Calcium Vitamin D
Mrs BK, a 55-year-old lady of Bangladeshi origin, presented to her GP complaining of various non-specific symptoms including generalized aches and pains and muscle weakness when walking, particularly going upstairs. Investigations showed her to have a serum calcium level of 2.02 mmol/L in association with a raised alkaline phosphatase of 358 U/L and an elevated PTH concentration. Serum vitamin D concentrations were measured and found to be below the seasonal normal range. Her symptoms resolved with calcium and vitamin D supplementation.
Vitamin D deficiency is common, particularly in patients of Asian background and the elderly living alone on poor diets. In northern European populations there is a marked seasonal variation in normal serum concentrations related to varying day-light lengths. Low vitamin D levels cause hypocalcaemia, compensated for by the development of secondary hyperparathyroidism which maintains the serum calcium at low normal or mildly suppressed levels. Untreated, vitamin D deficiency can lead to the development of rickets in children or osteomalacia in adults (Fig. 51a), both associated with characteristic bone abnormalities. Recently an increase in vitamin D deficiency has been noted in children from more affluent European backgrounds with limited sun exposure due to overzealous sun protection.
Vitamins are not generally considered to be hormones, but organic dietary factors essential for healthy life. The term ‘vitamin’ is perhaps a misnomer therefore for the substances called vitamin D. The term ‘vitamin D’ refers to two steroid-like chemicals, namely ergocalciferol and cholecalciferol. Osteomalacia is the softening of bones in adults who suffer from a deficiency of vitamin D in the diet, or of sunlight, or both.
Synthesis of vitamin D
The active form of vitamin D is 1-alpha, 25-dihydroxyvitamin D3 (1,25-(OH)2-D3). Ultraviolet irradiation in sunlight photoisomerizes a cholesterol precursor, 7-dehydrocholesterol, which converts it to previtamin D, which then undergoes a thermal isomerization to cholecalciferol (vitamin D3; Fig. 51b). Cholecalciferol binds in the dermis to a binding protein, which transports it in the plasma, and it is converted in the liver to 25-hydroxyvitamin D3 (25-OH-D3). This metabolite circulates, and in the kidney it is converted into the active metabolite 1,25-(OH)2-D3.
Regulation of metabolism
The regulation of vitamin D3 metabolism is linked to parathyroid hormone (PTH; Fig. 51c). PTH secretion from the parathyroid glands is stimulated by hypocalcaemia. PTH stimulates the kidney cortex mitochondrial enzyme 1-alpha-hydroxylase, which is also stimulated by low concentrations of phosphate. The 1,25-(OH)2-D3 thus formed enters the circulation and promotes calcium resorption from bone. Calcium absorption from
the gastrointestinal tract (GIT) stimulates the reabsorption of calcium from the kidney and the excretion of phosphate. The hypercalcaemia created inhibits further production of PTH, which in turn limits the synthesis of 1,25-(OH)2-D3. The active metabolite is inactivated by conversion to 24,25-(OH)2-D3. 1,25-(OH)2-D3 may also feed back to the parathyroid glands to inhibit the release of PTH. The glands do possess receptors for 1,25-(OH)2-D3.
Mechanism of action
The 1,25-(OH)2-D3 receptor belongs to a superfamily of nuclear hormone receptors, which bind to their ligand and alter transcription (see Chapter 4). The hormone travels in the bloodstream in equilibrium between bound and free forms. The latter form is freely able to enter cells, due to its lipophilic nature. The plasma 1,25-(OH)2-D3-binding protein (DBP) recognizes the hormone specifically. 1,25-(OH)2-D3 binds to the nuclear receptor; the complex binds to specific hormone response elements on the target gene upstream of transcriptional activation sites, and new mRNA and protein synthesis result (Fig. 51d). New proteins synthesized include osteocalcin, an important bone protein whose synthesis is suppressed by glucocorticoids. In the GIT, a calcium-binding transport protein (CaBP) is synthesized in response to the hormone receptor activation of the genome.
Physiological actions of vitamin D Bone. Vitamin D stimulates resorption of calcium from bone as part of its function to maintain adequate circulating concen- trations of the ion (Fig. 51e). It also stimulates osteocalcin synthesis.
Gastrointestinal tract. 1,25-(OH)2-D3 stimulates calcium and phosphate absorption from the gut through an active transport process. The hormone promotes the synthesis of calcium transport by enhancing synthesis of the cytosolic calcium-binding protein CaBP, which transports calcium from the mucosal to the serosal cells of the gut.
Kidney. 1,25-(OH)2-D3 may stimulate reabsorption of calcium into the tubule cells while promoting the excretion of phosphate. The tubule cells do possess receptors for vitamin D and CaBP.
Muscle. Muscle cells have vitamin D receptors, and the hormone may mediate muscle contraction through effects on the calcium fluxes, and on consequent adenosine triphosphate (ATP) synthesis.
Pregnancy. During pregnancy, there is increased calcium absorption from the GIT, and elevated circulating concentrations of 1,25-(OH)2-D3, DBP, calcitonin and PTH. During the last 6 months prior to birth, calcium and phosphorus accumulate in the fetus. The placenta synthesizes 1,25-(OH)2-D3, as does the fetal kidney and bone. Nevertheless, the fetus still requires maternal vitamin D.
Other roles. Vitamin D may be involved in the maturation and proliferation of cells of the immune system, for example of the haematopoietic stem cells, and in the function of mature B and T cells.