ENDOCRINOLOGY Parathyroid disease

Parathyroid gland disease

Functional anatomy and physiology:
 The four parathyroid glands lie behind the lobes of the thyroid and
weigh between 25 and 40 mg.
 The parathyroid chief cells secrete parathyroid hormone (PTH) in
response to decrease in serum calcium concentration.
 Serum calcium levels are tightly regulated on a moment-to-moment
basis by the actions of parathyroid hormone (PTH) and vitamin D.
 PTH is a single-chain polypeptide of 84 amino acids. It acts on
1. Renal tubules to promote reabsorption of calcium and reduce
reabsorption of phosphate.
2. Increase osteoclastic bone resorption and bone formation.
3. Promotes the conversion of 25-hydroxyvitamin D to the active
metabolite, 1,25-dihydroxyvitamin D.
 Active vitamin D acts on three organ systems to achieve and maintain
normal serum calcium: bone, intestine, and kidney.
1. Bone resorption is increased,
2. Intestinal uptake of dietary calcium is increased,
3. Excretion of calcium through the kidney is decreased.
 More than 99% of total body calcium is in bone.
 The differential diagnosis of disorders of calcium metabolism requires
measurement of calcium, phosphate, alkaline phosphatase, renal
function, PTH and 25-hydroxyvitamin D.
 Although the parathyroid glands detect and respond to ionized calcium
levels, most clinical laboratories measure only total serum calcium
levels. About 50% of total calcium is bound to organic ions, such as
citrate or phosphate, and to proteins, especially albumin.
 Accordingly, if the serum albumin level is reduced, total calcium
concentrations should be ‘corrected’ by adjusting the value for calcium
upward by 0.8 g/dL for each 1 g/dL reduction in albumin below 4 g/dL.

Corrected calcium = S. Ca+ + 0.8 (4 – Patient albumin)

 Calcitonin which secreted from the parafollicular C cells of the thyroid

gland is of no clinical relevance to calcium homeostasis in humans.

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ENDOCRINOLOGY Parathyroid disease

Presenting problems in parathyroid disease

Hypercalcemia:
 Hypercalcemia is marked by serum calcium levels above the normal
range, usually greater than 10.5 mg/dL (2.6mmol/L).
 Most patients are asymptomatic, and hypercalcemia may be noted
incidentally on laboratory tests obtained for other reasons.
 Primary hyperparathyroidism and malignancy are by far the most
common causes of hypercalcemia.
 Causes of hypercalcemia divided into PTH related and non-related
causes:

With normal or elevated PTH level (PTH related)

Primary or tertiary hyperparathyroidism
Lithium-induce hyperparathyroidism
Familial hypocalciuric hypercalcemia
With low PTH level (PTH non related)
Malignancy (lung, breast, myeloma, renal, lymphoma, thyroid)
Elevated 1,25-dihydroxyvitamin D (vitamin D intoxication, Sarcoidosis, HIV,
Granulomatous diseases)
Thyrotoxicosis
Paget’s disease with immobilization
Milk-alkali syndrome
Thiazide diuretics
Glucocorticoid deficiency

Clinical features:

 Symptoms may occur with any degree of hypercalcemia but are

more likely when serum calcium levels exceed 12 mg/dL.
 Generalised aches and pains.
 Polyuria, polydipsia, nocturia, renal colic, acute kidney injury due to
profound dehydration, and increased creatinine concentration.
 Anorexia, nausea, dyspepsia, constipation, peptic ulceration and
pancreatitis.
 Depression, drowsiness and impaired cognition.

Investigation:

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ENDOCRINOLOGY Parathyroid disease

When serum calcium elevation is noted, repeat measurement of

serum calcium is indicated, and if a second hypercalcemic level is noted,
the next step is determining if the hypercalcemia is PTH or non-PTH–
mediated by simultaneous measurement of serum calcium, phosphate
and intact PTH levels.
Treatment of Hypercalcemia:
 Treatment of hypercalcemia should focus on decreasing serum calcium
level by increasing calcium excretion and decreasing bone resorption
or intestinal calcium absorption, as well as volume repletion.
 Indications for hospitalization include those with marked mental status
changes, acute kidney injury, or calcium levels greater than 12 mg/dL.

 First-line therapy is aggressive intravenous fluid resuscitation. Once

the patient is volume replete, an intravenous loop diuretic should
be added if the calcium level has not normalized.
 Intravenous bisphosphonate (Zoledronic acid) therapy is usually
given for longer-term control of hypercalcemia.
 Calcitonin acts rapidly to increase calcium excretion and to reduce
bone resorption, and can be combined with fluid and
bisphosphonate for the first 24 - 48 hours in patients with life-
threatening hypercalcaemia.
 In patients resistant to or intolerant of bisphosphonate therapy, off-
label use of denosumab, which also reduces osteoclast-mediated
bone resorption, can be used.
 For patients who present with serum calcium levels greater than 18
mg/dL with neurologic symptoms or compromised kidney function,
hemodialysis is indicated to quickly reduce calcium levels.
 Attention should be turned as quickly as possible to treatment of
the underlying cause of the patient's hypercalcemia to ensure long-
term maintenance of normocalcemia.

Parathyroid Hormone–Mediated Hypercalcemia

Primary Hyperparathyroidism:

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ENDOCRINOLOGY Parathyroid disease

o Primary hyperparathyroidism is the most common cause of PTH-

mediated hypercalcemia. The incidence peaks in the 7th decade &
affects mostly women (75%).
o Most commonly, primary hyperparathyroidism is due to a single
parathyroid adenoma; however, rarely it may be attributed to
multigland hyperplasia (ESRD or MENS) or parathyroid gland
carcinoma (calcium is typically >14 mg/dL and intact PTH levels >250)
on presentation.
o Presentation often describe with
Bones, stones, abdominal groans and psychic moans
o Diagnosis made with a simultaneously elevated serum calcium level,
with an inappropriately normal or elevated intact PTH level. Also there
will be low or low normal phosphate level and increase 24 hour urinary
calcium excretion.
o When biochemical diagnosis confirm, imaging (Sestamibi scans, high-
definition ultrasound) studies can be used to localize the lesion.
o Parathyroidectomy is the treatment for primary hyperparathyroidism.
o Indications of surgery are:
1. Age 50 years or younger
2. Increase serum calcium level ≥1 mg/dL above upper limit of normal.
3. Creatinine clearance must be <60 mL/min (0.06 L/min)
4. DEXA scan of −2.5 or worse at the lumbar spine, total hip, femoral
neck, or distal radius
5. When medical surveillance is neither desired nor possible.
o It is critical that an experienced surgeon perform the surgery to avoid
increased risk of postoperative hypoparathyroidism (hypocalcemia)
and damage to the recurrent laryngeal nerve.
o In patients who do not meet the criteria for surgery, surveillance is
recommended annual measurement of serum calcium and creatinine
levels.

Tertiary Hyperparathyroidism:
 Continuous stimulation of the parathyroids over a prolonged period of
time results in adenoma formation and autonomous PTH secretion.
This is most commonly seen in individuals with advanced chronic
kidney disease.
 Severe bone loss and other symptoms make surgical resection the
treatment of choice.

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ENDOCRINOLOGY Parathyroid disease

 Cinacalcet is a calcimimetic that enhances the sensitivity of the

calcium-sensing receptor, so reducing PTH levels, and is licensed for
tertiary hyperparathyroidism.

Parathyroid Carcinoma:
o Parathyroid carcinoma is very rare, accounting for less than 1% of all
persons with primary hyperparathyroidism.
o Compare with benign primary hyperparathyroidism, parathyroid
carcinoma is equally prevalent in both sexes, more commonly presents
with kidney and bone involvement and a neck mass, and frequently is
associated with a total serum calcium level greater than 14 mg/dL and
very high parathyroid hormone levels, typically greater than four times
the upper limit of normal.
o In these patients, surgical resection is the treatment of choice.
o All patients should be screened for the HRPT2 gene, and if positive,
family members should be screened as well.

Familial Hypocalciuric Hypercalcemia:

 It is a rare autosomal dominant condition.
 These patients are frequently asymptomatic, but in rare cases may
present with pancreatitis.
 The disease caused by mutation in calcium–sensing receptor (CASR)
gene, these receptors are in the parathyroid glands and the kidneys.
The sensor mutation results in a shift upward in the “normal” range of
calcium that the receptor recognizes, resulting in a mildly elevated
serum calcium level (usually less than 11.0 mg/dL) and high normal or
mildly elevated PTH level.
 The diagnosis is made by measuring 24-hour urine calcium excretion
levels (less than 200mg/24hr) and calculation of the calcium-creatinine
clearance ratio (less than 0.01)
 FHH is usually a benign condition that requires no intervention but
should be recognized to prevent unnecessary parathyroidectomy.
Non–Parathyroid Hormone–Mediated Hypercalcemia
Malignancy-Associated Hypercalcemia:
There are several mechanisms of hypercalcemia of malignancy:
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ENDOCRINOLOGY Parathyroid disease

A. Local osteolytic: when lytic bone metastases are present,

hypercalcemia is the result of increased mobilization of calcium
from the bone.
B. Humoral hypercalcemia is less common and occurs when the tumor
itself produces parathyroid-related protein (PTHrP) that binds to
and activates the parathyroid receptor, raising serum calcium
levels. Squamous cell carcinomas, breast cancers, and renal cell
carcinomas are the tumors most commonly associated with
hypercalcemia of malignancy.
In multiple myeloma, the hypercalcemia is caused by the release of
factors that stimulate osteoclast activity.

Hypocalcemia:
o Hypocalcemia defined by serum calcium level below 9 mg/dl.
o It may be asymptomatic if mild. As calcium levels decrease, particularly
below 8.0 mg/dL, symptoms may develop.

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ENDOCRINOLOGY Parathyroid disease

o The most common cause of hypocalcemia is a low serum albumin

(decrease total calcium with normal ionised calcium concentration).
o Clinical features:
 The hallmark of acute hypocalcemia is Tetany, this is characterised
by muscle spasms due to increased excitability of peripheral nerves.
 Tetany is manifested clinically by both sensory and muscular
dysfunction: Sensory Symptoms typically begin with perioral and
acral (fingers and toes) paresthesias.
 The motor symptoms of tetany include stiffness, muscle spasms and
cramps. In the hands, the result is forced adduction of the thumb,
flexion of the metacarpophalangeal joints and wrists, and extension
of the fingers (carpopedal spasm). Spasm of the respiratory muscles
and of the glottis can cause stridor and cyanosis.
 Autonomic manifestations include diaphoresis, bronchospasm.
 The classic physical findings in patients with neuromuscular
irritability due to latent tetany are:
1. Trousseau's sign: induction of carpopedal spasm by inflation of a
sphygmomanometer above systolic pressure for three minutes.
2. Chvostek's sign: is contraction of the ipsilateral facial muscles
elicited by tapping the facial nerve just anterior to the ear.
 Hypocalcaemia can cause papilloedema.
 ECG finding of hypocalcemia include prolongation of the QT
interval, which may predispose to ventricular arrhythmias.
 Prolonged hypocalcaemia and hyperphosphataemia (as in
hypoparathyroidism) may cause calcification of the basal ganglia,
epilepsy (Grand mal, petit mal, and focal seizures can occur in
hypocalcemia and may be the sole presenting symptom), psychosis
and cataracts.

Causes of hypocalcemia:
Hypoparathyroidism are the commonest cause.
Other, less common causes of hypocalcemia include
1. Poor calcium intake,
2. Vitamin D deficiency
3. Chronic kidney disease

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ENDOCRINOLOGY Parathyroid disease

4. pseudohypoparathyroidism
5. Familial hypocalcemia hypercalciuric,
6. Increased phosphate binding in vascular space (rhabdomyolysis or
tumor lysis syndrome),
7. Increase citrate chelation with large volume blood transfusions,
8. Hypomagnesemia.

Diagnosis of Hypocalcemia:
Asymptomatic hypocalcemia may be noted incidentally on routine
laboratory tests. When this occurs, the calcium level should be repeated
in conjunction with a serum albumin level.
If hypocalcemia is confirmed, simultaneous intact PTH must be measured
to confirm if PTH is responding appropriately.

Treatment of Hypocalcemia:
o Emergency management of hypocalcemia associated with tetany is
10–20 mL 10% calcium gluconate IV over 10–20 minutes. Continuous
IV infusion may be required for several hours (equivalent of 10 mL 10%
calcium gluconate/hr) in severe cases. Goal calcium is 7.0 to 7.5 mg/dL
(1.8-1.9 mmol/L) with intravenous repletion.
o If associated with hypomagnesaemia, 50 mmol (1.23 g) magnesium
chloride IV over 24 hrs.
o Cardiac monitoring is recommended.
o If a patient requires chronic replacement (eg. Hypoparathyroidism)
calcium carbonate and calcium citrate are the most common oral
calcium formulations used in addition 1,25-dihydroxycholecalciferol
(Calcitriol).
o Calcium carbonate requires an acidic environment to be absorbed, so,
should not use with PPI.
o The overall goal of repletion is the low to low-normal range (serum
calcium 8.0-8.5 mg/dL [2.0-2.1 mmol/L]).

Hypoparathyroidism:
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ENDOCRINOLOGY Parathyroid disease

 The most common cause of hypoparathyroidism is damage to the

parathyroid glands (or their blood supply) during thyroid surgery.
 Other causes include radiation exposure, parathyroid gland infarction,
infiltrative diseases [hemochromatosis, Wilson disease, granulomas],
or autoimmune hypoparathyroidism.
 Acute manifestations of hypoparathyroidism are similar to that of
hypocalcemia.
 Manifestations of chronic hypoparathyroidism include basal ganglia
calcifications (Extrapyramidal signs, Parkinsonism, Dementia),
cataracts, dental abnormalities, and dry skin.
 Investigations show hypocalcemia, hyperphosphataemia and decrease
PTH level. Vitamin D should be assessed as well.
 Treatments of hypoparathyroidism are oral calcium salts and vitamin D
analogues, either 1α-hydroxycholecalciferol (alfacalcidol) or 1, 25-
dihydroxycholecalciferol (Calcitriol). Recombinant PTH is available as
subcutaneous injection, although not currently licensed, has been used
in hypoparathyroidism.

Pseudohypoparathyroidism:
o 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.
o Characterised by hypocalcaemia and hyperphosphataemia, 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
osteodystrophy (AHO).

Pseudopseudohypoparathyroidism:
The term pseudopseudohypoparathyroidism is used to describe patients
who have clinical features of AHO but normal serum calcium and PTH
concentrations.

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ENDOCRINOLOGY Parathyroid disease

Hypomagnesemia:
 Hypocalcaemia may also develop as a result of magnesium depletion
and should be considered in patients with malabsorption, those on
diuretic or proton pump inhibitor therapy, and/or those with a history
of alcohol excess.
 In patients with hypomagnesemia, hypocalcemia is difficult to correct
without first normalizing the serum magnesium concentration.
 Magnesium deficiency causes hypocalcaemia by impairing the ability of
the parathyroid glands to secrete PTH (resulting in PTH concentrations
that are low or inappropriately in the reference range) and may also
impair the actions of PTH on bone and kidney.
 Treated by correction of hypomagnesemia and oral calcium
supplementation.

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