BSI Case Study 58 Flashcards
PTH-rp, secreted by certain malignant tumors, is chemically homologous with PTH that is secreted by the parathyroid glands. PTH-rp has all of the biologic actions of PTH on bone and kidney. Given this information, why was Mr. Kessler hypercalcemic and hypophosphatemic? Why was his alkaline phosphatase level elevated?
PTH-rp has all the same effects on the bone and kidney as PTH. PTH-rp stimulates osteoclasts and increases bone resorption, bringing calcium and phosphate from the bone into the extracellular fluid; PTH-rp inhibits Na+ phosphate cotransport and renal phosphate reabsorption and causes phosphaturia; finally, PTH-rp stimulates calcium reabsorption in the kidney. This leads to increased serum calcium concentration and decreased serum phosphate concentration. Increased alkaline phosphatase activity is associated with increased osteoblastic activity in states of high bone turnover.
What was the significance of Mr. Kessler’s normal serum albumin level?
Although Mr. Kessler’s serum albumin levels were normal, his total serum calcium level was elevated. This means that that elevation was due to serum ionized calcium.
Why was Mr. Kessler’s serum PTH levels decreased?
Mr. Kessler’s circulating levels of PTH was decreased secondary to his hypercalcemia. PTH secretion is feedback regulated by serum calcium levels. When serum calcium is decreased, PTH secretion is stimulated. When serum calcium is increased, PTH secretion is inhibited. This points out the critical difference between hypercalcemia caused by primary hyperparathyroidism and hypercalcemia of malignancy. In primary hyperparathyroidism, by definition, PTH levels are increased. In humoral hypercalcemia of malignancy, PTH levels are decreased by feedback inhibition on the parathyroid gland.
After the 4-hour water deprivation test, Mr. Kessler’s serum osmolarity was 305 mOsm/L (normal, 290 mOsm/L) and his urine osmolarity was 90 mOsm/L. Administration of an ADH analogue (dDAVP) by nasal spray did not alter his serum or urine osmolarity. The physician concluded that Mr. Kessler had nephrogenic diabetes insipidus. Why? What might be the cause of this condition?
After a water deprivation test, Mr. Kessler’s serum osmolarity levels were elevated, but his urine osmolarity was very dilute. This is a sign of diabetes insipidus caused by ADH deficiency or by ADH resistance of the collecting ducts. The dDAVP nasal spray was used to put ADH in the body, and it still didn’t cause his urine to become more concentrated. His nephrogenic diabetes insipidus (or ADH resistance) was caused by hypercalcemia. Calcium deposition in the inner medulla of the kidney inhibits ADH-dependent adenylyl cyclase and prevents ADH action to increase water permeability of the collecting ducts. Thus, even in the presence of exogenous ADH, the urine cannot be concentrated.
Why did Mr. Kessler have polyuria and polydipsia?
Mr. Kessler had polyuria and polydipsia secondary to nephrogenic diabetes insipidus. Polyuria occurred because his collecting ducts were resistant to the action of ADH and therefore impermeable to water. Water that was not reabsorbed by the collecting ducts was excreted in the urine. Polydipsia occurred because increased urinary water excretion made his body fluids more concentrated. Increased serum osmolarity is a potent stimulus for thirst and drinking behavior through osmoreceptors in the hypothalamus.
How did treatment with saline and furosemide decrease his serum calcium concentration?
Furosemide inhibits the Na+, K+, 2Cl cotransporter in the thick ascending limb and therefore inhibits renal Na+ reabsorption. Furosemide also inhibits calcium reabsorption in the thick ascending limb, which is explained as follows. The Na+, K+, 2Cl cotransporter normally generates a lumen-positive potential difference in the thick ascending limb that drives calcium reabsorption from the lumen to the blood through a paracellular route. (The positive charge in the lumen repels the positive charges on calcium.) By inhibiting the Na+, K+, 2Cl cotransporter, furosemide eliminates the lumen-positive potential, thereby inhibiting paracellular calcium reabsorption. Thus, a portion of the filtered calcium that would otherwise have been reabsorbed was excreted in the urine, decreasing Mr. Kessler’s serum calcium concentration. Saline was administered with the furosemide to prevent extracellular volume contraction.
How was pamidronate expected to keep Mr. Kessler’s serum calcium in the normal range?
Pamidronate is a bisphosphonate compound that inhibits osteoclastic bone resorption. This inhibitor of bone resorption was given to offset the osteoclast-stimulating action of PTH-rp.
