Thyroid: I Thyroid Gland and Thyroid Hormones
Clinical scenario
Nodular thyroid disease is common, affecting approximately 5% of the
female population over the age of 50. Women are affected more commonly than men
and the incidence increases with age. A 59-year-old lady, Mrs RB, presented
with a long history of a swelling in the anterior neck. This had gradually
increased in size over the years and had now become quite obviously visible.
She had no dysphagia or dyspnoea, the thyroid gland was not painful, she did
not have a hoarse voice and there was no history of previous radiotherapy
treatment to the neck. She had no symptoms to suggest abnormal thyroid hormone
production and on examination she was clinically euthyroid. The thyroid gland
was asymmetrically enlarged with a 3 × 4 cm nodule palpable in the right lobe
together with three other palpable nodules. The gland moved freely on
swallowing and there was no associated lymphadenopathy. Her thyroid function
tests were normal as follows: fT4 18.3 pmol/L; TSH 0.85 mU/L; thyroid antibodies negative. Thyroid ultrasound scanning revealed a multinodular goitre.
Fine-needle aspiration of the dominant nodule was performed and cytology of the
aspirate showed no evidence of malignant cells. She decided to undergo conservative
management with regular clinical follow-up.
Clinical management of patients with nodular thyroid disease depends upon
excluding the presence of malignant disease and then treating the goitre
according to its size, patient preference and the likelihood of compression of
other structures in the neck and mediastinum (Fig. 13a). In patients with
compressive symptoms, CT scanning will reveal the extent of pressure on
adjoining structures in the neck.
Thyroid gland: anatomy and structure In humans, the thyroid gland
is situated anteriorly in the neck (Fig. 13b), and its function is the
synthesis and secretion of the thyroid hormones thyroxine (T4) and
tri-iodothyronine (T3). These hormones are essential for normal
development and growth and for homoeostasis in the body by regulating energy
production. The parathyroid glands, which secrete parathyroid hormone (see
Chapter 49) are embedded in the thyroid gland, and the parafollicular cells,
which are scattered between the thyroid follicles, produce calcitonin (see
Chapter 50). The human thyroid gland begins to develop at around 4 weeks after
conception, and moves down the neck while forming its characteristic bilobular
structure, which is completed by the third trimester.
In the normal adult, the gland has two lobes, weighs around 25 g and is
situated close to the trachea (Fig. 13b). The gland is composed of well over a
million clusters of cells, or follicles. These are spherical and consist of
cells surrounding a central space containing a jelly-like substance known as
colloid, whose function is to store thyroid hormones prior to their secretion.
Each thyroid cell has three functions: (i) exocrine, because it secretes
substances into the colloid; (ii) absorptive, because it takes up substances from the colloid by pinocytosis; and (iii)
endocrine, because it secretes hormones directly into the bloodstream.
Thyroid hormones
Synthesis. The follicle cells have in their basement membrane an
iodide-trapping mechanism which pumps dietary iodide into the cell (Fig.13c).
The pump is very powerful, and the cell can concentrate iodide to 25–50 times
its concentration in the plasma. Thyroid iodine content is normally around 600 μg/g
tissue.
Uptake enhancers include: (i) TSH; (ii) iodine deficiency; (iii) TSH receptor antibodies; and (iv)
autoregulation. Uptake inhibitors include: (i) I− ions; (ii)
cardiac glycosides (e.g. digoxin); (iii) thiocyanate (SCN−); and
(iv) perchlorate (PClO−). Inside the cell, iodide is rapidly
oxidized by a peroxidase system to the more reactive iodine, which immediately
reacts with tyrosine residues on a thyroid glycoprotein called thyroglobulin,
to form monoiodotyrosyl (T1) or diiodotyrosyl (T2)
thyroglobulin. These then couple to form tri-iodothyronine (T3) or
thyroxine (T4) residues (Fig. 13d), still attached to thy-roglobulin,
which is stored in the colloid (i.e. Tl + T2 = T3;
T2 + T2 = T4). This process is
stimulated by TSH.
Under TSH stimulation, colloid droplets are taken back up into the cell
cytoplasm by micropinocytosis, where they fuse with lysosomes and are
proteolysed to release the residues from the glycoprotein. T1 and T2
are rapidly deiodinated by halogenases, and the liberated iodine is recycled in
the follicle cell. Tri-iodothyronine and thyroxine (Fig. 13e) are released into
the circulation, where they are bound to plasma proteins, including
thyroxine-binding globulin (TGB), thyroxine-binding prealbumin (TBPA) and
albumin (see Chapter 15). Most is bound and physiologically inactive, while
only the free fraction is active. Metabolism (Fig. 13e). The thyroid
secretes a total of 80–100 μg of T3 and T4 per day, and
the ratio of T4:T3 is about 20:1. Although both T3
and T4 circulate, the tissues obtain 90% of their T3 by
deiodinating T4. Iodide liberated from thyroid hormone is excreted
in the urine or is recirculated to the thyroid, where it is concentrated by the
trapping mechanism. About one-third of T4 leaving the plasma is
conjugated with glucuronide or sulphate in the liver and excreted in the bile.
A small proportion of the free T4 is reabsorbed via the
enterohepatic circulation. The half-life of T4 in the plasma is
about 6–7 days; that of T3 is very much shorter, being about 1 day.
T3 is much more potent
than is T4.
Mechanism of action of thyroid hormone. There are multiple sites
of action of T3 in the cell. At the membrane, the hormone stimulates
the Na+/K+–ATPase pump, resulting in increased uptake of
amino acids and glucose, which causes calorigenesis (heat production). T3
combines with specific receptors on mitochondria to generate energy and with
intranuclear receptors which are transcription modulators, resulting in altered protein synthesis.
