Hyperthyroidism: MBChB 4, University of KwaZulu-Natal – 2018

Important: These notes are intended to complement the PowerPoint slides. References to
additional resources are included in the PowerPoint slides.

Useful reference:

Lancet, Volume 388, Issue 10047, 27 August–2 September 2016, Pages 906-918

General:

Hyperthyroidism is a common syndrome, with a number of different causes, leading to specific

symptoms and signs. The condition is more common in women and increases in frequency with
increasing age.

The Hypothalamic-pituitary-thyroid axis and thyroid physiology:

A brief review of the relevant physiology is important to understand the condition, including the
diagnostic biochemical tests.

Hypothalamic thyroid stimulating hormone-releasing hormone (TRH) stimulates the anterior

pituitary to release thyroid stimulating hormone (TSH). TSH binds to specific receptors on the thyroid
and stimulates the synthesis and release of the two important thyroid hormones thyroxine (T4) and
liothyronine (T3). T4 is synthesised in thyroid epithelial cells by the incorporation of iodine into the
amino acid tyrosine. Iodine is actively pumped into the thyroid epithelial cells and in the cytoplasm,
is organified by thyroid peroxidase. Mono- and di-iodinated tyrosine couple to form T4 and T3.
These hormones are stored in the thyroid colloid, until required. Release of thyroid hormone starts
with endocytosis of thyroglobulin-containing T4 and T3, hydrolysis of tyrosine and release of T4 and
T3 into the circulation. Most of the hormone produced by the thyroid is T4. Both T3 and T4 feed
back to the hypothalamus and pituitary to regulate TRH and TSH secretion. T4 is converted to T3 by
a de-iodinase enzyme and T3 binds to nuclear thyroid hormone receptors ( and ) to initiate the
physiologic effects of thyroid hormone. This process is shown in a number of diagrams in the
PowerPoint slides.

Hyperthyroidism: Aetiology

The conditions associated with thyrotoxicosis may be divided into those in which there is increased
thyroid hormone synthesis and release and those without increased activity of the thyroid gland.

Increased thyroid hormone synthesis:

 Graves’ disease
 Toxic multinodular goitre
 Toxic adenoma
 Iodine-induced hyperthyroidism
 Trophoblastic tumour
 TSH-secreting pituitary adenoma

Absence of increased thyroid hormone synthesis:

 Thyroiditis (immune-mediated, or post-infectious)
 Exogenous thyroid hormone
 Ectopic thyroid tissue
Graves’ disease, toxic multinodular goitre, toxic adenoma and Hashimoto’s (immune-mediated)
thyroiditis, account for > 90% of all cases of thyrotoxicosis.

Clinical features:

Symptoms:

General:

 Weight loss, despite increased appetite

 Weakness
 Heat intolerance and increased sweating
 Alopecia

Cardiovascular:
 Palpitations
 Decreased effort tolerance

Neuromuscular:
 Tremor
 Nervousness, anxiety
 Emotional lability
 Insomnia
 Poor concentration
 Muscle weakness
 Diplopia (selected instances)

Gastrointestinal:
 Frequent bowel movements
 Dysphagia may occur if there is retrosternal extension of a goitre and mediastinal
obstruction

Signs:

Thyroid:

 A goitre is not always present

 Graves’ disease is associated with diffuse enlargement of both thyroid lobes and a systolic
bruit may be heard over the lobes
 Multinodular goitre is irregular, firm, non-tender and does not have a bruit
 Thyroiditis may be associated with tender diffuse enlargement of the thyroid
 A large goitre may extend into the thoracic cavity and this may be associated with a positive
Pemberton’s sign. A description of Pemberton’s sign, with a video, may be found at: New
England Journal of Medicine, 31 May 2018, volume 378:e3. DOI: 10.1056/NEJMicm1712263
 Horner’s syndrome is rare and, if present, mandates consideration of malignant thyroid
disease
General signs:

 Warm, sweaty hands, with palmar erythema

 Thyroid acropachy – a rare extra-thyroidal manifestation of Graves’ disease. This has the
appearance of clubbing
 Thyroid dermopathy (pre-tibial myxoedema) – specific for Graves’ disease. This is thickened,
irregular skin, often pigmented, over the anterior shin and almost always occurring in
association with Graves’ orbitopathy. Photographs of this condition are in the PowerPoint
slides
 Cervical lymphadenopathy may occur in Graves’ disease

Cardiovascular:
 Tachycardia, increased pulse volume
 Systolic hypertension
 Arrhythmias – usually supra-ventricular (atrial fibrillation)
 High-output cardiac failure may occur
 Means-Lerman scratch – heard in the pulmonary area and thought to represent friction
between pericardial and pleural membranes in the hyperdynamic state

Eyes:
 Lid-lag and lid retraction occur in all forms of hyperthyroidism
 Exophthalmos is specific for Graves’ disease
o Eyes appear congested and red, with swelling of the eye lids and oedema of the
conjunctivae
o Ophthalmoparesis may be present and is due to thickening and weakness of extra-
ocular muscles
 Myasthenia gravis may coexist with Graves’ disease

Neuromuscular:
 Tremor
 Proximal myopathy

Diagnosis:
Clinical diagnosis requires laboratory confirmation as well as additional investigations to determine
the aetiology of the thyrotoxic state.

Laboratory diagnosis:
 Serum TSH is suppressed and undetectable in all cases, except the rare instance of a TSH-
secreting pituitary adenoma
 Serum free T4 and free T3 levels are increased and the degree of increase usually correlates
with the clinical severity of the condition
 In Graves’ disease, anti-TSH receptor antibodies are elevated as well as anti-thyroid
peroxidase and anti-thyroglobulin antibodies
 In Hashimoto’s (immune-mediated) thyroiditis, anti-thyroid peroxidase and anti-
thyroglobulin antibodies are usually markedly elevated and anti-TSH receptor antibody is not
detected
Thyroid ultrasound: Ultrasound does not provide any diagnostic information, but is useful in
determining the size and characteristics of the lobes of the thyroid and to assess in more detail for
retrosternal extension.

Isotope thyroid scan: Two isotopes are used to determine the functional state of the thyroid: 131
Iodine and Technetium 99. In the local setting, Technetium 99 is exclusively used as the diagnostic
isotope. Both are used to measure uptake of the isotope, as a reflection of the degree of activity of
the gland. Different patterns provide useful information in assigning an aetiology to the thyrotoxic
state:
 Diffuse increase in uptake: Graves’ disease, trophoblastic disease
 Patchy uptake with areas of increased and decreased uptake: toxic multinodular goitre
 Single area of increased uptake with suppression of the rest of the gland: toxic adenoma
 Generalised reduction in uptake: thyroiditis, exogenous or ectopic thyroid hormone excess
and iodine-induced thyrotoxicosis

Specific conditions:

Graves’ disease

Refer to: New England Journal of Medicine 20 October 2016; 375: 1552-1565.
DOI:10.1056/NEJMra1510030

Graves’ disease is a common form of hyperthyroidism, often affecting young women (male: female
ratio 1:10). The specific cause of the condition is unknown, but it is known that there is genetic
susceptibility, encoded in HLA genes as well as others (thyroglobulin gene, CTLA-4 gene). The
precipitating event is unknown and infections, emotional stress, exposure to iodine are postulated
precipitants. Treatment with an anti-CD52 antibody may lead to Graves’ disease. The combination of
genetic and environmental factors leads to the development of autoimmunity directed at the
thyroid. Specific IgG antibodies are produced, with specificity for the TSH receptor. Anti-TSH
receptor antibodies competitively bind to the thyroid TSH receptor and provide an unregulated
stimulus for thyroid hormone production, leading to the hyperthyroid state. Anti-TSH receptor
antibodies are present in over 80% of patients with Graves’ disease and the titre of the antibody has
prognostic value in determining the response to anti-thyroid therapy. In addition, in pregnancy, this
antibody crosses the placenta and stimulates the fetal thyroid. The majority of patients will also have
elevated levels of anti-thyroglobulin and anti-thyroid peroxidase antibodies. These are not involved
in the pathophysiology of the condition.

Clinical features of Graves’ disease:

Patients typically present with symptoms and signs of hyperthyroidism, associated with a smooth,
diffuse goitre, with a thyroid bruit. There may be evidence of thyroid dermopathy (pre-tibial
myxoedema), acropachy or ophthalmopathy. Graves’ disease may be associated with other organ-
specific autoimmune diseases, such as type 1 diabetes, myasthenia gravis, vitiligo and primary
adrenocortical insufficiency.

Graves’ ophthalmopathy:
This occurs in 25% of patients with Graves’ disease. There are 3 major pathophysiologic features:
inflammation of peri-orbital soft tissues, excess production of glycosaminoglycans by orbital
fibroblasts and hyperplasia of orbital adipose tissue. The extra-ocular muscles swell and weaken due
to infiltration with glycosaminoglycans. The increase in orbital content leads to the clinical
manifestations of this condition. The patients develop proptosis, diplopia, excess tear production
and watery eyes, with redness of the conjunctivae. In a small number of patients, the condition is
severe enough to threaten sight, due to compression of the optic nerve or exposure of the cornea.

Toxic multinodular goitre:

This usually affects older adults. A pre-existing goitre is often present and this may have been noted
for many years. As one or more of the nodules grows and becomes autonomous, progressive
hyperthyroidism develops. The patient usually has less severe hyperthyroidism than those with
Graves’ disease. On clinical examination, there is a multinodular goitre, with signs of
hyperthyroidism, excluding the signs that are only seen in Graves’ disease. Anti-TSH, anti-
thyroglobulin and anti-thyroid peroxidase antibodies are absent.

Toxic adenoma:
This is a condition that evolves slowly over time, as the single thyroid nodule grows and secretes
excess thyroid hormone in an autonomous fashion. Clinical hyperthyroidism is usually encountered
in adults in the 30-40 year age group. Palpation of the thyroid will disclose the presence of a single
nodule. Anti-TSH, anti-thyroglobulin and anti-thyroid peroxidase antibodies are absent.

Thyroiditis:
In thyroiditis, thyroid inflammation, either due to autoimmunity or following an infection, leads to
damage or destruction of thyrocytes and the release of pre-formed thyroid hormone into the
circulation. The inflammatory nature of the condition leads to anterior neck pain, which may radiate
to the jaw. Thyrotoxicosis is transient – as the inflammation subsides, normalisation of thyroid
hormone levels occurs. Hypothyroidism may develop if there has been significant thyroid injury. In
autoimmune thyroiditis (Hashimoto’s thyroiditis), there is infiltration of the thyroid with
lymphocytes and very high levels of anti-thyroglobulin and anti-thyroid peroxidase antibodies are
found. These antibodies are absent in the subacute post-infectious (de Quervain’s) thyroiditis.

Treatment of thyrotoxicosis:

The options of treatment are as follows:

 Symptomatic (beta-blockers)
 Anti-thyroid drug therapy (carbimazole)
 Radioactive iodine
 Surgery

Beta-blockers: Propranolol or atenolol (non-selective) beta-blockers control the heart rate and
decrease the tremor in patients with thyrotoxicosis. These are contraindicated in patients with
asthma and cardiac failure and are relatively contraindicated in patients with concomitant
myasthenia gravis.

Carbimazole: This is the only anti-thyroid drug in South Africa. Carbimazole is converted to
thiamazole (the active form) and this is actively transported into the thyroid where it inhibits thyroid
peroxidase, reducing iodine organification and inhibiting the coupling of iodotyrosines. Carbimazole
is used in a dose of 10 to 40 mg daily, depending on the severity of thyrotoxicosis. Minor adverse
effects include skin reactions and pruritus. Agranulocytosis is an infrequent but severe adverse effect
and is usually reversible if the drug is stopped. Hepatotoxicity is another potentially severe adverse
effect. Carbimazole is used to control various forms of hyperthyroidism, but it will not be effective in
thyroiditis.

Radioactive iodine: 131 Iodine is administered orally in a dose of 10-15 mCi (millicuries). The
radioactive iodine is taken up by the overactive thyroid and radiation is emitted into the thyroid
tissue; this destroys thyroid tissue over a period of weeks and thereby decreases thyroid hormone
production. The inflammatory response to tissue destruction may lead to increase in the size of the
goitre temporarily and there may be cross-reaction with orbital antigens, leading to exacerbation of
ophthalmopathy. The degree of thyroid destruction with radioactive iodine results in
hypothyroidism in the majority of patients treated with this modality. Radioactive iodine is
contraindicated in pregnancy and lactation and in patients with severe ophthalmopathy.

Surgery: Sub-total thyroidectomy effectively controls hyperthyroidism and is an important

treatment modality in selected patients. Prior to surgery, thyrotoxicosis must be fully controlled,
with carbimazole. Similarly to radioactive iodine, the majority of patients develop hypothyroidism
after surgery. Complications related to surgery include injury to the recurrent laryngeal nerve and
resection of parathyroid glands, leading to hypoparathyroidism.

Choice of therapy: Since none of the available therapies are curative, the modalities of treatment
are used in an individualised manner. General guidelines regarding the choice of therapy are as
follows:

 Graves’ disease in a younger patient: carbimazole for 18-24 months; in this period, 30-50% will
undergo spontaneous remission.
 Graves’ disease and adverse effects of carbimazole, or failure to remit after 24 months of
therapy: radioactive iodine.
 Graves’ disease in pregnancy: carbimazole (noting the potential for teratogenicity (aplasia cutis,
choanal atresia, oesophageal atresia, omphalocoele)).
 Any form of hyperthyroidism with retrosternal extension and mediastinal obstruction: surgery.
 Toxic multinodular goitre, toxic adenoma: radioactive iodine in the majority, surgery for
compressive effects.
 Thyroiditis: beta-blockers and if severe, a short course of glucocorticosteroids.
 Hyperthyroidism and cardiac failure: carbimazole and usual anti-failure therapy.

Specific issues:

 Graves’ ophthalmopathy: mild ophthalmopathy is treated with topical lubricants and topical
glucocorticosteroids. Severe disease is treated with intravenous methylprednisolone and sight-
threatening ophthalmopathy is managed with orbital decompression or orbital radiotherapy.

 Thyroid storm: a rare, severe form of hyperthyroidism, often associated with an acute illness.
Patients may have hyperpyrexia, cardiac arrhythmia, cardiac failure, agitation, delirium and
coma. Management includes high dose carbimazole (20 mg 6-hourly), Lugol’s iodine 0.25 ml 6-
hourly, propranolol 60-80 mg 4-6 hourly, hydrocortisone 100 mg 8-hourly, paracetamol and
supportive therapy. In addition, any associated acute illness requires treatment.