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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-dehydroxycholecalciferol, 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. Cholecalciferol is then converted to 25-hydroxycholecalciferol in the liver by vitamin D 25-hydroxylase. Vitamin D 25-hydroxylase is a member of the cytochrome P450 superfamily of enzymes.

The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids. Found in the liver, this enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into 25-hydroxyvitamin D (calcidiol), which is the major circulatory form of the vitamin. It should be noted that this process has a negative feedback mechanism that regulates the levels of 25-hydroxycholecalciferol in plasma.

Sources Vitamin D

Image by Lecturio

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-hydroxylase. This is the most active form of vitamin D. This process also requires the parathyroid hormone. Without this hormone, 1,25 dihydroxycholecalciferol will not be formed. Calcium levels above 10 mg/100 mL suppress the secretion of parathyroid hormone. Below this level, the parathyroid hormone helps in the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. However, levels of calcium above this suppress parathyroid hormone production and hinder the 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, License: CC BY 3.0

The active form of vitamin D has various effects on different systems including the renal, skeletal, and gastrointestinal systems, and regulates the absorption and excretion of calcium and phosphate.

Gastrointestinal tract

Calcium is absorbed in the small intestine by 2 general mechanisms: a transcellular active transport process located largely in the duodenum and upper jejunum, and a paracellular, passive process mediated by facilitated diffusion that functions throughout the length of the intestine.

The transcellular process involves 3 major steps: entry across the brush border through a molecular structure termed CaT1; intracellular diffusion, mediated largely by the cytosolic calcium-binding protein (calbindin D or CaBP); and extrusion, mediated largely by CaATPase. Chyme travels down the intestinal lumen in approx. 3 h, spending only minutes in the duodenum, but over 2 h in the distal half of the small intestine.

When calcium intake is low, transcellular calcium transport accounts for a substantial fraction of the absorbed calcium. When calcium intake is high, transcellular active transport accounts for only a minor portion of the absorbed calcium, because of the short transit time and because CaT1 and CaBP, which are both rate-limiting, are downregulated when calcium intake is high. Biosynthesis of CaBP is fully vitamin D-dependent, while the CaT1 function is approx. 90% vitamin D-dependent. Phosphate absorption in the intestines is also enhanced by vitamin D.

Kidney

In the kidneys, vitamin D promotes the 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 calcium absorption but phosphate excretion. The effects of the hormone on bone in the development of diseases such as rickets are discussed later.

Bones

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

Function Calcium

Image: Vitamin D – Roles for calcium. By Lecturio

Differential Analysis of Vitamin D Dysfunction and Deficiency

The differential diagnosis includes:

Dietary lack of vitamin D

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

Vitamin D Calcium Diet

Image: Vitamin D and calcium absorption from the diet. By Lecturio

Lack of exposure to sunlight

It is also plausible that geographical locations away from the equator and excessive exposure to winter (given that exposure to sunlight is decreased considerably) predisposes to vitamin D deficiency. The elderly also have a reduction in the synthesis of vitamin D in the skin and other problems such as achlorhydria that decrease the absorption of vitamin D.

Drug-induced

  • In women treated for osteoporosis and in those receiving drugs like bisphosphonates (such as raloxifene) and calcitonin, there is a risk of vitamin D deficiency
  • Enzyme inducers such as phenobarbital and phenytoin basically increase the metabolism of vitamin D.

Malabsorptive states

Vitamin D is a fat-soluble vitamin is affected by malabsorptive states, which also results in the disruption of enterohepatic circulation. Malabsorptive states include:

  • Cystic fibrosis
  • Bariatric surgery and gastrectomy are some other conditions that predispose to 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.

Chronic renal disease

The activation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) occurs in the kidney. This is important for the function of vitamin D. Thus, chronic renal failure negatively impacts this activation process.

Nephrotic syndrome

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

Advanced end-stage liver disease

Extensive skin burn, which prevents the synthesis of vitamin D

Nonspecific musculoskeletal pain. Patients with this disorder have vitamin D deficiency

Increase and decrease of vitamin D:

 Vitamin D deficiency Vitamin D end-organ resistance
 Vitamin DPlasma   ↓   ↑
 Plasma Ca2+   ↓   ↓
 Urine Ca2+   ↑   ↑
 Plasma PO42-   ↓   ↓
 Urine PO42-   ↑   ↑

Disorders Related to Vitamin D Deficiency

Rickets and osteomalacia

Rickets and osteomalacia have been explained in great detail in a separate article and readers are encouraged to review that article to enhance their 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 rickets.

Interpretation of Serum Calcium and Phosphate

The normal range of calcium is 8.8–10.3 mg/dL (2.2–4.6 mmol/L). Calcium is present in 3 forms in the body. Either it is bound to organic and inorganic anions like citrate (occurrence 15%), bound to albumin (occurrence 40%), or exists in the free active ionized form.

Although total calcium consists of both the bound and free forms, in diseases such as hypoalbuminemia, there is a disproportionate decline of bound calcium. It should also be noted that for the establishment of diagnosis, the concomitant measurement of parathyroid hormone levels and vitamin D is recommended.

In acute respiratory alkalosis, the increased binding of calcium to albumin (due to changes in the extracellular pH) causes a decrease in ionized calcium levels.

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

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

Simplified Calcium/Phosphate Interpretation:

 Serum calcium Serum phosphate
 Low vitamin D action  ↓  ↓ unless renal failure
 High vitamin D action  ↑  ↑
 Low PTH action  ↓  ↑
 High PTH (or PTHrP)  ↑  ↓ unless renal failure

Note: Calcium and phosphate tend to deviate together (both up or both down) in vitamin D derangements, whereas, they deviate in opposite directions in parathyroid disease.

In patients with chronic kidney disease, it is preferable to measure ionized serum calcium. This is because the estimation of ionized serum calcium from total serum calcium is unreliable due to the accompanying acidosis, and also because of the overestimated correction of the amount of calcium bound to serum albumin.

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

In rickets, there is also a decrease in serum calcium and serum phosphate along with an increase in bone-derived alkaline phosphatase. Vitamin D levels vary depending on the type of rickets. In vitamin D-sensitive rickets, there is a decrease in vitamin D levels but in vitamin D-resistant rickets there is a normal level of vitamin D.

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

Hypercalcemia

Hypercalcemia is an increase in calcium level to > 10.5–11 mg/dL. Measurement of serum calcium and phosphorus, along with renal function should be considered. Parathyroid hormone levels should also be measured.

If parathyroid hormone levels are normal, then the diagnosis of familial benign hypercalcemia is suggested. With the elevation of parathyroid hormone, primary hyperparathyroidism or tertiary hyperparathyroidism should be considered. For primary hyperparathyroidism, medical treatment is considered. If the patient is symptomatic and in case of tertiary hyperparathyroidism, surgery is the treatment of choice.

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