Plasma phosphate

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Changes in drug absorption are variably reported as diminished (particularly if the patient had been receiving aluminium salts by mouth to reduce the elevated plasma phosphate found in renal failure) or increased and the Vd of some compounds is increased. These appear to be relatively unimportant compared to the loss of excretory capacity. 

Regulation of 25-hydroxycholecalciferol 1-hydroxylase 1,25-diOH D3 is the most potent vitamin D metabolite. Its formation is tightly i regulated by the level of plasma phosphate and calcium ions (Figure 28.24). 25-Hydroxycholecalciferol1 -hydroxylase activity is I increased directly by low plasma phosphate or indirectly by bw I plasma calcium, which triggers the release of parathyroid hormone I... 

Plasma phosphate appears to be homeostahcally controlled. The primary organ concerned appears to be the kidney, although the skeleton also may play a role. Parathyroid hormone, by way of its direct action on the kidney and bone, is a significant hormonal factor. 

The amount of phosphorus excreted in the urine vanes with the level of ingested phosphorus and factors influencing phosphorus availability and utilization. It has been shown that in the dog, when plasma phosphate is normal or low, over 99% of the filtered ion is reabsorbed, presumably in die upper part of the proximal tubule. Increased plasma concentrations of alanine, glycine, and glucose depress phosphate reabsorption. 

The normal range of free inorganic phosphate, in plasma, is expressed as 2.0-4.3 mg phosphorus/1(K) ml. Hyperphosphatemia is defined as the condition where plasma phosphate levels rise above 5.0 mg phosphorus/100 ml. Hyperphosphatemia can result from overuse of laxatives or enemas that contain phosphate. Phosphate enemas are used in the hospital prior to examinations of the intestines for disease, such as colon cancer. However, hyperphosphatemia has occurred in the home situation with accidental drinking of enema formulas. Enema drinking... 

Hypoparathyroidism can result from decreased production of PTH or failure of target organs to respond to PTH. In rare cases, it involves the production of genetically defective PTH. PTH provokes the kidney to conserve calcium and to excrete phosphate. Thus, hypoparathyroidism results in low plasma calcium and high plasma phosphate levels. The disease may result in the calcification of soft tissues because of the high plasma phosphate level. Elevated phosphate levels result in an increased rate of precipitation of calcium and phosphate as the calcium phosphate salt. The disease is treated with oral calcium supplements and phosphate-binding antacids to minimize the absorption of dietary phosphate. 

Hypocalcemia commonly occurs during the first I or 2 days of life in premature, low-birth-weight infants. The exact mccKaiusm is not clear. Hypocalcemia can also present in newborns fed cow milk, because cow milk contains calcium and phosphorus in a ratio of about 1.34/1.0, by weight. Mother s milk contains relatively less phosphate the calcium/phosphorus ratio is 2.25/1,0. The excess phosphate in cow milk promotes hyperphosphatemia in the newborn. It is thought that plasma phosphate, in elevated concentrations, fonns a complex with plasma calcium. Formation of this complex reduces the levels of free calcium, resulting in symptoms of hypocalcemia. The newborn is not as able to make hormonal adjustments to maintain plasma calcium levels as is the older infant (Mizrachi et al., 1968). 

It appears that increased plasma phosphate concentrations are not directly toxic (Sutters et al 1996). Hypocalcemia and metastatic soft-tissue calcification caused by hyperphosphatemia result from the calcium/phosphate product exceeding that required for precipitation of calcium phosphate in the tissues (Macintire 1997, Sutters et al 1996). 

Fever accelerates lipid metabolism. The serum concentrations of cholesterol, nonesterified fatty acids, and the other lipids may decrease initially, but within a few days the free fatty acid concentration may increase. Fever is often associated with a respiratory alkalosis caused by hyperventilation. This pH increase causes a reduction of the plasma phosphate concentration, with an increased excretion of phosphate and other electrolytes. Serum iron and zinc concentrations decline with accumulation of both elements in the liver. The copper concentration increases because of increased production of ceruloplasmin by the liver. Some representative changes in serum composition induced by fever are listed in Table 17-12. 

Infusions of glucose solutions usually result in a reduction of both the plasma phosphate and potassium concentrations because these compounds are taken up by the erythrocytes. Infusions of solutions of albumin may increase... 

Normally less than 20% of the filtered load of phosphate is excreted into the urine, but above a plasma phosphate concentration of approximately 1.2mmol/L increments in urinary phosphate excretion increase linearly with the filtered load, suggesting that there is Tn, (tubular maximal uptake) for phosphate. Predictably the T , for phosphate is influenced by the circulating PTH concentration and the ratio of T for phosphate to GFR (T ,P/GFR). T,nP/GFR has been used as a test in the differential diagnosis of hypercalcemia. Although superseded in this context by modern PTH assays, it may still be useful in the investigation of inherited disorders of tubular phosphate handling. ... 

Kemp GJ, Blumsohn A, Morris BW. Circadian changes in plasma phosphate concentration, urinary phosphate excretion and cellular phosphate shifts. 

Parathyroidectomy is followed by a fall in urine phosphate excretion and a consequential rise in plasma inorganic phosphate concentration until a new equilibrium is established (Tl). In clinical hypoparathyroidism, plasma inorganic phosphate may be as high as 10 mg/100 ml, but the amount of phosphorus excreted in the urine by such patients really depends upon dietary intake. In these cases, therefore, phosphate clearance is usually low and is always low when considered in relation to the plasma phosphate concentration (K4, N6, Nil). 

Variations in plasma phosphate concentration produced by parathyroid activity are often greater than can be accounted for by the changes in urinary excretion of phosphate. This had led to the suggestion that parathyroid hormone may facilitate the migration of phosphate into cells (F3). The evidence on this point is not conclusive, but increased labeling... 

The relationship of the inorganic phosphate concentration to bone mineral is more complex. The normal range of plasma phosphate concentration is much larger than that of calcium, presumably because the phosphate concentration (unlike that of calcium) is influenced by dietary intake of phosphorus and by urinary excretion and because the parathyroids intervene to correct major changes in calcium concentration. The skeleton thus controls plasma calcium at a constant level but permits relatively large variations in plasma phosphate there is therefore no constant [calcium] [phosphate] product in plasma or tissue fluid... 

A wide range of plasma phosphorus concentration has been observed by other workers in primary hyperparathyroidism (C7) and explained in terms of diet and renal excretion. Unlike the calcium concentration, which is normally very constant regardless of dietary intake and urinary excretion, the concentration of inorganic phosphate in plasma is the resultant of the rate of phosphorus absorption from the gut and protein catabolism, on the one hand, and of renal excretion, on the other. Although the parathyroid hormone promotes phosphorus excretion, this is only one of the factors governing plasma phosphate concentration. Plasma phosphate in cases of hyperparathyroidism on a relatively high phosphorus intake may therefore not be distinguishable from that in normal subjects on a lower intake. 

Several phosphate excretion tests have been devised to assist in the assessment of parathyroid activity from the study of the renal excretion of phosphorus. All workers are agreed that plasma phosphate tends to be high and phosphate clearance low in hypoparathyroidism and that... 

A. The measurement of phosphate clearance from a timed sample of urine and a simultaneous blood sample (K6). The normal range is reported as 6.3-15.5 ml/min. Higher and lower values were found in a series of cases of hyper- and hypoparathyroidism, respectively. The authors have made no attempt to correct their clearances to take into account the effect of plasma phosphate concentration upon phosphate clearance (see below). 

B. The measurement of the phosphate/creatinine clearance ratio (Cp/Cc.r) from the phosphate and creatinine concentrations in an untimed urine sample and simultaneous blood sample (N5). Tubular reabsorption of phosphate (TRP) can be derived from this figure (TRP = 1 — Cp/Ccr) and has been widely used as a measure of parathyroid activity (C7, R5, T5). Its normal range is reported as 78-90 %. The authors do not make any correction for plasma phosphate concentration. 

C. The measurement of the phosphate excretion index (Nil). Since the phosphate/creatinine clearance ratio is normally directly related in a known manner to plasma phosphate concentration (MIO), the observed Cp/Ccr in any given case can be compared with the normal mean value at the same plasma concentration. The difference is called the Phosphate Excretion Index (PEI) and its normal range is —0.09 to +0.09. The values in hyperparathyroid cases usually lie above the upper normal limit and in hypoparathyroid cases below the lower limit (Nil) (Fig. 10). 

D. Phosphate reabsorption per 100 ml of glomerular filtrate. If the plasma phosphate concentration is multiplied by the phosphate/creatinine clearance ratio, an approximate figure is obtained for the amoimt of phosphate reabsorbed per 100 ml of glomerular filtrate (T7). The normal range of this value is approximately 2-4mg/100ml filtrate (Nil). 

Howard et al. (Hll, H12), who suggested that the rise in plasma phosphate produced by intravenous calcium was due to parathyroid suppression, and that this rise was smaller than normal in hyperparathyroidism. It has since been shown that the effect of intravenous calcium on plasma phosphate is not a measure of parathyroid activity (N5), and this may explain why calcium infusions have tended to fall into disfavor. The fall in urine phosphate which follows calcium infusion does, however, indicate parathyroid suppression (K5, N5). Table 5 shows the effect of a standard calcium infusion on the urinary phosphate/creatinine ratio... 

The combination of a reduced plasma calcium concentration (due to vitamin D deficiency) and a reduced plasma phosphate concentration (due to secondary hyperparathyroidism) produces a calcium X phosphate product below the threshold for calcification of new bone. 

It has been known for 40 years (H13) that rickets develops in children when the plasma [Ca] [P] product falls below about 30, and is either absent or healing when the plasma product exceeds 40. In adults the critical value of the product is about 20, below which level osteomalacia results. There are, however, exceptions to these general rules and, in particular, osteomalacia has been described in a case of postoperative hypoparathyroidism in which the plasma calcium was low but the plasma phosphate correspondingly high. The [Ca] [P] product in this case was... 

Talmage (T4) has determined the concentrations of calcium and phosphate in rat plasma after high-speed centrifugation. He has studied normal plasma and plasma to which calcium, phosphate and calcium orthophosphate had been added as well as plasma obtained after nephrectomy. There was a substantial variation in the final [Ca] [P] products (82-120) high products were obtained when the plasma phosphate concentration was high, as after nephrectomy. However, when his data are recalculated as [Ca] [P] as shown in Table 8, there is much less varia-... 

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