SECTION VIII THE ENDOCRINE SYSTEM Parathyroid Adenoan with Renal Calculi A 62-year-old mn entered the emergency room with right flank pain.Urinalysis revealed hematuria.and x-ray studies demonstrated a stome in the right ureter.The stone vas subsequently passed spontaneously,and analysis revealed it to be calcium oxalate.Further history disclosed two previous episodes of kidney stomes,10 and 20 years before.Recently,the patient had noted lethargy,polyuria.polydipsia, muscle weakness,and diffuse bone pain.Laboratory studies revealed the following levels:plasma calciun was 12.3 ne/dl,phosphate was 1.9 ng/dl,creatinine was 1.5 ag/dl,and albunin was 5.9 g/dl.Plasma alkaline phosphatase and urinary hydroxyproline were increased.Urinary caleium excretion was 380 me/24 hr.After overnight water deprivation,urine osnolality did not exceed 290 mOsn/kg. 1.Is it certain.that this patient has biologically significant hyperealcemia? How would you determine this? 2.What are the most likely hormonal causes of this patient's hypercalcemia? 3.For each hormonal cause,what are the mechanisns by which hypercalcemia is induced? 4.Which hormonal cause is most likely in view of the low plasma phosphate level? 5.For each hormonal cause,what would be the expected effect on the plasaa levels of the other calciun regulatory hormones? 6.If hyperparathyroidisn caused the patiemt's hypercalcenia,how would this explain the remal stooes?Would a direct effect of parathyroid bornone (PTH)on the renal tubules he responsible? 7.If hyperparathyroidisn were present,how would this explain the bone pain and the increases in alkaline phosphatase and urinary hydroxyproline? 8 Why did the patient have polyuria and exhibit inability to concentrate his urine?What would urinary cyelie AMP excretion be if he had hyperthyroidisn?
SECTION VIII THE ENDOCRINE SYSTEM Parathyroid Adenoma with Renal Calculi A 62-year-old man entered the emergency room with right flank pain. Urinalysis revealed hematuria, and x-ray studies demonstrated a stone in the right ureter. The stone was subsequently passed spontaneously, and analysis revealed it to be calcium oxalate. Further history disclosed two previous episodes of kidney stones, 10 and 20 years before. Recently, the patient had noted lethargy, polyuria, polydipsia, muscle weakness, and diffuse bone pain. Laboratory studies revealed the following levels: plasma calcium was 12.3 mg/dl, phosphate was 1.9 mg/dl, creatinine was 1.5 mg/dl, and albumin was 5.9 g/dl. Plasma alkaline phosphatase and urinary hydroxyproline were increased. Urinary calcium excretion was 380 mg/24 hr. After overnight water deprivation, urine osmolality did not exceed 290 mOsm/kg. 1. Is it certain, that this patient has biologically significant hypercalcemia? How would you determine this? 2. What are the most likely hormonal causes of this patient's hypercalcemia? 3. For each hormonal cause, what are the mechanisms by which hypercalcemia is induced? 4. Which hormonal cause is most likely in view of the low plasma phosphate level? 5. For each hormonal cause, what would be the expected effect on the plasma levels of the other calcium regulatory hormones? 6. If hyperparathyroidism caused the patient's hypercalcemia, how would this explain the renal stones? Would a direct effect of parathyroid hormone (PTH) on the renal tubules be responsible? 7. If hyperparathyroidism were present, how would this explain the bone pain and the increases in alkaline phosphatase and urinary hydroxyproline? 8. Why did the patient have polyuria and exhibit inability to concentrate his urine? What would urinary cyclic AMP excretion be if he had hyperthyroidism?
9.When a single.very large parathyroid gland was surgically renoved from the patient's neck,the serum calciun level might fall to 6 mg/dl.What two mechanisms would account for this?In each instance.what would you expect the plasms PTH and plasna phosphate levels to be? 10.If the patient hyperventilated when his plasta calcium level was low,what might occur？ ANSVER 1.Total plasna calciun consists of a protein-bound (approximtely 506)and an ionized portion (approximately 50%).An increase above normal in plasma albunin of 1 g/dl,as in this patiemt,could account for a 0.8 ng/dl increase in the total plasma calciun level without increasing the biologically active ionized calciun level.To be certain that the ionized calcium level is increased,ft must be neasured directly. 2.The most likely bormonal causes are vitanin D,1,25-(0H)2-vitamin D.PTH, and PTlrp.T4 and certain lynphokines and cytokines are less coamon causes. 3.If excess vitanin D were ingested,this would be converted to 24-0H-vitanin D and hence to 1.25-(001)2-vitamin D.The latter active metaholite of vitamin D primrily increases calciun absorption fron the gut.A second effect is to increase bone resorption.PTH might be secreted in excess by am enlarged neoplastic parathyroid gland.PTH increases reabsorption of calcium fron the distal remal tubules:PTH directly stimulates resorption of bone:PTH stimulates renal production of 1,25-(0)2-vitanin D froa 25-0H-vitanin D by activating the 1-hydroxylase enzyme and it leads to an increased absorption of calcium from the gut.PTHrp,a larger molecule with an N-terminal amino acid sequence identical to PTH,is secreted by a variety of tumors.This molecule mimics all the above actions of PTH by interacting with the PTH receptor.T4 and cytokines,such as interleukin-1 and tumor necrosis factor,stimulate bone resorption. 4.The low plasta phosphate suggests PTH or PTHrp as the causes of the hypercalcemia.Both molecules increase urinary phosphate excretion by inhibiting
9. When a single, very large parathyroid gland was surgically removed from the patient's neck, the serum calcium level might fall to 6 mg/dl. What two mechanisms would account for this? In each instance, what would you expect the plasma PTH and plasma phosphate levels to be? 10. If the patient hyperventilated when his plasma calcium level was low, what might occur? ANSWER 1. Total plasma calcium consists of a protein-bound (approximately 50%) and an ionized portion (approximately 50%). An increase above normal in plasma albumin of 1 g/dl, as in this patient, could account for a 0.8 mg/dl increase in the total plasma calcium level without increasing the biologically active ionized calcium level. To be certain that the ionized calcium level is increased, it must be measured directly. 2. The most likely hormonal causes are vitamin D, 1,25-(OH)2-vitamin D, PTH, and PTHrp. T4 and certain lymphokines and cytokines are less common causes. 3. If excess vitamin D were ingested, this would be converted to 24-OH-vitamin D and hence to 1,25-(OH)2-vitamin D. The latter active metabolite of vitamin D primarily increases calcium absorption from the gut. A second effect is to increase bone resorption. PTH might be secreted in excess by an enlarged neoplastic parathyroid gland. PTH increases reabsorption of calcium from the distal renal tubules; PTH directly stimulates resorption of bone; PTH stimulates renal production of 1,25-(OH)2-vitamin D from 25-OH-vitamin D by activating the 1-hydroxylase enzyme and it leads to an increased absorption of calcium from the gut. PTHrp, a larger molecule with an N-terminal amino acid sequence identical to PTH, is secreted by a variety of tumors. This molecule mimics all the above actions of PTH by interacting with the PTH receptor. T4 and cytokines, such as interleukin-l and tumor necrosis factor, stimulate bone resorption. 4. The low plasma phosphate suggests PTH or PTHrp as the causes of the hypercalcemia. Both molecules increase urinary phosphate excretion by inhibiting
reabsorption of phosphate in the proximal renal tubules.This keeps plasma phosphate low.In comtrast,1.25-(0H)2-vitamin D,lynpbokines and cytokines,and T4 all increase entry of phosphate into the plasma by stimulating bone resorption:thus plasna phosphate tends to rise. 5.An excess of 1,25-(0H)2-vitamin D would decrease the plasma PTH level by negative feedback from the hypercalcemia and also by direct repression of transcription of the PTH gene.An excess of PTH would increase plasma 1.25-(0H)2-vitanin Dby stimulating its production (see preceding answer).An excess of PTHrp would decrease plasna PTH by negative feedback from the hypercalcemia: 1.25-(0H)2-vitanin D would remain normal or increase depending on the affinity of the renal tubular PTH receptor for PTlrp.T4,cytokines,and lymphokines would decrease plasma PTH by negative feedback from the hyperealcemia.Some cytokines might increase 1.25-(00)2-vitanin D levels by stimulating its synthesis within mononuclear cells. 6.Excess PTH secretion elevates plasma calciun As long as the glomerular filtration rate remains norml,this elevation increases the filtered load of calefun enough to saturate tubular reabsorption mechanisms and to increase calcium concentration in the urine.If the solubility product of calciun oxalate is exceeded. crystals form and aggregate into renal stones. 7.Excess PTH stimulates osteoclasts to enlarge,change their shape,and release enzynes that dicest bone completely.Pain is associated vith weakened bone structure resulting from the accelerated hone reabsorption.The products of collagen breakdown yield increased anounts of hydroxyproline in the urine.Bone formation by osteoblasts is normlly coupled to bone resorption:therefore hone formation also increases,and this is indicated by an elevated plasaa alkaline phosphatase. 8.Calcium and sodium share remal tubular reabsorption nechanisms.A high filtered load of calcium decreases sodium reabsorption and causes an osrotic diuresis and polyuria.In addition.high calcium levels inhibit renal responses to ADH.In hyperparathyroidis,urinary cyclic AMP excretion is increased because cyelic AMP is the second messenger for PTH
reabsorption of phosphate in the proximal renal tubules. This keeps plasma phosphate low. In contrast, 1,25-(OH)2-vitamin D, lymphokines and cytokines, and T4 all increase entry of phosphate into the plasma by stimulating bone resorption; thus plasma phosphate tends to rise. 5. An excess of 1,25-(OH)2-vitamin D would decrease the plasma PTH level by negative feedback from the hypercalcemia and also by direct repression of transcription of the PTH gene. An excess of PTH would increase plasma 1,25-(OH)2-vitamin D by stimulating its production (see preceding answer). An excess of PTHrp would decrease plasma PTH by negative feedback from the hypercalcemia; 1,25-(OH)2-vitamin D would remain normal or increase depending on the affinity of the renal tubular PTH receptor for PTHrp. T4, cytokines, and lymphokines would decrease plasma PTH by negative feedback from the hypercalcemia. Some cytokines might increase 1,25-(OH)2-vitamin D levels by stimulating its synthesis within mononuclear cells. 6. Excess PTH secretion elevates plasma calcium. As long as the glomerular filtration rate remains normal, this elevation increases the filtered load of calcium enough to saturate tubular reabsorption mechanisms and to increase calcium concentration in the urine. If the solubility product of calcium oxalate is exceeded, crystals form and aggregate into renal stones. 7. Excess PTH stimulates osteoclasts to enlarge, change their shape, and release enzymes that digest bone completely. Pain is associated with weakened bone structure resulting from the accelerated bone reabsorption. The products of collagen breakdown yield increased amounts of hydroxyproline in the urine. Bone formation by osteoblasts is normally coupled to bone resorption; therefore bone formation also increases, and this is indicated by an elevated plasma alkaline phosphatase. 8. Calcium and sodium share renal tubular reabsorption mechanisms. A high filtered load of calcium decreases sodium reabsorption and causes an osmotic diuresis and polyuria. In addition, high calcium levels inhibit renal responses to ADH. In hyperparathyroidism, urinary cyclic AMP excretion is increased because cyclic AMP is the second messenger for PTH
9.A sharp fall in plasma calciun could result from previous suppression of the unimvolved normal parathyroid glands by hypercalcemia or froa their danage during surgery.In this case,plasma PTH would be low and plasna phosphate would be high because of the loss of the inhibitory effect of PTl on renal phosphate reabsorptioe.Alternatively,the fall in plasaa calciun could result froa a sudden cessation of excessive rates of bone resorption caused by the high PTH levels. Excessive bone formation could.however,continue until the coupling mechanisa restored it to normal.During this period of rebuilding bone,calciun uptake by boee would exceed caleiu release from bone,so that plasma calciun would tend to be low.Plasma PTH would be high because of negative feedback.Plasna phosphate would be low because phosphate is also required for bone formation:therefore its uptake by bone would exceed its release fron bone.In addition.the secondarily elevated PTH level would stirulate urinary phosphate excretion. 10.Hyperventilation would lead to hypocapnia and respiratory alkalosis.The increase in pH would increase caleium binding to plasma protein,and thereby lower the biologically active ionized fraction of calcium.This can produce neuromuscular irritability with mascle spasms (tetany)and abnormal sensations (paresthesias)
9. A sharp fall in plasma calcium could result from previous suppression of the uninvolved normal parathyroid glands by hypercalcemia or from their damage during surgery. In this case, plasma PTH would be low and plasma phosphate would be high because of the loss of the inhibitory effect of PTH on renal phosphate reabsorption. Alternatively, the fall in plasma calcium could result from a sudden cessation of excessive rates of bone resorption caused by the high PTH levels. Excessive bone formation could, however, continue until the coupling mechanism restored it to normal. During this period of rebuilding bone, calcium uptake by bone would exceed calcium release from bone, so that plasma calcium would tend to be low. Plasma PTH would be high because of negative feedback. Plasma phosphate would be low because phosphate is also required for bone formation; therefore its uptake by bone would exceed its release from bone. In addition, the secondarily elevated PTH level would stimulate urinary phosphate excretion. 10.Hyperventilation would lead to hypocapnia and respiratory alkalosis. The increase in pH would increase calcium binding to plasma protein, and thereby lower the biologically active ionized fraction of calcium. This can produce neuromuscular irritability with muscle spasms (tetany) and abnormal sensations (paresthesias)