Mini-Review :
Variable Responses to Vitamin-D Dosing
Gokhale SG and Gokhale Sankalp
Full-Text
Introduction
Background
Vitamin D deficiency is recognized
as a global public health problem, with deficiency states reported from various
countries [1-3]. Acting as a Pro-Hormone; this is a unique endogenously
synthesized vitamin. Besides its pivotal role in calcium homeostasis
and bone mineral metabolism,
the vitamin-D endocrine system is now recognized to sub-serve a wide range of
fundamental biological functions in cell differentiation, inhibition of cell
growth, and immunomodulation [3]. Vitamin-D deficiency
affects not only musculoskeletal health but also a wide range of acute and chronic
disease [4].
The metabolic product of vitamin-D
is a potent, pleiotropic, repair and maintenance; secosteroid hormone that
targets more than 200 human genes in a wide variety of tissues, meaning it has
as many mechanisms of action on genes it targets [5]. Two related sterol
compounds viz. Cholecalciferol
[Vitamin-D3] and Ergocalciferol [Vitamin-D2] are grouped as Vitamin-D.
Cholecalciferol is of animal origin and the other Ergocalciferol [Vitamin-D2]
is plant based. Interestingly, antirachitic properties of Vitamin-D2 and D3 are
identical [6]. After oral administration; Vitamin-D3 is absorbed better than D2
in small intestine; and bile is essential for absorption [6].
In animals
Under effects of Ultra Violet light
7-Dehydrocholesterol in skin is converted to Cholecalciferol [Vitamin-D3]. D2
and D3 are converted to 25-OH-cholecalciferol [25-OH-CC] in Liver. This is
first hydroxylation. 25-OH-CC /25-OH-D or Calcifediol is the
major circulating form of Vitamin-D and has a half life of 19 days; and serum concentrations
are 15-50 nanograms/ml with steady state pharmacokinetics [6]. 25-OH-CC
undergoes second hydrolysis to 1, 25-OH-CC, primarily in kidneys but to some
extent in extra-renal sites as Macrophages and Keratinocytes [6]. Calcitriol or
1, 25-OH-CC is the final active form of Vitamin-D. Both 25-OH-CC and 1, 25-OH- C
may undergo further hydrolysis in renal tubules to INACTIVE forms 24, 25-OH- CC
and 1, 24, 25-OH-CC [6]. The optimal level of 25[OH] Vitamin-D should be 50 –100
ng/ml. Blood levels
of 25[OH] Vitamin D exceeding 200ng/ml are considered potentially toxic.
Vitamin D toxicity is very rare [7,8].
Serum 25-hydroxyvitamin-D [25(OH)
D], Calcidiol, is the storage form of vitamin-D, and the most reliable
indicator of the vitamin D stores of an individual. It is therefore the one
tested for in routine assays to determine deficiency/adequacy of the vitamin.
The production of 25(OH) D is not regulated, and therefore the concentration of
the compound in serum reflects both cutaneous synthesis and absorption from the
diet. The half-life of 25(OH)-D is about six weeks. Biochemically, levels of
25(OH)-D more than 30 ng/ml (to convert ng/ml to nmol/ml multiply by 2.5) are
considered as normal. Levels between 20 and 30 ng/ml are defined as
insufficiency and levels less than 20ng/ml are defined as deficiency [3]. The
best option for estimation of vitamin- D levels in laboratory is LCMSMS-Liquid Chromatography Tandem Mass Spectrometry [9].
Suggestions to Treat the Deficiency
State
Various clinical trials
suggested different dose regimes to treat Vitamin-D deficiency. It was found
that an intake of 400 IU/day oral vitamin D3 did not sustain circulating
maternal 25(OH) D levels, and thus, supplied only extremely limited amounts of
vitamin-D to the nursing infant via breast milk. Infant levels achieved exclusively
through maternal supplementation were equivalent to levels in infants who received oral
vitamin-Dsupplementation. Studies showed that
a maternal intake of 4000 to 6400 IU/day vitamin-D elevated circulating 25(OH)
D in both mother and nursing infant [10-12]. NO-OBSERVED ADVERSE- EFFECT LEVEL (NOAEL)
were noted with this dose schedule [12].
Findings
In our study all the participants received 1200,000
IU of Vitamin-D and repeat levels were monitored over six months [13]. Yet in another
study of ours, in spite of four mega- doses of Vitamin-D injections [of 600,000
IU]; only two third or 9/14= 64.3% showed good response and 5/14 =35.7% failed to
achieve target serum levels of Vitamin-D [14]. Annual Single dose of Vitamin-D is
one of the few options tested by some authors. In our study of Annual Single Mega-dose
of Vitamin-D injection as Supplementation Therapy [15]; all eight members had normal
serum levels of vitamin-d to start with and they received one mega- dose of 600,000
IU intramuscular injection as maintenance dose. It has been noted that a single
dose of 600,000 IU of cholecalciferol
rapidly enhances 25(OH)-D with vitamin D deficiency [16,17]. This satisfactory response
to high dose vitamin-D was seen in Australian population [18]. We observed in
all our Vit-d projects that the response even with high mega-dose Vitamin-D
treatment is erratic and unpredictable. Few other authors have made similar observations
in population with Asian Indian ethnicity [19,20] in India and United Kingdom. Probably
this is multifacorial issue. Genetic factors seem more important than environmental
ones. These studies from different geographic locations rule out environmental
factors. So we are left with genetic factors to explain this odd phenomenon.
We tried to reason it out
1. Vitamin D-binding protein is coded
by Genes like TT, TK or KK. It has been shown that increments in serum 25(OH) D
in response to treatment depend on the heritability/ genotype of vitamin
D-binding protein carried by the individual. KK genotype shows highest increments
followed by TK and then last on list is TT variant [this is more frequently
found in people of Indian origin [21]. This may explain the variability or low levels
in spite of good dosing.
2. Secondly, high 24-25 Hydroxylase activity
is seen in Indians. This is also been proved in laboratory using tissue culture
techniques. This may change active form 25-OH- D to inactive one viz. 24-25-OH-D
[22]. This can be looked upon as a shunt operating to safeguard against the development
of high levels of Vitamin-D. Is it an adaptive mechanism?
3. For obvious reasons, the Skin pigmentation
factor cannot be counted. Melanin in the skin competes with 7dehydrocholesterol for
UVB rays. The greater the amount of melanin in the skin, the lower is the efficiency
of vitamin-D synthesis. Skin with darker pigmentation, like those of most Indians,
requires a longer duration of sun exposure to synthesize an equivalent amount
of vitamin-D as compared to Caucasian skin. Indians skin comes under type V
category.
4. After absorption, Vitamin-D3
circulates in association with Vitamin-D Binding Protein; specific Alpha
Globulin. The Vitamin-D disappears from blood with half-life of 30 hours, but
remains stored in fat depots for prolonged periods [6]. In our study; 47 participants
showed poor responses and all of these had BMI higher than their counterparts who
showed good response. Could it be that these POOR participants had Vitamin-D
stored in fat depots?
5. Probably there few other genetic
factors as well. Studies in Twins have confirmed role of genetic factors in
determining bone
resorption and formation, calcium excretion, and the hormones regulating
these processes [23].
References
1. P. Nicolaido u, Z.
Hatzistamatiou, A. Papadopoulou, J. Kaleyias. Clinical Investigations- Low
Vitamin D Status in Mother-Newborn Pairs in Greece (2006) Calcified Tissue
International 78:337342.
2. Ana Cecilia Garza-Gisholt, Rodolfo
Rivas-Ruiz, Patricia Clark. Maternal diet and vitamin D during pregnancy and
association with bone health during childhood-Review of the literature (2012)
Bol Med Hosp Infant Mex 69: 83-90.
3. Anshu Sharma. Bulletin of the
Nutrition Foundation of India (2014) Nutrition Foundation of India.
4. Arash Hossein-nezhad, Michael F.
Holick. Vitamin D for Health: A Global Perspective (2013) Mayo Clin Proc 88:
720-755.
5. JJ Cannell, BW Hollis, M Zasloff,
RP Heaney. Diagnosis and treatment of vitamin D deficiency (2008) Expert Opin
Pharmacother 9:1-12.
6. Brunton, Chabner, Knollmann.
Goodman and Gilmans (2006) In: The pharmacological basis of therapeutics
McGraw- Hill Company Pp: 1280-1283.
7. Joel M. Kauffman. Benefits of Vitamin
D Supplementation (2009) Journal of American Physicians and Surgeons 14.
8. Sarfraz Zaidi. Power of Vitamin D
(2012) STM Publishers Mumbai India
9. Michael Holick. The Vitamin D
solution (2011) Plume Publishers- Penguin Group First Plume Printing Pp:149-151
10. Caroll Wagner, Thomas C. Hulsey,
Deanna Fanning, Myla Ebeling, Bruce W. Hollis. High-Dose Vitamin D3
Supplementation in a Cohort of breastfeeding mothers and their Infants: A
6-Month Follow-Up Pilot Study (2006) Breast feeding medicine 1.
11. Bruce W Hollis, Carol L Wagner.
Vitamin D requirements during lactation: high-dose maternal supplementation as therapy
to prevent hypovitaminosis D for both the mother and the nursing infant (2004)
Am J Clin Nutr 80(suppl):1752S– 1758S.
12. Vieth R, Kimball S, Hu A,
Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate
intake versus 100 mcg (4000 IU) per day on biochemical responses and the
wellbeing of patients (2004) Nutr J 3: 8-18.
*Corresponding author
Sanjay G. Gokhale, Department of Pediatrics and Neonatology, Rajhans Hospital and Research Center, Saphale, India, Tel: 091-800-779-8400 E-mail: rajhanssanjay@gmail.com
Citation
Gokhale SG, Sankalp G (2017) Variable Responses to Vitamin-D Dosing. PVPE 1: 1-3
Keywords
Vitamin D deficiency, Cholecalciferol, Dose
