Vitamin D metabolism

Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D₂) de­rive from dietary sources (animal and fish liver, eggs, fish oils). Cholecalciferol is also produced in the skin from 7-dehydrocho- lesterol (pre-vitamin D₃), through the nonenzymatic effect of sunlight ultraviolet B rays (UVB, wavelengths 295-305 nm). 7- dehydrocholesterol is mostly stored in the cytoplasm of cells at the dermal-epidermal border and the effectiveness of its con­version to cholecalciferol is related to the amount of photochro- matic energy entering the skin. Photochromatic energy pene­trating the skin greatly depends from the incident angle of UVB rays: in winter, the shallow incident angle of sunlight results in lower energy reaching the epidermis and dermis and, there­fore, in lower production of vitamin D3.

Cholecalciferol, ergocalciferol are hydroxilated at carbon 25 in the liver and at carbon 1 in kidney tubules thanks to enzymatic systems including cytocrome P-450 and located at the inner mitochondrial membrane. PTH and hypophosphatemia en­hance the activity of renal 1 a-hydroxylase, but not that of liver 25-hydroxylase.

The final product, 1,25-dihydroxycholecalciferol (1,25(OH)₂D), is the active metabolite of vitamin D, although its serum con­centrations do not correlate with vitamin D stores. 1,25(OH)₂D promotes active and passive intestinal absorption of calcium and phosphate, and bone mineralization. Conversely, 1,25(OH)₂D suppresses PTH synthesis and parathyroid cell proliferation through a genomic activity. 1,25(OH)₂D₂ and 1,25(OH)₂D₃ have the same potency in activating intestinal cal­cium absorption and bone mineralization, whereas 1,25(OH)₂D₂ is less potent in suppressing parathyroid gland activity (1). Genomic effect of 1,25(OH)₂D is modulated by spe­cific cytosolic receptors for vitamin D (VDR) in target cells. VDR forms a heterodimer with the retinoid X receptor that en­ables the complex 1,25(OH)₂D-VDR to bind with high affinity to the vitamin D response element (VDRE) on the transcription promoters of vitamin D-sensitive genes. VDR has been detect­ed in vitamin D-sensitive tissues (bone, intestine, kidney and parathyroid glands) and even in tissues where vitamin D activi­ty is still unclear (myocardium, brain, pancreas and testis). In addition to the genomic effect, a rapid non-genomic effect of 1,25(OH)₂D was found in intestinal cells. The monohydroxylated metabolite, 25-hydroxycholecalciferol (25(OH)D), is 500 times less active than 1,25(OH)2D, but its serum concentration is the best indicator of vitamin D body stores. In spite of its low affinity for VDR, 25(OH)D maintains some biological effects, because its serum concentrations are 1000 times higher than those of 1,25(OH)₂D and compensate for the low affinity for VDR (2). The physiopathological rele­vance of 25(OH)D has been recently revaluated in population studies showing that low serum concentrations of 25(OH)D were associated with higher serum PTH in healthy elderly indi­viduals (3, 4). In these studies, the serum 25(OH)D concentration above which all values of serum PTH were normal, was 30 ng/ml (75 nmol/L). This threshold for secondary hyperparathy- roidism (HPT) was also confirmed in elderly individuals with el­evated creatinine clearance and in hemodialysis patients. Based on these findings, the normal range of 25(OH)D serum concentrations was recently redefined and concentra­tion above 30 ng/ml (75 nmol/L) are now generally recom­mended to prevent secondary HPT. Lower 25(OH)D serum concentrations were associated with increased risk of fracture and low bone mineral density (BMD) at different bone sites in young and elderly healthy individuals of both sexes. Accordingly, osteopenia and osteoporosis were more fre­quent in patients with 25(OH)D serum concentrations below 30 ng/ml (75 nmol/L) and osteomalacia was found in patients with 25(OH)D concentrations below 10 ng/ml (25 nmol/L). Serum 25(OH)D concentrations of 30 ng/ml (75 nmol/L) or higher were proposed as the target for the treatment of os­teodystrophy, even in hemodialysis patients. Hemodialy­sis patients with lower levels of 25(OH)D had more marked Looser’s zone on X-rays and decreased bone formation at bone histology regardless of 1,25(OH)₂D levels. Howev­er, excessively high 25(OH)D levels were associated with low turnover osteodystrophy. Thus, concentrations between 20 and 40 |jg/ml have been proposed as the most appropriate 25(OH)D target range for hemodialysis patients by other au­thors. The need to maintain normal vitamin D stores sug­gests that unknown vitamin D metabolites, besides 1,25(OH)₂D, may have a beneficial effect on bone and parathyroid metabo­lism in end stage renal disease.

D may have important functions besides mineral ion homeostasis. In patients with congestive heart failure, 1,25(OH)₂D concentrations were found to be significantly re­duced. Recently, it has been demonstrated that vitamin D therapy decreased myocardial hypertrophy in dialysis pa­tients. Moreover, vitamin D replacement downregulates the renin-angiotensin system and controls blood pressure in VDR knock-out mice. Paradoxically, low 1,25(OH)2D lev­els have been correlated with increased coronary calcification in patients at high risk for coronary heart disease. In­deed, many epidemiological studies have documented an as­sociation between vitamin D deficiency and autoimmune dis­eases, several types of cancers, and cardiovascular disease.

Parathyroid cells are characterized by a low turnover and rarely undergo mitoses. However, in the presence of low calcium, high phosphorus, vitamin D deficiency, and ure­mia, parathyroid cells leave quiescence and divide by increas­ing the activity of regulatory cell cycle enzymes and/or their in­hibitors. In secondary HPT, parathyroid gland growth is initially diffuse and polyclonal. Cell proliferation in the nod­ules then becomes monoclonal and aggressive. The rapid de-differentiation of hyperplastic parathyroid cells in culture precludes further assessment of the relative contribution of changes in calcium, phosphate, and vitamin D to the expres­sion of components of the cell cycle critical for growth control.
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