Parathyroid hormone (PTH) plays a key role in the regulation of calcium and phosphate homeostasis and vitamin D metabolism

1. DISORDERS OF PARATHYROID GLAND
ASSISTANT PROFESSOR DR BILAL NATIQ NUAMAN
CONSULTANT ENDOCRINOLOGIST
BOARD SUBSPECIALITY IN ENDOCRINOLOGY AND
DIABETES
Al-Iraqia Medical College
2024

2.  Parathyroid hormone (PTH) plays a key role in
the regulation of calcium and phosphate
homeostasis and vitamin D metabolism

4. PRIMARY HYPERPARATHYROIDISM
Primary hyperparathyroidism is caused by
autonomous secretion of PTH, usually by a single
parathyroid adenoma, which can vary in diameter
from a few millimeters to several centimeters. It
should be distinguished from secondary
hyperparathyroidism, in which there is a
physiological increase in PTH secretion to
compensate for prolonged hypocalcaemia (such
as in vitamin D deficiency); and from tertiary
hyperparathyroidism, in which continuous
stimulation of the parathyroids over a prolonged
period of time results in adenoma formation and
autonomous PTH secretion

6. The prevalence of primary
hyperparathyroidism is about 1 in 500 and
it is 2–3 times more common in women
than men; 90% of patients are over 50
years of age. It also occurs in the familial
MEN syndromes, in which case
hyperplasia or multiple adenomas of all
four parathyroid glands are more likely
than a solitary adenoma.

7. CLINICAL AND RADIOLOGICAL FEATURES
Parathyroid bone disease is now extremely
rare due to earlier diagnosis and treatment
and plain X-ray assessment is not routinely
recommended. Osteitis fibrosa results from
increased bone resorption by osteoclasts
with fibrous replacement in the lacunae. This
may present as bone pain and tenderness,
fracture and deformity. Chondrocalcinosis
can occur due to deposition of calcium
pyrophosphate crystals within articular
cartilage.

9.  It typically affects the menisci at the
knees and can result in secondary
degenerative arthritis or predispose to
attacks of acute pseudogout. Skeletal X-
rays are usually normal in mild primary
hyperparathyroidism but DXA should be
obtained as a matter of routine in people
with primary hyperparathyroidism to
exclude osteoporosis (a potential
indication for surgical intervention). Renal
imaging (typically ultrasound) is
recommended to screen for asymptomatic
nephrocalcinosis or nephrolithiasis.

10. INVESTIGATIONS
The diagnosis can be confirmed by finding a
raised (or inappropriately normal) PTH level in
the presence of Hypercalcaemia, provided that
FHH is excluded. Parathyroid scanning by
ultrasound examination is often sufficient to
localize an adenoma prior to surgery, although it
is highly dependent on an experienced operator.
Where ultrasound is equivocal, or does not
identify an adenoma, a range of additional
imaging modalities are available. These include
99mTc-sestamibi scintigraphy (MIBI, 99mTc-
SPECT/CT and, most recently, 18F-fluorocholine
PET/ CT. Negative imaging does not exclude the
diagnosis, however, and four- gland exploration
may be needed.

13. MANAGEMENT
 The treatment of choice for primary
hyperparathyroidism is surgery, with
excision of a solitary parathyroid
adenoma or hyperplastic glands.
Experienced surgeons will identify
solitary tumours in more than 90% of
cases. Patients with parathyroid bone
disease run a significant risk of
developing hypocalcaemia post-
operatively but the risk of this can be
reduced by correcting vitamin D
deficiency pre-operatively.

14. Surgery is usually indicated for individuals
with clear-cut symptoms or documented
complications (such as renal stones, renal
impairment or osteoporosis), and (in
asymptomatic patients) significant
Hypercalcaemia (corrected serum calcium
>2.85 mmol/L (>11.4 mg/dL)).
Patients who are treated conservatively
without surgery should have calcium
biochemistry and renal function checked
annually and bone density monitored
periodically. They should be encouraged
to maintain a high oral fluid intake to
avoid renal stones.

15. Occasionally, primary hyperparathyroidism
presents with severe life-threatening
hypercalcemia. This is often due to
dehydration and should be managed
medically with intravenous fluids and
bisphosphonates,. If this is not effective,
then urgent parathyroidectomy should be
considered.
Cinacalcet is a calcimimetic that enhances the
sensitivity of the calcium-sensing receptor,
so reducing PTH levels, and is licensed for
tertiary hyperparathyroidism and as a
treatment for patients with primary
hyperparathyroidism who are unwilling to
have surgery or are medically unfit.

16. FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA
FHH
 This autosomal dominant disorder is caused
by an inactivating mutation in one of the
alleles of the calcium-sensing receptor gene,
which reduces the ability of the parathyroid
gland to ‘sense’ ionised calcium
concentrations. As a result, higher than
normal calcium levels are required to
suppress PTH secretion. The typical
presentation is with mild hypercalcaemia
with PTH concentrations that are
‘inappropriately’ at the upper end of the
reference range or are slightly elevated.

17. . Calcium-sensing receptors in the renal tubules
are also affected and this leads to increased
renal tubular reabsorption of calcium and
hypocalciuria (as measured in the vitamin D-
replete individual by a fractional calcium
excretion or 24-hour calcium excretion). The
hypercalcaemia of FHH is always asymptomatic
and complications do not occur. The main risk
of FHH is that of the patient being subjected to
an unnecessary
(and ineffective) parathyroidectomy if
misdiagnosed as having primary
hyperparathyroidism. Testing of family
members for hypercalcaemia is helpful in
confirming the diagnosis and it is also possible
to perform genetic testing. No treatment is
necessary.

18. HYPOPARATHYROIDISM
The most common cause of
hypoparathyroidism is damage to the
parathyroid glands (or their blood
supply) during thyroid surgery.
Rarely, hypoparathyroidism can occur as
a result of infiltration of the glands with
iron in hemochromatosis or copper in
Wilson’s disease.

19.  There are a number of rare congenital or
inherited forms of hypoparathyroidism.
One form is associated with
autoimmune polyendocrine syndrome
type 1 and another with DiGeorge
syndrome. Autosomal dominant
hypoparathyroidism is the mirror image
of FHH , in that an activating mutation in
the calcium-sensing receptor reduces
PTH levels, resulting in hypocalcaemia
and hypercalciuria.

20. PSEUDOHYPOPARATHYROIDISM
In this disorder, the individual is functionally
hypoparathyroid but, instead of PTH deficiency,
there is tissue resistance to the effects of PTH,
such that PTH concentrations are markedly
elevated. The PTH receptor itself is normal but
the downstream signalling pathways are
defective.
There are several subtypes but the most common
(pseudohypoparathyroidism type 1a) is
characterised by hypocalcaemia and
hyperphosphatemia, in association with short
stature, short fourth metacarpals and
metatarsals, rounded face, obesity and
subcutaneous calcification; these features are
collectively referred to as Albright’s hereditary

21. The term pseudopseudohypoparathyroidism
is used to describe patients who have
clinical features of AHO but normal serum
calcium and PTH concentrations; paternal
inheritance is associated with skeletal and
other abnormalities in the absence of
hypocalcaemia and raised PTH values.

23. MANAGEMENT OF HYPOPARATHYROIDISM
Persistent hypoparathyroidism and pseudohypoparathyroidism
are treated with oral calcium salts and vitamin D analogues,
either 1α-hydroxycholecalciferol (alphacalcidol) or 1,25-
dihydroxycholecalciferol
(calcitriol). This therapy needs careful monitoring because of
the risks
of iatrogenic hypercalcaemia, hypercalciuria and
nephrocalcinosis.
Recombinant PTH is available as a subcutaneous injection and
has been
used in hypoparathyroidism (but not in
pseudohypoparathyroidism). It
is much more expensive than calcium and vitamin D analogues
and
remains a second-line therapy but has the advantage that it is
less likely
to cause hypercalciuria. There is no specific treatment for AHO

24. HYPERCALCAEMIA
 Hypercalcaemia is one of the most
common biochemical abnormalities and
is often detected during routine
biochemical analysis in asymptomatic
patients. However, it can present with
chronic symptoms, as described below,
and occasionally as an acute emergency
with severe hypercalcaemia and
dehydration.

26. Clinical assessment
Symptoms and signs of hypercalcaemia include polyuria and
polydipsia,
renal colic, lethargy, anorexia, nausea, dyspepsia and peptic
ulceration,
constipation, depression, drowsiness and impaired cognition.
Patients
with malignant hypercalcaemia can have a rapid onset of
symptoms and
may have clinical features that help to localize the tumour.
The classic symptoms of primary hyperparathyroidism are
described
by the adage ‘bones, stones and abdominal groans’, but few
patients
present in this way nowadays and the disorder is most often
picked up
as an incidental finding on biochemical testing. About 50% of
patients
with primary hyperparathyroidism are asymptomatic while others
have
non-specific symptoms such as polyuria, thirst, fatigue,
depression and

27. Investigations
The most discriminatory investigation is measurement of PTH.
If PTH
levels are detectable or elevated in the presence of
hypercalcaemia, then primary hyperparathyroidism is the
most likely diagnosis. High plasma phosphate and alkaline
phosphatase accompanied by renal impairment suggest
tertiary hyperparathyroidism. Hypercalcaemia may cause
nephrocalcinosis and renal tubular impairment, resulting in
hyperuricemia and hyperchloremia.
Patients with FHH can present with a similar biochemical
picture to primary hyperparathyroidism but typically have
low urinary calcium excretion (a ratio of urinary calcium
clearance to creatinine clearance of <0.01).
The diagnosis of FHH can be confirmed by screening family
members
for hypercalcaemia and/or identifying an inactivating mutation
in the gene encoding the calcium-sensing receptor. It is
important, when considering the differential diagnosis of

28.  If PTH is low and no other cause is
apparent, then malignancy with or
without bony metastases is likely. PTH-
related peptide, which is often
responsible for the hypercalcaemia
associated with malignancy, is not
detected by PTH assays, but can be
measured by a specific assay (although
this is not usually necessary). Unless the
source is obvious, the patient should be
screened for malignancy with a chest X-
ray, myeloma screen and CT as
appropriate.

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