Parathyroid hormone rickets

Vitamin D is really a small family of closely related molecnles that prevent the bone disease rickets in children and osteomalacia in adnlts. In both cases, inadeqnate mineralization of bone results in bone deformation and weakness. Calcinm, Ca +, homeostasis is one goal of vitamin D activity, a goal it shares with parathyroid hormone and calcitonin. Calcium is intimately involved in bone mineralization and distnrbances of calcium levels in the blood can resnlt in inadeqnate bone mineralization or excessive calcification of other tissues. 

Osteomalacia is the condition in which bone becomes demineralised due to deficiency of vitamin D. In this condition parathyroid hormone (PTH) acts on the bone to maintain serum calcium, resulting in demineralisation. Serum calcium is usually normal or slightly low alkaline phosphatase levels are high, reflecting excessive osteoblast activity, and serum phosphate falls as an effect of PTH on the kidney. The same condition in children results in defects in long bone formation, and is termed rickets. 

Vitamin D is obtained in the diet or by photolysis of 7-dehydrocholesterol in skin exposed to sunlight. Calcitriol works in concert with parathyroid hormone in Ca2+ homeostasis, regulating [Ca2+] in the blood and the balance between Ca2+ deposition and Ca2+ mobilization from bone. Acting through nuclear receptors, calcitriol activates the synthesis of an intestinal Ca2+-binding protein essential for uptake of dietary Ca2+. Inadequate dietary vitamin D or defects in the biosynthesis of calcitriol result in serious diseases such as rickets, in which bones are weak and malformed (see Fig. 10-20b). 

Certain human populations depend on dietary sources of vitamin D because of insufficient biosynthesis of the vitamin due to inadequate skin exposure to sunlight. The classic symptoms of vitamin D deficiency are rickets in children and osteomalacia in adults. 25-Hydroxyvitamin D3 is the major circulating metabolite in the blood, but the hormonally active form of the vitamin is 1,25-dihydroxyvitamin D3. The latter metabolite stimulates the intestine to absorb calcium and phosphate by two independent mechanisms and acts with parathyroid hormone to mobilize calcium, accompanied by phosphate, from the bone fluid compartment into the bloodstream. 1,25-dihydroxyvitamin D 3 is also involved in the formation of osteoclasts—giant cells that are solely responsible for the resorption of bone matrix (33). Resorption is an essential process for the development, growth, maintenance, and repair of bone. 

Vitamin D3 is a precursor of the hormone 1,25-dihy-droxyvitamin D3. Vitamin D3 is essential for normal calcium and phosphorus metabolism. It is formed from 7-dehydrocholesterol by ultraviolet photolysis in the skin. Insufficient exposure to sunlight and absence of vitamin D3 in the diet leads to rickets, a condition characterized by weak, malformed bones. Vitamin D3 is inactive, but it is converted into an active compound by two hydroxylation reactions that occur in different organs. The first hydroxylation occurs in the liver, which produces 25-hydroxyvita-min D3, abbreviated 25(OH)D3 the second hydroxylation occurs in the kidney and gives rise to the active product 1,25-dihydroxy vitamin D3 24,25 (OH)2D3 (fig. 24.13). The hydroxylation at position 1 that occurs in the kidney is stimulated by parathyroid hormone (PTH), which is secreted from the parathyroid gland in response to low circulating levels of calcium. In the presence of adequate calcium, 25(OH)D3 is converted into an inactive metabolite, 24,25 (OH)2D3. The active derivative of vitamin D3 is considered a hormone because it is transported from the kidneys to target cells, where it binds to nuclear receptors that are analogous to those of typical steroid hormones. l,25(OH)2D3 stimulates calcium transport by intestinal cells and increases calcium uptake by osteoblasts (precursors of bone cells). 

The plasma concentration of calcidiol is the most sensitive and usefiil index of vitamin D status, and is correlated with elevated plasma parathyroid hormone and alkaline phosphatase activity (Table 3.4). As shown in Table 3.2, the reference range of plasma calcidiol is between 20 to 150 nmol per L, with a twofold seasonal variation in temperate regions. Concentrations below 20 nmol per L are considered to indicate impending deficiency, and osteomalacia is seen in adults when plasma calcidiol falls below 10 nmol per L. In children, clinical signs of rickets are seen when plasma calcidiol faUs below 20 nmol per L. The plasma concentration of calcitriol does not give a useful indication of vitamin D status. The reference range is between 38 to 144 pmol per L and is maintained because of the stimulation of calcidiol 1-hydroxylation by parathyroid hormone secreted in response to faUing concentrations of calcium (Holick, 1990). 

Rickets, which is diagnosed by X-rays of leg bones, heals promptly with 4000 lU of oral vitamin D per day, with treatment for a month. In performing this treatment, the physician needs to monitor plasma 25 hydroxyvitamm D to make certain that they are raised to the normai range. The bone abnormalities (visible by X-ray) disappear gradually over the course of 3-9 months. Parents are instructed to take their infants outdoors for about 20 minutes per day with their faces exposed in order to prevent deficiency. Osteomalacia is treated by eating 2500 ID/day for about three months. Measurements of 25-hydroxyvitamin D, calcium, and parathyroid hormone are also part of the treatment process. 

Metabolic bone disease is a complication usually reported in adults and children receiving long-term home PN. This disorder in adults is characterized by osteomalacia with or without osteoporosis that may present without associated chnical, radiologic, or biochemical abnormalities. The diagnosis may not be made in premature infants until after the development of bone fractures or overt rickets. The etiology is poorly understood and likely multifactorial. Treatment options include pharmacologic intervention, calcimn and vitamin D supplementation, and exercise. Others have recommended removal of vitamin D from the PN in patients with low serum parathyroid hormone and 1,25-hydroxyvitamin D concentrations. ... 

C. The major action of vitamin D is to increase absorption of calcium from the small intestine. Deficiency of the vitamin leads to low blood calcium levels, stimulation of parathyroid hormone secretion, and acting synergistically, promotion of bone demineralization. Renal excretion of calcium is decreased by hypocalcemia but elevated parathyroid hormone levels promote renal excretion of phosphate, to prevent excessive accumulation of this product of bone demineralization. Although lack of exercise decreases bone density, it does not lead to rickets if vitamin D is sufficient. 

Vitamin D contributes to the calcemic action of the parathyroid hormone (C2, N14). Deficiency of vitamin D therefore results in a fall in ionic calcium concentration which stimulates the parathyroids. Parathyroid hypertrophy is seen in vitamin D-deficient animals (C3, H7, S7) and man (PI) and can be prevented by exposure to ultraviolet light (H7). A low plasma phosphorus concentration and high Cp/Ca are characteristic of osteomalacia and rickets, and the FEl is of the same order as that in parathyroid tumor (Nil) (Fig. 10). However, this high phosphate clearance, unlike that of parathyroid tumor, can be reduced to a normal or subnormal value by intravenous infusion of calcium (N5). 

Premature infants develop rachitic lesions more readily than term infants. An oral dose of vitamin D as small as 100 International units per day has prevented the development of rickets in term infants and active rickets has been cured with 300 Int. units per day. The recent observations indicating that parathyroid hormone is the trophic hormone necessary for the manufacture of the metabolically active form of vitamin D thereby maintaining calcium homeostasis would suggest that this vitamin should be employed relatively early during total parenteral alimentation in the infant. 

Vitamin D deficiency in young children causes rickets. As a child becomes vitamin D deficient, this results in a decrease in the efficiency of intestinal calcium absorption. There is a decline in blood-ionized calcium, which causes the parathyroid glands to produce and secrete more parathyroid hormone (PTH). PTH tries to conserve calcium by enhancing tubular reabsorption of calcium in the kidney. However, in the face of developing hypocalcemia, which could disturb neuromuscular function and a wide variety of metabolic and cellular processes, the body calls upon l,25(OH)2D and PTH to mobilize stem cells to become functional osteoclasts, which, in turn, mobilize calcium from the skeleton. In addition, PTH causes a loss of phosphorus into the urine causing hypophosphatemia. Thus, in early vitamin D deficiency the serum calcium is normal it is the low serum phosphorus that causes the extracellular CaXP04 to be too low for normal mineralization of... 

Phosphorus metabolism, like that of calcium, is disturbed in rickets, osteomalacia, and diseases of the parathyroid and thyroid glands. The steroid hormones likewise influence metabolism of this element (Chapter 21). 

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