Hyperparathyroidism

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Hyperparathyroidism\: excess secretion of PTH from the parathyroid glands; primary hyperparathyroidism is the most
common cause of hypercalcaemia.
Primary hyperparathyroidism\: caused by adenoma (85%), hyperplasia (14%), or carcinoma (\<1%); leads to hypercalcaemia
due to over-secretion of PTH.
Secondary hyperparathyroidism\: results from disorders a
secretion in response to low serum calcium.
Tertiary hyperparathyroidism\: chronic secondary hyperparathyroidism leading to autonomous PTH secretion; can cause
hypercalcaemia if the underlying condition is treated.
Symptoms\: often asymptomatic; if present, symptoms include fatigue, polyuria, polydipsia, constipation, abdominal pain,
vomiting, confusion, depression, bone pain, and renal stones.
Investigations\: corrected calcium, serum PTH (high in primary, low in malignancy), vitamin D, U&Es; imaging includes DEXA
scan, renal tract ultrasound, neck ultrasound, and nuclear imaging.
Di
diseases, other endocrine disorders, rhabdomyolysis.
Management\: acute severe hypercalcaemia requires IV
may only need monitoring; cinacalcet and bisphosphonates for medical management; surgery for symptomatic or severe
cases.
Surgical management\: parathyroidectomy indicated for symptoms, end-organ disease, or corrected calcium ≥2.85
mmol/L; complications include hypocalcaemia, nerve damage, bleeding, infection.
Complications\: osteoporosis, renal impairment and stones, pseudogout, pancreatitis, cardiovascular disease.
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Introduction

Hyperparathyroidism occurs when there is an excess of parathyroid hormone (PTH) being secreted from the parathyroid
glands in the neck.
It is a prevalent condition seen in both primary and secondary care as primary hyperparathyroidism is the most common
cause of hypercalcaemia, followed by malignancy.
1

Aetiology

Normal physiology
The parathyroid glands sit in the neck, on the posterior surface of the lateral lobes of the thyroid. Most adults have four,
which are commonly described in two pairs (the superior and inferior parathyroid glands), although their positions in the
neck can be highly variable.
2Figure 1. A diagram of the thyroid and
parathyroid glands.
3
Normally, the role of the parathyroid glands is to regulate serum calcium and phosphate levels via the secretion of PTH.
The chief cells of the parathyroid glands are responsible for the synthesis and secretion of PTH, as well as the sensing of
changes in serum calcium levels via the calcium-sensing receptor.
In response to hypocalcaemia, secretion of PTH is increased. PTH then raises serum calcium levels by acting on various
organs throughout the body\:
Bone\: promotes bone resorption and thus release of calcium into the blood
Kidneys\: stimulates calcium reabsorption in the distal convoluted tubule. It also inhibits phosphate reabsorption,
decreasing serum phosphate
Small intestine\: indirectly increases absorption of calcium by stimulating 1α-hydroxylase, the enzyme that activates
vitamin D in the kidneys
The subsequent rise in serum calcium then reduces PTH secretion, an example of a negative feedback loop.
4
Figure 2. A chart showing the e
serum calcium on PTH secretion and the
subsequent e
organs.
4
Classi
In hyperparathyroidism, the above homeostatic mechanism becomes decompensated, and the secretion of PTH is
inappropriately high.
There are several causes for this, leading to three di
Primary hyperparathyroidism
Primary hyperparathyroidism is the most common of the three types and is driven by a pathology of the glands. Here, one
or more of the parathyroid glands is over-secreting PTH despite normal serum calcium, which over time leads to
hypercalcaemia.
The aetiology can be adenoma (85%), hyperplasia (14%, may be associated with other conditions such as multiple
endocrine neoplasias), or carcinoma (\<1%).
Secondary hyperparathyroidism
Secondary hyperparathyroidism is due to a disorder in calcium-phosphate-bone metabolism.
In response to low serum calcium levels as a result of another condition, commonly chronic kidney disease or vitamin D
de
underlying condition.
Tertiary hyperparathyroidism
Tertiary hyperparathyroidism may occur following a prolonged period of secondary hyperparathyroidism. In response to
chronic PTH secretion, the glands may become hyperplastic and begin to secrete PTH autonomously. This can lead to
hypercalcaemia as in primary hyperparathyroidism, especially if the underlying condition impairing calcium metabolism is
treated.
1,5Table 1. A summary of the di
Type History Blood test results
Primary
hyperparathyroidism
Secondary
hyperparathyroidism
Tertiary
hyperparathyroidism
Often asymptomatic, may
have a family history if
associated with a genetic
condition like MEN
Conditions a
calcium metabolism such
as vitamin D de
CKD or nutritional calcium
de
As for secondary, often
with evidence of recent
treatment of the condition
such as vitamin D
replacement in de
↑PTH
↑Ca
2+
↑PTH
↓Ca
2+
↑PTH
↑Ca
2+

Risk factors

Most primary hyperparathyroidism is sporadic. Risk factors include being a post-menopausal woman, having previous
radiation exposure to the neck, and taking lithium. The condition may also be associated with inherited disorders such as
MEN.
6
Secondary and tertiary hyperparathyroidism are associated with conditions achronic
kidney disease).

Clinical presentation

History
Primary hyperparathyroidism is commonly asymptomatic and picked up incidentally on blood tests.
7
However, as the serum calcium increases, so does the probability of having symptoms. When present, the symptoms are
often non-speci
Typical symptoms of hypercalcaemia include\:
8
Fatigue
Polyuria and polydipsia
Constipation
Abdominal pain
Vomiting
Confusion
Depression
Bone pain
Renal stones
Mnemonic
The features of hypercalcaemia may be remembered by the mnemonic “stones (renal stones), bones (bone pain),
moans (abdominal pain and constipation) and groans (psychiatric - lethargy, depression)”
9.It is important to remember, however, that in most cases the symptoms of hypercalcaemia are mild and non-speci
Renal stones and bone pain suggest chronic hypercalcaemia.
Clinical examination
On examination, it is uncommon to
or bony tenderness.

Di

The di
The most important di
serum PTH is a useful test for this, if it is high or inappropriately normal (remember PTH should be suppressed when
serum calcium is high) then the diagnosis is likely to be primary hyperparathyroidism, if it is low then malignancy is more
likely.
Using the serum PTH is also useful in classifying the other causes of hypercalcaemia into PTH-dependent and PTH-
independent.
Table 2. The di
included as it does not result in hypercalcaemia).
10
PTH-dependent (↑ or high-normal
PTH-independent (↓ or low-normal
PTH)
PTH)
Primary hyperparathyroidism
Malignancy (most commonly breast,
lung or myeloma)
Tertiary hyperparathyroidism
Medications (including thiazide-type
diuretics and vitamin D)
Familial hypocalciuric hypercalcaemia
(an uncommon genetic condition
causing benign hypercalcaemia)
Granulomatous diseases – including
sarcoidosis, tuberculosis, GPA
Other endocrine disorders including
hyperthyroidism and acromegaly
Rhabdomyolysis

Investigations

Laboratory investigations
Relevant laboratory investigations include\:
Corrected calcium\: should be measured in patients with suspected primary hyperparathyroidism (such as those with
symptoms of hypercalcaemia, osteoporosis or fragility fracture, or a renal stone)
Serum PTH\: measure serum PTH with a paired corrected calcium. This is helpful in suggesting a cause for
hypercalcaemia. Primary hyperparathyroidism will show raised or inappropriately normal PTH. A low PTH suggests a
PTH-independent cause of hypercalcaemia such as malignancy.
Vitamin D\: if low, o
Urea & electrolytes\: advanced chronic kidney disease is a common cause of secondary hyperparathyroidism
Corrected calcium
Corrected calcium is also referred to as albumin-adjusted serum calcium.This is used because only 50% of serum calcium is in the free ionised form, which is biologically active. 40% is bound
to proteins such as albumin while 10% is bound to anions. 4
Thus, serum calcium without correction can be spuriously
abnormal in those with albumin abnormalities.
NICE recommend that direct ionised calcium testing should not be used to diagnose hyperparathyroidism.
11
Other relevant specialist laboratory investigations may include a 24-hour urinary calcium excretion test or calcium\:
creatinine clearance ratio to exclude familial hypocalciuric hypercalcaemia (FHH).
1,11
Imaging
Relevant imaging investigations include\:
11
DEXA scan\: to assess for reduced bone mineral density (osteoporosis)
Ultrasound of renal tract\: looking for renal stones
Ultrasound of the neck\: pre-operative planning and to identify adenomas (
Nuclear imaging (e.g. sestamibi scan)\: for pre-operative planning and to identify adenomas (second line)

Management

Acute, severe hypercalcaemia of any cause requires urgent management in secondary care including the administration
of intravenous
8
Mild primary hyperparathyroidism may not require any management other than monitoring symptoms and complications.
This includes annual tests for corrected calcium and creatinine or eGFR, as well as assessing cardiovascular and fracture
risk.
Medical management
Medical management includes\:
1,11
Bisphosphonates\: do not a
Cinacalcet (a calcium-sensing receptor agonist)\: reduces PTH secretion and therefore serum calcium. It is used in
patients with primary hyperparathyroidism in whom surgery would not be appropriate, has been declined or has been
unsuccessful
Secondary hyperparathyroidism should be managed by treating the underlying cause. Cinacalcet may be used for
patients in whom this fails or who are on dialysis. Phosphate binders and calcium/vitamin D supplements may also be
used, for example in chronic kidney disease.
Tertiary hyperparathyroidism may also be treated with surgical intervention (partial parathyroidectomy). Sometimes
residual parathyroid tissue is reimplanted elsewhere in the body (e.g the forearm), where it is more accessible if future
problems arise.
Surgical management
Curative therapy requires surgery (e.g. parathyroidectomy) and a referral can be considered for patients with con
primary hyperparathyroidism. NICE guidelines recommend referring for surgical management if\:
11
Symptoms of hypercalcaemia such as thirst, polyuria, or constipation
End-organ disease (renal stones, fragility fractures or osteoporosis)
Corrected calcium level of 2.85 mmol/litre or greater
Complications of surgery include hypocalcaemia, hoarseness and cough due to damage to the recurrent laryngeal nerve,
bleeding, infection, or failure of surgery.
5

Complications

Complications of primary hyperparathyroidism include osteoporosis, renal impairment and calculi, pseudogout,
pancreatitis and cardiovascular disease.
1References
Wass J, Owen K. Calcium and bone metabolism. In\: O x f o r d H a n d b o o k o f E n d o c r i n o l o g y a n d D i a b e t e s . Oxford University
Press 2014.
Drake R, Vogl W, Mitchell A. Neck. In\: G r a y’ s A n a t o m y f o r S t u d e n t s . Churchill Livingstone/Elsevier 2014.
Wikimedia Commons, Thyroid and Parathyroid Glands, License\: [Public domain]
Costanzo L. Endocrine physiology. In\: P h y s i o l o g y . Elsevier 2017.
Patient.info. Hyperparathyroidismt. Available from\: [LINK]
Mayo Clinic. Hyperparathyroidism - Symptoms and causes. Available from\: [LINK]
Khan AA, Hanley DA, Rizzoli R, e t a l . Primary hyperparathyroidism\: review and recommendations on evaluation, diagnosis,
and management. A Canadian and international consensus. O s t e o p o r o s I n t 2017;28. doi\:10.1007/S00198-016-3716-2
NICE Clinical Knowledge Summary. Hypercalcaemia. Available from\: [LINK]
Saint S, Chopra V. Hypercalcemia. In\: T h e S a i n t-C h o p r a G u i d e t o I n p a t i e n t M e d i c i n e . Oxford University Press 2018.
Mansoor AM. Hypercalcemia. In\: F r a m e w o r k s f o r I n t e r n a l M e d i c i n e . Wolters Kluwer 2018.
NICE. Hyperparathyroidism (primary)\: diagnosis, assessment and initial management. Available from\: [LINK]

Reviewer

Dr Michelle Emery
Consultant in Endocrinology and Diabetes

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Contents

Introduction
Aetiology
Risk factors
Clinical presentation
Di
InvestigationsSource\: geekymedics.com