Pyrophosphohydrolase activity and inorganic pyrophosphate content of cultured human skin fibroblasts. Elevated levels in some patients with calcium pyrophosphate dihydrate deposition disease.
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In calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, metabolic abnormalities favoring extracellular inorganic pyrophosphate (PPi) accumulation have been suspected. Elevations of intracellular PPi in cultured skin fibroblasts from a single French kindred with familial CPPD deposition (19) and elevated nucleoside triphosphate pyrophosphohydrolase activity (NTPPPH), which generates PPi in extracts of CPPD crystal-containing cartilages (14) favor this suspicion. To determine whether NTPPPH activity or PPi content of cells might be a disease marker expressed in extraarticular cells, human skin-derived fibroblasts were obtained from control donors and patients affected with the sporadic and familial varieties of CPPD (CPPD-S and CPPD-F) deposition. Intracellular PPi was elevated in both CPPD-S (P less than 0.05) and CPPD-F (P less than 0.01) fibroblasts compared with control fibroblasts. Ecto-NTPPPH activity was elevated in CPPD-S (P less than 0.01) but not CPPD-F. Intracellular PPi correlated with ecto-NTPPPH (P less than 0.01). Elevated PPi levels in skin fibroblasts may serve as a biochemical marker for patients with familial or sporadic CPPD crystal deposition disease; ecto-NTPPPH activity further separates the sporadic and familial disease types. Expression of these biochemical abnormalities in nonarticular cells implies a generalized metabolic abnormality. (+info)
Clinical disorders of phosphorus metabolism.
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Deranged phosphorus metabolism is commonly encountered in clinical medicine. Disturbances in phosphate intake, excretion and transcellular shift account for the abnormal serum levels. As a result of the essential role played by phosphate in intracellular metabolism, the clinical manifestations of hypophosphatemia and hyperphosphatemia are extensive. An understanding of the pathophysiology of various phosphate disorders is helpful in guiding therapeutic decisions. (+info)
Metabolic bone disease secondary to renal and intestinal disorders.
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Metabolic bone disease occurring in renal or intestinal disorders has been reviewed with particular reference to etiological factors. Hyperparathyroidism is seen as a recurring cycle of renal damage-hyperphosphatemia-hypocalcemia-parathyroid stimulation-mobilization of bone calcium and phosphate-renal tubular phosphate rejection. In intestinal cases, the initial stimulus is presumably hypocalcemia. Osteomalacia is seen as resulting from phosphate depletion for the following reasons:1. Experimentally, rickets results from dietary phosphate restriction in rats.2. Such rickets is not prevented by the presence of normally adequate amounts of dietary vitamin D, and may therefore be termed "resistant" in the clinical sense.3. Osteomalacia or rickets in intestinal malabsorption and renal tubular disorders is associated with hypophosphatemia due to excessive fecal or urinary loss.4. Renal tubular rickets has been healed by oral phosphate loading in some studies.5. Acidosis may induce osteomalacic changes, experimentally and clinically (for example, in uretero-sigmoidostomy). Reversal of systemic acidosis with oral bicarbonate has resulted in phosphate retention and a rising serum phosphate in one such case.6. Preliminary data from analysis of full-thickness bone biopsy in two osteomalacic patients shows a significant reduction in calcium and phosphate content.7. Despite the hyperphosphatemia of azotemic renal failure, over-all phosphate depletion may be present in this situation also due to: * Diminished dietary phosphate in low protein diets * Nausea and vomiting * Occasional diarrhea * The use of oral phosphatebinding antacids * Perpetuation of urinary phosphate losses by reduction in proportion of tubular reabsorbed phosphate (secondary hyperparathyroidism) and possibly high filtered load per nephron * Repeated losses of phosphate to bath fluid during dialysis. (+info)
Changes in serum and urinary calcium during phosphate depletion: studies on mechanisms.
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The changes in serum calcium and the renal handling of this ion were evaluated during phosphate depletion. 96 renal clearance studies were carried out in 10 dogs before and after prolonged phosphate depletion (30-160 days) and after repletion. Depletion was produced by reducing phosphate intake and administering aluminum hydroxide gel while intakes of sodium, calcium, and magnesium were constant. With phosphate depletion, serum phosphorus fell to less than 1.0 mg/100 ml and diffusible serum calcium either remained unchanged or rose transiently. Glomerular filtration rate (GFR) fell by 15 to 53%. Despite the reduced filtered load of calcium, its fractional excretion increased in most experiments. This hypercalciuria was not dependent upon changes in sodium or magnesium excretion, or the urinary concentration of complexing anions, and persisted after sodium restriction. Phosphate repletion reversed the effects on GFR and calcium excretion. The intravenous infusion of small quantities of phosphate (0.04 mmole/min) into either intact or thyroparathyroidectomized (T-PTX), phosphate-depleted animals caused a significant reduction in fractional excretion of calcium, but the intrarenal infusion of 0.02 mmole/min of phosphate into one kidney failed to produce an ipsilateral effect. The administration of parathyroid extract reduced fractional calcium excretion, but the latter remained significantly elevated. After T-PTX, fractional calcium excretion did not increase in the phosphate-depleted animals. Furthermore, serum calcium was normal after T-PTX until serum phosphorus increased slightly, and only then did hypocalcemia develop. These observations indicate that (a) phosphate depletion produces hypercalciuria through a reduction in tubular reabsorption of calcium which is not due to changes in the tubular reabsorption of other ions; this effect is not reversed by the direct intrarenal infusion of phosphate; (b) a state of functional hypoparathyroidsm occurs during phosphate depletion which may, in part, cause reduced tubular reabsorption of calcium; (c) other extra renal mechanism(s), possibly related to events occurring in bone as a result of phosphate depletion, may have an effect on urinary calcium excretion; and (d) in the phosphatedepleted state, parathyroid hormone is not required for the maintenance of a normal level of serum calcium. (+info)