: Seen in patients with chronic renal failure, mainly due to decreased synthesis of calcitriol in kidney.

Hypervitaminosis Doses above 1500 IU/day for long period may cause toxicity. Symptoms: Nausea, loss of appetite, increased thirst and loss of weight, Hypercalcemia results in deposition of calcium in soft tissues and kidneys resulting in calculi formation. Although Vit D is toxic in higher doses excessive exposure to sunlight does not result in Vit D toxicity, because excess D3 is destroyed by sunlight itself.

Calcitriol as a hormone Synthesized in the skin by uv-rays. Action on target tissues like bone, intestine and kidney. Action similar to steroid synthesis. Half life is short .

Why does vitamin D affect so many biologic processes?

Hypertension Millions of people are affected by hypertension worldwide. Low 1,25- dihydroxyvitamin D levels activate renin- angiostensin -aldosterone system in which could predispose patients to blood pressure.

Hypertension BP higher in winter. BP higher with increasing latitude. BP higher with darker skin pigmentation.

Heart Disease "Vitamin D deficiency is an unrecognized, emerging cardiovascular risk factor, Low vitamin D levels activate: Renin-angiotensin-aldosterone system and, in doing so, predispose patients to hypertension and a stiffening and thickening of the heart and blood vessels. Vitamin D deficiency also alters hormone levels and immune function, which can increase the risk of diabetes, a major contributor to CVD.

Recommendation Exposing to the sun during the right hours which is from 11:00am to 2:00pm to prevent various health consequences related to it.