JIMSA Oct. - Dec. 2014 Vol. 27 No.
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Hypervitaminosis D and Systemic Manifestations:
A Comprehensive Review
Anil Kumar Gupta*, Vinu Jamwal*, Sakul*, Pavan Malhotra**
Department of *Medicine, **Pharmacology & Therapeutics, Acharya Shri Chander College of Medical Sciences,
Sidhra, Jammu, J&K, India
Abstract: Hypervitaminosis is a rare but potentially serious condition which is manifested after mega dose replacement in addition to other sources as
well. Vitamin D toxicity may also be associated with hypercalcemia. To establish a diagnosis of hypervitaminosis D there has to be a clinical and bio-
chemical hypercalcemia along with calciuria and hypoparathyroidism with elevated serum vitamin D levels. The management primarily focuses on
reduced dietary calcium intake with proper attention to hydration along with discontinuation of vitamin D therapy. Corticosteroids especially predniso-
lone and bisphosphonate therapy may also be useful.
INTRODUCTION
V
itamin D is likely one of the oldest hormones, having existed for
at least 750 million years1. Studies have demonstrated that low
levels of vitamin D represent a problem of global dimensions2.
A recent Workshop Consensus for Vitamin D Nutritional Guidelines
estimated that approximately 50% and 60% of the elderly in North
America and the rest of the world, respectively, do not have satisfactory
vitamin D levels3. But recently hypervitaminosis has also come into the
limelight. Vitamin D toxicity, also called hypervitaminosis D, is a rare
but potentially serious condition that occurs when we have excessive
amounts of vitamin D in our body. Vitamin D toxicity is usually caused
by mega doses of vitamin D supplements not by diet or sun exposure.
Thats because our body regulates the amount of vitamin D produced by
sun exposure, and even fortified foods dont contain large amounts of
vitamin D. Vitamin D toxicity causes hypercalcemia and multiple other
adverse effects including potentially life-threatening ones4.
There are 2 major forms of vitamin D, vitamin D2 (ergocalciferol) and
vitamin D3 (cholecalciferol). Vitamin D2 is found in plants and can be
consumed in fortified food products or as a supplement. Vitamin D3 is
obtained from either dietary sources or through the conversion of 7-
dehydrocholesterol in the skin upon exposure to ultraviolet B (UVB)
radiation. Vitamin D3 from the skin is bound to the vitamin D-binding
protein, whereas vitamin D 2 and vitamin D3 from diet are bound to
vitaminD-binding protein and lipoproteins. Both forms are hydroxylated
in the liver to 25-hydroxyvitamin D [25(OH)D; D represents D2 or D3].
However, 25(OH)D is inactiveand requires hydroxylation in the kidney
to form 1,25-dihydroxyvitaminD/ [1,25(OH)2D,calcitriol]. Calcitriol
[1,25(OH)2D] maintains calcium in the blood and has an array of effects
on the bodys organs. Calcitriol acts in an endocrine manner to regulate
calcium metabolism by enhancing intestinal calcium absorption and
mobilizing calcium from the skeleton5,6,7.
SERUM LEVELS OF VITAMIN D
Although 1,25(OH)2D is considered to be the active form of vitamin D,
its levels in the serum do not correlate with overall vitamin D status.
Whereas the 25(OH)D level is a more clinically relevant marker8. Vitamin
D activity is measured in g of 25(OH)D (1 g = 40 International Units,
IU).
OPTIMUM 25(OH)D LEVELS
The vitamin D level needed to optimize intestinal calcium absorption
(34 ng/mL) is lower than the level needed for neuromuscular performance
(38 ng/mL) 9, 10. Experts however believe that the lower limit of adequate
25(OH) D levels should be 30 ng/mL5. Still others recommend a lower
Correspondence: Prof. Pavan Malhotra, Head of Department of
Pharmacology & Therapeutics, Acharya Shri Chander College of Medical
Sciences, Sidhra, Jammu, Jammu and Kashmir. 180 004, India
e-mail: pavanmalhotra@yahoo.com
limit of 40 ng/ml, since impaired calcium metabolism due to low serum
25(OH)D levels may trigger secondary hyperparathyroidism, increased
bone turnover and progressive bone loss11,12.
The proposed 25(OH) D cut-off for optimum skeletal health is the level
that reduces Parathyroid hormone (PTH) to a minimum and increases
calcium absorption to its maximum9,13. A level of < 20 ng/mL is associated
with suppressible levels of parathyroid hormone when challenged with
pharmacologic dosages of vitamin D. Several studies have shown that
PTH levels plateau at a minimum steady-state level as serum 25[OH]D
levels approach and rise above approximately 30 ng/mL (75 nmol/L)9,13,14.
The established consensus of several vitamin D cut-offs (Table 1). It is
noteworthy, however, that there is a continued debate and exchange of
knowledge with respect to the optimum cut-off for 25(OH)D.
Table 1: Diagnostic Cut-Offs of levels of serum 25[OH]D.
Dietary sources of vitamin D are limited to fattyfish (wild or farm salmon,
mackerel, tuna fish, sardines and cod liver oil) and products fortified
with vitamin D,which include dairy products, cereals, margarine, flour,
and orange juice.
The amount of UVB radiation required for vitamin D sufficiency can be
calculated from the amount of vitamin D produced from one minimal
erythemal dose (MED), or 10,00025,000 IU of oral vitamin D15.The
MED can be defined as the amount of time needed to cause skin to turn
pink. The length of time varies with geographical location, skin
pigmentation, percent of body fat, and age. Excessive exposure to sunlight
will not cause vitamin D intoxication because sunlight degrades any
excess vitamin D16.
The highest recorded individual serum 25[OH]D concentration obtained
from sunshine was from a farmer in Puerto Rico with a level of 225
nmol/L17. On the other hand, the highest recorded individual 25[OH]D
achieved from artificial ultraviolet light treatment sessions was 275 nmol/
l18.Vitamin D toxicity probably begins to occur after chronic consumption
of approximately 40,000 IU/day (100 of the 400 IU capsules)19.
VITAMIN D TOXICITY
Supplementation and food fortification
Vitamin D as a fat-soluble vitamin raised concerns about toxicity from
excessive supplementation. Wide-spread vitamin D fortification of foods
and drinks from the 1930s to 1950s in the United States and Europe led
to reported cases of toxicity20.
Iatrogenic
Iatrogenic vitamin D toxicity due to empirical administration of very
high doses of intramuscular vitamin D injections at frequent intervals is
JIMSA Oct. - Dec. 2014 Vol. 27 No. 4
not uncommon, especially in elderly21. It is increasingly being recognized
as one of the most common causes of hypervitaminosis D and
hypercalcemia.
Other causes
Endocrine disorders like primary hyperparathyroidism, MEN I & II
syndrome, malignancies such as hodgkins lymphoma and non hodgkins
lymphoma, granulomatous diseases like sarcoidosis and tuberculosis have
also been associated with hypervitaminosis D.
Hypercalcemia is responsible for producing most of the symptoms of
vitamin D toxicity. Early symptoms of vitamin D toxicity include
gastrointestinal disorders like anorexia, diarrhea, constipation, nausea,
and vomiting. Bone pain, drowsiness, continuous headaches, irregular
heartbeat, loss of appetite, muscle and joint pain are other symptoms
that are likely to appear within a few days or weeks; frequent urination,
especially at night, excessive thirst, weakness, nervousness and itching;
kidney stones22.
MECHANISM OF VITAMIN D TOXICITY
It involves increased concentration of vitamin D metabolites reaching
the VDR in the nucleus of target cells and causing exaggerated gene
expressions. To explain this, the three hypothesis are as follows23:
I. Whenever there are increased levels of plasma 1,25[OH]D, it leads to
increased intracellular concentration of the same. This hypothesis is
not well supported as only Mewar et al. who reported elevated 1,25[OH]
D with Vit D toxicity, and many other studies revealed that vitamin D
toxicity is associated with normal or marginally elevated 1,25[OH]D24.
II. Normal physiology is 1,25[OH] D has low affinity for the transport
protein DBP and high affinity for VDR making it an important ligand
with access to the transcriptional signal transduction machinery. In
hypervitaminosis D various vitamin D metabolites increase,
compromising the capacity of the DBP and allows other metabolites to
enter the cell nucleus. Among these inactive metabolites 25[OH] D has
the strongest affinity for the VDR, so at high concentrations it stimulates
transcription.
III. Vitamin D intake raises the concentration of many vitamin D metabolites
especially vitamin D itself and 25[OH] D. In hypervitaminosis D, vitamin
D metabolites such as vitamin D3, 25[OH]D3, 24,25[OH]2D3, 25,26
[OH]2D3 and 25[OH]D3-26,23-lactone increase significantly. These
concentrations exceed the DBP binding capacity and cause release of
free 1-alpha 25[OH]2D3, which enters target cells.
The various studies and reports of vitamin D intoxication indicate that
plasma 25[OH]D3 is a good biomarker for toxicity.
CLINICAL FEATURES OF HYPERVITAMINOSIS D
Clinical features of hypervitaminosis D are varied and mostly due to
hypercalcemia. A patient may present with fatigue and weight loss25,
recurrent vomiting,abdominal pain, polydipsia, anorexia, constipation26.
Hypervitaminosis D may present with one or more of the following
symptoms and signs in variable combinations4. (Table 2).
Table 2: Systemic symptomatology of hypervitaminosis D
DIAGNOSIS OF SYMPTOMATIC
HYPERVITAMINOSIS D
1. Clinical features of hypercalcemia
2. Elevated serum and urine level of calcium
3. Reduced serum level of parathormone (intact)
237
4. Serum 25(OH)D3level > 100ng/ml
MANAGEMENT OF HYPERVITAMINOSIS D
1. Hypercalcemia is usually controlled by restriction of dietary calcium
intake and appropriate attention to hydration27.Volume depletion results
from uncontrolled symptoms leading to decreased intake and enhanced
renal sodium loss. This tends to exacerbate or perpetuate the
hypercalcemia by increasing Na+ reabsorption in the thick ascending
limb of the loop of Henle (TALH). Thus, appropriate volume repletion
with isotonic sodium chloride solution is an effective short-term treatment
for hypercalcemia. Once volume is restored, simultaneous administration
of loop diuretics blocks Na+ and calcium reabsorption in the TALH.
Replacing ongoing sodium, potassium, chloride, and magnesium losses
is important if prolonged sodium chloride and loop diuretic therapy is
contemplated4.
2. Discontinuation of vitamin D, usually leads to resolution of
hypercalcemia.Reduction of dietary calcium and vitamin D intake is
effective for treating hypercalcemia due to increased intestinal calcium
absorption4.
3. Vitamin D stores in fat may be substantial, and vitamin D intoxication
may persist for weeks after Vitamin D ingestion is terminated. Such
patients are responsive to glucocorticoids, which in doses of 100mg/d
hydrocortisone or its equivalent usually return serum calcium levels to
normal over several days27.Prednisone may help reduce plasma calcium
levels by reducing intestinal calcium absorption4.
4. Hypercalcemia of vitamin D intoxication results from increased intestinal
absorption of calcium and from the direct effect of 1.25[OH]2D3 to
increase resorption of bone in severe cases. Therefore bisphosphonate
therapy can be usefully added to the regime28.
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