VITAMIN D DEFICIENCY

SPEAKER- DR. MIHIR ADHIKARI

CHAIRPERSON- PROF. N.M.BISWAS

Sunshine vitamin

Sunshine vitamin

INTRODUCTION

Vitamin D is an Fat-soluble vitamin .It is present in animals, plants and yeast & has several important functions in the body.

Technically it should be considerd as Hormone ( Secosteroid ) because -

-It is synthesized by the body(skin) from sunlight (UV-B ray, wave band-290-315 nm), -It is transported by blood, activated & then acts on

specific receptors in the target tissue. -Feedback regulation of Vit D activation occure by

plasma Ca level & by active form of Vit D.

HISTORYCAL BACKGROUND

In1919 it was established that Ricket was due to deficiency of a diatery factor & lack of sunlight.

American researchers Elmer McCollum and Marguerite Davis in 1922 discovered a substance in cod liver oil & its struture is determined in1935.

He called it vitamin D because it was the fourth vitamin to be named.

Sunshine vitamin

Sunshine vitamin

WHAT IS VITAMIN D Chemistry: There are two chemical forms of vitamin D,

-Vitamin D2 (Ergocalciferol) and -Vitamin D3 (Cholecalciferol). The natural form of vitamin D for animals and man is

vitamin D3; it can be produced in their bodies from cholesterol and 7-dehydrocholesterol.

An alternative vitamin D2 is commercially prepared from ergosterol that is present in yeast.

Cholesterol in animals and man is a precursor substance for all steroid hormones as well as vitamin D3.

The molecular structure of vitamin D is closely allied to that of the classical steroid hormones,

CHEMICAL STRUCTURE OF VITAMIN-D

SOURCES OF VITAMIN D

2 sources - 90% synthesised in skin via UVB light exposure

Cholecalciferol (vitD3 = inactive) - 10% from food – Ergocalciferol (vit D2= inactive)

Sunshine vitamin

Sunshine vitamin

DIETARY SOURCES

Fatty fish, like tuna, mackerel, and salmon. Cod liver oil Foods fortified with vitamin D, like some dairy

products, orange juice, soy milk, and cereals. Beef liver. Cheese. Egg yolks

8 oz milk = 115 IU

8 oz juice = 100 IU

1 egg = 29 IU

3 oz smoked salmon = 583 IU

RICHEST SOURCE - FISH LIVER OILCHEAPEST SOURCE - SUNLIGHT

DAILY REQUIRMENT

Children & adults –400IU(10µg/day)

Pregnancy and lactation – 400IU(10µg/day)

Over 70years- 800IU (20µg/day)

1microgram of vitamin D = 40 International Units

SYNTHESIS OF VITAMIN D

7DEHYDROXY CHOLESTEROL

7DEHYDROXY CHOLESTEROL

ERGOSTEROL

UV LIGHT

KIDNEY MITROCHONDRIA

KIDNEY MITROCHONDRIA

CHOLECALCIFEROL(VIT. D3)

CALCIFEROL (VIT. D2)

CALCIFEDOL (25-OH-D3)

CALCIFEDOL (25-OH-D3)

CALCIFEDOL 25-OH-D3

CALCITRIOL(1,25(OH)2 D3)

CALCITRIOL(1,25(OH)2 D3)

HUMAN(skin) PLANT(yeast)

LIVER MICROSOME

ACTIVE FORMS

METABOLISM

Source: Skin and diet Stores: 25 OH Vitamin D3 (calcidiol) Active form: 1,25(OH)2 Vitamin D (calcitriol) MOA: Steroid hormone. Binds to VDR in nucleus

to upregulate gene expression in target cells.

ABSORPTION

ABSORPTION

TRANSPORT

TRANSPORT

Synthesis of active form of vitamin D

Synthesis of active form of vitamin D

HORMONAL CONTROL LOOP FOR VITAMIN D METABOLISM AND FUNCTION

Mineralization of bone at low doses Mobilization of calcium from bone at high doses

Increased reabsorption of calcium and phosphorus Decreased excretion of calcium and phosphorus

Increases the intestinal absorption of calcium and phosphate by increased synthesis of calcium binding protein(calbinding D28k)

PTH EFFECTS Increases tubular reabsorption of

calcium and stimulates the kidney to produce 1,25 OH vitamin D3.

Stimulates the activation of osteoclasts, which dissolve mineralized collagen matrix in the bone, causing osteopenia and osteoporosis and increasing the risk of fracture.

Causes phosphaturia. A low Ca-Phos product leads to decreased mineralization of the collagen matrix= rickets in kids and osteomalacia in adults

ENDOCRINE, PARACRINE AND INTRACRINE FUNCTIONS OF VITAMIN D

VITAMIN D DEFICIENCY

VITAMIN D STATUS- 25(OH)D LEVEL (ng / ml)

Normal level of vitamin D - > 30 Vitamin D insufficiency -- 21-29 Vitamin D deficiency -- < 20 Severe deficiency -- <10 Exact cuts-off value for ‘deficiency’ & ‘insufficiency’ remain

controversial.

Researchers concluded that having low levels of vitamin D (<17.8 ng/mL) was independently associated with an increase in all-cause mortality in the general population.

RISK FACTORS FOR VITAMIN D DEFICIENCY Elderly Individuals older than 65 years Dark skin No sun exposure Strict vegan diet Obesity Nursing home residents Patients on medications that induce P-450 enzyme activity. Individuals with kidney disease (CRF) Individuals with low bone mass or osteoporosis Individuals with nonvertebral or hip fractures Individuals with a history of falls

CAUSES OF VITAMIN D DEFICIENCY

The main reasons for low levels of vitamin D are: Lack of vitamin D in the diet, often in

conjunction with inadequate sun exposure. Inability to absorb vitamin D from the

intestines. Inability to process vitamin D due to kidney

or liver disease.

CAUSES OF VITAMIN D DEFICIENCY. CONTD.

Inadequate sun exposure Sunscreen with SPF 15+ blocks 99% vitamin D synthesis Pigmented skin Aging (older than 65 years) Winter season Physical agents blocking UVR exposure,clothing, season,

air pollution, cloud cover, latitude & altitude.

Decreased absorption Bowel bypass surgery Crohn’s disease Celiac disease Fat and cholesterol absorption inhibitors.

CAUSES OF VITAMIN D DEFICIENCY. CONTD.

Inability to process vitamin D Impaired production of 25hydroxy vitamin D3 -

Liver disease Impaired production of 1,25 dihydroxy vitaminD3 -

Kidney disease,

Hypoparathyroidism, Oncogenic osteomalacia, X-linked hypophosphatemic rickets.

CAUSES OF VITAMIN D DEFICIENCY. CONTD

Other Causes Breastfeeding Medications; - Steroids decrease half life of vitamin D. - Barbiturates, Phenytoin, and Rifampin can induce

hepatic p450 enzymes to accelerate the catabolism of vitamin,

- Ketoconazole impaired 25-hydroxylation. - Increased degradation of 25 (OH) D -Drugs such as,

Rifampicin, Isoniazid, Phenytoin, Glucocorticoids. Target organ resistance- Vitamin D receptor

mutation.

VITAMIN D DEFICIENCY: INDIAN SCENARIO

India is a country with abundant sunshine but still a high prevalence (> 70%) of Vitamin D deficiency has been documented.

Subclinical Vit D deficiency is very common in India in all the age groups and both sexes across the country.

Skin complexion, poor sun exposure, vegetarian food habits and lower intake of vitamin D fortified foods could be attributed to the high prevalence of VDD in India

Malabsorption is the commonest cause of Vit.D deficiency in India

Vitamin D deficiency is likely to play an important role in the very high prevalence of rickets, osteoporosis, cardiovascular diseases, diabetes, cancer and infections such as tuberculosis in India.

VITAMIN D DEFICIENCY RELATED SYSTEMIC DISORDER

1. Autoimmune disorders- Rheumatoid arthritis Inflammatory Bowel disorder Type I diabetes mellitus SLE Psoriasis

2. Cardiovascular disorders- Hypertension CAD Cardiomyopathy CHF Coronary calcification Peripheral vascular disease

VITAMIN D DEFICIENCY RELATED SYSTEMIC DISORDER. CONTD..

3. Endocrine & metabolism- Primary hyperparathyroidism Type I & 2 DM Metabolic syndrome

4. Heamatopoietic system- Anemia Leukaemia5. Infection Childhood asthma Recurrent URTI Tuberculosis

VITAMIN D DEFICIENCY RELATED SYSTEMIC DISORDER. CONTD..

6. Musculoskeletal system Rickets & Osteomalasia Osteoporesis & fracture Myopathy Fibromyalgia

7. Malignancy- Breaast Ca Colon Ca Pancreatic Ca Ovarian Ca Prostate Ca

VITAMIN D DEFICIENCY RELATED SYSTEMIC DISORDER. CONTD..

8. Nervous system- Multiple sclerosis Stroke Headache9. Psychiatric disorder- Depression Mood swings10. Reproductive system- Dysmenorrhoea PCOD Gestational diabetes Preeclampsia

RICKETS in Children OSTEOMALACIA in Adults Increase the risk of Osteoporosis .

Rickets and osteomalacia are disorders of the mineralization of newly synthesized bone matrix(osteoid).

In children, defects occur in the growth plate and in the mineralization of cartilage, leading to characteristic deformities; ie. Rickets.

In adults, it occurs after epiphyseal closure, & involves only bone; ie. Osteomalasia.

Age incidence- 4m-2y Clinical Feature: Symptom-• Irritability & restlessness• Rocking of head in pillow & sweating of forehead• Delayed dentation & Delayed milestones Sign-• Craniotabes - Pot belly• Frontal bossing - Harrison’s sulcus• Rickety rosary -Pegion chest• Bowed legs or Knocked knee• Delayed closure of ant. frontanelle

Radiological changes: Cupping widening & fraying of lower end of radius & ulna. Widening of wrist (soft tissue shadow)o Biochemical changes Increased alkaline phosphatase Hypophosphataemia Hypocalcimia Decreased plasma 25(OH)D3 levelo Treatment- 6 lakhs IU of Vit-D3 oraly or im induce

rapid healing within 3-4 wks & then 400IU per day.

FREATURES OF RICKETS

VITAMIN D RESISTANT RICKETS

Vitamin D-resistant rickets type I Autosomal recessive. Failure of 1,25 vitamin D synthesis due to inactivating mutation

in renal 25(OH)D-1-alpha hydroxylase enzyme. Clinical features are similar to those of infantile rickets . Diagnosis is usually first suspected when the patient fails to

respond to vitamin D supplementation. Biochemical features of type I disease are similar to vitamin D

deficiency, except that levels of 25(OH)D are normal. Treated with the active vitamin D metabolites, 1,25 (OH)2D3

(calcitriol) with or without calcium supplements. Initial doses are 0.25–2 μmg/day.

VITAMIN D RESISTANT RICKETS. CONTD..

Vitamin D-resistant rickets type II Autosomal recessive. Defect in the vitamin D receptor which impair its ability to

activate transcription & impaired response to 1,25(OH)2D3. Most patients present during infancy although less severely

affected patients may not be diagnosed until adulthood. Approximately 50–70% of children have alopecia which tends to

be associated with a more severe form of the disease. Here 25(OH)D is normal but PTH and 1,25(OH)2D3 values

are raised. It is extremely difficult to treat but some times responds partially

to very high doses of active vitamin D metabolites and calcium and phosphate supplements.

HYPOPHOSPHATAEMIC RICKETS(X-LINKED DOMINANT)

The disorder is inherited in an X-linked dominant manner.This means the defective gene is located on the X chromosome.

It is associated with mutations in PHEX, FGF23 & DMPA1 gene. Only one copy of the defective gene is sufficient to cause the

disorder when inherited from a parent who has the disorder. Males are normally hemizygous for the X chromosome,having only

one copy. As a result, X-linked dominant disorders usually show higher expressivity

in males than

females.

HYPOPHOSPHATAEMIC RICKETS. CONTD..

Defects in phosphate and pyrophosphate metabolism. The most apparent abnormality is decreased renal

tubular reabsorption of phosphate. The diagnosis is made on the basis of the early age

at onset and presence of hypophosphataemia with renal phosphate wasting in the absence of vitamin D deficiency.

Treatment is with phosphate supplements (1–4 g daily) and active metabolites of vitamin D to promote intestinal calcium and phosphate absorption.

Osteomalacia is the softening of the bones caused by defective bone mineralization secondary to hypocalcemia , hypophosphatemia & vitamin D deficiency.

The causes of adult osteomalacia are varied, but ultimately result in a vitamin D deficiency:

Even in the presence of normal calcium and phosphate levels, chronic acidosis and drugs such as bisphosphonates (etidronate ) & phosphate-binding antacids can lead to osteomalacia.

Demineralization occurs mainly in spine, pelvis & lower extremities.

It manifest with bone pain, severe malaise, proximal muscle weakness & waddling gait.

Radiological feature -Pseudo fracture- or Looser’s Zones of decalcification along the course of major arteries. Biochemical changes - Decreased serum calcium or phosphorus. Decreased serum 25-hydroxyvitamin D . Increased Serum ALP & PTH. Treatment - Vit D deficiency corrected by 60000 IU once weekly for 4-6 wk. followed by once a month.

DIAGNOSIS OF VITAMIN D DEFICIENCY

The key diagnostic test in vitamin D deficiency is demonstration of a decreased serum 25(OH)D3 value.

Low values of 1,25(OH)2D3 and normal levels of 25(OH)D3 suggest a defect in 1-hydroxylase that may be genetic or acquired as a result of loss of renal function or tumor-induced osteomalacia.

High levels of 1,25(OH)2D3 and normal levels of 25(OH)D3 are seen in patients with vitamin D receptor defects.

TREATMENT: VITAMIN D DEFICIENCY

Treatment of vitamin D deficiency should be directed at the underlying disorder & severity of the condition.

Vitamin D should always be repleted in conjunction with calcium supplementation since most of the consequences of vitamin D deficiency are a result of impaired mineral ion homeostasis.

In patients in whom 1α-hydroxylation is impaired, metabolites that do not require this activation step are the treatment of choice. They include 1,25(OH)2D3 [calcitriol , 0.25–0.5 g/d] and 1α-hydroxyvitamin D2 ( 2.5-5 g/d).

TREATMENT: VITAMIN D DEFICIENCY. CONTD.

If the pathway required for activation of vitamin D is intact, severe vitamin D deficiency can be treated with initially 50,000 IU of Vit D weekly for 3–12 weeks, followed by maintenance therapy (800 IU daily).

Calcium supplementation should include 1.5–2 g/d of elemental calcium. Normocalcemia is usually observed within one week of the institution of therapy, although increases in PTH and alkaline phosphatase levels may persist for three to six months.

MONITORING OF TREATMENT

The most efficacious methods to monitor treatment of vitamin D deficiency are serum and urinary calcium measurements.

In patients who are vitamin D replete and are taking adequate calcium supplementation, the 24-hour urinary calcium excretion should be in the range of 100–250 mg/ 24 hours.

Lower levels suggest problems with adherence to the treatment regimen or with absorption of calcium or vitamin D supplements.

Levels >250 mg/24 hours predispose to nephrolithiasis and should lead to a reduction in vitamin D dosage and/or calcium supplementation.

TOXICITY Side effects of vitamin D are uncommon unless the 25(OH)D level becomes very elevated (>100ng/ml or 250 mmol/L) and the person is taking high dose calcium supplement. Avoid taking multiple products that contain vitamin D

(eg, multivitamin and vitamin D). The upper limit of intake has been set at 4000IU/day. Toxic feature: Anorexia, nausea , vomiting Deposition of calcium in soft tissue like kidney, arteries Kidney stone , Metastatic calcificationo Treatment: stop vitamin D & calcium , low calcium

diet, acidify the urine and steroids.

VITAMIN D PREPARATIONS

CALCIFEROL (Vit D2) Dose- 12,000 to 500,000 IU cap daily. CHOLECALCIFEROL (Vit. D3) Dose- 400 to 1000 IU orally/day or 6,00000 IU orally/inj. every 3-4 wks. Interval. CALCITRIOL (1,25(OH)2D3). Dose- 0.25-1ug daily / alternate day orally / inj. ALFA CALCIDOL (1 alfa (OH)D3 )- Prodrug rapidly

hydrolysed in liver to Calcitriol /1,25(OH)2D3. Dose-1-2ug/day orally. DIHYDROTACHYSTEROL- A synthetic analogue of

Vit. D2. Dose- 0.25-0.5 mg/day.

PREVENTION OF VITAMIN D DEFICIENCY

Sensible sun exposure- 5-30 minutes of exposure of arms and legs between 10 am and 3 pm twice a week is often adequate.

To prevent vitamin D deficiency, the American Academy of Pediatrics (AAP) recommends that infants and children receive at least 400 IU per day from diet and supplements.

All pregnant & lactating mother should take 400IU vitamin D supplements daily

Evidence shows that vitamin D supplementation of at least 700 to 800 IU per day reduces fracture and fall rates in adults.

Fortification of food with Vitamin D such as milk, butter chapatiflour, maida, cereals etc.

REFFERENCE : Harrison’s Principles Of Internal Medicine , 18th ed, chapter 352 Williams Textbook of Endocrinology, 10th ed. Davidson’s Principles and Practice of Medicine 21st ed, chapter25 Medical Pharmacology 6th edition , chapter24 Manual of practical medicine, Alagappan, 5th ed , chapter 2 Bedside clinics in medicine part I , 6th ed. Evaluation, Treatment, and Prevention of Vitamin D Deficiency:-

Journal of Clinical Endocrinology & Metabolism, July 2011, Vitamin D Status in India – Its Implications and Remedial

Measures http://www.japi.org/january_2009 http://www.uptodate.com/contents/vitamin-d-deficiency-beyond-the-basics http://emedicine.medscape.com/article/128762-overview http://www.medicinenet.com/vitamin_d_deficiency/related-conditions/index.htm