Chronic Hypophosphatemia Research Articles

Effect of Dermacentor albipictus (Acari:Ixodidae) on blood composition, weight gain and hair coat of moose, Alces alces.

The physiological effects of the winter tick, Dermacentor albipictus, on moose, Alces alces, were investigated. Blood composition, weight gain, food intake and change in the hair coat of moose calves, four infested with D. albipictus larvae, and eight uninfested, were monitored. Infested moose groomed extensively, apparently in response to feeding nymphal and adult ticks, and developed alopecia. Other clinical signs included: chronic weight loss, anemia, hypoalbuminemia, hypophosphatemia, and transient decreases in serum aspartate transaminase and calcium during the period of nymphal and adult female tick engorgement. Infested animals did not become anorexic. Two moose with severe hair loss had increases in gamma globulin shortly after the onset of female tick engorgement. Results suggest that alopecia is associated with tick resistance. Animals that groom and develop hair loss likely carry fewer ticks and therefore suffer less severely from blood loss.

Osteomalacia as a Very Late Manifestation of Primary Hyperparathyroidism

An 86-year-old woman with a history of treated hyperthyroidism and a 20-year history of untreated primary hyperparathyroidism developed generalized bone pain and a pseudofracture of the midshaft of the left femur. Laboratory examinations revealed elevated serum calcium, alkaline phosphatase, and C-terminal parathyroid hormone levels. Serum inorganic phosphate was below normal and 25-hydroxyvitamin D levels were low-normal. An undecalcified transiliac bone biopsy specimen following tetracycline double labeling revealed osteomalacia and osteitis fibrosa. Following treatment with vitamin D and phosphate, the serum inorganic phosphate level rose to normal. There was a decrease in bone pain, and the pseudofracture healed. However, the serum calcium, alkaline phosphatase, and C-terminal parathyroid hormone levels remained elevated. Longstanding primary hyperparathyroidism causes chronic hypophosphatemia and may lead to osteomalacia. Osteomalacia and its consequences may be part of the spectrum of bone disease seen in patients with longstanding primary hyperparathyroidism.

Hypophosphataemia and vitamin D metabolism in sheep.

The effect of dietary induced hypophosphataemia on vitamin D metabolism was studied in four conscious sheep. No change in the plasma concentrations of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) were found during hypophosphataemia when compared with normophosphataemia. In addition both the metabolic clearance rate and the production rate of plasma 1,25(OH)2D3 were unaltered during hypophosphataemia. This suggests that changes in circulating levels of 1,25(OH)2D3 were not necessary for the increased efficiency of intestinal phosphorus absorption seen in phosphorus-depleted hypophosphataemic sheep, and may explain why there is no increase in efficiency of intestinal calcium absorption in phosphorus depleted sheep. Increases in phosphataemia induced acutely by intravenous phosphate infusion for 3 h also had no effect on plasma 1,25(OH)2D3 concentration. It is concluded that in the sheep, unlike non-ruminant animals, chronic hypophosphataemia does not increase plasma 1,25(OH)2D3 concentrations and plays no physiological role in regulating its production or metabolism.

Erythrocyte adenosine triphosphate depletion during voluntary hyperventilation.

Chronic hypophosphatemia in humans is associated with a slow depletion of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) in erythrocytes, combined with shape alteration, impaired deformability, and viability of the cells. Likewise, incubation of erythrocytes in alkaline solution is associated with ATP depletion. Since in hyperventilation both hypophosphatemia and alkalosis are present, we have investigated red cell organic phosphates, shape, deformability, and osmotic fragility before, during, and after 20 min of voluntary hyperventilation. On the average, red cell ATP decreased by 42%, the blood pH increased by 0.2 units, and plasma inorganic phosphorus decreased by 46% compared with the initial values. Red cell 2,3-DPG, shape, deformability, and osmotic fragility remained unchanged. After the end of hyperventilation ATP increased rapidly to control values in parallel with the normalization of the blood pH, whereas inorganic plasma phosphorus remained at the low level observed during hyperventilation. It is concluded that the combined effects of hypophosphatemia and alkalosis in acute hyperventilation lead to an isolated fall of red cell ATP, which occurs as rapid as after total inhibition of red cell glycolysis in vitro.

Left ventricular function in patients with chronic hypophosphatemia

Left ventricular function in patients with chronic hypophosphatemia

Bone response to phosphate and vitamin D metabolites in the hypophosphatemic male mouse.

The hypophosphatemic male mouse (Hyp/y), the proposed model for human vitamin D-resistant rickets (VDRR), is characterized by chronic hypophosphatemia, dwarfism, and rachitic and osteomalacic bone lesions. We have reported that treatment of Hyp/y mice with phosphate salts (Pi) heals rickets but does not correct the defective endosteal bone mineralization. In an attempt to cure osteomalacia, mutant male animals were treated with Pi combined with 25-hydroxyvitamin D3 (25OHD3, 1 microgram/kg/day), 24,25-dihydroxyvitamin D3 [24,25(OH)2D3, 0.5 microgram/kg/day], or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0.05--0.25 microgram/kg/day] infused constantly for 3 weeks. The biochemical and skeletal effects of treatment were assessed by analytical methods and bone histomorphometry. The results show that only 1,25(OH)2D3 produced a dose-dependent elevation of serum calcium and phosphorus, and greatly improved bone mineralization at doses high enough to increase serum calcium and phosphorus concentrations within or above the normal range. Better improvement of bone mineralization was obtained when Pi was combined to 1,25(OH)2D3. In conjunction with the correction of hypocalcemia, Pi + 1,25(OH)2D3 suppressed the stimulation of bone turnover induced by Pi supplementation. The results show that, as in VDRR children, 1,25(OH)2D3 produces beneficial effects on bone lesions in Hyp/y mice, mainly through enhancement of mineral availability. However, the persistence of osteomalacia despite correction of serum mineral concentrations suggests that there is a specific bone cell resistance to mineral and/or hormonal influences in Hyp/y mice.

Parathyroid hormone evaluation in normal horses and horses with renal failure

Immunoreactive parathyroid hormone (iPTH), calcium, and inorganic phosphorus levels were measured in the serum of 13 apparently normal horses and in six horses with renal insufficiency. Serum iPTH levels were measured by radioimmunoassay using an antisera produced by immunization of guinea pigs with bovine parathyroid hormone. The antisera reacts primarily with the carboxy-terminal hormone fragment. Serum iPTH level in the normal horses was 504.5 ± 191.4 pg/ml and varied from 246 to 750 pg/ml. Serum iPTH levels in three horses with chronic renal failure, hypercalcemia and hypophosphatemia were below the limits of detection for the assay (<165 pg/ml). The hypercalcemia and hypophosphatemia were thus considered not to be the result of increased parathyroid hormone. Three horses with renal insufficiency which were not hypercalcemic had serum iPTH levels which were normal or greater than normal.

Chronic hypophosphatemia in the renal homograft recipient.

Tubular dysfunctions of renal homograft cases have been reported from several aspects (I). However, chronic hypophosphatemia of the kidney transplant recipient is a relatively new topic (4). It is encountered frequently and is considered to be very important in differential diagnosis of persistent hyper­ parathyroidism. We studied this chronic hypophosphatemia in our intrafamiliar renal homograft recipients.

Effects of experimental phosphate deficiency on action potential characteristics and contractile performance of rat myocardium

Chronic hypophosphataemia is associated with reversible depression in myocardial performance of the intact heart. To define the basis for this, were studied the mechanical and electrical properties of isolated left ventricular papillary muscles from rats with 6 weeks of phosphorus depletion (P6), 6 weeks of phosphorus repletion and age-matched controls (C). Muscles were perfused with Tyrode's solution (Ca2+ 2.4 mmol.liter-1, 7 = 4.0 mmol . litre-1, dextrose = 5.5 mmol . litre-1) and driven at 0.1 Hz. P6 muscles had slowed isometric relaxation (T1/2R), depressed velocity of shortening and relaxation and prolongation of the transmembrane action potential to 75% of complete repolarisation. These results suggest that the slow relaxation phase may be the result of the prolonged APD75 and that the depressed myocardial performance in the intact heart may be based on impaired relaxation and reduced the velocity of shortening associated with hypophosphataemia. This view is supported by our finding that these alterations are reversible with phosphate repletion.

Hypophosphatemia and osteoblast function in human bone disease.

There is experimental evidence from both.in vitro and in vivo studies for three main effects of hypophosphatemia and phosphate depletion on bone. These are — an increase in osteoclastic resorption,1,3 a decrease in the rate of collagen synthesis by osteoblasts, 3,4 and defective bone mineralization.3,5 Studies in the intact rat using tetracycline labeling were reviewed by Ivey and colleagues at a previous Phosphate Workshop.6 This paper summarizes the relationship between osteoblast function studied by double tetracycline labeling7 and plasma inorganic phosphate (P) in various human metabolic bone diseases associated with chronic hypophosphatemia.

Should hypophosphatemia be treated?

The answer to the question is yes. Phosphate treatment is necessary when hypophosphatemia is part of a true phosphate depletion syndrome (PDS). However, hypophosphatemia, even as low as 1.0–2.0 mg/dl in adults or 2.0–3.0 mg/dl in preadolescent children, does not necessarily mean or cause PDS. There are many examples in adult and child medicine of chronic hypophosphatemia caused by a high renal clearance of phosphorus (P) (low TmP/GFR) i.e. liberal amounts of P in the urine with low serum P. These do not develop a PDS unless there is superimposed a true lack of available P for the metabolic and growth needs of the patient. In the latter setting P excretion decreases markedly or disappears completely from the urine. This intense tubular reabsorption of P is an invariable feature of true phosphate depletion.

Hypophosphatemia and glucose intolerance: evidence for tissue insensitivity to insulin.

Although hypophosphatemia is commonly present in diabetics, little is known about its isolated effects on glucose and insulin metabolism. We therefore investigated glucose metabolism in six nondiabetic subjects with chronic hypophosphatemia. When glucose was infused to maintain a constant hyperglycemic level (125 mg per deciliter [6.9 mmol per liter] above basal levels), the glucose infusion rate was 36 per cent less in the hypophosphatemic group than in controls (4.90 +/- 0.34 mg per kilogram of body weight per minute vs. 7.64 +/- 0.37, P < 0.001), although responses to endogenous insulin were similar. When exogenous insulin was infused at a constant rate to maintain an insulin level about 100 microU per milliliter (718 pmol per liter) above basal levels and glucose was infused as necessary to maintain fasting glucose levels, the infusion rate of glucose was 43 per cent lower in the hypophosphatemic group than in controls (3.80 +/- 0.58 mg per kilogram per minute vs. 6.70 +/- 0.33, P < 0.001), although the clearance rate of insulin was similar in both groups. These results indicate that hypophosphatemia is associated with impaired glucose metabolism in both the hyperglycemic and euglycemic states, and that this associated primarily reflects decreased tissue sensitivity to insulin. (N Engl J Med. 1980; 303; 1259-63.).

Lack of involvement of sarcoplasmic reticulum in myopathy of acute phosphorous depletion.

Acute and chronic hypophosphatemia are known to cause metabolic myopathy. It has been proposed that impaired Ca transport in subcellular membranes is involved in its genesis. In the present study, calcium transport in the sarcoplasmic reticulum (SR), concentrations of ions or nucleotides and transmembrane potential were investigated in muscles of acutely hypophosphatemic rats, i.e. animals with chronic dietary phosphorous deprivation (PD) and superimposed acute hypophosphatemia resulting from the administration of insulin and glucose. Despite hypophosphatemia and low muscle phosphorous concentration, no significant change of the initial rate of Ca uptake or Ca concentrating ability was observed in the SR of PD rats. Storing capacity was decreased; this may result from altered vesicle geometry. Water content, Na concentration, the concentration of several nucleotides and transmembrane potential of muscle were unchanged in PD rats. The findings document that no intrinsic abnormality of vectorial Ca transport is present in the SR of acutely hypophosphatemic PD animals.

Chronic hypophosphatemia in kidney transplanted children and young adults.

Different mechanisms have been suggested to account for the frequently observed hypophosphatemia after renal transplantation. One may propose, along this line, the persistence of a pretransplant hyperparathyroidism1,2, the post-transplant administration of oral hydroxide antacids3, the post-transplant steroid therapy4 a deficiency in vitamin D active metabolites4,5, a tubular dysfunction6, or an abnormality in intestinal phosphate absorption7. In an attempt to analyse the respective importance of these factors, serial measurements of biochemical and radioimmunological parameters have been performed in the twelve subjects transplanted during the year 1976 in the Department of Pediatric Nephrology (Pr. M. Broyer) and considered as successful kidney transplantation.

Acute and chronic phosphate depletion as a modulator of glucose uptake in rat skeletal muscle

The effect of acute and chronic hypophosphatemia on rat hindlimb skeletal muscle glucose uptake was examined. Acute hypophosphatemia had no effect on glucose uptake whereas chronic hypophosphatemia had a direct linear effect on glucose uptake.

Effects of phosphate depletion on acid-base status in dogs

Hyperchloremic acidosis may occur in patients with severe hypophosphatemia, including some with hyperparathyroidism. In experimental models of phosphate depletion, metabolic acidosis has not been a consistent feature. In some studies, arterial pH values have been normal, but have been associated with high rates of urinary bicarbonate loss. In other studies, metabolic acidosis has been observed associated with a decreased capacity for renal bicarbonate reabsorption. The present study was designed to examine the effects of both phosphate depletion upon systemic acid-base status in dogs and chronic hypophosphatemia upon renal bicarbonate reabsorption. Studies were performed upon three groups. All received a standard diet markedly diminished in phosphate content. Normal dogs (group I) received a dietary supplement of phosphate (31 m M/day). Group II dogs received no supplemental phosphate. Group III dogs were parathyroidectomized and also received a phosphate-deficient diet. Deprivation of dietary phosphate in groups II and III resulted in severe hypophosphatemia (Serum phosphate = 1.1 mg phosphorus/dl). Renal fractional phosphate reabsorption was increased significantly in both groups. Despite phosphate deprivation for up to 14 wk, arterial pH and bicarbonate values remained normal. Values for fasting urine pH and bicarbonate excretion were similar in the three groups. Renal bicarbonate conservation was normal in groups II and III as observed under fasting conditions. During bicarbonate infusion studies, patterns of bicarbonate reabsorption/glomerular filtration rate were obtained and maximal rates of renal bicarbonate reabsorption were assessed. To correct for possible differences ascribable to the effects of extracellular fluid volume expansion, the ratio of absolute bicarbonate/absolute sodium reabsorption was also examined. Over a wide range of plasma bicarbonate concentrations, no significant differences in this ratio were observed among the three groups. Maximal rates of renal bicarbonate reabsorption were similar in the three groups. The studies demonstrate that prolonged dietary phosphate deprivation in dogs, while resulting in severe hypophosphatemia, may be associated with the maintenance of normal plasma pH and bicarbonate values. Abnormal rates of urinary bicarbonate loss have not been observed. In the absence of metabolic acidosis, bicarbonate reabsorptive capacity and bicarbonate reabsorptive patterns are normal. The study suggests that other causes for the metabolic acidosis in severe phosphate depletion should be sought.

Renal tubular effects of chronic phosphate depletion.

The effects of chronic phosphate depletion on renal tubular function were evaluated by micropuncture and free water clearance studies in the dog. Proximal tubular punctures demonstrated that chronic hypophosphatemia led to a reduction in ratio of tubular fluid to plasma inulin in late superficial tubular from 1.59+/-0.08 in control animals to 1.29+/-0.06 in phosphate-depleted dogs, with proportional inhibition of calcium and sodium reabsorption. The chronic decrease in proximal tubular fluid reabsorption was confirmed by the analysis of sustained water diuresis in conscious, phosphate-depleted dogs, before and after repletion of body PO4 stores, and in control animals. Urine flow rate/100 ml glomerular filtration rate (V/GFR) was significantly higher in PO4 DEPLETION THAN CONTROL (15.8+/-1.1 VS. 10.7+/-0.82). In addition, acetazolamide infusion did not increase V/GFR in phosphate-depleted dogs (15.8+/-1.1 vs. 17.16+/-0.9), supporting the conclusion that inhibition of proximal tubular fluid reabsorption was responsible for the elevated urine flow rate. PO4 repletion over 5 days reduced V/GFR to 9.2+/-0.7 despite no change in urine osmolality and no change in GFR, further suggesting a specific reversible alteration in proximal tubular reabsorption in phosphate depletion. Although hypercalciuria was a constant finding in phosphate depletion (fractional excretion of calcium of 2.04+/-0.4% vs. 0.47+/-0.13% in controls), the enhanced distal delivery of calcium was not a crucial factor; acute phosphate infusion reduced urinary calcium excretion to control values without affecting the reduced proximal tubular reabsorption in either intact or thyroparathyroidectomized phosphate-depleted dogs the change in distal nephron calcium reabsorption was independent of parathyroid hormone (PTH) levels since infusion of PTH failed to alter urinary calcium excretion. We conclude that chronic phosphate depletion leads to a reversible, sustained inhibition in proximal tubular reabsorptive fuction as well as a specific decrease in distal nephron calcium reabsorption. This latter reabsorptive defect is sensitive to phosplate infusion but not corrected by PTH.

Occurrence of hyperparathyroidism in children with X-linked hypophosphatemia under treatment with vitamin D and phsophate.

X-linked familial hypophosphatemia (XLH) is a hereditary disorder of phosphate metabolism. The marked reduction of renal tubular phosphate reabsorption is followed by chronic hypophosphatemia with rickets and growth retardation. The rickets are resistant to a normal dosage of vitamin D, but they can be healed or prevented by pharmacological doses of vitamin D. An additional oral phosphate substitution was shown by West (1) and Glorieux (2) to induce growth acceleration.KeywordsTubular ReabsorptionSerum Parathyroid HormonePhosphate ReabsorptionPhosphate LoadingOral PhosphateThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Hemoglobin-oxygen affinity in hypophosphatemic rickets.

In 14 patients with simple X-linked hypophosphatemic rickets, 5 were below the third percentile in height and 9 were between the third and twenty-fifth percentile. Although the mean serum inorganic phosphorus level was only 2.01 +/- 0.65 (normal range for all age groups is 3.8 to 6.0 mg/100 ml), both the mean values for red cell 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP) were normal at 4.78 +/- 1.23 and 1.02 +/- 0.17 mumol/ml of red blood cells respectively. Moreover, the mean P50 value was normal at 26.4 +/- 0.9 mmHg. These normal oxygen transport data make unlikely any proposal that short stature seen in these patients is secondary to chronic tissue hypoxia. They also indicate that the intra-erythrocytic organic phosphate levels are maintained at normal levels despite profound chronic hypophosphatemia.

Serum calcium and phosphorus abnormalities in leukemia

The records of all cases of leukemia at the University of California Medical Center during the five year period from January 1960 to December 1964 were reviewed for data on serum calcium, phosphorus and alkaline phosphatase determinations and roentgenologic examination of the skeleton. A total of 260 cases were found, 123 of which included a calcium and phosphorus determination. Three patients (2.5 per cent) had hypercalcemia, and twenty-two (18 per cent) in whom renal function was not impaired had hyperphosphatemia. Increased alkaline phosphatase activity was found in 34 per cent of the patients tested. Hyperphosphatemia and increased alkaline phosphatase activity could not be correlated with other clinical or laboratory findings. Roentgenologic evidence of bone disease was found in eleven of twenty children examined, but in only ten of fifty-three adult patients.Seven cases of leukemia with hypercalcemia are reported. Six of the patients had acute leukemia; in the seventh case, however, the hypercalcemia was not related to the coexisting chronic lymphocytic leukemia. Symptoms of hypercalcemia preceded other evidence of acute leukemia in one case and in two reported previously. Early recognition of these cases is important since the hypercalcemia and its symptoms were reversed by corticosteroid therapy in all three instances. Roentgenologic evidence of bone disease was not always present at the time the hypercalcemia was discovered but usually appeared later. Serum phosphorus levels are usually normal or elevated in association with the hypercalcemia of leukemia, suggesting an osteolytic action other than that of parathyroid hormone. In one case of chronic lymphatic leukemia, hypercalcemia, hypophosphatemia and low tubular resorption of phosphate were corrected by removal of a parathyroid adenoma. In the first case, and in one reported previously, with hypercalcemia and hypophosphatemia, there was no evidence of parathyroid abnormality.