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vitamin D

Monday 23 March 2009

Humans have two possible sources of vitamin D: endogenous synthesis in the skin and diet. There are large amounts of the precursor 7-dehydrocholesterol in the skin; ultraviolet light in sunlight converts it to vitamin D3.

Depending on the skin’s level of melanin pigmentation, which absorbs ultraviolet light, and the amount of exposure to sunlight, about 80% of the vitamin D needed can be endogenously derived. The remainder must be obtained from dietary sources such as deep-sea fish, plants, and grains.

In plant sources, vitamin D is present in its precursor form (ergosterol), which is converted to vitamin D2 in the body. In many countries, various foods are fortified with vitamin D2. Since D3 and D2 undergo identical metabolic transformations and have identical functions, both are hereafter referred to as vitamin D.

The metabolism of vitamin D can be outlined as follows:
- Absorption of vitamin D in the gut or synthesis from precursors in the skin
- Binding to a plasma α1-globulin (D-binding protein) and transport to liver
- Conversion to 25-hydroxyvitamin D, 25(OH)D by 25-hydroxylase in the liver
- Conversion of 25(OH)D to 1,25(OH)2D by α1-hydroxylase in the kidney; biologically this is the most active form of vitamin D.

The production of 1,25(OH)2D by the kidney is regulated by three mechanisms:
- In a feedback loop, increased levels of 1,25(OH)2D down-regulate synthesis of this metabolite by inhibiting the action of α1-hydroxylase, and decreased levels have the opposite effect.
- Hypocalcemia stimulates secretion of parathyroid hormone (PTH), which in turn augments the conversion of 25(OH)D to 1,25(OH)2D by activating α1-hydroxylase.
- Hypophosphatemia directly activates α1-hydroxylase and thus increases formation of 1,25(OH)2D.

Functions of Vitamin D

1,25(OH)2D, the biologically active form of vitamin D, is best regarded as a steroid hormone. Like other steroid hormones, it acts by binding to a high-affinity receptor that is widely distributed.

However, the essential function of vitamin D-the maintenance of normal plasma levels of calcium and phosphorus-involves actions on the intestines, bones, and kidneys.

The active form of vitamin D has several important actions:
- Stimulates intestinal absorption of calcium and phosphorus
- Collaborates with PTH in the mobilization of calcium from bone
- Stimulates the PTH-dependent reabsorption of calcium in the distal renal tubules.

How 1,25(OH)2D stimulates intestinal absorption of calcium and phosphorus is still somewhat unclear. The weight of evidence favors the view that it binds to epithelial receptors, activating the synthesis of calcium transport proteins. The increased absorption of phosphorus is independent of the effects on calcium transport.

The effects of vitamin D on bone depend on the plasma levels of calcium. On the one hand, with hypocalcemia, 1,25(OH)2D collaborates with PTH in the resorption of calcium and phosphorus from bone to support blood levels. On the other hand, vitamin D is required for normal mineralization of epiphyseal cartilage and osteoid matrix. It is still not clear how the resorptive function is mediated, but direct activation of osteoclasts is ruled out. It is more likely that vitamin D favors differentiation of osteoclasts from their precursors (monocytes).

The precise details of mineralization of bone when vitamin D levels are adequate are also uncertain. It is widely believed that the main function of vitamin D is to maintain calcium and phosphorus at supersaturated levels in the plasma. However, vitamin D-mediated increases in the synthesis of the calcium-binding proteins osteocalcin and osteonectin in the osteoid matrix may also play a role.

Equally unclear is the role of vitamin D in renal reabsorption of calcium. PTH is clearly necessary, but it is believed that vitamin D is also. There is no convincing evidence that vitamin D participates in renal reabsorption of phosphorus.

Deficiency States

Rickets in growing children and osteomalacia in adults are worldwide skeletal diseases; but in developed countries, they rarely occur as a result of dietary deficiencies. Recent studies suggest, however, that deficiency of vitamin D is far more common than was suspected earlier. It is especially prevalent in the elderly because of inadequate sun exposure and inadequate intake. Even healthy young adults living in northern climates develop vitamin D deficiencies in winter.73 Both rickets and osteomalacia may result from deranged vitamin D absorption or metabolism or, less commonly, from disorders that affect the function of vitamin D or disturb calcium or phosphorus homeostasis.

Whatever the basis, a deficiency of vitamin D tends to cause hypocalcemia. When hypocalcemia occurs, PTH production is increased, which :
- (1) activates renal α1-hydroxylase, thus increasing the amount of active vitamin D and calcium absorption;
- (2) mobilizes calcium from bone;
- (3) decreases renal calcium excretion;
- (4) increases renal excretion of phosphate.

Thus, the serum level of calcium is restored to nearly normal, but hypophosphatemia persists, and so mineralization of bone is impaired.

An understanding of the morphologic changes in rickets and osteomalacia is facilitated by a brief summary of normal bone development and maintenance.

The development of flat bones in the skeleton involves intramembranous ossification, while the formation of long tubular bones reflects endochondral ossification. With intramembranous bone formation, mesenchymal cells differentiate directly into osteoblasts, which synthesize the collagenous osteoid matrix on which calcium is deposited.

In contrast, with endochondral ossification, growing cartilage at the epiphyseal plates is provisionally mineralized and then progressively resorbed and replaced by osteoid matrix, which undergoes mineralization to create bone.


The basic derangement in both rickets and osteomalacia is an excess of unmineralized matrix. The changes that occur in the growing bones of children with rickets, however, are complicated by inadequate provisional calcification of epiphyseal cartilage deranging endochondral bone growth.

The following sequence ensues in rickets:
- Overgrowth of epiphyseal cartilage due to inadequate provisional calcification and failure of the cartilage cells to mature and disintegrate
- Persistence of distorted, irregular masses of cartilage, many of which project into the marrow cavity
- Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants
- Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction
- Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone because of microfractures and stresses on the inadequately mineralized, weak, poorly formed bone
- Deformation of the skeleton due to the loss of structural rigidity of the developing bones.

The conformation of the gross skeletal changes depends on the severity of the rachitic process, its duration, and in particular the stresses to which individual bones are subjected. During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses.

The softened occipital bones may become flattened, and the parietal bones can be buckled inward by pressure; with the release of the pressure, elastic recoil snaps the bones back into their original positions (craniotabes). An excess of osteoid produces frontal bossing and a squared appearance to the head. Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the "rachitic rosary."

The weakened metaphyseal areas of the ribs are subject to the pull of the respiratory muscles and thus bend inward, creating anterior protrusion of the sternum (pigeon breast deformity). The inward pull at the margin of the diaphragm creates Harrison’s groove, girdling the thoracic cavity at the lower margin of the rib cage. The pelvis may become deformed. When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and long bones (e.g., tibia), causing, most notably, lumbar lordosis and bowing of the legs.

In adults, the lack of vitamin D deranges the normal bone remodeling that occurs throughout life. The newly formed osteoid matrix laid down by osteoblasts is inadequately mineralized, thus producing the excess of persistent osteoid characteristic of osteomalacia. Although the contours of the bone are not affected, the bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks.

On histologic examination, the unmineralized osteoid can be visualized as a thickened layer of matrix (which stains pink in hematoxylin and eosin preparations) arranged about the more basophilic, normally mineralized trabeculae.

Persistent failure of mineralization in adults leads eventually to loss of skeletal mass, referred to as osteopenia. It is then difficult to differentiate osteomalacia from other osteopenias such as osteoporosis.

Osteoporosis, unlike osteomalacia, results from reduced production of osteoid, the protein matrix of the bone. Studies suggest that vitamin D may also be essential for preventing demineralization of bones. In certain familial forms of osteoporosis, the defect has been localized to the vitamin D receptor. It appears that certain genetically determined variants of the vitamin D receptor are associated with an accelerated loss of bone minerals with aging.