3173 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

hypercalcemia can also be the earliest manifestation of malignancy, the

second most common cause of hypercalcemia in the adult. The causes

of hypercalcemia are numerous (Table 410-1), but hyperparathyroidism and cancer account for 90% of all cases.

Before undertaking a diagnostic workup, it is essential to be sure

that true hypercalcemia, not a false-positive laboratory test, is present.

A false-positive diagnosis of hypercalcemia is usually the result of

inadvertent hemoconcentration during blood collection or elevation

in serum proteins such as albumin. Hypercalcemia is in most cases a

chronic problem, and it is cost-effective to obtain several serum calcium measurements; these tests need not be in the fasting state.

Clinical features are helpful in differential diagnosis. Hypercalcemia

in an adult who is asymptomatic is usually due to primary hyperparathyroidism. In malignancy-associated hypercalcemia, the disease is

usually not occult; rather, symptoms of malignancy bring the patient

to the physician, and hypercalcemia is discovered during the evaluation. In such patients, the interval between detection of hypercalcemia

and death, especially without vigorous treatment, is often <6 months.

Accordingly, if an asymptomatic individual has had hypercalcemia or

some manifestation of hypercalcemia such as kidney stones for >1 or

2 years, it is unlikely that malignancy is the cause. Nevertheless, differentiating primary hyperparathyroidism from occult malignancy can

occasionally be difficult, and careful evaluation is required, particularly

when the duration of the hypercalcemia is unknown. Hypercalcemia

not due to hyperparathyroidism or malignancy can result from excessive vitamin D action, impaired metabolism of 1,25(OH)2

D, high bone

turnover from any of several causes, or renal failure (Table 410-1).

Dietary history and a history of ingestion of vitamins or drugs are often

helpful in diagnosing some of the less frequent causes. Immunometric

PTH assays serve as the principal laboratory test in establishing the

diagnosis.

Hypercalcemia from any cause can result in fatigue, depression,

mental confusion, anorexia, nausea, vomiting, constipation, reversible

renal tubular defects, increased urine output, a short QT interval in

the electrocardiogram, and, in some patients, cardiac arrhythmias.

There is a variable relation from one patient to the next between the

severity of hypercalcemia and the symptoms. Generally, symptoms are

more common at calcium levels >2.9–3.0 mmol/L (11.6–12.0 mg/dL),

but some patients, even at this level, are asymptomatic. When the calcium level is >3.2 mmol/L (12.8 mg/dL), calcification in kidneys, skin,

vessels, lungs, heart, and stomach occurs, and renal insufficiency may

develop, particularly if blood phosphate levels are normal or elevated

due to impaired renal excretion. Severe hypercalcemia, usually defined

as ≥3.7–4.5 mmol/L (14.8–18.0 mg/dL), can be a medical emergency;

coma and cardiac arrest can occur.

Acute management of the hypercalcemia is usually successful. The

type of treatment is based on the severity of the hypercalcemia and the

nature of associated symptoms, as outlined below.

■ PRIMARY HYPERPARATHYROIDISM

Pathophysiology • NATURAL HISTORY AND INCIDENCe Primary hyperparathyroidism is a generalized disorder of calcium, phosphate, and bone metabolism due to an increased secretion of PTH.

The elevation of circulating hormone usually leads to hypercalcemia

and hypophosphatemia. There is great variation in the manifestations.

Patients may present with multiple signs and symptoms, including

recurrent nephrolithiasis, peptic ulcers, mental changes, and, less frequently, extensive bone resorption. However, with greater awareness

of the disease and wider use of multiphasic screening tests, including

measurements of blood calcium, the diagnosis is frequently made in

patients who have no symptoms and minimal, if any, signs of the disease other than hypercalcemia and elevated levels of PTH. The manifestations may be subtle, and the disease may have a benign course

for many years or a lifetime. This milder form of the disease is usually

termed asymptomatic hyperparathyroidism. Rarely, hyperparathyroidism develops or worsens abruptly and causes severe complications such

as marked dehydration and coma, so-called hypercalcemic parathyroid

crisis.

The annual incidence of the disease is calculated to be as high as

0.2% in patients >60 years old, with an estimated prevalence, including

undiscovered asymptomatic patients, of ≥1%; some reports suggest the

incidence may be declining. If confirmed, these changing estimates

may reflect less frequent routine testing of serum calcium in recent

years, earlier overestimates in incidence, or unknown factors. The

disease has a peak incidence between the third and fifth decades but

occurs in young children and the elderly.

ETIOLOGY Parathyroid tumors are most often encountered as isolated adenomas without other endocrinopathy. They may also arise in

hereditary syndromes such as MEN syndromes. As many as 10% of

patients with hyperparathyroidism are found to have mutations in 1 of

11 genes (see below). Parathyroid tumors may also arise as secondary

to underlying disease (excessive stimulation in secondary hyperparathyroidism, especially chronic renal failure), or after other forms of

excessive stimulation such as lithium therapy. These etiologies are

discussed below.

Solitary Adenomas A single abnormal gland is the cause in ~80% of

patients; the abnormality in the gland is usually a benign neoplasm

or adenoma and rarely a parathyroid carcinoma. Some surgeons and

pathologists report that the enlargement of multiple glands is common;

double adenomas are reported. In ~15% of patients, all glands are

hyperfunctioning; chief cell parathyroid hyperplasia is usually hereditary and frequently associated with other endocrine abnormalities.

Hereditary Syndromes and Multiple Parathyroid Tumors Hereditary hyperparathyroidism can occur without other endocrine abnormalities but is

usually part of a MEN syndrome (Chap. 388). MEN 1 (Wermer’s syndrome) consists of hyperparathyroidism and tumors of the pituitary

and pancreas, often associated with gastric hypersecretion and peptic

ulcer disease (Zollinger-Ellison syndrome). MEN 2A is characterized

by pheochromocytoma and medullary carcinoma of the thyroid,

as well as hyperparathyroidism; MEN 2B has additional associated

features such as multiple neuromas but usually lacks hyperparathyroidism. Each of these MEN syndromes is transmitted in an apparent

TABLE 410-1 Classification of Causes of Hypercalcemia

I. Parathyroid-Related

A. Primary hyperparathyroidism

1. Adenoma(s)

2. Multiple endocrine neoplasia

3. Carcinoma

B. Lithium therapy

C. Familial hypocalciuric hypercalcemia

II. Malignancy-Related

A. Solid tumor with metastases (breast)

B. Solid tumor with humoral mediation of hypercalcemia (lung, kidney)

C. Hematologic malignancies (multiple myeloma, lymphoma, leukemia)

III. Vitamin D–Related

A. Vitamin D intoxication

B. ↑ 1,25(OH)2

D; sarcoidosis and other granulomatous diseases, lymphoma

C. ↑ 1,25(OH)2

D; impaired 1,25(OH)2

D metabolism due to 24-hydroxylase

deficiency or increased 1,25(OH)2

D synthesis due to inactivating

mutations involving the sodium-dependent phosphate co-transporters

IV. Associated with High Bone Turnover

A. Hyperthyroidism

B. Immobilization

C. Thiazides

D. Vitamin A intoxication

E. Fat necrosis

V. Associated with Renal Failure

A. Severe secondary hyperparathyroidism

B. Aluminum intoxication and adynamic bone disease

C. Milk-alkali syndrome

3174 PART 12 Endocrinology and Metabolism

autosomal dominant manner, although, as noted below, the genetic

basis of MEN 1 involves biallelic loss of a tumor suppressor.

The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in

families with parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors. This disorder is caused by mutations

in CDC73 (HRPT2), and mutations in this gene are also observed

in sporadic parathyroid cancers. Some kindreds exhibit hereditary

hyperparathyroidism without other endocrinopathies, which has been

referred to as nonsyndromic familial isolated hyperparathyroidism

(FIHP). In some of these familial cases, the disease co-segregated with

heterozygous mutations in GCM2. Inactivating or activating mutations

in this parathyroid-specific transcription factor had initially been identified in familial forms of hypoparathyroidism. However, identification

of a GCM2 mutation in a parathyroid adenoma raised the possibility

that mutations in this gene could also be causing some forms of FIHP.

Furthermore, there is speculation that some FIHP cases may be examples of variable expression of the other syndromes such as MEN 1,

MEN 2, or the HPT-JT syndrome, but they may also have distinctive,

still unidentified genetic causes.

Genetic Defects Associated with Hyperparathyroidism As

in many other types of neoplasia, two fundamental types of genetic

defects have been identified in parathyroid gland tumors: (1) overactivity of protooncogenes and (2) loss of function of tumor-suppressor

genes. The former, by definition, can lead to uncontrolled cellular

growth and function by activation (gain-of-function mutation) of a

single allele of the responsible gene, whereas the latter requires loss

of function of both allelic copies. Biallelic loss of function of a tumorsuppressor gene is usually characterized by a germline defect (all cells)

and an additional somatic deletion/mutation in the tumor (Fig. 410-3).

Mutations in the MEN1 gene locus, encoding the protein MENIN,

on chromosome 11q13 are responsible for causing MEN 1; the normal

allele of this gene fits the definition of a tumor-suppressor gene. Inheritance of one mutated allele in this hereditary syndrome, followed by

loss of the other allele via somatic cell mutation, leads to monoclonal

expansion and tumor development. Also, in ~15–20% of sporadic

parathyroid adenomas, both alleles of the MEN1 locus on chromosome

11 are somatically deleted, implying that the same defect responsible

for MEN 1 can also cause the sporadic disease (Fig. 410-3A). Consistent with the Knudson hypothesis for two-step neoplasia in certain

inherited cancer syndromes (Chap. 71), the earlier onset of hyperparathyroidism in the hereditary syndromes reflects the need for only one

mutational event to trigger the monoclonal outgrowth. In sporadic

adenomas, typically occurring later in life, two different somatic events

must occur before the MEN1 gene is silenced.

Other presumptive anti-oncogenes involved in hyperparathyroidism include a still unidentified gene mapped to chromosome 1p seen

in 40% of sporadic parathyroid adenomas and a gene mapped to chromosome Xp11 in patients with secondary hyperparathyroidism and

renal failure, who progressed to “tertiary” hyperparathyroidism, now

known to reflect monoclonal outgrowths within previously hyperplastic glands.

A more complex pattern, still incompletely resolved, arises with

genetic defects and carcinoma of the parathyroids. This appears to

be due to biallelic loss of a functioning copy of a gene, HRPT2 (or

CDC73), originally identified as the cause of the HPT-JT syndrome.

Several inactivating mutations have been identified in HRPT2 (located

on chromosome 1q21-31), which encodes a 531-amino-acid protein

called parafibromin. The responsible genetic mutations in HRPT2 (or

another gene) appear to be necessary, but not sufficient, for parathyroid

cancer.

In general, the detection of additional genetic defects in these

parathyroid tumor–related syndromes and the variations seen in phenotypic expression/penetrance indicate the multiplicity of the genetic

factors responsible. Nonetheless, the ability to detect the presence

of the major genetic contributors has greatly aided a more informed

management of family members of patients identified in the hereditary

syndromes such as MEN 1, MEN 2, and HPT-JT.

Normal

copy

Chromosome 11

Mutant

copy

Somatic

deletion/mutation

of remaining

normal allele

Benign

tumor

Clonal progenitor cell lacks

functional gene product

Chromosome 1 Somatic

deletion/mutation

of remaining

normal allele

Parathyroid

carcinoma

Somatic mutation of one copy of the

HRPT2 tumor suppressor gene on

1q21–31 no adverse consequences

to parathyroid cell

Clonal progenitor cell lacks

functional HRPT2 gene product

Mutant copy of putative tumor

suppressor gene on 11q13 is

inherited in MEN1 and present

in all parathyroid cells

Mutation of one allele of same

gene may occur somatically in

other patients, present in specific

parathyroid cell(s)

Normal

copy

Mutant

copy

PTH

  Coding

Break

PTH

 Coding

PTH 5'

  Regulatory

Centromere

Break

PRAD1

Normal

PTH 5'

  Regulatory

PRAD1

Inverted

A B

FIGURE 410-3 A. Schematic diagram indicating molecular events in tumor susceptibility. The patient with the hereditary abnormality (multiple endocrine neoplasia [MEN])

is envisioned as having one defective gene inherited from the affected parent on chromosome 11, but one copy of the normal gene is present from the other parent. In

the monoclonal tumor (benign tumor), a somatic event, here partial chromosomal deletion, removes the remaining normal gene from a cell. In nonhereditary tumors,

two successive somatic mutations must occur, a process that takes a longer time. By either pathway, the cell, deprived of growth-regulating influence from this gene,

has unregulated growth and becomes a tumor. A different genetic locus also involving loss of a tumor-suppressor gene termed HRPT2 is involved in the pathogenesis

of parathyroid carcinoma. B. Schematic illustration of the mechanism and consequences of gene rearrangement and overexpression of the PRAD1 protooncogene

(pericentromeric inversion of chromosome 11) in parathyroid adenomas. The excessive expression of PRAD1 (a cell cycle control protein, cyclin D1) by the highly active

PTH gene promoter in the parathyroid cell contributes to excess cellular proliferation. (Image A reproduced with permission from A Arnold: Genetic basis of endocrine

disease 5. Molecular genetics of parathyroid gland neoplasia. J Clin Endocrinol Metab 77:1108, 993. Image B reproduced with permission from J Habener, in L DeGroot, JL

Jameson (eds): Endocrinology, 4th ed. Philadelphia, PA: Saunders; 2001.)

3175 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

An important contribution from studies on the genetic origin of

parathyroid carcinoma has been the realization that the mutations

involve a different pathway than that involved with the benign gland

enlargements. Unlike the pathogenesis of genetic alterations seen in

colon cancer, where lesions evolve from benign adenomas to malignant

disease by progressive genetic changes, the alterations commonly seen

in most parathyroid cancers (HRPT2 mutations) are infrequently seen

in sporadic parathyroid adenomas.

Abnormalities at the Rb gene were the first to be noted in parathyroid cancer. The Rb gene, a tumor-suppressor gene located on chromosome 13q14, was initially associated with retinoblastoma but has since

been implicated in other neoplasias, including parathyroid carcinoma.

Early studies implicated allelic deletions of the Rb gene in many parathyroid carcinomas and decreased or absent expression of the Rb protein. However, because there are often large deletions in chromosome

13 that include many genes in addition to the Rb locus (with similar

findings in some pituitary carcinomas), it remains possible that other

tumor-suppressor genes on chromosome 13 may be playing a role in

parathyroid carcinoma.

Study of the parathyroid cancers found in some patients with the

HPT-JT syndrome has led to identification of a much larger role for

mutations in the HRPT2 gene in most parathyroid carcinomas, including those that arise sporadically, without apparent association with the

HPT-JT syndrome. Mutations in the coding region have been identified in 75–80% of all parathyroid cancers analyzed, leading to the conclusion that, with addition of presumed mutations in the noncoding

regions, this genetic defect may be seen in essentially all parathyroid

carcinomas. Of special importance was the discovery that, in some

sporadic parathyroid cancers, germline mutations have been found;

this, in turn, has led to careful investigation of the families of these

patients and a new clinical indication for genetic testing in this setting.

Hypercalcemia occurring in family members (who are also found

to have the germline mutations) can lead to the finding, at parathyroid

surgery, of premalignant parathyroid tumors.

Overall, it seems there are multiple factors in parathyroid cancer,

in addition to the HRPT2 and Rb gene, although the HRPT2 gene

mutation is the most invariant abnormality. RET encodes a tyrosine

kinase type receptor; specific inherited germline mutations lead to a

constitutive activation of the receptor, thereby explaining the autosomal dominant mode of transmission and the relatively early onset of

neoplasia. In the MEN 2 syndrome, the RET protooncogene may be

responsible for the earliest disorder detected, the polyclonal disorder

(C-cell hyperplasia, which then is transformed into a clonal outgrowth—a medullary carcinoma with the participation of other, still

uncharacterized genetic defects).

In some parathyroid adenomas, activation of a protooncogene has

been identified (Fig. 410-3B). A reciprocal translocation involving

chromosome 11 has been identified that juxtaposes the PTH gene

promoter upstream of CCND1, encoding a cyclin D protein that plays

a key role in normal cell division. This translocation plus other mechanisms that cause an equivalent overexpression of cyclin D1 are found

in 20–40% of parathyroid adenomas.

Mouse models have confirmed the role of several of the major identified genetic defects in parathyroid disease and the MEN syndromes.

Loss of the MEN1 gene locus and overexpression of the CCND1 protooncogene or the mutated RET protooncogene have been analyzed by

genetic manipulation in mice, with the expected onset of parathyroid

tumors or medullary carcinoma, respectively.

Pathology Adenomas are most often located in the inferior parathyroid glands, but in 6–10% of patients, parathyroid adenomas may

be located in the thymus, the thyroid, the pericardium, or behind the

esophagus. Adenomas are usually 0.5–5 g in size but may be as large as

10–20 g (normal glands weigh 25 mg on average). Chief cells are predominant in both hyperplasia and adenoma. With chief cell hyperplasia, the enlargement may be so asymmetric that some involved glands

appear grossly normal. If generalized hyperplasia is present, however,

histologic examination reveals a uniform pattern of chief cells and

disappearance of fat even in the absence of an increase in gland weight.

Thus, microscopic examination of biopsy specimens of several glands

is essential to interpret findings at surgery.

Parathyroid carcinoma is often not aggressive. Long-term survival

without recurrence is common if at initial surgery the entire gland

is removed without rupture of the capsule. Recurrent parathyroid

carcinoma is usually slow growing with local spread in the neck, and

surgical correction of recurrent disease may be feasible. Occasionally, however, parathyroid carcinoma is more aggressive, with distant

metastases (lung, liver, and bone) found at the time of initial operation.

It may be difficult to appreciate initially that a primary tumor is carcinoma; increased numbers of mitotic figures and increased fibrosis of

the gland stroma may precede invasion. The diagnosis of carcinoma

is often made in retrospect. Hyperparathyroidism from a parathyroid

carcinoma may be indistinguishable from other forms of primary

hyperparathyroidism but is usually more severe clinically. A potential

clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with

care to avoid capsular rupture. Recent findings concerning the genetic

basis of some patients with parathyroid carcinoma (distinct from that

of benign adenomas) indicate the need, in these kindreds, for family

screening (see below).

Signs and Symptoms Many patients with hyperparathyroidism

are asymptomatic. Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement, due

either to deposition of calcium in the renal parenchyma or to recurrent

nephrolithiasis, was present in 60–70% of patients prior to 1970. With

earlier detection, renal complications occur in <20% of patients in

many large series. Renal stones are usually composed of either calcium

oxalate or calcium phosphate. In occasional patients, repeated episodes

of nephrolithiasis or the formation of large calculi may lead to urinary

tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.

The distinctive bone manifestation of hyperparathyroidism is

osteitis fibrosa cystica, which occurred in 10–25% of patients in series

reported 50 years ago. Histologically, the pathognomonic features are

an increase in the giant multinucleated osteoclasts in scalloped areas on

the surface of the bone (Howship’s lacunae) and a replacement of the

normal cellular and marrow elements by fibrous tissue. X-ray changes

include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption). In recent years, osteitis fibrosa cystica is

very rare in primary hyperparathyroidism, probably due to the earlier

detection of the disease.

Dual-energy x-ray absorptiometry of the spine provides reproducible quantitative estimates (within a few percent) of spinal bone

density. Similarly, bone density in the extremities can be quantified

by densitometry of the hip or of the distal radius at a site chosen to be

primarily cortical. CT is a very sensitive technique for estimating spinal

bone density, but reproducibility of standard CT is no better than 5%.

Newer CT techniques (spiral, “extreme” CT) are more reproducible but

are currently available in a limited number of medical centers. Cortical

bone density is reduced, while cancellous bone density, especially in the

spine, is relatively preserved.

In symptomatic patients, dysfunctions of the central nervous system

(CNS), peripheral nerve and muscle, gastrointestinal tract, and joints

also occur. It has been reported that severe neuropsychiatric manifestations may be reversed by parathyroidectomy. When present in symptomatic patients, neuromuscular manifestations may include proximal

muscle weakness, easy fatigability, and atrophy of muscles and may be

so striking as to suggest a primary neuromuscular disorder. The distinguishing feature is the complete regression of neuromuscular disease

after surgical correction of the hyperparathyroidism.

Gastrointestinal manifestations are sometimes subtle and include

vague abdominal complaints and disorders of the stomach and pancreas. Again, cause and effect are unclear. In MEN 1 patients with

hyperparathyroidism, duodenal ulcer may be the result of associated pancreatic tumors that secrete excessive quantities of gastrin

3176 PART 12 Endocrinology and Metabolism

(Zollinger-Ellison syndrome). Pancreatitis has been reported in association with hyperparathyroidism, but the incidence and the mechanism

are not established.

Much attention has been paid in recent years to the manifestations

of and optimum management strategies for asymptomatic hyperparathyroidism. This is now the most prevalent form of the disease. Asymptomatic primary hyperparathyroidism is defined as biochemically

confirmed hyperparathyroidism (elevated or inappropriately normal

PTH levels despite hypercalcemia) with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such

as features of renal or bone disease.

Four conferences on the topic have been held in the United States

over the past two decades, with the most recent in 2014. The published

proceedings include discussion of more subtle manifestations of disease,

its natural history (without parathyroidectomy), and guidelines both for

indications for surgery and medical monitoring in nonoperated patients.

Issues of concern include the potential for cardiovascular deterioration, the presence of subtle neuropsychiatric symptoms, and the

longer-term status of skeletal integrity in patients not treated surgically.

The current consensus is that medical monitoring rather than surgical

correction of hyperparathyroidism may be justified in certain patients.

The current recommendation is that patients who show mild disease,

as defined by the meeting guidelines (Table 410-2), can be safely followed under management guidelines (Table 410-3). There is, however,

growing uncertainty about subtle disease manifestations and whether

surgery is therefore indicated in most patients. Among the issues is the

evidence of eventual (>8 years) deterioration in bone mineral density

after a decade of relative stability. There is concern that this late-onset

deterioration in bone density in nonoperated patients could contribute

significantly to the well-known age-dependent fracture risk (osteoporosis). Significant and sustained improvements in bone mineral density

are seen after successful parathyroidectomy, and there is some evidence

for reduction in fractures.

Cardiovascular disease including left ventricular hypertrophy, cardiac functional defects, and endothelial dysfunction have been reported

as reversible in European patients with more severe symptomatic disease after surgery, leading to numerous studies of these cardiovascular

features in those with milder disease. There are reports of endothelial

dysfunction in patients with mild asymptomatic hyperparathyroidism,

but the expert panels concluded that more observation is needed, especially regarding whether there is reversibility with surgery.

A topic of considerable interest and some debate is assessment

of neuropsychiatric status and health-related quality of life status

in hyperparathyroid patients both before surgery and in response

to parathyroidectomy. Several observational studies have suggested

improvements in symptom score after surgery. Randomized studies

of surgery versus observation, however, have yielded inconclusive

results, especially regarding benefits of surgery. Many studies report

that hyperparathyroidism is associated with increased neuropsychiatric

symptoms, but it is not possible at present to determine which patients

might improve after surgery.

Diagnosis The diagnosis is typically made by detecting an elevated

immunoreactive PTH level in a patient with asymptomatic hypercalcemia (Fig. 410-4) (see “Differential Diagnosis: Special Tests,” below).

Serum phosphate is usually low but may be normal, especially if renal

failure has developed.

Several modifications in PTH assays have been introduced in

efforts to improve their utility in light of information about metabolism of PTH (as discussed above). First-generation assays were based

on displacement of radiolabeled PTH from antibodies that reacted

with PTH (often also PTH fragments). Double-antibody or immunometric assays (one antibody that is usually directed against the

carboxyl-terminal portion of intact PTH to capture the hormone and

TABLE 410-2 Guidelines for Surgery in Asymptomatic Primary

Hyperparathyroidisma

PARAMETER GUIDELINE

Serum calcium (above

normal)

>1 mg/dL

Renal Creatinine clearance <60 mL/min

24-h urine for calcium >400 mg/d and increased stone

risk by biochemical stone risk analysis

Presence of nephrolithiasis or nephrocalcinosis by

x-ray, ultrasound, or CT

Skeletal BMD by DXA: T score <–2.5 at lumbar spine, total hip,

femoral neck, or distal one-third radius

Vertebral fracture by x-ray, CT, MRI, or VFA

Age <50

Abbreviations: BMD, bone mineral density; CT, computed tomography; DXA,

dual-energy x-ray absorptiometry; MRI, magnetic resonance imaging; VFA, vertebral

fracture assessment.

a

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.

TABLE 410-3 Guidelines for Monitoring in Asymptomatic Primary

Hyperparathyroidism

PARAMETER GUIDELINE

Serum calcium Annually

Renal eGFR, annually; serum creatinine, annually. If renal

stones suspected, 24-h biochemical stone profile, renal

imaging by x-ray, ultrasound, or CT

Serum creatinine Annually

Skeletal Every 1–2 years (3 sites), x-ray or VFA of spine if

clinically indicated (e.g., height loss, back pain)

Abbreviations: CT, computed tomography; eGFR, estimated glomerular filtration rate;

VFA, vertebral fracture assessment.

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.

Hyperparathyroidism

Hypercalcemia of malignancy

Hypoparathyroidism

1000

800

600

500

400

300

200

100

20

1

Parathyroid hormone 1–84 (pg/mL)

0

0 6 7 8 9 10 11 12 13 14 15 16 1918

Calcium (mg/dL)

FIGURE 410-4 Levels of immunoreactive parathyroid hormone (PTH) detected in

patients with primary hyperparathyroidism, hypercalcemia of malignancy, and

hypoparathyroidism. Boxed area represents the upper and normal limits of blood

calcium and/or immunoreactive PTH. (Reproduced with permission from SR

Nussbaum et al (eds): Endocrinology, 4th ed. Philadelphia, PA: Saunders; 2001.)

3177 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

a second radio- or enzyme-labeled antibody that is usually directed

against the amino-terminal portion of intact PTH) greatly improved

the diagnostic discrimination of the tests by eliminating interference

from circulating biologically inactive fragments, detected by the original first-generation assays. Double-antibody assays are now referred

to as second-generation. Such PTH assays have, in some centers and

testing laboratories, been replaced by third-generation assays after it

was discovered that large PTH fragments, devoid of only the extreme

amino-terminal portion of the PTH molecule, are also present in

blood and are detected, incorrectly as full-length PTH. These aminoterminally truncated PTH fragments were prevented from registering

in the newer third-generation assays by use of a detection antibody

directed against the extreme amino-terminal epitope. These assays

may be useful for clinical research studies as in management of chronic

renal disease, but the consensus is that either second- or third-generation assays are useful in the diagnosis of primary hyperparathyroidism

and for the diagnosis of high-turnover bone disease in CKD.

TREATMENT

Hyperparathyroidism

Surgical excision of the abnormal parathyroid tissue is the definitive therapy for this disease. As noted above, medical surveillance

without operation for patients with mild, asymptomatic disease

is, however, still preferred by some physicians and patients, particularly when the patients are more elderly. Evidence favoring

surgery, if medically feasible, is growing because of concerns about

skeletal, cardiovascular, and neuropsychiatric disease, even in mild

hyperparathyroidism.

Two surgical approaches are generally practiced. The conventional parathyroidectomy procedure was neck exploration with

general anesthesia; this procedure is being replaced in many centers, whenever feasible, by an outpatient procedure with local anesthesia, termed minimally invasive parathyroidectomy.

Parathyroid exploration is challenging and should be undertaken

by an experienced surgeon. Certain features help in predicting the

pathology (e.g., multiple abnormal glands in familial cases). However, some critical decisions regarding management can be made

only during the operation.

With conventional surgery, one approach is still based on the

view that typically only one gland (the adenoma) is abnormal. If an

enlarged gland is found, a normal gland should be sought. In this

view, if a biopsy of a normal-sized second gland confirms its histologic (and presumed functional) normality, no further exploration,

biopsy, or excision is needed. At the other extreme is the minority

viewpoint that all four glands be sought and that most of the total

parathyroid tissue mass be removed. The concern with the former

approach is that the recurrence rate of hyperparathyroidism may be

high if a second abnormal gland is missed; the latter approach could

involve unnecessary surgery and an unacceptable rate of hypoparathyroidism. When normal glands are found in association with one

enlarged gland, excision of the single adenoma usually leads to cure

or at least years free of symptoms. Long-term follow-up studies to

establish true rates of recurrence are limited.

Recently, there has been growing experience with new surgical

strategies that feature a minimally invasive approach guided by

improved preoperative localization and intraoperative monitoring

by PTH assays. Preoperative 99mTc sestamibi scans with singlephoton emission CT (SPECT) are used to predict the location of an

abnormal gland and intraoperative sampling of PTH before and at

5-min intervals after removal of a suspected adenoma to confirm a

rapid fall (>50%) to normal levels of PTH. In several centers, a combination of preoperative four-dimensional (4D) CT and ultrasound

examination and, less frequently, sestamibi imaging, cervical block

anesthesia, minimal surgical incision, and intraoperative PTH measurements has allowed successful outpatient surgical management

with a clear-cut cost benefit compared to general anesthesia and

more extensive neck surgery. The use of these minimally invasive

approaches requires clinical judgment to select patients unlikely to

have multiple-gland disease (e.g., MEN or secondary hyperparathyroidism). The growing acceptance of the technique and its relative

ease for the patient has lowered the threshold for surgery.

Severe hypercalcemia may provide a preoperative clue to the

presence of parathyroid carcinoma. In such cases, when neck

exploration is undertaken, the tissue should be widely excised; care

is taken to avoid rupture of the capsule to prevent local seeding of

tumor cells.

Multiple-gland hyperplasia, as predicted in familial cases, poses

more difficult questions of surgical management. Once a diagnosis

of hyperplasia is established, all the glands must be identified. Two

schemes have been proposed for surgical management. One is to

totally remove three glands with partial excision of the fourth gland;

care is taken to leave a good blood supply for the remaining gland.

Other surgeons advocate total parathyroidectomy with immediate

transplantation of a portion of a removed, minced parathyroid

gland into the muscles of the forearm, with the view that surgical

excision is easier from the ectopic site in the arm if there is recurrent hyperfunction.

In a minority of cases, if no abnormal parathyroid glands are

found in the neck, the issue of further exploration must be decided.

There are documented cases of five or six parathyroid glands and of

unusual locations for adenomas such as in the mediastinum.

When a second parathyroid exploration is indicated, the minimally invasive techniques for preoperative localization such as

ultrasound, CT scan, and isotope scanning are combined with

venous sampling and/or selective digital arteriography in one of

the centers specializing in these procedures. Intraoperative monitoring of PTH levels by rapid PTH immunoassays may be useful

in guiding the surgery. At one center, long-term cures have been

achieved with selective embolization or injection of large amounts

of contrast material into the end-arterial circulation feeding the

parathyroid tumor.

A decline in serum calcium occurs within 24 h after successful surgery; usually, blood calcium falls to low-normal values for

3–5 days until the remaining parathyroid tissue resumes full hormone secretion. Acute postoperative hypocalcemia is likely only if

severe bone mineral deficits are present or if injury to all the normal

parathyroid glands occurs during surgery. In general, there are few

problems encountered in patients with uncomplicated disease such

as a single adenoma (the clear majority), who do not have symptomatic bone disease or a large deficit in bone mineral, who are

vitamin D and magnesium sufficient, and who have good renal and

gastrointestinal function. The extent of postoperative hypocalcemia

varies with the surgical approach. If all glands are biopsied, hypocalcemia may be transiently symptomatic and more prolonged.

Hypocalcemia is more likely to be symptomatic after second parathyroid explorations, particularly when normal parathyroid tissue

was removed at the initial operation and when the manipulation

and/or biopsy of the remaining normal glands are more extensive

in the search for the missing adenoma.

Patients with hyperparathyroidism have efficient intestinal

calcium absorption due to the increased levels of 1,25(OH)2

D

stimulated by PTH excess. Once hypocalcemia signifies successful surgery, patients can be put on a high-calcium intake or be

given oral calcium supplements. Despite mild hypocalcemia, most

patients do not require parenteral therapy. If the serum calcium falls

to <2 mmol/L (8 mg/dL), and if the phosphate level rises simultaneously, the possibility that surgery has caused hypoparathyroidism

must be considered. With unexpected hypocalcemia, coexistent

hypomagnesemia should be considered, as it interferes with PTH

secretion and causes functional hypoparathyroidism (Chap. 409).

Signs of hypocalcemia include symptoms such as muscle twitching, a general sense of anxiety, and positive Chvostek’s and Trousseau’s signs coupled with serum calcium consistently <2 mmol/L

(8 mg/dL). Parenteral calcium replacement at a low level should be

instituted when hypocalcemia is symptomatic. The rate and duration of IV therapy are determined by the severity of the symptoms

3178 PART 12 Endocrinology and Metabolism

and the response of the serum calcium to treatment. An infusion

of 0.5–2 mg/kg per hour or 30–100 mL/h of a 1-mg/mL solution

usually suffices to relieve symptoms. Usually, parenteral therapy is

required for only a few days. If symptoms worsen or if parenteral

calcium is needed for >2–3 days, therapy with a vitamin D analogue and/or oral calcium (2–4 g/d) should be started (see below).

It is cost-effective to use calcitriol (doses of 0.5–1 μg/d) because

of the rapidity of onset of effect and prompt cessation of action

when stopped, in comparison to other forms of vitamin D. A rise

in blood calcium after several months of vitamin D replacement

may indicate restoration of parathyroid function to normal. It is

also appropriate to monitor serum PTH serially to estimate gland

function in such patients.

If magnesium deficiency is present, it can complicate the postoperative course since magnesium deficiency impairs the secretion

of PTH. Hypomagnesemia should be corrected whenever detected.

Magnesium replacement can be effective orally (e.g., MgCl2

, MgOH2

),

but parenteral repletion is usual to ensure postoperative recovery, if

magnesium deficiency is suspected due to low blood magnesium

levels. Because the depressant effect of magnesium on central and

peripheral nerve functions does not occur at levels <2 mmol/L

(normal range 0.8–1.2 mmol/L), parenteral replacement can be

given rapidly. A cumulative dose as great as 0.5–1 mmol/kg of body

weight can be administered if severe hypomagnesemia is present;

often, however, total doses of 20–40 mmol are sufficient.

MEDICAL MANAGEMENT

The guidelines for recommending surgical intervention, if feasible

(Table 410-2), as well as for monitoring patients with asymptomatic

hyperparathyroidism who elect not to undergo parathyroidectomy (Table 410-3), reflect the changes over time since the first

conference on the topic in 1990. Medical monitoring rather than

corrective surgery is still acceptable, but it is clear that surgical

intervention is the more frequently recommended option for the

reasons noted above. Tightened guidelines favoring surgery include

lowering the recommended level of serum calcium elevation, more

careful attention to skeletal integrity through reference to peak

skeletal mass at baseline (T scores) rather than age-adjusted bone

density (Z scores), as well as the presence of any fragility fracture.

The other changes noted in the two guidelines (Tables 410-2 and

410-3) reflect accumulated experience and practical consideration,

such as a difficulty in quantity of urine collections. Despite the usefulness of the guidelines, the importance of individual patient and

physician judgment and preference is clear in all recommendations.

When surgery is not selected or not medically feasible, there is

interest in the potential value of specific medical therapies. There

is no long-term experience regarding specific clinical outcomes

such as fracture prevention, but it has been established that bisphosphonates increase bone mineral density significantly without

changing serum calcium (as does estrogen, but the latter is not

favored because of reported adverse effects in other organ systems).

Calcimimetics that lower PTH secretion lower calcium but do not

affect bone mineral density (BMD).

■ OTHER PARATHYROID CAUSES OF

HYPERCALCEMIA

Lithium Therapy Lithium, used in the management of bipolar

depression and other psychiatric disorders, causes hypercalcemia in

~10% of treated patients. The hypercalcemia is dependent on continued lithium treatment, remitting and recurring when lithium is

stopped and restarted. The parathyroid adenomas reported in some

hypercalcemic patients with lithium therapy may reflect the presence

of an independently occurring parathyroid tumor; a permanent effect

of lithium on parathyroid gland growth need not be implicated as

most patients have complete reversal of hypercalcemia when lithium is

stopped. However, long-standing stimulation of parathyroid cell replication by lithium may predispose to development of adenomas (as

is documented in secondary hyperparathyroidism and renal failure).

At the levels achieved in blood in treated patients, lithium can be

shown in vitro to shift the PTH secretion curve to the right in response

to calcium; i.e., higher calcium levels are required to lower PTH secretion, probably acting at the calcium sensor (see below). This effect can

cause elevated PTH levels and consequent hypercalcemia in otherwise

normal individuals. Fortunately, there are usually alternative medications for the underlying psychiatric illness. Parathyroid surgery should

not be recommended unless hypercalcemia and elevated PTH levels

persist after lithium is discontinued.

■ GENETIC DISORDERS CAUSING

HYPERPARATHYROIDISM-LIKE SYNDROMES

Familial Hypocalciuric Hypercalcemia FHH (also called familial benign hypercalcemia) is inherited as an autosomal dominant trait.

Affected individuals are discovered because of asymptomatic hypercalcemia. Most cases of FHH (FHH1) are caused by an inactivating

mutation in a single allele of the CaSR (see below), leading to inappropriately normal or even increased secretion of PTH, whereas another

hypercalcemic disorder, namely the exceedingly rare Jansen’s disease, is

caused by a constitutively active PTH/PTHrP receptor in target tissues.

Neither FHH1 nor Jansen’s disease, however, is a growth disorder of the

parathyroids. Other forms of FHH are caused either by heterozygous

mutations in GNA11 (encoding Gα11), one of the signaling proteins at

the CaSR (FHH2), or by heterozygous mutations in AP1A1 (FHH3).

The pathophysiology of FHH1 is now understood. The primary

defect is abnormal sensing of the blood calcium by the parathyroid

gland and renal tubule, causing inappropriate secretion of PTH and

excessive reabsorption of calcium in the distal renal tubules. The

CaSR is a member of the third family of GPCRs (type C or type III).

The receptor responds to increased ECF calcium concentration by

suppressing PTH secretion through second-messenger signaling at

the CaSR involving the G proteins, Gα11 and Gαq, thereby providing negative-feedback regulation of PTH secretion. Many different

inactivating CaSR mutations have been identified in patients with

FHH1. These mutations lower the capacity of the sensor to bind

calcium, and the mutant receptors function as though blood calcium

levels were low; excessive secretion of PTH occurs from an otherwise

normal gland. Approximately two-thirds of patients with FHH have

mutations within the protein-coding region of the CaSR gene. The

remaining one-third of kindreds may have mutations in the promoter/

introns of the CaSR gene or are caused by mutations in other genes.

Even before elucidation of the pathophysiology of FHH, abundant

clinical evidence served to separate the disorder from primary hyperparathyroidism; these clinical features are still useful in differential

diagnosis. Patients with primary hyperparathyroidism have <99% renal

calcium reabsorption, whereas most patients with FHH have >99%

reabsorption. The hypercalcemia in FHH is often detectable in affected

members of the kindreds in the first decade of life, whereas hypercalcemia rarely occurs in patients with primary hyperparathyroidism or the

MEN syndromes who are aged <10 years. PTH may be elevated in the

different forms of FHH, but the values are usually normal or lower for

the same degree of calcium elevation than is observed in patients with

primary hyperparathyroidism. Parathyroid surgery performed in a few

patients with FHH before the nature of the syndrome was understood

led to permanent hypoparathyroidism; nevertheless, hypocalciuria

persisted, establishing that hypocalciuria is not PTH-dependent (now

known to be due to the abnormal CaSR in the kidney).

Few clinical signs or symptoms are present in patients with FHH,

while other endocrine abnormalities are not. Most patients are detected

as a result of family screening after hypercalcemia is detected in a

proband. In those patients inadvertently operated upon for primary

hyperparathyroidism, the parathyroids appeared normal or moderately

hyperplastic. Parathyroid surgery is not appropriate, nor, in view of

the lack of symptoms, does medical treatment seem needed to lower

the calcium. One striking exception to the rule against parathyroid

surgery in this syndrome is the occurrence, usually in consanguineous

marriages (due to the rarity of the gene mutation), of a homozygous

or compound heterozygote state, resulting in severe impairment of