Reviews in Endocrine & Metabolic Disorders 2000;1:247±252# 2000 Kluwer Academic Publishers. Manufactured in The Netherlands.

Diagnosis and Treatment of Hyperparathyroidism

Robert MarcusStanford University Veterans Affairs Medical Center, Palo Alto,

CA 94304

Key Words. parathyroid hormone (PTH), immunoradiometricassay, bone mineral density, parathyroid surgery,calcimimetic agents, medical management

Primary hyperparathyroidism (HPT) remains a ``bread

and butter'' disorder for clinical Endocrinologists.

Reviews of this disease typically enumerate recent

dramatic changes in its clinical presentation from a

highly symptomatic condition to one in which most

patients, at least in ®rst world nations, are asymptomatic.

For comprehensive discussion of the clinical variability

of HPT, consult Bilezikian and Silverberg of this volume.

This chapter reviews current status of patient diagnosis

and management.

Diagnosis of HPTThe term ``hyperparathyroidism'' connotes a situation in

which circulating concentrations of parathyroid hormone

(PTH) exceed upper limits of the age-speci®c normal

range. Because the circulating half-life of this peptide

hormone is a few minutes, high plasma concentrations

re¯ect PTH hypersecretion. This can be a normal

response to calcemic stress. If a person suffers

malabsorption or dietary calcium lack, compensatory

hypersecretion of PTH restores the blood calcium

concentration toward normal. By contrast, primaryHPT is characterized by high concentrations of PTH in

association with elevated plasma calcium concentrations.

HypercalcemiaUnder standard conditions of fasting and hydration, total

serum calcium concentrations average 9:6+0:3 mg/dl.

Recognizing that samples are generally not standardized,

most clinical laboratories cite 10.4 mg/dl as an upper

normal limit. Up to 60% of patients who are mildly

hypercalcemic on a single specimen later prove normal

[1], so hypercalcemia must be con®rmed. One must

remember that several drugs and supplements, such as

thiazide diuretics and high dose vitamins A and D, may

provoke hypercalcemia and must be stopped prior to

additional testing.

About 50% of circulating calcium is not bound to

plasma proteins or inorganic anions. Attempts have been

made to improve diagnostic accuracy by estimating this

biologically relevant fraction or by using equations to

normalize total calcium values for the albumin con-

centration. Measured properly, ionized calcium activity

offers great diagnostic utility, particularly when the

hypercalcemia is only intermittent. For validity, speci-

mens must be processed quickly and anaerobically. As

most clinical laboratories are not this rigorous, accuracy

suffers. Absent prompt access to high quality ionized

calcium analysis, adjustment of total serum calcium for

albumin represents a satisfactory compromise. This

correction is made by adding or subtracting a ®xed

amount of calcium (usually 0.8 mg/dl) for every gram/dl

by which albumin deviates from 4.0 gm/dl. Although

useful, corrected values are approximations. When

ambiguity persists regarding the presence of hypercal-

cemia, proper determination of ionized calcium activity

is recommended.

Assessment of parathyroid functionUntil about 1975, diagnosis of HPT relied primarily on

indirect tests of parathyroid function. These included

assessment of basal and perturbed renal phosphorus and

calcium handling. Reliance on functional tests waned as

PTH radioimmunoassays (RIA) emerged. As the inade-

quacies of early RIA became evident, new functional

tests were introduced. Some were new iterations of old

concepts, such as novel methods to express urinary

phosphorus excretion [2]. Others, such as the assessment

of urinary cyclic 30,50 AMP excretion, exploited new

information about PTH actions [3]. Despite these

modi®cations, improved PTH assays have relegated

functional tests to a subsidiary role, and they are rarely

obtained.

Measurement of parathyroid hormoneUtility of early PTH RIA was poor. Polyvalent antisera

were generated against bovine PTH, which differs

substantially from the human hormone. Much of the

immunoreactivity of these antisera resided in the

carboxyl-terminal portion of the PTH molecule. As the

biological activity of PTH resides within its ®rst 34

amino-terminal amino acids, and as its normal routes of

catabolism generate inert carboxyl-terminal fragments,

247

early RIA were confounded by unimportant fragments,

particularly in the setting of diminished renal function,

where fragments accumulate. Subsequent PTH RIA

employing antisera against speci®c regions of human

PTH (e.g., amino acids 44±68) improved greatly. Using

these assays, a combination of hypercalcemia and

elevated PTH concentration afforded greater than 90%

accuracy in con®rming the diagnosis of HPT [4,5].

However, they were limited because of a disturbing rate

of false positive results (up to 25%) in patients with

malignancy-related hypercalcemias [6].

A substantial advance in PTH assay occurred with

immunoradiometric (IRMA) techniques [7]. IRMA

employ two monoclonal antibodies, each directed against

a different region of the PTH molecule, one carboxyl-

terminal the other amino-terminal. Recognition by both

antibodies thus requires the presence of both amino- and

carboxyl-terminal epitopes. As most PTH fragments

would possess only one epitope, IRMA should be highly

speci®c for ``intact'' PTH. IRMA-PTH quickly showed

advantages over RIA. Superior accuracy, convenience,

precision, and lack of non-speci®c binding all favored

IRMA. Intact PTH assays identi®ed HPT patients with

equivalent or superior sensitivity to the best RIA, giving

minimal overlap with malignancy hypercalcemia. For the

past decade, IRMA intact PTH has been accepted as the

industry standard.

A new and unexpected development in PTH assayThe rapid success of ``intact'' PTH assays gave

clinicians a sanguine view that fundamental issues

concerning PTH measurement were resolved. An

important challenge to this view came from the

demonstration that HPLC elution of serum peptides

yielded two peaks of immunoreactive ``intact PTH''

(Fig. 1) [8]. The smaller of these proved to be a PTH(7±

84) fragment recognized by both antibodies in standard

IRMA systems. Since the amino-terminal antibodies

used in ``intact'' assays recognize epitopes in the [14±

34] region of PTH, cleavage of a few amino acids from

that end would not diminish their immunoreactivity.

Monoclonal antibodies directed against PTH(1±6)

permitted distinction of PTH(1±84) (called ``Whole''

PTH) from a mixture of PTH(1±84) and PTH(7±84). In a

recent comparison [9], ``intact'' PTH showed identical

cross-reactivity to both human PTH(1±84) and human

PTH [7±84] fragment, while ``Whole'' PTH recognized

only the full-length peptide. The PTH(7±84) fragment

accounts for approximately 2/3 of total ``intact'' PTH in

normal people, thus representing a major confound for

interpreting hormonal data. Additional work is required

to clarify the precise clinical role of the ``whole'' PTH

assay. Of particular interest will be its status in those few

surgically con®rmed HPT patients whose PTH values

were normal in multiple assays, including ``intact''

IRMA.

Management of PrimaryHyperparathyroidism

Surgery remains the treatment of choice for patients with

symptomatic or complicated HPT [10]. Some patients

who would bene®t from surgery are poor risks or refuse

an operation. For them, medical therapy may normalize

biochemical abnormalities and ameliorate skeletal or

renal deterioration. For patients with few or no

symptoms, in whom preliminary testing indicates no

serious renal or bone mineral density (BMD) risk, long-

term surveillance may represent acceptable management.

A large prospective surveillance study [11] con®rms that

calcemia and BMD remain stable for years with little

progressive end organ damage. As some patients do

show continued loss of bone or renal function, long-term

periodic biochemical and BMD assessment is impera-

tive. However, that patients followed in this manner may

Fig. 1. HPLC pro®les of circulating ``intact'' PTH in two pools ofuremic samples. Nominal PTH concentrations for top graph�* 60 pmol/L, for the bottom graph� * 100 pmol/L. Samples wereassayed using three different commercial assays for intact PTH.Continuous line�Nichols; dotted line� Incstar; dashed line�DSL.Left arrow indicates a hPTH [7±84] standard; the right arrowindicates a hPTH [1±84] standard (reproduced from reference 8 withpermission).

248 Marcus

enjoy a benign outcome does not detract from real

advantages offered by surgery. Removal of a parathyroid

adenoma most often results in complete cure, substan-

tially diminishing the need for surveillance. Surgically-

treated patients sustain progressive increases in BMD

over several years, with gains of 10% or more equaling

those achieved with antiresorptive medication [11].

Conservative management of mild HPT is not trivial. It

is labor and laboratory intensive, with considerable non-

compliance. Thus, for a reasonable and agreeable

operative candidate, surgery remains the treatment of

choice. This is particularly true for younger patients, as

spontaneous remissions of HPT do not occur, and long-

term observation entangles the patient for decades of

testing and clinic visits.

Principles of medical managementThe general principles for treating symptomatic hyper-

calcemia in HPT are those for treating hypercalcemia of

any etiology [12]. Fluid support, cessation of medica-

tions known to aggravate calcemia, such as thiazides or

lithium, and attempts to mobilize patients, are essential.

Calcemia in HPT ¯uctuates with dietary calcium,

particularly when circulating 1,25-dihydroxyvitamin D

is elevated. However, calcium restriction may worsen

PTH hypersecretion, consequently jeopardizing skeletal

integrity. Consequently, a dietary calcium intake of 500±

1000 mg/day is recommended for most patients.

Speci®c pharmacologic therapiesInterest persists in achieving biochemical and sympto-

matic control of HPT by pharmacological means, thereby

avoiding surgery, even in symptomatic patients. Agents

proposed for this purpose include phosphorus salts,

reproductive steroids, adrenergic and histamine antago-

nists, bisphosphonates, calcitonin, and, most recently,

calcimimetic drugs. Comprehensive reviews of this topic

are published [13, 14]. This chapter will contain focused

remarks about a few approaches. Drugs that improve

calcemia and calciuria in HPT fall into two categories:

inhibitors of PTH action and inhibitors of PTH secretion.

Inorganic phosphorus. Oral phosphate lowers cal-

cemia and urinary calcium excretion for weeks to

months. In patients with elevated serum 1; 25(OH)2D

concentrations, 1,500 mg/d of elemental phosphorus

improved metabolic abnormalities over a 1 year period

without adverse events, although circulating PTH and

cyclic AMP excretion increased [15]. The effects of

phosphate primarily re¯ected decreased calcium absorp-

tion mediated by a fall in vitamin D activation. Phosphate

may bene®t selected patients, but long-term effects on

kidney, bone, and soft tissues are not clear. The

dangerous use of intravenous phosphorus to reverse

acute hypercalcemia has been rendered obsolete by more

effective and safer agents (e.g., bisphosphonates).

Reproductive steroid hormonesEstrogens normalize calcemia and calciuria in older

women with HPT [16±18]. As * 2/3 of patients with

HPT are postmenopausal women, the number of patients

who might bene®t from this approach is substantial.

Estrogen does not suppress PTH secretion, but primarily

constrains its skeletal actions. Ten-year follow-up of 10

estrogen-treated patients [19] showed persistent bio-

chemical control in those who remained on therapy.

Androgenic progestins, e.g., norethindrone, also show

bene®cial metabolic effects in HPT [18], but nonandro-

genic C-21 progestins (e.g., medroxyprogesterone

acetate) are inert in this regard [19].

Regardless of whether reproductive hormones suc-

cessfully normalize calcemia and calciuria in HPT, their

long-term use appears to conserve bone mineral density

(BMD), presumably lowering fracture risk as well [20±

22]. Given the complexity of issues surrounding

hormone replacement therapy, the decision to prescribe

it for control of HPT must be multifaceted and

individualized.

Bisphosphonates. These potent osteoclast inhibitors

are important in the treatment of Paget disease,

osteoporosis, and malignancy hypercalcemia [23]. The

®rst agent of this class to be tried in HPT was etidronate,

which even at high dose did not correct hypercalcemia.

Clodronate, a potent bisphosphonate available only in

Europe, improved hypercalcemia, calciuria, and bone

turnover in short-term HPT trials [24], but increasing

calcemia over time [25] makes this agent non-useful for

long-term management of HPT.

Short-term lowering of calcemia and bone turnover

has been noted with another potent aminobisphospho-

nate, pamidronate, which is given by intravenous

infusion [26,27]. Oral risedronate [28] and alendronate

[29], have also been tried. The latter have not controlled

calcemia, but appear to protect BMD [29,30]. Of the

currently available bisphosphonates, pamidronate is the

most effective in the acute management of the

hypercalcemia associated with HPT. Achieving potential

long-term skeletal bene®ts of bisphosphonates in HPT

may be limited by rises in circulating PTH with possible

secondary effects on renal and intestinal calcium

handling. It is unknown whether the potent bisphos-

phonates now under development will overcome those

limitations.

Calcitonin. This peptide hormone inhibits osteoclastic

bone resorption and promotes renal calcium excretion.

Calcitonins from diverse species have been successfully

Diagnosis and Treatment of Hyperparathyroidism 249

used to treat hypercalcemia, particularly in patients with

malignancy. Calcitonin is rapid in onset and well-

tolerated, but its use is limited by lack of potency and

short effect duration. For that reason, Calcitonin is not

attractive for long-term management of HPT.

Inhibitors of PTH Secretion. Agents that decrease

PTH secretion should theoretically correct most, if not all

of the manifestations of HPT. This approach is more

disease-speci®c than those described above. There is

modest literature support for the use of b-adrenergic and

Histamine receptor antagonists to lower PTH concentra-

tions and control manifestations of HPT. These agents

did not ful®ll initial promise and are not currently used

for this indication. A similar fate befell an organic

thiophosphate, WR-2721, which had been shown to

inhibit PTH release from parathyroid cells [31].

Vitamin D metabolites. The demonstration that

1; 25(OH)2D directly inhibits PTH gene transcription

[32] led to clinical trials of several vitamin D analogs in

mild HPT [33,34]. Preliminary results suggest that

1; 25(OH)2D3 might be effective in decreasing PTH

secretion and lowering the serum calcium concentra-

tions. Non-calcemic analogs of 1; 25(OH)2D such as 22-

oxacalcitriol [35] and 19-nor-1,25(OH)2D [36] suppress

PTH secretion, thereby offering another potential

approach to the treatment of HPT.

Antibodies against PTH. Direct antagonism of the

activity or binding of PTH represents a speci®c means to

decreasing its target organ effects. Experience is limited

to a single patient with metastatic parathyroid carcinoma

resistant to standard therapy [37]. Intradermal injection

of human and bovine PTH peptides to induce antibodies

greatly diminished free PTH and serum calcium

concentrations with clinical improvement that was

maintained for 6 months. By contrast, a PTH analog

that inhibited PTH action in vitro had no effect on serum

ionized calcium activity or PTH concentration when

given to patients with HPT [38].

Calcimimetic agents. Calcimimetic agents represent

the most exciting pharmacological approach to

decreasing PTH secretion in HPT. These drugs mimic

the action of calcium on the calcium-sensing receptor

which regulates PTH secretion [39]. This classical G-

protein-coupled receptor enables parathyroid cells to

translate elevations in extracellular calcium into

increases in intracellular calcium and decreases in PTH

secretion [40,41]. Inactivating mutations of this receptor

may result in familial hypocalciuric hypercalcemia

(FHH) whereas activating mutations are a cause of

familial hypoparathyroidism [41].

Calcimimetics increased cytosolic calcium concen-

trations and decreased PTH secretion from cultured

bovine and human parathyroid adenoma cells [39].

Administration of one of these, R-568, a low molecular

weight organic molecule, to rats, rapidly lowered plasma

concentrations of PTH and calcium and decreased serum

PTH and calcium concentrations in normal older women

[42]. Silverberg et al. [43] enrolled 20 postmenopausal

women with mild HPT into a 36-hour placebo-controlled

study of R-568. A dose-related decline in serum PTH

concentration reached a nadir 2 hours after drug

administration with normalization by 8 hours. The

highest dose decreased PTH concentrations by 50%

and serum calcium values by 4%. The drug was well-

tolerated. Collins et al. used R-568 to treat refractory

hypercalcemia in a 78-year-old man with long-standing

metastatic parathyroid carcinoma [44]. After a period of

non-responsive severe hypercalcemia with mental

deterioration the patient received up to 400 mg daily of

R-568. During the next 3 weeks, his clinical improve-

ment paralleled a dose-related decrease in serum PTH

and calcium concentrations. After discharge from

hospital, he continued treatment with up to 600 mg

daily and remained clinically improved with stable

hypercalcemia despite gradually increasing serum PTH

concentrations. Great interest persists in the use of

calcimimetic drugs in the treatment of both secondary

and primary froms of HPT, and clinical trials of second

generation drugs are in progress.

Special Topics

Imaging techniques in preoperative parathyroiddiagnosisThe diagnosis of HPT requires meeting biochemical

criteria, not the presence of an abnormal imaging

procedure. Multiple imaging techniques have been

explored to assist surgeons locate an adenoma or de®ne

multiple gland enlargement. Such a technique might

permit exploration of only one portion of the neck for

single gland disease, thereby reducing operative time.

This topic has been extensively reviewed by Doppman

[45]. Technicium labeled sestamibi has enjoyed recent

notoriety and is widely considered to provide excellent

diagnostic accuracy. Two recent evaluations reported

discrepant experiences with sestamibi scanning. One

[46] found a sensitivity of 91%, with 93% of patients

achieving cure from unilateral exploration. In the other

[47] sestamibi located an adenoma in only 54% of

patients. Nonetheless, the study did permit the surgeons

to undertake unilateral operations in 43% of patients, all

of whom achieved cure.

These results notwithstanding, prevailing wisdom

250 Marcus

among experienced parathyroid clinicians holds that a

®rst operation requires careful dissection and identi®ca-

tion of all 4 glands. With an experienced parathyroid

surgeon, identi®cation and removal of an adenoma

achieves a cure in about 90% of patients. One of the

memorable quotes in the parathyroid ®eld was uttered by

the late Dr. John Doppman, an eminent radiologist, in his

talk at the 1991 NIH HPT Consensus Development

Conference [10]: ``the greatest challenge in parathyroid

localization is to localize a good parathyroid surgeon.''

Thus, endocrinologists with expertise in HPT do not

generally consider localization studies to be essential

prior to a ®rst neck exploration. However, should a

patient undergo an unsuccessful neck exploration, the

resulting distortion of normal neck anatomy mandates

localizing studies, including sestamibi scans and,

perhaps, venous catheterization with regional sampling

for PTH concentrations, prior to further operations.

Management of HPT during pregnancy. Pregnancy

has long been considered a state of physiologic

hyperparathyroidism. With the emergence of intact

PTH assays it was recognized that this physiologic

adaptation is due to increasing concentrations of the

related hormone, PTHrP, rather than to PTH itself [48].

Development of genuine HPT in pregnant women is

unusual, but not rare. For the most part, patients report no

symptoms attributable to HPT [49], but pancreatitis and

severe hypercalcemia have been reported [50]. Because

infants of severely affected mothers may experience

neonatal hypocalcemia and tetany, parathyroidectomy

during the second trimester has been been considered the

standard of care. Although the risks to the fetus of

untreated mild maternal hypercalcemia are not well

understood, drugs used to treat hypercalcemia have not

been studied during pregnancy. Anecdotal experience

suggests that nonsurgical, nonpharmacological followup

of pregnant patients with mild PHP is safe provided that

hydration and adequate surveillance of serum calcium

concentrations are maintained.

Summary and Conclusions

There is currently no ideal long-term medical manage-

ment for HPT. Estrogen remains an excellent option for

selected postmenopausal women. Bisphosphonates pro-

vide skeletal protection even though hypercalcemia

persists. Calcimimetic drugs appear to offer the best

promise for future treatment. For patients who need

stabilization as a prelude to surgery, intravenous

pamidronate may be very useful. Even if effective long-

term therapy is developed for HPT, it must be considered

with respect to surgery, which, if successful, is relatively

inexpensive and curative. Long-term medical follow-up

requires close scrutiny on an inde®nite basis. Components

of such scrutiny will include periodic health history and

physical examination, serum calcium and creatinine

concentrations , creatinine clearance, 24 hour urinary

calcium excretion, and BMD determinations [10]. If

speci®c drug therapy is given, more frequent monitoring

for adverse effects would probably be required.

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