Primary Hyperparathyroidism

Primary
hyperparathyroidism
Straight to the point of care
Last updated: Sep 21, 2021

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 5
Case history 6
Diagnosis 7
Approach 7
History and exam 9
Risk factors 11
Investigations 13
Differentials 16
Management 18
Approach 18
Treatment algorithm overview 21
Treatment algorithm 23
Emerging 30
Secondary prevention 30
Patient discussions 30
Follow up 31
Monitoring 31
Complications 32
Prognosis 33
Guidelines 34
Diagnostic guidelines 34
Treatment guidelines 35
References 37
Disclaimer 48
Primary hyperparathyroidism Overview
Summary
Diagnosis of primary hyperparathyroidism is confirmed biochemically with synchronous elevation of serum
calcium and inappropriate elevation of parathyroid hormone (PTH).
OVERVIEW
Normal serum intact PTH in the setting of hypercalcaemia does not rule out disease.
Depression, cognitive changes, change in sleep pattern, fatigue, and myalgia or muscle weakness are non-
specific subjective complaints. There may be a history of nephrolithiasis or low bone mineral density.
Physical examination is usually normal, but examination of the neck is essential to look for a hard, dense
mass, suggestive of parathyroid carcinoma.
Parathyroidectomy is the only definitive cure. Monitoring is an option for patients who have mild
hypercalcaemia without surgical indications, which include lack of ensured follow-up, renal stones, impaired
renal function, or osteoporosis.
Definition
Primary hyperparathyroidism (PHPT) is an endocrine disorder in which autonomous overproduction of
parathyroid hormone (PTH) results in derangement of calcium metabolism. In approximately 80% of cases,
over-production of PTH is due to a single parathyroid adenoma and, less commonly, multi-gland involvement
may occur. Diagnosis occurs through testing for a concurrent elevated serum calcium level with a raised or
inappropriately normal (i.e., non-suppressed) plasma PTH level.[1] [2] Inherited forms, affecting a minority of
patients, lead to hyperfunctioning parathyroid glands. Importantly, hyperparathyroidism is rarely caused by
parathyroid cancer characterised by severe hypercalcaemia.[3]
Normocalcaemic PHPT is recognised as a variant of PHPT, and has yet to be thoroughly characterised.[4]
It presents with high levels of parathyroid hormone in the setting of normal serum and ionised calcium
levels, after secondary causes of PTH elevation have been excluded.[5] It is sometimes detected during
the evaluation of patients with low bone mineral density.[6] Some, but not all, patients will go on to develop
PHPT.[1] [2] [5]
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Primary hyperparathyroidism Theory
Epidemiology
Primary hyperparathyroidism (PHPT) is a relatively common disorder affecting 1 in 500 women and 1 in 2000
men aged over 40 years.[10]
THEORY
In the 1970s, the incidence of PHPT in developed countries rose dramatically with the onset of widespread
routine use of multi-channel analysers that included measurements of serum calcium levels.[4] [6] Incidence
rates have since decreased for largely undetermined reasons.[11] The estimated incidence in the US
between 1998 and 2010 was 50 per 100,000 person-years.[12] [13] A reasonable estimate of prevalence
is approximately 1 per 1000.[11] [14] The incidence and prevalence of PHPT is highest in black people
compared to other racial groups.[12]
While the condition may affect all age groups, it is uncommon in the first two decades of life, in the absence
of inherited syndromes. It is most commonly found in women between 50 and 60 years of age, with a two to
three times greater incidence in women compared with men.[1] [6] The incidence and prevalence globally are
similar to that of the US, but presentation varies greatly. In the US and Europe, most (80%) patients present
with asymptomatic disease, but in resource-poor nations, most (>80%) patients present with symptoms.[2]
[6] In countries where routine biochemical screening is less common, patients with PHPT are likely to present
with symptomatic disease at a younger age and with more severe clinical and biochemical abnormalities.[15]
[16] [17] [18]
Aetiology
Primary hyperparathyroidism is caused by the inappropriate secretion of parathyroid hormone (PTH), leading
to hypercalcaemia.
• Parathyroid adenomas are the most common aetiology. Around 80% are a single, benign adenoma,
which in most cases is sporadic.[4] Multiple adenomas and hypertrophy of all 4 glands are less
common.
• Inherited forms, affecting 5% to 10% of patients, lead to hyperfunctioning parathyroid glands.[19] A
history of family members with PHPT should prompt suspicion of multi-gland disease. These disorders
include multiple endocrine neoplasia (MEN) 1, MEN 2, and MEN 4; HPT-jaw tumour syndrome; and
familial isolated hyperparathyroidism.
• MEN 1, MEN 2, and MEN 4 are autosomal dominant traits. PHPT is the presenting symptom
of 90% of patients with MEN 1.[9] Clinical features of MEN 1 include multi-gland parathyroid
disease, pancreatic neuroendocrine tumours, and anterior pituitary tumours.[9] In MEN
2A, PHPT occurs in 20% to 30% of patients.[9] The PHPT disease is either multi-gland
or an adenoma. Other manifestations of MEN 2A include medullary thyroid cancer and
phaeochromocytomas.[9] MEN 4 is characterised by the occurrence of parathyroid and anterior
pituitary tumours.[20]
• HPT-jaw tumour syndrome characteristically includes parathyroid adenomas or carcinomas,
mandibular or maxillary fibro-osseous lesions, and renal cysts and tumours.[21] Inherited in an
autosomal dominant fashion.
• Familial isolated PHPT is a genetic mutation similar to MEN, but without manifestations of other
endocrinopathies. Inheritance is autosomal dominant. Parathyroid cells are insensitive to serum
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 21, 2021.
calcium levels due to germline-inactivating mutations.[22] Patients usually have 4-gland disease
(multi-gland disease).[23]
• Only ≤1% of cases are due to parathyroid malignancies.[4]
• Hyperparathyroidism may also result from external neck irradiation.[24] [25] Lithium therapy, often
THEORY
used to treat patients with bipolar disorder, can lead to the over-stimulation of parathyroid glands, by
altering feedback inhibition of PTH secretion, known as the PTH set point.[26] This phenomenon may
persist after the drug is stopped if parathyroid hormone production has become autonomous.[27]
Pathophysiology
Low serum calcium ordinarily stimulates parathyroid hormone (PTH) secretion, whereas high calcium
levels suppress PTH secretion. In primary hyperparathyroidism, PTH secretion is not suppressed (as would
typically be expected) by high calcium levels. Excessive PTH leads to over-stimulation of bone resorption,
with cortical bone affected more than cancellous bone.[6] PTH also stimulates the kidneys to reabsorb
calcium and to convert 25-hydroxyvitamin D3 to its more active form of 1,25-dihydroxyvitamin D3. This active
vitamin D is responsible for the gastrointestinal absorption of calcium.
Over-stimulation of PTH receptors, specifically type-2 PTH receptors, is thought to play a role in the
subjective neurocognitive and affective symptoms.[28] Hypercalcuria may also lead to nephrolithiasis.[6]
Classification
Primary hyperparathyroidism: clinical phenotypes[2] [7] [8]
The clinical presentation of primary hyperparathyroidism has changed over the years and varies across
countries, depending on availability of biochemical screening tests.
Symptomatic PHPT: the patient overtly exhibits 'classic' symptoms of renal (e.g., reduced renal function,
nephrolithiasis) and skeletal (e.g. fragility fractures, skeletal deformities) complications. The neuromuscular
system (e.g. proximal neuromuscular weakness) can also be involved. Other 'non-classical' manifestations
attributed to PHPT include the cardiovascular system (e.g., hypertension, atherosclerotic heart disease)
and neurocognitive features (e.g., anxiety, poor concentrating ability, cognitive decline). Gastrointestinal
symptoms may be present.
Asymptomatic PHPT: the patient has biochemical evidence of the disease and may have manifestations
of PHPT, but does not exhibit any of the classic symptoms. Usually an incidental finding of mildly elevated
calcium and PTH levels (typically within two times the upper limit of normal). The patient may exhibit a
constellation of subjective non-specific symptoms.
Normocalcaemic PHPT: an asymptomatic biochemical phenotype with normal calcium levels and a mildly
elevated PTH level (usually similar or slightly lower than in the hypercalcaemic form of asymptomatic PHPT).
It is sometimes detected during the evaluation of patients with low bone mineral density, however, this is
likely due to selection bias, as data from community cohorts suggest no differences in bone mineral density
between those with normocalcaemic PHPT and those with normal PTH levels.[6]
5
Case history
Case history #1
THEORY
At a routine examination, a 55-year-old woman is discovered to have hypercalcaemia. Follow-up

laboratory tests show synchronously elevated serum calcium and intact parathyroid hormone, with low
phosphorus and mildly elevated alkaline phosphatase. 25-hydroxyvitamin D is in the low normal range.
Past medical history is significant for hypertension and coronary artery disease. Review of symptoms
includes complaints of fatigue, feeling achy, and vague depression and mental fatigue. The patient has
a history of nephrolithiasis and newly detected osteopenia. Family history is negative for renal stones or
calcium disorders.
Other presentations
Ninety percent of people with multiple endocrine neoplasia, type 1 (MEN 1) first present with PHPT.
These patients may have a history of nephrolithiasis with an onset in their early twenties or a family
history of PHPT or pancreatic or pituitary tumours.[9]
Primary hyperparathyroidism Diagnosis
Approach
In the US and Europe, most instances of hyperparathyroidism are detected incidentally when routine
laboratory tests are done.[7] Hypercalcaemia and primary hyperparathyroidism are only rarely diagnosed
clinically, and the definitive diagnosis relies on laboratory tests. In resource-poor countries, the majority of
patients present with symptoms.[6]
History and physical examination

Initial assessment should include both a detailed personal and family history.[1] Primary
hyperparathyroidism (PHPT) is 2 to 3 times more common in women than in men.[6] Prevalence
increases with age and is especially common in postmenopausal women.[6]
Symptoms of PHPT are most likely not to be related to hypercalcaemia itself and instead relate to
its effect on key target organs.[4] Medical history may reveal a history of skeletal (e.g., osteopenia
or osteoporosis) or renal (e.g., kidney stones) involvement.[4] There may also be a family history of
hyperparathyroidism or, where this was undiagnosed, a family history of conditions suggestive of
hypercalcaemia or other endocrine gland involvement.[1] Other features such as neuropsychological
symptoms (overt neuromuscular dysfunction is now uncommon), cardiovascular disease abnormalities, or
gastrointestinal symptoms are considered to be non-specific.[4] [6]
The following non-specific features are most common:
• Fatigue
• Poor sleep
• Myalgias
• Anxiety
• Depression
• Memory loss
Gastrointestinal symptoms that can be attributed to hypercalcaemia, such as anorexia, constipation, and
abdominal pain (such as from pancreatitis), are now uncommon.[4] [6]
DIAGNOSIS
Non-specific symptoms that may have been previously attributed to other disorders or ageing may be
attributed to hyperparathyroidism once it is diagnosed. Surgical cure may lead to apparent resolution of
symptoms; patients who are considered to be asymptomatic sometimes report improvements in quality of
life following surgery.[34]
Physical examination of the neck is usually unremarkable. A palpable neck mass is most likely to be a
thyroid lesion but a hard, dense mass may be suggestive of parathyroid carcinoma.[35]
Laboratory
Diagnosis of PHPT is confirmed with repeat measurements of serum calcium and serum intact
parathyroid hormone (PTH). Repeat measurements are required given that patients with PHPT may
occasionally have temporarily normal calcium levels despite being hypercalcaemic most of the time.[1] If
the patient is being treated with thiazide diuretics, medicine should be stopped 2 weeks before calcium
measurements. During blood drawing, venous stasis should be avoided to ensure accurate results. Serum
calcium levels should be adjusted for the serum albumin concentration.[1] [2] This is done by adding
0.20 mmol/L (0.8 mg/dL) to the total serum calcium level for every 10 g/L (1 g/dL) the serum albumin
concentration is <40 g/L (4 g/dL).
7
Intact serum PTH (entire 84-amino acid sequence) is measured by immunoradiometric or
immunochemical assay. Of note, if the serum intact PTH level is normal with hypercalcaemia,
hyperparathyroidism is not excluded, since it is the appropriateness of the PTH level relative to the
calcium level that is relevant.[6]
Patients with normocalcaemic PHPT have normal serum and ionised calcium levels. Therefore, a normal
ionised calcium is necessary to establish the diagnosis of normocalcaemic PHPT, but not hypercalcaemic
PHPT.[1]
The 25-hydroxyvitamin D level should also be assessed because a low vitamin D may lead to a
physiologically compensatory PTH level that normalises on the repletion of the vitamin.[1] [2] [36]
Alkaline phosphatase levels are not necessary for diagnosis, but they might help in determining the
extent of the bone disease. Pre-operative elevated alkaline phosphatase levels predict postoperative
hypocalcaemia following parathyroidectomy.
Serum phosphorous levels might be in the lower range of normal, indicating concomitant electrolyte shifts.
Patients with PHPT may have a low or low-normal blood phosphorus level.
In patients with presumed hyperparathyroidism, urinary calcium measurements should be performed

with a 24-hour measurement of urinary creatinine and calcium.[1] [2] This quantifies urinary calcium
excretion and explores the differential diagnosis of familial hypocalciuric hypercalcaemia (FHH). FHH
can often be differentiated from PHPT by measuring the renal calcium to creatinine excretion ratio, which
generally is much lower in patients with FHH than in patients with PHPT due to other causes. FHH should
be considered in patients with long-standing hypercalcaemia with urinary calcium levels less than 100
mg/24 hours, and a calcium to creatinine clearance ratio less than 0.01.[1] FHH can now be confirmed
with genetic testing.
Radiographic studies
The diagnosis of PHPT is based on biochemical parameters. Parathyroid localisation studies serve no
purpose in diagnosis, but represent a guide to the operating surgeon once the decision has been made to
DIAGNOSIS
proceed with parathyroidectomy.[37] These studies should not be a surrogate for diagnosis of PHPT.
In surgical management, pre-operative imaging is used to help localise the suspected adenoma(s).
Parathyroid glands are usually located at the 4 poles of the thyroid gland, although they may be found in
other locations and can therefore be difficult to locate. Lack of positive imaging is not a reason to avoid
carrying out parathyroidectomy in a patient with a clear biochemical diagnosis of PHPT as an experienced
parathyroid surgeon will still be able to find abnormal parathyroid tissue.[2] [38]
Several imaging modalities are available, but no one is singly preferred.[39] Given the significant regional
variation in imaging accuracy, candidates for parathyroidectomy should be referred to an expert clinician
to decide on the best imaging modalities based on their knowledge of local imaging availability.[1] [40]
Many institutions use Tc-99m sestamibi scanning, often in conjunction with ultrasonography.[37] [41]
Ultrasonography can also be used to identify concomitant thyroid disease, which is present in 12% to
67% of patients with hyperparathyroidism.[1] The use of single-photon emission computed tomography
(CT) in combination with sestamibi scanning improves the utility of the imaging studies with a sensitivity
of 88% and specificity of 98.8%.[42] [27] Four-dimensional CT has emerged as a useful imaging tool and
is now the initial imaging modality of choice (over ultrasound and sestamibi scans) in some centres in
North America. It appears to have at least a similar diagnostic performance compared to tomographic
parathyroid scintigraphy but a higher radiation dose.[37] Magnetic resonance imaging (MRI) is also an
option, although this is less commonly used except in certain circumstances such as pregnancy.[1] A
number of studies have examined the role of radiolabelled choline PET, which can be combined with CT
(PET/CT) or magnetic resonance imaging (PET/MRI), for the detection of hyperfunctioning parathyroid
glands in patients with primary hyperparathyroidism with encouraging results.[43] Further prospective
studies are required to validate these findings.
Combining functional and anatomical tests is more effective than any one test alone.
Pre-operative ultrasound-directed fine-needle aspiration biopsy of parathyroid lesions is not routinely

recommended and may only be considered in unusual, difficult cases of PHPT and not in suspected
parathyroid carcinoma. This is because it is rarely necessary and is associated with a number of adverse
effects.[1]
Once diagnosis is confirmed, a dual-energy x-ray absorptiometry (DXA) scan should be completed to
assess progression of disease in 3 sites: lumbar spine, hip, and forearm. An ultrasound scan of the
kidneys will establish whether there is asymptomatic renal calcification. Asymptomatic renal calcification is
an indication for parathyroidectomy.[1]
The trabecular bone score (TBS) is an imaging technology adapted directly from the DXA image of the
lumbar spine that provides information about skeletal microstructure. Several studies have assessed
TBS in patients with PHPT, and their results suggest that TBS may identify trabecular abnormalities not
captured by lumbar spine bone mineral density in PHPT.[44]
History and exam

Key diagnostic factors
incidental finding on biochemical testing (common)
• In the US and Europe, most (80%) patients present with asymptomatic disease and are diagnosed on
DIAGNOSIS
routine tests.[6] [7]
history of osteoporosis or osteopenia (common)

• Bone loss occurs as result of bone resorption due to excess PTH.[4] May have associated bone pain
or pathological fracture. Osteoporosis was found in 46% of patients with PHPT in one review.[47]
family history of hyperparathyroidism or features suggestive of

hypercalcaemia (uncommon)
• A history of family members with PHPT should prompt suspicion of multi-gland disease. In such
cases, pre-operative localisation studies are not as sensitive, and this should be taken into account
during pre-operative planning.[1] Inherited forms include multiple endocrine neoplasia (MEN) 1, MEN
2, MEN 4, HPT-jaw tumour syndrome, familial hypocalciuric hypercalcaemia, and familial isolated
hyperparathyroidism. Genetic counselling should be considered for patients with PHPT and a positive
family history of PHPT, and for patients with apparent syndromic manifestations.[1]
nephrolithiasis (uncommon)
• If the patient has a history of kidney stones composed of calcium oxalate, hypercalciuria is very
likely.[45] Nephrolithiasis is found in 10% to 20% of US patients with PHPT.[6] Silent nephrolithiasis
9
and/or nephrocalcinosis is an indication for parathyroidectomy even in the absence of symptoms of
PHPT.[1]
• The incidence of kidney stones has declined over the past decades, but the incidence of hypercalciuria
has not.[46] Renal calcium excretion is not directly related to kidney stones, but an evaluation of a
patient with PHPT should include a 24-hour urine test for creatinine clearance and calcium level.[1]
Hypercalcaemia can impair renal function. Hypercalciuria (24-hour urine calcium level >100 mmol/L
[>400 mg/dL]) with increased stone risk is an indication for parathyroidectomy even in the absence of
symptoms of PHPT.[1]
Other diagnostic factors

poor sleep (common)
• The prevalence of sleep disturbance in patients with PHPT is between 44% to 62%.[34] Mechanisms
of disruption of sleep quality are unknown, but may be related to alterations in circadian rhythm. Sleep
disturbance is one of the most common complaints in patients with PHPT, and resolution of insomnia
is seen in 70% of patients following parathyroidectomy.[34]
fatigue (common)
• Most patients with PHPT have considerable symptomatology compared with healthy people. The most
common profound non-specific symptoms is fatigue.[34]
myalgia (common)
• Classic PHPT is commonly associated with muscle weakness and high fatigability. This was originally
described as a distinct neuromuscular syndrome characterised by atrophy of type II muscle cells.[4] [6]
anxiety (common)
• Most patients with PHPT have considerable psychiatric symptomatology compared with healthy
people. Rates of anxiety in patients undergoing parathyroidectomy for PHPT are between 43.1% to
53.0%.[48] The severity of symptoms was not linearly related to the degree of hypercalcaemia or to
serum intact PTH levels.[34]
DIAGNOSIS
depression (common)
• In a US population 10% of patients with PHPT met criteria for major depression.[49]
memory loss (common)

• Neurocognitive impairments were 30% in a US population, with impaired executive functioning present
in 13% of patients with PHPT, which decreased to 2% following cure. Impaired cognitive processing
speed was detected in 26% of patients pre-operatively, but in only 6% after parathyroidectomy.[50]
overt neuromuscular dysfunction (uncommon)

• Such as proximal neuromuscular weakness is now rare, but one of the criteria for symptomatic
hyperparathyroidism, along with other target organ complications such as severe bone disease/
fractures or renal stones.[4] [6]
cardiovascular and metabolic dysfunction (uncommon)

• The link between PHPT and cardiovascular disease remains controversial. Published data
derived from observational studies exist linking symptomatic and mild PHPT with hypertension,
echocardiographic changes, arrhythmias, endothelial dysfunction, glucose metabolism impairment,
and metabolic syndrome.[51] [52] [53] [54] However, the data are inconsistent, with little evidence
to suggest that parathyroidectomy results in improved outcomes. For this reason, at present
cardiovascular involvement is not considered among the criteria required for parathyroidectomy.
features suggestive of hypercalcaemia (uncommon)

• Gastrointestinal symptoms that can be attributed to hypercalcemia, such as anorexia, constipation,
and abdominal pain (such as from pancreatitis), are now uncommon.[4] [6]
hard and dense neck mass (uncommon)

• A hard, immobile neck mass may suggest a parathyroid carcinoma.[35] A palpable neck mass is more
likely to be a thyroid lesion, but up to 50% of parathyroid carcinomas are palpable.[35] Around 1% of
patients with PHPT will have a parathyroid carcinoma. The index of suspicion rises in the presence of
a markedly raised calcium and PTH.[1]
Risk factors
Strong
female sex
• PHPT is 2 to 3 times more common in women than in men.[1]
age ≥50-60 years

• PHPT incidence increases with age, being especially common in post-menopausal women.[6]
family history of PHPT

• Familial isolated PHPT is a genetic mutation similar to multiple endocrine neoplasia (MEN), but without
manifestations of other endocrinopathies. Inheritance is autosomal dominant fashion. Parathyroid cells
are insensitive to serum calcium levels due to germline-inactivating mutations.[22] Patients usually
have 4-gland disease (multi-gland disease).[23] A history of family members with PHPT should prompt
DIAGNOSIS
suspicion of multi-gland disease. In such cases, pre-operative localisation studies are not as sensitive.
Genetic counselling is recommended for patients younger than 40 years old with PHPT and multi-
gland disease, and should be considered for those with a positive family history of PHPT.[1]
multiple endocrine neoplasia (MEN) 1, 2A, or 4

• MEN 1, MEN 2A, and MEN 4 are autosomal dominant traits.
• PHPT is the presenting symptom of 90% of patients with MEN 1.[9] Clinical features of MEN 1 include
multi-gland parathyroid disease, pancreatic neuroendocrine tumours, and anterior pituitary tumours.[9]
In MEN 2A, PHPT occurs in 20% to 30% of patients.[9] MEN 4 is characterised by the occurrence of
parathyroid and anterior pituitary tumours.[20] The PHPT disease is either multi-gland or an adenoma.
Other manifestations of MEN 2A include medullary thyroid cancer and phaeochromocytomas.[9]
Genetic counselling should be considered for patients presenting with PHPT who have an apparent
syndromic manifestation.[1]
current or historical lithium treatment

• Ten percent to 15% of patients taking lithium have hypercalcaemia with or without symptoms of
hyperparathyroidism (HPT).[29] Although the precise mechanism has not been elucidated, studies
suggest that lithium causes hypercalcaemia and HPT by altering feedback inhibition of PTH secretion
11
and raising the 'set point' at which serum calcium inhibits PTH secretion.[26] The prevalence of multi-
gland disease in PHPT after chronic lithium therapy is higher than in PHPT due to other causes. The
presence of (or potential for) multigland disease is important to be aware of when planning surgery.[1]
hyperparathyroidism-jaw tumour syndrome

• Characteristically includes parathyroid adenomas or carcinomas, mandibular or maxillary fibro-
osseous lesions, and renal cysts and tumours.[21] Inherited in an autosomal dominant fashion.
• Males tend to show greater penetrance.[30] Parathyroid carcinomas occur in up to 15% of affected
people.[31] It tends to have a more aggressive course, and patients often have more severe
hypercalcaemia.
Weak
history of head and neck irradiation
• One study has shown that 14% of patients with exposure to neck irradiation developed PHPT.[25] With
irradiation, there is a higher risk of multi-gland involvement.[32]
• Parathyroid adenomas are usually monophenotypic, probably the result of growth from a single
genetically dysfunctional cell.[33] The cell dysfunction could be due to a mutation that reflects a
consequence of exposure to external mutagens such as irradiation.
DIAGNOSIS
Investigations
1st test to order
Test Result
serum calcium from high-normal to
raised
• If elevated, suggests disease. If high-normal and high suspicion,
should be rechecked on separate day after fast. Diagnosis of PHPT
requires elevated serum calcium, inappropriately unsuppressed
serum intact PTH levels, and a normal or raised urinary calcium in
the presence of normal renal function. Patients with normocalcaemic
PHPT have normal serum and ionised calcium levels.[1] Fasting
and avoiding venous stasis in blood draw will aid in accuracy. Also if
taking a thiazide diuretic, this medicine should be stopped at least 2
weeks before a blood draw. When testing for serum intact PTH level,
should repeat simultaneous calcium level.
serum intact PTH with immunoradiometric or immunochemical from high-normal to
assay elevated
• The diagnosis of PHPT, along with repeated elevated serum calcium,
is confirmed with an inappropriate elevation in serum intact PTH.
If calcium is high, and the feedback loop is intact, PTH should be
low. If instead PTH is high, then it is inappropriately elevated and the
diagnosis of PHPT is secured so long as the urinary calcium is not
low (instead suggestive of familial hypocalciuric hypercalcaemia).
When testing for serum intact PTH level, should repeat simultaneous
calcium level.
• The diagnosis of PHPT has been greatly facilitated by the
development of immunometric 'sandwich' assays.[55] The assay uses
a pair of antibodies that recognise different regions of PTH. One of
these antibodies, preferentially monoclonal, is immobilised, whereas
a polyclonal antiserum with greater affinity is labelled with radio-
iodine or chemiluminescence. Because of the 2, the 'sandwich' assay
is more sensitive than either test alone. The immunometric assay is
DIAGNOSIS
specific and sensitive for serum intact PTH. The process is fast and
the analysis can be done in 15 to 30 minutes.
13
Other tests to consider
Test Result
25-hydrox yvitamin D level may be low
• Vitamin D deficiency and PHPT frequently co-exist. However, a low
vitamin D may artificially elevate the PTH level in patients without
PHPT and mislead the diagnosis.[36]
serum alkaline phosphatase may be raised
• Patients with elevated alkaline phosphatase with other normal liver
enzymes have high turnover bone disease and are susceptible to
post-parathyroidectomy hypocalcaemia.
serum phosphorus low or low normal
• Concomitant electrolyte shifts occur typically as a result of multiple
endocrine neoplasia 1 or 2.
24-hour urinary calcium high or normal in
PHPT; low in familial
• In patients with presumed hyperparathyroidism, urinary calcium
hypocalciuric
measurements should be performed.[1] This quantifies urinary
hypercalcaemia
calcium excretion and explores the differential diagnosis of familial
hypocalciuric hypercalaemia (FHH). FHH can often be differentiated
from PHPT by measuring the renal calcium to creatinine excretion
ratio, which generally is much lower in patients with FHH than in
patients with PHPT due to other causes. FHH can now be confirmed
with genetic testing.
• A 24-hour urine calcium in benign FHH is <100 mg calcium/24
hours,[1] which is generally lower than in patients with PHPT or other
causes.
dual-energy x-ray absorptiometry (DXA) scan T-score: -1 to +1 = normal;
-1 to -2.5 = osteopenia; <
• Once diagnosis of PHPT is confirmed, a DXA scan should be
-2.5 = osteoporosis
completed to assess progression of disease in 3 sites: lumbar spine,
hip, and forearm.[1]
• This is a non-invasive test assessing risk of fractures. Two values
DIAGNOSIS
are given: young normal and age-matched. Young normal (T-score)

compares bone mineral density (BMD) versus the optimal density of
a 30- to 40-year-old healthy adult and then assesses the fracture risk.
Age-matched (Z-score) compares the BMD to the expected result
at the patient's age and size; it may be useful for evaluation of pre-
menopausal women or men aged under 50 years.
trabecular bone score low TBS value
correlates with weaker
• The trabecular bone score (TBS) is an imaging technology adapted
skeletal texture (a
directly from the DXA image of the lumbar spine that provides
reflection of degraded
information about skeletal microstructure. Several studies have
microarchitecture)
assessed TBS in patients with PHPT, and their results suggest that
TBS may identify trabecular abnormalities not captured by lumbar
spine bone mineral density (BMD) in PHPT.[44]
Tc-99m sestamibi scanning and ultrasonography may be positive for
• Not for diagnosis, but important for localisation of disease in planning solitary adenoma or
multi-gland involvement
surgery. Cervical ultrasonography will also assess for concomitant
thyroid disease.[1] Combining tests is more effective than any one
test alone.
Test Result
single photon emission CT + sestamibi scanning may be positive for
surgery. Cervical ultrasonography will also assess for concomitant
thyroid disease.[1] Combining tests is more effective than any one
test alone.
• Sensitivity of 88%[42] and specificity of 98.8%.[27]
CT neck may be positive for
surgery. A protocol with 2 contrast phases seems to offer a good
balance of acceptable sensitivity (sensitivity 76% [95% CI 71% to
87%]) with limitation of radiation exposure, compared with protocols
with 1 or 3 contrast phases (sensitivity of 71% [95% CI 61% to 80%]
and 80% [95% CI 74% to 86%], respectively).[56] Combining tests is
more effective than any one test alone.
4-Dimensional (4D) CT neck may be positive for
• Not for diagnosis but important for localisation of disease in planning solitary adenoma or
surgery. The 4D refers to time. This is now the initial imaging modality multi-gland involvement
of choice (over ultrasound and sestamibi scans) in some centres
in North America. It appears to have at least a similar diagnostic
performance compared to tomographic parathyroid scintigraphy but a
higher radiation dose.[37]
MRI neck may be positive for
surgery. Less commonly used except in certain circumstances (e.g., multi-gland involvement
pregnancy).[1] Combining tests is more effective than any one test
alone.
Emerging tests
Test Result
DIAGNOSIS
radiolabelled choline PET may be positive for
solitary adenoma or
• A number of studies have examined the role of radiolabelled
choline PET, which can be combined with CT (PET/CT) or magnetic
resonance imaging (PET/MRI), for the detection of hyperfunctioning
parathyroid glands in patients with primary hyperparathyroidism with
encouraging results.[43] Further prospective studies are required to
validate these findings.
15
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Familial hypocalciuric • Patients with FHH appear • Renal calcium to creatinine
hypercalaemia (FHH) healthy. There may be a clearance ratio is lower
positive family history of compared with patients with
other members with high PHPT.
serum calcium without • Diagnosis can be confirmed
objective symptoms of with genetic testing.
nephrolithiasis or bone
disease.
Humoral hypercalcaemia • Positive history of solid • Intact serum PTH is

of malignancy tumour malignancy. Other appropriately low, but PTHrP
manifestations of systemic would be elevated if the
signs of illness such as source is from a malignancy.
weight loss, fatigue, pain, • Mild hypokalaemic
and feelings of ill health. hypochloraemic alkalosis
• Humoral hypercalcaemia may be present.
of malignancy occurs in • CT scan of the thorax,
patients with solid tumours abdomen, and pelvis is used
of the lung, breast, kidney, to evaluate for malignancies.
ovary, and head and neck;
there is typically no bone
metastasis. This process
is mediated primarily by
PTH-related-protein/peptide
(PTHrP). PTHrP also plays
a role in the hypercalcaemia
associated with bone
metastases and multiple
myeloma.
DIAGNOSIS
Multiple myeloma • There may be weight loss or • Serum protein

back pain. electrophoresis shows
monoclonal gammopathy.
• Presence of Bence-Jones
protein in urine.
• Bone x-ray may show lytic
bone lesions, characteristic
of multiple myeloma.
• There may be anaemia.
Milk-alkali syndrome • A history of excessive intake • Calcium levels are high, but
of antacids. serum intact PTH is low.
Sarcoidosis • Can present with a dry • CXR shows thoracic

cough, breathlessness, or lymphadenopathy and
tender red skin lumps. parenchymal lung disease.
• Angiotensin-converting
enzyme levels may be
elevated.
• May have eosinophilia
or elevated erythrocyte
sedimentation rate (ESR).
Condition Differentiating signs / Differentiating tests

symptoms
• Calcium is high, but serum
intact PTH is low.
Hypervitaminosis D • History of excessive vitamin • 25-hydroxyvitamin D level

D intake (usually within >100 nanograms/mL
the context of over-treated indicates hypervitaminosis
vitamin D deficiency or self- D.
medication). • Calcium is high, but serum
intact PTH is low.
Thyrotoxicosis • Tachycardia, weight • TSH is low.

loss, nervousness, and • Calcium is high, but serum
anxiousness are present in intact PTH is low.
thyrotoxicosis.
Chronic or acute • Infections, fever, weight • FBC may show anaemia,

leukaemia loss, lymphadenopathy, leukocytosis, or leukopenia.
and abnormal bleeding are • Calcium is high, as well as
present in acute or chronic PTH-related-protein/peptide.
leukaemia. PTH levels are low.
Immobilisation • Patients have a history • Serum calcium levels are

of being bed-bound or often high with a low serum
hospitalised for long intact PTH level.
periods of time, but
may be without specific
hyperparathyroid symptoms
(e.g., nephrolithiasis).
Thia zide use • Patients usually have a • Serum calcium levels should
history of hypertension decrease when thiazide
and are on thiazide diuretic medicine is discontinued.
therapy. Intact serum PTH levels are
low.
DIAGNOSIS
17
Primary hyperparathyroidism Management
Approach
Parathyroid surgery is the definitive treatment for primary hyperparathyroidism (PHPT). It is indicated for
all symptomatic patients, and is recommended for many asymptomatic patients.[1] [57] If the patient is
asymptomatic and meets criteria for medical management, declines surgery, or is not a surgical candidate,
monitoring is an option.[1] [2]
Symptomatic; or asymptomatic with surgical indications

Parathyroidectomy is indicated for all patients with symptomatic hyperparathyroidism.[1] [4] [6] [58] [59]
Parathyroidectomy, is recommended in patients with asymptomatic hyperparathyroidism with evidence of
subclinical target organ complications such as bone disease (osteoporosis/fractures) or renal involvement
(reduced renal function, occult stones) and in those at risk of disease progression.[1] [4] [6]
In asymptomatic patients with PHPT, advantages of surgery are that it corrects the underlying
abnormality, and may improve bone mineral density and fracture-free survival.[2] [60] [61] Patients
who are considered to be asymptomatic sometimes report improvements in quality of life following
surgery.[34] However, the benefits of parathyroidectomy for non-skeletal/renal outcomes symptoms
remains controversial.[59] [62]
Indications for surgery in asymptomatic patients, according to some authorities, include:[6] [8]
• Age <50 years

• Inability to ensure appropriate follow-up
• Serum calcium >0.25 mmol/L (>1 mg/dL) above normal range
• Creatinine clearance <60 mL/minute
• Bone mineral density (BMD) T-score <-2.5 at lumbar spine, total hip, femoral neck, or distal third of
radius, and/or vertebral fracture by x-ray, computed tomography (CT), magnetic resonance imaging
(MRI), or vertebral fracture assessment (VFA) using dual-energy x-ray absorptiometry (DXA; T-
score compares BMD versus the optimal density of a 30- to 40-year-old healthy adult and then
assesses the fracture risk)
• 24-hour urinary calcium >400 mg/day and increased stone risk by biochemical stone risk analysis
• Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or CT.
Pre-operative preparation includes adequate hydration and pre-operative localisation tests. Dietary
restriction of calcium is not advised, and pre-operative vitamin D replacement is recommended for
patients who are vitamin D deficient. Subjective assessment of voice quality is also recommended pre-
operatively.[1]
Parathyroidectomy can often be performed on an outpatient basis with same-day discharge. It generally
has morbidity and mortality rates of ≤1%.[63] [64] Potential significant complications include bleeding,
haematoma, hoarseness from recurrent laryngeal nerve injury, voice change from superior laryngeal
nerve injury, pneumothorax, or hypocalcaemia (transient or permanent).
When imaging studies are positive for location of a solitary adenoma (occurring in approximately
MANAGEMENT
85% of patients with PHPT), the patient is a candidate for a focused or minimally-invasive, directed
parathyroidectomy.[65] In people with multiple-gland disease (sporadic or familial), complete cervical
exploration with identification of all 4 glands and subtotal resection of parathyroid tissue is the surgical
approach.[66] Rarely, the hypercalcaemia of hyperparathyroidism may be severe (>3.5 mmol/L [>14 mg/
dL]); for example, in patients with parathyroid carcinoma). These patients require pre-operative medical
management for acute severe hypercalcaemia, such as intravenous fluids and furosemide.
If patients decline surgery or are not surgical candidates, serum calcium and creatinine levels should be
measured every 12 months and bone density measured every 1 to 2 years.[2] [8] Patients with vitamin
D deficiency should be offered supplementation.[2] Patients should avoid medications that increase
serum calcium levels (e.g., thiazide diuretics, lithium).[4] If symptoms of mental status change or lethargy
occur, admission for intravenous hydration and a parathyroidectomy should ensue, if possible. A definitive
parathyroidectomy can be performed at any point if the patient agrees and is a surgical candidate.
Bisphosphonates or cinacalcet are adjunctive therapies that may be considered, in addition to monitoring,
for patients who do not undergo parathyroidectomy.[2]
• Bisphosphonates may increase BMD in the lumbar spine at 1 to 2 years and decrease bone
turnover, although fracture outcomes are not available.[67] [68] They may be considered if
osteoporosis is present.[2]
• Cinacalcet has been shown to lower serum calcium and serum intact parathyroid hormone
(PTH).[68] [69] It is a calcimimetic that modulates the activity of the calcium-sensing receptor, the
principal regulator of serum intact PTH secretion. Cinacalcet binds to the transmembrane region
of the receptor and induces a conformational change that increases the receptor's sensitivity to
calcium. The most common adverse effects, nausea and vomiting, lead to poor tolerance and must
be monitored very closely. Resulting volume depletion may worsen hypercalcaemia. Previously
approved for management of difficult-to-treat secondary hyperparathyroidism and inoperable
parathyroid carcinoma, it may now be used in selected cases of primary hyperparathyroidism; for
example, in those who are symptomatic but not surgical candidates or who decline surgery.[2]
Surgical approach
Once the diagnosis is confirmed and surgery planned, pre-operative imaging is important to provide
accurate localisation of the disease. Several modalities are available, but no one is singly preferred. Given
the significant regional variation in imaging accuracy, candidates for parathyroidectomy should be referred
to an expert clinician to decide on the best imaging modalities based on their knowledge of local imaging
availability.[1]
Many institutions use Tc-99m sestamibi scanning, often in conjunction with ultrasonography.[41] The use
of single-photon emission CT in combination with sestamibi scanning improves the utility of the imaging
studies with a sensitivity of 88% and specificity of 98.8%.[42] [27] [70] Four-dimensional CT has emerged
as a useful imaging tool and is now the initial imaging modality of choice (over ultrasound and sestamibi
scans) in some centres in North America. It appears to have at least a similar diagnostic performance
compared to tomographic parathyroid scintigraphy but a higher radiation dose.[37] MRI is also an
option, although this is less commonly used except in certain circumstances, such as pregnancy.[1]
Selective parathyroid venous sampling has been suggested as a useful tool in patients with inconclusive
preoperative non-invasive imaging, although its invasive nature precludes routine use.[71] Combining
tests is more effective than any one test alone.
MANAGEMENT
The success rate for surgeons who perform fewer than 10 parathyroidectomies per year is lower than for
surgeons with more experience; an inverse correlation exists between volume of operations and risk of
complications and length of hospital stay. Therefore, it is recommended that parathyroidectomies are only
carried out by surgeons with adequate training and experience specific to PHPT management.[1]
19
When investigations are positive for location of a solitary adenoma (occurring in approximately
85% of patients with PHPT), the patient is a candidate for a focused or minimally invasive, directed
parathyroidectomy.[1] [65] Compared with 4-gland (bilateral) exploration, a minimally-invasive approach
appears to have similar recurrence, persistence, and re-operation rates, but lower overall complication
rates and somewhat shorter operative times.[72] The lower rate of complications seen with minimally-
invasive surgery relates primarily to a reduced risk of transient postoperative hypocalcaemia and a lower
risk of recurrent laryngeal nerve injury.[73] [64] The minimally-invasive procedure may be performed
under general or local anaesthesia and various techniques, including video-assisted, endoscopic, radio-
guided, or a focused lateral approach.
Intra-operative serum intact PTH serves to inform the operating surgeon that hyperfunctioning tissue has
been removed.[74] A decline of >50% from baseline to 5 minutes and 10 minutes post-excision suggests
adequate removal of hyperfunctioning tissue.[75] Intra-operative parathyroid hormone monitoring reduces
the risk of missing multiple-gland disease during minimally-invasive parathyroidectomy. The cure rate
for minimally-invasive parathyroidectomy has been reported to be 97% to 99%, and there is probably an
added marginal increase in cure rate in experienced hands.[1]
Intra-operative adjuncts are complementary to pre-operative localisation and assist in localising

parathyroid glands, confirming parathyroid tissue and establishing remission. The most widely used
surgical adjunct is intra-operative parathyroid hormone monitoring (IPM). Other adjuncts can assist with
confirmation of resected parathyroid tissue (frozen section analysis, ex vivo parathyroid aspiration), gland
visualisation (methylene blue, near infrared fluorescence, or infrared spectroscopy), and gland localisation
(intra-operative ultrasonography, bilateral jugular venous sampling, or gamma-probe guidance).[1]
In people with multiple-gland disease (sporadic or familial), complete bilateral cervical exploration with
identification of all 4 glands and subtotal resection of parathyroid tissue is the surgical approach.[66]
It is also the recommended approach when pre-operative imaging is non-localising or discordant, or
when intra-operative parathyroid hormone monitoring is not available.[1] Indications for converting from a
minimally-invasive approach to complete cervical exploration are the intra-operative discovery of multiple-
gland disease, and failure to achieve an adequate decrease in intra-operative parathyroid hormone
levels.[1] Complete cervical exploration has long-term success rates of over 95% when carried out by a
skilled endocrine surgeon.[76] [77]
If there is suspicion of parathyroid carcinoma during surgery, complete dissection avoiding capsular
disruption is recommended and improves the chance of cure. This may involve en bloc resection of
adjacent adherent tissue.[1]
Asymptomatic without surgical indications

Indications for surgery in asymptomatic patients, according to some authorities, include:[1] [2] [6] [8]
• Age <50 years

• Inability to ensure appropriate follow-up
• Serum calcium >0.25 mmol/L (>1 mg/dL) above normal range
• Creatinine clearance reduced to <60 mL/minute
MANAGEMENT
• BMD T-score <-2.5 at lumbar spine, total hip, femoral neck, or distal third of radius, and/or vertebral
fracture by x-ray, CT, MRI, or VFA
• 24-hour urinary calcium >400 mg/day and increased stone risk by biochemical stone risk analysis
• Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or CT.
Patients without these specific indications may be monitored, but there is some epidemiological evidence
to suggest that even mild/asymptomatic primary hyperparathyroidism may be associated with multiple
negative outcomes, including overall mortality and cardiovascular disease, that in turn may be linked to
high baseline parathyroid hormone concentrations.[78] [79]
In patients being monitored, serum calcium and creatinine levels should be measured every 12 months
and bone density measured every 1 to 2 years.[2] [8] Patients with vitamin D deficiency should be
offered supplementation.[2] Patients should avoid medications that increase serum calcium levels (i.e.,
thiazide diuretics, lithium).[4] A definitive parathyroidectomy can be performed at any point if symptoms or
indications ensue, or if the patient prefers surgery and is a surgical candidate.
Vitamin D repletion in patients with concurrent vitamin D

deficiency
Vitamin D supplementation is recommended by a number of practice guidelines for patients with PHPT
and concurrent vitamin D deficiency.[1] [2] [80] Definitions for deficiency vary. The Fourth International
Workshop on Asymptomatic Primary Hyperparathyroidism recommended repletion at levels of ≤50 nmol/L
(≤20 ng/mL).[80] Low levels of vitamin D appear to be associated with a greater severity of bone disease
in PHPT, and with a greater risk of hungry bone syndrome following parathyroidectomy.[81]
Vitamin D replacement may improve bone mineral density in patients with PHPT but the evidence is not
conclusive.[82] [83] A concern is that repleting vitamin D will worsen hypercalcaemia and renal calcium
excretion in patients with PHPT.
One systematic review and meta-analysis looking at vitamin D repletion in patients with mild PHPT
found that supplementation improved serum 25-hydroxyvitamin D level without worsening of pre-existing
hypercalcaemia or hypercalciuria.[84] However, an observational study of 21 patients with mild PHPT
treated with vitamin D found that while treatment did not result in a mean increase in serum calcium
concentrations across the treatment group, 2 patients experienced an increase in urinary calcium
excretion to >400 mg/24 hours. This suggests that some patients with PHPT may experience an increase
in urinary calcium excretion after vitamin D repletion. In one patient, serum calcium increased from 2.6
mmol/L to 3.0 mmol/L (10.5 mg/dL to 11.9 mg/dL).[85]
On balance, the authors recommend replacement of vitamin D in the setting of deficiency. However,
in patients with raised urinary calcium levels, due to a risk of kidney stone formation, caution is
recommended to monitor urinary calcium excretion, particularly if parathyroidectomy is not planned during
a shorter time frame. Specific treatment regimens based on clinical trial data are not yet available.
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
MANAGEMENT
21
Ongoing ( summary )
asymptomatic with surgical
indications or symptomatic
1st parathyroidectomy
adjunct vitamin D supplementation
2nd monitoring
adjunct bisphosphonate
adjunct cinacalcet
asymptomatic with no surgical

indications
1st monitoring
2nd parathyroidectomy

MANAGEMENT
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
MANAGEMENT
23
Ongoing
asymptomatic with surgical
indications or symptomatic
1st parathyroidectomy
» There is consensus that parathyroidectomy

is indicated for symptomatic
hyperparathyroidism.[6] [58] Indications for
surgery in asymptomatic patients include: age
<50 years; inability to ensure appropriate follow-
up; serum calcium >0.25 mmol/L (>1 mg/dL)
above normal range; calculated creatinine
clearance <60 mL/minute; bone mineral density
(BMD) T-score <-2.5 at lumbar spine, total
hip, femoral neck, or distal third of radius
and/or vertebral fracture by x-ray, computed
tomography (CT), magnetic resonance imaging
(MRI), or vertebral fracture assessment (VFA)
using dual-energy x-ray absorptiometry (DXA);
24-hour urinary calcium >400 mg/day and
increased stone risk by biochemical stone
risk analysis; presence of nephrolithiasis or
nephrocalcinosis by x-ray, ultrasound or CT.[6]
[8] Pre-operative preparation includes adequate
hydration and pre-operative localisation tests.
Dietary restriction of calcium is not advised,
and pre-operative vitamin D replacement is
recommended for patients who are vitamin D
deficient. Subjective assessment of voice quality
is also recommended pre-operatively.[1]
» Parathyroidectomy can often be performed on

an outpatient basis with same-day discharge.
It generally has morbidity and mortality rates of
no more than 1%.[63] [64] Potential significant
complications include bleeding, haematoma,
hoarseness from recurrent laryngeal nerve
injury, voice change from superior laryngeal
nerve injury, pneumothorax, or hypocalcaemia
(transient or permanent).
» When imaging studies are positive for

location of a solitary adenoma (occurring in
approximately 85% of patients with PHPT), the
patient is a candidate for a minimally-invasive,
directed parathyroidectomy.[65] Compared with
complete bilateral exploration, a minimally-
invasive approach appears to have similar
recurrence, persistence, and re-operation
rates, but lower overall complication rates and
somewhat shorter operative time. The lower rate
MANAGEMENT
of complications seen with minimally-invasive

surgery primarily relates to a reduced risk of
transient postoperative hypocalcaemia and a
lower risk of recurrent laryngeal nerve injury.[73]
[64] The minimally-invasive procedure may be
performed under general or local anesthesia
Ongoing
and uses various techniques, including video-
assisted, endoscopic, radio-guided, or a focused
lateral approach. Intra-operative serum intact
PTH serves to inform the operating surgeon that
hyperfunctioning tissue has been removed.[74]
A decline of >50% from baseline to 5 minutes
and 10 minutes post excision suggests adequate
removal of hyperfunctioning tissue.[75]
» In people with multiple-gland disease (sporadic

or familial), complete cervical exploration
with identification of all 4 glands and subtotal
resection of parathyroid tissue is the surgical
approach.[66] It is also the recommended
approach when pre-operative imaging is
non-localising or discordant, or when intra-
operative parathyroid hormone monitoring is not
available.[1]
» Rarely, the hypercalcaemia of

hyperparathyroidism may be severe (>3.5 mmol/
L [>14 mg/dL]); for example, in patients with
parathyroid carcinoma. These patients require
pre-operative medical management for acute
severe hypercalcaemia, such as intravenous
fluids and furosemide.
» If there is suspicion of parathyroid carcinoma

during surgery, complete dissection avoiding
capsular disruption is recommended and
improves the chance of cure. This may involve
en bloc resection of adjacent adherent tissue.[1]
Treatment recommended for SOME patients in
selected patient group
Primary options
» ergocalciferol: consult specialist for

guidance on dose
OR
» colecalciferol: consult specialist for

guidance on dose
» Preoperative vitamin D repletion is advised

in the setting of deficiency.[1] Patients who are
vitamin D deficient should continue to receive
vitamin D supplementation after apparently
successful parathyroidectomy.[1] Specific
MANAGEMENT
treatment regimens based on clinical trial data

are not available.
2nd monitoring
25
Ongoing
» If patients decline surgery or are not surgical
candidates, serum calcium and creatinine levels
should be measured every 12 months and bone
density measured every 1 to 2 years.[8] Vitamin
D levels should also be checked.[2]
» Patients should avoid medications that

increase serum calcium levels (e.g., thiazide
diuretics, lithium).[4]
» If symptoms of mental status change or

lethargy occur, admission for intravenous
hydration and a parathyroidectomy should
ensue, if possible. A definitive parathyroidectomy
can be performed at any point if the patient
agrees and is a surgical candidate.
adjunct bisphosphonate
Primary options
» alendronic acid: 10 mg orally once daily; or

70 mg orally once weekly
OR
» risedronate sodium: 5 mg orally once daily;

or 35 mg orally once weekly
OR
» ibandronic acid: 150 mg orally once

monthly; or 3 mg intravenously once every 3
months
OR
» zoledronic acid: 5 mg intravenously once

annually
» Can be considered adjunctively if osteoporosis

is present.[67] Bisphosphonates may increase
BMD in the lumbar spine at 1 to 2 years and
decrease bone turnover, although fracture
outcomes are not available.
adjunct cinacalcet
MANAGEMENT
Primary options
» cinacalcet: 30 mg orally once daily,

increase gradually to 30 mg twice daily until
serum calcium levels have normalised
Ongoing
» Cinacalcet has been shown to lower serum
calcium and serum intact PTH.[68] [69] It is a
calcimimetic that modulates the activity of the
calcium-sensing receptor, the principal regulator
of serum intact PTH secretion. Cinacalcet binds
to the transmembrane region of the receptor and
induces a conformational change that increases
the receptor's sensitivity to calcium. The most
common adverse effects, nausea and vomiting,
lead to poor tolerance and must be monitored
very closely. Resulting volume depletion may
worsen hypercalcaemia.
» Previously approved for management of

difficult-to-treat secondary hyperparathyroidism
and inoperable parathyroid carcinoma, it may
now be used in selected cases of primary
hyperparathyroidism; for example, in those who
are symptomatic but not surgical candidates or
who decline surgery.[2]
Primary options

guidance on dose
OR

guidance on dose
» For patients who decline surgery or who are

not surgical candidates, vitamin D replacement
is recommended for those who are vitamin D
deficient.[2] Specific treatment regimens based
on clinical trial data are not available.
asymptomatic with no surgical
indications
1st monitoring
» Indications for surgery in asymptomatic

patients include: age <50 years; inability to
ensure appropriate follow-up; serum calcium
>1 mg/dL above normal range; calculated
creatinine clearance <60 mL/minute; BMD T-
score <-2.5 at lumbar spine, total hip, femoral
MANAGEMENT
neck, or distal third of radius, and/or vertebral

fracture by x-ray, CT, MRI, or vertebral fracture
assessment (VFA) using DXA; 24-hour urinary
calcium >400 mg/day and increased stone risk
by biochemical stone risk analysis; presence
of nephrolithiasis or nephrocalcinosis by x-
27
Ongoing
ray, ultrasound or CT.[6] [8] Patients without
these specific indications may be monitored,
but there is some epidemiological evidence to
suggest that even mild/asymptomatic primary
hyperparathyroidism may be associated with
multiple negative outcomes, including overall
mortality and cardiovascular disease, that in
turn may be linked to high baseline parathyroid
hormone concentrations.[78] [79]
» In patients being monitored, serum calcium

and creatinine levels should be measured every
12 months and bone density measured every
1 to 2 years.[8] Vitamin D levels should also be
checked.[2]
» Patients should avoid medications that

increase serum calcium levels (e.g., thiazide
diuretics, lithium).[4]
Primary options

guidance on dose
OR

guidance on dose
» For patients who are candidates for monitoring,

vitamin D replacement is recommended for
those who are vitamin D deficient.[2] Specific
are not available.
2nd parathyroidectomy
» A definitive parathyroidectomy can be

performed at any point if symptoms or
indications ensue, or if the patient prefers
surgery and is a surgical candidate.
Primary options
MANAGEMENT

guidance on dose
OR
Ongoing
guidance on dose
» Preoperative vitamin D repletion is advised

in the setting of deficiency.[1] Patients who are
vitamin D deficient should continue to receive
vitamin D supplementation after apparently
successful parathyroidectomy.[1] Specific
are not available.
MANAGEMENT
29
Emerging
Alcohol ablation
Alcohol ablation therapy to the in situ parathyroid glands has also been tried, with mixed results.[86] [87] [88]
In this procedure, ethanol is injected percutaneously into the adenoma under ultrasonographic guidance.
Long-term eucalcaemia has not been consistently observed. Injury to the recurrent laryngeal nerve was
noted.
Robotic surgery
Randomised controlled trials are needed to assess outcomes of robotic-assisted parathyroidectomy.[89] [90]
Ultrasound-guided high-intensity focused ultrasound

A small-scale study has shown reduction in serum calcium in a majority of patients, but not eradication of
primary hyperparathyroidism. Side effects were of concern and included transitory vocal cord impairment in
23% of patients.[91]
Machine learning to identify multigland disease

Machine learning is a growing field with many different applications. It involves applying a collection
of methods that allow a computer to learn rules from known/existing data sets to make predictions.
Some researchers are exploring its use to distinguish between multigland disease and single adenomas
preoperatively, thereby optimising operative planning.[92]
Secondary prevention
Family members should be warned of the possibility, albeit rare (<5%), of familial disease. First-degree
relatives should consider serum calcium assessments.
Patient discussions
Following parathyroidectomy, patients are warned to look for signs and symptoms of hypocalcaemia,
which include tingling and numbness of the fingers or peri-oral region. If these are present, they are
instructed to take oral calcium replacement therapy. If acute swelling or difficulty breathing occurs,
patients are instructed to go immediately to the nearest emergency department.
MANAGEMENT
Primary hyperparathyroidism Follow up
Monitoring
Monitoring
FOLLOW UP
After surgical intervention, clinicians should monitor for the development of a cervical haematoma,
observe wound healing, check voice quality, and perform laboratory evaluation as necessary.
Postoperative management involves determining surgical success and monitoring for complications.
Some guidelines recommend considering short-term prophylaxis against hypocalcaemia following

parathyroidectomy with calcium and/or vitamin D supplementation, although the evidence in favour of this
is weak.[1] Twenty-four to 36 hours after surgery, the serum calcium level should be at an all-time low. In
patients who develop hypocalcaemia, onset of symptoms most commonly occurs on postoperative day
number 2 or 3; only patients with extreme elevations of calcium pre-operatively occasionally present with
symptoms on postoperative day 1. Patients almost never develop symptoms on the day of surgery.[97]
The serum intact parathyroid hormone (PTH) level should be normal within 30 hours, but the secretory
response may not restore to normal for weeks. Standard surveillance for seizures should be maintained.
Outpatient management is appropriate for selected patients. An overnight stay is more likely to be
required for patients undergoing re-operation, extensive surgery or subtotal parathyroidectomy, and for
those with severe vitamin D deficiency.[1]
After parathyroidectomy, monitoring of serum calcium levels for 6 months is advisable, and can be done
on an outpatient basis.[1] This is necessary, especially if a particularly large adenoma was removed. If
calcium and serum PTH levels are elevated postoperatively, another adenoma or incomplete resection is
a possible cause. Also, malignancy or misdiagnosis is possible. Cure of primary hyperparathyroidism is
defined as the re-establishment of normal calcium homeostasis. In a subset of patients, serum PTH will
remain elevated despite normalisation of serum calcium; causes of secondary hyperparathyroidism need
to be carefully investigated and managed appropriately.[104]
Annual serum calcium checks are recommended on a long-term basis. Around 8% of patients with a
sporadic parathyroid adenoma will go on to develop recurrent primary parathyroidism.[2] Recurrent
primary hyperparathyroidism is defined as a recurrence of hypercalcaemia after a normocalcaemic
interval of greater than 6 months post-parathyroidectomy.[1] It is more common in patients with double
thyroid adenomas compared with those with a single adenoma or hyperplasia.[58] Management
for recurrent primary hyperparathyroidism should take place within a specialist centre and involves
localisation studies (to identify ectopic glands) followed by re-operation, if necessary.[105] [2]
In patients being monitored without parathyroid surgery, serum calcium and creatinine levels should be
measured every 12 months and bone density measured every 1 to 2 years.[8] Patients should avoid
medications that increase serum calcium levels (e.g., thiazide diuretics, lithium).[4] Vitamin D levels
should be sufficient.[2] A definitive parathyroidectomy can be performed at any point if symptoms or
indications ensue, or if the patient prefers surgery and is a surgical candidate.
31
Complications
Complications Timeframe Likelihood

FOLLOW UP
neck haematoma following surgery short term low
Haematomas can occur as a result of technical problems related to inadvertent dislodging of clips
or sutures or rupture of previously ligated vessels. Postoperatively, patients should be observed in a
monitored setting to assess for the development of neck haematoma.[1] The corrective action is prompt
emergency haematoma evacuation and ligature placement. This problem typically resolves immediately on
correction.[95]
recurrent and superior laryngeal nerve injury following short term low
surgery
Injury to the superior or recurrent laryngeal nerve may occur during surgical intervention. Damage to the
superior laryngeal nerve may result in alteration in voice pitch. Injury to the recurrent laryngeal nerve
results in hoarseness. Recurrent and superior laryngeal nerve injury may be temporary or infrequently
permanent. If resolution does not occur within 6 months, vocal cord medialisation can be an effective
treatment. This procedure involves an external approach through the thyroid cartilage and placement of
alloplastic material to move the affected vocal fold to the midline.[96] Voice therapy may also be helpful.
hypocalcaemia following surgery short term low
Hypocalcaemia may occur due to the phenomenon of hungry bone syndrome due to previously calcium-
depleted bones benefiting from the reversal of the osteoclast activity and activation of osteoblasts. It
may also be caused by devascularisation or injury to other suppressed parathyroid glands during the
surgical procedure. Alternatively, hypocalcaemia may occur due to venous congestion of the parathyroid
glands as a result of pressure in the wound from a haematoma. It is more common in vitamin-D deficient
patients and in those who have received complete bilateral cervical exploration.[1] In patients who
develop hypocalcaemia, onset of symptoms most commonly occurs on postoperative day number 2 or
3; only patients with extreme elevations of calcium pre-operatively occasionally present with symptoms
on postoperative day 1. Patients almost never develop symptoms the day of surgery.[97] This problem
typically resolves within hours if calcium supplements are given orally or within 1 hour if calcium
supplements are given intravenously. In the event of temporary hypocalcaemia, the corrective action will
be oral calcium supplementation. Vitamin D should be given if the patient is deficient.[1] Some guidelines
recommend considering short-term prophylaxis against hypocalcaemia following parathyroidectomy with
calcium and/or vitamin D supplementation, although the evidence in favour of this is weak.[1]
pneumothorax following surgery short term low
This may occur if there is stretch or tear of the apical pleura during the dissection.[103] Occurrence
seems to be related to inferiorly placed glands or in cervical beds that have scarring from prior radiation
or surgical intervention. Observation with serial chest x-rays is common. If it is severe or symptomatic,
angiocatheter or chest tube placement resolves the extrapleural air leak.
osteoporosis long term medium
If persistent, non-curable, unresectable disease exists, protection of bone health with alendronic acid,
oestrogen, or raloxifene should be considered, after consultation with an endocrinologist with special
interest in bone health, although fracture data are unavailable.[67] [98] [99] [100] Surgical treatment and
anti-resorptive therapies increase bone mineral density (BMD) in mild PHPT similarly; the rate of bone loss
is slow in untreated mild PHPT.[101]
bone fractures long term medium
Complications Timeframe Likelihood

Secondary to the calcium leaching from bones due to persistently high PTH, osteopenia and osteoporosis
FOLLOW UP
may result in bony fracture, especially of long bones. Treatment involves consultation with an orthopaedic
surgeon and appropriate casting and splinting.
nephrolithiasis variable low
Due to increased serum and urinary calcium levels, calcium may precipitate and form oxalate crystals
and subsequent stones. Options involve treating the hypercalcaemia following treatment options for
hyperparathyroidism, and additionally considering lithotripsy or surgical options.[102] A urologist should be
consulted.
Prognosis
Medical observation
For asymptomatic patients who do not meet the criteria for surgical intervention, 75% have stable disease for
up to 10 years. Twenty-five percent of patients progress to meeting criteria for parathyroidectomy. However,
younger patients (patients <50 years of age) tend to progress to meeting criteria for parathyroidectomy in up
to 70%.[93] The most common cause of mortality of patients with PHPT is cardiovascular in origin (stroke,
myocardial infarction). Hypercalcaemic dysrhythmias are rare.
Parathyroidectomy
Parathyroidectomy has a cure rate of over 95% and may be as high as 97% for experienced endocrine
surgeons.[63] [94] In one large cohort study bone mineral density improved in 58% of those who had post-
operative measurements, and overall more than 85% of patients were satisfied with the results of their
procedure.[94]
33
Primary hyperparathyroidism Guidelines
Diagnostic guidelines
United Kingdom
Hyperparathyroidism (primary): diagnosis, assessment and initial

management (ht tps://www.nice.org.uk/guidance/ng132)
Published by: National Institute for Health and Care Excellence Last published: 2019
British Nuclear Medicine Society Clinical Guideline for Parathyroid

Scintigraphy (ht tps://cdn.ymaws.com/www.bnms.org.uk/resource/resmgr/
guidelines/parathyroid_scintigraphy_fin.pdf)
Published by: British Nuclear Medicine Society Last published: 2019
Europe
GUIDELINES
The EANM practice guidelines for parathyroid imaging (ht tps://

www.eanm.org/publications/guidelines/)
Published by: European Association of Nuclear Medicine Last published: 2021
Italian Society of Endocrinology consensus statement: definition, evaluation

and management of patients with mild primary hyperparathyroidism (ht tps://
link.springer.com/article/10.1007/s40618-015-0261-3)
Published by: Italian Society of Endocrinology Last published: 2015
International
Primary hyperparathyroidism: review and recommendations on evaluation,

diagnosis, and management. A Canadian and international consensus
(ht tps://link.springer.com/article/10.1007%2Fs00198-016-3716-2)
Published by: Osteoporosis International Last published: 2017
Guidelines for the management of asymptomatic primary

hyperparathyroidism: summary statement from the Fourth International
Workshop (ht tp://www.ncbi.nlm.nih.gov/pubmed/25162665)
Published by: Fourth International Workshop on the Management of Last published: 2014
Asymptomatic Primary Hyperparathyroidism
Diagnosis of asymptomatic primary hyperparathyroidism: proceedings

of the Fourth International Workshop (ht tp://www.ncbi.nlm.nih.gov/
pubmed/25162666)
North America
ACR–SPR Practice Parameter for the Performance of Parathyroid Scintigraphy

(ht tps://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-
Standards/Practice-Parameters-by-Modality)
Published by: American College of Radiology (ACR); Society for Last published: 2019
Pediatric Radiology (SPR)
The American Association of Endocrine Surgeons guidelines for

definitive management of primary hyperparathyroidism (ht tps://
www.endocrinesurgery.org/practice-guidelines---tools)
Published by: American Association of Endocrine Surgeons Last published: 2016
Treatment guidelines
GUIDELINES
United Kingdom
Hyperparathyroidism (primary): diagnosis, assessment and initial

management (ht tps://www.nice.org.uk/guidance/ng132)
Published by: National Institute for Health and Care Excellence Last published: 2019
Europe
Italian Society of Endocrinology consensus statement: definition, evaluation

and management of patients with mild primary hyperparathyroidism (ht tp://
www.ncbi.nlm.nih.gov/pubmed/25820553)
Published by: Italian Society of Endocrinology Last published: 2015
International
Guidelines for the management of asymptomatic primary

hyperparathyroidism: summary statement from the Fourth International
Workshop (ht tp://www.ncbi.nlm.nih.gov/pubmed/25162665)
The surgical management of asymptomatic primary hyperparathyroidism:

proceedings of the Fourth International Workshop (ht tp://
www.ncbi.nlm.nih.gov/pubmed/25162669)
35
North America
Primary hyperparathyroidism: review and recommendations on evaluation,

diagnosis, and management. A Canadian and international consensus
(ht tps://link.springer.com/article/10.1007%2Fs00198-016-3716-2)
Published by: Osteoporosis International Last published: 2017
The American Association of Endocrine Surgeons guidelines for

definitive management of primary hyperparathyroidism (ht tps://
www.endocrinesurgery.org/practice-guidelines-tools)
Published by: American Association of Endocrine Surgeons Last published: 2016
GUIDELINES
Primary hyperparathyroidism References
Key articles
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49
Contributors:
// Authors:
John Ayuk, MD
Consultant Endocrinologist
University Hospitals Birmingham, Birmingham, UK
DISCLOSURES: JA declares that he has no competing interests.
Neil Git toes, MD, PhD

Consultant Endocrinologist and Honorary Professor of Endocrinology
Associate Medical Director, University Hospitals Birmingham, Birmingham, UK
DISCLOSURES: NG has contributed to advisory boards for Takedo and Shire pharmaceuticals.
// Acknowledgements:
Dr John Ayuk and Professor Neil Gittoes would like to gratefully acknowledge Dr Fausto Palazzo, Dr
Swaroop Gantela, and Dr Nancy D. Perrier, the previous contributors to this topic. FP, SG, and NDP declare
that they have no competing interests.
// Peer Reviewers:
Bridget Sinnot t, MD
Clinical Assistant
Professor of Medicine, University of Illinois at Chicago, Chicago, IL
DISCLOSURES: BS declares that she has no competing interests.
Udaya Kabadi, MD
Professor of Medicine
Department of Internal Medicine, University of Iowa, Iowa City, IA
DISCLOSURES: UK declares that she has no competing interests.
Leonard Egede, MD
Professor of Medicine
Medical University of South Carolina, Charleston, SC
DISCLOSURES: LE declares that he has no competing interests.
Petros Perros, BSc, MBBS, MD, FRCP

Department of Endocrinology
Elliott Building, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
DISCLOSURES: PP declares that he has no competing interests.

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Primary

Straight to the point of care

Last updated: Sep 21, 2021

At a routine examination, a 55-year-old woman is discovered to have hypercalcaemia. Follow-up

History and physical examination

The following non-specific features are most common:

In patients with presumed hyperparathyroidism, urinary calcium measurements should be performed

Pre-operative ultrasound-directed fine-needle aspiration biopsy of parathyroid lesions is not routinely

History and exam

history of osteoporosis or osteopenia (common)

family history of hyperparathyroidism or features suggestive of

Other diagnostic factors

memory loss (common)

overt neuromuscular dysfunction (uncommon)

cardiovascular and metabolic dysfunction (uncommon)

features suggestive of hypercalcaemia (uncommon)

hard and dense neck mass (uncommon)

age ≥50-60 years

family history of PHPT

multiple endocrine neoplasia (MEN) 1, 2A, or 4

current or historical lithium treatment

hyperparathyroidism-jaw tumour syndrome

Other tests to consider

are given: young normal and age-matched. Young normal (T-score)

Condition Differentiating signs / Differentiating tests

Humoral hypercalcaemia • Positive history of solid • Intact serum PTH is

Multiple myeloma • There may be weight loss or • Serum protein

Sarcoidosis • Can present with a dry • CXR shows thoracic

Condition Differentiating signs / Differentiating tests

Hypervitaminosis D • History of excessive vitamin • 25-hydroxyvitamin D level

Thyrotoxicosis • Tachycardia, weight • TSH is low.

Chronic or acute • Infections, fever, weight • FBC may show anaemia,

Immobilisation • Patients have a history • Serum calcium levels are

Symptomatic; or asymptomatic with surgical indications

• Age <50 years

Intra-operative adjuncts are complementary to pre-operative localisation and assist in localising

Asymptomatic without surgical indications

• Age <50 years

Vitamin D repletion in patients with concurrent vitamin D

Treatment algorithm overview

adjunct vitamin D supplementation

adjunct vitamin D supplementation

asymptomatic with no surgical

adjunct vitamin D supplementation

adjunct vitamin D supplementation

» There is consensus that parathyroidectomy

» Parathyroidectomy can often be performed on

» When imaging studies are positive for

of complications seen with minimally-invasive

» In people with multiple-gland disease (sporadic

» Rarely, the hypercalcaemia of

» If there is suspicion of parathyroid carcinoma

» ergocalciferol: consult specialist for

» colecalciferol: consult specialist for

» Preoperative vitamin D repletion is advised

treatment regimens based on clinical trial data

» Patients should avoid medications that

» If symptoms of mental status change or

» alendronic acid: 10 mg orally once daily; or