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Wien Med Wochenschr (2013) 163:397402

DOI 10.1007/s10354-013-0235-z

Clinical aspects of primary hyperparathyroidism:

clinical manifestations, diagnosis, and therapy
Rudolf WolfgangGasser

Received: 17 July 2013 / Accepted: 29 July 2013 / Published online: 29 August 2013
Springer-Verlag Wien 2013

Summary Primary hyperparathyroidism (PHPT) is the

most common cause of hypercalcemia. An autonomous overproduction of parathyroid hormone leading
to hypercalcemia, which is not downregulated by the
calcium-sensing receptor, is the pathophysiological basis of the disease. The classical manifestations of PHPT
include a generalized bone disease, kidney stones, and
nephrocalcinosis, gastrointestinal, cardiovascular, neuromuscular and neuropsychiatric symptoms. Recently,
the clinical presentation of PHPT, however, has changed
in Western countries, it occurs oligo-asymptomatic in
up to 80%. Clinical examination, laboratory, and imaging techniques for the characterization of the disease
and the localization include the diagnostic procedure. If
possible, parathyroidectomy is the treatment of choice
for clinically overt PHPT, for asymptomatic PHPT guidelines were developed in order to decide in individual
cases between surgical and conservative approach; this
consists of monitoring, adequate calcium and vitamin
D intake, as well as hydration. Medical therapy includes
bisphosphonates and calcimimetics.
Keywords Primary hyperparathyroidism Hypercalcemia Asymptomatic primary hyperparathyroidism
Investigations in primary hyperparathyroidism Parathyroidectomy

Klinische Aspekte des primren

Hyperparathyreoidismus: klinische Symptomatik,
Diagnose und Therapie
Zusammenfassung Der PHPT ist die hufigste Ursache
einer Hyperkalzimie. Eine autonome berproduktion
von Parathormon, die zur Hyperkalzimie fhrt und
nicht ber den Kalzium-sensing Rezeptor downreguliert wird, ist die pathophysiologische Grundlage der
Erkrankung. Klassische Manifestationen des PHPT sind
eine generalisierte Knochenerkrankung, Nierensteine
und Nephrokalzinose, gastrointestinale, kardiovaskulre, neuromuskulre und neuropsychiatrische Symptome. In letzter Zeit hat sich die klinische Prsentation
des PHPT in den westlichen Lndern gendert, er tritt
in bis zu 80% oligo- bis asymptomatisch auf. Klinische
Untersuchung, Labor und bildgebende Verfahren zur
Charakterisierung des Krankheitsbildes und zur Lokalisationsdiagnostik umfassen die Diagnostik. Wenn mglich ist die Parathyreoidektomie die Therapie der Wahl
bei klinisch manifestem PHPT, fr den asymptomatischen PHPT wurden Richtlinien erarbeitet, um im Einzelfall zwischen Operation und konservativem Vorgehen
zu entscheiden; dieses besteht in Monitoring, adquater
Kalzium- und Vitamin D-Zufuhr sowie Hydrierung. Zur
medikamensen Therapie stehen Bisphosphonate und
Kalzimimetika zur Verfgung.
Schlsselwrter Primrer Hyperparthyreoidismus
Hyperkalzimie Asymptomatischer primrer Hyperparathyreoidismus Diagnostik bei primrem Hyperparathyreoidismus Parathyreoidektomie

Ao.Univ.-Prof. Dr.R. W.Gasser()

Department of Internal Medicine I,
Innsbruck Medical University
Anichstrae 35, 6020 Innsbruck, Austria
e-mail: rudolf.gasser@i-med.ac.at

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Introduction
Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia. It is mostly seen in people

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over 50 years, but can occur at any age. On the whole

most patients are female (74%), but before the age of 45
the incidence is similar in men and women [1, 2]. PHPT
is characterized by an increased secretion of parathyroid
hormone (PTH) together with hypercalcemia caused by
the increase of functional parathyroid tissue due to tumor
or hyperplasia. Elevated PTH is also seen in secondary
hyperparathyroidism, an adaptive hypersecretion of PTH
to chronic (latent) hypocalcemia due to kidney disease,
malnutrition, malabsorption, or vitamin D insufficiency/
deficiency. Tertiary hyperparathyroidism can develop
from chronic secondary hyperparathyroidism changing
to autonomic PTH hypersecretion with hypercalcemia in
parathyroid gland hyperplasia or adenoma.
During the last decades the clinical presentation of
PHPT has changed in Western countries from a symptomatic disease with hypercalcemic symptoms, overt
bone disease, nephrolithiasis, and neuromuscular symptoms to a condition mainly discovered incidentally on
screening for calcium with minor or no specific symptoms, called asymptomatic primary hyperparathyroidism; at present only about 2030% of all patients have
clinical symptoms at diagnosis among Western countries
[24].
This review describes the clinical presentation, the
diagnostic assessment, and therapeutic options in PHPT.

Pathophysiology, pathologic anatomy, and

etiology of primary hyperparathyroidism
PTH secretion by the parathyroid gland regulates calcium homeostasis. Decreasing serum ionized calcium
is sensed by the calcium sensing receptor (CaSR) on the
parathyroid chief cells. This causes an increased PTH
secretion leading to increasing serum calcium levels.
This is mediated by increased calcium reabsorption in
the renal tubulus, by osteoclast mediated bone resorption and increased production of 1,25 dihydroxyvitamin
D3 in the kidney causing an increased calcium absorption in the gut. Rising ionized calcium levels decrease
PTH production via CaSR in the parathyroid gland. In
PHPT, PTH is secreted independently of this control circuit and PTH is not downregulated by rising levels of ionized calcium.
A sporadic PTH secreting adenoma of parathyroid
chief cells causes PHPT in about 85% of patients; multiglandular hyperplasia is seen in 115% of all cases of
PHPT. Parathyroid carcinoma is very rare and is seen in
less than 1% of the patients. Ectopic located adenomas
are found in about 16% of the cases: in the mediastinum,
thymus, paratracheal/paraoesophageal area, and thyroid [2].
There are some hereditary states of hyperparathyroidism (MEN type 1, MEN 2A, and others). Familial hypocalciuric hypercalcemia (FHH) with an inactivating
mutation of the CaSR can mimic PHPT. Drugs (lithium
and thiazide diuretics) may alter calcium homeostasis.
A history of head and neck radiation can precede PHPT.

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Fig. 1 Cystic lesion of os metacarpale III in a female patient with

PHPT

Clinical manifestation of primary

hyperparathyroidism
Only 2030% of patients in Western countries have overt
symptoms of PTH excess and/or hypercalcemia, the
majority of them is oligo- or asymptomatic [2].
Bone disease: The classical manifestation of PHPT is osteitis fibrosa cystica (rarely seen today) which is characterized by generalized demineralization, bone pain, and typical radiological signs: subperiostal bone resorption in the
middle and distal phalanges, tapering of the distal clavicles
by subchondral resorption, salt and pepper appearance
of the skull, bone cysts (Fig.1) and brown tumors of the long
bones. More common bone symptoms are a decreased
bone mineral density (BMD) mainly at sites rich in cortical
bone (hip and forearm) and an increased fracture risk.
Kidney disease: Nephrolithiasis is seen in about 1520%
of patients with PHPT nowadays, stones are mostly composed of calcium oxalate but sometimes also of calcium
phosphate. Nephrocalcinosis is caused by a diffuse
deposition of calcium phosphate complexes in the renal
parenchyma. Other possible renal features of PHPT are
polyuria, hypercalciuria, and renal insufficiency. Additionally abnormalities of the renal tubular function can
occur, such as impaired urinary concentration ability or
reduced phosphate reabsorption [4].
Gastrointestinal disease:Patients with symptomatic
hypercalcemia may also suffer from anorexia, nausea,
peptic ulcer disease, and constipation; they may develop
pancreatitis.
Cardiovascular disease:Cardiovascular manifestations seen in patients with PHPT are: arterial hypertension, electrocardiogram abnormalities like QT interval
shortening, left ventricular hypertrophy, and diastolic
dysfunction or increased mean carotid intima-media
thickness. The risk of cardiovascular death is increased in
patients with symptomatic PHPT [3].

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Neuropsychiatric disease:Symptoms depend on the

rise of serum calcium level and include cognitive dysfunction, depression, lethargy, and with severe hypercalcemia also psychosis and coma.
Neuromuscular symptoms:Muscle weakness and
fatigue are symptoms observed in patients with PHPT.
Parathyroid crisis:This is a rare complication of
PHPT, characterized by severe hypercalcemia (usually
>3.8mmol/L) and mainly symptoms of nervous system
dysfunction (psychosis and coma). Also severe abdominal symptoms, such as pain, nausea, peptic ulcer, and
pancreatitis are possible manifestations [4].

Asymptomatic primary hyperparathyroidism

Nowadays, up to 80% of patients with PHPT have an
asymptomatic disease in Western countries. Measurement of serum calcium is done during biochemical
screening or an assessment for low bone mineral density. These patients mostly show mild or only intermittent hypercalcemia and the mean serum concentration
of calcium is less than 0.25 mmol/L (1.0 mg/dL) above
the upper limit of the normal range. These patients
either have no subjective complaints or show only mild
nonspecific symptoms, such as fatigue, weakness, mild
depression, and mild cognitive or neuromuscular dysfunction. A clear-cut discrimination between asymptomatic and symptomatic PHPT is not always possible
[46]. There also exists a normocalcemic PHPT (elevated
PTH and normal serum calcium), in this case secondary
hyperparathyroidism has to be excluded.

Diagnostic assessment in primary

hyperparathyroidism
Clinical investigation
The patient should be examined about bone pain, previous fragility fractures, renal stones, and symptoms of
hypercalcemia/-uria such as polyuria and polydipsia
and about gastrointestinal complaints. A history of head
and neck irradiation during childhood may be important
for the development of PHPT.
Parathyroid tumors are rarely palpable on a physical
examination of the neck, a palpable neck mass is usually caused by thyroid disease (goiter) or very seldom by
parathyroid carcinoma.

Laboratory investigation
Serum total calcium is typically raised, since about 45%
of calcium is protein-bound, mainly to albumin, the calcium value has to be corrected for albumin if there is a
dysproteinemia.

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Serum ionized calcium offers to determine free calcium concentration which may be also raised in normocalcemic PHPT.
Urinary calcium can be determined best in the 24h
urine (with concomitant determination of creatinine) or
in a spot urine, where a calcium/creatinine ratio can be
calculated. Urinary calcium is typically raised or highnormal in PHPT, whereas low urinary calcium with raised
serum calcium level and mildly elevated or normal PTH
is found in FHH.
Parathyroid hormone (PTH) is measured by immunoradiometric assays as intact PTH. In PHPT, PTH is
raised or high normal despite a raised serum calcium
level.
Serum calcium and PTH levels have to be correlated
in the evaluation of hypercalcemia: high serum calcium
and PTH values are found in PHPT, whereas high serum
calcium and low serum PTH are confirming a non-PTH
induced hypercalcemia (mainly malignancy-associated).
Serum phosphate values are low or low-normal and
the urinary phosphate excretion is increased (phosphaturic effect of PTH).
25 hydroxyvitamin D3 is normal in PHPT. If the level
is low coexisting vitamin D insufficiency or deficiency is
present, these patients may be hypocalciuric and secondary hyperparathyroidism may increase PTH further.
Repletion of vitamin D should increase the urinary calcium excretion in PHPT, persistent low urinary calcium
would confirm FHH.
1,25 dihydroxyvitamin D3 may be at upper limit of
normal or elevated due to increased conversion from 25
hydroxyvitamin D3.
Bone turnover markers:Bone formation and bone
resorption markers (bone alkaline phosphatase, osteocalcin, procollagen type I C and N-terminal propeptide,
C-terminal telopeptid of type I collagen, and other collagen crosslinks) are upregulated in PHPT and found
elevated in serum or urine corresponding to the severity
of the disease [7].
Serum creatinine: Determination of serum creatinine
enables assessment of renal function, and the estimated
glomerular filtration rate (GFRmL/min) is important
for therapeutic decisions in PHPT.

Imaging
Bone mineral density (BMD) should be measured by
dual x-ray absorption (DXA) method in lumbar spine,
hip, and distal one-third forearm. Compared to healthy
people patients with PHPT show a decreased BMD [8],
which is preferentially reduced at sites enriched in cortical bone (distal one-third forearm and hip). BMD measurement is an essential part of disease management in
PHPT.

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parathyroid disease, which is superior to CT or technetium-99m sestamibi scanning alone [12, 13].

Therapeutic options in PHPTsurgery

Fig. 2 Parathyroid adenoma dorsocaudal of the left thyroid

lobe, Tc-99m sestamibi scintigraphy of a 67-year-old man
(reproduced with permission from the Department of Nuclear
Medicine, Innsbruck Medical University, Austria)

Radiography:In case of reduced BMD x-ray of thoracic and lumbar spine for vertebral fracture assessment
should be performed, in cases of severe hyperparathyroidism additional x-rays of further skeletal locations
(hands, skull).
Renal ultrasonography is mandatory to rule out kidney stones or nephrocalcinosis in PHPT, nephrolithiasis
is found in 7% of patients with asymptomatic PHPT [9].
Localization techniques: Once a PHPT is proven clinically and biochemically, a localization study has to be
done before planned surgery, especially in the case of a
minimally invasive technique [10].
Ultrasonography has a high sensitivity for preoperative localization of a parathyroid adenoma.
Technetium-99m sestamibi scintigraphy (MIBI scintigraphy) enables a functional proof of a PTH secreting
tumor. Planar images are obtained shortly after injection
of 99mTc-sestamibi and again at 2 h to identify hyperfunctioning parathyroid tissue, where the radiotracer is
retained (Fig.2).
Sestamibi single photon emission computed tomography (MIBI-SPECT) is a 3D method, which provides
high resolution imaging.
These scintigraphic methods enable to detect parathyroid tumors also at ectopic sites such as mediastinum,
thymus, or paratracheal/paraoesophageal area [11].
Computed tomography (CT) and magnetic resonance tomography (MRT) of the neck are further techniques to localize a parathyroid tumor.
MIBI-SPECT and CT fusion:Image fusion of MIBISPECT and CT allows a preoperative localization of
enlarged parathyroid glands and a multiglandular hyper-

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Parathyroidectomy (removing the abnormal parathyroid tissue) is always indicated in patients with symptomatic PHPT if there is no contraindication to surgery.
Symptoms of active disease are, as mentioned before,
nephrolithiasis, polyuria, polydipsia, osteoporosis, fragility fractures, pancreatitis, peptic ulcer disease, or
neurocognitive dysfunction. Patients with mild hypercalcemia (<3mmol/l) do not need preoperative therapy
regarding serum calcium. In the case of higher calcium
levels a preoperative treatment with adequate hydration,
calcimimetics (cinacalcet), or intravenous bisphosphonates is indicated to reduce serum calcium and therefore
to minimize the risk of complications by severe hypercalcemia [3].
Also in patients with asymptomatic PHPT parathyroidectomy is a valuable therapeutic option. There is
evidence for lowering fracture risk after surgery and normalizing serum calcium level and PTH in patients with
asymptomatic PHPT [14], also a reduction of incidence
of renal stones and a minor improvement in neurocognitive dysfunction was observed [2]. Since there are certain patients with asymptomatic PHPT in which medical
monitoring is appropriate instead of surgery guidelines
for the management of asymptomatic PHPT were published [15]. The recommended criteria for parathyroidectomy in patients with asymptomatic PHPT are shown
in Table 1. Any patient who meets one of these criteria
should undergo surgery if there is no contraindication
against it. In contrast to previous guidelines hypercalciuria in the absence of nephrolithiasis is no longer an
indication for parathyroidectomy, but a 24 h urine calcium determination has to remain a part of the initial
examination of the patient.
Monitoring instead of surgery in asymptomatic PHPT
or in patients who refuse surgery or are unable for it
includes the determination of serum calcium, PTH, 25
hydroxyvitamin D3 and creatinine and urinary calcium
annually and BMD measurement in hip, lumbar spine,
and distal one-third forearm every (1-)2 years.
Table 1Guidelines for the management of asymptomatic
primary hyperparathyroidism [15]
Measurement

Criteria

Serum calcium

>0.25mmol/L above upper limits

of normal

24h urine calcium

Not indicated

Calculated creatinine clearance

<60ml/min

Bone mineral density

T score of 2.5 or less at any site or

previous fragility fracture (or both)

Age

<50 years

Surgery indicated in asymptomatic patients who meet any one of these

conditions

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Table 2 Management of PHPT

Surgical procedures
Minimally invasive endoscopic parathyroid exploration is preferred to remove a single parathyroid adenoma
if an unequivocal localization is possible. This technique
has emerged as the procedure of choice and is as effective
as bilateral cervical exploration [16]. Initial bilateral neck
exploration is indicated in multiglandular parathyroid
disease and in other more complicated situations (reoperation in persistent or recurrent parathyroid disease,
concomitant thyroid pathology, and negative preoperative imaging studies). In case of an atypical adenoma
localization a special surgical approach is indicated.
Intraoperative PTH-monitoring is a useful tool to
demonstrate successful removal of all hyperfunctional
parathyroid tissue. A reduction of at least 50% of the preoperative PTH level confirms a successful parathyroidectomy [16].
Hungry bone syndrome:After a successful parathyroidectomy in severe PHPT associated with hyperparathyroid bone disease a profound and prolonged postoperative hypocalcemia may occur concomitant with
hypophosphatemia and hypomagnesemia. This condition is named hungry bone syndrome and is a rare, but
serious adverse effect of parathyroidectomy. The hypocalcemia is thought to be caused by an increased influx
of calcium into the bone, due to the decrease of PTH and
the consecutive decrease of bone remodeling [17].

Therapeutic options in PHPTmedical therapy

If parathyroidectomy is not recommended to the patient,
refused by the patient or not possible due to a contraindication appropriate supportive-preventive measures
and a pharmacologic treatment are alternative options to
surgery.
Preventive measures: Adequate hydration can reduce
the risk of nephrolithiasis. In order to avoid an aggravation of hypercalcemia thiazide diuretics or lithium carbonate should not be administered, a high calcium diet
(>1,000mg/day) is contraindicated. On the other hand,
a moderate calcium intake (1,000 mg/day) is recommended, since a low calcium diet may further increase the
PTH level. Patients with high calcitriol serum levels should
keep a moderate calcium restriction (<800mg/day).
In the case of vitamin D deficiency (25 hydroxyvitamin
D3<20ng/ml or <50nmol/l) moderate vitamin D supplementation is indicated [18].

Symptomatic

Asymptomatic

Surgery

Yes

Yes, if one criterium positive

according to Bilezikian [15]

Conservative

Yes, if surgery is impossible

Cacinacalcet
BMDbisphosphonate

Yes, if no criteria according

to Bilezikian [15].
Yes, if surgery is impossible

25 OH vitamin
D supplementation at vitamin
D <20ng/ml

Yes

Yes

Supportive
measures:
hydration, moderate calcium
intake

Yes

Yes

BMD bone mineral density

Calcimimetics (cinacalcet) inhibit PTH secretion by

activating the calcium-sensing receptor in the parathyroid glands. Cinacalcet reduces the serum calcium level
in most patients with PHPT, but an increase of BMD
could not have been demonstrated yet [19].
Estrogenprogestin replacement in postmenopausal
women with PHPT is a second line therapy and has been
found effective in increasing BMD in some trials [18].
Raloxifene in postmenopausal women with PHPT
reduced mean serum calcium in a short term study [20],
but further studies are needed before recommending
this therapy.

Conclusion
At present PHPT is usually diagnosed at an asymptomatic
stage, only about 2030% of patients have clinical symptoms at diagnosis among the Western countries. Once
PHPT is confirmed, monitoring and therapy of the disease depend on clinical symptoms as well as on the published criteria of the guidelines for the management of
asymptomatic PHPT [15]. Table2 summarizes the management of PHPT according to the current guidelines.
Parathyroidectomy is the only curative therapy option.
Monitoring and symptom-oriented treatment is adequate for selected patients who are unable or unwilling
to undergo parathyroidectomy and for those who do not
meet the criteria for surgery according to the guidelines.
Conflict of interest
The author declares that there is no conflict of interest.

References

Drug therapy
Bisphosphonates are recommended for patients with
osteopenia/osteoporosis and PHPT. There are some studies with alendronate showing an increase of BMD in lumbar spine and hip, but fracture data are not available [18].

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PHPT

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