Endocrinology: Thyroid and Parathyroid

Question 1

Thyroid function in the foetus

Answer 1

1) Although T3 and T4 reach the foetal circulation from the mother, the foetus depends on its own thyroid gland for thyroid hormones.

2) Thyroid gland fully differentiated by 11 weeks gestation, but probably not until about 18 weeks that thyroid hormone production commences.

3) By 28 weeks free T4 values reach adult levels. Failure of thyroid gland development or hormone synthesis results in cretinism.

Question 2

Cretinism

Answer 2

Gross mental retardation due to failure of brain development, and a failure of skeletal development leading to dwarfism.
Maternal TSH receptor stimulating antibodies may cross the placenta; this can lead to transient neonatal hyperthyroidism. Maternal TSH receptor blocking antibodies may likewise result in foetal hypothyroidism

Question 3

Structure and function of thyroid gland

Answer 3

Spherical follicles of thyroid epithelial cells surrounding colloid (principally thyroglobulin) within a lumen. In addition, parafollicular or C-cells secrete calcitonin.

In each follicle, the epithelial cells are cuboidal when ‘resting’ and ‘columnar’ when under TSH stimulation

Question 4

Thyroid follicular cells

Answer 4

• secrete thyroglobulin (Tg) and iodine into colloid

• absorb thyroglobulin from colloid

• secrete triiodothyronine (T3) and thyroxine (T4)
directly into the blood stream

Question 5

Thyroid function: I and Na pump

Answer 5

Thyroid gland incorporates iodide into its cells from plasma by an active transport mechanism in which Iodine follows Na.

This ‘pump’ is influenced positively by TSH and TSH receptor antibodies (in Graves’ disease). Iodine can be blocked for example, digoxin.

Question 6

Thyroid function: Within the follicular cell I

Answer 6

Iodide is quickly oxidised by thyroid peroxidase (TPO) and hydrogen peroxide and bound to thyroglobulin forming monoiodotyrosine (MIT) and diiodotyrosine (DIT)

Then transferred to the luminal colloid. MIT and DIT combine in a reaction catalysed by TPO, positively regulated by TSH to produce either triiodothyronine (T3) or thyroxine (T4) – all within the colloid.

Question 7

Thyroid function: Within the follicular cell II

Answer 7

1) Under continued TSH control, colloid droplets are taken up by the thyroid cell via a process of endocytosis, lysosomes fuse with the droplets and proteolysis of thyroglobulin occurs.

2) In the plasma the hormones conjugate with thyroxine-binding globulin (TBG) produced by the liver that binds 70% of T3 and T4, to thyroxine-binding prealbumin, and to albumin.

3) Protein bound, T3 and T4 are inactive and thus are a ‘store’ of bound hormone allowing regulation of the levels of unbound active ‘free’ T3 and T4 available to the tissues.

Question 8

Thyroid function: T3 and T4

Answer 8

Free T3 is the active hormone. Most T3 production (80%) is extrathyroidal from deiodination of T4. The half life of T3 is one day and of T4 is one week. Thus T4 appears to act as an immediately available source and regulator of T3 rather than as an hormone in its own right.

Question 9

Control of thyroid function

Answer 9

1) Thyroid-stimulating hormone (TSH), from the anterior pituitary, has a stimulating effect on T3/T4 production.

2) Thyrotrophin-releasing hormone (TRH), which
is stored in the hypothalamus, stimulates TSH production and release.

3) Rising levels of T3/T4 (primarily a rising T3 concentration) have an inhibitory effect on the TRH/TSH axis.

Question 10

Iodine and thyroid control

Answer 10

1) Thyroid autoantibodies may stimulate or inhibit thyroid function. TSH receptor antibodies may be stimulatory producing hyperthyroidism (Graves’ Disease) or have a blocking action producing hypothyroidism (atrophic thyroiditis).

4) Anti-TPO (thyroid peroxidase) autoantibodies are found in 90% of patients with Graves’ Disease and lymphocytic thyroiditis.

Question 11

Mechanism of action of thyroid hormones

Answer 11

1) T3 and T4 have major effects on the growth, development and function of most tissues.

2) The main effects are seen on the cell membrane, on the mitochondria and on the cell nucleus.

3) At the cell membrane level there is increased uptake of amino acids when T3 stimulation occurs.

4) The effect on mitochondria is to increase
energy production.

5) T3 combines with T3 receptors within the nucleus, this causes increased or decreased mRNA expression with consequent effects on protein synthesis.

Question 12

Effects of thyroid hormone

Answer 12

These are widespread and include energy and heat production, an overall catabolic effect – particularly on glucose and fat metabolism, cardiovascular and adrenergic effects, effects on production of other hormones, effects
on bone, foetal development and growth.

Question 13

Effects of thyroid hormone: heat production

Answer 13

Heat production is brought about by the T3 effect
on mitochondria: there is increased O2 uptake by the mitochondria with production of ATP in most tissues, although not in the brain.

Thyroid hormone is responsible for the increase in basal metabolic rate (BMR) that occurs in hyperthyroidism, and consequently the heat intolerance described by patients.

.

Question 14

Effects of thyroid hormone: Catabolic effects

Answer 14

Thyroid hormones stimulate glycogenolysis in the liver, an increase in insulin breakdown and a rise in glucose absorption from the gut.

Hyperthyroidism is associated with insulin resistance and glucose intolerance, diabetes may be ‘unmasked’ or, its control in a patient with established diabetes may be more difficult.

Question 15

Effects of thyroid hormone: Cardiovascular and adrenergic effects

Answer 15

The number of alpha adrenergic receptors in cardiac muscle increase

Consequently thyroid hormones have a positive inotropic effect. In patients with thyrotoxicosis, the cardiac output and heart rate increase. Alpha adrenergic receptor activity also increases in other tissues, including skeletal muscle.

The management of the tachycardia and dysrhythmia associated with thyrotoxicosis logically includes a-adrenergic receptor blocker such as propranolol or metoprolol.

In hypothyroidism cardiac output is reduced; pericardial effusions may occur.

Question 16

Effects of thyroid hormone: Effects on bone

Answer 16

T3 and T4 increase metabolic activity in bone, there
is increased bone resorption and bone formation.
The catabolic effect is predominant in thyrotoxicosis
which results in a net reduction in bone density.
Hypercalcaemia (rarely severe) and hypercalciuria
can occur in thyrotoxicosis, PTH levels will be normal or low.

Question 17

Effects of thyroid hormone: Gastrointestinal effects

Answer 17

Weight loss and diarrhoea are common symptoms
reported by patients with hyperthyroidism. Constipation, loss of appetite and weight gain are frequent symptoms in hypothyroidism.

Question 18

Investigation of thyroid function

Answer 18

Low TSH and high fT4 and /or fT3 will ordinarily indicate thyrotoxicosis.

High TSH with low thyroid hormone indicate a hypothyroid state.

In pregnancy there is a rise in TBG with a consequent rise in total T3 and T4 levels: however, the free T3 and T4 levels are little changed.

In very early pregnancy the free T3 and T4 levels may increase due to the effects of hCG. The thyroid gland often increases in size during pregnancy. Post-partum thyroid dysfunction is common (15%).

Question 19

Thyroid and paediatrics

Answer 19

In children, free T4 levels reach the normal adult range by the end of the first year. Free T3 levels remain high in childhood and early adolescence. In sick patients with non thyroidal illness, a transient rise in TSH and low free T4 and free T3 is often seen. With recovery from the illness, thyroid function tests return to normal.

Question 20

Thyroid antibodies

Answer 20

Thyroid autoantibody status should also be determined. In patients with Graves’ disease TPO antibodies are positive in approximately 80% of patients. Approximately 90% of patients with Hashimoto’s disease have positive TPO antibodies. It should be remembered that in itself positive antibody status does not constitute a diagnosis of thyroid disorder as at least a third of the normal population will have a positive antibody titre.

Question 21

Thyroid tumour markers

Answer 21

Thyroglobulin in patients with differentiated (papillary or follicular) thyroid who have undergone complete eradication of thyroid tissue by the combination of surgery and postoperative radioactive iodine therapy.

A rise in thyroglobulin levels indicates persistent or recurrent disease.

Calcitonin is measured in patients with medullary thyroid cancer (MTC) (a tumour that arises from thyroid C cells).

Calcitonin levels are also measured in patients who have undergone surgery for MTC; a raised or increasing level of calcitonin indicates residual or recurrent disease.

Question 22

Thyroid pathology investigation

Answer 22

1) FNA distinguishes solid from cystic thyroid enlargement.

2) Ultrasound of the thyroid is very sensitive at detecting abnormal thyroid tissue but not specific, and rarely contributes to the diagnosis of thyroid swellings. Useful for targeted FNA and reduces the number of unsatisfactory needle aspirates.

2) Thyroid CT and MRI can delineate the extent of thyroid enlargement in the neck and chest as well as the encroachment/invasion of adjacent structures in benign and malignant disease.

Question 23

Hypothyroidism

Answer 23

1) Caused by a deficiency of or resistance to thyroid hormone.

2) Primary hypothyroidism is the cause of 95% of adult cases; Hashimoto’s disease (chronic lymphocytic thyroiditis) is responsible for 70% of these.

3) Patients with hypothyroidism sometimes present with a goitre to surgeons. The combination of abnormal thyroid function tests, positive TPO autoantibodies and sometimes aspiration cytology is sufficient to confirm the diagnosis.

Question 24

Myxoedema

Answer 24

1) Myxoedema, the end result of severe long
standing hypothyroidism, is associated with marked
symptoms and signs, characteristic skin changes and in extreme cases, confusion and coma associated with a very high mortality.

2) The patient has profound hypothermia, and may demonstrate hypoglycaemia, water retention, and hypoventilation.

3) In generalised myxoedema there is accumulation of glycosaminoglycans within soft tissues, and facial and cutaneous oedema (containing mucopolysaccarides, hyaluronic acid and chondroitin sulphate).

Question 25

Hypothyroidism treatment

Answer 25

1) Lifelong thyroxine is the treatment of choice and in most cases is associated with a reduction in size of the goitre as TSH levels fall.

2) Thyroid lymphoma is more common in patients with lymphocytic thyroiditis. A nodule or continued enlargement of the thyroid in a patient with Hashimoto’s disease despite thyroxine treatment must be viewed with suspicion and aggressively investigated.

3) The surgeon should be aware of the many manifestations of hypothyroidism. Some patients will be asymptomatic despite significant degrees of biochemical dysfunction.

4) The patient who presents with constipation without an obvious mechanical cause requires thyroid function tests. Other risk groups the surgeon should consider are individuals who have previously undergone thyroid surgery who may become hypothyroid as a delayed consequence of surgery or, as a result of failure to take thyroxine medication.

Question 26

Hyperthyroidism

Answer 26

1) This is defined as thyroid over-activity with a sustained increase in production of thyroid hormones. Thyrotoxicosis is the clinical syndrome that results from an increase in the serum concentration of thyroid hormones.

2) The commonest cause of thyrotoxocosis is Graves’ disease (60%), an autoimmune condition
in which TSH receptor antibodies are present which
stimulate thyroid cell activity and growth.

3) Other common causes of hyperthyroidism include toxic multinodular goitre and toxic adenoma. The clinical features of thyrotoxicosis include diffuse or nodular thyroid enlargement, and systemic manifestations of raised blood thyroid hormone levels.

Question 27

Graves Disease

Answer 27

1) In Graves’ disease, eye signs (thyroid associated opthalmopathy: TAO) occur that may be clinically inapparent but are evident on screening in up to 90% of patients. Signs of TAO, unilateral in 10% of cases, include lid retraction, lid lag and proptosis.

2) Less than 10% of patients will develop severe eye changes that include diplopia, opthalmoplegia and sight loss. The histological findings in the soft tissues within the orbit in TAO include oedema, lymphocyte infiltration, glycosaminoglycan deposition and inflammatory changes in the extra ocular muscles with fibrosis.

3) The aetiology of TAO is unclear, predisposing
factors include male sex and smoking, immunogenetic factors have little if any effect.

4) Radioiodine leads to a worsening of eye disease in some patients. Patients with Graves’ disease may develop pretibial myxoedema (thyroid associated dermopathy) and thyroid acropachy.

Question 28

Treatment options for Graves’ disease

Answer 28

• Antithyroid drugs
• Radio-iodine treatment
• Surgery

Question 29

Antithyroid drugs: The thionamides

Answer 29

The thionamides –carbimazole and propylthiouracil (PTU) are most commonly used.

1) They block thyroid peroxidase activity (inhibition of
iodine organifi cation and iodotyrosyl coupling); in
addition PTU inhibits deiodination.

2) Thionamides also have an immunomodulatory effect on the disease process, probably as a result of a direct action on thyroid cells.

3) They control thyroid hormone production
as long as they are continued and are used as primary treatment in Graves’disease. They can be given either to partially reduce thyroid hormone production to achieve a euthyroid state (titration regimen) or at a high dose to render the patient hypothyroid; thyroxine is then introduced (block and replace regimen).

Question 30

Antithyroid drugs: The thionamides

Answer 30

1) Patients remain on treatment for a variable period of time – at least six months, sometimes a year or more, medication is then discontinued.

2) Approximately 40% of patients with Graves’ have a sustained remission after antithyroid drug treatment. A higher chance of relapse can be predicted in patients with large goitre, severe hyperthyroidism and a long duration of symptoms.

Question 31

Thyroid pathology: beta blockers and relapse

Answer 31

1) Beta blockers are prescribed to thyrotoxic patients to control symptoms whilst waiting for antithyroid drugs to work.

2) Patients with Graves’ disease who relapse after a course of antithyroid drugs or who cannot tolerate
them because of side effects require some form of
definitive treatment.

Question 32

Thyroid pathology: Pregnancy

Answer 32

1) Carbimazole and propylthiouracil, if given in high dose may block foetal thyroid function: PTU is the drug of choice in pregnant women with hyperthyroidism.

Question 33

Radioiodine

Answer 33

1) Iodide is removed from plasma largely by the kidneys and the thyroid. Salivary tissue and gastric mucosa to a much lesser degree also transport iodide.

2) This property enables interstitial irradiation to
be delivered by 131 Iodine to thyroid cells from within.

3) It is the treatment of choice when relapse occurs after surgery, in patients who have completed their families and in patients over 55.

4) It must not be used in pregnancy – male and female patients are advised to avoid conception for six months after treatment. TAO and large goitres are relative contraindications to its use.

Question 34

Surgery in thyroid pathology

Answer 34

1) This should be considered when radioiodine
is contraindicated, when there is a possible
associated thyroid cancer, the patient prefers to avoid radioidine, and in patients who have relapsed after radioiodine treatment.

2) The patient should be euthyroid following the use
of antithyroid drugs. In non-compliant toxic patients
who require surgery, treatment with anti-thyroid medication, beta blockers and iodine can be given under inpatient supervision. Iodine administration transiently inhibits T3 formation (the Wolff–Chaikoff effect) and deiodination, as well as reducing the thyroid vascularity that is increased in thyrotoxicosis.

3) For patients with Graves’ disease and those with toxic multinodular goitre, total thyroidectomy or near total thyroidectomy is the treatment of choice. Total lobectomy alone is required for patients with toxic adenoma (who can be as well treated with radioiodine).

Question 35

Benign thyroid disease (euthyroid)

Answer 35

Thyroid enlargement may be physiological (puberty,
pregnancy) or pathological (due to iodine deficiency, goitrogens, genetic disorders of thyroid hormone synthesis or action or, benign neoplasia).

Clinical examination categorises gland enlargement as diffuse or nodular. Nodular enlargement (which may be solid or cystic) is further categorised as solitary, multinodular or dominant (a larger nodule in a background of multiple nodules) nodular change.

Question 36

Benign thyroid disease (euthyroid): investigations and treatment

Answer 36

Investigations as described above are performed, surgery is indicated if the nodule/gland is large and/or causes compressive symptoms of the trachea or oesophagus, if enlargement is retrosternal,or there is suspicion of malignancy.

Total lobectomy
or total thyroidectomy is performed depending upon
whether the abnormality is unilateral or bilateral.

Question 37

Malignant thyroid disease: Papillary cancer

Answer 37

1) Approximately 1% of all malignant disease arises in the thyroid.

2) Papillary cancer is the commonest tumour (70%),
the peak incidence is around the third decade. The
patient usually presents with a lump in the thyroid
gland or, with an enlarged lymph node in the neck.

3) It may be identified as an incidental finding after thyroid surgery for an unrelated condition. It is often multifocal within the thyroid; early spread to pre and para-tracheal nodes can occur. It is, however, an indolent disease in most young adults if treated appropriately.

4) It is more aggressive in children and the elderly.

Question 38

Malignant thyroid disease: Follicular cancer

Answer 38

1) Follicular cancer (20%) presents more commonly
in the fourth and fifth decades.

2) Thyroid cytology cannot distinguish benign follicular lesions (hyperplasia, adenoma) from malignant follicular lesions. The diagnosis of malignancy requires histological evidence of capsular and/or vascular invasion. Patients generally present with a lump in the thyroid. The prognosis of the differentiated thyroid cancers is good – particularly for the papillary tumours.

3) Adverse factors include increasing age at presentation, male sex, increasing lesion size, extrathyroidal invasion, incomplete tumour resection, distant metastases (lungs and bone).

Question 39

Malignant thyroid disease: Treatment

Answer 39

1) Total thyroidectomy is the recommended initial
treatment for most patients with differentiated thyroid cancer. Patients with small (less than 2 cm) low risk cancers are sometimes treated with thyroid lobectomy alone.

Question 40

Postop thyroid: Postop

Answer 40

After total thyroidectomy, the patient is given T3 as thyroid hormone replacement (it has a shorter half life than T4). This is stopped and two weeks later, TSH levels are checked. If the TSH is markedly elevated an ablation dose of 131I is given whilst the TSH drive is high. The ß-particles emitted by the radio-active iodine will destroy residual thyroid and thyroid cancer cells.

Secondly, TSH is a potent growth stimulus to benign and malignant thyroid cells. Suppression of TSH levels by the lifelong administration of higher doses of thyroxine than are given to patients with benign disease as replacement therapy reduces the risk of tumour recurrence.

Thirdly, patients who have undergone total thyroidectomy and post-operative radioiodine ablation should have very low or undetectable serum thyroglobulin levels. Recurrent disease is associated with a rise in thyroglobulin.

Question 41

Anaplastic cancer

Answer 41

Anaplastic cancer usually affects the elderly. Prognosis is very poor. Thyroid lymphoma usually arises in patient with pre-existing Hashimoto’s disease. When the diagnosis is made by FNA and core biopsy, treatment is non-surgical.

Question 42

Medullary thyroid cancer (MTC)

Answer 42

Medullary thyroid cancer (MTC) represents 5%–10%
of thyroid cancers and arises from thyroid C cells
(parafollicular cells).

In 75% of cases it is sporadic and in 25% inherited as part of a genetic syndrome (MEN 2A, MEN 2B, FMTC).

All patients with MTC should undergo biochemical testing to exclude an unsuspected phaeochromocytoma prior to surgery and be appropriately counselled to undergo genetic
testing.

Onset of sporadic disease may occur at any
age but is mainly in the fifth decade. The patient
presents with a thyroid nodule, diffuse thyroid mass
or lymph node enlargement. The tumour secretes calcitonin which appears to have no physiological effect, and other peptides which cause diarrhoea in advanced disease.

Diagnosis is confirmed by FNA and elevated calcitonin levels in blood. Treatment is total thyroidectomy and lymph node dissection.

There is currently no effective systemic treatment for MTC. The prognosis is highly variable; many patients live for years with metastases in liver, lung and bone.

Question 43

Control of PTH secretion

Answer 43

PTH causes a rise in serum calcium. High levels of
ionised calcium in plasma inhibit PTH secretion and vice versa by interaction with calcium sensing receptor proteins on the parathyroid cell surface. Activation of the receptors leads to an inhibition of PTH secretion. This is a negative feedback control mechanism.

The relationship is very sensitive. A small change in calcium levels results in large changes in PTH concentration. PTH secretion is also decreased by the action of vitamin D on PTH gene transcription.

Question 44

Physiological effects of PTH

Answer 44

PTH regulates the serum calcium level by a specific
receptor mediated effect on bone and kidney. In bone the effect is to produce resorption via osteoclastic activity.

The osteoclast binds to the bone surface and dissolves bone by the secretion of proteolytic enzymes. In the proximal tubule of the kidney, PTH increases the excretion of phosphate and increases the 1A-hydroxylation of 25-hydroxy-vitamin D; in the distal tubule PTH promotes calcium reabsorption.

PTH may also reduce, or inhibit, bicarbonate resorption in the renal tubules, resulting in an acidosis which will increase the degree of calcium ionisation and consequent resorption of calcium from bone. This will be reflected in a hyperchloraemic acidosis.

Question 45

Biochemical effects of raised PTH

Answer 45

Therefore, the biochemical changes which can
accrue from a raised, PTH level include:
• hypercalcaemia
• hypophosphataemia
• hyperchloraemia
• hypercalciuria (calcium resorption is
overwhelmed).

Question 46

Calcium homeostasis

Answer 46

1) In the body the main calcium store is in bone.

2) Lesser mounts are present in the soft tissues and extracellular fluid. Only a tiny fraction of the total body calcium is found in the intracellular compartment. There is a very tight regulation of both intra- and extracellular calcium
concentrations.

Question 47

Calcium production/Vitamin D

Answer 47

Calcium increased by:
PTH and 1,25-dihydroxy-vitamin D. PTH is the
more important for the immediate control of extracellular Ca2+ concentration.

Calcium decreased by:

Vitamin D (cholecalciferol) is synthesised from precursor 7 – dehydrocholesterol by sunlight on skin. Transported to liver and undergoes hydroxylation to produce 25-hydroxy-vitamin D.

The second hydroxylation takes place in the kidney
under the influence of PTH to form
1,25-dihydroxy-vitamin D, the most active metabolite.

In the gut a nuclear receptor stimulates a calcium binding protein that facilitates calcium absorption.

The effect of vitamin D on bone itself is complex:
at normal concentrations osteoblastic activity
is favoured. In excess, hypercalcaemia can arise from osteoclastically derived bone resorption.

A deficiency of vitamin D results in osteomalacia.

Calcitonin inhibits bone resorption by an effect on osteoclasts. It also favours the increased renal tubular excretion of calcium, with conservation of Mg2+. Its physiological role is unclear.

Patients who have had total thyroidectomy do not suffer from calcitonin deficiency. Therapeutic calcitonin is used in patients with severe Paget’s disease – the effects being mediated via its inhibitory effect on osteoclasts.

Question 48

Hypercalcaemia causes

Answer 48

Hypercalcaemia can occur as a result of:

• Hyperparathyroidism

• Disseminated malignancy due to bone destruction
or tumour secretion of PTH related peptide

• Sarcoidosis (due to production of 1,25(OH)2
vitamin D from its inactive form by a hydroxylase
enzyme in the macrophages of sarcoid tissue)

• Patients on vitamin D preparations, and those
on absorbable antacids for dyspepsia (milk-alkali
syndrome)

• Thyrotoxicosis, where there is a catabolic effect
of thyroxine on bone and a hyperdynamic state
of bone

• Thiazide diuretics

• Lithium

Question 49

Hyperparathyroidism

Answer 49

Hyperparathyroidism occurs in the following clinical
scenarios

• Primary hyperparathyroidism

• Secondary hyperparathyroidism

• Tertiary hyperparathyroidism

• Familial hyperparathyroidism

Question 50

Primary hyperparathyroidism

Answer 50

Primary hyperparathyroidism (HPT): Single benign adenoma in >80% of cases, remainder by multiple gland disease.

Parathyroid carcinoma is extremely rare. Symptoms which often do not correlate with the level of calcium or PTH include renal calculi, polyuria, polydipsia, bone pains, proximal myopathy, pancreatitis.

Non-specific symptoms such as fatigue and constipation are common. Pathological fractures are now extremely rare.

The biochemical changes in blood, favouring a diagnosis of hyperparathyroidism, include:

• Hypercalcaemia in the presence of an
inappropriately normal or elevated PTH

• Hyperchloraemia

• Raised alkaline phosphatase

• Hypophosphataemia

Radiological changes include
1) Generalised demineralisation of bone (best confirmed by low bone densitometry on DEXA-Dual-Energy X-ray Absorptiometry scan)
2) A ‘ground-glass’ appearance to the skull
3) Loss of lamina dura around the teeth (a sign almost pathognomonic of hyperparathyroidism)
4) Presence of ‘bone cysts’ – which are tumours comprising osteoclastic cells.

Question 51

Secondary hyperparathyroidism

Answer 51

Typically in patients with renal failure.

Reduced renal hydroxylation of vitamin D, hypocalcaemia and hyperphosphataemia result in chronic stimulation of
parathyroid gland growth and function.

Hypocalcaemia causes hyperplasia of all four glands = Asymmetric gland enlargement.

Investigations will usually show normal calcium, high phosphate levels and alkaline phosphatase, and very high levels of PTH.

Question 52

Tertiary hyperparathyroidism

Answer 52

Tertiary hyperparathyroidism This occurs when
parathyroid function becomes autonomous after renal transplantation and is associated with hypercalcaemia.

Question 53

Familial hyperparathyroidism

Answer 53

Familial hyperparathyroidism This is also seen in
the multiple endocrine neoplasia (MEN) syndromes and with non-MEN familial hyperparathyroidism (very rare).

Question 54

Familial benign hypocalciuric

Answer 54

Familial benign hypocalciuric hypercalcaemia (FBHH) is an autosomal dominant inherited disorder presenting with a mild hypercalcaemia and elevation of PTH.

It occurs as a result of an inactivating mutation of the calcium sensing receptor gene and is usually completely asymptomatic. Apart from hypocalciuria the condition may be biochemically indistinguishable from hyperparathyroidism.

The family history can assist in distinguishing the two complaints. Patients do not develop the complications of hypercalcaemia seen in HPT.

Surgery has no part in the management of these patients.

Question 55

Treatment of hypercalcaemia

Answer 55

Medical treatment of severe hypercalcaemia includes rehydration to correct dehydration caused by osmotic diuresis and intravenous bisphosphonate therapy.

Question 56

Hypocalcaemia

Answer 56

Hypocalcaemia most often an acute onset iatrogenic condition arising after planned total parathyroidectomy in patients with secondary hyperparathyroidism or, as a
result of the inadvertent removal or ischaemic injury
of the parathyroid glands during thyroidectomy.

Others:
1) Autoimmune polyglandular syndrome type 1
2) DiGeorge’s syndrome (absent parathyroid glands, immunodeficiency due to thymic aplasia and cardiac defects arising from abnormal embryological development of branchial pouches 3, 4 and 5)
3) Haemochromatosis
4) Wilson’s disease.

Question 57

Biochemical changes of hypocalcaemia

Answer 57

Hypocalcaemia
Inappropriately low or absent PTH and hyperphosphataemia. When hypoparathyroidism occurs acutely the patient
will complain of paraesthesia, i.e. tingling in the
fingers or in the lips, and carpopedal spasm.

Untreated severe hypocalcaemia can result in convulsions, tetany and cardiac arrhythmia. Chronic hypocalcaemia is associated in addition with cataract formation and demineralisation of bone.

Treatment of acute severe symptomatic hypocalcaemia includes intravenous calcium and in the longer term oral 1-alpha vitamin D, and calcium supplementation.

Question 58

Multiple Endocrine Neoplasia

Answer 58

MEN 1, 2A and 2B, and familial (non MEN) medullary thyroid cancer (FMTC) are autosomal dominant inherited syndromes associated with endocrine tumour formation.

MEN 1 occurs as a result of loss of function mutations of the MEN 1 tumour suppressor gene on chromosome 11 that encodes the nuclear protein Menin.

MEN 2A and 2B and FMTC are associated with an
activating mutation of the RET proto oncogene on
chromosome 10 that encode a tyrosine kinase receptor.

Question 59

MEN 1

Answer 59

1) Hyperparathyroidism is the most common component of MEN I. Multiple gland disease is invariable; supernumary glands are common (15%–20%).

2) Pancreatic and duodenal neuroendocrine
tumours are multiple; they may be functioning (gastrinoma !insulinoma!glucagonoma) and/or nonfunctioning and have malignant potential. Malignant duodeno-pancreatic disease is the most common cause of MEN 1-related death in these patients.

3) Anterior pituitary tumours > prolactinoma >growth hormone >ACTH) are usually diagnosed at approximately 40 years of age.

Question 60

MEN 2

Answer 60

Medullary thyroid carcinoma
occurs in 100% of gene carriers. MTC arises
from C cells that become hyperplastic then undergo
neoplastic transformation; the MTC is invariably bilateral and multifocal.

Onset in MEN 2B occurs in the first year of life, in MEN 2A around the age of five and in FMTC in late teens or early in the third decade.

Phaeochromocytoma may be asymptomatic, bilateral (synchronous or metachronous) and rarely malignant. Biochemical screening of gene carriers allows earlier diagnosis and treatment.