Case 17.2 – Hyperthyroidism (Graves Disease)

Italics = common symptoms

General:

• Weight loss despite normal or increased appetite
• Heat intolerance
• Fatigue, apathy
• Osteoporosis (fracture, loss of height)

Gastrointestinal:

• Diarrhoea, steatorrhoea, hyperdefecation
• Anorexia
• Vomiting

Cardiovascular:

• Palpitations
• Dyspnoea on exertion
• Angina
• Ankle swelling
• Exacerbation of asthma

Neuromuscular:

• Anxiety, irritability, emotional lability, psychosis
• Tremor
• Muscle weakness
• Periodic paralysis (predominantly in Chinese)

Dermatological:

• Sweating
• Pruritis
• Alopecia

Reproductive:

• Amenorrhoea/oligomenorrhoea
• Infertility
• Spontaneous abortion
• Loss of libido, impotence

Ocular:

• Grittiness, red eyes
• Excessive lacrimation
• Diplopia
• Loss of acuity

Italics = most common, Bold = Graves specific

General:

• Weight loss
• Goitre with bruit

Cardiovascular:

• Sinus tachycardia
• Atrial fibrillation
• Systolic hypertension/increased pulse pressure
• Cardiac failure

Haematological:

• Lymphadenopathy (rare)

Neuromuscular:

• Tremor
• Hyper-reflexia
• Ill-sustained clonus
• Proximal myopathy
• Bulbar myopathy (particularly in the elderly)

Dermatological:

• Palmar erythema
• Pretibial myxoedema
• Finger clubbing (thyroid acropachy)
• Spider naevi (rare)
• Onycholysis (rare)
• Pigmentation (rare)
• Vitiligo

Reproductive:

• Gynaecomastia

Ocular (Graves specific):

• Lid retraction, lid lag
• Chemosis
• Exophthalmos
• Periorbital oedema
• Corneal ulceration
• Ophthalmoplegia
• Papilloedema

TSH	T4	T3	Most likely interpretation(s)
Undetectable	Raised	Raised	Primary thyrotoxicosis
Undetectable	Normal	Raised	Primary T3-toxicosis
Undetectable	Normal	Normal	Subclinical thyrotoxicosis
Undetectable	Raised	Low, normal or raised	Sick euthyroidism/non-thyroidal illness
Undetectable	Low	Low	Secondary hypothyroidism (pituitary/hypothalamic disease) or transient thyroiditis in evolution
Elevated	High	High	Non-compliance with T4 replacement-recent 'loading' dose; Secondary thyrotoxicosis-TSH-secreting pituitary tumour; Thyroid hormone resistance

Pathophysiology of Graves' Disease:

• Graves thyrotoxicosis results from the production of IgG antibodies directed against the TSH receptor on the thyroid follicular cell
• These antibodies stimulate thyroid hormone production and, in the majority, goitre formation
• These antibodies are termed thyroid-stimulating immunoglobulins or TSH receptor antibodies (TRAb)
• Can be detected in the serum of 80-95% of patients with Graves' disease
• The concentration of TRAb in the serum is presumed to fluctuate to account for the natural history of Graves' thyrotoxicosis
• The ultimate thyroid failure seen in some patients is thought to result from the presence of blocking antibodies against the TSH receptor, and from tissue destruction by cytotoxic antibodies and cell-mediated immunity

Genetic factors:

• In Caucasians there is an association of Graves' disease with HLA-B8, DR3 and DR2
• Association with inability to secrete the water-soluble glycoprotein form of the ABO blood group antigens
• 50% of monozygotic twins are concordant for thyrotoxicosis, as opposed to 5% of dizygotic twins

Triggers:

• Infection with viruses or bacteria (unproven)
• Iodine supplementation (in regions of iodine deficiency, but only in those with pre-existing subclinical Graves' disease)
• Smoking is weakly associated with Graves' thyrotoxicosis, but strongly linked with the development of ophthalmopathy

Other Causes of Hyperthyroidism:

• Multinodular goitre
• Autonomously functioning solitary thyroid nodule
• Thyroiditis:
  • Subacute (de Quervain's)
  • Post-partum
• Iodine induced:
  • Drugs (e.g. amiodarone)
  • Radiographic contrast media
  • Iodine prophylaxis programme
• Extrathyroidal:
  • Factitious hyperthyroidism
  • Struma ovarii (Ovarian teratoma containing thyroid tissue)
• TSH induced:
  • TSH-secreting pituitary adenoma
  • Choriocarcinoma and hydatidiform mole (HCG is thyroid stimulating)
• Follicular carcinoma ± metastases

	Antibodies to:
	Thyroid peroxidase1	Thyroglobulin	TSH receptor2
Normal population	8-27%	5-20%	0%
Graves' disease	50-80%	50-70%	80-95%
Autoimmune hypothyroidism	90-100%	80-90%	10-20%
Multinodular goitre	30-40%	30-40%	0%
Transient thyroiditis	30-40%	30-40%	0%

¹Thyroid peroxidase antibodies are the principal component of what was previously measured as thyroid 'microsomal' antibodies.

²TSH receptor antibodies (TRAb) can be agonists (causing Graves' thyrotoxicosis) or antagonists (causing hypothyroidism).

Radio-iodine uptake tests measure the proportion of isotope which is trapped in the whole gland, but have been largely superseded by ^99mtechnetium scintigraphy scans which also measure trapping, are quicker to perform with a lower dose of radioactivity, and provide a higher resolution image.

Scintigraphy findings in different conditions:

• Graves' disease: Diffuse uptake of isotope throughout the gland
• Multinodular goitre (MNG): Relatively low, patchy uptake within the nodules; such an appearance is not always associated with a palpable thyroid
• Toxic adenoma: Lack of uptake of isotope by normal dormant gland due to suppression of serum TSH
• Low-uptake thyrotoxicosis (viral, post-partum or iodine-induced thyroiditis): Negligible isotope detected in the region of the thyroid, although uptake is apparent in nearby salivary glands

Definitive treatment of thyrotoxicosis depends on the underlying cause, and may include antithyroid drugs, radioactive iodine or surgery.

Beta-blockers (all patients):

• A non-selective β-adrenoceptor antagonist (β-blocker) will alleviate but not abolish symptoms within 24-48 hours
• Cannot be recommended for long-term treatment
• Extremely useful in the short term, e.g. for patients awaiting hospital consultation or following ¹³¹I therapy

Treatment	Common indications	Contraindications	Disadvantages/complications
Antithyroid drugs (e.g. carbimazole, propylthiouracil)	First episode in patients < 40 yrs Breastfeeding (propylthiouracil suitable)		>50% relapse rate usually within 2 years of stopping drug Hypersensitivity rash 2% Agranulocytosis 0.2%
Subtotal thyroidectomy	Large goitre Poor drug compliance, especially in young patients Recurrent thyrotoxicosis after course of antithyroid drugs in young patients	Previous thyroid surgery Dependence upon voice, e.g. opera singer	Hypothyroidism (25%) Transient hypocalcaemia (10%) Permanent hypoparathyroidism (1%) Recurrent laryngeal nerve palsy (1%)
Radio-iodine	Patients > 40 yrs Recurrence following surgery irrespective of age Other serious comorbidity	Pregnancy or planned pregnancy within 6 months of treatment Active Graves' ophthalmopathy	Hypothyroidism, approx. 40% in first year, 80% after 15 years Most likely treatment to result in exacerbation of ophthalmopathy

a) Mechanism of action of radioactive iodine:

• Radioactive iodine, ¹³¹I, is administered orally as a single dose and is trapped and organified in the thyroid
• Although it will decay within the thyroid in a few weeks, the effects of its radiation are long-lasting, with cumulative effects on follicular cell survival and replication
• The variable radio-iodine uptake and radiosensitivity of the gland means that the choice of dose is empirical
• Effective in 75% of patients within 4-12 weeks
• During the lag period, symptoms can be controlled by a β-blocker or, in more severe cases, by carbimazole
• However, carbimazole reduces the efficacy of ¹³¹I therapy because it prevents organification of ¹³¹I in the gland, and so should be avoided until 48 hours after radio-iodine administration
• If thyrotoxicosis persists after 12-24 weeks, a further dose of ¹³¹I should be employed
• The disadvantage of ¹³¹I treatment is that the majority of patients eventually develop hypothyroidism and long-term follow-up is, therefore, necessary

b) Surgery (Subtotal thyroidectomy):

Indications:

• Large goitre
• Poor drug compliance, especially in young patients
• Recurrent thyrotoxicosis after course of antithyroid drugs in young patients

Preparation:

• Patients must be rendered euthyroid with antithyroid drugs before operation
• Potassium iodide is often added before surgery to inhibit thyroid hormone release and reduce the size and vascularity of the gland, making surgery technically easier

Complications:

• Hypothyroidism (25%)
• Transient hypocalcaemia (10%)
• Permanent hypoparathyroidism (1%)
• Recurrent laryngeal nerve palsy (1%)
• Note: It is not only vocal cord palsy due to recurrent laryngeal nerve damage which alters the voice; the superior laryngeal nerves are frequently transected and result in minor changes in voice quality

Outcome:

• One year after surgery, 80% of patients are euthyroid, 15% are permanently hypothyroid and 5% remain thyrotoxic
• Thyroid failure within 6 months of operation may be temporary
• Long-term follow-up is necessary, as the late development of hypothyroidism and recurrence of thyrotoxicosis are well recognised

Thyrotoxic crisis ('thyroid storm'):

This is a rare, life-threatening increase in the severity of the clinical features of thyrotoxicosis.

The most prominent signs are:

• Fever
• Agitation
• Confusion
• Tachycardia or AF (and possibly cardiac failure in the older patient)

Why it is an emergency:

• It is a medical emergency
• Despite early recognition and treatment, the mortality rate is 10%

Precipitating factors:

• Most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis
• May develop shortly after subtotal thyroidectomy in an ill-prepared patient
• May occur within a few days of ¹³¹I therapy when acute irradiation damage may lead to a transient rise in serum thyroid hormone levels