JOURNAL OF BONE A N D MINERAL RESEARCH Volume 6, Supplement 2, 1991 Mary Ann Liebert, Inc., Publishers
Pathophysiology of Primary Hyperparathyroidism ALLEN M. SPIEGEL
ABSTRACT Primary hyperparathyroidism (PHPT) is characterized by hypersecretion of parathyroid hormone (PTH) leading to hypercalcemia and relative hypophosphatemia. PTH acts by binding to cell surface receptors coupled to G proteins. Cyclic AMP is the classic second messenger of PTH action, but substantial evidence indicates that PTH also acts to stimulate formation of the dual second messengers, inositol trisphosphate and diacylglycerol, thereby mobilizing intracellular calcium. The physiologic actions of PTH include (1) an increase in extracellular fluid ionized calcium through direct actions on kidney and bone, the classic target organs for PTH, and (2) a decrease in extracellular fluid phosphate primarily through renal action. The pathophysiologic effects of PTH arise from (1) direct actions of PTH on bone and kidney, and possibly on nonclassic target organs, and (2) indirect effects of altered mineral homeostasis. PTH hypersecretion in PHPT can lead to bony demineralization, nephrolithiasis, and hypercalcemic crisis. PHPT may also be associated with mental disturbances, neuromuscular disease, hypertension, and glucose intolerance.
INTRODUCTION (PHPT) is characterized by excessive secretion of parathyroid hormone (PTH) leading to hypercalcemia and a tendency toward hypophosphatemia. PTH-related protein (PTHrP), a recently discovered polypeptide associated with hypercalcemia of malignancy, shares sequence homology and both hypercalcemic and hypophosphatemic actions with PTH. Messenger RNA for PTHrP has been found in some parathyroid tumors, but measurement of circulating PTHrP argues against a role for this peptide in the hypercalcemia of PHPT."' In the majority of cases of PHPT, hypersecretion of PTH is caused by benign neoplastic growth of a single parathyroid gland (adenoma). The etiology of parathyroid neoplasia and the basis for abnormal PTH secretion in P H P T are discussed in the next paper, by Marx. The present paper focuses on the mechanisms whereby hypersecretion of PTH disrupts mineral homeostasis and causes disease.
P
RIMARY HYPERPARATHYROIDISM
MECHANISM OF PTH ACTION PTH, like many other polypeptide hormones and monoamine neurotransmitters, binds to specific cell surface re-
ceptors on its target tissues. PTH receptors most likely belong to the G protein-coupled receptor gene superfamily. Receptors in this family, upon activation by bound hormone, interact with signal transducers termed G proteins.'2' The latter, in turn, interact with membrane-bound effector molecules, often enzymes that generate so-called second messengers. Cyclic AMP is the classic second messenger that mediates many of the actions of PTH,"' but it is likely that the dual second messenger products of phosphoinositide breakdown also mediate certain effects of PTH in both kidneyI4' and boneIs 6 , cells. Second messengers mediate PTH action by mobilizing int racellular calcium stores, as well as controlling protein phosphorylation. Structure-activity studies indicate that the ability to stimulate cyclic AMP production resides completely within the 1-34 amino-terminal portion of the 84 amino acid polypeptide.") Dissociation between the ability of certain PTH analogs to increase cyclic AMP in vitro versus serum calcium in vivo may reflect PTH receptor heterogeneit^.'^,^' It is possible that distinct PTH receptors couple to distinct G proteins to mediate stimulation of cyclic AMP formation and mobilization of intracellular calcium, respectively. The latter pathway may in fact be more relevant than stimulation of cyclic AMP formation in mediating the bone-resorbing action of PTH.[6)
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
s15
S16
SPIEGEL
The classic target organs for PTH action are bone and kidney. Within bone, PTH receptors have been convincingly identified on osteoblastic cells, but not on osteoclasts. In kidney, PTH receptors are found in the renal cortex on proximal and distal tubular cells. Less clearly proven is the occurrence of PTH receptors in various "nonclassic" sites, including circulating lymphocytes and monocytes, skin fibroblasts, liver, fat, and vascular endothelium and smooth muscle.
PHYSIOLOGIC ACTIONS OF PTH PTH raises serum calcium through direct actions on bone and kidney and indirect action on the gut.'8' In bone, PTH mobilizes calcium and phosphate into the extracellular fluid; in kidney, PTH enhances renal calcium reabsorption and stimulates the formation of 1,25-dihydroxyvitamin D, the active metabolite that increases intestinal calcium absorption. The phosphaturic action of PTH in the kidney counteracts the rise in serum phosphate caused by the skeletal action of the hormone and promotes relative hypophosphatemia. PTH also increases renal bicarbonate excretion. The net effect of PTH on renal calcium excretion is a complex function of increased filtered load (derived from skeletal calcium mobilization and/or enhanced intestinal absorption) and the renal anticalciuretic action. The net effect of PTH on bone is also complex and may be a function of both frequency and amplitude of PTH secretion, as well as other factors, such as vitamin D status. PTH can clearly cause an increase in osteoclastic resorption, particularly in cortical bone, but under certain experimental conditions PTH has also been found to stimulate bone formation."'
PATHOPHYSIOLOGIC EFFECTS OF PTH HYPERSECRETION Adverse clinical effects of PTH hypersecretion may be due to the hypercalcemia and/or hypophosphatemia caused by the hormone or to additional effects of elevated PTH itself. Normal cellular function depends on tightly regulated serum ionized calcium concentration and, to a lesser extent, serum phosphate concentration. Elevated serum calcium in symptomatic P H P T may cause widespread organ dysfunction. Symptoms include anorexia, nausea, vomiting, polydipsia, polyuria, lethargy, and, with extreme hypercalcemia, coma and death. Extreme elevations of circulating PTH dramatically increase osteoclastic bone resorption, culminating in "osteitis fibrosa cystica," the classic presentation of the disease, rarely seen t ~ d a y . ' ~Whether .~' mild P H P T is associated with a clinically significant loss of bone mineral and at what sites (trabecular versus cortical), is controversia1.(9.'0' This important question is discussed in detail in several papers in this volume. Increased urinary calcium excretion in P H P T can lead to nephrolithiasis. Why certain patients with P H P T develop hypercalciuria and nephrolithiasis and others with equiva-
lent hypercalcemia d o not is not clear. Earlier suggestions") that patients with nephrolithiasis represent a subgroup with higher serum 1,25-dihydroxyvitamin D causing intestinal calcium hyperabsorption have recently been questioned.'"l In the latter study, evidence of cortical bone demineralization was found in patients both with and without nephrolithiasis. Serum 1,25-dihydroxyvitamin D, moreover, was not significantly higher in the subgroup with nephrolithiasis. Nephrocalcinosis, or ectopic calcification in other sites, appears to be rare in uncomplicated PHPT, and progressive reduction in renal function due to mild hypercalcemia has not been well documented. Proximal muscle weakness, probably secondary to a neuropathic loss of type I1 muscle fibers, is another manifestation of PHPT."'' There is objective evidence for an increase in muscular strength following successful parathyroidectomy."." A variety of neuropsychiatric disorders, including depression and other nonspecific symptoms, such as fatigue and headache, are often encountered in individuals with PHPT, but it is difficult to prove that these are of increased incidence caused by PTH e x ~ e s s . ' ' ~Reports ' of peptic ulcer disease in P H P T may be due primarily to the association of Zollinger-Ellison syndrome with P H P T in multiple endocrine neoplasia type I , although hypercalcemia clearly potentiates gastric acid secretion. Abnormal glucose tolerance, possibly related to peripheral insulin resistance, has been reported as a reversible consequence of PHPT.l'sl The clinical significance of disturbed carbohydrate metabolism in PHPT, however, is unclear. Reports of the increased incidence of hypertension in P H P T are difficult to assess."6' Both diseases are relatively common and could coincide on a chance basis. PTH has been claimed to have a direct vasodilatory effect There are also data suggesting abnormalities in circulating calciotropic hormones in patients with some forms of hypertension.'I8) There is substantial controversy, however, as to the role of dietary calcium and calciotropic hormones in the pathogenesis and treatment of hypertension. Some, but not all, studies show reversibility of hypertension after successful surgery for PHPT.L'9' This area clearly requires further study. Hypercalcemia in P H P T has also been suggested to be a risk factor for the development of pancreatitis, atherosclerotic cardiovascular disease, and malignancy.(14)The putative mechanisms involved are rather speculative, and proof of a cause-and-effect relationship is lacking. Designing studies to assess accurately the morbidity and mortality of untreated "asymptomatic" P H P T and to determine the potential reversibility of any morbidity after successful parathyroidectomy represents a significant
REFERENCES Burtis W J , Brady TG, Orloff JJ, Ersbak JB, Warrell RP Jr. Olson BR, Wu TL, Mitnick ME, Broadus AE, Stewart A F 1990 lmmunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 322: 1106-1 112. Spiegel AM 1989 Receptor-effector coupling by G-proteins:
PATHOPHYSIOLOGY OF HYPERPARATHYROIDISM
3.
7.
8.
9.
10.
II.
Implications for endocrinology. Trends Endocrinol Metab 1: 72-76. Aurbach GD, Marx SJ, Spiegel AM 1985 Parathyroid hormone. calcitonin, and the calciferols. In: Wilson JD, Foster DW (eds.) Williams Textbook of Endocrinology. W.B. Saundcrs, Philadelphia, p. 1155. Hruska KA, Moskowitz D, Esbrit P, Civitelli R, Westbrook S, Huskey M 1987 Stimulation of inositol trisphosphate and diacylglycerol production in renal tubular cells by parathyroid hormone. J Clin Invest 79:230-239. Cosman F. Morrow B, Kopal M, Bilezikian J P 1989 Stimulation of inositol phosphate formation in ROS 17/2.8 cell membranes by guanine nucleotide, calcium, and parathyroid hormone. J Bone Miner Res 4:413-420. Lowik CW, van Lecuwen J P , van der Meer JM, van Zecland JK, Scheven BA, Herrmann-Erlee M P 1985 A two-receptor model for the action of parathyroid hormone on osteoblasts: A role for intracellular free calcium and CAMP. Cell Calcium 6~311-326. Aurbach GD, Marx SJ, Spiegel AM 1985 Parathyroid hormone. calcitonin, and the calciferols. In: Wilson JD, Foster DW (eds.) Williams Textbook of Endocrinology. W.B. Saunders, Philadelphia, p. 1147. Broadus AE 1982 Primary hyperparathyroidism viewed as a bihormonal disease process. Miner Electrolyte Metab 8:199214. Parisien M, Silverberg SJ, Shane E, Dempstcr D W , Bilezikian J P 1990 Bone disease in primary hyperparathyroidism. Endocrinol Metabol Clin North Am 19:19-34. Rao US, Wilson R J , Kleerekoper M, Parfitt AM 1988 Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: Evidence for biphasic disease course. J Clin Endocrinol Metab 67: 1294- 1298. Silverberg SJ, Shanc E. Jacobs T P , Siris ES, Gartcnberg F, Scldin D, Clcmens TL, Bilezikian J P 1990 Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am
S17 J Med 89:327-334. 12. Patten BM, Bilezikian J P , Mallette LE, Prince A , E:ngcl WK, Aurbach G D 1974 Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 80: 182-193. 13. Wersall-Robertson E, Hamberger B, Ehren H , Erikyson I
Pathophysiology of Primary Hyperparathyroidism ALLEN M. SPIEGEL
ABSTRACT Primary hyperparathyroidism (PHPT) is characterized by hypersecretion of parathyroid hormone (PTH) leading to hypercalcemia and relative hypophosphatemia. PTH acts by binding to cell surface receptors coupled to G proteins. Cyclic AMP is the classic second messenger of PTH action, but substantial evidence indicates that PTH also acts to stimulate formation of the dual second messengers, inositol trisphosphate and diacylglycerol, thereby mobilizing intracellular calcium. The physiologic actions of PTH include (1) an increase in extracellular fluid ionized calcium through direct actions on kidney and bone, the classic target organs for PTH, and (2) a decrease in extracellular fluid phosphate primarily through renal action. The pathophysiologic effects of PTH arise from (1) direct actions of PTH on bone and kidney, and possibly on nonclassic target organs, and (2) indirect effects of altered mineral homeostasis. PTH hypersecretion in PHPT can lead to bony demineralization, nephrolithiasis, and hypercalcemic crisis. PHPT may also be associated with mental disturbances, neuromuscular disease, hypertension, and glucose intolerance.
INTRODUCTION (PHPT) is characterized by excessive secretion of parathyroid hormone (PTH) leading to hypercalcemia and a tendency toward hypophosphatemia. PTH-related protein (PTHrP), a recently discovered polypeptide associated with hypercalcemia of malignancy, shares sequence homology and both hypercalcemic and hypophosphatemic actions with PTH. Messenger RNA for PTHrP has been found in some parathyroid tumors, but measurement of circulating PTHrP argues against a role for this peptide in the hypercalcemia of PHPT."' In the majority of cases of PHPT, hypersecretion of PTH is caused by benign neoplastic growth of a single parathyroid gland (adenoma). The etiology of parathyroid neoplasia and the basis for abnormal PTH secretion in P H P T are discussed in the next paper, by Marx. The present paper focuses on the mechanisms whereby hypersecretion of PTH disrupts mineral homeostasis and causes disease.
P
RIMARY HYPERPARATHYROIDISM
MECHANISM OF PTH ACTION PTH, like many other polypeptide hormones and monoamine neurotransmitters, binds to specific cell surface re-
ceptors on its target tissues. PTH receptors most likely belong to the G protein-coupled receptor gene superfamily. Receptors in this family, upon activation by bound hormone, interact with signal transducers termed G proteins.'2' The latter, in turn, interact with membrane-bound effector molecules, often enzymes that generate so-called second messengers. Cyclic AMP is the classic second messenger that mediates many of the actions of PTH,"' but it is likely that the dual second messenger products of phosphoinositide breakdown also mediate certain effects of PTH in both kidneyI4' and boneIs 6 , cells. Second messengers mediate PTH action by mobilizing int racellular calcium stores, as well as controlling protein phosphorylation. Structure-activity studies indicate that the ability to stimulate cyclic AMP production resides completely within the 1-34 amino-terminal portion of the 84 amino acid polypeptide.") Dissociation between the ability of certain PTH analogs to increase cyclic AMP in vitro versus serum calcium in vivo may reflect PTH receptor heterogeneit^.'^,^' It is possible that distinct PTH receptors couple to distinct G proteins to mediate stimulation of cyclic AMP formation and mobilization of intracellular calcium, respectively. The latter pathway may in fact be more relevant than stimulation of cyclic AMP formation in mediating the bone-resorbing action of PTH.[6)
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
s15
S16
SPIEGEL
The classic target organs for PTH action are bone and kidney. Within bone, PTH receptors have been convincingly identified on osteoblastic cells, but not on osteoclasts. In kidney, PTH receptors are found in the renal cortex on proximal and distal tubular cells. Less clearly proven is the occurrence of PTH receptors in various "nonclassic" sites, including circulating lymphocytes and monocytes, skin fibroblasts, liver, fat, and vascular endothelium and smooth muscle.
PHYSIOLOGIC ACTIONS OF PTH PTH raises serum calcium through direct actions on bone and kidney and indirect action on the gut.'8' In bone, PTH mobilizes calcium and phosphate into the extracellular fluid; in kidney, PTH enhances renal calcium reabsorption and stimulates the formation of 1,25-dihydroxyvitamin D, the active metabolite that increases intestinal calcium absorption. The phosphaturic action of PTH in the kidney counteracts the rise in serum phosphate caused by the skeletal action of the hormone and promotes relative hypophosphatemia. PTH also increases renal bicarbonate excretion. The net effect of PTH on renal calcium excretion is a complex function of increased filtered load (derived from skeletal calcium mobilization and/or enhanced intestinal absorption) and the renal anticalciuretic action. The net effect of PTH on bone is also complex and may be a function of both frequency and amplitude of PTH secretion, as well as other factors, such as vitamin D status. PTH can clearly cause an increase in osteoclastic resorption, particularly in cortical bone, but under certain experimental conditions PTH has also been found to stimulate bone formation."'
PATHOPHYSIOLOGIC EFFECTS OF PTH HYPERSECRETION Adverse clinical effects of PTH hypersecretion may be due to the hypercalcemia and/or hypophosphatemia caused by the hormone or to additional effects of elevated PTH itself. Normal cellular function depends on tightly regulated serum ionized calcium concentration and, to a lesser extent, serum phosphate concentration. Elevated serum calcium in symptomatic P H P T may cause widespread organ dysfunction. Symptoms include anorexia, nausea, vomiting, polydipsia, polyuria, lethargy, and, with extreme hypercalcemia, coma and death. Extreme elevations of circulating PTH dramatically increase osteoclastic bone resorption, culminating in "osteitis fibrosa cystica," the classic presentation of the disease, rarely seen t ~ d a y . ' ~Whether .~' mild P H P T is associated with a clinically significant loss of bone mineral and at what sites (trabecular versus cortical), is controversia1.(9.'0' This important question is discussed in detail in several papers in this volume. Increased urinary calcium excretion in P H P T can lead to nephrolithiasis. Why certain patients with P H P T develop hypercalciuria and nephrolithiasis and others with equiva-
lent hypercalcemia d o not is not clear. Earlier suggestions") that patients with nephrolithiasis represent a subgroup with higher serum 1,25-dihydroxyvitamin D causing intestinal calcium hyperabsorption have recently been questioned.'"l In the latter study, evidence of cortical bone demineralization was found in patients both with and without nephrolithiasis. Serum 1,25-dihydroxyvitamin D, moreover, was not significantly higher in the subgroup with nephrolithiasis. Nephrocalcinosis, or ectopic calcification in other sites, appears to be rare in uncomplicated PHPT, and progressive reduction in renal function due to mild hypercalcemia has not been well documented. Proximal muscle weakness, probably secondary to a neuropathic loss of type I1 muscle fibers, is another manifestation of PHPT."'' There is objective evidence for an increase in muscular strength following successful parathyroidectomy."." A variety of neuropsychiatric disorders, including depression and other nonspecific symptoms, such as fatigue and headache, are often encountered in individuals with PHPT, but it is difficult to prove that these are of increased incidence caused by PTH e x ~ e s s . ' ' ~Reports ' of peptic ulcer disease in P H P T may be due primarily to the association of Zollinger-Ellison syndrome with P H P T in multiple endocrine neoplasia type I , although hypercalcemia clearly potentiates gastric acid secretion. Abnormal glucose tolerance, possibly related to peripheral insulin resistance, has been reported as a reversible consequence of PHPT.l'sl The clinical significance of disturbed carbohydrate metabolism in PHPT, however, is unclear. Reports of the increased incidence of hypertension in P H P T are difficult to assess."6' Both diseases are relatively common and could coincide on a chance basis. PTH has been claimed to have a direct vasodilatory effect There are also data suggesting abnormalities in circulating calciotropic hormones in patients with some forms of hypertension.'I8) There is substantial controversy, however, as to the role of dietary calcium and calciotropic hormones in the pathogenesis and treatment of hypertension. Some, but not all, studies show reversibility of hypertension after successful surgery for PHPT.L'9' This area clearly requires further study. Hypercalcemia in P H P T has also been suggested to be a risk factor for the development of pancreatitis, atherosclerotic cardiovascular disease, and malignancy.(14)The putative mechanisms involved are rather speculative, and proof of a cause-and-effect relationship is lacking. Designing studies to assess accurately the morbidity and mortality of untreated "asymptomatic" P H P T and to determine the potential reversibility of any morbidity after successful parathyroidectomy represents a significant
REFERENCES Burtis W J , Brady TG, Orloff JJ, Ersbak JB, Warrell RP Jr. Olson BR, Wu TL, Mitnick ME, Broadus AE, Stewart A F 1990 lmmunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 322: 1106-1 112. Spiegel AM 1989 Receptor-effector coupling by G-proteins:
PATHOPHYSIOLOGY OF HYPERPARATHYROIDISM
3.
7.
8.
9.
10.
II.
Implications for endocrinology. Trends Endocrinol Metab 1: 72-76. Aurbach GD, Marx SJ, Spiegel AM 1985 Parathyroid hormone. calcitonin, and the calciferols. In: Wilson JD, Foster DW (eds.) Williams Textbook of Endocrinology. W.B. Saundcrs, Philadelphia, p. 1155. Hruska KA, Moskowitz D, Esbrit P, Civitelli R, Westbrook S, Huskey M 1987 Stimulation of inositol trisphosphate and diacylglycerol production in renal tubular cells by parathyroid hormone. J Clin Invest 79:230-239. Cosman F. Morrow B, Kopal M, Bilezikian J P 1989 Stimulation of inositol phosphate formation in ROS 17/2.8 cell membranes by guanine nucleotide, calcium, and parathyroid hormone. J Bone Miner Res 4:413-420. Lowik CW, van Lecuwen J P , van der Meer JM, van Zecland JK, Scheven BA, Herrmann-Erlee M P 1985 A two-receptor model for the action of parathyroid hormone on osteoblasts: A role for intracellular free calcium and CAMP. Cell Calcium 6~311-326. Aurbach GD, Marx SJ, Spiegel AM 1985 Parathyroid hormone. calcitonin, and the calciferols. In: Wilson JD, Foster DW (eds.) Williams Textbook of Endocrinology. W.B. Saunders, Philadelphia, p. 1147. Broadus AE 1982 Primary hyperparathyroidism viewed as a bihormonal disease process. Miner Electrolyte Metab 8:199214. Parisien M, Silverberg SJ, Shane E, Dempstcr D W , Bilezikian J P 1990 Bone disease in primary hyperparathyroidism. Endocrinol Metabol Clin North Am 19:19-34. Rao US, Wilson R J , Kleerekoper M, Parfitt AM 1988 Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: Evidence for biphasic disease course. J Clin Endocrinol Metab 67: 1294- 1298. Silverberg SJ, Shanc E. Jacobs T P , Siris ES, Gartcnberg F, Scldin D, Clcmens TL, Bilezikian J P 1990 Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am
S17 J Med 89:327-334. 12. Patten BM, Bilezikian J P , Mallette LE, Prince A , E:ngcl WK, Aurbach G D 1974 Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 80: 182-193. 13. Wersall-Robertson E, Hamberger B, Ehren H , Erikyson I
