3179 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

CaSR function. In this condition, neonatal severe hypercalcemia, total

parathyroidectomy is mandatory, but calcimimetics 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.

Jansen’s Disease Activating mutations in the PTH/PTHrP receptor (PTHR1) 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. Besides often severe hypercalcemia, patients

affected by Jansen’s disease have 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. Other genetic mutations

in the parathyroid gland or PTH target cells that affect Ca2+ metabolism

are illustrated in Figure 410-5.

■ MALIGNANCY-RELATED HYPERCALCEMIA

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 tumors such

as lung carcinoma), often severe and difficult to manage, and, on rare

occasions, difficult to distinguish from primary hyperparathyroidism.

Although malignancy is usually 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 mediates 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

Acrodysostosis with

hormonal resistance

Acrodysostosis

(with or without

hormonal resistance)

ADHH

FHH1,

NSHPT

McCune-Albright

syndrome

Pseudohypoparathyroidism

PARATHYROID CELL

Proto-oncogenes and

tumor-supressor genes

CaSR

Ca2+

Transcription factors, e.g.

GATA3, GCM2, AIRE, FAM111A

PIP2 IP3

PTH

Jansen’s metaphyseal

chondrodysplasia

Blomstrand’s lethal

chondrodysplasia

PTHrP

PLC Gq/11

AC

Gs PDE

TARGET CELL

(e.g. kidney, bone, or cartilage)

PTH/PTHrP ATP

receptor

Brachydactyly

short stature

PIP2

IP3 + DAG

cAMP AMP

Cellular events,

including HDAC4

activation

Active

PKA

Catalytic

subunit

Inactive PKA

Regulatory

subunit

(PRKAR1A)

G

PLC

Gq/11

R

R

C

C

R

R

C

C

cAMP

FIGURE 410-5 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 Gs

α that is linked to adenylate cyclase (AC), the enzyme responsible for producing

cyclic AMP (cAMP) (also illustrated are Gαq/Gα11, 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) and homozygous mutations

(both alleles mutated) and neonatal severe 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 Gs

α activity in the kidney

(see text for details). Acrodysostosis can occur with (mutant regulatory subunit of PKA) or without hormonal resistance (mutant PDE4D or PDE3A). Jansen’s metaphyseal

chondrodysplasia and McCune-Albright syndrome represent gain-of-function mutations in the PTH/PTHrP receptor and Gs

α protein, respectively.

3180 PART 12 Endocrinology and Metabolism

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)2

D, produced by the abnormal lymphocytes or adjacent macrophages.

In the more common mechanism, usually termed humoral hypercalcemia of malignancy (HHM), 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

PTHR1, 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 HHM have elevated

urinary nephrogenous cyclic AMP excretion, hypophosphatemia, and

increased urinary phosphate clearance. However, in HHM, 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 HHM may have low to normal levels of

1,25(OH)2

D, instead of elevated levels as in true hyperparathyroidism.

In some patients with the HHM, 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.

Diagnostic Issues 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 (see “General Approach to Hypercalcemic States” below). 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

Vitamin D–mediated hypercalcemia can be due to excessive ingestion

of vitamin D analogs 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)2

D (Chap. 409).

The regulation of 1α-hydroxylase and the normal feedback suppression

by 1,25(OH)2

D 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)2

D production in infants with Williams’ syndrome

(see below) and in adults with sarcoidosis or lymphoma.

Vitamin D Intoxication 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, since some estimates

are that in elderly individuals in northern latitudes, ≥2000 U/d 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)2

D (the latter may not be elevated in vitamin D

intoxication). These actions lead to both increased intestinal absorption of calcium and increased release of calcium from bone. 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)2

D. Hence concentrations of 25(OH)D are elevated severalfold in patients with excess vitamin D intake.

The diagnosis is substantiated by documenting elevated levels of

25(OH)D >100 ng/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, because of the increased bone

resorption caused by high levels of vitamin D, simple cessation of

calcium intake is often insufficient therapy. Further, 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 40–100 mg/d of prednisone 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)2

D is synthesized in

macrophages or other cells in the granulomas. Indeed, increased

1,25(OH)2

D levels have been reported in anephric patients with sarcoidosis and hypercalcemia. Macrophages obtained from granulomatous

tissue convert 25(OH)D to 1,25(OH)2

D at an increased rate. There is

3181 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

a positive correlation in patients with sarcoidosis between 25(OH)D

levels (reflecting vitamin D intake) and the circulating concentrations

of 1,25(OH)2

D, whereas normally, there is no increase in 1,25(OH)2

D

with increasing 25(OH)D levels due to multiple feedback controls

on renal 1α-hydroxylase (Chap. 409). The usual regulation of active

metabolite production by calcium and phosphate or by PTH does not

operate in these patients. Instead, macrophages increase their production of the vitamin D receptor and of the 1α-hydroxylase in response

to tumor necrosis factor and other inflammatory stimuli. Clearance of

1,25(OH)2

D from blood may be decreased in sarcoidosis as well. PTH

levels are usually low and 1,25(OH)2

D 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)2

D 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)2

D, as well as the response

to it in target organs.

Hypercalcemia of Infancy Several variants of this rare abnormality of calcium homeostasis are now known. For example, Williams’

syndrome is an autosomal dominant disorder characterized by multiple

congenital development defects, including supravalvular aortic stenosis, intellectual disability, 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, where

it was thought, incorrectly, to be caused by the fortification of milk

with vitamin D. The cardiac and developmental abnormalities were

independently described, but the connection between these defects

and hypercalcemia was not described until later. Levels of 1,25(OH)2

D

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)2

D 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. Other more recently defined causes of hypercalcemia

in infants and young children can be 24-hydroxylase deficiency that

impairs metabolism of 1,25(OH)2

D or homozygous mutations involving the sodium-dependent phosphate transporters (NPT2a mutations

lead to more severe hypercalcemia than NPT2c mutations).

■ HIGH-BONE-TURNOVER STATES

Hyperthyroidism 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. 384). 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 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.

Thiazides Administration of benzothiadiazines (thiazides) can

cause hypercalcemia in patients with high rates of bone turnover.

Commonly, 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 Vitamin A intoxication is a rare cause of

hypercalcemia and is most commonly a side effect of dietary faddism

(Chap. 333). 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 hydrocortisone or its equivalent leads

to a rapid return of the serum calcium to normal.

■ RENAL FAILURE–ASSOCIATED HYPERCALCEMIA

Severe Secondary Hyperparathyroidism The pathogenesis of

secondary hyperparathyroidism in CKD 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. 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 1α-hydroxylase, and the FGF23-

dependent reduction in 1,25(OH)2

D thus 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. 409), including deficiency of vitamin D action and PHP

(deficient response to PTH downstream of PTHR1 in the proximal

renal tubules). For both disorders, hypocalcemia seems to be the

common denominator in initiating the development of secondary

hyperparathyroidism. Primary and secondary 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 CKD

(e.g., tertiary hyperparathyroidism; see below).

3182 PART 12 Endocrinology and Metabolism

Patients with secondary hyperparathyroidism may develop bone

pain, ectopic calcification, and pruritus. The bone disease seen in

patients with secondary hyperparathyroidism and CKD 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 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 PTHR1. The low PTH level is

thought to contribute to low bone formation and consequent decreased

ability of the skeleton to incorporate circulating calcium into bone

matrix.

TREATMENT

Hypercalcemia in 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 aluminumcontaining antacids to prevent aluminum-induced bone disease.

However, synthetic gels that also bind phosphate (such as sevelamer;

Chap. 311) 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.

■ OTHER CAUSES OF HYPERCALCEMIA

Aluminum Intoxication 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.

Milk-Alkali Syndrome 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, as 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 OF HYPERCALCEMIA

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. 410-6). 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.

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. 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. 410-4).

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

3183 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

Hypercalcemia

Key historical considerations

 • Confirm if ↑Ca2+ chronic

 • Clues from history and physical findings

Acute (or unknown) duration Chronic duration (months)

1˚ Hyperpara-

 thyroidism

 Consider MEN

 syndromes

Consider

 malignancy

 PTHrP assay

 Clinical evaluation

Other causes

 Granulomatous

 disease

 FHH

 Milk-alkali syndrome

 Medications

 (lithium, thiazides)

 Immobilization

 Vit D or Vit A

 intoxication

 Adrenal insufficiency

 Hyperthyroidism

Screen

negative

PTH high PTH low PTH low PTH high

Hyperpara-

 thyroidism

 Consider FHH

or MEN

 syndromes

FIGURE 410-6 Algorithm for the evaluation of patients with hypercalcemia. PTH levels (high or low) should be interpreted in the context of serum calcium levels, as they

may be inappropriately high or low for the level of serum calcium. See text for details. FHH, familial hypocalciuric hypercalcemia; MEN, multiple endocrine neoplasia; PTH,

parathyroid hormone; PTHrP, parathyroid hormone–related peptide; Vit, vitamin.

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 but can be due to heterotopic antibodies. 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)2

D levels are elevated in many (but not all) patients with

primary hyperparathyroidism. In other disorders associated with

hypercalcemia, concentrations of 1,25(OH)2

D 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)2

D

levels and not all nonparathyroid hypercalcemic patients have suppressed 1,25(OH)2

D. Measurement of 1,25(OH)2

D is, however, critically valuable in establishing the cause of hypercalcemia in sarcoidosis

and certain lymphomas.

A useful general approach is outlined in Fig. 410-6. 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

General Approach to Hypercalcemic States

The approach to medical treatment of hypercalcemia varies with its

severity. 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 (Table 410-4). By using a combination of approaches

in severe hypercalcemia, the serum calcium concentration can be

decreased 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 is 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, AND 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

3184 PART 12 Endocrinology and Metabolism

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. Since

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 410-4).

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 boneseeking 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.

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. Though

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 >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 per 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, though 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.

DENOSUMAB

Denosumab is the most recent antiresorptive therapy to be approved

for the treatment of hypercalcemia, a monoclonal antibody that

binds to RANK ligand (RANKL) and prevents it from binding to

the receptor RANK on osteoclast precursors and mature osteoclasts. The inhibition of differentiation, activation, and function

of osteoclasts leads to a reduction in bone resorption. It has a profound suppressive effect on biochemical markers of bone resorption

and is the most powerful antiresorptive agent currently available.

Repeated doses of denosumab, 120 mg given subcutaneously, may

be effective in patients with hypercalcemia of malignancy who have

lost responsiveness to bisphosphonates.

TABLE 410-4 Therapies for Severe Hypercalcemia

TREATMENT

ONSET OF

ACTION DURATION OF ACTION ADVANTAGES DISADVANTAGES

Most Useful Therapies

Hydration with normal saline Hours During infusion Rehydration invariably needed Volume overload

Forced diuresis; normal 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 (lasts longer) Same as pamidronate above

Denosumab 1-2 days >3 weeks Strongest antiresorptive Occasional severe hypocalcemia, rarely jaw

necrosis, skin infections

Special Use Therapies

Calcitonin Hours 1–2 days Rapid onset of action; useful as adjunct in

severe hypercalcemia

Rapid tachyphylaxis

Phosphate oral 24 h During use Chronic management (with

hypophosphatemia); low toxicity if P <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 lifethreatening hypercalcemia

Complex procedure, reserved for extreme or

special circumstances

Source: Data from JP Bilezikian et al: Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the Fourth International

Workshop. J Clin Endocrinol Metab 99:3561, 2014.)

3185 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

OTHER THERAPIES

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 initially often effective. 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. 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 0.7–2.2 mmol/L (3–9 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. 409). Correcting hypophosphatemia lowers

the serum calcium concentration by several mechanisms, including bone/calcium exchange. The usual oral treatment is 1–1.5 g

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 410-4.

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. IV pamidronate or zoledronate or subcutaneous denosumab should be administered. 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.

■ HYPOCALCEMIA

(See also Chap. 54)

Pathophysiology Chronic hypocalcemia is less common than

hypercalcemia; causes include CKD, hereditary and acquired

hypoparathyroidism, vitamin D deficiency, PTH resistance, and

hypomagnesemia.

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.

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.

Classification of Hypocalcemia The classification of hypocalcemia shown in Table 410-5 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 a mutant PTH is secreted, 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.

PTH Absent Hereditary or acquired forms of hypoparathyroidism

have a number of common components. The disease is rare with estimates from all causes to be ~25–35 patients/100,000 of the population