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Medical Progress

H

YPERPARATHYROID

AND

H

YPOPARATHYROID

D

ISORDERS

S

TEPHEN

J. M

ARX

, M.D.

From the Metabolic Diseases Branch, National Institute of Diabetes andDigestive and Kidney Diseases, Bethesda, Md. Address reprint requests toDr. Marx at the National Institute of Diabetes and Digestive and KidneyDiseases, Bldg. 10, Rm. 9C-101, National Institutes of Health, 9000Rockville Pike, Bethesda, MD 20892-1802, or at [email protected].

2000, Massachusetts Medical Society.

HE four parathyroid glands, through the secre-tion of parathyroid hormone, regulate serumcalcium concentrations and bone metabolism.

1

In turn, serum calcium concentrations regulate par-athyroid hormone secretion; high concentrations in-hibit secretion by the parathyroid glands of parathy-roid hormone and low concentrations stimulate it.

2

Low or falling serum calcium concentrations act with-in seconds to stimulate parathyroid hormone secre-tion, initiated by means of a calcium-sensing receptoron the surface of the parathyroid cells.

2

This receptor

is a heptahelical molecule, like the receptors for light,odorants, catecholamines, and many peptide hor-mones.

3

Parathyroid hormone secretion is 50 per-cent of the maximal level at a serum ionized calciumconcentration of 4 mg per deciliter (1 mmol per li-ter); this is considered the calcium set point for par-athyroid hormone secretion. A slower regulation ofparathyroid hormone secretion occurs over a periodof hours as a result of cellular changes in parathyroidhormone messenger RNA (mRNA). Vitamin D andits metabolites 25-hydroxyvitamin D and 1,25-dihy-droxyvitamin D, acting through vitamin D receptors,decrease the level of parathyroid hormone mRNA,

4

and hypocalcemia increases the level of that mRNA.

5,6

The slowest regulation of parathyroid hormone se-cretion occurs over days or even months and reflectschanges in the growth of the parathyroid glands.Metabolites of vitamin D directly inhibit the mass ofparathyroid cells

7

; hypocalcemia stimulates the growthof parathyroid cells independently of the contraryaction of vitamin D metabolites.

8,9

Disruptions inthese processes cause hyperparathyroidism or hypo-parathyroidism.

STRUCTURE AND ACTIONS OF

PARATHYROID HORMONE

Parathyroid hormone is stored and secreted main-ly as an 84-amino-acid peptide.

1

A synthetic amino-

terminal fragment, parathyroid hormone (134), isfully active; modifications at the amino terminal, par-ticularly at the first two residues, can abolish its bio-

T

logic activity.

10

The effects of parathyroid hormone onmineral metabolism are initiated by the binding ofparathyroid hormone to the type 1 parathyroid hor-mone receptor in the target tissues.

11

Parathyroid hor-mone thereby regulates large calcium fluxes acrossbone, kidneys, and intestines

1

(Fig. 1). Another par-

athyroid hormone receptor (type 2) has been foundin the brain and the intestines. Its main ligand is a pep-tide different from parathyroid hormone

12

; the func-tions of this receptor are not known.

Parathyroid hormonerelated peptide is a distanthomologue of parathyroid hormone and is not a truehormone. It is synthesized in cartilage and in manymore tissues than is parathyroid hormone, and its se-cretion is not regulated by serum calcium.

13

Its localrelease activates the type 1 parathyroid hormone re-ceptor, and its affinity for this receptor is similar tothat of parathyroid hormone (Fig. 1).

MEASUREMENT OF PARATHYROID

HORMONE IN SERUM

Measurements of serum calcium, parathyroid hor-mone, 25-hydroxyvitamin D, and 1,25-dihydroxyvi-tamin D are used regularly in the diagnosis and treat-ment of hyperparathyroidism and hypoparathyroidism;only the measurement of serum parathyroid hormoneis covered here. Serum calcium should usually bemeasured at the same time as serum parathyroid hor-mone; since the ionized fraction of serum calcium isthe biologically active form, it is a more useful indexof hyperparathyroidism and hypoparathyroidism thanare other indexes of calcium in serum. It is thereforethe preferred form of serum calcium to measure.

Current assays for serum parathyroid hormone aretwo-site assays designed to detect both amino-termi-nal and carboxy-terminal epitopes of the peptide.

14,15

The better assays are those that are well standardized,do not cross-react with parathyroid hormonerelat-ed peptide, and are sufficiently sensitive that normal

values can be distinguished from subnormal values(Fig. 2). Parathyroid hormone molecules that are re-active in these two-site immunoassays are consideredintact, but some have no bioactivity.

14-17

For exam-ple, a loss of only six amino acids to yield parathyroidhormone (784) eliminates all bioactivity but doesnot affect the immunoreactivity measured in most orall of these assays.

10

In fact, about half of the para-thyroid hormone detected with these assays in theserum of patients with chronic renal disease is bio-logically inactive.

16,17

Measurements of parathyroid hormone can helpcharacterize parathyroid tumors. Parathyroid hormonecan be measured in fluid obtained from a lesion byfine-needle aspiration (usually guided ultrasonograph-ically) or in serum from the veins of the neck andmediastinum, catheterized selectively.

18

Serum test re-sults that can be obtained in 10 to 15 minutes allowphysicians to assess the completeness of the removal


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The New England Journal of Medicine

of hyperfunctioning parathyroid tissue during the

operation.

19

PRIMARY HYPERPARATHYROIDISM

Most patients with primary hyperparathyroidismhave high serum parathyroid hormone concentrations.Most also have high serum calcium concentrations,and even more have high serum ionized calcium con-centrations. The most important diagnostic tests forthis disorder are thus measurements of serum para-thyroid hormone and ionized calcium (Fig. 2).

The Parathyroid Gland in Primary Hyperparathyroidism

Solitary parathyroid adenomas are monoclonal oroligoclonal tumors.

20

Similarly, in multiglandular hy-perparathyroidism, most of the parathyroid tumors aremonoclonal or oligoclonal,

21

reflecting overgrowthfrom somatic or germ-line mutations in parathyroid-tumor precursor cells. The underlying genes that de-

velop mutations in hyperparathyroidism have beenidentified only in a minority of tumors. They help topinpoint the molecular pathway of oncogenesis andthus help to determine possible targets for treatment

Figure 1.

The Parathyroid Axis.

The synthesis of parathyroid hormone (PTH) and parathyroid hormonerelated peptide (PTHrP) is shown on the left, and their targetsites of action are shown on the right. Both act by means of the same receptor (also termed the type 1 PTH receptor). Negative

feedback of 1,25-dihydroxyvitamin D is not shown. See the text for further descriptions. An excess or deficiency of parathyroid hor-mone may be treated either at the level of parathyroid hormone release (and the parathyroid hormone receptors) or at selectedsites distal to the parathyroid hormone receptors. Blue arrows indicate extracellular calcium flow.

Calcium-

sensing

receptor

Calcium-

sensing

receptor

Renal

tubule

Extracellular ionized

calcium

Bone

Parathyroid cell

PTH

Endocrine

mechanism

PTHrP

PTHrP

Autocrineparacrine

mechanism

PTH receptor

PTH

receptor

1,25(OH)2D

Duodenal

lumen

Cartilage and PTHrP

target cells in many

other tissues

Blood and other

extracellular fluid

Ca2+

Ca2+

Ca2+


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(Fig. 3).

22-27

As in other tumors, it is likely that twoor more genes have mutated in parathyroid adenomas,reflecting a stepwise development of the adenoma.

28-31

Many of the known and unknown genes that havemutated in parathyroid tumors are probably tumor-suppressor genes; that is to say, they contribute to theformation of the tumor through a sequential inacti-

vation of both copies of the gene.

31-34

The multipleendocrine neoplasia type 1 gene (

MEN1

) is a tumor-suppressor gene and the known gene that most of-ten has somatic mutations in both copies in parathy-roid adenomas (in 20 percent of cases).

35

Since thecalcium-sensing receptor and the vitamin D receptoralso mediate the inhibition of parathyroid-gland func-tion, it is noteworthy that no inactivating mutationof either gene has been identified in parathyroid ad-enomas.

35-38

A small minority of parathyroid adenomas have

activating mutations of the cyclin D1 gene(

CCND1

).

20,24,39

These mutations result in the over-expression of the protein cyclin D1, but cyclin D1overexpression is even more common in parathyroidadenomas without cyclin D1 mutations.

40

The abnormal parathyroid cells in primary (andsecondary) hyperparathyroidism have deficient sen-sitivity to inhibition by calcium; this may result in partfrom a deficiency of calcium-sensing receptors on par-athyroid cells.

41

Deficiency of these receptors is prob-ably a consequence and not a cause of neoplastic pri-mary hyperparathyroidism.

Categories and Causes of Sporadic PrimaryHyperparathyroidism

Solitary parathyroid adenomas account for 85 per-cent of cases of primary hyperparathyroidism; hyper-function in multiple parathyroid glands (a broad cat-

Figure 2.

Serum Calcium and Parathyroid Hormone Concentrations in Patients with Hypercalcemia andHypocalcemia Due to Various Causes.

The diagnosis of a serious mineral disorder is usually clear, as illustrated by the nonoverlapping do-mains in the figure, but in the early stages of these disorders, the values for either serum calcium or

parathyroid hormone may overlap with the normal ranges. The following diagnoses are not shown:familial hypocalciuric hypercalcemia (midpoint of the range for serum calcium, 11.5 mg per deciliter,and for serum parathyroid hormone, 30 pg per milliliter); neonatal severe primary hyperparathyroid-

ism (midpoint for serum calcium, 18 mg per deciliter, and for serum parathyroid hormone, 500 pg permilliliter); hypercalciuric hypocalcemia (midpoint for serum calcium, 7 mg per deciliter, and for serumparathyroid hormone, 10 pg per milliliter); tertiary uremic hyperparathyroidism (midpoint for serum

calcium, 11 mg per deciliter, and for serum parathyroid hormone, 2000 pg per milliliter); tertiary hy-perparathyroidism after renal transplantation that corrected uremia (midpoint for serum calcium, 12mg per deciliter, and for serum parathyroid hormone, 200 pg per milliliter); and adynamic bone dis-

ease with uremia (midpoint for serum calcium, 9 mg per deciliter, and for serum parathyroid hormone,

50 pg per milliliter). To convert values for serum calcium to millimoles per liter, multiply by 0.25, andto convert values for serum parathyroid hormone to picomoles per liter, multiply by 0.11.

10,000

6

1

Primaryhyperpara-thyroidism

Primaryhyperparathyroidism

Tumorhypercalcemia

Normal

Lower limitof detection

Uremichyperpara-

thyroidism

10

100

1,000

7 8 9 10 11 12 13 14 15

Serum Calcium (mg/dl)

SerumP

arathyroidHormon

e(pg/ml)


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egory that includes hyperplasia, multiple adenomas,and polyclonal hyperfunction) occurs in most of theremainder; and a few patients (less than 1 percent)have parathyroid carcinoma. About 75 percent of pa-tients with sporadic primary hyperparathyroidism are

women; the average age at diagnosis is 55 years. The

annual incidence of primary hyperparathyroidismamong postmenopausal women in Olmsted County,Minnesota, peaked at 112 per 100,000 in 1974; thehigh number of diagnoses in that year is attributableto the introduction of screening measurements of se-rum calcium. The annual incidence then fell markedly

Figure 3.

Protein That Causes Parathyroid-Gland Hyperfunction When Mutated.

Mutation may occur through inheritance (germ-line mutation) or postnatally (somatic mutation) in abnormal parathyroid tissue. In-activating mutations characterize tumor-suppressorencoded proteins (menin [the product of the MEN1

tumor-suppressor gene],p53, and retinoblastoma protein [pRb]), which are shown in red. Similarly, the calcium-sensing receptor is a growth suppressor

(shown in red). Activating mutations characterize proto-oncoproteins (cyclin D1 and RET) and are shown in yellow. Menin binds toJunD, a transcription factor, which dimerizes (connects) with another member of the JunFos family of transcription factors; meninthereby inhibits transcriptional activation by JunD.

22

The p53 protein binds to DNA through a specific DNA response element.

23

Cyclin D1 is a cell-cycle regulator that activates the catalytic units of cyclin-dependent kinases (CDK) 4 and 6.

24

One substrate forphosphorylation (P) and thus blockade by CDK 4 or 6 is pRb,

25

which binds to the transcription factor E2F as well as to several othertranscription factors.

25

Black T bars indicate binding to a specific sequence of DNA. Calcium ions probably bind to the calcium-

sensing receptor in the plasma membrane, which transmits information on extracellular calcium to an unidentified guanine-nucle-otidebinding protein (G

?

) in the cytoplasm.

26

The RET

-encoded tyrosine kinase in the plasma membrane (RET [yellow]) is a dimerthat phosphorylates Src-homology collagen (SHC) and other substrates. RET is regulated by an extracellular RET receptor attached

to the membrane by its glycosylphosphatidylinositol anchor (RR-GPI [turquoise]).

27

There are at least four extracellular RET recep-tors, each with different extracellular protein ligands (RRL). The full mechanisms by which any of these mutant proteins contributeto tumor formation are not known. Arrows show the flow of a molecule to or away from the plasma membrane.

JunDMenin

PTH

CDK 4 or 6

CyclinD1

pRb

SHC

RET

CDK 4 or 6

CyclinD1

pRb

DNA

P E2FE2F

p53

SHC

RET

RR-GPI

RRL

Calcium-sensing

receptor

Secretory

granule

Ca2+

G?

Cytoplasm

Plasma membrane

Nucleus


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Multiple Endocrine Neoplasia Type 2a

Multiple endocrine neoplasia type 2a is character-ized primarily by medullary thyroid carcinoma andpheochromocytoma.

27

Primary hyperparathyroidismcan occur by the age of 70 in up to 70 percent ofpatients and is usually mild.

51

Multiple endocrine neo-plasia type 2a is caused by an activating mutation ofthe RET

proto-oncogene and is inherited as an au-tosomal dominant trait.

27

HyperparathyroidismJaw Tumor Syndrome

The hyperparathyroidismjaw tumor syndrome israre and is characterized by hyperparathyroidism, ce-mento-ossifying fibromas of the jaw, renal cysts,

Wilms tumor, and renal hamartomas.47,52,53 By the ageof 40, about 80 percent of patients with this syn-drome have hyperparathyroidism, and about 10 per-cent of those have a parathyroid carcinoma. Often,at the first presentation of hyperparathyroidism, onlyone parathyroid adenoma is present, but multiple ad-

enomas can occur either simultaneously or at differ-ent times. The disorder is caused by a mutation inan unknown gene on chromosome 1q2452 and is in-herited as an autosomal dominant trait.

Manifestations of Primary Hyperparathyroidism

The parathyroids are small endocrine glands, andincreases in their size or enhancements of their func-tion have no effect on neighboring tissues. Instead,the effects of an excessive secretion of parathyroid hor-mone are manifested chemically as abnormal fluxes ofcalcium and phosphate in bone, in the kidneys, andin the gastrointestinal tract (Fig. 1). The main resultsare hypercalcemia, hypercalciuria, and increased rates

of bone turnover.Primary hyperparathyroidism is usually first sus-

pected when a patient is found on biochemical screen-ing to have hypercalcemia; less often it is suspectedbecause nephrolithiasis or osteopenia is present. Theanticalciuric effect of thiazide drugs can raise serumcalcium concentrations slightly, thereby uncoveringoccult hyperparathyroidism. With the current restric-tions on reimbursement for biochemical screening,the proportion of newly diagnosed cases of hyper-parathyroidism that are asymptomatic should decrease.

Currently, most patients in whom hyperparathy-roidism is diagnosed at first appear to be asympto-matic,54,55 but up to half of them have subtle neuro-

behavioral symptoms such as fatigue and weakness.56,57In many of these patients, the fact that fatigue or

weakness is a symptom of hyperparathyroidism be-comes clear only after a successful parathyroidectomy,

when the symptom resolves. About 20 percent ofpatients with hyperparathyroidism have nephrolithi-asis.55 Primary hyperparathyroidism can cause cardi-ac calcifications and left ventricular hypertrophy; thelatter can occur in the absence of hypertension andcan be partially reversed after parathyroidectomy.58

There is some controversy about whether any of thesechanges decrease life expectancy. A recent population-based study found that there was no excess mortalityamong all patients with hyperparathyroidism, butthere was excess mortality among the patients in thehighest quartile for serum calcium concentrations.59

Effects on Bone

Parathyroid hormone increases the rate of boneturnover, and its effects on bone may be catabolic oranabolic, depending on the age of the patient, theskeletal site, and the pattern of serum concentrationsof the hormone over time.60,61In general, persistent-ly high serum parathyroid hormone concentrationshave catabolic effects on bone, whereas intermittentmild increases have anabolic effects.

On balance, the effects of mild primary hyperpara-thyroidism on bone seem to be slightly anabolic.62

However, the disorder can cause a demineralization

of bone, distributed variably between cortical sites (i.e.,mainly long bones) and trabecular sites (i.e., mainlyvertebrae).63,64Approximately one in four patients hasosteopenia (a z score lower than 2; z refers to thenumber of standard deviations from an age- and sex-matched mean) in cortical or trabecular bone.63,64

Overall, the risk of bone fractures in patients withmild hyperparathyroidism is similar to that in matchednormal subjects (one new fracture per decade); still,the presence of hyperparathyroidism significantly in-creased the risk of fracture in several bones, particu-larly the vertebrae, in a population-based, controlledstudy.65Successful parathyroidectomy is followed byan increase in bone mass over a period of 6 to 12

months,55,63,66

with continued increases for up to 10years after surgery.55

Natural History and Treatment of PrimaryHyperparathyroidism

In most patients, primary hyperparathyroidism pro-gresses slowly, if at all. Among asymptomatic patients,only about 25 percent have progressive disease, whichis usually manifested as a decrease in bone mass dur-ing a 10-year period of follow-up.55Thus, there hasbeen some controversy regarding the indications forsurgery, the only effective treatment. A consensus con-ference of the National Institutes of Health conclud-ed in 1990 that surgery was not routinely needed in

asymptomatic patients 50 years old or older whohad a serum calcium concentration 1.0 to 1.6 mg perdeciliter (0.25 to 0.40 mmol per liter) above the up-per limit of normal, a level of urinary calcium excre-tion of less than 400 mg (100 mmol) per day, a cre-atinine clearance of at least 70 percent of normal, ora z score higher than 2 for bone mass.67These arestill reasonable guidelines, but surgery may be rec-ommended for many of these patients because of theevidence that it ameliorates neurobehavioral symp-


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toms that may be hard to detect.56,57Surgery is notonly an effective but also a safe treatment for primaryhyperparathyroidism, even in patients who are morethan 70 years old.68

Several methods for characterizing overactive par-athyroid glands are available, including ultrasonog-

raphy and imaging with technetium-99m sestamibibefore or during surgery (Fig. 4), but these are notused routinely.69-71Rapid assays for measuring serumparathyroid hormone during surgery are also available,as discussed above. So-called minimally invasive sur-gical methods have become possible because imagingcan be used to detect parathyroid adenomas and cansometimes be coupled with a rapid assay of parathy-roid hormone during surgery.72Such approaches candecrease the duration of the surgery, but the rate ofsuccess may not match that of standard parathyroid-ectomy.73,74When patients require repeated operation,every effort should be made to identify abnormaltissue preoperatively, and intraoperative testing is of-

ten included as well.18,19Patients who do not undergo surgery should be

evaluated clinically, and serum calcium, creatinine,and parathyroid hormone should be measured at6-to-12-month intervals, and cortical and trabecularbone density at 12-month intervals. Such patientsshould be advised to avoid dehydration and to keeptheir calcium intake at or below 1000 mg per day.

Some patients with more severe primary hyper-parathyroidism may not undergo surgery because ofcontraindications or because they decline the proce-dure; in others, surgery may have been unsuccessful.For these patients, several treatments directed at thetarget tissues of parathyroid hormone action are avail-

able (Table 2).75Bisphosphonates such as alendronateand clodronate inhibit bone resorption; however, theymay be less effective in patients with hyperparathy-roidism than in those with hypercalcemia from othercauses.76Estrogen increases bone density in postmeno-pausal women with hyperparathyroidism but has littleeffect on serum calcium concentrations.77A calcium-sensingreceptor agonist acts directly on parathyroidcells by way of the calcium-sensing receptor (and isthus calcimimetic) in order to inhibit the secretionof parathyroid hormone78; the further developmentof drugs of this type may provide effective treatmentsfor primary and secondary hyperparathyroidism.79 Pa-tients with primary hyperparathyroidism who havesevere symptomatic hypercalcemia should be treated

with intravenous saline, a bisphosphonate, furosemide,and in some cases dialysis.75

Most of these treatments for primary hyperpara-thyroidism change the abnormal transfer of calciumfrom the serum to only one target tissue of parathy-roid hormone action (Table 2 and Fig. 1). Most treat-ments for hypoparathyroidism also affect the transferof calcium along only one of these pathways, albeitin the opposite direction.

HYPERCALCEMIA MEDIATED BY

PARATHYROID HORMONERELATED

PEPTIDE

Hypercalcemia is sometimes caused by serum fac-tors, which may be released by nonparathyroid tu-mors, whether or not there are skeletal metastases.Most of these tumors are malignant and secrete par-athyroid hormonerelated peptide.13In contrast, hy-

persecretion of parathyroid hormone by a nonparathy-roid tumor is extremely rare.

UREMIC HYPERPARATHYROIDISM

Secondary and Tertiary Hyperparathyroidism

Hypocalcemia from any cause stimulates parathy-roid hormone secretion, and chronic hypocalcemiaalso stimulates the growth of the parathyroid glands.This secondary hyperparathyroidism usually resolves

with the treatment of the underlying cause of hypo-calcemia. However, in patients with chronic renal fail-ure, secondary hyperparathyroidism often lasts longerand is more severe than in patients with other hypo-calcemic disorders, such as a deficiency or malabsorp-tion of vitamin D.80Eventually, either before or, moreoften, after renal transplantation, secondary hyperpara-thyroidism can develop into a disorder of oversecre-tion of parathyroid hormone with hypercalcemia (ter-tiary hyperparathyroidism).

The Parathyroid Gland in Uremia

Hypercalcemia in patients with uremia who havetertiary hyperparathyroidism might reflect an excessof nearly normal parathyroid cells with a consequent-

Figure 4.Anterior Planar Image of the Neck and Chest of a Pa-tient with Primary Hyperparathyroidism Obtained with Techne-tium-99m Sestamibi, Showing a Parathyroid Adenoma in the

Mediastinum.

The patient had undergone an unsuccessful parathyroid explo-ration. The image shown was obtained two hours after the ad-ministration of 20 mCi of the radionuclide. The lobes of the thy-

roid and the salivary glands are clearly visible. (Image courtesyof Dr. Clara Chen.)

Parotid

Submandibular

Thyroid

Mediastinalparathyroid

Heart


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ly high and nonsuppressible base-line secretion ofparathyroid hormone; in fact, however, it most oftenreflects the secretory dysfunction of autonomouslyfunctioning parathyroid cells.21,80,81Overactive para-thyroid glands that have been removed from patients

with uremia are usually overgrown with monoclonalor oligoclonal components.22,82-84The cause of pro-gression from early, presumably polyclonal, secondaryhyperplasia of the parathyroid to later monoclonal oroligoclonal tumors is poorly understood.21,80,84Prob-ably, some of the genes that are mutated in the par-athyroid glands of patients with secondary or tertiaryhyperparathyroidism are different from those that aremutated in primary hyperparathyroidism; in partic-ular, MEN1mutations are less frequent in the para-thyroid glands of patients with uremia than in tumorsof patients with sporadic primary hyperparathyroid-ism.82,83

Bone Disease in Patients with Chronic Renal Diseaseand Hyperparathyroidism

Bone disease in patients with chronic renal diseaseis caused by both hyperparathyroidism and other fac-tors.85,86Some patients with chronic renal disease havehyperparathyroid uremic bone disease, which is char-acterized by an activation of osteoblasts and osteo-clasts with excess bone resorption. Other patients havean adynamic bone disease or osteomalacia. Adynam-ic bone disease is characterized by low activity of thebone cells, no excess accumulation of matrix, and lit-tle parathyroid hypersecretion.86,87Osteomalacia inrenal failure is characterized by excess accumulationof osteoid and a minimal degree of hyperparathy-roidism and has been associated with the accumula-tion of aluminum in bone. This disorder has becomeless common as a result of the minimization of useof products with high concentrations of aluminum,such as are found in some antacids and dialysis flu-ids.86,87The frequency of hyperparathyroid bone dis-

ease among patients with uremia is similar to the fre-quency of adynamic bone diseases.86,87

Uremic hyperparathyroid bone disease is best treat-ed by raising serum calcium concentrations and there-by decreasing parathyroid hormone secretion. Thecause of adynamic bone disease is not known, andthere is no specific treatment.88,89

Treatment of Hyperparathyroidism in Patientswith Chronic Renal Diseases

In patients with chronic renal failure, secondary hy-perparathyroidism is caused by hypocalcemia, which,in turn, is caused by hyperphosphatemia and decreasedrenal production of 1,25-dihydroxyvitamin D. Treat-ment is based on raising serum calcium concentra-

tions by the oral administration of calcium salts; thesesalts also ameliorate hyperphosphatemia by chelatingphosphate in the intestines. Additional measures fortreating hypocalcemia include raising the calciumconcentration in the dialysis fluid and administeringsome form of vitamin D. When treatment is initiatedearly, severe secondary hyperparathyroidism can beprevented or at least delayed. There is some contro-

versy regarding the most appropriate dosage, type, androute of administration of vitamin D or vitamin Danalogue90,91 and the most appropriate phosphatebinder for these patients.921,25-Dihydroxyvitamin D3(calcitriol) has sometimes been given intravenouslyin pulsed doses in the hope of inhibiting parathyroidhormone secretion without raising serum calcium con-centrations,90,91but calcitriol given orally has similareffects.93

Severe secondary hyperparathyroidism is an im-portant indication for parathyroidectomy in patients

with chronic renal disease who cannot be treated ad-equately with the measures described above.94Para-thyroidectomy is also appropriate for some patients

with tertiary hyperparathyroidism.After renal transplantation, secondary hyperpara-

*This treatment is not currently available.

TABLE2.TREATMENTSFORHYPERPARATHYROIDISMANDHYPOPARATHYROIDISM.

PROCESSAFFECTEDBYTREATMENT

TREATMENTSFORHYPERPARATHYROIDISM

TREATMENTSFORHYPOPARATHYROIDISM

Secretion of parathyroid hormone by parathyroid gland Parathyroidectomy

Calcium-sensingreceptor agonist*

Parathyroid autograft

Activation of receptor for parathyroid hormone Blocker of type 1 receptor* Parathyroid hormone (134)*

Release of calcium from bone BisphosphonatesEstrogen

Uptake of calcium from gut Blocker of vitamin D receptor* Vitamin D analogueCalcium salts

Excretion of calcium in urine Forced natriuresis Thiazide

Exchange with extracorporeal calcium pool Dialysis Intravenous calcium


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thyroidism usually regresses over a period of 1 to 10years, but the regression may be incomplete, as re-flected in persistently high serum parathyroid hor-mone concentrations.95About one third of patients

who receive renal transplants have parathyroid hor-moneinduced hypercalcemia postoperatively that,

depending on its magnitude and duration, can presenta threat to the renal graft and to other functions.The hypercalcemia usually subsides within months orat most a few years, but 1 to 3 percent of patients re-quire parathyroidectomy an average of three years af-ter renal transplantation because of persistent hyper-calcemia.96

HYPOPARATHYROIDISM

Hypoparathyroidism can cause hypocalcemia withconsequent paresthesias, muscle spasms (i.e., tetany),and seizures, especially when it occurs rapidly. In con-trast, chronic hypoparathyroidism generally causes hy-pocalcemia so gradually that the only symptom may

be visual impairment from cataracts caused by yearsof hypoparathyroidism.

Diagnosis and Causes

Like hyperparathyroidism, hypoparathyroidism isdiagnosed on the basis of measurements of serumcalcium and parathyroid hormone (Fig. 2).14,15Thecauses of hypoparathyroidism are diverse, represent-ing disruptions of one or more of the steps in thedevelopment and maintenance of parathyroid hor-mone secretion.

Damage to the Parathyroid Glands from Surgery

Injury to or removal of the parathyroid glands dur-

ing neck surgery is the most common cause of acuteor chronic hypoparathyroidism.

Developmental Defects in the Parathyroid Glands

Agenesis of the parathyroid glands occurs in in-fants with the DiGeorge syndrome (and the closelyrelated velocardiofacial syndrome). The manifestationsof these syndromes include incomplete developmentin the branchial arches, resulting in varying degreesof parathyroid and thymic hypoplasia, conotruncalcardiac defects, facial malformations, and learning dis-ability. Both syndromes are associated with rearrange-ments and microdeletions affecting an unknown geneor genes on the short arm of chromosome 22.97Anyresultant defect should be treated, depending on itsseverity.98Isolated agenesis of the parathyroid glandsin one family has been attributed to a recessive de-letion in the gene on chromosome 6 that normallyencodes a transcription factor.99

Autoimmune Hypoparathyroidism

Hypoparathyroidism is a prominent componentof autoimmune polyglandular syndrome type 1, alsoknown as autoimmune polyendocrinopathycandi-

diasisectodermal dystrophy syndrome.100The hypo-parathyroidism, like other manifestations of the syn-drome, occurs during childhood; for this reason andbecause of such associated abnormalities as hypoadre-nalism and intestinal malabsorption, the hypoparathy-roidism may be difficult to treat. The syndrome is in-

herited as an autosomal recessive trait and is caused bymutations in an autoimmune regulator gene (AIRE)

with a known sequence but an unknown function.101

Defects in the Parathyroid Hormone Molecule

A few cases of familial hypoparathyroidism havebeen described in which the cause was a mutation inthe gene for parathyroid hormone that resulted in thesynthesis of a defective parathyroid hormone mole-cule and undetectable amounts of parathyroid hor-mone in serum.102

Defective Regulation of Parathyroid Hormone Secretion

Hypocalcemia and hypercalciuria are the chief fea-

tures of autosomal dominant hypercalciuric hypocal-cemia, which is caused by activating mutations of theparathyroid and renal calcium-sensing receptor. Thesemutations cause excessive calcium-induced inhibitionof parathyroid hormone secretion. The hypocalcemiais usually mild and asymptomatic. When it is mild,it should be treated cautiously, if at all, because rais-ing serum calcium concentrations further increasesurinary calcium excretion and may cause nephrocal-cinosis.41,103

TREATMENT OF HYPOPARATHYROIDISM

Calcium and Vitamin D Analogues

The main treatments available for patients with

acute or chronic hypoparathyroidism are calcium salts,vitamin D or vitamin D analogues, and drugs thatincrease renal tubular reabsorption of calcium (i.e., thi-azides) (Table 2). The parathyroid hormonedepend-ent renal production of 1,25-dihydroxyvitamin D isdeficient in all hypoparathyroid states. Therefore, ther-apy with a vitamin D analogue is used to ensure thatthere is a steady serum concentration of an active vi-tamin D analogue. If parathyroid hormone is absentor nonfunctional, its hypocalciuric action cannot oc-cur; therefore, raising the serum calcium concentra-tion may cause hypercalciuria, nephrolithiasis, andrenal damage.

Patients in whom hypocalcemia develops suddenly for example, after neck surgery are best treated

with intravenous calcium and with oral or intravenouscalcitriol. Those with chronic hypocalcemia shouldbe treated with oral calcium and either calcitriol or

vitamin D. Patients in whom the efficacy of treatmentmay vary, such as those with autoimmune polyglan-dular syndrome type 1, are best treated with vitamin Danalogues that have a short half-life. Calcitriol raisesserum calcium concentrations within one or twodays after treatment begins, and its action dissipates


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equally rapidly; the action of vitamin D begins anddissipates over a period of two to four weeks.

Parathyroid-Tissue Transplantation or ParathyroidHormone

Transplantation of parathyroid tissue is appealing

but rarely possible. A parathyroid allograft would re-quire immunosuppression and so would be more dan-gerous than the disease it was meant to treat. Parathy-roid autografts are sometimes placed in the forearmand can consist of either fresh parathyroid tissue orparathyroid tissue removed earlier and cryopreserved.The indication for a parathyroid autograft is a highlikelihood of postoperative hypoparathyroidism. Asmany as half of these grafts fail, and among thosethat survive and function, the potential for late auto-graft-mediated recurrences of hyperparathyroidismis substantial, since the parathyroid tissue used forthe graft was abnormal.84,94

Patients with hypoparathyroidism have been treated

successfully with synthetic human parathyroid hor-mone (134) given subcutaneously once daily.104Theincrease in urinary calcium excretion in these patients

was smaller than that which occurs in patients treat-ed with calcium and calcitriol or vitamin D. Howev-er, synthetic human parathyroid hormone (134) isnot currently available.

GENETIC DISORDERS OF PARATHYROID

HORMONE ACTION

Hereditary defects in parathyroid hormone actionare rare but informative. Each confirms the role of animportant signaling molecule. To some extent, thesestates mimic disorders of parathyroid hormone excess

or deficiency.

Defects of the Type 1 Parathyroid Hormone Receptor

Two defects with opposite effects on the type 1parathyroid hormone receptor have a surprisingly sim-ilar effect on bone growth.11,13

Jansens Chondrodystrophy

Jansens chondrodystrophy is characterized by shortlimbs, mild hypercalcemia, and low serum parathyroidhormone concentrations. It is caused by activating mu-tations of the type 1 parathyroid hormone receptor105

and is inherited as an autosomal dominant trait. It isassociated with increased proliferation and delayedmaturation of chondrocytes, which may weaken thegrowth plates, thereby causing the short limbs.

Blomstrands Chondrodystrophy

Blomstrands chondrodystrophy is characterized bygrowth impairment, primarily in the form of shortlimbs. It has been lethal prenatally, and therefore theregulation of serum calcium has not been evaluatedin vivo. It is caused by inactivating mutations of thetype 1 parathyroid hormone receptor106and is inher-

ited as an autosomal recessive trait. The growth platesshow accelerated calcification and a near-absence ofproliferating chondrocytes.

Defects of the Stimulatory Guanine-NucleotideBindingProtein

Parathyroid hormone signaling in cells is mediatedby the type 1 parathyroid hormone receptor, whichthen acts on a stimulatory guanine-nucleotidebind-ing (Gs) protein, which is composed of three sub-units (a, b, and g). The Gsasubunit (encoded by theGNAS1gene) mediates cyclic AMP stimulation byparathyroid hormone and by several other peptidehormones, including thyrotropin.26

Pseudohypoparathyroidism Type 1a

Pseudohypoparathyroidism type 1a is characterizedby short stature and other skeletal abnormalities, whichare known collectively as Albrights hereditary osteo-dystrophy, as well as hypocalcemia and high serum

concentrations of parathyroid hormone. It is causedby inactivating mutations in the asubunit of Gs

26andis inherited as an autosomal dominant trait. Many pa-tients with pseudohypoparathyroidism type 1a haveresistance not only to parathyroid hormone but alsoto thyrotropin.

Pseudo-pseudohypoparathyroidism

Pseudo-pseudohypoparathyroidism occurs in fam-ilies with pseudohypoparathyroidism type 1a. It con-sists of a combination of inactivating mutations ofGNAS1and Albrights osteodystrophy without theresistance to multiple hormones that characterizespseudohypoparathyroidism. The hormone resistance

is suppressed when the mutated GNAS1gene is in-herited from the father (i.e., paternal imprinting, orsuppression, of the mutant copy occurs in selectedtissues).107,108

Pseudohypoparathyroidism Type 1b

Pseudohypoparathyroidism type 1b is characterizedby isolated resistance to parathyroid hormone with-out the accompanying Albrights osteodystrophy. It isassociated with defective methylation within GNAS1,

which is most likely caused by a mutation in or nearGNAS1.109

Hypocalcemia in patients with pseudohypoparathy-roidism type 1a or 1b should be treated in the same

way as it is in patients with true hypoparathyroidism.

CONCLUSIONS

Despite a confusing disease nomenclature that isa remnant of past eras, substantial insight has beengained into many disorders of the parathyroid axis.

With the advent of reliable and specific assays for par-athyroid hormone, the diagnosis of parathyroid dys-function has become much easier. Treatments are gen-erally satisfactory and are logically related to the defects


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in the parathyroid gland or to their expression in thetarget organs. Controversies persist, however, particu-larly about the treatment of primary hyperparathy-roidism.

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