Vitamin D is a fat-soluble substance vitamin. This vitamin is essential for proper function of the human body and is considered a hormone rather than a vitamin. Its synthesis takes place in the body – under ideal conditions, it may not be required in our diet. In bone tissue, where vitamin D is required the most, it is needed for deposition of calcium in bone and its lack usually leads to various pathologies including rickets in children and osteomalacia in adults. To understand the pathology of these diseases, we must first learn how this vitamin is produced and the effects it has on various systems in the human body.

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the sun

Image: “The sun.” by Lykaestria at the English language Wikipedia. License: CC BY-SA 3.0


Production and Effects of Vitamin D

Source of vitamin D

7-Dehydrocholecalciferol, a substance normally found in skin, is broken down by UV radiation from the sun to form cholecalciferol (vitamin D3). Cholecalciferol can also be ingested in various food compounds such as egg yolk, cod liver oil and beef liver. The cholecalciferol is then converted to 25-hyroxycholecalciferol in the liver. It should be noted that this process has a negative feedback mechanism that regulates the levels of 25-hydroxycholecalciferol in plasma.

Activation of vitamin D

25-hydroxycholecalciferol moves to the proximal tubules of the kidney where it is hydroxylated to 1,25 dihydroxycholecalciferol by the action of α1-hyroxylase. This is the most active form of vitamin D. It is to be noted that this process also requires parathyroid hormone. Without this hormone, 1,25 dihydroxycholecalciferol will not be formed. It is thus of paramount importance that this hormone is present.

Calcium levels above 10mg/100ml suppress the secretion of parathyroid hormone. Below this level, parathyroid hormone helps in the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. But levels of calcium above this suppress parathyroid hormone production and hinder production of 1,25-dihydrocholecalciferol. Instead, another compound with no vitamin D effect, known as 24,25 dihydrocholecalciferol is formed. High levels of plasma calcium thus impair the formation of 1,25- dihydroxycholecalciferol.

Function of vitamin D

synthesis of vitamin d in the human body

Image: “Synthesis of vitamin D in the human body.” by OpenStax College – Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. License: CC BY 3.0

The active form of vitamin D has various effects on different systems including the renal system, skeletal system and the gastro–intestinal system and regulates absorption as well as excretion of calcium and phosphate.

Gastrointestinal tract

In the intestines, vitamin D promotes intestinal absorption of calcium by formation of a calcium binding protein in intestinal epithelia. This protein acts on the brush border and transports calcium across the cell to the basolateral membrane of the cells by facilitated diffusion. This proteins remain in these cells days up to weeks after the 1,25-dihydroxycholecalciferol has been broken down and eliminated. Phosphate absorption in the intestines is also enhanced by vitamin D.

Kidney

In the kidneys it promotes absorption of both calcium and phosphate by the epithelial cells of the renal tubules. This is unlike the effects of parathyroid hormone on the kidney which promotes absorption of calcium but promotes phosphate excretion. We shall later see the effects of the hormone on bone in developing diseases such as rickets.

Bones

In bone, vitamin D in high quantities causes resorption of bone. Without it, the effect of parathyroid hormone on bone resorption is significantly reduced. Thus it helps in the cumulative effect of the parathyroid hormone. In small amounts, it enhances bone mineralization. Thus, in small quantities it enhances the deposition of calcium and phosphate on the bone.

Differential Analysis of Vitamin D Dysfunction and Deficiency

The differential diagnosis involves:

  1. Dietary lack of the vitamin D

This is especially important in the setting of developing countries, where the fortified source of vitamin D in the food is unavailable for consumption.

  1. Lack of the exposure to sunlight

It is also plausible that the geographical location of the place away from the equator and with excessive exposure to winter (given that the exposure to sunlight decreases to a considerable extent) predisposes to the development of deficiency of vitamin D. Concurrently, the elderly have a reduction in the synthesis of vitamin D in the skin and other problems such as achlorhydria which decreases the absorption of vitamin D.

  1. Drug-induced

  • In women who were treated for osteoporosis and on the therapy like bisphosphonates such as raloxifene and calcitonin, there occurs a risk of vitamin D deficiency

  • On any enzyme inducers such as phenobarbital and phenytoin. These drugs basically increase the metabolism of vitamin D.

  1. Malabsorpative states

Vitamin D being a fat soluble vitamin is affected in the malabsorptive states, which also results in the disruption of enterohepatic circulation. Malabsorptive states are for example:

  • Cystic fibrosis
  • The bariatric surgery and gastrectomy are some of the other reason which predisposes to the vitamin D deficiency.
  • Reduction in the absorptive area of the intestine following the removal and resection of the segment of the bowel (small bowel syndrome), celiac sprue.
  1. Chronic renal disease

This is because the activation of 25 hydroxyvitamin D to 1,25 dihydroxyvitamin also known as calcitriol occurs in the kidney. This is important for the function of vitamin D.

  1. Nephrotic syndrome

In patients with nephrotic syndrome, due to the excretion of vitamin D binding proteins (25 hydroxyvitamin D is bounded to this protein in the serum) there occurs decrease in the concentration of 25 hydroxyvitamin d in the serum.

  1. Advanced end stage liver disease

  2. Extensive skin burn,  which prevents the synthesis of the vitamin D

  3. Nonspecific musculoskeletal pain have vitamin D deficiency.

Disorders Related to Vitamin D Deficiency

Rickets and osteomalacia

Rickets and osteomalacia have been explained in great detail in a separate article and the readers are encouraged to have a read at the same to have greater knowledge on the topic. Both the occurrence of vitamin D dependent type 1 rickets and vitamin D resistant rickets have been discussed. Osteomalacia is the adult counterpart of the rickets.

Interpretation of Serum Calcium and Phosphate

The normal range of calcium is 8.8 to 10.3 mg/dl (2.2-4.6 mmol/L). Calcium is present in 3 forms in the body. Either, it may be bound to the organic and inorganic anions like citrate (which constitutes 15 %) or it might be bound to albumin (which constitutes 40 %) or it might exist in the free active ionized form.

Though the total calcium consists of both the bound as well as free form, in diseases such as hypoalbuminemia, there occurs a mismatch decline in the level of the total and free calcium. It should also be noted that for the establishment of the diagnosis, the concomitant measurement of the parathyroid hormone and also of vitamin D is recommended.

Acute Respiratory Alkalosis

In the condition such as acute respiratory alkalosis, the increase in the binding of calcium to that of albumin (due to the change in the extracellular pH) causes a decrease in the ionised calcium level.

Multiple Myeloma

In multiple myeloma, there occurs an increase in the total calcium in the body (due to the binding of calcium to the protein), increase in the free calcium level (due to the activation of the osteolytic activity leading) and elevation of the phosphate level.

Vitamin D

In the deficiency state of vitamin D, the level of calcium may be corrected by the compensatory secretion of parathyroid hormone.

Chronic Kidney Disease

In patients with chronic kidney disease, it is preferred to measure the ionised serum calcium. This is because of the variability in the estimation of the ionised serum calcium from that of the total serum calcium (due to the accompanying acidosis and also the overestimated correction of the calcium for the serum albumin with that of the formula).

Osteomalacia

In case of the osteomalacia, the scenario will be a decrease in the serum vitamin D, decrease in the serum and urinary calcium, decrease in the phosphate level, along with compensatory elevation in the PTH and the elevation in the alkaline phosphatase.

Rickets

Even in the rickets there occurs a decrease in the serum calcium and serum phosphate along with increase in the serum alkaline phosphatase. The vitamin D level varies depending on the type of rickets. In vitamin D sensitive rickets, there occurs decrease in the vitamin D level but in vitamin D resistant rickets there occurs a normal level of the vitamin D hormone.

It should be noted that in hypocalcemia which occurs following vitamin D deficiency, the concomitant increase in the parathyroid hormone level, which occurs as a compensatory mechanism, masks the development of hypocalcemia and at the same time increases the urinary phosphate excretion leading to the development of hypophosphatemia. The circulating 25 hydroxy vitamin D also known as calcidiol is the best index for the sufficiency of vitamin D in the body.

Hypercalcemia

Hypercalcemia is an increase in the calcium level greater than 10.5 to 11 mg/dl. Initially, the serum calcium, phosphorus along with renal function is to be considered. The parathyroid hormone can also be measured. In persons with hypercalcemia, the serum phosphorus should be evaluated.

Then the parathormone is evaluated. If the parathormone is normal, then the diagnosis of familial benign hypercalcemia is considered. With the elevation of the parathormone the primary hyperparathyroidism or tertiary hyperparathyroidism. For the primary hyperparathyroidism, medical treatment is considered and in case of tertiary hyperparathyroidism, surgery is the treatment.

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