Pathogenesis of Hypercalcemia

Parathyroid Hormone-Related Protein

By far the most common cause of hypercalcemia in cancer is secretion of a protein similar to parathyroid hormone (PTH).5-6 The PTHrP is a distinct gene product with sequence homology to PTH only in a limited domain at the aminoterminal end of the molecule, where 8 of the first 13 amino acids in the two proteins are identical (Fig. 61-1). Although tightly circumscribed, this region of homology is critical, for the aminoterminal domain is the region required for activation of the receptor shared by the two proteins, the PTH-PTHrP receptor. Overall, PTHrP is 139 to 173 amino acids long compared with the 84-amino acid PTH molecule.

TABLE 61-1. Mediators of Hypercalcemia j

Tumor

Humoral or Local

Mediators

Lung carcinoma

Humoral

PTHrP (>90%)

Breast cancer

Humoral (50%)

PTHrP

Local (50%)

PTHrP (?)

Other solid tumors

Humoral or local

PTHrP (80%)

PTH (rare)

Prostaglandins

(rare)

Multiple myeloma

Local

?TNF-p, IL-1(J

Humoral (rare)

PTHrP

Lymphoma

Humoral (>50%)

1,25-(0H)2-D

PTHrP (uncommon)

Local (<50%)

?

Leukemia

Local

7

Humoral (rare)

PTHrP

Adult T-cell

Humoral

PTHrP

leukemia

syndrome

PTHrP - parathyroid hormone-related protein; PTH - parathyroid

hormona; TNF - tumor necrosis tactor; IL =

interleukin.

The two are cousins not only structurally but also in ancestry; shared features of gene structure and chromosomal location indicate that their genes arose from a common ancestral gene.9

Because PTH and PTHrP share a receptor, it can be anticipated that their biologic actions and the clinical syndrome they produce will be similar.10 Both produce humoral hypercalcemia by increasing resorption of bone throughout the skeleton and by increasing the renal resorption of calcium, and both produce relative hypophosphatemia through a phosphatide effect at the kidney.6 Most tumors that produce PTHrP, such as squamous and renal carcinomas (see Table 61-1), cause hypercalcemia without bone metastasis in a large fraction of cases (Table 61-2). Even in squamous and renal carcinoma patients who do have bone metastasis, the primary cause of hypercalcemia is probably humoral secretion of PTHrP because the serum level of PTHrP is better correlated with the serum calcium and phosphorus than is the number or size of bone metastases.

Overall, about 80% of hypercalcemic cancer patients have increased serum levels of PTHrP, which can be measured in two-site, aminoterminal, or midregion assays (Fig. 61-2).1115 This group includes most solid tumor patients but only a few patients with multiple myeloma, lymphoma, or leukemia. However, one leukemia, the adult T-cell leukemia syndrome, produces hypercalcemia in an extraordinarily high percentage of cases (about 60%) by direct secretion of PTHrP from malignant T lymphocytes.16"18 This is of particular interest because the adult T-cell leukemia syndrome, which is rare in the United States but endemic in Japan and the Caribbean basin, is caused by infection with a retrovirus, human T-cell leukemia-lymphoma virus (HTLV) type 1. It appears that a protein encoded in the genome of HTLV-I can directly activate transcription of the PTHrP gene in T cells.19

It is likely that, in addition to humoral hypercalcemia, PTHrP can produce local osteolytic hypercalcemia by direct activation of osteoclasts in the vicinity of bone metastases. The best example is breast carcinoma. Unlike most other solid tumors, breast carcinoma produces hypercalcemia mainly in patients with extensive bone metastases (see Table 61-2). About 50% of these patients have elevated serum levels of PTHrP,1115 presumably indicative of humoral hypercalcemia. However, metastases to bone are immunohistochemically positive for PTHrP in 92% of cases compared with 17% of nonosseous metastases.20 This suggests either that tumor cells that secrete PTHrP have an advantage in bone (perhaps because they induce local resorption) or that the bone environment induces the expression of PTHrP. In either case, PTHrP could act locally to produce osteolysis. Transfection of the PTHrP gene into breast carcinoma cells increases the number of bone metastases, and animals with such metastases are hypercalcemic but do not have increased levels of circulating PTHrP.21 On the basis of this evidence, it seems likely that PTHrP can act as either a humoral factor or a local osteolytic factor in breast carcinoma.

Secretion of PTHrP also causes hypercalcemia in a few benign conditions. The best example is pheochromocy-toma.22,23 Hypercalcemia can also be a part of the watery diarrhea with hypokalemic alkalosis syndrome produced by tumors that secrete vasoactive intestinal peptide. Because these are closely related to pheochromocytomas in their histology and origin, it is likely that PTHrP will be incriminated as the cause of hypercalcemia in these tumors as well, but this has yet to be confirmed. PTHrP is produced by the mammary gland and appears to be associated with hypercalcemia in two benign conditions of the breast: hypercalcemia complicating lactation24 and massive mammary hypertrophy and hypercalcemia.25

FIGURE 61-1. Primary structures of the aminoterminal part of parathyroid hormone-related protein (PTHrP) and of parathyroid hormone. The human sequences 1 to 34 are compared. Identical amino acids are highlighted.

hPTHrP(1-34)

hPTH(1-34)

TABLE 61—2. Malignancy-Associated Hypercalcemia

Primary Site

No. Of Patients

%

Known Metastatic Disease {%)

Lung

111

25.0

62

Breast

87

19.6

92

Multiple myeloma

43

9.7

100

Head and neck

36

8.1

73

Renal and urinary

35

7.9

36

tract

Esophagus

25

5.6

53

Female genital

24

5.4

81

Unknown primary

23

5.2

Lymphoma

14

3.2

91

Colon

8

1.8

Liver-biliary

7

1.6

Skin

6

1.3

Other

25

5.6

Total

444

100

Data from Strewler GJ, Nissenson RA. Adv Intern Med 1987:32:235. Used with permission.

Data from Strewler GJ, Nissenson RA. Adv Intern Med 1987:32:235. Used with permission.

Although PTHrP was not identified until 1983 and was not purified and cloned until 1987, there is now little doubt about its primary role in the causation of hypercalcemia in solid tumor patients. Less certain, but of intense interest, is the role of this protein in normal physiology. It appears that, unlike PTH, the humoral regulator of calcium homeostasis, PTHrP is a local regulator of growth and differentiation.26 Its best established role is to stimulate the proliferation of chondrocytes in the growth plate and retard the mineralization of hypertrophic cartilage. Targeted ablation of the PTHrP gene in the mouse produced an embryonic lethal disorder characterized by short-limbed dwarfism and premature mineralization of cartilage.27 In postnatal life, PTHrP appears to regulate the differentiation of skin and skin appendages28 (its expression in keratinocytes probably explains the high incidence of hypercalcemia in squamous carcinomas that originate from this cell type). In addition, PTHrP is involved in regulation of the mammary gland29 and is secreted into milk at levels 10,000-fold higher than serum levels.30 As a product of a variety of smooth muscle beds (vascular,31 gastrointestinal, bladder,32 uterine33) that is released in response to stretch32-33 and functions as a smooth muscle relaxant,34"36 PTHrP is a candidate for short-loop, local regulation of smooth muscle tone.

1,25-Dihydroxyvitamin D

Probably the most important cause of hypercalcemia in lymphoma is production of the active vitamin D metabolite 1,25-dihydroxyvitamin D(l,25-(OH)2-D) in lymphoma tissue.37 About half of lymphoma patients who present with hypercalcemia have inappropriately high serum l,25-(OH)2-D levels.38-39 In a few cases, lymph node tissue from such patients has been shown to produce l,25-(OH)2-D

FIGURE 61-2. Plasma concentrations of parathyroid hormone-related protein (PTHrP) in patients with hyperparathyroidism (HPT), normocalcemic patients with malignancy (Normocalc), and patients with hypercalcemia of malignancy resulting from a solid tumor (Solid) or a hematologic malignancy (Hematol). Radioimmunoassay (RIA) was used for aminoterminal PTHrP(l-34) (left), an immunoradiometric assay for PTHrP(l-74) (middle), and an RIA for midregion PTHrP(53-84) (right). The hatched area represents the normal ranges, and the dotted line represents the limits of detection; the numbers attached to each group indicate the number of patients. In the PTHrP(l-74) assay, the group Solid includes five patients classified as having the local osteolytic type of hypercalcemia (delta) and two patients with lymphoma. Note the different scales of the y axes. (Modified from Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807; Burtis WJ, Brady TJ, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl I Med 1990;322:1106; and Blind E, Raue F, Gotzmann J, et al. Circulating levels of midregional parathyroid hormone-related protein in hypercalcemia of malignancy. Clin Endocrinol [Oxf] 1992;37:290.)

FIGURE 61-2. Plasma concentrations of parathyroid hormone-related protein (PTHrP) in patients with hyperparathyroidism (HPT), normocalcemic patients with malignancy (Normocalc), and patients with hypercalcemia of malignancy resulting from a solid tumor (Solid) or a hematologic malignancy (Hematol). Radioimmunoassay (RIA) was used for aminoterminal PTHrP(l-34) (left), an immunoradiometric assay for PTHrP(l-74) (middle), and an RIA for midregion PTHrP(53-84) (right). The hatched area represents the normal ranges, and the dotted line represents the limits of detection; the numbers attached to each group indicate the number of patients. In the PTHrP(l-74) assay, the group Solid includes five patients classified as having the local osteolytic type of hypercalcemia (delta) and two patients with lymphoma. Note the different scales of the y axes. (Modified from Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807; Burtis WJ, Brady TJ, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl I Med 1990;322:1106; and Blind E, Raue F, Gotzmann J, et al. Circulating levels of midregional parathyroid hormone-related protein in hypercalcemia of malignancy. Clin Endocrinol [Oxf] 1992;37:290.)

in vitro from 25-OHD.40 Challenge of normocalcemic lymphoma patients with the precursor sterol 25-OHD resulted in increased serum l,25-(OH)2-D levels, increased serum calcium levels, and suppression of PTH.40 In contrast, healthy individuals regulate the conversion of substrate to l,25-(OH)2-D so precisely that virtually no abnormality of calcium homeostasis is induced by the administration of vitamin D. The abnormal responsiveness of normocalcemic lymphoma patients to vitamin D indicates that the fundamental abnormality in lymphoma, unregulated extrarenal production of l,25-(OH)2-D, is actually more common than hypercalcemia. As would be expected from this interpretation, hypercalciuria is more common than hypercalcemia in lymphoma patients39 and presumably provides a compensatory mechanism to deal with the inappropriate synthesis of 1,25-(OH)2-D. In all regards, this syndrome resembles the hypercalcemia of sarcoidosis, the first proven instance of extrarenal production of l,25-(OH)2-D in hypercalcemia.41'42 As in sarcoidosis, hypercalcemia in lymphoma is frequently responsive to administration of corticosteroids.

Parathyroid Hormone

Ectopic secretion of genuine PTH from extraparathyroid tumors, once thought to be common, is now recognized as extremely rare. Only a few authenticated cases have been reported,43,44 including a single case that fulfills the most rigorous criterion for proof of ectopic hormone production: demonstration of an arteriovenous (AV) gradient for PTH across the tumor.45 Most of the tumors reported to secrete PTH ectopically have had small-cell histology. The diagnosis should be considered in patients with malignant tumors (particularly small-cell tumors), hypercalcemia, and elevated PTH levels. However, most cases meeting this definition prove to have a malignant tumor with coincident primary hyperparathyroidism because this coincidence is more likely than the truly rare syndrome of ectopic PTH secretion. Thus, exploration of the parathyroid glands is indicated in patients with a malignant nonparathyroid tumor who require treatment for hypercalcemia, unless the malignant neoplasm can be shown to produce PTH by immunohistochemistry or, better, by demonstration of an AV gradient for PTH across the tumor. The diagnosis of ectopic hyperparathyroidism has been made to date by exclusion in patients with normal parathyroid glands.

Prostaglandins

Once thought to be the dominant mechanism by which non-parathyroid tumors produce hypercalcemia, the production of prostaglandins is now thought to be a rare cause of hypercalcemia. It is not possible to give a precise incidence or to describe a unique clinical syndrome. Nonetheless, a few well-documented cases in which prostaglandins were high and hypercalcemia was reversed by inhibition of prostaglandin synthesis seem authentic.46

Local Osteolytic Hypercalcemia

Local osteolysis around osseous tumors can produce hypercalcemia. The predominant mechanism involves the activation of osteoclasts by secretion of bone-resorbing cytokines. The list of cytokines with osteoclast-activating activity includes interleukin-1, tumor necrosis factor a, interleukin-6, and transforming growth factor a, as well as PTHrP.47 As discussed, there is accumulating evidence that PTHrP is the local osteolytic factor that produces hypercalcemia in breast carcinoma. The other classic example of local osteolytic hypercalcemia is multiple myeloma. Although this is a very common syndrome, with at least one third of myeloma patients experiencing hypercalcemia at some time during their disease, the offending cytokine has not been identified with certainty. Cultured human myeloma cell lines produce bone-resorbing factors that can be neutralized with antisera to interleukin-1 p48 or tumor necrosis factor (3 (lymphotoxin).49 However, it is not clear whether either of these, or a third factor, is responsible for the syndrome observed in patients.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment