Hyperparathyroidism Phosphorus

The management of secondary hyperparathyroidism involves correction of serum calcium and phosphorus levels, and decreasing parathyroid hormone secretion. 

As kidney function continues to decline and the GFR falls less than 60 mL/minute/1.73 m2, phosphorus excretion continues to decrease and calcitriol production decreases, causing PTH levels to begin to rise significantly, leading to secondary hyperparathyroidism (sHPT). The excessive production of PTH leads to hyperplasia of the parathyroid glands, which decreases the sensitivity of the parathyroid glands to serum calcium levels and calcitriol feedback, further promoting sHPT. 

Renal osteodystrophy is a complex disorder with several pathogenic factors. Histological evidence of bone disease is common in early renal failure and deficits in calcitriol synthesis seems to be an important factor in the pathogenesis of secondary hyperparathyroidism in early CRF. The most common component is osteitis fibrosa manifested as subperiosteal resorption of bone. This is due to decreased excretion as well as increased secretion of parathyroid hormone. In CRF small increments of serum phosphorus cause small decreases in serum calcium. 

There can be increases in calcium and phosphorus loss because of effects on both the kidney and the bowel, with increased excretion and reduced resorption (131). Tetany, which has been seen in patients receiving high-dose longterm intravenous glucocorticoids, has been explained as being due to hypocalcemia, and there are also effects on bone. Tetany has also been reported in a patient with latent hyperparathyroidism after the administration of a glucocorticoid (122). 

The metabolism of phosphorus (P) is largely related to that of calcium (Ca). The Ca P ratio in the diet affects the absorption and excretion of these elements (Harper 1969). Any increase in serum phosphorus results in a decrease of serum calcium by mechanisms which are still unknown. For example, increased serum phosphorus levels and decreased serum calcium levels are seen in uremia (renal retention of phosphorus), hypoparathyroidism, hypocalcemia (decreased serum calcium levels), and hyperphosphatemia (increased serum phosphorus levels), and the reverse is seen in hypercalcemia (increased serum calcium levels) and hyperparathyroidism. Hypophosphatemia (low serum phosphorus levels) is seen in ricketts (vitamin D deficiency) (Harper 1969 Tietz 1970). 

Alterations in systemic calcium-to-phosphorus ratios are another known cause of band keratopathy. This includes hypercalcemia caused by conditions such as hyperparathyroidism, sarcoidosis, and vitamin D intoxication, as well as the elevated serum phosphorus commonly foimd with kidney feilure. Gout can also cause band keratopathy. 

There is increased sensitivity to vitamin D in patients who are undergoing renal dialysis and who have an abnormal calcium/phosphorus ratio. Patients on continuous ambulatory peritoneal dialysis (CAPD) who develop secondary hyperparathyroidism may already have low bone turnover or adynamic bone lesions, and if treated indiscriminately with calcitriol their low bone turnover can get worse (62). 

Lmdberg JS, Moe SM, Goodman WG, Coburn JW, Sprague SM, Liu W, et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 2003 63 248-54. 

Signs and symptoms associated with CKD become more prevalent in Stages 3,4, and 5. Anemia, abnormalities of calcium and phosphorus metabolism (and therefore secondary hyperparathyroidism), malnutrition, and fluid and electrolyte abnormalities become more common as kidney function deteriorates (see Chap. 44). 

Martinez I, Saracho R, Montenegro J, Llach F. The importance of dietary calcium and phosphorus in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 1997 29 496-502. 

Management of hyperphosphatemia, calcium balance, and secondary hyperparathyroidism includes dietary phosphorus restriction, use of phosphate binding agents, and vitamin D therapy. 

Calcium and phosphorus balance is mediated through the complex interplay of hormones and their effects on bone, the Gi tract, kidney, and parathyroid gland. What begins as relatively minor imbalances in phosphorus and calcium homeostasis leads to secondary hyperparathyroidism (sHPT) in the short term and ultimately renal osteodystrophy (ROD) if these metabolic abnormalities are not corrected. 

Slatopolsky E, Dusso A, Brown AJ. The role of phosphorus in the development of secondary hyperparathyroidism and parathyroid cell proliferation in chronic renal failure. Am J Med Sci 1999 317 370-376. 

Increased renal losses of phosphorus can occur in hyperparathyroid (primary and secondary) patients with normal renal function and... 

Other chronic disorders cause osteomalacia. " " Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenic osteomalacia (potentially phosphaturic effect) can cause osteomalacia. Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix. Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization. Renal tubular disorders secondary to Fanconi s syndrome, hereditary diseases (e.g., Wilson s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees. Chronic wastage of phosphorus and/or calcium limits mineralization, which may be further compromised by acidosis and secondary hyperparathyroidism. 

G29. Gutman, A. B., Tyson, T. L., and Gutman, E. B., Serum calcium, inorganic phosphorus and phosphatase activity in hyperparathyroidism, Paget s disease, multiple myeloma and neoplastic diseases of the bones. Arch. Intern. Med. 57, 379-413 (1936). 

Hypophosphatemia is a less constant feature of primary hyperparathyroidism than hypercalcemia, despite the well-documented effect of parathyroid hormone upon phosphate excretion. Figure 9 shows the plasma calcium and phosphorus values in 346 cases of primary hyperparathyroidism diagnosed at the Mayo Clinic. It will be seen that the diagnosis was rarely made in the presence of a normal plasma calcium, although this occasionally has been done (M8), but was frequently made when the phosphorus concentration was normal. The data also suggest a slight inverse correlation between the plasma calcium and phosphorus concentrations in cases with normal renal function the phosphorus was usually low when the calcium concentration exceeded 12 mg/100 ml. 

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. 

Cinacalcet is available in 30-, 60-, and 90-mg tablets. Optimal doses have not been defined. The recommended starting dose for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis is 30 mg once daily, with a maximum of 180 mg/day. For treatment of parathyroid carcinoma, a starting dose of 30 mg twice daily is recommended, with a maximum of 90 mg four times daily. The starting dose is titrated upward every 2 to 4 weeks to maintain the PTH level between 150 and 300 pg/mL (secondary hyperparathyroidism) or to normalize serum calcium (parathyroid carcinoma). The principal adverse event with cinacalcet is hypocalcemia. Thus, the drug should not be used if the initial serum calcium concentration is less than 8.4 mg/dL serum calcium and phosphorus concentrations should be measured within 1 week, and PTH should be measured within 4 weeks after initiating therapy or after changing dosage. 

The bone resorption is responsible for a high alkaline phosphatase level in the serum. The activity of the alkaline phosphatase in the serum can be correlated with the degree of bone demineralization. Of course, alkaline phosphatase is of diagnostic value only if diseases of the hepatic system have been ruled out. The serum inorganic phosphorus levels are reduced in hyperparathyroidism. 

The phosphorus levels of the blood are high in secondary hyperparathyroidism. This is likely to result from phosphorus retention due to tubular damage. Reduced phosphorus filtration through the glomeruli has been eliminated. In renal insufficiency, the renal tubules either resorb more phosphorus than normal, or the phosphorus secretion is blocked. Since tubular secretion of phosphorus has not been established conclusively, one must assume that the phosphorus retention results from accelerated resorption. Calcium and phosphate ions are maintained in equilibrium in the blood. The calcium levels in the blood will be reduced in the presence of higher levels of phosphate ions, but again, the theory postulates that calcium levels are low in patients with renal insufficiency. 

Most of the calcium that is lost from the body is excreted in the faeces, this being mainly unabsorbed dietary calcium. However, the digestive secretions all contain small amounts of calcium, and individuals on a calcium-free diet continue to excrete faecal calcium. The normal daily excretion is of the order of 0-1-0-3 g (2-5-7-5 mmol). The quantity of phosphorus excreted daily varies with the dietary intake. As with calcium an appreciable proportion of ingested phosphorus remains unabsorbed and is eliminated in the faeces. Phosphorus is also excreted in the urine, almost entirely in the form of orthophosphates (e.g. NaH2P04 and Na2HP04). Their role in the regulation of acid-base balance is discussed on page 395. Urinary excretion of phosphate is increased in hyperparathyroidism. 

Disorders of the calcium-phosphate metabolism are additional risk factors for renal disease progression. Several factors related to disturbed calcium-phosphorus metabolism, such as hyperphosphatemia, hyperparathyroidism, lack of... 

Hyperphosphatemia is common in patients with end-stage renal disease (ESRD), since a large fraction (60-70%) of dietary phosphorus is absorbed and normally excreted by the kidneys, and as kidney function deteriorates, less phosphorus is exereted by the kidneys (Emmett 2004). Dietary restrictions have insuffieient effect. The condition may have serious consequences. Hyperphosphatemia stimulates parathyroid hormone and suppresses vitamin D3 production, and thus induces hyperparathyroid bone disease. In addition, it leads to myocardial and vascular calcification and cardiac microcirculatory abnormalities, which results in cardiac causes of death. Phosphate levels henee should be eontrolled early in the... 

---