2. 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.
3. 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
4. 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,
6. 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
7. 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 OIL
CHEAPEST SOURCE - SUNLIGHT
8. 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
16. 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)
17. 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
19. 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.
20. 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
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
28. 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
30. RICKETS in Children
OSTEOMALACIA in Adults
Increase the risk of Osteoporosis .
31. 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.
32. 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
33. 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 level
o Treatment- 6 lakhs IU of Vit-D3 oraly or im induce
rapid healing within 3-4 wks & then 400IU per day.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41.
42. 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.
43. 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).
44. 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.
45. 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.
46. 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 calcification
o Treatment: stop vitamin D & calcium , low calcium
diet, acidify the urine and steroids.
47. 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.
48. 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.
49. 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-basic
http://emedicine.medscape.com/article/128762-overview
http://www.medicinenet.com/vitamin_d_deficiency/related-conditions/ind
Editor's Notes
A secosteroid is a type of steroid with a &quot;broken&quot; ring
Vitamin D plays an important role in many places throughout the body, including the development and calcification of the bones.
Adequate exposure to sunlight and the use of dairy products with vitamin D have significantly reduced the incidence of vitamin D deficiency. However, vitamin D deficiency is still a common problem in many populations, particularly older adults.
It helps to absorb dietary calcium and phosphorus from the intestines.
It suppresses the release of parathyroid hormone, a hormone that causes bone resorption.
Any organic compounds which are essential for normal growth and nutrition and are required in small quantities in the diet because they cannot be synthesized by the body is called vitamin.
A hormone is a class of signaling molecules produced by glands in multicellular organisms that are transported by the circulatory system to target distant organs to regulate physiology and behaviou
Multiple studies show decreased vit D at end of Winter
IS AN ALFA GLOBULIN SYNTHESIZED IN LIVER
A reduction in the serum calcium below ∼2.2 mmol/L (8.8 mg/dL) prompts a proportional increase in the secretion of parathyroid hormone (PTH) and so mobilizes additional calcium from the bone. PTH promotes the synthesis of 1,25(OH)2D in the kidney, which in turn stimulates the mobilization of calcium from bone and intestine and regulates the synthesis of PTH by negative feedback.
Calcitriol increases blood calcium levels ([Ca2+]) by promoting absorption of dietary calcium from the gastrointestinal tract and increasing renal tubular reabsorption of calcium, thus reducing the loss of calcium in the urine. Calcitriol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL, which in turn activates osteoclasts
Osteopenia is a condition in which bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis. More specifically, osteopenia is defined as a bone mineral density T-score between -1.0 and -2.5
Parathyroid hormone (PTH), is secreted by the chief cells of the parathyroid glands. It acts to increase the concentration of calcium (Ca2+) in the blood, whereas calcitonin (a hormone produced by the parafollicular cells (C cells) of the thyroid gland) acts to decrease calcium concentration.
PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney, which means more phosphate is excreted through the urine.
However, PTH enhances the uptake of phosphate from the intestine and bones into the blood.
Endocrine system refers to the collection of glands that secrete hormones directly into the circulatory system to be carried towards a distant target organ.
PARACRINE Function is an endocrine function in which effects of a hormone are localized to adjacent or nearby cells.
Intracrine refers to a hormone that acts inside a cell, regulating intracellular events. Steroid hormones act through intracellular (mostly nuclear) receptors and, thus, may be considered to be intracrines
Different kinds of medicines to control cholesterol.
HMG-CoA Reductase Inhibitors(also called Statins)
Bile Acid Sequestrants
Fibrates
Niacin
Cholesterol Absorption Inhibitors
Omega-3 Fatty Acid
Vitamin D fortified milk from Amul® (an Indian dairy cooperative, located in Anand, Gujarat, India) is the only fortified milk product found in the general market’
Kellogg’s breakfast cereals fortified with vitamin D along with other micronutrients are also available. However, the exorbitant prices of these products are essentially prohibitive for consumption by the common people of India
Vitamin D deficiency activates the renin-angiotensin-aldosterone system and can predispose to hypertension and left ventricular hypertrophy.
Proposed mechanism: The 1,25 OH vitamin D produced in the kidney enters the circulation and stimulates insulin secretion in the islet cells of the pancreas
Additionally, vitamin D deficiency causes an increase in parathyroid hormone, which increases insulin resistance secondary to down regulation of insulin receptors and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk.
Metabolic syndrome is a cluster of conditions —(HTN+DM+OBESITY) increased blood pressure, a high blood sugar level, excess body fat around the waist and abnormal cholesterol levels — that occur together, increasing your risk of heart disease, stroke and diabetes
The probable mechanism is that colon, prostate and breast express 25-OH vitamin D 1-alpha hydroxylase and produce 1,25 OH vitamin D locally to control genes that help prevent cancer by limiting cellular proliferation and differentiation by inhibiting angiogenesis and inducing apoptosis
Multiple sclerosis (MS), also known as disseminated sclerosis or encephalomyelitis disseminata, is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged
Prolonged inadequate intake of vitamin D will lead to impaired bone metabolism. In children, under mineralization of bone causes soft and deformed bones and can lead to the condition known as rickets. Rickets is rare in the US today, but was fairly common as recently as 100 years ago. When children developed rickets, their legs were too weak to hold their weight, resulting in bowed legs, which often persisted into adulthood. Osteomalacia is the adult form of rickets, and leads to impaired mobility and bone fractures. And osteoporosis, a condition that leads to weak and porous bones.
Craniotabes -earliest manifestation.
Harrison’s sulcus- linear transvers depression by the side of the xiphoid process.
fraying –saucer deformity.
If mother is affected chance of affection is equal among boy & girl, but if father is affected boys are escaped, only girl childs are affected.
Expressivity-The term is analogous to the severity of a condition in clinical medicine.
Tumor-induced osteomalacia is usually referred to as a paraneoplastic phenomenon. osteosarcoma and fibrosarcoma produce FGF23 (fibroblast growth factor 23) which inhibits phosphate transport in the renal tubule and reduces calcitriol production by the kidney.
The 1,25(OH)2D levels may be normal in vitamin D deficiency, because of a maximal stimulation of 1-hydroxylase by the low serum phosphorus and high PTH levels.
ALFA CALCIDOL – it does not requre hydroxylation at position 1, limiting step in the active form of vitD take place in kidney. So it is used in- Renal bone disease ,vitD resistant Ricket. Hypoparathyroidism ( ie. Indication of Calcitriol) & osteoporesis.