Dr.

Sirwan Mohammed Ismail – Sess 4– Lec 1

Parathyroid gland diseases
Classification of diseases of PTG

Hypercalcaemia
 Hypercalcaemia is one of the most common biochemical abnormalities .
 Often detected during routine biochemical analysis in asymptomatic pts.
 However, it can present with chronic symptoms & occasionally as an acute medical
emergency with severe hypercalcaemia & dehydration.

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Classification of Causes of Hypercalcemia
1. Parathyroid-related
Primary hyperparathyroidism :Adenoma(s), MEN ,Carcinoma
Tertiary hyperparathyroidism
Lithium therapy
Familial hypocalciuric hypercalcemia(FHH)
II. Malignancy-related
Solid tumor with metastases (breast)
Solid tumor with humoral mediation of hypercalcemia(lung,thyroid,kidn)
Hematologic malignancies (MM,lymphoma,leukemia)
III. Vitamin D—related
Vitamin D intoxication
1,25(OH)2D; sarcoidosis ,HIV,and other granulomatous diseases
Idiopathic hypercalcemia of infancy
IV. Associated with high bone turnover
Hyperthyroidism
Paget’s disease
Thiazides
Vitamin A intoxication
Glucocorticoid deficiency
V. Associated with renal failure
Severe secondary hyperparathyroidism
Aluminum intoxication
Milk-alkali syndrome.

Clinical assessment
 Symptoms & signs of hypercalcemia include: polyuria & polydipsia, renal colic,
lethargy, anorexia, nausea, peptic ulceration, constipation, depression, drowsiness
& impaired cognition.
 Pts with malignant hypercalcemia can have a rapid onset of symptoms & may have c.f
that help to localise the tumour.

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  The classic symptoms of primary HPT are described by the adage, bones, stones &
abdominal groans, but few pts present in this way nowadays & the dis. is most often
picked up as an incidental finding on biochemical testing.
 About 50% of pts with primary HPT are asymptomatic, while others have non-specific
symptoms such as fatigue, depression & generalised aches & pain.
 Some present with renal stone & it is estimated that 5% of first stone formers & 15%
of recurrent stone formers have primary HPT.
 HTN is a common feature of HPT.
 Parathyroid tumours are almost never palpable.
 A family history of hypercalcaemia raises the possibility of FHH or MEN.

Symptoms of hypercalcaemia
 CNS: Impaired mental function, loss of memory, depression, somnolence, coma
 Neuromuscular: Weakness, arthralgias, severe pruritus (metast. calcification of skin),
restless leg syn (no comfortable position)
 CVS :HTN, bradycardia , shortening of QT
 Renal : Polyuria(Nephrogenic DI),nephrocalcinosis, recurrent Ca nephrolithiasis
 GIT:Anorexia, vomiting, constipation,PU,pancreatitis
 Rheumatologic : Gout,pseudogout ,chondrocalcinosis
Investigations
 The most discriminant investigation is measurement of PTH.
 If PTH levels are detectable or elevated in the presence of hypercalcaemia, then
primary HPT is the most likely dx.
 High plasma phosphate & ALP accompanied by renal impairment suggests Tertiary
HPT (when long standing secondary hyperplasia becomes autonomous in spite of
correction of underlying stimulant(renal transplant).
 Hypercalacemia may cause nephrocalcinosis & renal tubular impairment resulting in
hyperuricaemia & hyperchloraemia.
 Pts with FHH can present with a similar biochem. picture to primary HPT but typically
have low urinary Ca excretion.
 The dx. of FHH can be confirmed by screening family members for hypercalcaemia.
 If PTH is low & no other cause is apparent, then malignancy with or without bony
metastases is likely.

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  PTH-related peptide (PTHrP)which is often responsible for hypercalcaemia associated
with malignancy is not detected by PTH assay but can be measured by specific assay.
 Unless the source is obvious ,the pt should be screened for malignancy with a CXR,
myeloma screen & CT-scan as appropriate.
Management
Medical management of severe hypercalcaemia:

 IV 0.9% salaine 2-4L/day

 Zoledronate 4mg IV or pamidronate 60-90mg IV
 IM/SC calcitonin 100U 3 times daily for first 24-48 hours in life threatening
hypercalcaemia

Hypocalcaemia
Differential Diagnosis of Hypocalcaemia

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Magnesium deficiency causes hypocalcaemia by impairing the ability of the parathyroid
glands to secrete PTH and may also impair the actions of PTH on bone and kidney

Clinical assessment of hypocalcemia

 Mild hypocalcaemia is often asymptomatic but with more profound reductions in serum
Ca, Tetany can occur.
 Tetany is characterised by muscle spasm due to increased excitability of peripheral
nerves.
 Children are more reliable to develop Tetany than adults & present with a
characteristic triad of carpopedal spasm,stridor & convulsions.

 Adults can also develop carpopedal spasm in association with tingling of the hands &
feet & around the mouth but stridor & fits are rare.
 Latent tetany may be detected by Trousseau’s sign & Chvostek’s sign.
 Hypocalcaemia may cause papilloedema & prolongation of QT interval on ECG which
may predispose to ventricular arrhythmias.

Prolonged hypocalcaemia & hyperphosphataemia as in hypoparathyroidism may cause

calcification of basal ganglia, grand mal epilepsy, psychosis & cataracat.
Hypocalcaemia associated with hypophosphataemia as in Vit D deficiency causes rickets
in children & osteomalacia in adults

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Management of severe hypocalcaemia
Immediate management
• 10–20 mL 10% calcium gluconate IV over 10–20 mins
• Continuous IV infusion may be required for several hrs
• Cardiac monitoring is recommended

If associated with hypomagnesaemia

* 50mmol magnesium chloride IV over 24 hrs
* Most parentral magnesium will be excreted in the urine, so further doses may be required
to replenish body stores.

Hyperparathyroidism
Primary hyperparathyroidism
 It is caused by autonomous secretion of PTH, usually by a single PT adenoma which
can vary in diameter from a few mm to several cm.
 It should be distinguished from secondary & tertiary HPT.
 The prevalence of primary HPT is about 1/ 800
 Its 2-3 times more common in women than men, 90% of pts > 50 yrs of age.

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Clinical & radiological features
 Features of hypercalcaemia as described before.

 PT bone disease is now rare due to earlier dx & Rx.

 Osteitis fibrosa results from increased bone resorption by osteoclasts with fibrous
replacement in the lacunae. This may present as bone pain & tenderness, fracture &
deformity.
 Chondrocalcinosis can occur due to deposition of Ca pyrophosphate crystals within
articular cartilage. It typically affects the mensci at the knees & can result in secondary
degenerative arthritis or predispose to attacks of Acute Pseudogout
 Skeletal x-rays are usually normal in mild primary HPT, but in pts with advanced
disease characteristic changes are observed. In the early stages there is
demineralisation, with subperiosteal erosions & terminal resorption in the phalanges.
 A pepper-pot appearance may be seen on lateral skull x-ray. Reduced bone mineral
density ,resulting in either osteopenia or osteoporosis is now the most common skeletal
manifestation of HPT. This require assessment by DEXA scan.
 In nephrocalcinosis , scattered opacities may be visible within the renal outline.
 There may be soft tissue calcification in arterial walls & hands & in the cornea.

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Investigations
 The dx can be confirmed by finding a raised PTH level in the presence of
hypercalcaemia, provided that FHH is excluded.
 PT scanning by Tc 99m sestamibi scintigraphy & or U/S exam. can be performed
prior to surgery in an attempt to localise an adenoma & allow a targeted resection.
 However, negative imaging does not exclude the dx.

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Management
 The Rx of choice for primary HPT is surgery with excision of a solitary PT adenoma or
hyperplastic glands.
 Experienced surgeons will identify solitary tumours in more than 90% of cases.
 Pts with parathyroid bone disease run a significant risk of developing hypocalcaemia
postoperatively , but the risk of this can be reduced by correcting vit. D deficiency
pre-operatively.
 Surgery is usually indicated in :
 Individuals aged < 50 yrs.
 Clear cut symptoms or documented complications ( such as PU, renal stones, renal
impairment or osteoporosis ) .
 Asymptomatic pts with significant hypercalcaemia) ( corrected Ca > 11.4 mg/dl).

 Pts who are treated conservatively without surgery should have S.Calcium & renal
function checked annually & bone density monitored periodically.
 They should be encouraged to maintain a high oral fluid intake to avoid renal stones.
 Occasionally, primary HPT presents with severe life-threatening hypercalcaemia, this
is often due to dehydration & should be managed medically with IV fluid &
bisphosphonate.
If this is not effective, then urgent parathyroidectomy should be considered.
 Cinacalcet is a calcimimetic which enhances the sensitivity of the Ca sensing receptors,
so reducing PTH levels & is licensed for Tertiary HPT & as a Rx for pts with primary
HPT who are unwilling to have surgery or are medically unfit.

Familial Hypocalciuric Hypercalcaemia

 This AD disease is caused by an inactivating mutation in one of the alleles of the Ca
sensing receptor gene, which reduces the ability of the PTG to sense ionised Ca
concentration .
 As a result higher than normal Ca levels are required to suppress PTH secretion.
 The typical presentation is with mild hypercalcemia with PTH concentration that are
inappropriately at the upper end of the reference range or are slightly elevated.
 Ca –sensing receptors in the renal tubules are also affected & this leads to increased
renal tubular reabsorption of Ca & hypocalciuria. The hypercalcaemia of FHH is
always asymptomatic & complications do not occur.

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  The main risk of FHH is of the pt being subjected to an unnecessary (& ineffective)
parathyroidectomy if misdiagnosed as having primary HPT.
 Testing of family members for hypercalcaemia is helpful in confirming the dx & its also
possible to perform genetic testing . No treatment is necessary.

Hypoparathyroidism
 The most common cause of hypoparathyroidism is damage to PTG (or their blood
supply) during thyroid surgery; post-operative hypocalcaemia develops in 5.5% of pts
overall but 9% of pts undergoing total thyroidectomy.
 Rarely hypoparathyroidism can occur as a result of infiltration of the glands with iron in
Haemochromatosis or copper in Wilson’s disease.
 There are a number of rare congenital or inherited forms of hypoparathyroidism.
 One form is associated with autoimune polyendocrine syndrome type 1 & another
with DiGeorge syndrome.
 AD hypoparathyroidism (ADH) is the mirror image of FHH in that an activating
mutation in the Ca –sensing receptor reduces PTH levels, resulting in hypocalcaemia
& hypercalciuria.

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 concentration
are markedly elevated.

 There are several subtypes but the most common (pseudohypoparathyroidism

type1a) which is charcterised by hypocalcaemia & hyperphosphataemia, in
association with short stature, short 4th metacarpals & metatarsals, rounded face,
dental problems,obesity & subcutaneous calcification.
 These features are collectively referred to as Albright’s hereditary osteodystrophy (
AHO).

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  The term pseudopseudohypoparathyroidism is used to describe pts who have clinical
features of AHO but normal serum Ca & PTH concentration.

 The inheritance of these disease is an example of genetic imprinting.

 The difference in clinical features occurs as a result of the fact that renal cells
exclusively express the maternal GNAS1 allele, whereas both maternal & paternal
alleles are expressed in other cell types.
 This explains why maternal inheritance is associated with hypocalcaemia & resistance
to PTH & why paternal inheritance is associated with skeletal & other abnormalities in
the absence of hypocalcaemia & raised PTH level.
Management of hypoparathyroidism
 Persistent hypoparathyroidism & pseudohypoparathyroidism are treated with oral Ca
salts & vitamin D , either 1-alpha hydroxycholecalciferol ( alfacalcidol) or 1,25
dihydroxycholecalciferol (calcitriol).
 This therapy needs careful monitoring because of the risks of iatrogenic
hypercalcaemia, hypercalciuria & nephrocalcinoosis.

 Recombinant PTH is available as SC injection therapy for osteoporosis, & although

currently not licensed , has been used in hypoparathyroidism (but not in
pseudohypoparathyroidism).
 It is much more expensive than Ca & vitamin D therapy, but has the advantage that it
is less likely to cause hypercalciuria.
 ADH usually does not require therapy.

The PTG in old age

Osteoporosis: always exclude osteomalacia & HPT by checking vit. D & Ca conc.
Primary HPT: more common with ageing. Older people can often be observed without
surgical intervention.
Hypercalcaemia: may cause confusion.
Vit. D deficiency: common because of poor diet & limited exposure to the sun.

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