ABSTRACT

A reduction in serum calcium can stimulate parathyroid hormone (PTH) release which may then increase bone resorption, enhance renal calcium reabsorption, and stimulate renal conversion of 25-hydroxyvitamin D, to the active moiety 1,25-dihydroxyvitamin D [1,25(OH)₂D] which then will enhance intestinal calcium absorption. These mechanisms restore the serum calcium to normal and inhibit further production of PTH and 1,25(OH)₂D. Normal serum concentrations of total calcium generally range between 8.5 and 10.5 mg/dL (2.12 to 2.62 mM) and ionized calcium between 4.65-5.30 mg/dL (1.16-1.31 mM). Decreased PTH and decreased 1,25(OH)₂D should accompany hypercalcemia unless PTH or 1,25(OH)₂D is causal. Hypercalcemia may be caused by: Endocrine Disorders with Excess PTH including primary sporadic and familial hyperparathyroidism(syndromic and non-syndromic), and tertiary hyperparathyroidism; Endocrine Disorders Without Excess PTH including hyperthyroidism, pheochromocytoma, VIPoma, hypoadrenalism, and Jansen's Metaphyseal Chondrodysplasia; Malignancy-Associated Hypercalcemia, which can be caused by elevated PTH-related protein (PTHrP), or other factors (e.g. increased 1,25(OH)₂D in lymphomas); Inflammatory Disorders including Granulomatous Diseases, where excess 1,25(OH)₂D production may be causal, and viral syndromes (HIV); Pediatric Syndromes including Williams Syndrome and Idiopathic Infantile Hypercalcemia, where inappropriate levels of 1,25(OH)₂D may occur due to a mutation in the 25-hydroxyvitamin D-24-hydroxylase gene (CYP24A1); medication, including thiazide diuretics, lithium, vitamin D, vitamin A, antiestrogens, theophylline; and prolonged immobilization, particularly in states of high bone turnover. Treatment should be aimed at the underlying disorder, however, if serum calcium exceeds 12 to 14mg/dL (3 to 3.5mM), acute hydration and agents that inhibit bone resorption are required. Under selected conditions, calcimimetics, calciuresis, glucocorticoids, or dialysis may be needed. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

DEFINITION OF HYPERCALCEMIA

Hypercalcemia can be defined as a serum calcium greater than 2 standard deviations above the normal mean in a reference laboratory. Calcium in the blood is normally transported partly bound to plasma proteins (about 45%), notably albumin, partly bound to small anions such as phosphate and citrate (about 10%) and partly in the free or ionized state (about 45%) (1). Although only the ionized calcium is metabolically active i.e., subject to transport into cells and capable of activating cellular processes, most laboratories report total serum calcium concentrations. Concentrations of total calcium in normal serum generally range between 8.5 and 10.5 mg/dL (2.12 to 2.62 mM) and levels above this are considered to be consistent with hypercalcemia. Nevertheless, reference ranges may vary between laboratories. The normal range of ionized calcium is generally 4.65-5.25 mg/dL (1.16-1.31 mM), but again values may vary slightly between laboratories. When protein concentrations, and especially albumin concentrations, fluctuate substantially, total calcium levels may vary, whereas the ionized calcium may remain relatively stable. Thus, dehydration, or hemoconcentration during venipuncture may elevate serum albumin, and a falsely elevated total serum calcium may be reported (“pseudo-hypercalcemia”). Such elevations in total calcium, when albumin levels are increased, can be "corrected" by subtracting 0.8 mg/dL from the total calcium for every 1.0 g/dL by which the serum albumin concentration is >4 g/dL. Conversely when albumin levels are low, total calcium can be corrected by adding 0.8 mg/dL for every 1.0 g/dL by which the albumin is <4 g/dL. Thus, to correct for an abnormally high or low serum albumin the following formula can be used: Corrected calcium (mg/dL) = measured total serum calcium (mg/dL) + [4.0- serum albumin (g/dL) X 0.8] or Corrected calcium (mM) = measured total Ca (mM) + [40 - serum albumin (g/L)] X 0.02. Nevertheless, although algorithms to adjust for albumin levels are widely used, their accuracy may be poor. Even in the presence of a normal serum albumin, changes in blood pH can alter the equilibrium constant of the albumin-Ca++ complex, with acidosis reducing the binding and alkalosis enhancing it. Consequently, when major shifts in serum protein or pH are present it is most prudent to directly measure the ionized calcium level in order to determine the presence of hypercalcemia.

PHYSIOLOGY OF CALCIUM HOMEOSTASIS

The extracellular fluid (ECF) concentration of calcium is tightly maintained within a rather narrow range because of the importance of the calcium ion to numerous cellular functions including cell division, cell adhesion and plasma membrane integrity, protein secretion, muscle contraction, neuronal excitability, glycogen metabolism, and coagulation.

The skeleton, the gut and the kidney play a major role in assuring calcium homeostasis. Overall, in a typical individual, if 1000 mg of calcium are ingested in the diet per day, approximately 200 mg will be absorbed. Approximately 10 g of calcium will be filtered daily through the kidney and most will be reabsorbed with about 200 mg being excreted in the urine. The normal 24-hour excretion of calcium may however vary between approximately 100 and 300 mg per day (2.5 to 7.5 mmoles per day). The skeleton, a storage site of about 1 kg of calcium, is the major calcium reservoir in the body and bone turnover (bone formation coupled with bone resorption) will determine the net entry of calcium into or egress of calcium out of the skeleton. When bone turnover is balanced, approximately 500 mg of calcium is released from bone per day and the equivalent amount is accreted per day (Fig. 1).

Figure 1.

Calcium balance. On average, if, in a typical adult approximately 1g of elemental calcium (Ca⁺²) is ingested per day, about 200mg/day will be absorbed and 800mg/day excreted. Approximately 1kg of Ca⁺² is stored in bone and about 500mg/day is released by resorption or deposited during bone formation. Of the 10g of Ca⁺² filtered through the kidney per day only about 200mg appears in the urine, the remainder being reabsorbed.

Tight regulation of the ECF calcium concentration is maintained through the action of calcium-sensitive cells which modulate the production of hormones (2-5). These hormones act on specific cells in bone, gut and kidney which can respond by altering fluxes of calcium to maintain ECF calcium. The parathyroid glands detect ECF calcium via a calcium sensing receptor (CaSR) (6). Thus, a reduction in ECF calcium can reduce stimulation of the parathyroid CaSR and facilitate release of parathyroid hormone (PTH) from the parathyroid glands in the neck. PTH can then act to enhance calcium reabsorption in the kidney while at the same time inhibit phosphate reabsorption producing phosphaturia. Reduced ECF calcium per se can also act via a CaSR in the loop of Henle to allow renal calcium reabsorption.

PTH and hypocalcemia can both stimulate the conversion of the inert metabolite of vitamin D, 25-hydroxyvitamin D [25(OH)D], to the active moiety 1,25-dihydroxyvitamin D [1,25(OH)₂D] (7), which in turn will enhance intestinal calcium absorption, and to a lesser extent phosphate reabsorption. 1,25(OH)₂D can stimulate the production of the hormone fibroblast growth factor 23 (FGF23) from osteocytes in bone and the released FGF23 can inhibit phosphate transport in the renal proximal tubule and therefore cause phosphaturia and hypophosphatemia. PTH can also increase bone resorption and liberate both calcium and phosphate from the skeleton. The net effect of the increased reabsorption of renal calcium, the increased absorption of calcium from the gut, and the mobilization of calcium from bone, is to restore the ECF calcium to normal and to inhibit further production of PTH and 1,25(OH)₂D. FGF23 elevation will also reduce 1,25(OH)₂D production. The opposite sequence of events i.e., diminished PTH and 1,25(OH)₂D secretion should occur when the ECF calcium is raised above the normal range and the effect of suppressing the release of these hormones should diminish skeletal calcium release, intestinal calcium absorption, and renal calcium reabsorption and restore the elevated ECF calcium to normal. Consequently, decreased levels of PTH and decreased levels of 1,25(OH)₂D should accompany hypercalcemia unless the PTH or 1,25(OH)₂D is the cause of the hypercalcemia.

REGULATION OF THE PRODUCTION AND ACTION OF HUMORAL MEDIATORS OF CALCIUM HOMEOSTASIS

Parathyroid Hormone Related Protein (PTHrP)

PTHrP was discovered as the mediator of the syndrome of "humoral hypercalcemia of malignancy" (HHM) (63). In this syndrome a variety of cancers, essentially in the absence of skeletal metastases, produce a PTH-like substance which can cause a constellation of biochemical abnormalities including hypercalcemia, hypophosphatemia, and increased urinary cyclic AMP excretion. These mimic the biochemical effects of PTH but occur in the absence of detectable circulating levels of this hormone.

PTHrP is encoded by a single-copy gene, PTHLH, located on chromosome 12 whereas the gene encoding PTH is found on chromosome 11. Nevertheless, these two chromosomes encode many similar genes and are believed to have arisen by an ancient duplication event. Consequently, PTHLH and PTH may be members of a single gene family (64,65). The human PTHLH gene which is driven by at least three promoters, contains at least seven exons, shows several patterns of alternative splicing, and is considerably more complex than the PTH gene. Each gene encodes a leader or "pre" sequence, a "pro" sequence and a mature form. In the case of human PTH, the mature form is 84 amino acids. In the case of human PTHrP, 3 isoforms of 139, 141 and 173 residues can occur by alternate splicing, and sequences of these isoforms are identical through residue 139. Several common structural features of the PTHLH and PTH genes suggest that they are related. Thus, the major coding exon of both genes starts precisely at the same nucleotide, one base before the codons encoding the Lys-Arg residues of the prohormone sequences of each hormone. In the NH₂ terminus of both peptides, 8 of the first 13 amino acid residues are identical. These identities although limited are believed to be responsible for the similar bioactivities of the NH₂ terminal domains of these peptides (66), such that synthetic PTH (1-34) and synthetic PTHrP (1-34) interact with a common receptor (PTHR1) (26,27) and have similar effects on calcium and phosphate homeostasis. Thus, PTHrP is the second member of the PTH family to have been discovered. A hypothalamic peptide called tuberoinfundibular peptide of 39 residues (TIP 39) appears to represent a third member of the PTH gene family (67) and can interact at a second PTH receptor termed the type II receptor (PTHR2) (68) (to which PTHrP does not bind (Fig. 2). The precise physiologic role of TIP 39 (also called PTH2) and of PTHR2 remain to be elucidated, however the TIP39/PTHR2 system has been implicated in the control of nociception, fear and fear incubation, anxiety and depression-like behaviors, and maternal and social behaviors. It also appears to influence thermoregulation and potentially auditory responses (69).

Figure 2.

PTH and PTHR gene families: PTHrP, PTH and TIP39 appear to be products of a single gene family. Although only nine amino acids in the NH2-terminal domains of these three peptides are conserved these are functionally important residues. The receptors for these peptides, PTHR1 and PTHR2, are both 7 transmembrane-spanning G protein-coupled receptors which seem to be products of a single gene family. PTHrP binds and activates PTHR1; it binds weakly to PTHR2 and does not activate it. PTH can bind and activate both PTHR1 and PTHR2. TIP39 can bind to and activate PTHR2 but not PTHR1.

REGULATION OF PTHrP PRODUCTION

In contrast to PTH, whose expression is limited mainly to parathyroid cells, PTHrP is widely expressed in many fetal and adult tissues (70). This is compatible with its primary role as a modulator of cell growth and differentiation. A major locus of regulation of PTHrP production is at the level of gene transcription although both regulated and constitutive secretion of the hormone have been described in various cell types (71,72).

Key stimulators of gene transcription are a variety of growth factors and cytokines (73) including epidermal growth factor (EGF) (74), IGF-1 (75), and transforming growth factor b (TGFb) (76). Inhibition of growth factor action, by employing a farnesyl transferase inhibitor to decrease ras-mediated cell signaling, has proved effective in inhibiting PTHrP production in vitro and in studies in vivo using an animal model of malignancy which overproduced PTHrP (77). Hypercalcemia associated with these tumors was also diminished.

Several steroidal hormones including 1,25(OH)₂D (78), glucocorticoids (79), and androgens (80) have been reported to be potent inhibitors of PTHrP gene expression. This prompted the use of 1,25(OH)₂D (81) and of low calcemic analogues of vitamin D (82) in studies with tumor cells, both in vitro and in animals in vivo, to determine if overproduction of PTHrP by these tumors could be inhibited. Indeed, PTHrP production was inhibited, the associated hypercalcemia was reduced, and survival of the animals was increased.

PTHrP is biosynthesized as a precursor form, proPTHrP and the propeptide must be cleaved to the mature peptide in order to achieve optimal bioactivity. This occurs by prohormone convertase activity (83). This processing locus was attacked using a furin antisense approach to block prohormone convertase activity in an animal tumor model which overproduces PTHrP (84). Bioactive PTHrP production was diminished with this intervention, and, in vivo, the hypercalcemia associated with the control tumor was not observed.

Serine proteases may also act on PTHrP internally, in various cell types, to cleave an NH₂ terminal fragment, a midregion fragment (85) and carboxyl terminal fragments (86) from the mature forms, each with apparently distinct bioactivities. The in vivo significance of this processing remains to be determined. Nevertheless, PTHrP has been described as a polyhormone.

PTHrP ACTIONS

The major effects of PTHrP appear to be mediated by binding of an NH₂ terminal domain, PTHrP (1-36), to the PTHR1 linked to adenylate cyclase, or phospholipase C. In some developing tissues, e.g., teeth. PTHrP is expressed in epithelial cells whereas the PTHR1 is in adjacent mesenchymal cells facilitating epithelial-mesenchymal interactions (87).

A mid-region domain of PTHrP (37-86) has been implicated in placental calcium transport (85) and a COOH terminal region (107-139) has been reported to inhibit osteoclasts (86). Nevertheless, distinct receptors for these putative bioactive regions have not been described.

A bipartite nuclear localization sequence (NLS) has been discovered in PTHrP at sequence positions 87 to 106 and has been shown to be capable, in vitro, of directing PTHrP to the nucleus and, in fact, to the nucleolus (88). Translocation from the cytoplasm to the nucleus is facilitated by binding to importin beta and seems cell cycle dependent. Although cyclin-dependent (cdc2) kinase can phosphorylate PTHrP this may not be the sole regulator of PTHrP nuclear import (89). Inasmuch as PTHrP contains a presequence or leader sequence which directs it to the secretory pathway, 3 pathways have been postulated which could lead it to access to the cytoplasm and thence the nucleus. Thus, PTHrP has been shown in some studies to be internalized after secretion and to access the cytoplasm by this route (90). Reverse transport of PTHrP from the endoplasmic reticulum to the cytoplasm has been reported in other studies (91). Finally, alternate initiation of translation at downstream non-AUG codons that allowed nascent PTHrP to bypass ER transit and localize to the nucleus and nucleolus has also been reported (92). In vitro studies have suggested that nuclear localization of PTHrP may be involved in its proliferative activity and/or in inhibition of apoptosis (87), and in vivo, PTHrP “knockin” mice have been reported which express truncated forms of PTHrP that lack the NLS and the carboxyl -terminus but retain the amino terminus and the capacity to bind to PTHR1. The resulting mutants show growth retardation, defects in multiple organs and early lethality. Consequently, these studies indicate a functional in vivo role for the nuclear localization of this protein (93,94).

Overall, reported physiologic effects of PTHrP can be grouped into those relating to ion homeostasis; those relating to smooth muscle relaxation; and those associated with cell growth, differentiation and apoptosis. The majority of the physiological effects of PTHrP appear to occur by short-range i.e., paracrine/autocrine and intracrine mechanisms rather than long-range i.e. endocrine mechanisms.

With respect to ion homeostasis PTHrP can modulate placental calcium transport and appears necessary for normal fetal calcium homeostasis (95). In the adult, however the major role in calcium and phosphorus homeostasis appears to be carried out by PTH rather than by PTHrP in view of the fact that PTHrP concentrations in normal adults are either very low or undetectable. This situation reverses when neoplasms constitutively hypersecrete PTHrP in which case PTHrP mimics the effects of PTH on bone and kidney and the resultant hypercalcemia suppresses endogenous PTH secretion.

PTHrP has been shown to cause smooth muscle relaxation in a variety of tissues including blood vessels (96) (leading to dilatation), uterus (97), and bladder (98). The physiologic significance of these effects however remains to be determined.

Finally, PTHrP has been shown to modify cell growth, differentiated function and programmed cell death in a variety of different fetal and adult tissues. Most notable have been breast (99), skin (100), nervous tissue (101) and pancreatic islets (102) where PTHrP appears to function to assure normal development. The most striking developmental effects of PTHrP however have been in the skeleton. Targeted deletion of the PTHrP gene in mice produces a lethal chondrodysplasia (103,104), demonstrating the important and non-redundant role of PTHrP in endochondral bone formation. Animals die at birth, although the cause of death is uncertain. A major alteration appears to occur in the cartilaginous growth plate where, in the absence of PTHrP, chondrocyte proliferation is reduced and accelerated chondrocyte differentiation and apoptosis occurs. Increased bone formation occurs, apparently due to secondary hyperparathyroidism (42) and the overall effect is a severely deformed skeleton. Even more severe skeletal dysplasia occurs when either the gene encoding the PTHR1 itself (105) or the genes encoding both PTH and PTHrP are deleted (42). Both models produce similar phenotypes in mice. In the PTHrP knock-in mice that express PTHrP (1-84) but not the NLS or carboxyl terminus, the epiphyseal growth plate was markedly abnormal in this model, but the abnormality consisted of a reduced proliferative zone but normal hypertrophic zone architecture, suggesting that secreted and intracellular PTHrP may act synergistically to regulate the growth plate. In humans, an inactivating mutation of the PTHR1 produces a similar lethal chondro-osseous dysplasia termed Blomstrand's Syndrome (106,107). Consequently these in vivo observations demonstrate that PTHrP is essential, at least for normal development of the cartilaginous growth plate and endochondral bone formation. Interestingly mice that are heterozygous for PTHrP ablation appear normal at birth but develop reduced trabecular bone as they age demonstrating an osseous phenotype due to haploinsufficiency (37). This has been shown to be via a paracrine effect of PTHrP located in osteoblastic cells (108). Furthermore, hypoparathyroid mice that have PTHrP haploinsufficiency do not develop the increased trabecular bone mass that is a characteristic of hypoparathyroidism (109). PTHrP knock-in mice that express PTHrP (1-84) but lack the NLS and carboxyl terminus also appear to develop reductions in osteoblastic activity again suggesting synergy between the extra-cellular and intracellular actions of PTHrP (110). In humans, variants of the PTHLH gene have been associated with achievement of peak bone mass and in genome wide association studies have been associated with reduced bone mineral density. Overall, therefore the two ligands of PTHR1 i.e., PTH and PTHrP appear to have differing roles in utero and post-natally. In the fetus PTH appears to exert anabolic activity in trabecular bone whereas PTHrP regulates the orderly development of the growth plate. In contrast, in postnatal life, PTHrP acting as a paracrine/autocrine modulator assumes an anabolic role for bone whereas PTH predominantly defends against a decrease in extracellular fluid calcium by resorbing bone.

MEDIATORS OF BONE REMODELING

Normal adult bone is constantly undergoing "turnover" or remodeling (111). This is characterized by sequences of activation of osteoclasts followed by osteoclastic bone resorption followed by osteoblastic bone formation, which occur on the same bone surface. The process of bone modelling is the predominant event in the growing skeleton and can lead to changes in skeletal shape, but the process can also persist into adult bone; modelling is characterized by bone-forming osteoblasts and bone-resorbing osteoclasts acting on different bone surfaces and acting independent of each other, resulting in changes in bone size and shape. The sequential cellular activities in remodeling occur on the same bone surface in focal and discrete packets in both trabecular and cortical bone and are termed bone remodeling units or bone multicellular units (BMUs). This coupling of osteoblastic bone formation to bone resorption may occur via the action of growth factors released by resorbed bone e.g., TGFb, IGF-1 and fibroblast growth factor (FGF) which can induce osteoclast apoptosis and also induce chemotaxis of osteoblast precursors, including mesenchymal stem cells, and facilitate their proliferation and differentiation at the site of repair. Homodimeric platelet-derived growth factor (PDGF) composed of two B units (PDGF-BB) may also be released from matrix and induce blood vessel formation that may also provide progenitor cells for later differentiation into osteoblasts and bone formation (112). In addition, direct activation of cells of the osteoblast phenotype by osteoclast family members appears to occur, and such “coupling “mechanisms include a number of secreted factors, as well as molecules involved in direct cell–cell communication between osteoclasts and the osteoblast lineage. Although a number of molecular signals regulating this direct osteoclast-osteoblast coupling process have been described (113), their precise in vivo role remains to be established. A number of additional systemic and local factors regulate the process of bone remodeling. In general, those factors which enhance bone resorption may do so by creating an imbalance between the depth of osteoclastic bone erosion and the extent of osteoblastic repair or by increasing the numbers of remodeling units which are active at any given time i.e., by increasing the activation frequency of bone remodeling. These latter processes can also result in thinning and ultimately in perforation of trabecular bone and in increased porosity of cortical bone. One predominant example in which osteoblastic activity does not completely repair and replace the defect left by previous resorption is in multiple myeloma; in this case it has been reported that myeloma cells may release inhibitors of the Wnt signaling pathway such as the protein Dickoff (Dkk) which inhibit osteoblast production (114), while stimulation of osteoclastic resorption continues. Such an imbalance can occasionally also occur in association with some advanced solid malignancies.

Systemic hormones such as PTH, PTHrP and 1,25(OH)₂D can all initiate osteoclastic bone resorption and increase the activation frequency of bone remodeling. Thyroid hormone receptors are present in osteoblastic cells and triiodothyronine can stimulate osteoclastic bone resorption and produce a high turnover state in bone (115). Vitamin A has a direct stimulatory effect on osteoclasts and can induce bone resorption as well (116).

A variety of local factors are critical for physiologic bone resorption and regulation of the normal bone-remodeling sequence and can be produced by osteoblastic, osteoclastic and immune cells. Thus, for example, interleukin-1 (IL-1) and M-CSF can be produced by both osteoblastic cells and by cells of the osteoclastic lineage. TNFα is released by monocytic cells, TNFβ (lymphotoxin) by activated T lymphocytes, and interleukin-6 (IL-6) by osteoclastic cells (117). All can enhance osteoclastic bone resorption. Leukotrienes are eicosanoids that are produced from arachidonic acid via a 5-lipoxygenase enzyme and can also induce osteoclastic bone resorption. Prostaglandins, particularly of the E series, may also stimulate bone resorption in vitro but appear to predominantly increase formation in vivo (118). Consequently, a variety of cytokines, growth factors, and eicosanoids may be produced in the bone environment and act to regulate the bone remodeling sequence. The inappropriate production of these regulators in pathologic conditions such as cancer (Fig. 3) may therefore contribute to altered bone dynamics, altered calcium fluxes through bone, and ultimately in altered ECF calcium homeostasis.

Figure 3.

Production of bone resorbing substances by neoplasms. Tumor cells may release proteases which can facilitate tumor cell progression through unmineralized matrix. Tumors cells can also release PTHrP, cytokines, eicosanoids and growth factors (eg EGF) which can act on cells of the osteoblastic lineage to increase production of cytokines such as M-CSF and RANKL and to decrease production of OPG. RANKL can bind to its cognate receptor RANK in osteoclastic cells, which are of hepatopoietic origin, and increase production and activation of multinucleated osteoclasts which can resorb mineralized bone.

HYPERCALCEMIC DISORDERS

Hypercalcemic disorders can be broadly grouped into Endocrine Disorders, Malignant Disorders, Inflammatory Disorders, Pediatric Syndromes, Medication-Induced Hypercalcemia, and Immobilization (Table 1) (119). Approximately 90% of patients with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy-associated hypercalcemia (MAH).

ENDOCRINE DISORDERS ASSOCIATED WITH HYPERCALCEMIA

Endocrine Disorders Associated with Excess PTH Production

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A detailed discussion of primary hyperparathyroidism appears in an associated Endotext chapter. Consequently, only selected issues will be addressed here.

SPORADIC PRIMARY HYPERPARATHYROIDISM

Sporadic PHPT is generally (at least 85-90% of cases) associated with a single parathyroid adenoma which overproduces PTH. Although 10-15% of cases may be associated with multigland hyperplasia, it seems prudent to consider that at least some if not most of these cases represent familial rather than sporadic disease (120). The presence of multiple adenomas should also suggest the possibility that all glands are involved as part of a familial syndrome. Malignant sporadic PHPT may occur as a consequence of parathyroid carcinoma, but is a relatively rare event (about 1% of cases).

To date, the genes that are the most strongly implicated in parathyroid adenomas underlying sporadic benign PHPT are an oncogene CCND1, that encodes a key regulator of the cell cycle (cyclin D1) and MEN1, a tumor suppressor gene, also implicated in familial multiple endocrine neoplasia type I (121). Mutations in CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes, including EZH2, ZFX, CTNNB1/β-catenin, have been seen in smaller subsets of sporadic adenomas (122). as have other cyclin-dependent kinase inhibitor genes, including CDKN1A, CDKN2B, and CDKN2C which have each been implicated in familial forms of PHPT. Rare germline mutations in CDC73 (HRPT2, a tumor suppressor gene associated with the Hyperparathyroidism-Jaw Tumor syndrome (123), and implicated in most sporadic parathyroid carcinomas (124). can occasionally be observed in sporadic adenomas. Additionally, mutations in CASR, which has also been implicated in a familial form of PHPT (Familial Hypocalciuric Hypercalcemia), has occasionally been observed in sporadic PHPT (125). The glial cells missing 2 (GCM2) gene (previously called GCMB) encodes the GCM2 transcription factor, which is essential to the development of the parathyroid glands and subsequent PTH expression. Activating variants of GCM2, which have been implicated in familial isolated hyperparathyroidism (FIHP) have also been reported as potential predisposition alleles in sporadic parathyroid tumors (126-129).

Other important parathyroid regulatory pathways that may play a role in the pathogenesis of hyperparathyroidism are those related to the principal regulators or parathyroid cell proliferation and PTH secretion i.e., 1,25(OH)₂D, Ca⁺² and phosphate. Rarely, sporadic hyperparathyroidism with hypocalciuria may occur, caused by inhibitory antibodies to the calcium-sensing receptor. This syndrome has been termed Autoimmune Hypocalciuric Hypercalcemia (130). The clinical manifestations of these disorders are caused by the overproduction of PTH and its effect on bone resorption, on its capacity to stimulate renal 1,25(OH)₂D production and renal calcium reabsorption, and on the resultant elevation of ECF calcium which can result in an increased filtered renal load of calcium. Increased ECF calcium can itself increase calcium excretion by stimulating the renal tubular CaSR and inhibiting tubular calcium reabsorption (Fig. 4).

Three major clinical subtypes of benign sporadic PHPT, the most common form of PHPT, have been described (131). In Symptomatic PHPT, the symptoms and signs of hypercalcemia are present and are determined by the rate of increase in serum calcium, and the severity of the hypercalcemia. Symptomatic PHPT may also be associated with overt skeletal and renal complications that may include fractures and/or osteitis fibrosa cystica, and/or, chronic kidney disease, nephrolithiasis and/or nephrocalcinosis.

In Asymptomatic PHPT, there are no overt symptoms or signs of hypercalcemia and the disorder is generally discovered by biochemical screening. After evaluation, target organ involvement may or may not be found. In the third subgroup, normocalcemic PHPT, skeletal or renal complications may or may not be found after clinical evaluation.

About 80% of cases of patients with benign sporadic PHPT present as mild or “asymptomatic” hyperparathyroidism in which hypercalcemia is generally less than 1mg/dL (0.25 mM) above the upper limit of normal and may be normal intermittently (132). However significant increases in serum calcium may occur even after 13 years of follow up. Excess PTH production can produce significant bone loss. Classically this is manifested by discrete lesions including subperiosteal bone resorption of the distal phalanges, osteitis fibrosa cystica characterized by bone cysts and "brown tumors" (i.e., collections of osteoclasts intermixed with poorly mineralized woven bone), and ultimately fractures. However, although these manifestations were commonly seen in the past, they are less frequently seen today (2% of cases) (133136). Whether this severe bone disease reflects a delay in detecting primary hyperparathyroidism early, or as seems equally plausible, is a manifestation of excess PTH action in the face of marginal or deficient vitamin D and calcium intake (137), remains to be determined. The more common skeletal manifestation of excess circulating PTH, reflects the "catabolic bone activity" of PTH, (138) and production of an osteoporosis clinical picture. Consequently, the severity of bone disease appears considerably diminished.

Possibly as a consequence of less severe bone disease, hypercalcemia is also less marked, the filtered load of renal calcium is lower and the incidence of kidney stones and particularly of nephrocalcinosis has declined as well. Nevertheless, hypercalciuria still occurs in 35-40% of patients with primary benign sporadic hyperparathyroidism and kidney stones occur in 15-20% (139). About 25% of patients with mild (“asymptomatic”) sporadic PHPT have been reported to develop renal manifestations within 10 years, including renal concentrating defects or kidney stones. In regions of the globe, where relative or absolute vitamin D deficiency may limit the severity of hypercalcemia and therefore the filtered load of calcium, the incidence of nephrolithiasis (10-40%) does not appear to be as different as is the incidence of bone disease.

The higher incidence of benign sporadic PHPT in women and in an older age group (140) also appears to distinguish the current presentation of this disorder in certain regions of the world. Overall, in countries where routine biochemical screening is common (with tests including serum calcium and albumin), although the incidence of PHPT rises, the presentation changes toward the asymptomatic and even the normocalcemic variants of PHPT. Healthcare system practices, as well as more routine biochemical screening of the population both appear to account for this (141,142).

Figure 4.

Disordered mineral homeostasis in hyperparathyroidism. In primary sporadic hyperparathyroidism PTH is generally overproduced by a single parathyroid adenoma. Increased PTH secretion leads to a net increase in skeletal resorption with release of Ca⁺² and Pi (inorganic phosphate) from bone. PTH also increases renal 1α (OH)ase activity leading to increased production of 1,25(OH)₂D from 25(OH)D and increased Ca⁺² and Pi absorption from the small intestine. PTH also enhances renal Ca⁺² reabsorption and inhibits Pi reabsorption resulting in increased urine Pi excretion. The net result is an increase in ECF calcium and a decrease in ECF phosphate.

Abnormalities other than skeletal and renal have been associated with benign sporadic PHPT. These include gastrointestinal manifestations such as dyspepsia and acute pancreatitis. The incidence of peptic ulcer disease in sporadic PHPT is currently estimated to be about 10%, the same as in the general population but, the presence of multiple peptic ulcers may suggest the presence of multiple endocrine neoplasia type I (MENI). Acute pancreatitis. may be a manifestation of hypercalcemia per se but is estimated to occur in only 1.5% of those with sporadic PHPT. Neuromuscular abnormalities manifested by weakness and fatigue and accompanied by EMG changes may occur although the pathophysiology is uncertain. The relationship of hypertension and other cardiovascular manifestations as well as neuropsychiatric symptoms to the hyperparathyroidism remains unclear inasmuch as the former is generally not reversible when the hyperparathyroidism is treated and the latter is quite common in the population at large and difficult to ascribe to hyperparathyroidism. Rarely, primary sporadic PHPT may present with severe acute hypercalcemia (parathyroid crisis) (143).

Surgical removal of the parathyroid adenoma currently remains the treatment of choice if the serum calcium is consistently greater than 1mg/dL (0.25mM) above normal; if there is evidence of bone disease [i.e. a BMD T-score of <−2.5 at the lumbar spine, total hip, femoral neck, or 33% radius (1/3 site), and/or a previous fracture fragility or a fracture diagnosed on imaging ( densitometric vertebral fracture assessment [ VFA] or vertebral X-ray) ]; if there is evidence of renal involvement [i.e. if eGFR or creatinine clearance is reduced to <60 ml/min, the urinary calcium excretion is greater than 250mg/d (>6.2 mmol) for women or greater than 300mg/d (>7.48 mmol) for men, or it there is evidence of nephrocalcinosis or nephrolithiasis by ultrasound or x-ray or other imaging modality; (144). Surgery is also indicated if the patient is less than age 50. and in patients for whom medical surveillance is either not desired or not possible (145).

Parathyroid imaging is not recommended to establish or confirm the diagnosis of PHPT, but has become routine for preoperative localization of the abnormal parathyroid tissue. The most commonly employed preoperative parathyroid imaging techniques are radionuclide imaging (i.e., technetium-99 m-sestamibi subtraction scintigraphy), high resolution neck ultrasound and contrast-enhanced four dimensional (4D) computed tomography (CT). Magnetic resonance imaging, and positron emission tomography scanning, arteriography, and selective venous sampling for PTH are usually reserved for patients who have not been cured by previous explorations or for whom other localization techniques are not informative or are discordant.

The type of surgical procedure i.e., noninvasive or standard, and the use of operative adjuncts (e.g., rapid PTH assay) is institution specific and should be based on the expertise and resource availability of the surgeon and institution. Where more than one gland is enlarged it is reasonable to assume that this is multiple glandular disease and removal of 3½ glands is indicated. Severe, chronic hypercalcemia is more commonly associated with parathyroid carcinoma. Complete resection of the primary lesion is urgent in this case.

For those patients with PHPT who meet guidelines for surgery but are unable or unwilling to undergo parathyroidectomy, medical therapy may be considered. Calcium intake should be 800 mg/day for women <50 and men <70 years of age, 1000 mg/day for women >50 and men >70 years old (corresponding to the U.S. Institute of Medicine nutritional guidelines). If necessary, vitamin D should be supplemented to achieve levels of 25OHD which are >30 ng/mL (70mmol/L) but less than the upper limit of normal for the laboratory reference range. The calcimimetic agent cinacalcet (146) (that mimics or potentiates the action of calcium at the CaSR) may be used be used in patients with PHPT with severe chronic hypercalcemia who are not surgical candidates, in order to reduce the serum calcium concentration into the normal range. Bisphosphonates, e.g., alendronate (147), or denosumab, can be employed to increase bone density if there are no contraindications. Bisphosphonates or denosumab in combination with cinacalcet can be considered to lower the serum calcium and to increase BMD.

Although estrogen therapy has been advocated for the treatment of PHPT in postmenopausal women (148) potential adverse effects of estrogen therapy, including breast cancer and cardiovascular complications, make this option unattractive. The effect of conjugated estrogen on the reduction of serum calcium is inconsistent (149,150). Although selective estrogen receptor modulators may be an alternative (149), and a very short-term report with raloxifene demonstrated a significant reduction in the serum calcium concentration, (151) few long-term studies have been done to assess this.

FAMILIAL SYNDROMIC PRIMARY HYPERPARATHYROIDISM

Although familial PHPT syndromes are dominantly inherited, approximately 10% may occur through de novo pathogenic variants. Genetic evaluation should be considered for patients <30 years old, those with multigland disease by history or imaging, and/or those with a family history of hypercalcemia and/or a syndromic disease. Family history was the strongest predictor of hereditary PHPT in a recently reported cohort (152).

Multiple Endocrine Neoplasia, Type 1 and 4 (MEN1 and 4)

MEN1 is a familial disorder with an autosomal dominant pattern of inheritance which is characterized by tumors in the anterior pituitary, parathyroid, and enteropancreatic endocrine cells (although tumors in several other endocrine and non-endocrine tissues may also be associated with the syndrome) (153) (Fig. 5). Patients exhibit loss-of-function germline mutations in the tumor suppressor gene, MEN1, which encodes the nuclear protein, menin (154).

Tumors in a proband in at least 2 MEN1 sites (pituitary, parathyroid, or enteropancreatic endocrine cells) and in at least one of these sites in a first-degree relative confirms the clinical phenotype. The most common and the earliest endocrinopathy is PHPT (80-100% of cases) (155). In contrast to sporadic PHPT however MEN1 occurs in both sexes equally and patients are younger at the time of diagnosis. Furthermore, in contrast to the frequent occurrence of a single adenoma in sporadic disease, multigland involvement in an asymmetric fashion is the norm in MEN1. Enteropancreatic tumors are usually multiple and gastrinomas are the most common. These may produce the Zollinger-Ellison Syndrome, and occur in the duodenum as well as in the pancreatic islets. Gastrinomas can potentially produce considerable morbidity due to the potential for ulcers and the possibility of metastatic disease. Insulinomas, glucagonomas, VIPomas, and other islet tumors can occur as well. A variety of functioning anterior pituitary tumors can occur although prolactinomas are most frequent and anterior pituitary tumors may also be non-functioning. Finally, foregut carcinoids and other endocrine tumors have been described with lesser frequency and skin tumors such as facial angiofibromas and truncal collagenomas may occur and appear specific for MEN1.

Probands or kindreds with MEN1-like features with germline autosomal dominant mutation of the cyclin dependent kinase inhibitor CDKN1B, encoding P27 (Kip1) have been described and the syndrome named MEN4. Patients with MEN4 are characterized by the same combination of tumors as MEN1 but MEN4 is a rarer cause of hereditary PHPTH; thus, the prevalence of MEN4 among all MEN1 probands plus MEN1-like probands is approximately 1%.

Figure 5.

Familial hyperparathyroidism. Familial hyperparathyroidism (FHPT) can occur in the MENI Syndrome, in which MEN1 is mutated; in MEN4 in which CDKN1B is mutated; in the MEN2A Syndrome, in which RET is mutated; in FHH and NSHPT in which CaSR, GNA11 or AP2S1 is mutated; and in the Hyperparathyroidism-Jaw Tumor (HPT-JT) Syndrome in whichCDC73 is mutated. Familial isolated hyperparathyroidism (FIH) refers to familial hyperparathyroidism in the absence of the specific features of the other documented syndromes and suggests that other genes relevant to parathyroid neoplasia await identification, although variants of several genes identified with syndromic FHPT have been found in some with this disorder.(eg MEN1, CDKN1B, CDC73, and GCM2).

Patients with hyperparathyroidism due to MEN1 have multiglandular disease and surgical resection of fewer than 3 glands lead to high rates of recurrence. Consequently, either subtotal parathyroidectomy with 3½ gland removal or total parathyroidectomy is recommended.

Multiple Endocrine Neoplasia, Type 2A (MEN2A)

MEN2A is an autosomal dominant familial syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, and hyperparathyroidism (156,157). This syndrome results from activating germline mutations in the rearranged during transfection (RET) protooncogene which is a receptor tyrosine kinase (158). Two variants of this disorder are MEN2B (also called MEN3) which includes familial MTC, familial pheochromocytomas, mucosal and intestinal neuromas, and a Marfanoid habitus, but no hyperparathyroidism, and familial MTC alone (159). Two other variants of MEN2 include MEN2 with cutaneous lichen amyloidosis, and MEN2 with Hirschsprung's disease. Analyses of RET mutations in these syndromes have provided good genotype-phenotype correlations (160).

The dominant feature of the MEN2A syndrome is MTC, a calcitonin-secreting neoplasm of thyroid C cells (161). Genetic testing for mutations in the RET oncogene is of value in considering prophylactic thyroidectomy to prevent MTC. Another major feature is pheochromocytomas which are frequently bilateral but which generally have low malignant potential.

Hyperparathyroidism is milder and less frequent (5-20%) in MEN2A than in MEN1 but is also associated with multigland involvement in which gland enlargement may be asymmetric. The treatment of the hyperparathyroidism is as for MEN1.

Hyperparathyroidism-Jaw Tumor Syndrome

Hyperparathyroidism - Jaw Tumor Syndrome (HPT-JT) is an autosomal-dominant syndrome with incomplete penetrance and variable expression, caused by germline inactivating pathogenic variants in the tumor suppressor gene, Cell Division Cycle 73 (CDC73) (formerly called HRPT2), which encodes a protein termed parafibromin. Patients may present with early onset of single or multiple cystic parathyroid adenomas which may develop asynchronously, and ossifying fibromas of the mandible and maxilla. These jaw tumors lack osteoclasts and therefore differ from "brown tumors" (162,163). Affected individuals also have an increased risk (15–38%) of developing parathyroid carcinoma. Surgical removal of the affected parathyroid tissue is clearly indicated in this disorder. A variety of renal tumors have been described in some kindreds and other e.g., uterine tumors have been described in others. Mutations in CDC73, have been implicated in this syndrome (123), in sporadic parathyroid cancer (124), and in a minority of families with isolated hyperparathyroidism (164). Genetic testing in relatives can result in identification of individuals at risk for parathyroid carcinoma, enabling preventative or curative parathyroidectomy.

FAMILIAR NON-SYNDROMIC PRIMARY HYPERPARATHYROIDISM

Familial Isolated Hyperparathyroidism (FIH)

Familial Isolated Hyperparathyroidism (FIH) has been reported in which familial PHPT occurs in the absence of any other manifestation of the familial disorders described. The genetic etiology of FIHP is not fully understood but can arise due to pathogenic variants in genes associated with syndromic PHPT such as MEN1, CDKN1B and CDC73, which raises the possibility that FIHP is an incomplete manifestation of a syndromic form of PHPT. FIHP can also occur with activating pathogenic variants in GCM2. Such activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease (165). Undoubtedly additional research will uncover new genetic mutations which contribute to the pathogenesis of these cases.

Familial Hypocalciuric Hypercalcemia (FHH) and Neonatal Severe Primary Hyperparathyroidism (NSHPT)

Familial hypocaliciuric hypercalcemia (FHH) (166), also called Familial Benign Hypercalcemia (FBH) (167) is an autosomal dominant inherited trait, causing a lifelong generally benign disorder of hypercalcemia. Inasmuch as the increased ECF calcium is inadequately sensed by altered CaSR function in the parathyroid gland, mild hyperplasia may also occur and "normal" levels or elevated levels of PTH are secreted despite the hypercalcemia. While most patients with FHH are asymptomatic, chondrocalcinosis and acute pancreatitis have occasionally been observed. Patients with FHH have often been misdiagnosed as having PHPT, since both disorders can have elevated or inappropriately normal PTH levels with elevated serum calcium. The hallmark feature of FHH is an inappropriately low urine calcium in relationship to the prevailing hypercalcemia i.e., a calcium/ creatinine clearance ratio (CCCR), which is typically < 0.01; nevertheless, 20% of FHH patients may have a CCCR > 0.01, and therefore be indistinguishable from individuals with PHPT.

The molecular basis, in most cases, is a loss-of-function mutation in the calcium-sensing receptor (CaSR) gene (168) in which case the syndrome is now called FHH1. The protein product, CaSR, is a G-protein coupled receptor that predominantly signals via the G-protein subunit alpha-11 (Gα11) to regulate calcium homeostasis. As a consequence, in heterozygotes, diminished ability of the CaSR in the parathyroid cell and in the CTAL of the kidney to detect ECF calcium occurs leading to increased PTH secretion and enhanced renal tubular reabsorption of calcium and magnesium respectively, leading to hypercalcemia, and often hypermagnesemia. Inactivating variants in the GNA11 gene, encoding Gα11 have also been reported to cause the syndrome, now termed FHH2. Hypercalcemia may be milder in FHH2 than in FHH1 (159). Adaptor protein-2 δ-subunit (AP2 δ) plays a pivotal role in clathrin-mediated endocytosis of CaSR Missense variants of the AP2S1 gene, encoding AP2 δ may also occur. causing the syndrome, FHH3, which is associated with the highest serum calcium levels. All FHH forms are inherited in an autosomal dominant fashion.

Genetic testing may be of particular value when hypocalciuric hypercalcemia occurs in an isolated patient without access to additional family members or familial isolated hyperparathyroidism (FIH) occurs in the absence of classical features of FHH.

In view of the fact that the increased renal reabsorption of calcium related to loss of CaSR function, and therefore hypercalcemia, persist after parathyroidectomy, and that the patients are generally asymptomatic, it is important to identify these patients to ensure that they are not subjected to parathyroidectomy.

Individuals who are homozygous for the mutated genes, or who are compound heterozygotes and therefore have little functional CaSR, can develop Neonatal Severe Hyperparathyroidism (NSHPT) (169). This disorder generally presents within a week of birth and is characterized by severe life-threatening hypercalcemia, hypermagnesemia, increased circulating PTH concentrations, massive hyperplasia of the parathyroid glands and relative hypocalciuria. Skeletal abnormalities include demineralization, widening of the metaphyses, osteitis fibrosa and fractures. This disorder may be lethal without urgent total parathyroidectomy.

Heterozygous inactivating variants in CASR can also present in the neonatal period with a less severe, intermediate form of PHPT.

Autoimmune Hypocalciuric Hypercalcemia

A biochemical phenotype of PTH-dependent hypercalcemia resembling that caused by heterozygous inactivating mutations of the CaSR in FHH1 can be observed in patients with antibodies to the extracellular domain of CaSR, which appear to inhibit activation of the CaSR by ECF Ca, and thereby stimulate PTH release. Autoimmune hypocalciuric hypercalcemic is an acquired disorder of extracellular calcium sensing that should be differentiated from that caused by inactivating mutations of the CasR (170).

TERTIARY HYPERPARATHYROIDISM

Tertiary hyperparathyroidism, is a clinical state due to the autonomous function of parathyroid tissue that develops in the face-of-long-standing secondary hyperparathyroidism (171).

Tertiary hyperparathyroidism may occur with monoclonal expansion of nodular areas of the parathyroid gland. These in turn can be associated with decreased VDR and decreased CaSR expression which may lead to an increased set point for PTH secretion. The most common circumstance in which this occurs is in chronic renal failure where 1,25(OH)₂D deficiency, hyperphosphatemia and hypocalcemia produce chronic stimulation of the parathyroid glands. However, tertiary hyperparathyroidism may occur in malabsorption syndromes (e.g., active celiac disease, extensive bowel resection, gastric bypass surgery)., and has also been described in some cases of X-linked hypophosphatemic rickets, or other hypophosphatemic osteomalacias, after long-term treatment with supplemental phosphate which is believed to induce intermittent slight decreases in ECF calcium and stimulation of PTH secretion. Tertiary hyperparathyroidism should be readily identified by the clinical context in which the hypercalcemia presents. In symptomatic patients, the use of the calcimimetic agent, cinacalcet, which enhances the capacity of ECF calcium to stimulate the CaSR, may be tried or surgical treatment may be required, i.e., either sub-total removal of the parathyroid mass or total parathyroidectomy.

MALIGNANCY-ASSOCIATED HYPERCALCEMIA

It has been estimated that hypercalcemia can occur in up to 10% of malignancies. Malignancy-associated hypercalcemia (MAH) can occur in the presence or the absence of elevated PTHrP production. Using two-site immunoradiometric assays for PTHrP several groups have confirmed that 50-90% of patients with solid tumors and hypercalcemia and 20-60% of patients with hematologic malignancies and hypercalcemia have elevated circulating PTHrP. MAH both with and without elevated serum PTHrP concentrations will therefore be discussed.

MAH With Elevated PTHrP

HISTORICAL CONSIDERATIONS

The association between hypercalcemia and neoplastic disease was first reported in the 1920's and the suggestion was made that the direct osteolytic action of malignant cells was responsible for the release of calcium from bone, resulting in hypercalcemia (183). An association between neoplasia and hypercalcemia was later reported in the English medical literature (184). In 1941 Fuller Albright, while discussing a case of a patient with a renal cell carcinoma, who in fact had a bone metastasis, noted that hypophosphatemia should not have accompanied the hypercalcemia if the tumor was simply producing hypercalcemia by causing osteolysis (185). He suggested that the tumor might be secreting a hypercalcemic substance which was also phosphaturic. Consequently, the concept of "ectopic" PTH production by tumors arose and lead to the term “ectopic hyperparathyroidism” (186) or “pseudohyperparathyroidism”. Nevertheless, immunoreactive PTH could not be detected in the circulation of these patients (187) and PTH mRNA could not be detected in their tumors (188). To circumvent these issues, bioassays sensitive to PTH were employed to identify PTH-like bioactivity in blood and tumor extracts (189,190) and eventually to identify a novel protein (191), PTHrP. Despite the limited homology of PTH and PTHrP within the NH₂-terminal 13 amino acids, PTH (1-34) and PTHrP (1-34) exhibit similar effects on raising blood calcium and lowering blood phosphorus, reducing renal calcium clearance, and inhibiting the renal tubular reabsorption of phosphate. The molecular basis of these effects was shown to be cross-reactivity at the PTHR1. In animal models of MAH associated with high PTHrP secretion, passive immunization with PTHrP antiserum reduced hypercalcemia (192,193). Initially after passive immunization, urine calcium increased reflecting reduction in PTHrP induced renal calcium reabsorption; only subsequently did urine calcium decline as bone resorption was neutralized and the filtered load of calcium fell (193). Consequently, the hypercalcemia induced by PTHrP involved a renal mechanism as well as an osseous one. Other similarities were noted between PTHrP and PTH including similar capacities to raise 1,25(OH)₂D levels (194) and effects on bone characterized, for both PTHrP and PTH, by enhanced bone turnover and increased bone formation as well as resorption (195).

HUMORAL HYPERCALCEMIA OF MALIGNANCY

The classic neoplasms associated with hypercalcemia and excess PTHrP have few or no skeletal metastases, and are solid tumors (Fig. 6). This constellation has been termed humoral hypercalcemia of malignancy (HHM). The availability of assays to detect PTHrP demonstrated a broad spectrum of tumors that produce the peptide (196-200). Hypercalcemia is notably associated with squamous cell tumors arising in most sites including esophagus, cervix, vulva, skin, and head and neck, but especially in lung. Renal cell carcinomas are also commonly associated with the syndrome as are bladder and ovarian carcinomas. On the other hand, patients with colon, gastric, prostate, thyroid, and non-squamous cell lung cancers manifest hypercalcemia much less commonly.

Figure 6.

Growth factor-regulated PTHrP production in tumor states. Tumor cells at a distance from bone may be stimulated by autocrine growth factors (GF) to increase production of PTHrP which can then travel to bone via the circulation and enhance bone resorption. Tumor cells metastatic to bone (inset) may secrete PTHrP which can resorb bone and release growth factors which in turn can act in a paracrine manner to further enhance PTHrP production. PTHrP may itself promote tumor growth and progression.

Inasmuch as PTHrP is broadly distributed in normal tissues, PTHrP secretion by tumors likely represents eutopic overproduction rather than ectopic PTHrP production. Although demethylation of the PTHrP promoter (201) and gene amplification (202) have been implicated as mechanisms responsible for PTHrP overproduction by malignancies, it seems likely that in most cases overproduction of PTHrP is driven by enhanced gene transcription of tumor growth factors and by oncogenes which are signaling molecules in the growth factor pathways, e.g., TGF-β which can increase the Gli2 signaling molecule and stimulate PTHrP (203).

Patients who manifest hypercalcemia usually present with advanced disease. These tumors are generally obvious clinically when hypercalcemia occurs, and carry a poor prognosis. Elevated PTHrP per se may be an independent prognostic factor signaling a poor prognosis (204). This appears to be because in addition to its role in hypercalcemia, (205) PTHrP produced by tumor cells acts in an intracrine manner, increasing cell survival, apoptosis resistance, and anoikis evasion, and in autocrine manner via the PTHR1 to increase tumor cell proliferation, survival, apoptosis resistance. PTHrP is also a potential candidate for premetastatic niche formation in bone marrow, causing expansion of myeloid cells required for forming a conducive niche for metastatic growth in bone. PTHrP can also upregulate tumor-surface expression of the GPCR,CXCR4(C-X-C chemokine receptor type 4) (206). PTHrP and TGFβ can also co-stimulate tumor cell production of IL-8, which can then further enhance CXCR4 expression. CXCL12, the natural ligand of CXCR4, is highly expressed in the bone microenvironment (as well as in other potential metastatic sites including lung and liver) and acts as a chemoattractant of circulating tumor cells, facilitating the homing of tumor cells to bone (207) and metastatic seeding.

Thus, PTHrP participates in all steps of the metastatic process, including tumor growth, progression, invasion, migration and survival in bone in order to skeletal support metastases (208).

Hypercalcemia in association with malignancy is generally more acute and severe than in association with primary hyperparathyroidism. (209). Nevertheless, as in primary hyperparathyroidism hypercalcemia is accompanied by hypophosphatemia, reduced tubular reabsorption of phosphorus, enhanced tubular reabsorption of calcium, and increased excretion of nephrogenous cyclic AMP, reflecting the PTH-like actions of PTHrP. Nevertheless, serum 1,25(OH)₂D concentrations which are generally high or high normal in hyperparathyroidism are frequently low or low normal in HHM (210). This may reflect the higher levels of ambient calcium observed in HHM which may directly inhibit the renal 1a(OH)ase enzyme. In hyperparathyroidism, bone resorption is increased but osteoblastic bone formation is also accelerated reflecting a relatively balanced increase in turnover. However, in HHM, osteoclastic bone resorption is markedly increased and osteoblastic bone formation may be reduced (211). The reasons for this uncoupling are unclear and could reflect the action of osteoblast inhibitory factors co-released from the tumor or in the bone microenvironment or perhaps the effect of the very high levels of calcium per se.

SOLID TUMORS WITH ELEVATED PTHrP AND SKELETAL METASTASES

Several studies have indicated that elevated PTHrP correlates better with hypercalcemia than does the presence or absence of skeletal metastases (196,198,200). This appears particularly relevant to certain neoplasms such as breast cancer which is commonly associated with hypercalcemia but is even more commonly associated with osteolytic skeletal metastases. Elevated circulating PTHrP concentrations (198,199) may contribute to the development of hypercalcemia in these cases in part through augmented bone resorption and in part through increased renal calcium reabsorption. PTHrP may also contribute to the pathogenesis of local osteolytic lesions (212,213). PTHrP per se may be a supportive factor for the growth and progression of cancers by acting in paracrine, autocrine and intracrine modes to modulate tumor cell proliferation, apoptosis, survival, and anoikis, and can therefore influence cell processes which enhance the capacity for tumor dissemination and metastasis (205). In addition, tumors, such as breast tumors that are metastatic to bone, may release PTHrP in the bone microenvironment which will bind to cells of the osteoblastic lineage (including stromal cells, osteoblasts and likely osteocytes), release RANKL ligand (RANKL) and decrease osteoprotegerin (OPG), stimulate osteoclasts to resorb bone and release, in addition to calcium, growth factors such as TGFb (214), IGF-1 FGF, PDGF and BMP; released growth factors can then stimulate further PTHrP release from the tumor, thus setting up a positive feedback loop (Fig. 6, see above). PTHrP released from cancers such as osteoblasts may also release the chemokine and angiogenic factor CCL2/MCP-1 from osteoblasts which may also increase osteoclastic activity and potentially angiogenesis, and further enhance tumor proliferation (215). Consequently, the presence of skeletal metastases in association with a malignancy is not mutually exclusive with high circulating PTHrP, which can contribute to the hypercalcemia, through both osseous and renal mechanisms; at the same time, locally released PTHrP may contribute to the focal osteolysis. It is in fact uncertain whether local osteolysis per se ever effectively raises ECF calcium in the absence of some cause of reduced renal calcium excretion.

HEMATOLOGIC MALIGNANCIES WITH ELEVATED PTHrP

Hematologic malignancies that may cause hypercalcemia (216,217) include non-Hodgkin's lymphoma, chronic myeloid and lymphoblastic leukemia, adult T cell leukemia/lymphoma (ATL) and multiple myeloma.

ATL is an aggressive malignancy that develops after 20-30 years of latency in about 5% of individuals infected with human T-cell lymphotrophic virus type I (HTLV-I). This tumor can be associated with hypercalcemia and increased PTHrP production (218). The mechanism of PTHrP production appears to be stimulation of the PTHrP promoter by the viral protein TAX in the infected lymphoid cells, causing increased PTHrP gene transcription.

Non-Hodgkin's lymphoma may also be associated with increased PTHrP secretion and hypercalcemia and this appears to occur predominantly in patients with late-stage disease and high-grade pathology (217). Multiple Myeloma, although frequently associated with hypercalcemia (about 30% of cases) is rarely associated with increased PTHrP production.

UTILITY OF PTHrP ASSAYS

PTHrP assays that recognize NH₂-terminal regions or mid-regions of the molecule, and two-site assays detecting two molecular epitopes have been developed. These assays have generally been quite sensitive and specific and successful in detecting PTHrP in MAH where PTHrP overproduction occurs. Circulating levels in normal individuals are generally low or undetectable. Studies have also shown that PTHrP levels do not fall after treatment of the hypercalcemia of MAH but do fall after reducing the tumor burden (198,219). Consequently, the assays may prove useful to track PTHrP as a tumor marker to monitor the course of therapy. Detection of elevated serum PTHrP concentrations in malignancy may, however, predict a poor prognosis (220). Nevertheless, further work is necessary to understand the identity of circulating PTHrP fragments in order to produce even more useful assays. In most reported NH₂-terminal or mid-region assays, PTHrP levels may be elevated in some normocalcemic cancer patients. Whether this represents the detection of bioinert fragments which might be useful as tumor markers or the detection of bioactive PTHrP which presages the development of hypercalcemia and therefore also has predictive value needs to be clarified.

INFLAMMATORY DISORDERS CAUSING HYPERCALCEMIA

Granulomatous Disorders

Both infectious and non-infectious granuloma-forming disorders have been associated with 1,25(OH)₂D-mediated hypercalcemia (231). Noninfectious disorders include sarcoidosis, silicone-induced granulomatosis, paraffin-induced granulomatosis, berylliosis, Wegener's granulomatosis, eosinophilic granuloma, NOD2 pediatric granulomatous arthritis, Crohn`s disease, Langerhan cell histiocytosis, and infantile fat necrosis. Infectious disorders include tuberculosis, candidiasis, cryptococcosis, leprosy, histoplasmosis, coccidiomycosis, and Bartonella Hensalae infection (cat-scratch disease). The disorder in which the hypercalcemia was first noted, is perhaps best documented, and has best been studied is sarcoidosis. Consequently, this will be discussed as a prototype of granulomatous diseases.

Up to 50% of patients with sarcoidosis will become hypercalciuric during the course of their disease and mild to severe hypercalcemia will be detected in 10% (232). Hypercalciuria and hypercalcemia generally occur in patients who have widespread disease and high serum angiotensin-converting enzyme activity. Normocalcemic patients with sarcoidosis are prone to the development of hypercalciuria and hypercalcemia after receiving small amounts of dietary vitamin D or after exposure to UV light (233). This is due to the fact the serum 1,25(OH)₂D levels in active sarcoidosis are exquisitely sensitive to increases in the 25(OH)D substrate levels. This leads to inappropriately elevated serum 1,25(OH)₂D concentrations and absorption of high fractions of dietary calcium (Fig. 7). PTH is suppressed and its calcium reabsorptive effect in the kidney is lost leading to hypercalciuria. However urinary calcium often exceeds dietary calcium intake suggesting a role for 1,25(OH)₂D-mediated bone resorption as an alternate or additional source of filtered calcium and indeed accelerated trabecular bone loss and decreased bone mass has been documented in patients with active sarcoidosis (234,235). The source of the inappropriate 1,25(OH)₂D is believed to be an extra-renal 1a(OH)ase (as in malignant lymphoproliferative disease) produced by macrophages which are prominent components of the sarcoid granuloma (236). This enzyme exhibits similar kinetics and substrate specificity as the renal 1a(OH)ase but is clearly not regulated as is the renal 1a(OH)ase by PTH, 1,25(OH)₂D, calcium, or phosphorus. This extra-renal 1a(OH)ase does however appear to be suppressible by glucocorticoids (237), chloroquine (238) analogs, and cytochrome P-450 inhibitors such as ketoconazole (239).

Figure 7.

Disordered calcium homeostasis in granulomatous disease. Production of an extra-renal 1α(OH)ase by macrophages in a granuloma can increase conversion of circulating 25(OH)D to 1,25(OH)₂D. This secosteroid will increase Ca⁺² absorption from the gut and Ca⁺² resorption from bone resulting in an increased ECF Ca⁺². The increased ECF Ca⁺² and 1,25(OH)₂D will inhibit PTH production by the parathyroid glands. The increased filtered load of Ca⁺² through the kidney and suppressed PTH will contribute to hypercalciuria.

Therapy of hypercalcemia associated with granulomatous disease is therefore aimed at reducing dietary intake of calcium and vitamin D, limiting sunlight exposure, and treating the underlying disease. Glucocorticoid therapy, if not already indicated for treating the underlying disease, or chloroquine analogs or ketoconazole should be considered to specifically decrease 1,25(OH)₂D concentrations.

PEDIATRIC SYNDROMES

MEDICATION-INDUCED HYPERCALCEMIA

ALTERATIONS IN MUSCLE AND BONE

CLINICAL ASSESSMENT OF THE HYPERCALCEMIC PATIENT

This discussion of the clinical assessment of the hypercalcemic patient will focus primarily on adult patients. Although many of the approaches are relevant to childhood and even neonates, detailed discussion of the issues relevant exclusively to the pediatric age group is beyond the scope of this chapter.

Laboratory Examination

Laboratory testing should be guided by the results of a careful history and a detailed physical examination and should be geared toward assessing the extent of the alteration in calcium homeostasis and toward establishing the underlying diagnosis and determining its severity. Useful laboratory screening may include a complete blood count (CBC), serum total and ionized calcium, PTH, 25(OH)D, 1,25(OH)₂D, phosphorus, serum creatinine and calculation of estimated glomerular filtration rate (GFR), urinalysis and 24-hour urine collection for calcium and creatinine.

To establish the diagnosis of PHPT the most common cause of hypercalcemia in the ambulatory setting, documentation of at least two elevated corrected (or ionized) serum calcium levels with concomitant elevated, or at least normal, serum PTH levels, at least 2 weeks apart, is required (levels of PTH within the normal range are “inappropriate” and consistent with PHPT, because serum PTH should be suppressed in the setting of hypercalcemia,) (Figure1). A serum PTH level is the most useful initial test to distinguish between PTH-dependent and PTH-independent hypercalcemia. Two site assays for PTH are currently the method of choice (265), and the sensitivity of second-generation intact and third-generation “whole” PTH 2-site immunometric assays is similar and is approximately 90%. PTH levels are elevated in approximately 80% of patients, although temporal trends suggest lower levels compared with past decades. Normocalcemic PHPT may be diagnosed if normal corrected total calcium and normal ionized calcium concentrations occur in association with an elevated intact serum PTH on at least two occasions over 3–6 months, and all causes of secondary hyperparathyroidism have been excluded.

FHH, should also be considered in the presence of hypercalcemia and normal or elevated PTH however FHH patients generally exhibit a urinary calcium /creatinine clearance ratio <0.01 if testing serum and urine calcium in three relatives discloses hypercalcemia and relative hypocalciuria, then this diagnosis is likely and parathyroid surgery is to be avoided. Lithium and thiazide diuretics may also be associated with hypercalcemia and elevated PTH, as may ectopic PTH secretion by tumors,

To evaluate renal involvement, estimated glomerular filtration rate (eGFR) or preferably, creatinine clearance, 24-hour urinary calcium and imaging for nephrolithiasis/nephrocalcinosis should be obtained. To evaluate skeletal involvement, bone mineral density (BMD) should be determined by dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine, hip, and distal 1/3 radius, and imaging should be performed for vertebral fractures (vertebral fracture assessment [VFA] or vertebral X-rays); trabecular bone score (TBS) could be included if available. These studies should provide a baseline of disease extent before parathyroidectomy. Pre-operative localization of a parathyroid adenoma, generally by nuclear imaging (MIBI scans) or ultrasound has been helpful (266). Ultimately an experienced surgeon is the best guarantee for a successful neck exploration.

The presence of a family history of hypercalcemia or of kidney stones should raise suspicion of MEN1 or MEN2a or MEN4. If, in addition to HPT in the proband, one or more first-degree relatives are found have at least one of the three tumors characterizing MEN1 (parathyroid, pituitary, pancreas) or MEN2a (parathyroid, medullary thyroid carcinoma, pheochromocytoma) then it is highly likely that the disease is familial. Documentation of familial HPT should be transmitted to the surgeon so that multigland disease can be dealt with. The presence of ossifying fibromas of the mandible and maxilla, and renal lesions such as cysts and hamartomas in addition to HPT would suggest HPT-jaw tumor syndrome.

If hypercalcemia is associated with very low or suppressed serum PTH levels, then malignancy would be an important consideration, either in association with elevated serum PTHrP or in its absence, in which case it is generally as a result of the production of other cytokines. Hypercalcemia is however frequently a late manifestation of malignancy and the presentation of hypercalcemia is often acute and severe. When malignancy-associated hypercalcemia is suspected then an appropriate malignancy screen should be done including skeletal imaging to identify skeletal metastases. As well appropriate biochemical assessment such as a complete blood count, serum creatinine, and serum and urine protein electrophoresis to exclude multiple myeloma would be appropriate. Detection of elevated serum 1,25(OH)₂D levels may point toward the need for a search for lymphoma or for infectious or non-infectious granulomatous disease. Other testing (e.g., a TSH level) could be done for specific clinical disorders based on the findings on the history and physical examination. Although increased PTHrP may be associated with pheochromocytoma, serum PTH levels are suppressed in hypercalcemia in association with thyrotoxicosis, pheochromocytoma, VIPoma, and hypoadrenalism. Although these disorders may be suspected from clinical examination, detailed biochemical evaluation is required for confirmation.

An approach to laboratory assessment of the hypercalcemic patient is shown in Figure 8.

Figure 8.

Laboratory approach to the diagnosis of hypercalcemia. Abbreviations used are: BMD= bone mineral density, eGFR=estimated glomerular filtration rate,Li=lithium therapy MAH=malignancy-associated hypercalcemia, PHPT=primary hyperparathyroidism, SPEP=serum protein electrophoresis, UPEP=urine protein electrophoresis.

MANAGEMENT OF HYPERCALCEMIA

If the patient is asymptomatic and the patient's serum calcium concentration is less than 12 mg/dL (3 mM) then treatment of the hypercalcemia should be aimed solely at treatment of the underlying disorder. Nevertheless, calcium intake of greater than 1000 mg/d, and immobilization should be avoided. If feasible, thiazide diuretics should be discontinued.

If the patient has symptoms and signs of acute hypercalcemia as described above and serum calcium is greater than 12 mg/dL (3mM) then a series of urgent measures should be instituted (Table 3). These measures are almost always required with a serum calcium above 14 mg/dL (3.5 mM)

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