The four parathyroid glands are located posterior to the thyroid gland. They produce parathyroid hormone (PTH), which is the primary regulator of calcium physiology. PTH acts directly on bone, where it induces calcium release; on the kidney, where it enhances calcium reabsorption in the distal tubules; and in the proximal renal tubules, where it synthesizes 1,25-dihydroxyvitamin D (1,25[OH]2D), a hormone that increases gastrointestinal calcium absorption. Serum PTH levels are tightly regulated by a negative feedback loop. Calcium, acting through the calcium-sensing receptor, and vitamin D, acting through its nuclear receptor, reduce PTH release and synthesis. Additional evidence indicates that fibroblast growth factor 23 (FGF23), a phosphaturic hormone, can suppress PTH secretion. Understanding the hormonal pathways that regulate calcium levels and bone metabolism is essential for effective diagnosis and management of a wide array of hyper- and hypocalcemic disorders.
Hyperparathyroidism, characterized by excess production of PTH, is a common cause of hypercalcemia and is usually the result of autonomously functioning adenomas or hyperplasia. Surgery for this disorder is highly effective and has been shown to reverse some of the deleterious effects of long-standing PTH excess on bone density. Humoral hypercalcemia of malignancy is also common and is usually due to the overproduction of parathyroid hormone–related peptide (PTHrP) by cancer cells. The similarities in the biochemical characteristics of hyperparathyroidism and humoral hypercalcemia of malignancy, first noted by Albright in 1941, are now known to reflect the actions of PTH and PTHrP through the same G protein–coupled PTH/PTHrP receptor.
The genetic basis of multiple endocrine neoplasia (MEN) types 1 and 2, familial hypocalciuric hypercalcemia (FHH), different forms of pseudohypoparathyroidism, Jansen’s syndrome, disorders of vitamin D synthesis and action, and the molecular events associated with parathyroid gland neoplasia have provided new insights into the regulation of calcium homeostasis. PTH and possibly some of its analogues are promising therapeutic agents for the treatment of postmenopausal or senile osteoporosis, and calcimimetic agents, which activate the calcium-sensing receptor, have provided new approaches for PTH suppression.
The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. The hormone acts directly on bone and kidney and indirectly on the intestine through its effects on synthesis of 1,25(OH)2D to increase serum calcium concentrations; in turn, PTH production is closely regulated by the concentration of serum ionized calcium. This feedback system is the critical homeostatic mechanism for maintenance of ECF calcium. Any tendency toward hypocalcemia, as might be induced by calcium- or vitamin D–deficient diets, is counteracted by an increased secretion of PTH. This in turn (1) increases the rate of dissolution of bone mineral, thereby increasing the flow of calcium from bone into blood; (2) reduces the renal clearance of calcium, returning more of the calcium and phosphate filtered at the glomerulus into ECF; and (3) increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH)2D. Immediate control of blood calcium is due to PTH effects on bone and, to a lesser extent, on renal calcium clearance. Maintenance of steady-state calcium balance, on the other hand, probably results from the effects of 1,25(OH)2D on calcium absorption (Chap. 423). The renal actions of the hormone are exerted at multiple sites and include inhibition of phosphate transport (proximal tubule), augmentation of calcium reabsorption (distal tubule), and stimulation of the renal 25(OH)D-1α-hydroxylase. As much as 12 mmol (500 mg) of calcium is transferred between the ECF and bone each day (a large amount in relation to the total ECF calcium pool), and PTH has a major effect on this transfer. The homeostatic role of the hormone can preserve calcium concentration in blood at the cost of bone demineralization.
PTH has multiple actions on bone, some direct and some indirect. PTH-mediated changes in bone calcium release can be seen within minutes. The chronic effects of PTH are to increase the number of bone cells, both osteoblasts and osteoclasts, and to increase the remodeling of bone; these effects are apparent within hours after the hormone is given and persist for hours after PTH is withdrawn. Continuous exposure to elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast-mediated bone resorption. However, the intermittent administration of PTH, elevating hormone levels for 1–2 h each day, leads to a net stimulation of bone formation rather than bone breakdown. Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. PTH (1–34) as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.
Osteoblasts (or stromal cell precursors), which have PTH/PTHrP receptors, are crucial to this bone-forming effect of PTH; osteoclasts, which mediate bone breakdown, lack such receptors. PTH-mediated stimulation of osteoclasts is indirect, acting in part through cytokines released from osteoblasts to activate osteoclasts; in experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone (Chap. 423).
PTH is an 84-amino-acid single-chain peptide. The amino-terminal portion, PTH (1–34), is highly conserved and is critical for the biologic actions of the molecule. Modified synthetic fragments of the amino-terminal sequence as small as PTH (1–11) are sufficient to activate the PTH/PTHrP receptor (see below). The carboxyl-terminal region of the full-length PTH (1–84) molecule also can bind to a separate binding protein/receptor (cPTH-R), but this receptor has been incompletely characterized. Fragments shortened at the amino-terminus possibly by binding to cPTH-R can reduce, directly or indirectly, some of the biologic actions of full-length PTH (1–84) and of PTH (1–34).
BIOSYNTHESIS, SECRETION, AND METABOLISM
Parathyroid cells have multiple methods of adapting to increased needs for PTH production. Most rapid (within minutes) is secretion of preformed hormone in response to hypocalcemia. Second, within hours, PTH mRNA expression is induced by sustained hypocalcemia. Finally, protracted challenge leads within days to cellular replication to increase parathyroid gland mass.
PTH is initially synthesized as a larger molecule (preproparathyroid hormone, consisting of 115 amino acids). After a first cleavage step to remove the “pre” sequence of 25 amino acid residues, a second cleavage step removes the “pro” sequence of 6 amino acid residues before secretion of the mature peptide comprising 84 residues. Mutations in the preprotein region of the gene can cause hypoparathyroidism by interfering with hormone synthesis, transport, or secretion.
Transcriptional suppression of the PTH gene by calcium is nearly maximal at physiologic calcium concentrations. Hypocalcemia increases transcriptional activity within hours. 1,25(OH)2D strongly suppresses PTH gene transcription. In patients with renal failure, IV administration of supraphysiologic levels of 1,25(OH)2D or analogues of this active metabolite can dramatically suppress PTH overproduction, which is sometimes difficult to control due to severe secondary hyperparathyroidism. Regulation of proteolytic destruction of preformed hormone (posttranslational regulation of hormone production) is an important mechanism for mediating rapid (within minutes) changes in hormone availability. High calcium increases and low calcium inhibit the proteolytic destruction of stored hormone.
Regulation of PTH Secretion
PTH secretion increases steeply to a maximum value of about five times the basal rate of secretion as the calcium concentration falls from normal to the range of 1.9–2.0 mmol/L (7.6–8.0 mg/dL; measured as total calcium). However, the ionized fraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion (see below).
ECF calcium controls PTH secretion by interaction with a calcium-sensing receptor (CaSR), a G protein–coupled receptor (GPCR) for which Ca2+ ions act as the primary ligand (see below). This receptor is a member of a distinctive subgroup of the GPCR superfamily that mediates its actions through the alpha-subunits of two related signaling G proteins, namely Gq and G11, and is characterized by a large extracellular domain suitable for “clamping” the small-molecule ligand. Stimulation of the CaSR by high calcium levels suppresses PTH secretion. The CaSR is present in parathyroid glands and the calcitonin-secreting cells of the thyroid (C cells), as well as in multiple other sites, including brain and kidney. Genetic evidence has revealed a key biologic role for the CaSR in parathyroid gland responsiveness to calcium and in renal calcium clearance. Heterozygous loss-of-function mutations in CaSR cause the syndrome of FHH, in which the blood calcium abnormality resembles that observed in hyperparathyroidism but with hypocalciuria; two more recently defined variants of FHH, FHH2 and FHH3, are caused either by heterozygous mutations in G11, one of the signaling proteins downstream of the CaSR, or by heterozygous mutations in AP2S1. Homozygous loss-of-function mutations in the CaSR are the cause of severe neonatal hyperparathyroidism, a disorder that can be lethal if not treated within the first days of life. On the other hand, heterozygous gain-of-function mutations cause a form of hypocalcemia resembling hypoparathyroidism (see below).
The secreted form of PTH is indistinguishable by immunologic criteria and by molecular size from the 84-amino-acid peptide (PTH[1–84]) extracted from glands. However, much of the immunoreactive material found in the circulation is smaller than the extracted or secreted hormone. The principal circulating fragments of immunoreactive hormone lack a portion of the critical amino-terminal sequence required for biologic activity and, hence, are biologically inactive fragments (so-called middle and carboxyl-terminal fragments). Much of the proteolysis of the hormone occurs in the liver and kidney. Peripheral metabolism of PTH does not appear to be regulated by physiologic states (high versus low calcium, etc.); hence, peripheral metabolism of hormone, although responsible for rapid clearance of secreted hormone, appears to be a high-capacity, metabolically invariant catabolic process.
The rate of clearance of the secreted 84-amino-acid peptide from blood is more rapid than the rate of clearance of the biologically inactive fragment(s) corresponding to the middle and carboxyl-terminal regions of PTH. Consequently, the interpretation of results obtained with earlier PTH radioimmunoassays was influenced by the nature of the peptide fragments detected by the antibodies.
Although the problems inherent in PTH measurements have been largely circumvented by use of double-antibody immunometric assays, it is now known that some of these assays detect, besides the intact molecule, large amino-terminally truncated forms of PTH, which are present in normal and uremic individuals in addition to PTH(1–84). The concentration of these fragments relative to that of intact PTH(1–84) is higher with induced hypercalcemia than in eucalcemic or hypocalcemic conditions and is higher in patients with impaired renal function. PTH(7–84) has been identified as a major component of these amino-terminally truncated fragments. Growing evidence suggests that the PTH(7–84) (and probably related amino-terminally truncated fragments) can act, through yet undefined mechanisms, as an inhibitor of PTH action and may be of clinical significance, particularly in patients with chronic kidney disease. In this group of patients, efforts to prevent secondary hyperparathyroidism by a variety of measures (vitamin D analogues, higher calcium intake, higher dialysate calcium, phosphate-lowering strategies, and calcimetic drugs) can lead to oversuppression of the parathyroid glands since some amino-terminally truncated PTH fragments, such as PTH(7–84), react in many immunometric PTH assays (now termed second-generation assays; see below under “Diagnosis”), thus overestimating the levels of biologically active, intact PTH. Such excessive parathyroid gland suppression in chronic kidney disease can lead to adynamic bone disease (see below), which has been associated with further impaired growth in children and increased bone fracture rates in adults, and can furthermore lead to significant hypercalcemia. The measurement of PTH with newer third-generation immunoassays, which use detection antibodies directed against extreme amino-terminal PTH epitopes and thus detect only full-length PTH(1–84), may provide some advantage to prevent bone disease in chronic kidney disease.
PARATHYROID HORMONE–RELATED PROTEIN (PTHrP)
PTHrP is responsible for most instances of humoral hypercalcemia of malignancy (Chap. 121), a syndrome that resembles primary hyperparathyroidism but without elevated PTH levels. Most cell types normally produce PTHrP, including brain, pancreas, heart, lung, mammary tissue, placenta, endothelial cells, and smooth muscle. In fetal animals, PTHrP directs transplacental calcium transfer, and high concentrations of PTHrP are produced in mammary tissue and secreted into milk, but the biologic significance of the very high concentrations of this hormone in breast milk is unknown. PTHrP also plays an essential role in endochondral bone formation and in branching morphogenesis of the breast, and possibly in uterine contraction and other biologic functions.
PTH and PTHrP, although products of different genes, exhibit considerable functional and structural homology (Fig. 424-1) and have evolved from a shared ancestral gene. The structure of the gene encoding human PTHrP, however, is more complex than that of PTH, containing multiple additional exons, which can undergo alternate splicing patterns during formation of the mature mRNA. Protein products of 139, 141, and 173 amino acids are produced, and other molecular forms may result from tissue-specific degradation at accessible internal cleavage sites. The biologic roles of these various molecular species and the nature of the circulating forms of PTHrP are unclear. In fact, it is uncertain whether PTHrP circulates at any significant level in adults. As a paracrine factor, PTHrP may be produced, act, and be destroyed locally within tissues. In adults, PTHrP appears to have little influence on calcium homeostasis, except in disease states, when large tumors, especially of the squamous cell type as well as renal cell carcinomas, lead to massive overproduction of the hormone and hypercalcemia.
Schematic diagram to illustrate similarities and differences in structure of human parathyroid hormone (PTH) and human PTH-related peptide (PTHrP). Close structural (and functional) homology exists between the first 30 amino acids of hPTH and hPTHrP. The PTHrP sequence may be ≥144 amino acid residues in length. PTH is only 84 residues long; after residue 30, there is little structural homology between the two. Dashed lines in the PTHrP sequence indicate identity; underlined residues, although different from those of PTH, still represent conservative changes (charge or polarity preserved). Ten amino acids are identical, and a total of 20 of 30 are homologues.
PTH AND PTHrP HORMONE ACTION
Both PTH and PTHrP bind to and activate the PTH/PTHrP receptor. The PTH/PTHrP receptor (also known as the PTH-1 receptor, PTH1R) belongs to a subfamily of GPCRs that includes the receptors for calcitonin, glucagon, secretin, vasoactive intestinal peptide, and other peptides. Although both ligands activate the PTH1R, the two peptides induce distinct responses in the receptor, which explains how a single receptor without isoforms can serve two biologic roles. The extracellular regions of the receptor are involved in hormone binding, and the intracellular domains, after hormone activation, bind G protein subunits to transduce hormone signaling into cellular responses through the stimulation of second messenger formation. A second receptor that binds PTH, originally termed the PTH-2 receptor (PTH2R), is primarily expressed in brain, pancreas, and testis. Different mammalian PTH1Rs respond equivalently to PTH and PTHrP, at least when tested with traditional assays, whereas only the human PTH2R responds efficiently to PTH (but not to PTHrP). PTH2Rs from other species show little or no stimulation of second-messenger formation in response to PTH or PTHrP. The endogenous ligand of the PTH2R was shown to be a hypothalamic peptide referred to as tubular infundibular peptide of 39 residues, TIP39, that is distantly related to PTH and PTHrP. The PTH1R and the PTH2R can be traced backward in evolutionary time to fish; in fact, the zebrafish genome contains, in addition to the PTH1R and the PTH2R orthologs, a third receptor, the PTH3R, that is more closely related to the fish PTH1R than to the fish PTH2R. The evolutionary conservation of structure and function suggests important biologic roles for these receptors, even in fish, which lack discrete parathyroid glands but produce two molecules that are closely related to mammalian PTH.
Studies using the cloned PTH1R confirm that it can be coupled to more than one G protein and second-messenger pathway, apparently explaining the multiplicity of pathways stimulated by PTH. Activation of protein kinases (A and C) and calcium transport channels is associated with a variety of hormone-specific tissue responses. These responses include inhibition of phosphate and bicarbonate transport, stimulation of calcium transport, and activation of renal 1α-hydroxylase in the kidney. The responses in bone include effects on collagen synthesis, alkaline phosphatase, ornithine decarboxylase, citrate decarboxylase, and glucose-6-phosphate dehydrogenase activities; phospholipid synthesis; and calcium and phosphate transport. Ultimately, these biochemical events lead to an integrated hormonal response in bone turnover and calcium homeostasis. PTH also activates Na+/Ca2+ exchangers at renal distal tubular sites and stimulates translocation of preformed calcium transport channels, moving them from the interior to the apical surface to increase tubular uptake of calcium. PTH-dependent stimulation of phosphate excretion (reducing reabsorption—the opposite effect from actions on calcium in the kidney) involves the downregulation of two sodium-dependent phosphate co-transporters, NPT2a and NPT2c, and their expression at the apical membrane, thereby reducing phosphate reabsorption in the proximal renal tubules. Similar mechanisms may be involved in other renal tubular transporters that are influenced by PTH. Recent studies reaffirm the critical linkage of blood phosphate lowering to net calcium entry into blood by PTH action and emphasize the participation of bone cells other than osteoclasts in the rapid calcium-elevating actions of PTH.
PTHrP exerts important developmental influences on fetal bone development and in adult physiology. A homozygous ablation of the gene encoding PTHrP (or disruption of the PTH1R gene) in mice causes a lethal phenotype in which animals are born with pronounced acceleration of chondrocyte maturation that resembles a lethal form of chondrodysplasia in humans that is caused by homozygous or compound heterozygous, inactivating PTH1R mutations (Fig. 424-2). Heterozygous PTH1R mutations in humans furthermore can be a cause of delayed tooth eruption, and mice that are heterozygous for ablation of the PTHrP gene display reduced mineral density consistent with osteoporosis. Experiments with these mouse models point to a hitherto unappreciated role of PTHrP as a paracrine/autocrine factor that modulates bone metabolism in adults as well as during bone development.
Dual role for the actions of the PTH/PTHrP receptor (PTH1R). Parathyroid hormone (PTH; endocrine-calcium homeostasis) and PTH-related peptide (PTHrP; paracrine–multiple tissue actions including growth plate cartilage in developing bone) use the single receptor for their disparate functions mediated by the amino-terminal 34 residues of either peptide. Other regions of both ligands interact with other receptors (not shown).
(See also Chap. 408) Calcitonin is a hypocalcemic peptide hormone that in several mammalian species acts as an indirect antagonist to the calcemic actions of PTH. Calcitonin seems to be of limited physiologic significance in humans, at least with regard to calcium homeostasis. It is of medical significance because of its role as a tumor marker in sporadic and hereditary cases of medullary carcinoma and its medical use as an adjunctive treatment in severe hypercalcemia and in Paget’s disease of bone.
The hypocalcemic activity of calcitonin is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance. These effects are mediated by receptors on osteoclasts and renal tubular cells. Calcitonin exerts additional effects through receptors present in the brain, the gastrointestinal tract, and the immune system. The hormone, for example, exerts analgesic effects directly on cells in the hypothalamus and related structures, possibly by interacting with receptors for related peptide hormones such as calcitonin gene–related peptide (CGRP) or amylin. Both of these ligands have specific high-affinity receptors that share considerable structural similarity with the PTH1R and can also bind to and activate calcitonin receptors. The calcitonin receptor shares considerable structural similarity with the PTH1R.
The thyroid is the major source of the hormone, and the cells involved in calcitonin synthesis arise from neural crest tissue. During embryogenesis, these cells migrate into the ultimobranchial body, derived from the last branchial pouch. In submammalian vertebrates, the ultimobranchial body constitutes a discrete organ, anatomically separate from the thyroid gland; in mammals, the ultimobranchial gland fuses with and is incorporated into the thyroid gland.
The naturally occurring calcitonins consist of a peptide chain of 32 amino acids. There is considerable sequence variability among species. Calcitonin from salmon, which is used therapeutically, is 10–100 times more potent than mammalian forms in lowering serum calcium.
There are two calcitonin genes, α and β; the transcriptional control of these genes is complex. Two different mRNA molecules are transcribed from the α gene; one is translated into the precursor for calcitonin, and the other message is translated into an alternative product, CGRP. CGRP is synthesized wherever the calcitonin mRNA is expressed (e.g., in medullary carcinoma of the thyroid). The β, or CGRP-2, gene is transcribed into the mRNA for CGRP in the central nervous system (CNS); this gene does not produce calcitonin, however. CGRP has cardiovascular actions and may serve as a neurotransmitter or play a developmental role in the CNS.
The circulating level of calcitonin in humans is lower than that in many other species. In humans, even extreme variations in calcitonin production do not change calcium and phosphate metabolism; no definite effects are attributable to calcitonin deficiency (totally thyroidectomized patients receiving only replacement thyroxine) or excess (patients with medullary carcinoma of the thyroid, a calcitonin-secreting tumor) (Chap. 408). Calcitonin has been a useful pharmacologic agent to suppress bone resorption in Paget’s disease (Chap. 426e) and osteoporosis (Chap. 425) and in the treatment of hypercalcemia of malignancy (see below). However, bisphosphonates are usually more effective, and the physiologic role, if any, of calcitonin in humans is uncertain. On the other hand, ablation of the calcitonin gene (combined because of the close proximity with ablation of the CGRP gene) in mice leads to reduced bone mineral density, suggesting that its biologic role in mammals is still not fully understood.
(See also Chap. 65) Hypercalcemia can be a manifestation of a serious illness such as malignancy or can be detected coincidentally by laboratory testing in a patient with no obvious illness. The number of patients recognized with asymptomatic hypercalcemia, usually hyperparathyroidism, increased in the late twentieth century.
Whenever hypercalcemia is confirmed, a definitive diagnosis must be established. Although hyperparathyroidism, a frequent cause of asymptomatic hypercalcemia, is a chronic disorder in which manifestations, if any, may be expressed only after months or years, hypercalcemia can also be the earliest manifestation of malignancy, the second most common cause of hypercalcemia in the adult. The causes of hypercalcemia are numerous (Table 424-1), but hyperparathyroidism and cancer account for 90% of all cases.
TABLE 424-1Classification of Causes of Hypercalcemia ||Download (.pdf) TABLE 424-1 Classification of Causes of Hypercalcemia
Multiple endocrine neoplasia
Familial hypocalciuric hypercalcemia
Solid tumor with metastases (breast)
Solid tumor with humoral mediation of hypercalcemia (lung, kidney)
Hematologic malignancies (multiple myeloma, lymphoma, leukemia)
Vitamin D intoxication
↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases
↑ 1,25(OH)2D; impaired 1,25(OH)2D metabolism due to 24-hydroxylase deficiency
Associated with High Bone Turnover
Vitamin A intoxication
Associated with Renal Failure
Severe secondary hyperparathyroidism
Before undertaking a diagnostic workup, it is essential to be sure that true hypercalcemia, not a false-positive laboratory test, is present. A false-positive diagnosis of hypercalcemia is usually the result of inadvertent hemoconcentration during blood collection or elevation in serum proteins such as albumin. Hypercalcemia is a chronic problem, and it is cost-effective to obtain several serum calcium measurements; these tests need not be in the fasting state.
Clinical features are helpful in differential diagnosis. Hypercalcemia in an adult who is asymptomatic is usually due to primary hyperparathyroidism. In malignancy-associated hypercalcemia, the disease is usually not occult; rather, symptoms of malignancy bring the patient to the physician, and hypercalcemia is discovered during the evaluation. In such patients, the interval between detection of hypercalcemia and death, especially without vigorous treatment, is often <6 months. Accordingly, if an asymptomatic individual has had hypercalcemia or some manifestation of hypercalcemia such as kidney stones for more than 1 or 2 years, it is unlikely that malignancy is the cause. Nevertheless, differentiating primary hyperparathyroidism from occult malignancy can occasionally be difficult, and careful evaluation is required, particularly when the duration of the hypercalcemia is unknown. Hypercalcemia not due to hyperparathyroidism or malignancy can result from excessive vitamin D action, impaired metabolism of 1,25(OH)2D, high bone turnover from any of several causes, or renal failure (Table 424-1). Dietary history and a history of ingestion of vitamins or drugs are often helpful in diagnosing some of the less frequent causes. Immunometric PTH assays serve as the principal laboratory test in establishing the diagnosis.
Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urine output, a short QT interval in the electrocardiogram, and, in some patients, cardiac arrhythmias. There is a variable relation from one patient to the next between the severity of hypercalcemia and the symptoms. Generally, symptoms are more common at calcium levels >2.9–3.0 mmol/L (11.6–12.0 mg/dL), but some patients, even at this level, are asymptomatic. When the calcium level is >3.2 mmol/L (12.8 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal excretion. Severe hypercalcemia, usually defined as ≥3.7–4.5 mmol/L (14.8–18.0 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.
Acute management of the hypercalcemia is usually successful. The type of treatment is based on the severity of the hypercalcemia and the nature of associated symptoms, as outlined below.
Natural History and Incidence
Primary hyperparathyroidism is a generalized disorder of calcium, phosphate, and bone metabolism due to an increased secretion of PTH. The elevation of circulating hormone usually leads to hypercalcemia and hypophosphatemia. There is great variation in the manifestations. Patients may present with multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers, mental changes, and, less frequently, extensive bone resorption. However, with greater awareness of the disease and wider use of multiphasic screening tests, including measurements of blood calcium, the diagnosis is frequently made in patients who have no symptoms and minimal, if any, signs of the disease other than hypercalcemia and elevated levels of PTH. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime. This milder form of the disease is usually termed asymptomatic hyperparathyroidism. Rarely, hyperparathyroidism develops or worsens abruptly and causes severe complications such as marked dehydration and coma, so-called hypercalcemic parathyroid crisis.
The annual incidence of the disease is calculated to be as high as 0.2% in patients >60, with an estimated prevalence, including undiscovered asymptomatic patients, of ≥1%; some reports suggest the incidence may be declining. If confirmed, these changing estimates may reflect less frequent routine testing of serum calcium in recent years, earlier overestimates in incidence, or unknown factors. The disease has a peak incidence between the third and fifth decades but occurs in young children and in the elderly.
Parathyroid tumors are most often encountered as isolated adenomas without other endocrinopathy. They may also arise in hereditary syndromes such as MEN syndromes. Parathyroid tumors may also arise as secondary to underlying disease (excessive stimulation in secondary hyperparathyroidism, especially chronic renal failure) or after other forms of excessive stimulation such as lithium therapy. These etiologies are discussed below.
A single abnormal gland is the cause in ~80% of patients; the abnormality in the gland is usually a benign neoplasm or adenoma and rarely a parathyroid carcinoma. Some surgeons and pathologists report that the enlargement of multiple glands is common; double adenomas are reported. In ~15% of patients, all glands are hyperfunctioning; chief cell parathyroid hyperplasia is usually hereditary and frequently associated with other endocrine abnormalities.
HEREDITARY SYNDROMES AND MULTIPLE PARATHYROID TUMORS
Hereditary hyperparathyroidism can occur without other endocrine abnormalities but is usually part of a multiple endocrine neoplasia (MEN) syndrome (Chap. 408). MEN 1 (Wermer’s syndrome) consists of hyperparathyroidism and tumors of the pituitary and pancreas, often associated with gastric hypersecretion and peptic ulcer disease (Zollinger-Ellison syndrome). MEN 2A is characterized by pheochromocytoma and medullary carcinoma of the thyroid, as well as hyperparathyroidism; MEN 2B has additional associated features such as multiple neuromas but usually lacks hyperparathyroidism. Each of these MEN syndromes is transmitted in an apparent autosomal dominant manner, although, as noted below, the genetic basis of MEN 1 involves biallelic loss of a tumor suppressor.
The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in families with parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors. This disorder is caused by mutations in CDC73 (HRPT2), and mutations in this gene are also observed in parathyroid cancers. Some kindreds exhibit hereditary hyperparathyroidism without other endocrinopathies. This disorder is often termed nonsyndromic familial isolated hyperparathyroidism (FIHP). There is speculation that these families may be examples of variable expression of the other syndromes such as MEN 1, MEN 2, or the HPT-JT syndrome, but they may also have distinctive, still unidentified genetic causes.
Adenomas are most often located in the inferior parathyroid glands, but in 6–10% of patients, parathyroid adenomas may be located in the thymus, the thyroid, the pericardium, or behind the esophagus. Adenomas are usually 0.5–5 g in size but may be as large as 10–20 g (normal glands weigh 25 mg on average). Chief cells are predominant in both hyperplasia and adenoma. With chief cell hyperplasia, the enlargement may be so asymmetric that some involved glands appear grossly normal. If generalized hyperplasia is present, however, histologic examination reveals a uniform pattern of chief cells and disappearance of fat even in the absence of an increase in gland weight. Thus, microscopic examination of biopsy specimens of several glands is essential to interpret findings at surgery.
Parathyroid carcinoma is often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule. Recurrent parathyroid carcinoma is usually slow-growing with local spread in the neck, and surgical correction of recurrent disease may be feasible. Occasionally, however, parathyroid carcinoma is more aggressive, with distant metastases (lung, liver, and bone) found at the time of initial operation. It may be difficult to appreciate initially that a primary tumor is carcinoma; increased numbers of mitotic figures and increased fibrosis of the gland stroma may precede invasion. The diagnosis of carcinoma is often made in retrospect. Hyperparathyroidism from a parathyroid carcinoma may be indistinguishable from other forms of primary hyperparathyroidism but is usually more severe clinically. A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with care to avoid capsular rupture. Recent findings concerning the genetic basis of parathyroid carcinoma (distinct from that of benign adenomas) indicate the need, in these kindreds, for family screening (see below).
GENETIC DEFECTS ASSOCIATED WITH HYPERPARATHYROIDISM
As in many other types of neoplasia, two fundamental types of genetic defects have been identified in parathyroid gland tumors: (1) overactivity of protooncogenes and (2) loss of function of tumor-suppressor genes. The former, by definition, can lead to uncontrolled cellular growth and function by activation (gain-of-function mutation) of a single allele of the responsible gene, whereas the latter requires loss of function of both allelic copies. Biallelic loss of function of a tumor-suppressor gene is usually characterized by a germline defect (all cells) and an additional somatic deletion/mutation in the tumor (Fig. 424-3).
A. Schematic diagram indicating molecular events in tumor susceptibility. The patient with the hereditary abnormality (multiple endocrine neoplasia [MEN]) is envisioned as having one defective gene inherited from the affected parent on chromosome 11, but one copy of the normal gene is present from the other parent. In the monoclonal tumor (benign tumor), a somatic event, here partial chromosomal deletion, removes the remaining normal gene from a cell. In nonhereditary tumors, two successive somatic mutations must occur, a process that takes a longer time. By either pathway, the cell, deprived of growth-regulating influence from this gene, has unregulated growth and becomes a tumor. A different genetic locus also involving loss of a tumor-suppressor gene termed HRPT2 is involved in the pathogenesis of parathyroid carcinoma. (From A Arnold: J Clin Endocrine Metab 77:1108, 1993. Copyright 1993, The Endocrine Society.) B. Schematic illustration of the mechanism and consequences of gene rearrangement and overexpression of the PRAD1 protooncogene (pericentromeric inversion of chromosome 11) in parathyroid adenomas. The excessive expression of PRAD1 (a cell cycle control protein, cyclin D1) by the highly active parathyroid hormone (PTH) gene promoter in the parathyroid cell contributes to excess cellular proliferation. (From J Habener et al, in L DeGroot, JL Jameson [eds]: Endocrinology, 4th ed. Philadelphia, Saunders, 2001; with permission.)
Mutations in the MEN1 gene locus, encoding the protein MENIN, on chromosome 11q13 are responsible for causing MEN 1; the normal allele of this gene fits the definition of a tumor-suppressor gene. Inheritance of one mutated allele in this hereditary syndrome, followed by loss of the other allele via somatic cell mutation, leads to monoclonal expansion and tumor development. Also, in ~15–20% of sporadic parathyroid adenomas, both alleles of the MEN1 locus on chromosome 11 are somatically deleted, implying that the same defect responsible for MEN 1 can also cause the sporadic disease (Fig. 424-3A). Consistent with the Knudson hypothesis for two-step neoplasia in certain inherited cancer syndromes (Chap. 101e), the earlier onset of hyperparathyroidism in the hereditary syndromes reflects the need for only one mutational event to trigger the monoclonal outgrowth. In sporadic adenomas, typically occurring later in life, two different somatic events must occur before the MEN1 gene is silenced.
Other presumptive anti-oncogenes involved in hyperparathyroidism include a still unidentified gene mapped to chromosome 1p seen in 40% of sporadic parathyroid adenomas and a gene mapped to chromosome Xp11 in patients with secondary hyperparathyroidism and renal failure, who progressed to “tertiary” hyperparathyroidism, now known to reflect monoclonal outgrowths within previously hyperplastic glands.
A more complex pattern, still incompletely resolved, arises with genetic defects and carcinoma of the parathyroids. This appears to be due to biallelic loss of a functioning copy of a gene, HRPT2 (or CDC73), originally identified as the cause of the HPT-JT syndrome. Several inactivating mutations have been identified in HRPT2 (located on chromosome 1q21-31), which encodes a 531-amino-acid protein called parafibromin. The responsible genetic mutations in HRPT2 appear to be necessary, but not sufficient, for parathyroid cancer.
In general, the detection of additional genetic defects in these parathyroid tumor–related syndromes and the variations seen in phenotypic expression/penetrance indicate the multiplicity of the genetic factors responsible. Nonetheless, the ability to detect the presence of the major genetic contributors has greatly aided a more informed management of family members of patients identified in the hereditary syndromes such as MEN 1, MEN 2, and HPT-JT.
An important contribution from studies on the genetic origin of parathyroid carcinoma has been the realization that the mutations involve a different pathway than that involved with the benign gland enlargements. Unlike the pathogenesis of genetic alterations seen in colon cancer, where lesions evolve from benign adenomas to malignant disease by progressive genetic changes, the alterations commonly seen in most parathyroid cancers (HRPT2 mutations) are infrequently seen in sporadic parathyroid adenomas.
Abnormalities at the Rb gene were the first to be noted in parathyroid cancer. The Rb gene, a tumor-suppressor gene located on chromosome 13q14, was initially associated with retinoblastoma but has since been implicated in other neoplasias, including parathyroid carcinoma. Early studies implicated allelic deletions of the Rb gene in many parathyroid carcinomas and decreased or absent expression of the Rb protein. However, because there are often large deletions in chromosome 13 that include many genes in addition to the Rb locus (with similar findings in some pituitary carcinomas), it remains possible that other tumor-suppressor genes on chromosome 13 may be playing a role in parathyroid carcinoma.
Study of the parathyroid cancers found in some patients with the HPT-JT syndrome has led to identification of a much larger role for mutations in the HRPT2 gene in most parathyroid carcinomas, including those that arise sporadically, without apparent association with the HPT-JT syndrome. Mutations in the coding region have been identified in 75–80% of all parathyroid cancers analyzed, leading to the conclusion that, with addition of presumed mutations in the noncoding regions, this genetic defect may be seen in essentially all parathyroid carcinomas. Of special importance was the discovery that, in some sporadic parathyroid cancers, germline mutations have been found; this, in turn, has led to careful investigation of the families of these patients and a new clinical indication for genetic testing in this setting.
Hypercalcemia occurring in family members (who are also found to have the germline mutations) can lead to the finding, at parathyroid surgery, of premalignant parathyroid tumors.
Overall, it seems there are multiple factors in parathyroid cancer, in addition to the HRPT2 and Rb gene, although the HRPT2 gene mutation is the most invariant abnormality. RET encodes a tyrosine kinase type receptor; specific inherited germline mutations lead to a constitutive activation of the receptor, thereby explaining the autosomal dominant mode of transmission and the relatively early onset of neoplasia. In the MEN 2 syndrome, the RET protooncogene may be responsible for the earliest disorder detected, the polyclonal disorder (C cell hyperplasia, which then is transformed into a clonal outgrowth—a medullary carcinoma with the participation of other, still uncharacterized genetic defects).
In some parathyroid adenomas, activation of a protooncogene has been identified (Fig. 424-3B). A reciprocal translocation involving chromosome 11 has been identified that juxtaposes the PTH gene promoter upstream of a gene product termed PRAD-1, encoding a cyclin D protein that plays a key role in normal cell division. This translocation plus other mechanisms that cause an equivalent overexpression of cyclin D1 are found in 20–40% of parathyroid adenomas.
Mouse models have confirmed the role of several of the major identified genetic defects in parathyroid disease and the MEN syndromes. Loss of the MEN1 gene locus or overexpression of the PRAD-1 protooncogene or the mutated RET protooncogene have been analyzed by genetic manipulation in mice, with the expected onset of parathyroid tumors or medullary carcinoma, respectively.
Many patients with hyperparathyroidism are asymptomatic. Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970. With earlier detection, renal complications occur in <20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients, repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.
The distinctive bone manifestation of hyperparathyroidism is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago. Histologically, the pathognomonic features are an increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship’s lacunae) and a replacement of the normal cellular and marrow elements by fibrous tissue. X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption). In recent years, osteitis fibrosa cystica is very rare in primary hyperparathyroidism, probably due to the earlier detection of the disease.
Dual-energy x-ray absorptiometry (DEXA) of the spine provides reproducible quantitative estimates (within a few percent) of spinal bone density. Similarly, bone density in the extremities can be quantified by densitometry of the hip or of the distal radius at a site chosen to be primarily cortical. Computed tomography (CT) is a very sensitive technique for estimating spinal bone density, but reproducibility of standard CT is no better than 5%. Newer CT techniques (spiral, “extreme” CT) are more reproducible but are currently available in a limited number of medical centers. Cortical bone density is reduced while cancellous bone density, especially in the spine, is relatively preserved. In symptomatic patients, dysfunctions of the CNS, peripheral nerve and muscle, gastrointestinal tract, and joints also occur. It has been reported that severe neuropsychiatric manifestations may be reversed by parathyroidectomy. When present in symptomatic patients, neuromuscular manifestations may include proximal muscle weakness, easy fatigability, and atrophy of muscles and may be so striking as to suggest a primary neuromuscular disorder. The distinguishing feature is the complete regression of neuromuscular disease after surgical correction of the hyperparathyroidism.
Gastrointestinal manifestations are sometimes subtle and include vague abdominal complaints and disorders of the stomach and pancreas. Again, cause and effect are unclear. In MEN 1 patients with hyperparathyroidism, duodenal ulcer may be the result of associated pancreatic tumors that secrete excessive quantities of gastrin (Zollinger-Ellison syndrome). Pancreatitis has been reported in association with hyperparathyroidism, but the incidence and the mechanism are not established.
Much attention has been paid in recent years to the manifestations of and optimum management strategies for asymptomatic hyperparathyroidism. This is now the most prevalent form of the disease. Asymptomatic primary hyperparathyroidism is defined as biochemically confirmed hyperparathyroidism (elevated or inappropriately normal PTH levels despite hypercalcemia) with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such as features of renal or bone disease.
Three conferences on the topic have been held in the United States over the past two decades, with the most recent in 2008. The published proceedings include discussion of more subtle manifestations of disease, its natural history (without parathyroidectomy), and guidelines both for indications for surgery and medical monitoring in nonoperated patients.
Issues of concern include the potential for cardiovascular deterioration, the presence of subtle neuropsychiatric symptoms, and the longer-term status of skeletal integrity in patients not treated surgically. The current consensus is that medical monitoring rather than surgical correction of hyperparathyroidism may be justified in certain patients. The current recommendation is that patients who show mild disease, as defined by specific criteria (Table 424-2), can be safely followed under management guidelines (Table 424-3). There is, however, growing uncertainty about subtle disease manifestations and whether surgery is therefore indicated in most patients. Among the issues is the evidence of eventual (>8 years) deterioration in bone mineral density after a decade of relative stability. There is concern that this late-onset deterioration in bone density in nonoperated patients could contribute significantly to the well-known age-dependent fracture risk (osteoporosis). One study reported significant and sustained improvements in bone mineral density after successful parathyroidectomy, again raising the issue regarding benefits of surgery. Other randomized studies, however, did not report major gains after surgery.
TABLE 424-2Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidisma ||Download (.pdf) TABLE 424-2 Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidisma
|Parameter ||Guideline |
|Serum calcium (above normal) ||>1 mg/dL |
|24-h urinary calcium ||No indication |
|Creatinine clearance (calculated)b ||If <60 mL/min |
|Bone density ||T score <−2.5 at any of 3 sitesc |
|Age ||<50 |
TABLE 424-3Guidelines for Monitoring in Asymptomatic Primary Hyperparathyroidisma ||Download (.pdf) TABLE 424-3 Guidelines for Monitoring in Asymptomatic Primary Hyperparathyroidisma
|Parameter ||Guideline |
|Serum calcium ||Annually |
|24-h urinary calcium ||Recommended |
|Creatinine clearance ||Recommended |
|Serum creatinineb ||Annually |
|Bone density ||Annually (3 sites)a |
Cardiovascular disease including left ventricular hypertrophy, cardiac functional defects, and endothelial dysfunction have been reported as reversible in European patients with more severe symptomatic disease after surgery, leading to numerous studies of these cardiovascular features in those with milder disease. There are reports of endothelial dysfunction in patients with mild asymptomatic hyperparathyroidism, but the expert panels concluded that more observation is needed, especially regarding whether there is reversibility with surgery.
A topic of considerable interest and some debate is assessment of neuropsychiatric status and health-related quality of life (QOL) status in hyperparathyroid patients both before surgery and in response to parathyroidectomy. Several observational studies suggest considerable improvements in symptom score after surgery. Randomized studies of surgery versus observation, however, have yielded inconclusive results, especially regarding benefits of surgery. Most studies report that hyperparathyroidism is associated with increased neuropsychiatric symptoms, so the issue remains a significant factor in decisions regarding the impact of surgery in this disease.
The diagnosis is typically made by detecting an elevated immunoreactive PTH level in a patient with asymptomatic hypercalcemia (see “Differential Diagnosis: Special Tests,” below). Serum phosphate is usually low but may be normal, especially if renal failure has developed.
Several modifications in PTH assays have been introduced in efforts to improve their utility in light of information about metabolism of PTH (as discussed above). First-generation assays were based on displacement of radiolabeled PTH from antibodies that reacted with PTH (often also PTH fragments). Double-antibody or immunometric assays (one antibody that is usually directed against the carboxyl-terminal portion of intact PTH to capture the hormone and a second radio- or enzyme-labeled antibody that is usually directed against the amino-terminal portion of intact PTH) greatly improved the diagnostic discrimination of the tests by eliminating interference from circulating biologically inactive fragments, detected by the original first-generation assays. Double-antibody assays are now referred to as second-generation. Such PTH assays have in some centers and testing laboratories been replaced by third-generation assays after it was discovered that large PTH fragments, devoid of only the extreme amino-terminal portion of the PTH molecule, are also present in blood and are detected, incorrectly, as intact PTH. These amino-terminally truncated PTH fragments were prevented from registering in the newer third-generation assays by use of a detection antibody directed against the extreme amino-terminal epitope. These assays may be useful for clinical research studies as in management of chronic renal disease, but the consensus is that either second- or third-generation assays are useful in the diagnosis of primary hyperparathyroidism and for the diagnosis of high-turnover bone disease in chronic kidney disease.
Many tests based on renal responses to excess PTH (renal calcium and phosphate clearance; blood phosphate, chloride, magnesium; urinary or nephrogenous cyclic AMP [cAMP]) were used in earlier decades. These tests have low specificity for hyperparathyroidism and are therefore not cost-effective; they have been replaced by PTH immunometric assays combined with simultaneous blood calcium measurements (Fig. 424-4).
Levels of immunoreactive parathyroid hormone (PTH) detected in patients with primary hyperparathyroidism, hypercalcemia of malignancy, and hypoparathyroidism. Boxed area represents the upper and normal limits of blood calcium and/or immunoreactive PTH. (From SR Nussbaum, JT Potts, Jr, in L DeGroot, JL Jameson [eds]: Endocrinology, 4th ed. Philadelphia, Saunders, 2001; with permission.)
Surgical excision of the abnormal parathyroid tissue is the definitive therapy for this disease. As noted above, medical surveillance without operation for patients with mild, asymptomatic disease is, however, still preferred by some physicians and patients, particularly when the patients are more elderly. Evidence favoring surgery, if medically feasible, is growing because of concerns about skeletal, cardiovascular, and neuropsychiatric disease, even in mild hyperparathyroidism.
Two surgical approaches are generally practiced. The conventional parathyroidectomy procedure was neck exploration with general anesthesia; this procedure is being replaced in many centers, whenever feasible, by an outpatient procedure with local anesthesia, termed minimally invasive parathyroidectomy.
Parathyroid exploration is challenging and should be undertaken by an experienced surgeon. Certain features help in predicting the pathology (e.g., multiple abnormal glands in familial cases). However, some critical decisions regarding management can be made only during the operation.
With conventional surgery, one approach is still based on the view that typically only one gland (the adenoma) is abnormal. If an enlarged gland is found, a normal gland should be sought. In this view, if a biopsy of a normal-sized second gland confirms its histologic (and presumed functional) normality, no further exploration, biopsy, or excision is needed. At the other extreme is the minority viewpoint that all four glands be sought and that most of the total parathyroid tissue mass be removed. The concern with the former approach is that the recurrence rate of hyperparathyroidism may be high if a second abnormal gland is missed; the latter approach could involve unnecessary surgery and an unacceptable rate of hypoparathyroidism. When normal glands are found in association with one enlarged gland, excision of the single adenoma usually leads to cure or at least years free of symptoms. Long-term follow-up studies to establish true rates of recurrence are limited.
Recently, there has been growing experience with new surgical strategies that feature a minimally invasive approach guided by improved preoperative localization and intraoperative monitoring by PTH assays. Preoperative 99mTc sestamibi scans with single-photon emission CT (SPECT) are used to predict the location of an abnormal gland and intraoperative sampling of PTH before and at 5-min intervals after removal of a suspected adenoma to confirm a rapid fall (>50%) to normal levels of PTH. In several centers, a combination of preoperative sestamibi imaging, cervical block anesthesia, minimal surgical incision, and intraoperative PTH measurements has allowed successful outpatient surgical management with a clear-cut cost benefit compared to general anesthesia and more extensive neck surgery. The use of these minimally invasive approaches requires clinical judgment to select patients unlikely to have multiple gland disease (e.g., MEN or secondary hyperparathyroidism). The growing acceptance of the technique and its relative ease for the patient has lowered the threshold for surgery.
Severe hypercalcemia may provide a preoperative clue to the presence of parathyroid carcinoma. In such cases, when neck exploration is undertaken, the tissue should be widely excised; care is taken to avoid rupture of the capsule to prevent local seeding of tumor cells.
Multiple-gland hyperplasia, as predicted in familial cases, poses more difficult questions of surgical management. Once a diagnosis of hyperplasia is established, all the glands must be identified. Two schemes have been proposed for surgical management. One is to totally remove three glands with partial excision of the fourth gland; care is taken to leave a good blood supply for the remaining gland. Other surgeons advocate total parathyroidectomy with immediate transplantation of a portion of a removed, minced parathyroid gland into the muscles of the forearm, with the view that surgical excision is easier from the ectopic site in the arm if there is recurrent hyperfunction.
In a minority of cases, if no abnormal parathyroid glands are found in the neck, the issue of further exploration must be decided. There are documented cases of five or six parathyroid glands and of unusual locations for adenomas such as in the mediastinum.
When a second parathyroid exploration is indicated, the minimally invasive techniques for preoperative localization such as ultrasound, CT scan, and isotope scanning are combined with venous sampling and/or selective digital arteriography in one of the centers specializing in these procedures. Intraoperative monitoring of PTH levels by rapid PTH immunoassays may be useful in guiding the surgery. At one center, long-term cures have been achieved with selective embolization or injection of large amounts of contrast material into the end-arterial circulation feeding the parathyroid tumor.
A decline in serum calcium occurs within 24 h after successful surgery; usually blood calcium falls to low-normal values for 3–5 days until the remaining parathyroid tissue resumes full hormone secretion. Acute postoperative hypocalcemia is likely only if severe bone mineral deficits are present or if injury to all the normal parathyroid glands occurs during surgery. In general, there are few problems encountered in patients with uncomplicated disease such as a single adenoma (the clear majority), who do not have symptomatic bone disease or a large deficit in bone mineral, who are vitamin D and magnesium sufficient, and who have good renal and gastrointestinal function. The extent of postoperative hypocalcemia varies with the surgical approach. If all glands are biopsied, hypocalcemia may be transiently symptomatic and more prolonged. Hypocalcemia is more likely to be symptomatic after second parathyroid explorations, particularly when normal parathyroid tissue was removed at the initial operation and when the manipulation and/or biopsy of the remaining normal glands are more extensive in the search for the missing adenoma.
Patients with hyperparathyroidism have efficient intestinal calcium absorption due to the increased levels of 1,25(OH)2D stimulated by PTH excess. Once hypocalcemia signifies successful surgery, patients can be put on a high-calcium intake or be given oral calcium supplements. Despite mild hypocalcemia, most patients do not require parenteral therapy. If the serum calcium falls to <2 mmol/L (8 mg/dL), and if the phosphate level rises simultaneously, the possibility that surgery has caused hypoparathyroidism must be considered. With unexpected hypocalcemia, coexistent hypomagnesemia should be considered, because it interferes with PTH secretion and causes functional hypoparathyroidism (Chap. 423).
Signs of hypocalcemia include symptoms such as muscle twitching, a general sense of anxiety, and positive Chvostek’s and Trousseau’s signs coupled with serum calcium consistently <2 mmol/L (8 mg/dL). Parenteral calcium replacement at a low level should be instituted when hypocalcemia is symptomatic. The rate and duration of IV therapy are determined by the severity of the symptoms and the response of the serum calcium to treatment. An infusion of 0.5–2 mg/kg per hour or 30–100 mL/h of a 1-mg/mL solution usually suffices to relieve symptoms. Usually, parenteral therapy is required for only a few days. If symptoms worsen or if parenteral calcium is needed for >2–3 days, therapy with a vitamin D analogue and/or oral calcium (2–4 g/d) should be started (see below). It is cost-effective to use calcitriol (doses of 0.5–1 μg/d) because of the rapidity of onset of effect and prompt cessation of action when stopped, in comparison to other forms of vitamin D. A rise in blood calcium after several months of vitamin D replacement may indicate restoration of parathyroid function to normal. It is also appropriate to monitor serum PTH serially to estimate gland function in such patients.
If magnesium deficiency was present, it can complicate the postoperative course since magnesium deficiency impairs the secretion of PTH. Hypomagnesemia should be corrected whenever detected. Magnesium replacement can be effective orally (e.g., MgCl2, MgOH2), but parenteral repletion is usual to ensure postoperative recovery, if magnesium deficiency is suspected due to low blood magnesium levels. Because the depressant effect of magnesium on central and peripheral nerve functions does not occur at levels <2 mmol/L (normal range 0.8–1.2 mmol/L), parenteral replacement can be given rapidly. A cumulative dose as great as 0.5–1 mmol/kg of body weight can be administered if severe hypomagnesemia is present; often, however, total doses of 20–40 mmol are sufficient. MEDICAL MANAGEMENT
The guidelines for recommending surgical intervention, if feasible (Table 424-2), as well as for monitoring patients with asymptomatic hyperparathyroidism who elect not to undergo parathyroidectomy (Table 424-3), reflect the changes over time since the first conference on the topic in 1990. Medical monitoring rather than corrective surgery is still acceptable, but it is clear that surgical intervention is the more frequently recommended option for the reasons noted above. Tightened guidelines favoring surgery include lowering the recommended level of serum calcium elevation, more careful attention to skeletal integrity through reference to peak skeletal mass at baseline (T scores) rather than age-adjusted bone density (Z scores), as well as the presence of any fragility fracture. The other changes noted in the two guidelines (Tables 424-2 and 424-3) reflect accumulated experience and practical consideration, such as a difficulty in quantity of urine collections. Despite the usefulness of the guidelines, the importance of individual patient and physician judgment and preference is clear in all recommendations.
When surgery is not selected, or not medically feasible, there is interest in the potential value of specific medical therapies. There is no long-term experience regarding specific clinical outcomes such as fracture prevention, but it has been established that bisphosphonates increase bone mineral density significantly without changing serum calcium (as does estrogen, but the latter is not favored because of reported adverse effects in other organ systems). Calcimimetics that lower PTH secretion lower calcium but do not affect bone mineral density.
OTHER PARATHYROID-RELATED CAUSES OF HYPERCALCEMIA
Lithium, used in the management of bipolar depression and other psychiatric disorders, causes hypercalcemia in ~10% of treated patients. The hypercalcemia is dependent on continued lithium treatment, remitting and recurring when lithium is stopped and restarted. The parathyroid adenomas reported in some hypercalcemic patients with lithium therapy may reflect the presence of an independently occurring parathyroid tumor; a permanent effect of lithium on parathyroid gland growth need not be implicated as most patients have complete reversal of hypercalcemia when lithium is stopped. However, long-standing stimulation of parathyroid cell replication by lithium may predispose to development of adenomas (as is documented in secondary hyperparathyroidism and renal failure).
At the levels achieved in blood in treated patients, lithium can be shown in vitro to shift the PTH secretion curve to the right in response to calcium; i.e., higher calcium levels are required to lower PTH secretion, probably acting at the calcium sensor (see below). This effect can cause elevated PTH levels and consequent hypercalcemia in otherwise normal individuals. Fortunately, there are usually alternative medications for the underlying psychiatric illness. Parathyroid surgery should not be recommended unless hypercalcemia and elevated PTH levels persist after lithium is discontinued.
GENETIC DISORDERS CAUSING HYPERPARATHYROID-LIKE SYNDROMES
Familial Hypocalciuric Hypercalcemia
FHH (also called familial benign hypercalcemia) is inherited as an autosomal dominant trait. Affected individuals are discovered because of asymptomatic hypercalcemia. Most cases of FHH (FHH1) are caused by an inactivating mutation in a single allele of the CaSR (see below), leading to inappropriately normal or even increased secretion of PTH, whereas another hypercalcemic disorder, namely the exceedingly rare Jansen’s disease, is caused by a constitutively active PTH/PTHrP receptor in target tissues. Neither FHH1 nor Jansen’s disease, however, is a growth disorder of the parathyroids. Other forms of FHH are caused either by heterozygous mutations in GNA11 (encoding G11), one of the signaling proteins downstream of the CaSR (FHH2), or by mutations in AP2S1 (FHH3).
The pathophysiology of FHH1 is now understood. The primary defect is abnormal sensing of the blood calcium by the parathyroid gland and renal tubule, causing inappropriate secretion of PTH and excessive reabsorption of calcium in the distal renal tubules. The CaSR is a member of the third family of GPCRs (type C or type III). The receptor responds to increased ECF calcium concentration by suppressing PTH secretion through second-messenger signaling involving the G protein alpha-subunits G11 and Gq, thereby providing negative-feedback regulation of PTH secretion. Many different inactivating CaSR mutations have been identified in patients with FHH1. These mutations lower the capacity of the sensor to bind calcium, and the mutant receptors function as though blood calcium levels were low; excessive secretion of PTH occurs from an otherwise normal gland. Approximately two-thirds of patients with FHH have mutations within the protein-coding region of the CaSR gene. The remaining one-third of kindreds may have mutations in the promoter of the CaSR gene or are caused by mutations in other genes.
Even before elucidation of the pathophysiology of FHH, abundant clinical evidence served to separate the disorder from primary hyperparathyroidism; these clinical features are still useful in differential diagnosis. Patients with primary hyperparathyroidism have <99% renal calcium reabsorption, whereas most patients with FHH have >99% reabsorption. The hypercalcemia in FHH is often detectable in affected members of the kindreds in the first decade of life, whereas hypercalcemia rarely occurs in patients with primary hyperparathyroidism or the MEN syndromes who are age <10 years. PTH may be elevated in the different forms of FHH, but the values are usually normal or lower for the same degree of calcium elevation than is observed in patients with primary hyperparathyroidism. Parathyroid surgery performed in a few patients with FHH before the nature of the syndrome was understood led to permanent hypoparathyroidism; nevertheless, hypocalciuria persisted, establishing that hypocalciuria is not PTH-dependent (now known to be due to the abnormal CaSR in the kidney).
Few clinical signs or symptoms are present in patients with FHH, whereas other endocrine abnormalities are not. Most patients are detected as a result of family screening after hypercalcemia is detected in a proband. In those patients inadvertently operated upon for primary hyperparathyroidism, the parathyroids appeared normal or moderately hyperplastic. Parathyroid surgery is not appropriate, nor, in view of the lack of symptoms, does medical treatment seem needed to lower the calcium. One striking exception to the rule against parathyroid surgery in this syndrome is the occurrence, usually in consanguineous marriages (due to the rarity of the gene mutation), of a homozygous or compound heterozygote state, resulting in severe impairment of CaSR function. In this condition, neonatal severe hypercalcemia, total parathyroidectomy is mandatory, but calcimetics have been used as a temporary measure. Rare but well-documented cases of acquired hypocalciuric hypercalcemia are reported due to antibodies against the CaSR. They appear to be a complication of an underlying autoimmune disorder and respond to therapies directed against the underlying disorder.
Activating mutations in the PTH/PTHrP receptor (PTH1R) have been identified as the cause of this rare autosomal dominant syndrome. Because the mutations lead to constitutive activation of receptor function, one abnormal copy of the mutant receptor is sufficient to cause the disease, thereby accounting for its dominant mode of transmission. The disorder leads to short-limbed dwarfism due to abnormal regulation of chondrocyte maturation in the growth plates of the bone that are formed through the endochondral process. In adult life, there are numerous abnormalities in bone, including multiple cystic resorptive areas resembling those seen in severe hyperparathyroidism. Hypercalcemia and hypophosphatemia with undetectable or low PTH levels are typically observed. The pathogenesis of the growth plate abnormalities in Jansen’s disease has been confirmed by transgenic experiments in which targeted expression of the mutant PTH/PTHrP receptor to the proliferating chondrocyte layer of growth plate emulated several features of the human disorder. Some of these genetic mutations in the parathyroid gland or PTH target cells that affect Ca2+ metabolism are illustrated in Fig. 424-5.
Illustration of some genetic mutations that alter calcium metabolism by effects on the parathyroid cell or target cells of parathyroid hormone (PTH) action. Alterations in PTH production by the parathyroid cell can be caused by changes in the response to extracellular fluid calcium (Ca2+) that are detected by the calcium-sensing receptor (CaSR). Furthermore, PTH (or PTH-related peptide [PTHrP]) can show altered efficacy in target cells such as in proximal tubular cells, by altered function of its receptor (PTH/PTHrP receptor) or the signal transduction proteins, G proteins such as Gsα, which is linked to adenylate cyclase (AC), the enzyme responsible for producing cyclic AMP (cAMP) (also illustrated are Gq/11, which activate an alternate pathway of receptor signal transmission involving the generation of inositol triphosphate [IP3] or diacylglycerol [DAG]). Heterozygous loss-of-function mutations in the CaSR cause familial benign hypocalciuric hypercalcemia (FBHH), homozygous mutations (both alleles mutated), and severe neonatal hyperparathyroidism (NSHPT); heterozygous gain-of-function causes autosomal dominant hypercalciuric hypocalcemia (ADHH). Other defects in parathyroid cell function that occur at the level of gene regulation (oncogenes or tumor-suppressor genes) or transcription factors are discussed in the text. Blomstrand’s lethal chondrodysplasia is due to homozygous or compound heterozygous loss-of-function mutations in the PTH/PTHrP receptor, a neonatally lethal disorder, while pseudohypoparathyroidism involves inactivation at the level of the G proteins, specifically mutations that eliminate or reduce Gsα activity in the kidney (see text for details). Acrodysostosis can occur with (acrodysostosis with hormonal resistance [ADOHR]; mutant regulatory subunit of PKA) or without hormonal resistance (ADOP4; mutant PDE4D). Jansen’s metaphyseal chondrodysplasia and McCune-Albright syndrome represent gain-of-function mutations in the PTH/PTHrP receptor and Gsα protein, respectively.
Clinical Syndromes and Mechanisms of Hypercalcemia
Hypercalcemia due to malignancy is common (occurring in as many as 20% of cancer patients, especially with certain types of tumor such as lung carcinoma), often severe and difficult to manage, and, on rare occasions, difficult to distinguish from primary hyperparathyroidism. Although malignancy is often clinically obvious or readily detectable by medical history, hypercalcemia can occasionally be due to an occult tumor. Previously, hypercalcemia associated with malignancy was thought to be due to local invasion and destruction of bone by tumor cells; many cases are now known to result from the elaboration by the malignant cells of humoral mediators of hypercalcemia. PTHrP is the responsible humoral agent in most solid tumors that cause hypercalcemia.
The histologic character of the tumor is more important than the extent of skeletal metastases in predicting hypercalcemia. Small-cell carcinoma (oat cell) and adenocarcinoma of the lung, although the most common lung tumors associated with skeletal metastases, rarely cause hypercalcemia. By contrast, many patients with squamous cell carcinoma of the lung develop hypercalcemia. Histologic studies of bone in patients with squamous cell or epidermoid carcinoma of the lung, in sites invaded by tumor as well as areas remote from tumor invasion, reveal increased bone resorption.
Two main mechanisms of hypercalcemia are operative in cancer hypercalcemia. Many solid tumors associated with hypercalcemia, particularly squamous cell and renal tumors, produce and secrete PTHrP that causes increased bone resorption and mediate the hypercalcemia through systemic actions on the skeleton. Alternatively, direct bone marrow invasion occurs with hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. Lymphokines and cytokines (including PTHrP) produced by cells involved in the marrow response to the tumors promote resorption of bone through local destruction. Several hormones, hormone analogues, cytokines, and growth factors have been implicated as the result of clinical assays, in vitro tests, or chemical isolation. The etiologic factor produced by activated normal lymphocytes and by myeloma and lymphoma cells, originally termed osteoclast activation factor, now appears to represent the biologic action of several different cytokines, probably interleukin 1 and lymphotoxin or tumor necrosis factor (TNF). In some lymphomas, there is a third mechanism, caused by an increased blood level of 1,25(OH)2D, produced by the abnormal lymphocytes.
In the more common mechanism, usually termed humoral hypercalcemia of malignancy, solid tumors (cancers of the lung and kidney, in particular), in which bone metastases are absent, minimal, or not detectable clinically, secrete PTHrP measurable by immunoassay. Secretion by the tumors of the PTH-like factor, PTHrP, activates the PTH1R, resulting in a pathophysiology closely resembling hyperparathyroidism, but with normal or suppressed PTH levels. The clinical picture resembles primary hyperparathyroidism (hypophosphatemia accompanies hypercalcemia), and elimination or regression of the primary tumor leads to disappearance of the hypercalcemia.
As in hyperparathyroidism, patients with the humoral hypercalcemia of malignancy have elevated urinary nephrogenous cAMP excretion, hypophosphatemia, and increased urinary phosphate clearance. However, in humoral hypercalcemia of malignancy, immunoreactive PTH is undetectable or suppressed, making the differential diagnosis easier. Other features of the disorder differ from those of true hyperparathyroidism. Although the biologic actions of PTH and PTHrP are exerted through the same receptor, subtle differences in receptor activation by the two ligands must account for some of the discordance in pathophysiology, when an excess of one or the other peptide occurs. Other cytokines elaborated by the malignancy may contribute to the variations from hyperparathyroidism in these patients as well. Patients with humoral hypercalcemia of malignancy may have low to normal levels of 1,25(OH)2D instead of elevated levels as in true hyperparathyroidism. In some patients with the humoral hypercalcemia of malignancy, osteoclastic resorption is unaccompanied by an osteoblastic or bone-forming response, implying inhibition of the normal coupling of bone formation and resorption.
Several different assays (single- or double-antibody, different epitopes) have been developed to detect PTHrP. Most data indicate that circulating PTHrP levels are undetectable (or low) in normal individuals except perhaps in pregnancy (high in human milk) and elevated in most cancer patients with the humoral syndrome. The etiologic mechanisms in cancer hypercalcemia may be multiple in the same patient. For example, in breast carcinoma (metastatic to bone) and in a distinctive type of T cell lymphoma/leukemia initiated by human T cell lymphotropic virus I, hypercalcemia is caused by direct local lysis of bone as well as by a humoral mechanism involving excess production of PTHrP. Hyperparathyroidism has been reported to coexist with the humoral cancer syndrome, and rarely, ectopic hyperparathyroidism due to tumor elaboration of true PTH is reported.
Levels of PTH measured by the double-antibody technique are undetectable or extremely low in tumor hypercalcemia, as would be expected with the mediation of the hypercalcemia by a factor other than PTH (the hypercalcemia suppresses the normal parathyroid glands). In a patient with minimal symptoms referred for hypercalcemia, low or undetectable PTH levels would focus attention on a possible occult malignancy (except for very rare cases of ectopic hyperparathyroidism).
Ordinarily, the diagnosis of cancer hypercalcemia is not difficult because tumor symptoms are prominent when hypercalcemia is detected. Indeed, hypercalcemia may be noted incidentally during the workup of a patient with known or suspected malignancy. Clinical suspicion that malignancy is the cause of the hypercalcemia is heightened when there are other signs or symptoms of a paraneoplastic process such as weight loss, fatigue, muscle weakness, or unexplained skin rash, or when symptoms specific for a particular tumor are present. Squamous cell tumors are most frequently associated with hypercalcemia, particularly tumors of the lung, kidney, head and neck, and urogenital tract. Radiologic examinations can focus on these areas when clinical evidence is unclear. Bone scans with technetium-labeled bisphosphonate are useful for detection of osteolytic metastases; the sensitivity is high, but specificity is low; results must be confirmed by conventional x-rays to be certain that areas of increased uptake are due to osteolytic metastases per se. Bone marrow biopsies are helpful in patients with anemia or abnormal peripheral blood smears.
TREATMENT Malignancy-Related Hypercalcemia
Treatment of the hypercalcemia of malignancy is first directed to control of tumor; reduction of tumor mass usually corrects hypercalcemia. If a patient has severe hypercalcemia yet has a good chance for effective tumor therapy, treatment of the hypercalcemia should be vigorous while awaiting the results of definitive therapy. If hypercalcemia occurs in the late stages of a tumor that is resistant to antitumor therapy, the treatment of the hypercalcemia should be judicious as high calcium levels can have a mild sedating effect. Standard therapies for hypercalcemia (discussed below) are applicable to patients with malignancy.
VITAMIN D–RELATED HYPERCALCEMIA
Hypercalcemia caused by vitamin D can be due to excessive ingestion or abnormal metabolism of the vitamin. Abnormal metabolism of the vitamin is usually acquired in association with a widespread granulomatous disorder. Vitamin D metabolism is carefully regulated, particularly the activity of renal 1α-hydroxylase, the enzyme responsible for the production of 1,25(OH)2D (Chap. 423). The regulation of 1α-hydroxylase and the normal feedback suppression by 1,25(OH)2D seem to work less well in infants than in adults and to operate poorly, if at all, in sites other than the renal tubule; these phenomena may explain the occurrence of hypercalcemia secondary to excessive 1,25(OH)2D production in infants with Williams’ syndrome (see below) and in adults with sarcoidosis or lymphoma.
Chronic ingestion of 40–100 times the normal physiologic requirement of vitamin D (amounts >40,000–100,000 U/d) is usually required to produce significant hypercalcemia in otherwise healthy individuals. The stated upper limit of safe dietary intake is 2000 U/d (50 μg/d) in adults because of concerns about potential toxic effects of cumulative supraphysiologic doses. These recommendations are now regarded as too restrictive, because some estimates are that in elderly individuals in northern latitudes, 2000 U/d or more may be necessary to avoid vitamin D insufficiency.
Hypercalcemia in vitamin D intoxication is due to an excessive biologic action of the vitamin, perhaps the consequence of increased levels of 25(OH)D rather than merely increased levels of the active metabolite 1,25(OH)2D (the latter may not be elevated in vitamin D intoxication). 25(OH)D has definite, if low, biologic activity in the intestine and bone. The production of 25(OH)D is less tightly regulated than is the production of 1,25(OH)2D. Hence concentrations of 25(OH)D are elevated several-fold in patients with excess vitamin D intake.
The diagnosis is substantiated by documenting elevated levels of 25(OH)D >100 mg/mL. Hypercalcemia is usually controlled by restriction of dietary calcium intake and appropriate attention to hydration. These measures, plus discontinuation of vitamin D, usually lead to resolution of hypercalcemia. However, vitamin D stores in fat may be substantial, and vitamin D intoxication may persist for weeks after vitamin D ingestion is terminated. Such patients are responsive to glucocorticoids, which in doses of 100 mg/d of hydrocortisone or its equivalent usually return serum calcium levels to normal over several days; severe intoxication may require intensive therapy.
Sarcoidosis and Other Granulomatous Diseases
In patients with sarcoidosis and other granulomatous diseases, such as tuberculosis and fungal infections, excess 1,25(OH)2D is synthesized in macrophages or other cells in the granulomas. Indeed, increased 1,25(OH)2D levels have been reported in anephric patients with sarcoidosis and hypercalcemia. Macrophages obtained from granulomatous tissue convert 25(OH)D to 1,25(OH)2D at an increased rate. There is a positive correlation in patients with sarcoidosis between 25(OH)D levels (reflecting vitamin D intake) and the circulating concentrations of 1,25(OH)2D, whereas normally there is no increase in 1,25(OH)2D with increasing 25(OH)D levels due to multiple feedback controls on renal 1α-hydroxylase (Chap. 423). The usual regulation of active metabolite production by calcium and phosphate or by PTH does not operate in these patients. Clearance of 1,25(OH)2D from blood may be decreased in sarcoidosis as well. PTH levels are usually low and 1,25(OH)2D levels are elevated, but primary hyperparathyroidism and sarcoidosis may coexist in some patients.
Management of the hypercalcemia can often be accomplished by avoiding excessive sunlight exposure and limiting vitamin D and calcium intake. Presumably, however, the abnormal sensitivity to vitamin D and abnormal regulation of 1,25(OH)2D synthesis will persist as long as the disease is active. Alternatively, glucocorticoids in the equivalent of 100 mg/d of hydrocortisone or equivalent doses of glucocorticoids may help control hypercalcemia. Glucocorticoids appear to act by blocking excessive production of 1,25(OH)2D, as well as the response to it in target organs.
Idiopathic Hypercalcemia of Infancy
This rare disorder, usually referred to as Williams’ syndrome, is an autosomal dominant disorder characterized by multiple congenital development defects, including supravalvular aortic stenosis, mental retardation, and an elfin facies, in association with hypercalcemia due to abnormal sensitivity to vitamin D. The hypercalcemia associated with the syndrome was first recognized in England after fortification of milk with vitamin D. The cardiac and developmental abnormalities were independently described, but the connection between these defects and hypercalcemia were not described until later. Levels of 1,25(OH)2D can be elevated, ranging from 46 to 120 nmol/L (150–500 pg/mL). The mechanism of the abnormal sensitivity to vitamin D and of the increased circulating levels of 1,25(OH)2D is still unclear. Studies suggest that genetic mutations involving microdeletions at the elastin locus and perhaps other genes on chromosome 7 may play a role in the pathogenesis. Another cause of hypercalcemia in infants and young children is a 24-hydroxylase deficiency that impairs metabolism of 1,25(OH)2D.
HYPERCALCEMIA ASSOCIATED WITH HIGH BONE TURNOVER
As many as 20% of hyperthyroid patients have high-normal or mildly elevated serum calcium concentrations; hypercalciuria is even more common. The hypercalcemia is due to increased bone turnover, with bone resorption exceeding bone formation. Severe calcium elevations are not typical, and the presence of such suggests a concomitant disease such as hyperparathyroidism. Usually, the diagnosis is obvious, but signs of hyperthyroidism may occasionally be occult, particularly in the elderly (Chap. 405). Hypercalcemia is managed by treatment of the hyperthyroidism. Reports that thyroid-stimulating hormone (TSH) itself normally has a bone-protective effect suggest that suppressed TSH levels also play a role in hypercalcemia.
Immobilization is a rare cause of hypercalcemia in adults in the absence of an associated disease but may cause hypercalcemia in children and adolescents, particularly after spinal cord injury and paraplegia or quadriplegia. With resumption of ambulation, the hypercalcemia in children usually returns to normal.
The mechanism appears to involve a disproportion between bone formation and bone resorption; the former decreased and the latter increased. Hypercalciuria and increased mobilization of skeletal calcium can develop in normal volunteers subjected to extensive bed rest, although hypercalcemia is unusual. Immobilization of an adult with a disease associated with high bone turnover, however, such as Paget’s disease, may cause hypercalcemia.
Administration of benzothiadiazines (thiazides) can cause hypercalcemia in patients with high rates of bone turnover. Traditionally, thiazides are associated with aggravation of hypercalcemia in primary hyperparathyroidism, but this effect can be seen in other high-bone-turnover states as well. The mechanism of thiazide action is complex. Chronic thiazide administration leads to reduction in urinary calcium; the hypocalciuric effect appears to reflect the enhancement of proximal tubular resorption of sodium and calcium in response to sodium depletion. Some of this renal effect is due to augmentation of PTH action and is more pronounced in individuals with intact PTH secretion. However, thiazides cause hypocalciuria in hypoparathyroid patients on high-dose vitamin D and oral calcium replacement if sodium intake is restricted. This finding is the rationale for the use of thiazides as an adjunct to therapy in hypoparathyroid patients, as discussed below. Thiazide administration to normal individuals causes a transient increase in blood calcium (usually within the high-normal range) that reverts to preexisting levels after a week or more of continued administration. If hormonal function and calcium and bone metabolism are normal, homeostatic controls are reset to counteract the calcium-elevating effect of the thiazides. In the presence of hyperparathyroidism or increased bone turnover from another cause, homeostatic mechanisms are ineffective. The abnormal effects of the thiazide on calcium metabolism disappear within days of cessation of the drug.
Vitamin A intoxication is a rare cause of hypercalcemia and is most commonly a side effect of dietary faddism (Chap. 96e). Calcium levels can be elevated into the 3–3.5-mmol/L (12–14 mg/dL) range after the ingestion of 50,000–100,000 units of vitamin A daily (10–20 times the minimum daily requirement). Typical features of severe hypercalcemia include fatigue, anorexia, and, in some, severe muscle and bone pain. Excess vitamin A intake is presumed to increase bone resorption.
The diagnosis can be established by history and by measurement of vitamin A levels in serum. Occasionally, skeletal x-rays reveal periosteal calcifications, particularly in the hands. Withdrawal of the vitamin is usually associated with prompt disappearance of the hypercalcemia and reversal of the skeletal changes. As in vitamin D intoxication, administration of 100 mg/d of hydrocortisone or its equivalent leads to a rapid return of the serum calcium to normal.
HYPERCALCEMIA ASSOCIATED WITH RENAL FAILURE
Severe Secondary Hyperparathyroidism
The pathogenesis of secondary hyperparathyroidism in chronic kidney disease is incompletely understood. Resistance to the normal level of PTH is a major factor contributing to the development of hypocalcemia, which, in turn, is a stimulus to parathyroid gland enlargement. However, recent findings have indicated that an increase of FGF23 production by osteocytes (and possibly osteoblasts) in bone occurs well before an elevation in PTH is detected. FGF23 is a potent inhibitor of the renal 1-alpha hydroxylase, and the FGF23-dependent reduction in 1,25(OH)2 vitamin D seems to be an important stimulus for the development of secondary hyperparathyroidism.
Secondary hyperparathyroidism occurs not only in patients with renal failure but also in those with osteomalacia due to multiple causes (Chap. 423), including deficiency of vitamin D action and pseudohypoparathyroidism (deficient response to PTH downstream of PTHR1). For both disorders, hypocalcemia seems to be the common denominator in initiating the development of secondary hyperparathyroidism. Primary (1°) and secondary (2°) hyperparathyroidism can be distinguished conceptually by the autonomous growth of the parathyroid glands in primary hyperparathyroidism (presumably irreversible) and the adaptive response of the parathyroids in secondary hyperparathyroidism (typically reversible). In fact, reversal over weeks from an abnormal pattern of secretion, presumably accompanied by involution of parathyroid gland mass to normal, occurs in patients with osteomalacia who have been treated effectively with calcium and vitamin D. However, it is now recognized that a true clonal outgrowth (irreversible) can arise in long-standing, inadequately treated chronic kidney disease (e.g., tertiary [3°] hyperparathyroidism; see below).
Patients with secondary hyperparathyroidism may develop bone pain, ectopic calcification, and pruritus. The bone disease seen in patients with secondary hyperparathyroidism and chronic kidney disease is termed renal osteodystrophy and affects primarily bone turnover. However, osteomalacia is frequently encountered as well and may be related to the circulating levels of FGF23.
Two other skeletal disorders have been frequently associated in the past with chronic kidney disease (CKD) patients treated by long-term dialysis, who received aluminum-containing phosphate binders. Aluminum deposition in bone (see below) leads to an osteomalacia-like picture. The other entity is a low-turnover bone disease termed “aplastic” or “adynamic” bone disease; PTH levels are lower than typically observed in CKD patients with secondary hyperparathyroidism. It is believed that the condition is caused, at least in part, by excessive PTH suppression, which may be even greater than previously appreciated in light of evidence that some of the immunoreactive PTH detected by most commercially available PTH assays is not the full-length biologically active molecule (as discussed above) but may consist of amino-terminally truncated fragments that do not activate the PTH1R.
TREATMENT Secondary Hyperparathyroidism
Medical therapy to reverse secondary hyperparathyroidism in CKD includes reduction of excessive blood phosphate by restriction of dietary phosphate, the use of nonabsorbable phosphate binders, and careful, selective addition of calcitriol (0.25–2 μg/d) or related analogues. Calcium carbonate became preferred over aluminum-containing antacids to prevent aluminum-induced bone disease. However, synthetic gels that also bind phosphate (such as sevelamer; Chap. 335) are now widely used, with the advantage of avoiding not only aluminum retention, but also excess calcium loading, which may contribute to cardiovascular calcifications. Intravenous calcitriol (or related analogues), administered as several pulses each week, helps control secondary hyperparathyroidism. Aggressive but carefully administered medical therapy can often, but not always, reverse hyperparathyroidism and its symptoms and manifestations.
Occasional patients develop severe manifestations of secondary hyperparathyroidism, including hypercalcemia, pruritus, extraskeletal calcifications, and painful bones, despite aggressive medical efforts to suppress the hyperparathyroidism. PTH hypersecretion no longer responsive to medical therapy, a state of severe hyperparathyroidism in patients with CKD that requires surgery, has been referred to as tertiary hyperparathyroidism. Parathyroid surgery is necessary to control this condition. Based on genetic evidence from examination of tumor samples in these patients, the emergence of autonomous parathyroid function is due to a monoclonal outgrowth of one or more previously hyperplastic parathyroid glands. The adaptive response has become an independent contributor to disease; this finding seems to emphasize the importance of optimal medical management to reduce the proliferative response of the parathyroid cells that enables the irreversible genetic change.
Aluminum intoxication (and often hypercalcemia as a complication of medical treatment) in the past occurred in patients on chronic dialysis; manifestations included acute dementia and unresponsive and severe osteomalacia. Bone pain, multiple nonhealing fractures, particularly of the ribs and pelvis, and a proximal myopathy occur. Hypercalcemia develops when these patients are treated with vitamin D or calcitriol because of impaired skeletal responsiveness. Aluminum is present at the site of osteoid mineralization, osteoblastic activity is minimal, and calcium incorporation into the skeleton is impaired. The disorder is now rare because of the avoidance of aluminum-containing antacids or aluminum excess in the dialysis regimen (Chap. 429).
The milk-alkali syndrome is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. It is much less frequent since proton pump inhibitors and other treatments became available for peptic ulcer disease. For a time, the increased use of calcium carbonate in the management of secondary hyperparathyroidism led to reappearance of the syndrome. Several clinical presentations—acute, subacute, and chronic—have been described, all of which feature hypercalcemia, alkalosis, and renal failure. The chronic form of the disease, termed Burnett’s syndrome, is associated with irreversible renal damage. The acute syndromes reverse if the excess calcium and absorbable alkali are stopped.
Individual susceptibility is important in the pathogenesis, because some patients are treated with calcium carbonate and alkali regimens without developing the syndrome. One variable is the fractional calcium absorption as a function of calcium intake. Some individuals absorb a high fraction of calcium, even with intakes ≥2 g of elemental calcium per day, instead of reducing calcium absorption with high intake, as occurs in most normal individuals. Resultant mild hypercalcemia after meals in such patients is postulated to contribute to the generation of alkalosis. Development of hypercalcemia causes increased sodium excretion and some depletion of total-body water. These phenomena and perhaps some suppression of endogenous PTH secretion due to mild hypercalcemia lead to increased bicarbonate resorption and to alkalosis in the face of continued calcium carbonate ingestion. Alkalosis per se selectively enhances calcium resorption in the distal nephron, thus aggravating the hypercalcemia. The cycle of mild hypercalcemia → bicarbonate retention → alkalosis → renal calcium retention → severe hypercalcemia perpetuates and aggravates hypercalcemia and alkalosis as long as calcium and absorbable alkali are ingested.
DIFFERENTIAL DIAGNOSIS: SPECIAL TESTS
Differential diagnosis of hypercalcemia is best achieved by using clinical criteria, but immunometric assays to measure PTH are especially useful in distinguishing among major causes (Fig. 424-6). The clinical features that deserve emphasis are the presence or absence of symptoms or signs of disease and evidence of chronicity. If one discounts fatigue or depression, >90% of patients with primary hyperparathyroidism have asymptomatic hypercalcemia; symptoms of malignancy are usually present in cancer-associated hypercalcemia. Disorders other than hyperparathyroidism and malignancy cause <10% of cases of hypercalcemia, and some of the nonparathyroid causes are associated with clear-cut manifestations such as renal failure.
Algorithm for the evaluation of patients with hypercalcemia. See text for details. FHH, familial hypocalciuric hypercalcemia; MEN, multiple endocrine neoplasia; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide.
Hyperparathyroidism is the likely diagnosis in patients with chronic hypercalcemia. If hypercalcemia has been manifest for >1 year, malignancy can usually be excluded as the cause. A striking feature of malignancy-associated hypercalcemia is the rapidity of the course, whereby signs and symptoms of the underlying malignancy are evident within months of the detection of hypercalcemia. Although clinical considerations are helpful in arriving at the correct diagnosis of the cause of hypercalcemia, appropriate laboratory testing is essential for definitive diagnosis. The immunoassay for PTH usually separates hyperparathyroidism from all other causes of hypercalcemia (exceptions are very rare reports of ectopic production of excess PTH by nonparathyroid tumors). Patients with hyperparathyroidism have elevated PTH levels despite hypercalcemia, whereas patients with malignancy and the other causes of hypercalcemia (except for disorders mediated by PTH such as lithium-induced hypercalcemia) have levels of hormone below normal or undetectable levels. Assays based on the double-antibody method for PTH exhibit very high sensitivity (especially if serum calcium is simultaneously evaluated) and specificity for the diagnosis of primary hyperparathyroidism (Fig. 424-4).
In summary, PTH values are elevated in >90% of parathyroid-related causes of hypercalcemia, undetectable or low in malignancy-related hypercalcemia, and undetectable or normal in vitamin D–related and high-bone-turnover causes of hypercalcemia. In view of the specificity of the PTH immunoassay and the high frequency of hyperparathyroidism in hypercalcemic patients, it is cost-effective to measure the PTH level in all hypercalcemic patients unless malignancy or a specific nonparathyroid disease is obvious. False-positive PTH assay results are rare. Immunoassays for PTHrP are helpful in diagnosing certain types of malignancy-associated hypercalcemia. Although FHH is parathyroid-related, the disease should be managed distinctively from hyperparathyroidism. Clinical features and the low urinary calcium excretion can help make the distinction. Because the incidence of malignancy and hyperparathyroidism both increase with age, they can coexist as two independent causes of hypercalcemia.
1,25(OH)2D levels are elevated in many (but not all) patients with primary hyperparathyroidism. In other disorders associated with hypercalcemia, concentrations of 1,25(OH)2D are low or, at the most, normal. However, this test is of low specificity and is not cost-effective, as not all patients with hyperparathyroidism have elevated 1,25(OH)2D levels and not all nonparathyroid hypercalcemic patients have suppressed 1,25(OH)2D. Measurement of 1,25(OH)2D is, however, critically valuable in establishing the cause of hypercalcemia in sarcoidosis and certain lymphomas.
A useful general approach is outlined in Fig. 424-6. If the patient is asymptomatic and there is evidence of chronicity to the hypercalcemia, hyperparathyroidism is almost certainly the cause. If PTH levels (usually measured at least twice) are elevated, the clinical impression is confirmed and little additional evaluation is necessary. If there is only a short history or no data as to the duration of the hypercalcemia, occult malignancy must be considered; if the PTH levels are not elevated, then a thorough workup must be undertaken for malignancy, including chest x-ray, CT of chest and abdomen, and bone scan. Immunoassays for PTHrP may be especially useful in such situations. Attention should also be paid to clues for underlying hematologic disorders such as anemia, increased plasma globulin, and abnormal serum immunoelectrophoresis; bone scans can be negative in some patients with metastases such as in multiple myeloma. Finally, if a patient with chronic hypercalcemia is asymptomatic and malignancy therefore seems unlikely on clinical grounds, but PTH values are not elevated, it is useful to search for other chronic causes of hypercalcemia such as occult sarcoidosis. A careful history of dietary supplements and drug use may suggest intoxication with vitamin D or vitamin A or the use of thiazides.
TREATMENT Hypercalcemic States
The approach to medical treatment of hypercalcemia varies with its severity (Table 424-4). Mild hypercalcemia, <3 mmol/L (12 mg/dL), can be managed by hydration. More severe hypercalcemia (levels of 3.2–3.7 mmol/L [13–15 mg/dL]) must be managed aggressively; above that level, hypercalcemia can be life-threatening and requires emergency measures. By using a combination of approaches in severe hypercalcemia, the serum calcium concentration can be decreased by 0.7–2.2 mmol/L (3–9 mg/dL) within 24–48 h in most patients, enough to relieve acute symptoms, prevent death from hypercalcemic crisis, and permit diagnostic evaluation. Therapy can then be directed at the underlying disorder—the second priority.
Hypercalcemia develops because of excessive skeletal calcium release, increased intestinal calcium absorption, or inadequate renal calcium excretion. Understanding the particular pathogenesis helps guide therapy. For example, hypercalcemia in patients with malignancy is primarily due to excessive skeletal calcium release and is, therefore, minimally improved by restriction of dietary calcium. On the other hand, patients with vitamin D hypersensitivity or vitamin D intoxication have excessive intestinal calcium absorption, and restriction of dietary calcium is beneficial. Decreased renal function or ECF depletion decreases urinary calcium excretion. In such situations, rehydration may rapidly reduce or reverse the hypercalcemia, even though increased bone resorption persists. As outlined below, the more severe the hypercalcemia, the greater the number of combined therapies that should be used. Rapid-acting (hours) approaches—rehydration, forced diuresis, and calcitonin—can be used with the most effective antiresorptive agents such as bisphosphonates (since severe hypercalcemia usually involves excessive bone resorption). HYDRATION, INCREASED SALT INTAKE, MILD AND FORCED DIURESIS
The first principle of treatment is to restore normal hydration. Many hypercalcemic patients are dehydrated because of vomiting, inanition, and/or hypercalcemia-induced defects in urinary concentrating ability. The resultant drop in glomerular filtration rate is accompanied by an additional decrease in renal tubular sodium and calcium clearance. Restoring a normal ECF volume corrects these abnormalities and increases urine calcium excretion by 2.5–7.5 mmol/d (100–300 mg/d). Increasing urinary sodium excretion to 400–500 mmol/d increases urinary calcium excretion even further than simple rehydration. After rehydration has been achieved, saline can be administered, or furosemide or ethacrynic acid can be given twice daily to depress the tubular reabsorptive mechanism for calcium (care must be taken to prevent dehydration). The combined use of these therapies can increase urinary calcium excretion to ≥12.5 mmol/d (500 mg/d) in most hypercalcemic patients. Because this is a substantial percentage of the exchangeable calcium pool, the serum calcium concentration usually falls 0.25–0.75 mmol/L (1–3 mg/dL) within 24 h. Precautions should be taken to prevent potassium and magnesium depletion; calcium-containing renal calculi are a potential complication.
Under life-threatening circumstances, the preceding approach can be pursued more aggressively, but the availability of effective agents to block bone resorption (such as bisphosphonates) has reduced the need for extreme diuresis regimens (Table 424-4). Depletion of potassium and magnesium is inevitable unless replacements are given; pulmonary edema can be precipitated. The potential complications can be reduced by careful monitoring of central venous pressure and plasma or urine electrolytes; catheterization of the bladder may be necessary. Dialysis treatment may be needed when renal function is compromised. BISPHOSPHONATES
The bisphosphonates are analogues of pyrophosphate, with high affinity for bone, especially in areas of increased bone turnover, where they are powerful inhibitors of bone resorption. These bone-seeking compounds are stable in vivo because phosphatase enzymes cannot hydrolyze the central carbon-phosphorus-carbon bond. The bisphosphonates are concentrated in areas of high bone turnover and are taken up by and inhibit osteoclast action; the mechanism of action is complex. The bisphosphonate molecules that contain amino groups in the side chain structure (see below) interfere with prenylation of proteins and can lead to cellular apoptosis. The highly active nonamino group–containing bisphosphonates are also metabolized to cytotoxic products.
The initial bisphosphonate widely used in clinical practice, etidronate, was effective but had several disadvantages, including the capacity to inhibit bone formation as well as blocking resorption. Subsequently, a number of second- or third-generation compounds have become the mainstays of antiresorptive therapy for treatment of hypercalcemia and osteoporosis. The newer bisphosphonates have a highly favorable ratio of blocking resorption versus inhibiting bone formation; they inhibit osteoclast-mediated skeletal resorption yet do not cause mineralization defects at ordinary doses. Although the bisphosphonates have similar structures, the routes of administration, efficacy, toxicity, and side effects vary. The potency of the compounds for inhibition of bone resorption varies more than 10,000-fold, increasing in the order of etidronate, tiludronate, pamidronate, alendronate, risedronate, and zoledronate. The IV use of pamidronate and zoledronate is approved for the treatment of hypercalcemia; between 30 and 90 mg pamidronate, given as a single IV dose over a few hours, returns serum calcium to normal within 24–48 h with an effect that lasts for weeks in 80–100% of patients. Zoledronate given in doses of 4 or 8 mg/5-min infusion has a more rapid and more sustained effect than pamidronate in direct comparison.
These drugs are used extensively in cancer patients. Absolute survival improvements are noted with pamidronate and zoledronate in multiple myeloma, for example. However, although still rare, there are increasing reports of jaw necrosis, especially after dental surgery, mainly in cancer patients treated with multiple doses of the more potent bisphosphonates. CALCITONIN
Calcitonin acts within a few hours of its administration, principally through receptors on osteoclasts, to block bone resorption. Calcitonin, after 24 h of use, is no longer effective in lowering calcium. Tachyphylaxis, a known phenomenon with this drug, seems to explain the results, since the drug is often effective in the first 24 h of use. Therefore, in life-threatening hypercalcemia, calcitonin can be used effectively within the first 24 h in combination with rehydration and saline diuresis while waiting for more sustained effects from a simultaneously administered bisphosphonate such as pamidronate. Usual doses of calcitonin are 2–8 U/kg of body weight IV, SC, or IM every 6–12 h. OTHER THERAPIES
Denosumab, an antibody that blocks the RANK ligand (RANKL) and dramatically reduces osteoclast number and function, is approved for therapy of osteoporosis. It also appears to be an effective treatment to reverse hypercalcemia of malignancy, but is not yet approved for this indication. Plicamycin (formerly mithramycin), which inhibits bone resorption, and gallium nitrate, which exerts a hypocalcemic action also by inhibiting bone resorption, are no longer used because of superior alternatives such as bisphosphonates.
Glucocorticoids have utility, especially in hypercalcemia complicating certain malignancies. They increase urinary calcium excretion and decrease intestinal calcium absorption when given in pharmacologic doses, but they also cause negative skeletal calcium balance. In normal individuals and in patients with primary hyperparathyroidism, glucocorticoids neither increase nor decrease the serum calcium concentration. In patients with hypercalcemia due to certain osteolytic malignancies, however, glucocorticoids may be effective as a result of antitumor effects. The malignancies in which hypercalcemia responds to glucocorticoids include multiple myeloma, leukemia, Hodgkin’s disease, other lymphomas, and carcinoma of the breast, at least early in the course of the disease. Glucocorticoids are also effective in treating hypercalcemia due to vitamin D intoxication and sarcoidosis. Glucocorticoids are also useful in the rare form of hypercalcemia, now recognized in certain autoimmune disorders in which inactivating antibodies against the receptor imitate FHH. Elevated PTH and calcium levels are effectively lowered by the glucocorticoids. In all the preceding situations, the hypocalcemic effect develops over several days, and the usual glucocorticoid dosage is 40–100 mg prednisone (or its equivalent) daily in four divided doses. The side effects of chronic glucocorticoid therapy may be acceptable in some circumstances.
Dialysis is often the treatment of choice for severe hypercalcemia complicated by renal failure, which is difficult to manage medically. Peritoneal dialysis with calcium-free dialysis fluid can remove 5–12.5 mmol (200–500 mg) of calcium in 24–48 h and lower the serum calcium concentration by 0.7–3 mmol/L (3–12 mg/dL). Large quantities of phosphate are lost during dialysis, and serum inorganic phosphate concentration usually falls, potentially aggravating hypercalcemia. Therefore, the serum inorganic phosphate concentration should be measured after dialysis, and phosphate supplements should be added to the diet or to dialysis fluids if necessary.
Phosphate therapy, PO or IV, has a limited role in certain circumstances (Chap. 423). Correcting hypophosphatemia lowers the serum calcium concentration by several mechanisms, including bone/calcium exchange. The usual oral treatment is 1–1.5 g of phosphorus per day for several days, given in divided doses. It is generally believed, but not established, that toxicity does not occur if therapy is limited to restoring serum inorganic phosphate concentrations to normal.
Raising the serum inorganic phosphate concentration above normal decreases serum calcium levels, sometimes strikingly. Intravenous phosphate is one of the most dramatically effective treatments available for severe hypercalcemia but is toxic and even dangerous (fatal hypocalcemia). For these reasons, it is used rarely and only in severely hypercalcemic patients with cardiac or renal failure where dialysis, the preferable alternative, is not feasible or is unavailable. SUMMARY
The various therapies for hypercalcemia are listed in Table 424-4. The choice depends on the underlying disease, the severity of the hypercalcemia, the serum inorganic phosphate level, and the renal, hepatic, and bone marrow function. Mild hypercalcemia (≤3 mmol/L [12 mg/dL]) can usually be managed by hydration. Severe hypercalcemia (≥3.7 mmol/L [15 mg/dL]) requires rapid correction. Calcitonin should be given for its rapid, albeit short-lived, blockade of bone resorption, and IV pamidronate or zoledronate should be administered, although its onset of action is delayed for 1–2 days. In addition, for the first 24–48 h, aggressive sodium-calcium diuresis with IV saline should be given and, following rehydration, large doses of furosemide or ethacrynic acid, but only if appropriate monitoring is available and cardiac and renal function are adequate. Intermediate degrees of hypercalcemia between 3 and 3.7 mmol/L (12 and 15 mg/dL) should be approached with vigorous hydration and then the most appropriate selection for the patient of the combinations used with severe hypercalcemia.
TABLE 424-4Therapies for Severe Hypercalcemia ||Download (.pdf) TABLE 424-4 Therapies for Severe Hypercalcemia
|Treatment ||Onset of Action ||Duration of Action ||Advantages ||Disadvantages |
|Most Useful Therapies |
|Hydration with saline ||Hours ||During infusion ||Rehydration invariably needed ||Volume overload |
|Forced diuresis; saline plus loop diuretic ||Hours ||During treatment ||Rapid action ||Volume overload, cardiac decompensation, intensive monitoring, electrolyte disturbance, inconvenience |
|Pamidronate ||1–2 days ||10–14 days to weeks ||High potency; intermediate onset of action ||Fever in 20%, hypophosphatemia, hypocalcemia, hypomagnesemia, rarely jaw necrosis |
|Zoledronate ||1–2 days ||>3 weeks ||Same as for pamidronate (may last longer) ||Same as pamidronate above |
|Calcitonin ||Hours ||1–2 days ||Rapid onset of action; useful as adjunct in severe hypercalcemia ||Rapid tachyphylaxis |
|Special Use Therapies |
|Phosphate oral ||24 h ||During use ||Chronic management (with hypophosphatemia); low toxicity if phosphate <4 mg/dL ||Limited use except as adjuvant or chronic therapy |
|Glucocorticoids ||Days ||Days, weeks ||Oral therapy, antitumor agent ||Active only in certain malignancies, vitamin D excess and sarcoidosis; glucocorticoid side effects |
|Dialysis ||Hours ||During use and 24–48 h afterward ||Useful in renal failure; onset of effect in hours; can immediately reverse life-threatening hypercalcemia ||Complex procedure, reserved for extreme or special circumstances |
PATHOPHYSIOLOGY OF HYPOCALCEMIA: CLASSIFICATION BASED ON MECHANISM
Chronic hypocalcemia is less common than hypercalcemia; causes include chronic renal failure, hereditary and acquired hypoparathyroidism, vitamin D deficiency, pseudohypoparathyroidism, and hypomagnesemia (Table 424-5).
TABLE 424-5Functional Classification of Hypocalcemia (Excluding Neonatal Conditions) ||Download (.pdf) TABLE 424-5 Functional Classification of Hypocalcemia (Excluding Neonatal Conditions)
|PTH Absent |
|Hereditary hypoparathyroidism ||Hypomagnesemia |
|Acquired hypoparathyroidism || |
|PTH Ineffective |
|Chronic kidney disease ||Active vitamin D ineffective |
|Active vitamin D lacking || Intestinal malabsorption |
| ↓ Dietary intake or sunlight || Vitamin D–dependent rickets type II |
| Defective metabolism: ||Pseudohypoparathyroidism |
| Anticonvulsant therapy || |
| Vitamin D–dependent rickets type I || |
|PTH Overwhelmed |
|Severe, acute hyperphosphatemia ||Osteitis fibrosa after parathyroidectomy |
| Tumor lysis || |
| Acute kidney injury || |
| Rhabdomyolysis || |
Acute rather than chronic hypocalcemia is seen in critically ill patients or as a consequence of certain medications and often does not require specific treatment. Transient hypocalcemia is seen with severe sepsis, burns, acute kidney injury, and extensive transfusions with citrated blood. Although as many as one-half of patients in an intensive care setting are reported to have calcium concentrations of <2.1 mmol/L (8.5 mg/dL), most do not have a reduction in ionized calcium. Patients with severe sepsis may have a decrease in ionized calcium (true hypocalcemia), but in other severely ill individuals, hypoalbuminemia is the primary cause of the reduced total calcium concentration. Alkalosis increases calcium binding to proteins, and in this setting, direct measurements of ionized calcium should be made.
Medications such as protamine, heparin, and glucagon may cause transient hypocalcemia. These forms of hypocalcemia are usually not associated with tetany and resolve with improvement in the overall medical condition. The hypocalcemia after repeated transfusions of citrated blood usually resolves quickly.
Patients with acute pancreatitis have hypocalcemia that persists during the acute inflammation and varies in degree with disease severity. The cause of hypocalcemia remains unclear. PTH values are reported to be low, normal, or elevated, and both resistance to PTH and impaired PTH secretion have been postulated. Occasionally, a chronic low total calcium and low ionized calcium concentration are detected in an elderly patient without obvious cause and with a paucity of symptoms; the pathogenesis is unclear.
Chronic hypocalcemia, however, is usually symptomatic and requires treatment. Neuromuscular and neurologic manifestations of chronic hypocalcemia include muscle spasms, carpopedal spasm, facial grimacing, and, in extreme cases, laryngeal spasm and convulsions. Respiratory arrest may occur. Increased intracranial pressure occurs in some patients with long-standing hypocalcemia, often in association with papilledema. Mental changes include irritability, depression, and psychosis. The QT interval on the electrocardiogram is prolonged, in contrast to its shortening with hypercalcemia. Arrhythmias occur, and digitalis effectiveness may be reduced. Intestinal cramps and chronic malabsorption may occur. Chvostek’s or Trousseau’s sign can be used to confirm latent tetany.
The classification of hypocalcemia shown in Table 424-5 is based on an organizationally useful premise that PTH is responsible for minute-to-minute regulation of plasma calcium concentration and, therefore, that the occurrence of hypocalcemia must mean a failure of the homeostatic action of PTH. Failure of the PTH response can occur if there is hereditary or acquired parathyroid gland failure, if PTH is ineffective in target organs, or if the action of the hormone is overwhelmed by the loss of calcium from the ECF at a rate faster than it can be replaced.
Whether hereditary or acquired, hypoparathyroidism has a number of common components. Symptoms of untreated hypocalcemia are shared by both types of hypoparathyroidism, although the onset of hereditary hypoparathyroidism can be more gradual and associated with other developmental defects. Basal ganglia calcification and extrapyramidal syndromes are more common and earlier in onset in hereditary hypoparathyroidism. In previous decades, acquired hypoparathyroidism secondary to surgery in the neck was more common than hereditary hypoparathyroidism, but the frequency of surgically induced parathyroid failure has diminished as a result of improved surgical techniques that spare the parathyroid glands and increased use of nonsurgical therapy for hyperthyroidism. Pseudohypoparathyroidism, an example of ineffective PTH action rather than a failure of parathyroid gland production, may share several features with hypoparathyroidism, including extraosseous calcification and extrapyramidal manifestations such as choreoathetotic movements and dystonia.
Papilledema and raised intracranial pressure may occur in both hereditary and acquired hypoparathyroidism, as do chronic changes in fingernails and hair and lenticular cataracts, the latter usually reversible with treatment of hypocalcemia. Certain skin manifestations, including alopecia and candidiasis, are characteristic of hereditary hypoparathyroidism associated with autoimmune polyglandular failure (Chap. 408).
Hypocalcemia associated with hypomagnesemia is associated with both deficient PTH release and impaired responsiveness to the hormone. Patients with hypocalcemia secondary to hypomagnesemia have absent or low levels of circulating PTH, indicative of diminished hormone release despite a maximum physiologic stimulus by hypocalcemia. Plasma PTH levels return to normal with correction of the hypomagnesemia. Thus hypoparathyroidism with low levels of PTH in blood can be due to hereditary gland failure, acquired gland failure, or acute but reversible gland dysfunction (hypomagnesemia).
Genetic Abnormalities and Hereditary Hypoparathyroidism
Hereditary hypoparathyroidism can occur as an isolated entity without other endocrine or dermatologic manifestations. More typically, it occurs in association with other abnormalities such as defective development of the thymus or failure of other endocrine organs such as the adrenal, thyroid, or ovary (Chap. 408). Hereditary hypoparathyroidism is often manifest within the first decade but may appear later.
Genetic defects associated with hypoparathyroidism serve to illuminate the complexity of organ development, hormonal biosynthesis and secretion, and tissue-specific patterns of endocrine effector function (Fig. 424-5). Often, hypoparathyroidism is isolated, signifying a highly specific functional disturbance. When hypoparathyroidism is associated with other developmental or organ defects, treatment of the hypocalcemia can still be effective.
A form of hypoparathyroidism associated with defective development of both the thymus and the parathyroid glands is termed the DiGeorge syndrome, or the velocardiofacial syndrome. Congenital cardiovascular, facial, and other developmental defects are present, and patients may die in early childhood with severe infections, hypocalcemia and seizures, or cardiovascular complications. Patients can survive into adulthood, and milder, incomplete forms occur. Most cases are sporadic, but an autosomal dominant form involving microdeletions of chromosome 22q11.2 has been described. Smaller deletions in chromosome 22 are seen in incomplete forms of the DiGeorge syndrome, appearing in childhood or adolescence, that are manifest primarily by parathyroid gland failure. The chromosome 22 defect is now termed DSG1; more recently, a defect in chromosome 10p is also recognized—now called DSG2. The phenotypes seem similar. Studies on the chromosome 22 defect have pinpointed a transcription factor, TBX1. Deletions of the orthologous mouse gene show a phenotype similar to the human syndrome.
Another autosomal dominant developmental defect, featuring hypoparathyroidism, deafness, and renal dysplasia (HDR), has been studied at the genetic level. Cytogenetic abnormalities in some, but not all kindreds, point to translocation defects on chromosome 10, as in DiGeorge syndrome. However, the lack of immunodeficiency and heart defects distinguishes the two syndromes. Mouse models, as well as deletional analysis in some HDR patients, has identified the transcription factor GATA3, which is important in embryonic development and is expressed in developing kidney, ear structures, and the parathyroids.
Another pair of linked developmental disorders involving the parathyroids is recognized. Kenney-Caffey syndrome type I features hypoparathyroidism, short stature, osteosclerosis, and thick cortical bones. A defect seen in Middle Eastern patients, particularly in Saudi Arabia, termed Sanjad-Sakati syndrome, also exhibits growth failure and other dysmorphic features. This syndrome, which is clearly autosomal recessive, involves a gene on chromosome 1q42-q43. Both syndromes apparently involve a chaperone protein, called TBCE, relevant to tubulin function. Recently, a defect in FAM111A was identified as the cause of Kenney-Caffey syndrome type 2.
Hypoparathyroidism can occur in association with a complex hereditary autoimmune syndrome involving failure of the adrenals, the ovaries, the immune system, and the parathyroids in association with recurrent mucocutaneous candidiasis, alopecia, vitiligo, and pernicious anemia (Chap. 408). The responsible gene on chromosome 21q22.3 has been identified. The protein product, which resembles a transcription factor, has been termed the autoimmune regulator, or AIRE. A stop codon mutation occurs in many Finnish families with the disorder, commonly referred to as polyglandular autoimmune type 1 deficiency, whereas another AIRE mutation (Y85C) is typically observed in Jews of Iraqi and Iranian descent.
Hypoparathyroidism is seen in two disorders associated with mitochondrial dysfunction and myopathy, one termed the Kearns-Sayre syndrome (KSS), with ophthalmoplegia and pigmentary retinopathy, and the other termed the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Mutations or deletions in mitochondrial genes have been identified.
Several forms of hypoparathyroidism, each rare in frequency, are seen as isolated defects; the genetic mechanisms are varied. The inheritance includes autosomal dominant, autosomal recessive, and X-linked modes. Three separate autosomal defects involving the parathyroid gene have been recognized: one is dominant and the other two are recessive. The dominant form has a point mutation in the signal sequence, a critical region involved in intracellular transport of the hormone precursor. An Arg for Cys mutation interferes with processing of the precursor and is believed to trigger an apoptotic cellular response, hence acting as a dominant negative. The other two forms are recessive. One point mutation also blocks cleavage of the PTH precursor but requires both alleles to cause hypoparathyroidism. The third involves a single-nucleotide base change that results in an exon splicing defect; the lost exon contains the promoter—hence, the gene is silenced. An X-linked recessive form of hypoparathyroidism has been described in males, and the defect has been localized to chromosome Xq26-q27, perhaps involving the SOX3 gene.
Abnormalities in the CaSR are detected in three distinctive hypocalcemic disorders. All are rare, but more than 10 different gain-of-function mutations have been found in one form of hypocalcemia termed autosomal dominant hypocalcemic hypercalciuria (ADHH). The receptor senses the ambient calcium level as excessive and suppresses PTH secretion, leading to hypocalcemia. The hypocalcemia is aggravated by constitutive receptor activity in the renal tubule causing excretion of inappropriate amounts of calcium. Recognition of the syndrome is important because efforts to treat the hypocalcemia with vitamin D analogues and increased oral calcium exacerbate the already excessive urinary calcium excretion (several grams or more per 24 h), leading to irreversible renal damage from stones and ectopic calcification.
Other causes of isolated hypoparathyroidism include homozygous, inactivating mutations in the parathyroid-specific transcription factor GCM2, which lead to an autosomal recessive form of the disease, or heterozygous point mutations in GCM2, which have a dominant negative effect on the wild-type protein and thus lead to an autosomal dominant form of hypoparathyroidism. Furthermore, heterozygous mutations in G11, one of the two signaling proteins downstream of the CaSR, have been identified as a cause of autosomal dominant hypoparathyroidism.
Bartter’s syndrome is a group of disorders associated with disturbances in electrolyte and acid/base balance, sometimes with nephrocalcinosis and other features. Several types of ion channels or transporters are involved. Curiously, Bartter’s syndrome type V has the electrolyte and pH disturbances seen in the other syndromes but appears to be due to a gain of function in the CaSR. The defect may be more severe than in ADHH and explains the additional features seen beyond hypocalcemia and hypercalciuria.
As with autoimmune disorders that block the CaSR (discussed above under hypercalcemic conditions), there are autoantibodies that at least transiently activate the CaSR, leading to suppressed PTH secretion and hypocalcemia. This disorder may wax and wane.
Acquired chronic hypoparathyroidism is usually the result of inadvertent surgical removal of all the parathyroid glands; in some instances, not all the tissue is removed, but the remainder undergoes vascular supply compromise secondary to fibrotic changes in the neck after surgery. In the past, the most frequent cause of acquired hypoparathyroidism was surgery for hyperthyroidism. Hypoparathyroidism now usually occurs after surgery for hyperparathyroidism when the surgeon, facing the dilemma of removing too little tissue and thus not curing the hyperparathyroidism, removes too much. Parathyroid function may not be totally absent in all patients with postoperative hypoparathyroidism.
Rare causes of acquired chronic hypoparathyroidism include radiation-induced damage subsequent to radioiodine therapy of hyperthyroidism and glandular damage in patients with hemochromatosis or hemosiderosis after repeated blood transfusions. Infection may involve one or more of the parathyroids but usually does not cause hypoparathyroidism because all four glands are rarely involved.
Transient hypoparathyroidism is frequent following surgery for hyperparathyroidism. After a variable period of hypoparathyroidism, normal parathyroid function may return due to hyperplasia or recovery of remaining tissue. Occasionally, recovery occurs months after surgery.
TREATMENT Acquired and Hereditary Hypoparathyroidism
Treatment involves replacement with vitamin D or 1,25(OH)2D (calcitriol) combined with a high oral calcium intake. In most patients, blood calcium and phosphate levels are satisfactorily regulated, but some patients show resistance and a brittleness, with a tendency to alternate between hypocalcemia and hypercalcemia. For many patients, vitamin D in doses of 40,000–120,000 U/d (1–3 mg/d) combined with ≥1 g elemental calcium is satisfactory. The wide dosage range reflects the variation encountered from patient to patient; precise regulation of each patient is required. Compared to typical daily requirements in euparathyroid patients of 200 U/d (or in older patients as high as 800 U/d), the high dose of vitamin D (as much as 100-fold higher) reflects the reduced conversion of vitamin D to 1,25(OH)2D. Many physicians now use 0.5–1 μg of calcitriol in management of such patients, especially if they are difficult to control. Because of its storage in fat, when vitamin D is withdrawn, weeks are required for the disappearance of the biologic effects, compared with a few days for calcitriol, which has a rapid turnover.
Oral calcium and vitamin D restore the overall calcium-phosphate balance but do not reverse the lowered urinary calcium reabsorption typical of hypoparathyroidism. Therefore, care must be taken to avoid excessive urinary calcium excretion after vitamin D and calcium replacement therapy; otherwise, nephrocalcinosis and kidney stones can develop, and the risk of CKD is increased. Thiazide diuretics lower urine calcium by as much as 100 mg/d in hypoparathyroid patients on vitamin D, provided they are maintained on a low-sodium diet. Use of thiazides seems to be of benefit in mitigating hypercalciuria and easing the daily management of these patients.
There are now trials of parenterally administered PTH (either PTH[1–34] or PTH[1–84]) in patients with hypoparathyroidism providing greater ease of maintaining serum calcium and reducing urinary calcium excretion (desirable to protect any renal damage). However, PTH therapy for the treatment of hypoparathyroidism is not approved as of yet.
Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L) is associated with hypocalcemia (Chap. 423). Restoration of the total-body magnesium deficit leads to rapid reversal of hypocalcemia. There are at least two causes of the hypocalcemia—impaired PTH secretion and reduced responsiveness to PTH. For further discussion of causes and treatment of hypomagnesemia, see Chap. 423.
The effects of magnesium on PTH secretion are similar to those of calcium; hypermagnesemia suppresses and hypomagnesemia stimulates PTH secretion. The effects of magnesium on PTH secretion are normally of little significance, however, because the calcium effects dominate. Greater change in magnesium than in calcium is needed to influence hormone secretion. Nonetheless, hypomagnesemia might be expected to increase hormone secretion. It is therefore surprising to find that severe hypomagnesemia is associated with blunted secretion of PTH. The explanation for the paradox is that severe, chronic hypomagnesemia leads to intracellular magnesium deficiency, which interferes with secretion and peripheral responses to PTH. The mechanism of the cellular abnormalities caused by hypomagnesemia is unknown, although effects on adenylate cyclase (for which magnesium is a cofactor) have been proposed.
PTH levels are undetectable or inappropriately low in severe hypomagnesemia despite the stimulus of severe hypocalcemia, and acute repletion of magnesium leads to a rapid increase in PTH level. Serum phosphate levels are often not elevated, in contrast to the situation with acquired or idiopathic hypoparathyroidism, probably because phosphate deficiency is often seen in hypomagnesmia (Chap. 393).
Diminished peripheral responsiveness to PTH also occurs in some patients, as documented by subnormal response in urinary phosphorus and urinary cAMP excretion after administration of exogenous PTH to patients who are hypocalcemic and hypomagnesemic. Both blunted PTH secretion and lack of renal response to administered PTH can occur in the same patient. When acute magnesium repletion is undertaken, the restoration of PTH levels to normal or supranormal may precede restoration of normal serum calcium by several days.
Repletion of magnesium cures the condition. Repletion should be parenteral. Attention must be given to restoring the intracellular deficit, which may be considerable. After IV magnesium administration, serum magnesium may return transiently to the normal range, but unless replacement therapy is adequate, serum magnesium will again fall. If the cause of the hypomagnesemia is renal magnesium wasting, magnesium may have to be given long-term to prevent recurrence (Chap. 423).
PTH is not sufficiently active to fully prevent hypocalcemia (although retaining phosphaturic activity, for example). This problem occurs when the PTH1R–signaling protein complex is defective (as in the different forms of pseudohypoparathyroidism [PHP], discussed below); when PTH action to promote calcium absorption from the diet via the synthesis of 1,25(OH)2D is insufficient because of vitamin D deficiency or because vitamin D is ineffective (defects in vitamin D receptor or vitamin D synthesis); or in CKD in which the calcium-elevating action of PTH is impaired.
Typically, hypophosphatemia is more severe than hypocalcemia in vitamin D deficiency states because of the increased secretion of PTH, which, although only partly effective in elevating blood calcium, is readily capable of promoting urinary phosphate excretion.
PHP, on the other hand, has a pathophysiology that is different from the other disorders of ineffective PTH action. PHP resembles hypoparathyroidism (in which PTH synthesis is deficient) and is manifested by hypocalcemia and hyperphosphatemia, yet elevated PTH levels. The cause of the disorder is defective PTH-dependent activation of the stimulatory G protein complex or the downstream effector protein kinase A, resulting in failure of PTH to increase intracellular cAMP or to respond to elevated cAMP levels (see below).
Improved medical management of CKD now allows many patients to survive for decades and hence allows time enough to develop features of renal osteodystrophy, which must be controlled to avoid additional morbidity. Impaired production of 1,25(OH)2D is now thought to be the principal factor that causes calcium deficiency, secondary hyperparathyroidism, and bone disease; hyperphosphatemia typically occurs only in the later stages of the disease. Low levels of 1,25(OH)2D due to increased FGF23 production in bone are critical in the development of hypocalcemia. The uremic state also causes impairment of intestinal absorption by mechanisms other than defects in vitamin D metabolism. Nonetheless, treatment with supraphysiologic amounts of vitamin D or calcitriol can correct the impaired calcium absorption. Because increased FGF23 levels are seen even in early stages of CKD and have been reported to correlate with increased mortality and left ventricular hypertrophy, there is current interest in approaches to lower intestinal phosphate absorption early during the course of kidney disease and to thereby lower FGF23 levels. However, there is concern as to whether vitamin D supplementation increases the circulating FGF23 levels in CKD patients. Although vitamin D analogs improve survival in this patient population, it is notable that there are often dramatic elevations of FGF23.
Hyperphosphatemia in CKD lowers blood calcium levels by several mechanisms, including extraosseous deposition of calcium and phosphate, impairment of the bone-resorbing action of PTH, and reduction in 1,25(OH)2D production by remaining renal tissue.
TREATMENT Chronic Kidney Disease
Therapy of CKD (Chap. 335) involves appropriate management of patients prior to dialysis and adjustment of regimens once dialysis is initiated. Attention should be paid to restriction of phosphate in the diet; avoidance of aluminum-containing phosphate-binding antacids to prevent the problem of aluminum intoxication; provision of an adequate calcium intake by mouth, usually 1–2 g/d; and supplementation with 0.25–1 μg/d calcitriol or other activated forms of vitamin D. Each patient must be monitored closely. The aim of therapy is to restore normal calcium balance to prevent osteomalacia and severe secondary hyperparathyroidism (it is usually recommended to maintain PTH levels between 100 and 300 pg/mL) and, in light of evidence of genetic changes and monoclonal outgrowths of parathyroid glands in CKD patients, to prevent secondary hyperparathyroidism from becoming autonomous hyperparathyroidism. Reduction of hyperphosphatemia and restoration of normal intestinal calcium absorption by calcitriol can improve blood calcium levels and reduce the manifestations of secondary hyperparathyroidism. Because adynamic bone disease can occur in association with low PTH levels, it is important to avoid excessive suppression of the parathyroid glands while recognizing the beneficial effects of controlling the secondary hyperparathyroidism. These patients should probably be closely monitored with PTH assays that detect only the full-length PTH(1–84) to ensure that biologically active PTH and not inactive, inhibitory PTH fragments are measured. Use of phosphate-binding agents such as sevelamer is approved only in end-stage renal disease, but it may be necessary to initiate such treatment much earlier during the course of kidney disease to prevent the increase in FGF23 and its “off-target” effects.
Vitamin D Deficiency due to Inadequate Diet and/or Sunlight
Vitamin D deficiency due to inadequate intake of dairy products enriched with vitamin D, lack of vitamin supplementation, and reduced sunlight exposure in the elderly, particularly during winter in northern latitudes, is more common in the United States than previously recognized. Biopsies of bone in elderly patients with hip fracture (documenting osteomalacia) and abnormal levels of vitamin D metabolites, PTH, calcium, and phosphate indicate that vitamin D deficiency may occur in as many as 25% of elderly patients, particularly in northern latitudes in the United States. Concentrations of 25(OH)D are low or low-normal in these patients. Quantitative histomorphometric analysis of bone biopsy specimens from such individuals reveals widened osteoid seams consistent with osteomalacia (Chap. 423). PTH hypersecretion compensates for the tendency for the blood calcium to fall but also increases renal phosphate excretion and thus causes osteomalacia.
Treatment involves adequate replacement with vitamin D and calcium until the deficiencies are corrected. Severe hypocalcemia rarely occurs in moderately severe vitamin D deficiency of the elderly, but vitamin D deficiency must be considered in the differential diagnosis of mild hypocalcemia.
Mild hypocalcemia, secondary hyperparathyroidism, severe hypophosphatemia, and a variety of nutritional deficiencies occur with gastrointestinal diseases. Hepatocellular dysfunction can lead to reduction in 25(OH)D levels, as in portal or biliary cirrhosis of the liver, and malabsorption of vitamin D and its metabolites, including 1,25(OH)2D, may occur in a variety of bowel diseases, hereditary or acquired. Hypocalcemia itself can lead to steatorrhea, due to deficient production of pancreatic enzymes and bile salts. Depending on the disorder, vitamin D or its metabolites can be given parenterally, guaranteeing adequate blood levels of active metabolites.
Defective Vitamin D Metabolism
Anti-convulsant therapy with any of several agents induces acquired vitamin D deficiency by increasing the conversion of vitamin D to inactive compounds and/or causing resistance to its action. The more marginal the vitamin D intake in the diet, the more likely that anticonvulsant therapy will lead to abnormal mineral and bone metabolism.
VITAMIN D–DEPENDENT RICKETS TYPE I
Vitamin D–dependent rickets type I, previously termed pseudo-vitamin D–resistant rickets, differs from true vitamin D–resistant rickets (vitamin D–dependent rickets type II, see below) in that it is typically less severe and the biochemical and radiographic abnormalities can be reversed with appropriate doses of the vitamin’s active metabolite, 1,25(OH)2D. Physiologic amounts of calcitriol cure the disease (Chap. 423). This finding fits with the pathophysiology of the disorder, which is autosomal recessive, and is now known to be caused by mutations in the gene encoding 25(OH)D-1α-hydroxylase. Both alleles are inactivated in affected patients, and compound heterozygotes, harboring distinct mutations, are common.
Clinical features include hypocalcemia, often with tetany or convulsions, hypophosphatemia, secondary hyperparathyroidism, and osteomalacia, often associated with skeletal deformities and increased alkaline phosphatase. Treatment involves physiologic replacement doses of 1,25(OH)2D (Chap. 423).
VITAMIN D–DEPENDENT RICKETS TYPE II
Vitamin D–dependent rickets type II results from end-organ resistance to the active metabolite 1,25(OH)2D. The clinical features resemble those of the type I disorder and include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets but also partial or total alopecia. Plasma levels of 1,25(OH)2D are elevated, in keeping with the refractoriness of the end organs. This disorder is caused by mutations in the gene encoding the vitamin D receptor; treatment is difficult and requires regular, usually nocturnal calcium infusions, which dramatically improve growth but do not restore hair growth (Chap. 423).
PHP refers to a group of distinct inherited disorders. Patients affected by PHP type Ia (PHP-Ia) are characterized by symptoms and signs of hypocalcemia in association with distinctive skeletal and developmental defects. The hypocalcemia is due to a deficient response to PTH, which is probably restricted to the proximal renal tubules. Hyperplasia of the parathyroids, a response to hormone-resistant hypocalcemia, causes elevation of PTH levels. Studies, both clinical and basic, have clarified some aspects of these disorders, including the variable clinical spectrum, the pathophysiology, the genetic defects, and their mode of inheritance.
A working classification of the various forms of PHP is given in Table 424-6. The classification scheme is based on the signs of ineffective PTH action (low calcium and high phosphate), low or normal urinary cAMP response to exogenous PTH, the presence or absence of Albright’s hereditary osteodystrophy (AHO), and assays to measure the concentration of the Gsα subunit of the adenylate cyclase enzyme. Using these criteria, there are four types: PHP types Ia and Ib; pseudopseudohypoparathyroidism (PPHP), and PHP-II.
TABLE 424-6Classification of Pseudohypoparathyroidism (PHP) and Pseudopseudohypoparathyroidism (PPHP) ||Download (.pdf) TABLE 424-6 Classification of Pseudohypoparathyroidism (PHP) and Pseudopseudohypoparathyroidism (PPHP)
|Type ||Hypocalcemia, Hyperphosphatemia ||Response of Urinary cAMP to PTH ||Serum PTH ||Gsα Subunit Deficiency ||AHO ||Resistance to hormones other than PTH |
|PHP-Ia ||Yes ||↓ ||↑ ||Yes ||Yes ||Yes |
|PPHP ||No ||Normal ||Normal ||Yes ||Yes ||No |
|PHP-Ib ||Yes ||↓ ||↑ ||No ||No ||Yes (in some patients) |
|PHP-II ||Yes ||Normal ||↑ ||No ||No ||No |
|Acrodysostosis with hormonal resistance ||Yes ||Normal (but ↓ phosphaturic response) ||↑ ||No ||Yes ||Yes |
Individuals with PHP-I, the most common of the disorders, show a deficient urinary cAMP response to administration of exogenous PTH. Patients with PHP-I are divided into type Ia and type Ib. Patients with PHP-Ia show evidence for AHO and reduced amounts of Gsα protein/activity, as determined in readily accessible tissues such as erythrocytes, lymphocytes, and fibroblasts. Patients with PHP-Ib typically lack evidence for AHO and they have normal Gsα activity. PHP-Ic, sometimes listed as a third form of PHP-I, is really a variant of PHP-Ia, although the mutant Gsα shows normal activity in certain in vitro assays.
Most patients who have PHP-Ia reveal characteristic features of AHO, which consist of short stature, round face, obesity, skeletal anomalies (brachydactyly), intellectual impairment, and/or heterotopic calcifications. Patients have low calcium and high phosphate levels, as with true hypoparathyroidism. PTH levels, however, are elevated, reflecting resistance to hormone action.
Amorphous deposits of calcium and phosphate are found in the basal ganglia in about one-half of patients. The defects in metacarpal and metatarsal bones are sometimes accompanied by short phalanges as well, possibly reflecting premature closing of the epiphyses. The typical findings are short fourth and fifth metacarpals and metatarsals. The defects are usually bilateral. Exostoses and radius curvus are frequent.
Inheritance and Genetic Defects
Multiple defects at the GNAS locus have now been identified in PHP-Ia, PHP-Ib, and PPHP patients. This gene, which is located on chromosome 20q13.3, encodes the α-subunit of the stimulatory G protein (Gsα), among other products (see below). Mutations include abnormalities in splice junctions associated with deficient mRNA production, point mutations, insertions, and/or deletion that all result in a protein with defective function resulting in a 50% reduction of Gsα activity in erythrocytes or other cells.
Detailed analyses of disease transmission in affected kindreds have clarified many features of PHP-Ia, PPHP, and PHP-Ib (Fig. 424-7). The former two entities, often traced through multiple generations, have an inheritance pattern consistent with genetic imprinting. The phenomenon of gene imprinting, involving methylation of genetic loci, independent of any mutation, impairs transcription from either the maternal or the paternal allele (Chap. 82). The Gsα transcript is biallelically expressed in most tissues; expression from paternal allele is silenced through as-of-yet unknown mechanisms in some tissues including the proximal renal tubules and the thyroid; consequently, inheritance of a defective paternal allele has no implications with regard to hormonal function. Thus, females affected by either PHP-Ia or PPHP will have offspring with PHP-Ia, if these children inherit the allele carrying the GNAS mutation; in contrast, if the mutant allele is inherited from a male affected by either disorder, the offspring will exhibit PPHP. Consistent with these data in humans, gene-ablation studies in mice have shown that inheritance of the mutant Gsα allele from the female causes much reduced Gsα protein in renal cortex, hypocalcemia, and resistance to PTH. Offspring inheriting the mutant allele from the male showed no evidence of PTH resistance or hypocalcemia.
Paternal imprinting of renal parathyroid hormone (PTH) resistance. An impaired excretion of urinary cyclic AMP and phosphate is observed in patients with pseudohypoparathyroidism type Ia (PHP-Ia). In the renal cortex, there is selective silencing of paternal Gsα expression. The disease becomes manifest only in patients who inherit the defective gene from an obligate female carrier (left). If the genetic defect is inherited from an obligate male gene carrier, there is no biochemical abnormality; administration of PTH causes an appropriate increase in the urinary cyclic AMP and phosphate concentration (pseudo-PHP [PPHP]; right). Both patterns of inheritance lead to Albright’s hereditary osteodystrophy (AHO), perhaps because of haplotype insufficiency—i.e., both copies of Gsα must be active for normal bone development.
Imprinting is tissue selective. Paternal Gsα expression is not silenced in most tissues. It seems likely, therefore, that the AHO phenotype recognized in PPHP as well as PHP-Ia reflects Gsα haploinsufficiency during embryonic or postnatal development.
The complex mechanisms that control the GNAS gene contribute to challenges involved in unraveling the pathogenesis of these disorders, especially that of PHP-Ib. Much intensive work with families in which multiple members are affected by PHP-Ib, as well as studies of the complex regulation of the GNAS gene locus, have now shown that PHP-Ib is caused by microdeletions within or upstream of the GNAS locus, which are associated with a loss of DNA methylation at one or several loci of the maternal allele (Table 424-6). These abnormalities in methylation silence the expression of the gene. This leads in the proximal renal tubules—where Gsα appears to be expressed exclusively from the maternal allele—to PTH resistance.
PHP-Ib, lacking the AHO phenotype in most instances, shares with PHP-Ia the hypocalcemia and hyperphosphatemia caused by PTH resistance, and thus the blunted urinary cAMP response to administered PTH, a standard test to assess the presence or absence of hormone resistance (Table 424-6). Furthermore, these endocrine abnormalities become apparent only if the disease-causing mutation is inherited maternally. Bone responsiveness may be excessive rather than blunted in PHP-Ib (and in PHP-Ia) patients, based on case reports that have emphasized an osteitis fibrosa–like pattern in several PHP-Ib patients.
PHP-II refers to patients with hypocalcemia and hyperphosphatemia, who have a normal urinary cAMP but an impaired urinary phosphaturic response to PTH. In a PHP-II variant, referred to as acrodysostosis with hormonal resistance (ADOHR), patients have a defect in the regulatory subunit of PKA (PRKAR1A) that mediates the response to PTH distal to cAMP production. Acrodysostosis without hormonal resistance is caused by mutations in the cAMP-selective phosphodiesterase 4 (ADOP4). It remains unclear why the PTH-resistance in some patients, labeled as PHP-II without bony abnormalities, resolves upon treatment with vitamin D supplements.
The diagnosis of these hormone-resistant states can usually be made without difficulty when there is a positive family history for features of AHO, in association with the signs and symptoms of hypocalcemia. In both categories—PHP-Ia and PHP-Ib—serum PTH levels are elevated, particularly when patients are hypocalcemic. However, patients with PHP-Ib or PHP-II without acrodysostosis present only with hypocalcemia and high PTH levels, as evidence for hormone resistance. In PHP-Ia and PHP-Ib, the response of urinary cAMP to the administration of exogenous PTH is blunted. The diagnosis of PHP-II, in the absence of acrodysostosis, is more complex, and vitamin D deficiency must be excluded before such a diagnosis can be entertained.
Treatment of PHP is similar to that of hypoparathyroidism, except that calcium and vitamin D doses are usually higher. Patients with PHP show no PTH-resistance in the distal tubules—hence, urinary calcium clearance is typically reduced, and they are not at risk of developing nephrocalcinosis as are patients with true hypoparathyroidism, unless overtreatment occurs, for example, after the completion of pubertal development and skeletal mutation, when calcium and 1,25(OH)2D treatment should be reduced. Variability in response makes it necessary to establish the optimal regimen for each patient, based on maintaining appropriate blood calcium level and urinary calcium excretion and keeping the PTH level within or slightly above the normal range.
Occasionally, loss of calcium from the ECF is so severe that PTH cannot compensate. Such situations include acute pancreatitis and severe, acute hyperphosphatemia, often in association with renal failure, conditions in which there is rapid efflux of calcium from the ECF. Severe hypocalcemia can occur quickly; PTH rises in response to hypocalcemia but does not return blood calcium to normal.
Severe, Acute Hyperphosphatemia
Severe hyperphosphatemia is associated with extensive tissue damage or cell destruction (Chap. 423). The combination of increased release of phosphate from muscle and impaired ability to excrete phosphorus because of renal failure causes moderate to severe hyperphosphatemia, the latter causing calcium loss from the blood and mild to moderate hypocalcemia. Hypocalcemia is usually reversed with tissue repair and restoration of renal function as phosphorus and creatinine values return to normal. There may even be a mild hypercalcemic period in the oliguric phase of renal function recovery. This sequence, severe hypocalcemia followed by mild hypercalcemia, reflects widespread deposition of calcium in muscle and subsequent redistribution of some of the calcium to the ECF after phosphate levels return to normal.
Other causes of hyperphosphatemia include hypothermia, massive hepatic failure, and hematologic malignancies, either because of high cell turnover of malignancy or because of cell destruction by chemotherapy.
TREATMENT Severe, Acute Hyperphosphatemia
Treatment is directed toward lowering of blood phosphate by the administration of phosphate-binding antacids or dialysis, often needed for the management of CKD. Although calcium replacement may be necessary if hypocalcemia is severe and symptomatic, calcium administration during the hyperphosphatemic period tends to increase extraosseous calcium deposition and aggravate tissue damage. The levels of 1,25(OH)2D may be low during the hyperphosphatemic phase and return to normal during the oliguric phase of recovery.
Osteitis Fibrosa after Parathyroidectomy
Severe hypocalcemia after parathyroid surgery is rare now that osteitis fibrosa cystica is an infrequent manifestation of hyperparathyroidism. When osteitis fibrosa cystica is severe, however, bone mineral deficits can be large. After parathyroidectomy, hypocalcemia can persist for days if calcium replacement is inadequate. Treatment may require parenteral administration of calcium; addition of calcitriol and oral calcium supplementation is sometimes needed for weeks to a month or two until bone defects are filled (which, of course, is of therapeutic benefit in the skeleton), making it possible to discontinue parenteral calcium and/or reduce the amount.
DIFFERENTIAL DIAGNOSIS OF HYPOCALCEMIA
Care must be taken to ensure that true hypocalcemia is present; in addition, acute transient hypocalcemia can be a manifestation of a variety of severe, acute illnesses, as discussed above. Chronic hypocalcemia, however, can usually be ascribed to a few disorders associated with absent or ineffective PTH. Important clinical criteria include the duration of the illness, signs or symptoms of associated disorders, and the presence of features that suggest a hereditary abnormality. A nutritional history can be helpful in recognizing a low intake of vitamin D and calcium in the elderly, and a history of excessive alcohol intake may suggest magnesium deficiency.
Hypoparathyroidism and PHP are typically lifelong illnesses, usually (but not always) appearing by adolescence; hence, a recent onset of hypocalcemia in an adult is more likely due to nutritional deficiencies, renal failure, or intestinal disorders that result in deficient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with a delayed onset of postoperative hypoparathyroidism. A history of seizure disorder raises the issue of anticonvulsive medication. Developmental defects may point to the diagnosis of PHP. Rickets and a variety of neuromuscular syndromes and deformities may indicate ineffective vitamin D action, either due to defects in vitamin D metabolism or to vitamin D deficiency.
A pattern of low calcium with high phosphorus in the absence of renal failure or massive tissue destruction almost invariably means hypoparathyroidism or PHP. A low calcium and low phosphorus pattern points to absent or ineffective vitamin D, thereby impairing the action of PTH on calcium metabolism (but not phosphate clearance). The relative ineffectiveness of PTH in calcium homeostasis in vitamin D deficiency, anticonvulsant therapy, gastrointestinal disorders, and hereditary defects in vitamin D metabolism leads to secondary hyperparathyroidism as a compensation. The excess PTH on renal tubule phosphate transport accounts for renal phosphate wasting and hypophosphatemia.
Exceptions to these patterns may occur. Most forms of hypomagnesemia are due to long-standing nutritional deficiency as seen in chronic alcoholics. Despite the fact that the hypocalcemia is principally due to an acute absence of PTH, phosphate levels are usually low, rather than elevated, as in hypoparathyroidism. Chronic renal failure is often associated with hypocalcemia and hyperphosphatemia, despite secondary hyperparathyroidism.
Diagnosis is usually established by application of the PTH immunoassay, tests for vitamin D metabolites, and measurements of the urinary cAMP response to exogenous PTH. In hereditary and acquired hypoparathyroidism and in severe hypomagnesemia, PTH is either undetectable or inappropriately in the normal range (Fig. 424-4). This finding in a hypocalcemic patient is supportive of hypoparathyroidism, as distinct from ineffective PTH action, in which even mild hypocalcemia is associated with elevated PTH levels. Hence a failure to detect elevated PTH levels establishes the diagnosis of hypoparathyroidism; elevated levels suggest the presence of secondary hyperparathyroidism, as found in many of the situations in which the hormone is ineffective due to associated abnormalities in vitamin D action. Assays for 25(OH)D can be helpful. Low or low-normal 25(OH)D indicates vitamin D deficiency due to lack of sunlight, inadequate vitamin D intake, or intestinal malabsorption. Recognition that mild hypocalcemia, rickets, and hypophosphatemia are due to anticonvulsant therapy is made by history.
TREATMENT Hypocalcemic States
The management of hypoparathyroidism, PHP, chronic renal failure, and hereditary defects in vitamin D metabolism involves the use of vitamin D or vitamin D metabolites and calcium supplementation. Vitamin D itself is the least expensive form of vitamin D replacement and is frequently used in the management of uncomplicated hypoparathyroidism and some disorders associated with ineffective vitamin D action. When vitamin D is used prophylactically, as in the elderly or in those with chronic anticonvulsant therapy, there is a wider margin of safety than with the more potent metabolites. However, most of the conditions in which vitamin D is administered chronically for hypocalcemia require amounts 50–100 times the daily replacement dose because the formation of 1,25(OH)2D is deficient. In such situations, vitamin D is no safer than the active metabolite because intoxication can occur with high-dose therapy (because of storage in fat). Calcitriol is more rapid in onset of action and also has a short biologic half-life.
Vitamin D (at least 1000 U/d [2–3 μg/d] [higher levels required in older persons]) or calcitriol (0.25–1 μg/d) is required to prevent rickets in normal individuals. In contrast, 40,000–120,000 U (1–3 mg) of vitamin D2 or D3 is typically required in hypoparathyroidism. The dose of calcitriol is unchanged in hypoparathyroidism, because the defect is in hydroxylation by the 25(OH)D-1α-hydroxylase. Calcitriol is also used in disorders of 25(OH)D-1α-hydroxylase; vitamin D receptor defects are much more difficult to treat.
Patients with hypoparathyroidism should be given 2–3 g of elemental calcium PO each day. The two agents, vitamin D or calcitriol and oral calcium, can be varied independently. Urinary calcium excretion needs to be monitored carefully. If hypocalcemia alternates with episodes of hypercalcemia in high-brittleness patients with hypoparathyroidism, administration of calcitriol and use of thiazides, as discussed above, may make management easier. Clinical trials with PTH(1–34) or PTH(1–84) are promising, but these alternative treatments have not yet been approved.