Clinical Pharmacology and Therapeutics

CHAPTER 38
THYROID
● Introduction 292
● Pathophysiology and principles of treatment 292
● Iodine 292
● Thyroxine and tri-iodothyronine 293
● Antithyroid drugs 293
● Special situations 295
INTRODUCTION
The thyroid secretes thyroxine (T 4 ) and tri-iodothyronine (T 3 ),
as well as calcitonin, which is discussed in Chapter 39. The
release of T 3 and T 4 is controlled by the pituitary hormone thyrotrophin
(thyroid-stimulating hormone, TSH). This binds to
receptors on thyroid follicular cells and activates adenylyl
cyclase, which stimulates iodine trapping, iodothyronine synthesis
and release of thyroid hormones. TSH is secreted by
basophil cells in the adenohypophysis. Secretion of TSH by the
anterior pituitary is stimulated by the hypothalamic peptide
thyrotrophin-releasing hormone (TRH). Circulating T 4 and T 3
produce negative-feedback inhibition of TSH at the pituitary
and hypothalamus.
Drug treatment is highly effective in correcting under- or
over-activity of the thyroid gland. The diagnosis of abnormal
thyroid function and monitoring of therapy have been greatly
facilitated by accurate and sensitive assays measuring TSH,
because the serum TSH level accurately reflects thyroid state,
whereas the interpretation of serum concentrations of T 3 and T 4
is complicated by very extensive and somewhat variable protein
binding. Negative feedback of biologically active thyroid hormones
ensures that when there is primary failure of the thyroid
gland, serum TSH is elevated, whereas when there is overactivity
of the gland, serum TSH is depressed. Hypothyroidism
caused by hypopituitarism is relatively uncommon and is associated
with depressed sex hormone and adrenal cortical function.
Hyperthyroidism secondary to excessive TSH is extremely rare.
Hyperthyroidism is also common and again autoimmune
processes are implicated. Treatment options comprise:
• antithyroid drugs;
• radioactive iodine;
• surgery.
Antithyroid drugs enable a euthyroid state to be maintained
until the disease remits or definitive treatment with radioiodine
or surgery is undertaken. Radioactive iodine is well
tolerated and free of surgical complications (e.g. laryngeal
nerve damage), whereas surgery is most appropriate when
there are local mechanical problems, such as tracheal
compression.
In older patients, the most common cause of hyperthyroidism
is multinodular toxic goitre. In young women it is
usually caused by Graves’ disease, in which an immunoglobulin
binds to and stimulates the TSH receptor, thereby promoting
synthesis and release of T 3 and T 4 independent of TSH. In
addition to a smooth vascular goitre, there is often deposition
of mucopolysaccharide, most notably in the extrinsic eye muscles
which become thickened and cause proptosis. Graves’ disease
has a remitting/relapsing course and often finally leads to
hypothyroidism. Other aetiologies of hyperthyroidism include
acute viral or autoimmune thyroiditis (which usually resolve
spontaneously), iatrogenic iodine excess (e.g. thyroid storm
following iodine-containing contrast media and hyperthyroidism
in patients treated with drugs, such as amiodarone;
see below and Chapter 32), and acute postpartum
hyperthyroidism.
PATHOPHYSIOLOGY AND PRINCIPLES OF
TREATMENT
Thyroid disease is more common in women than in men, and is
manifested either as goitre or as under- or over-activity of the
gland. Hypothyroidism is common, especially in the elderly.
It is usually caused by autoimmune destruction of the gland
and, if untreated, leads to the clinical picture of myxoedema.
Treatment is by lifelong replacement with thyroxine.
IODINE
The thyroid gland concentrates iodine. Dietary iodide normally
amounts to 100–200 mg per day and is absorbed from
the stomach and small intestine by an active process.
Following systemic absorption and uptake into the thyroid
gland, iodide is oxidized to iodine, which is the precursor to
various iodinated tyrosine compounds including T 3 and T 4 .
Iodine is used to treat simple non-toxic goitre due to iodine