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Vitamin D is essential for the proper functioning of the human body. Rich sources of vitamin D are oil derived from fish liver (e.g. cod liver oil) and egg yolk. In Europe, milk is enriched with vitamin D. One microgram of vitamin D is equivalent to 40 IU. Overdosing has toxic consequences. Calcium metabolism is fairly complicated: parathormone (PTH), vitamin D, calcitonin, the calcium-phosphorus product and the major calcium buffer in the skeleton all play a role. For details, see physiology and endocrinology textbooks.
The nomenclature of the various molecules is rather complicated. Not all the names are equally important. Here is an overview and brief summary:
Vitamin D is present in food as a fat-soluble provitamin. Vitamin D is regarded as a sterol, although the B ring of the molecular steroid squeleton is open. A photochemical conversion and two hydroxylations take place in the body before the final form is reached. The absorption of vitamin D is determined by the fat content of the food, by the proper functioning of the pancreas (lipase) and by the presence of sufficient bile. After absorption in the intestine, the provitamin is first transported to the skin, where a photochemical conversion takes place via ultraviolet light. Vitamin D3 is thus formed. This compound can also be produced via UVB radiation from an endogenous precursor, 7-dehydrocholesterol or pre-vitamin D3. [
Sunlight breaks the B ring of the cholesterol structure to form pre-D3. Pre-D3 then undergoes a thermal induced rearrangement to form D3. Continued irradiation of pre-D3 leads to the reversible formation of lumisterol and tachysterol which can revert back to pre-D3 in the dark.] Vitamin D3 is subsequently bound to a carrier protein and transported to the liver, where an initial hydroxylation takes place with the formation of 25-OH-D3. In the kidneys, 25-OH-D3 is further hydroxylated to the metabolically much more active form 1,25-(OH)2-D3 (calcitriol). A similar hydroxylation takes place in the placenta. Extrarenal synthesis of 1,25-(OH)2-D3 may occur in pathological conditions, such as sarcoidosis and other granulomatous disorders. In the blood there is approximately 500 times more 25-OH-D3 present than 1,25-(OH)2-D3. The receptor of 1,25-(OH)2-D3 is located in the cytoplasm of the cell. After binding, the complex migrates to the cell nucleus where (as a transcription factor) it mediates the expression of various genes. The most important functions of vitamin D are to promote normal bone formation by mineralization of the osteoid and to maintain calcium homeostasis (together with parathormone and calcitonin).*
Diet with provitamin and fat à intestine with bile and lipase à skin and sunlight à liver à kidneys à end organ.
Rickets and osteomalacia develop when there is insufficient vitamin D, when its metabolism is disturbed or when the tissues are resistant to its activity (e.g. mutation of the vitamin D receptor). By following the metabolic chain that leads to the active 1,25-(OH)2-D3 the various causes of osteomalacia/rickets can be visualized. For instance, the food may contain too few precursors. If there is insufficient fat in the diet, or there is insufficient bile and the fat is not absorbed (steatorrhoea), a deficiency of fat-soluble vitamins (ADEK) will occur. Prolonged treatment with cholestyramine is a risk factor. Insufficient exposure to sunlight is also an aetiological possibility. Dark-skinned people residing for a long time in the northern hemisphere are a high-risk group. This also applies to protective clothing and people who spend most of their time indoors (elderly people and Islamic women and children are high-risk groups). For instance, rickets/osteomalacia is not uncommon in Indian and Pakistani immigrants in Britain. A lack of direct sunlight and calcium (chelation of calcium by the phytates in their traditional diet and low intake of milk) contributes to the problem. Rarely, the conversion of 25-OH-D3 to 1,25-(OH)2-D3 in the liver may be disturbed by a genetic enzyme defect (type 1, genetic vitamin D-resistant rickets). Some anticonvulsants, such as phenobarbital, induce liver enzymes, resulting in the accelerated breakdown of 25-OH-D3. Phenytoin and phenobarbital moreover have an inhibiting effect on calcium absorption in the intestine. There are several diseases that may be associated with vitamin D deficiency, each of which, however, is rare, such as hypoparathyroidism, genetic diseases such as hereditary hypophosphataemia, or vitamin D-resistant rickets. Rarely, osteomalacia develops as a result of certain tumours.
Metabolic bone disease caused by vitamin D deficiency is known as rickets in children and as osteomalacia in adults. [NB. Watch out for possible confusion: rickets has nothing to do with rickettsiosis, which is an infectious disease.] These diseases result from common pathogenic factors but differ in their clinical and pathological expression because of the differences between growing and mature bones. In children, the calcification of osteoid in the developing bones is disturbed. The abnormalities are clearest in the areas of most active growth, i.e. the epiphyses. In chronic deficiency there is resorption of trabecular and cortical bone, which is not compensated by mineralisation of osteoid. Adequate treatment with vitamin D causes a rapid reversal of this situation. Normal enchondral bone formation is resumed. In adults, the changes are similar but are not limited to the extremities of the long bones.
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Maternal osteomalacia leads to changes in the bones of the foetus and even to tetany in the newborn (hypocalcaemia). Young infants with vitamin D deficiency are restless and sleep poorly. They have reduced mineralization of the skull (craniotabes). On the thorax, palpable lumps develop at the costochondral junctions: costochondral beading (rachitic rosary). Harrison’s groove, corresponding to the costal insertion of the diaphragm, may be present. In children from 1 to 4 years of age there is an increase in the width of the epiphyseal cartilages at the distal extremities of the tibia, fibula, ulna and radius ("erlenmeyer deformity"). Kyphoscoliosis may develop and walking is delayed. Older children and adolescents experience walking as painful and in extreme cases develop bowlegs or knock-knees.
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Bone changes, visible on X-rays, precede clinical signs, becoming evident in the 3rd or 4th month of life – sometimes even at birth if the mother is severely vitamin D deficient. Bone changes in rickets are most evident at the distal ends of the radius and ulna. The bony ends lose their sharp, clear outline. They are cup-shaped and show a spotty or frayed outline. Later, the distance between the ends of the radius and ulna and the metacarpal bones appears to be increased because the noncalcified ends are invisible on the X-ray. As healing begins, a thin white line of calcification appears at the epiphysis, becoming denser and thicker as calcification proceeds.
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In adults, osteomalacia occurs, particularly in the vertebrae, pelvis and legs. Fine lines appear in the cortex: ribbon-like areas of demineralization, the so-called pseudofractures or Looser's lines. Histologically they consist of focal accumulations of non-calcified osteoid. Preferential localizations for pseudofractures are the lateral edge of the scapula, femur neck, medial femoral shaft, ribs and ramus pubis. Looser’s lines are usually symmetrical, extending perpendicularly to the cortex, are manifestly shorter than the diameter of the bone and display no callus formation. As the bones soften, body weight may cause bowing of the long bones, vertical shortening of the vertebrae and flattening of the pelvic bones, which narrows the pelvic outlet. This may subsequently cause difficulties in childbirth.
The various vitamin D metabolites are measured in plasma. In healthy people, normal levels for 25-OH-D3 are 25 to 40 ng/mL (62 to 100 nmol/L) and 20 to 45 pg/mL (48 to 108 pmol/L) for 1,25-(OH)2-D3. In nutritional rickets and osteomalacia, 25-OH-D3 levels are very low and 1,25-(OH)2-D3 is undetectable. Hypophosphataemia and high serum alkaline phosphatase are characteristic. Calcaemia is low or normal, depending upon the effectiveness of parathormone (secondary hyperparathyroidism) in restoring serum calcium to normal. In hereditary vitamin D-dependent rickets, laboratory findings vary.
A review of the patient’s history may suggest nutritional problems. Rickets must be distinguished from scurvy (cf. scorbutic rosary), congenital syphilis (serologic tests) and from chondrodystrophy (large head, short extremities, thick bones; normal calcaemia, phosphataemia and alkaline phosphatase levels). Osteogenesis imperfecta, cretinism, congenital dislocation of the hip, hydrocephalus and poliomyelitis should be readily distinguishable. Tetany must be distinguished from convulsions due to other causes. Vitamin D-resistant rickets may be caused by severe renal damage, as in chronic renal tubular acidosis (e.g. Fanconi's syndrome or X-linked hypophosphataemia). Osteomalacia must be distinguished from other causes of bone decalcification, such as hyperparathyroidism, senile or postmenopausal osteoporosis, osteoporosis of hyperthyroidism, steroid use, Cushing's syndrome and atrophy of disuse. X-ray findings, hypocalcaemia, high alkaline phosphatase levels and serum vitamin D levels confirm the diagnosis.
Vitamin D is used to treat rickets, osteomalacia and renal osteodystrophy. The latter is a bone disease that occurs in chronic renal failure and is characterized by a combination of osteomalacia, osteoporosis and secondary hyperparathyroidism. In the treatment of rickets/osteomalacia it is recommended that the calcaemia be monitored since vitamin D supplements are very potent and can easily induce hypercalcaemia. With adequate calcium and phosphorus intake, and when the disease is caused by dietary deficiency or insufficient exposure to sunlight, treatment usually consists of vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol), in addition to dietary advice and light therapy. Rickets and osteomalacia can be treated with vitamin D 0.02-0.1 mg (800-4000 IU)/day for 6 weeks. Serum 25(OH)-D3 and 1,25(OH)2-D3 (calcitriol) levels begin to rise within 48 hours. Phosphataemia rises in about 10 days. After 6 weeks the dose can be reduced to a maintenance level of 10 µg (400 IU)/day. If tetany is present, vitamin D should be supplemented with calcium salts during the first week. Some cases require massive doses. In patients with renal failure the above-mentioned products are not active and alphacalcidol (1-alpha-hydroxyvitamin D3) should be used in preference. This product is converted in the liver into calcitriol, thus eliminating the need for renal metabolization. In patients with massive steatorrhoea, large doses must be used, e.g. 50,000 to 100,000 IU/day PO or 10,000 IU/day IM, together with adequate calcium and sunlight.
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Treatment summary:
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If dietary deficiency |
Calcium tablets with vitamin D (500 IU), 1 to 2 tablets/day |
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If malabsorption |
Parenteral calciferol, 7.5 mg/month |
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If vitamin D-resistance |
Trial therapy with calciferol, 10,000 IU/day PO |
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If renal osteomalacia |
Alfacalcidol, 1 µg/day PO and calcaemia monitoring |
Disease prevention is based upon health education and efforts must be made to ensure that the communities in question really understand and act on the information provided. Human breast milk is deficient in vitamin D (1.0 µg/L = 40 IU/L), whereas fortified cow’s milk contains ten times as much. Breastfed infants should therefore be given a supplement of vitamin D (300 IU)/day) from birth to 6 months, at which time they are given a more diversified diet. In the Far East, a single IM dose of 2.5 mg (100,000 IU) ergocalciferol is sometimes given to adolescents, which offers protection for several months.
When accidental or intentional high doses of vitamin D are taken, the clinical picture is dominated by hypercalcaemia. The rate at which the symptoms develop depends upon the dose and duration of excess vitamin D intake. The first symptoms are anorexia, nausea, vomiting, polyuria, polydipsia and pruritus. Polyuria is secondary to a massive increase of urinary calcium excretion. Complications consist of metastatic calcifications (nephrocalcinosis!) and renal failure.
Patients sometimes complain of eye irritation. Physical examination may reveal a bandlike grey-white opacity across the corneal surface: band keratopathy. Treatment consists of stopping further administration of vitamin D and giving corticosteroids. Urinary acidification is recommended. Diuretics serve no useful purpose. Bisphosphonates such as pamidronate (an osteoclast inhibitor) may be used in extreme cases.
