Vitamin D detailed information and diseases associated with vitamin D deficiency and toxicity covering about rickets and osteomalacia, information from Harrison's internal medicine and online resources like uptodate

1. VITAMIN D AND DISORDERS –
HYPO/HYPERVITAMINOSIS D
DR SANGAM H B

2. SYNTHESIS AND METABOLISM
• 1,25 dihydroxyvitamin D [1,25(OH)2 D] major steroid hormone
involved in regulation of mineral ion homeostasis
• Plant source – vitamin D2(ergocalciferol), Animal source – vitamin D3
(cholecalciferal)
• Skin is a major source of vitamin D which is synthesized upon skin
exposure to UV-B radiation (290-320nm)
• Except for fish, food (unless fortified) contains only limited amounts of
vitamin D

4. D 1-α hydroxylase
• PTH and hypophosphatemia are major inducers of this microsomal
enzyme in the kidney
• Calcium, FGF23, and 1,25(OH)2 D repress the enzyme
• Expressed in epidermal keratinocytes, trophoblastic layer of placenta,
produced by macrophages associated with granulomas and
lymphomas
• In pathologic states, enzyme induced by interferon ϒ and TNF α

5. ✓Major pathway for inactivation is additional hydroxylation by vitamin
D 24-hydroxylase
✓FGF 23 induces this enzyme thereby reduces 1,25(OH)2 D levels both
by inactivating and impairing synthesis
✓Mutation of the gene encoding this enzyme (CYP24 A1) can lead to
infantile hypercalcemia
• Polar metabolites of vitamin D is secreted into the bile and reabsorbed
via enterohepatic circulation. Impairment of this recirculation leads to
accelerated losses of vit D metabolites, seen with terminal ileal
diseases.

6. Actions of 1,25(OH)2 D
• 1,25(OH)2 D mediates its biologic effects by binding to nuclear
receptor subfamily, vitamin D receptor (VDR)
• VDR binds to target DNA sequences as heterodimer with the retenoid
X receptor, resulting in induction of target gene expression
• This hormone is a major inducer of calbindin 9K, calcium-binding
protein in intestine
• Major calcium transporters, TRPV5 and TRPV6 are also vitamin D
responsive

7. • VDR is expressed in osteoblasts and regulates the expression of genes
like bone matrix protein, osteocalcin and osteopontin
• Both 1,25(OH)2 D and PTH induce the expression of RANK ligand
which promotes osteoclast differentiation, by this mechanism
1,25(OH)2 D induces bone resorption
• The VDR is expressed in the parathyroid gland, and 1,25(OH)2 D has
shown to have antiproliferative effects on parathyroid cells and to
suppress transcription of the parathyroid hormone gene.
• 1,25(OH)2 D also has antiproliferative effect on keratinocytes, breast
cancer cells and prostate cancer cells

8. • Vitamin D is thought to be important for maintaining normal function
of many non skeletal tissues such as muscle (including heart muscle),
for immune function and for inflammation as well as for cell
proliferation and differentiation
• Studies have shown role of vitamin D in treatment of tuberculosis,
psoriasis, and multiple sclerosis or for the prevention of certain
cancers and also SARS CoV-19
• Insufficiency can increase risk of type 1 DM, cardiovascular disease
(insulin resistance, hypertension, low grade inflammation) or brain
dysfunction(depression)

9. Deficiency and resistance – impaired action
• Impaired availability of vitamin D, secondary to inadequate dietary
vitamin D, fat malabsorptive disorders and/or lack of sunlight
• Impaired hydroxylation by the liver to produce 25 hydroxyvitamin D
(liver disease, isoniazid, 25 hydroxylase mutation)
• Impaired hydroxylation by the kidney to produce 1,25
dihydroxyvitamin D (vitamin D dependent rickets type 1, chronic renal
insufficiency)

10. • End organ insensitivity to vitamin D metabolites (hereditary vitamin D
resistant rickets [HVDRR], vitamin D dependent rickets type 2)
• Glucocorticoids when used chronically in high doses, inhibit intestinal
vitamin D dependent calcium absorption, leads to osteoporosis and
fractures
• Drugs that induce cyt P 450 – barbiturates, phenytoin and rifampicin

12. Vitamin d sufficiency
• Most specific screening test for vitamin D deficiency is a serum
25(OH)vitamin D level
• Categorization of vitamin D status in adults
✓Vitamin D sufficiency:- > 20 ng/ml
✓Vitamin D insufficiency :- 12 to 20 ng/ml
✓Vitamin D deficiency:- <12 ng/ml
✓Risk of vitamin D toxicity:- > or = 100ng/ml

13. RDA

14. Osteomalacia
• Osteomalacia refers to impaired mineralization of bone matrix
• Clinical features-
✓Bone pain and muscle weakness
✓Bone tenderness
✓Fracture
✓Difficulty walking and waddling gait in four
✓Muscle spasms, cramps
• Most accurate way to diagnose – tetracycline labelling and
histomorphometric assessment

15. Rickets
• Rickets refers to deficient mineralization at the growth plate, as well as
architectural disruption of this structure
• Skeletal findings include-
✓Delayed closure of the fontanelles
✓Parietal and frontal bossing
✓Craniotabes (soft skull bones)
✓Rachitic rosary – beading of costochondral junction
✓Formation of Harrison sulcus at the lower margin of thorax by inward
pull of diaphragmatic attachments

18. Vitamin D dependent rickets
• Type 1 – 1 alpha hydroxylase defect
• Type 2 – vitamin D receptor defect
• Autosomal recessive disorder presents with syndrome of vitamin D
deficiency in the first year of life
• Presents with growth retardation, rickets and hypocalcemic seizures
• Treatment with vitamin D metabolites calcitriol, doxercalciferol. These
don’t require activation from the enzyme. Lifelong theraphy is
required

19. Vitamin D resistant rickets
• X linked dominant disorder, involving PHEX gene mutation
• Due to which there is FGF-23 level elevation which is a inhibitor of
enzyme 1 alpha hydroxylase, reduces PTH and cause phosphaturia
• Treatment – along with vitamin D supplementation, phosphate also
needs to be given

20. Vitamin D and COVID 19
• In patients with COVID 19, vitamin D supplementation may be necessary
to meet the recommended intake. Doses exceeding upper level intake
are not recommended.
• Vit D is considered as a facilitator of the innate immune response during
SARS-CoV 2 infection
• In large cohort study from UK Biobank, there was no association
between 25(OH)D levels and risk of or mortality from COVID 19.
subsequent studies have found positive COVID 19 test was higher in
those who were likely vitamin D deficient (<20ng/ml)
• and fewer patients on vitamin D supplementation required oxygen
therapy and ICU admission compared to general population

21. Vitamin D replenishment
• Preparation available –
✓Supplementation with cholecalciferol is suggested than with
ergocalciferol
✓Vitamin D3(Cholecaliferol) available in 400, 800, 1000, 2000, 5000,
10000, 50000,60000 unit oral capsule, solution, sachets. And also
3,00,000 and 6,00,000 unit injectable formulation
✓Vitamin D2(Ergocalciferol) is available for oral use in 200,400 and
50000 unit capsules or in liquid form 8000 units

22. Dosing
• In patients with normal absorptive capacity for every 100 unit of vit
D3, serum 25(OH)D concentration increase by approx. 0.7 to 1.0
ng/ml. larger increments seen in patients with lower baseline 25(OH)D
• For patients with serum 25(OH)D <12ng/ml 50,000 IU of D3 or D2
orally once per week for six to eight weeks and then 800IU of D3 daily
thereafter
• 25(OH)D levels >12 and < 20 ng/ml initial supplementation with 800
to 1000 IU daily may be sufficient. Repeat serum 25(OH)D level after 3
months to see if therapeutic goal is achieved

23. • If 25(OH)D level is 20 to 30ng/ml, 600 to 800 units of D3 daily may be
sufficient to maintain target range
• In patients with malabsorption oral dosing and duration depend upon
the absorptive capacity. High doses of vitamin D 10,000 to 50,000 IU
daily may be necessary to treat patients of gastrectomy or
malabsorption
• Vitamin D should always be given in conjunction with calcium
supplementation
• Calcium supplementation should include 1.5-2 gm/day of elemental
calcium

24. • To monitor treatment and resolution of vitamin D deficiency serum
and urinary calcium measurements are seen
• In patients who are vitamin D replete and are taking adequate calcium
supplements, 24 hour urinary calcium excretion should be in the
range of 100-250 mg/24 hr
• > 250mg/24 hr predispose to nephrolithiasis and should lead to a
reduction in vitamin D dosage and/or calcium supplementation.
• Lower levels suggests problem with adherence or with absorption of
calcium or vitamin D supplements

25. Vitamin D intoxication
• Occurs generally after inappropriate use of vitamin D supplements
• May occur in patients who consume megadoses of supplements or in
patients who take vitamin D replacement for malabsorption, renal
osteodystrophy, osteoporosis, or psoriasis
• Prolonged exposure of the skin to sunlight does not produce toxic
amounts of vitamin D3
• Upper limit of intake – 4000 IU/day

26. • Symptoms -
✓ Acute intoxication - hypercalcemia and include confusion, polyuria,
polydipsia, anorexia, vomiting and muscle weakness
✓Chronic intoxication – nephrocalcinosis, bone demineralization and
pain
• Treatment –
✓ Discontinuation of vitamin D and calcium supplements
✓ Treatment of hypercalcemia