Calcium Vitamin D
Clinical scenario
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.
Vitamin D
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.
