Prof. drh. Hastari Wuryastuty, M.Sc., Ph.D Bag. I.

Penyakit Dalam, FKH-UGM

Vitamin D
• • • • • • • • • Fat soluble Prohormone Derived from cholesterol Actually a group of analog steroid chemicals Synthesis from sun exposure = “Sunshine Vitamin” Insufficient sun exposure makes this a vitamin Activated by enzymes in liver and kidneys Responsible for proper utilization of Ca and P Deficiency can cause diseases

Definitions
 7-dehydrocholesterol: provitamin D3  Previtamin D3: cholecalciferol  Vitamin D3: produced in the skin from irradiated 7-DHC, isomerized previtamin D3  Vitamin D2: from plants, from irradiated ergosterol

produce same effect  Ergocalciferol (D2) Plant sources & supplements  Cholecalciferol (D3) Animal foods & made by body .Vitamin D  Conditionally essential  Different chemicals.

butter.Sources of Vitamin D RDA = 5 ug-15 ug • In foods: • Fortified milk. breads.7 mcg). cereals • Fish oils. herring. margarine (1 tsp = 0. egg (1 egg = 0. salmon. sardines. tuna • Livers.5 mcg) • Endogenous synthesis in the skin .

Sources of Vitamin D  Body makes it own: • Dehydrocholesterol in the skin exposed to sunlight • Energy transforms it into a pre-vitamin D molecule • Body heat provides energy to change previtamin D into inactive Vitamin D .

600 IU/day) for older Americans • Light skinned individuals can produce enough vitamin D to meet the AI from casual sun exposure • Infant are born with enough vitamin D to last ~9 months of age. .The Adequate Intake (AI) for Vitamin D • 5 ug/d (200 IU/day) for adults under age 51 • 10-15 ug/day (400 .

Vitamin D Synthesis .

Vitamin D Synthesis .

Absorption of Vitamin D • ~80% of vitamin D consumed is absorbed from micelles along with other fats • Absorbed in the distal small intestine and transported via chylomicrons • Cholesterol from the skin is bound to DBP and travels primarily to the liver through the lymphatic system. but can be picked up by other tissues (muscle and adipose) • Half-life in the blood 10-21 days. .

Sources: sunlight Main source of vitamin D is exposure to sunlight • whole body exposure 10-15 min midday sun in summer (~1 MED) Ξ 15 000 IU (375 g) orally • exposure of hands. face and arms (~15% body surface) to ~1/3 MED should produce ~1000 IU • less vitamin D synthesised in winter. time of day. skin type • short exposures to UV are more efficient: prolonged exposure to high UV doses may degrade pre-vitamin D . and those who cover up for cultural reasons or sun protection • amount of sun exposure to produce 1/3 MED varies with latitude. in those with dark skin or older. season.

Action spectra • UVB is the waveband required for vitamin D synthesis • The action spectra for sunburn. vitamin D synthesis does not continue. but DNA damage does . cyclobutane pyridine dimers all peak in the UVB range • With longer UVB exposure.

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SEASONAL CHANGES IN PTH AND CTx 1 PTH CTx Amplitude 0 UV -1 J F M A M J J A S O 25OHD N D Month .

PHASE SHIFTS Hip f ract ures Wrist f ract ures 1 P TH C Tx ude Amplit 0 UV -1 J F M A M J J A S O 25OHD N D Month .

UV exposure and skin damage • A balance is required between avoiding skin damage (skin cancer & wrinkling) and maintaining adequate vitamin D levels • Australia has highest reported rates of NMSC • Sun exposure causes ~99% NMSC and 95% melanoma • Sun protection required when UV index > 3 • Deliberate sun exposure between 10am-2pm in summer (11am –3pm Daylight saving time) is not advised • For regions south of 37o sun protection probably not needed during June-July .

Alternatives to UV exposure
 Exposure of hands, face and arms to ~1/3 MED of sunlight most days is considered adequate to produce sufficient endogenous vitamin D
 If adequate sunlight exposure is not possible, or practical, then vitamin D supplementation is recommended (at least 400 IU per day)  Because of high UV radiation, solaria are not recommended for boosting vitamin D levels
(National Radiological Protection Board, 2002)

Metabolism and Storage of Vitamin D
• Activation by the liver and the kidneys (25OH D) and (1,25 OH2 D) • Stored in fat tissue • Activate vitamin D when calcium is inadequate • Excretion of vitamin D mainly via bile

Functions of Vitamin D
• Regulate blood calcium level

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– 2. – 3.Vitamin D Functions: Helps bone grow • Works in three ways: – 1. Increases calcium retention in the kidney. tract. Increases Calcium Absorption from the G.I. Helps to withdraw calcium from bone. .

Vitamin D: Cell Differentiation  Vitamin D is able to influence differentiation and function of the some cells  Linked to reduction of breast. and prostate cancer development . colon.

Role in Bone Formation  Vitamin D creates a supersaturated Ca + Phos solution  Causes Ca + Phos to deposit in the bones  Strengthen bones  Rickets is the result of low vitamin D  Osteomalacia (soft bone) is rickets in the adult .

Vitamin D as a Medicine Type II (age-related) osteoporosis • Loss of bone mass • Limited ability to absorb vitamin D or produce it • 10-20 ug vitamin D/ day plus calcium decrease bone fracture • Risk for hypercalcemia Psoriasis • Skin disorder • Topical treatment .

Who is at risk for Deficiency ?  People at risk for vitamin D deficiency: those with limited mobility • elderly (institutionalised or housebound) • disabled (motor or intellectual disability)  Dark skin (melanin)  Skin conditions. post-organ transplant where sunlight avoidance is necessary  Fat Malabsorption .

Who is at Risk for Deficiency?  Drug exposures that synthesis or degradation 25OHD  Osteoporosis or minimal trauma fracture  Cultural or lifestyle choices  Vitamin D resistance  Resistance to the action of vitamin D  May be due to lack of calcitriol synthesis or inability to bind to nuclear receptor  Requires large doses of calcitriol .

Deficiency: rickets. vitamin K . osteomalacia Interaction with other nutrients: •Calcium. phosphorus.

low sun-exposure. repeated pregnancies.Vitamin D Deficiencies • In children: Rickets – malformed bones. bow legs • In adults: osteomalacia most often occurs in women with low Ca intake. and long breastfeeding with infants – loss of Calcium from bone and change of shape .

infiltrative disorders. illness.Causes of deficiency  Reduced intake or synthesis of cholecalciferol  sunlight: ageing. immobility  synthesis for a given UV exposure: ageing. dark skin  as above combined with low dietary intake  Disorders associated with abnormal gut function and malabsorption  small bowel disorders: coeliac disease. anticonvulsants . IBD. sprue. small bowel resection  pancreatic insufficiency: chronic pancreatitis. veiling. cirrhosis  drugs: rifampicin. cystic fibrosis  biliary obstruction: 1° biliary cirrhosis. external biliary drainage  Reduced synthesis or enhanced degradation of 25OHD  chronic hepatic disorders: hepatitis.

5 nmol/L osteomalacia (rare in Australia) bone and muscle pain. weakness and pseudofractures thickened unmineralised seams cortical thinning because 2 hyperparathyroidism .  bone turnover.Vitamin D deficiency & bone • Mild – 25OHD in range 25-50 nmol/L – increased PTH and high bone turnover • Moderate – 25OHD in range 12.  hip fracture risk • Severe – – – – – 25OHD < 12.5-25 nmol/L –  BMD.

Vitamin D insufficiency 25-OH vitamin D level • Optimal concentration remains undecided • In a meta-analysis of fracture prevention in the elderly. higher than currently recommended doses . showed that fracture prevention was greatest when 25-OH vitamin D levels were ~100 nmol/L: these studies used oral supplementation • This required vitamin D intakes of 700-800 IU/day.

tetany.Vitamin D: Indications • Dietary supplement • Treatment of vitamin D deficiency • Treatment and correction of conditions related to long-term deficiency: rickets. osteomalacia • Prevention of osteoporosis .

Forms of Vitamin D • • • • calcifediol (Calderol) calcitriol (Rocaltrol) dihydrotachysterol (Hytakerol. DHT) ergocalciferol (Calciferol) .

Vitamin D supplementation • Some Ca and MV preparations contain vitamin D (32-200 IU) – too low • Halibut or cod liver oil capsules (400 IU cholecalciferol) – cheap but also contain vitamin A (4000 IU) • Single pure vitamin D preparation in Australia is Ostelin 1000 (1000 IU ergocalciferol) @~24cents • Larger dose (50 000 IU) cholecalciferol available in NZ .

Mithal 2000) • Vitamin D examined in both 1o and 2o fracture prevention trials but differences in baseline PTH and 25OHD make comparisons difficult • Adequate calcium AND vitamin D likely to be required to reduce fracture risk . with low BMD • Unlikely that supplementation effective in vitamin D replete individuals but optimal 25OHD levels unknown: thresholds 50-110 nmol/L reported (Parfitt 1990.Supplementation and fractures • Greatest benefits: high-risk vitamin D-deficient patients.

Vitamin D supplementation • Prevention of fractures in the elderly • Prevention of falls in the elderly • Prevention of periodontal disease in the elderly .

Toxicity Warning • Vitamin D can be very toxic • Regular intake of 5-10x the AI can be toxic • Result from excess supplementation (not from sun exposure or milk consumption) • Sign and symptoms: over absorption of calcium (hypercalcemia). increase calcium excretion • Calcium deposits in kidneys. and blood vessels • Mental retardation in infants . heart.

headache.Vitamin D Toxicity: • Most potentially toxic of all vitamins!!!! – As little as 4 to 5 X RDA can be associated with toxic symptoms • minor: diarrhea. kidney. arteries – Major concern: those who take Vitamin D supplements • If some is good. nausea • major: calcium deposits in soft tissues of heart. more is NOT better!!!!! .

Toxicity: •Not possible from excess exposure to sunlight .

SCC • Melanoma .Ultraviolet radiation is a carcinogen • Sun exposure is the major environmental cause of skin cancer • BCC.

. burn easily. type and amount of exposure and susceptibility determine risk • Skin cancer risk is higher in susceptible populations living closer to the equator • The higher the total lifetime amount of UV exposure.e. many nevi are at greater risk of developing skin cancer .Ambient UV. tan poorly). the greater the risk of skin cancer • An intermittent pattern of intense exposure appears to increase the risk of melanoma • People with sun-sensitive skin (i. blue eyes.

UV: DNA damage • Cyclobutane pyrimidine dimers : signature mutation • 6-4 pyrimidine pyrimidone photoproducts • Single strand breaks • DNA protein crosslinks .

UV: membrane damage • Lipid peroxidation • Activation of surface receptors with induction of multiple signal transduction pathways: alteration in activation of many cellular proteins → alteration in gene expression and cellular function .

UV induces an alteration in immune surveillance • Decreased ability to eliminate cancerous growths • Interference with development of contact hypersensitivity .

Public health message: sun protection/skin cancer prevention • • • • • Shade Clothing Education Public policy Sunscreen use .

Colorectal neoplasia • Epidemiologic data are generally consistent with a protective effect of a higher 25(OH)D concentration and higher vitamin D intake • The biologic basis for the sensitivity of “digestive malignancies” to vitamin D status is unclear” • Randomized control studies are needed .

Prostate and breast cancer • Studies have shown geographic gradients in risk. • Case control studies and cohort studies have shown a decreased risk of these diseases with increased sunlight exposure • Hypothesis generating: Is it the vitamin D that is protective? • The potential for cancer prevention by oral intake of vitamin D must be tested in clinical trials .

Epidemiologic studies Less evidence exists for a role for sunlight in: • Multiple sclerosis • Diabetes .

Life is not so simple • Vitamin D is important for bone health • There is some data supporting vitamin D as protective against certain diseases • Agreement on appropriate levels of 25-OH vitamin D have not been established • Sunlight. is a carcinogen . a source of vitamin D.

25-dihydroxyvitamin D Cytokines Adaptive Innate Immune modulation .Noncalcemic Functions of 1.

25-dihydroxyvitamin D .Immunomodulatory Effects of 1.

blacks • Many people (such as teenagers. many adults) already are exposed to enough unprotected UV exposure that more UV exposure will not be helpful . weather dependent.What to do? • Some advocate for increased unprotected UV exposure • This advice is complex: latitude. It will not be effective in higher latitudes during the winter • It is inefficient in the elderly. time of day and season.

What to do? • Many advocate for taking vitamin D supplements • Advocate for increased fortification of foods where it is not in place .

Many people do not avoid the sun. Vitamin D supplementation for those at increased risk .What to do? 1. 2. and produce adequate vitamin D in the skin depending on the time of year. Incidental sun exposure throughout the year likely produces adequate vitamin D in the skin for many people 3.

What to do? • Further research on the role of sunlight and vitamin D in cancer prevention • Randomized controlled trials of dietary vitamin D as a cancer prevention agent .

shade and sunscreen during leisure time/occupational exposure  Standard use of sunscreens has not caused vitamin D deficiency .Sun protection messages  Remains important  Prevention of skin cancer and photoaging  Protection using hats. clothing.

and prostate cancer – ? Suppress metastasizes • Autoimmune Diseases – Prevent multiple sclerosis and type 1 diabetes • Cardiovascular Disease – Slow progression of atherosclerosis – Treat hypertension and congestive heart failure • Neuropsychiatric Disorders – Prevent schizophrenia and relieve depression . treat tuberculosis • Cancer – Prevent breast. colon.Benefits of Vitamin D • Skeletal-muscular – Strong muscles and bones • Infections – Prevent influenza.

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