Thyroid Gland

THE THYROID AXIS

 The metabolism of virtually all nucleated cells of
many tissues is controlled by the thyroid
hormones. Overactivity or underactivity of the
gland are the most common of all endocrine
problems.
ANATOMY AND HISTOLOGY
 The thyroid is one of the largest of endocrine organs,
weighing about 15 to 20 gm in adults, with each lobe
being approximately 4 cm (height) × 2 cm (width) × 2 to
2.5 cm (thickness).
 The thyroid gland consists of two lateral lobes connected
by an isthmus, which is approximately 2 cm in height and
width, and 0.5 cm in thickness. It is closely attached to the
thyroid cartilage and to the upper end of the trachea, and
thus moves on swallowing. It is often palpable in normal
women.
 Embryologically it originates from the base of the tongue
and descends to the middle of the neck. Remnants of
thyroid tissue can sometimes be found at the base of the
tongue (lingual thyroid) and along the line of descent. The
gland has a rich blood supply from superior and inferior
thyroid arteries.
 The gland is formed of follicles, which are filled with colloid
(the iodinated glycoprotein thyroglobulin) which is
synthesized by the follicular cells.
 From the apex of follicular cells, numerous microvilli extend
into colloid. It is at or near this surface of the cell that
iodination, exocytosis and the initial phase of hormone
secretion occur.
 Colloid contains thyroglobulin (Tg) molecules in which
thyroid hormones are present. The lining cells of the follicle
are cuboidal epithelioid cells in the inactive phase and
columnar in the active phase.
 About 20 to 40 follicles are grouped to form a lobule, which
is demarcated by connective tissue septa and supplied by a
single artery.
 Each follicle is surrounded by basement membrane,
between which are parafollicular cells containing calcitonin-
secreting C cells, which participates in calcium metabolism.
 SYNTHESIS AND SECRETION OF
THYROID HORMONES
 Synthesis. The thyroid synthesizes two iodine
containing hormones: Triiodothyronine (T3), which
acts at the cellular level and tetraiodothyronine or L-
thyroxine (T4), which is the prohormone.
 Iodide is a key substrate for thyroid hormone
synthesis; a dietary intake in excess of 100 μg/day is
required to maintain thyroid function in adults.
 After active uptake of iodine by the follicular cell,
inorganic iodide is oxidized by the enzyme thyroid
peroxidase (TPO), followed by iodination of tyrosine
molecules on the surface of thyroglobulin (Tg), a
protein secreted into the colloid of the follicle, to form
monoiodotyrosine (MIT) and diiodotyrosine (DIT).
 Monoiodotyrosine (MIT) and diiodotyrosine (DIT) are
then coupled in varying proportion to form T3 and T4,
a reaction also catalysed by TPO.
 Thyroglobulin (Tg) is then processed in lysosomes
to release T4 and T3 in circulation, while the
uncoupled MIT and DIT are deiodinated by
dehalogenase thereby recycling iodine.
 The thyroid gland contains enough stored
hormone to maintain a euthyroid state for at least
6 to 8 weeks.
 The thyroid secretes predominantly thyroxine (T4)
and only a small amount of triiodothyronine (T3);
approximately 85% of T3 in blood is produced
from T4 by a family of monodeiodinase enzymes
that are active in many tissues, including liver,
muscle, heart and kidney. Selenium is an integral
component of these monodeiodinases.
THYROID HORMONE TRANSPORT AND ACTION
 Thyroid hormone exists in circulation in both free
and bound form.
 In plasma, more than 99% of all T4 and T3 is
bound to hormone-binding proteins (thyroxine-
binding globulin, TBG; thyroid-binding
prealbumin, TBPA; and albumin). Only free
hormone is available for action in the target
tissues, where T3 binds to specific nuclear
receptors within target cells.
 Many drugs and other factors affect TBG; all may
result in confusing total T4 levels in blood. Most
laboratories therefore now measure free T4 levels
as they are not influenced by changes in the
concentration of binding proteins.
 For example, TBG levels are increased by
oestrogen (such as in the combined oral
contraceptive pill) and this will result in
raised total T3 and T4, although free thyroid
hormone levels are normal.
REGULATION OF THYROID HORMONE
SECRETION
 Thyroid stimulating hormone or thyrotrophin (TSH), released from
the anterior pituitary, stimulates all steps in the formation and
release of thyroid hormones, and the conversion of T4 to T3.
 Control of the hypothalamic-pituitary-thyroid axis.
 Thyrotrophin-releasing hormone (TRH), a peptide produced in the
hypothalamus, stimulates the anterior pituitary to secrete thyroid-
stimulating hormone (TSH). TSH in turn stimulates growth and activity of
the thyroid follicular cells via the G-protein coupled TSH membrane
receptor.
 The T3 and T4 subsequently secreted into the circulation by follicular cells
exert negative feedback on the hypothalamus. Circulating T4 is
peripherally deiodinated to T3 which binds to the thyroid hormone
nuclear receptor (TR) on target organ cells to cause modified gene
transcription.
 Somatostatin, glucocorticoids, cytokines such as IL-1 and TNF-α,
phenytoin and dopamine suppress TSH secretion.
 In turn, TSH and TRH secretion is inhibited by T4, forming a
negative feedback loop that keeps free T4 levels within a narrow
range.
 Production of T3 and T4 in the thyroid is
stimulated by thyrotrophin (thyroid-
stimulating hormone, TSH), a glycoprotein
released from the thyrotroph cells of the
anterior pituitary in response to the
hypothalamic tripeptide, thyrotrophin-
releasing hormone (TRH).
 There is a negative feedback of thyroid
hormones on the hypothalamus and pituitary
such that in thyrotoxicosis, when plasma
concentrations of T3 and T4 are raised, TSH
secretion is suppressed.
 Conversely, in hypothyroidism due to disease
of the thyroid gland, low T3 and T4 are
associated with high circulating TSH levels.
 The anterior pituitary is, though, very sensitive
to minor changes in thyroid hormone levels
within the reference range. For this reason,
TSH is usually regarded as the most useful
investigation of thyroid function.
 However, interpretation of TSH values without
considering thyroid hormone levels may be
misleading in patients with pituitary disease; for
example, TSH is inappropriately low or ‘normal’ in
secondary hypothyroidism.
 Moreover, TSH may take several weeks to ‘catch
up’ with T4 and T3 levels; for example,
levothyroxine therapy will raise T4 and T3 levels
within approximately 2 weeks but it may take 4–6
weeks for the TSH to reach a steady state.
 Other modalities commonly employed in the
investigation of thyroid disease include
measurement of
◦ antibodies against the TSH receptor or other thyroid
antigens,
◦ radioisotope imaging,
◦ fine needle aspiration biopsy and
◦ ultrasound.
Physiological effects of thyroid hormones.
IODINE DEFICIENCY DISORDERS (IDDs)
 Iodine is the key trace element required for thyroid hormonogenesis.
The recommended dietary allowance (RDA) for iodine in a non-
pregnant adult is 150 mcg/day, while that in a pregnant female is
200 mcg/day.
 Iodine content in food and water depends critically on the iodine
content of the soil. Soil iodine content is increased by plants that
concentrate iodine, colloids that absorb iodine and by an acid pH,
while it is decreased by repeated flooding and by an alkaline pH. Sea
food and sea weed are rich sources of dietary iodine.

 Iodide in the plasma is taken up via active transport into the thyroid
follicular cells, a process which becomes more efficient in the iodine
deficiency state. Iodine deficiency results in enlargement of the
thyroid to enhance the ability of the glands to trap iodine. The term
endemic goitre is used to describe goitre seen in a population with
iodine deficiency.
 An area is defined to be endemic if more than 5% of children,
between 6 to 12 years of age, are found to have goitre.
 Other manifestations of iodine deficiency depend on the
severity and age at exposure.
 Endemic cretinism is a state of severe congenital
hypothyroidism occurring in an endemic area.
 Two clinical types are recognised:
◦ neurological cretinism characterised by mental retardation,
abnormal speech and hearing, diplegia, and strabismus;
◦ myxoedematous type, characterised by prominent features of
hypothyroidism, mental retardation and short stature.
 Learning disability has been described even in euthyroid
children living in endemic areas.
 Exposure to iodine deficiency during pregnancy is also
associated with abortions, stillbirths, increased foetal
anomalies and perinatal mortality.
 Dietary iodine requirement.
 Globally, dietary iodine deficiency is a major
cause of thyroid disease, as iodine is an essential
requirement for thyroid hormone synthesis. The
recommended daily intake of iodine should be at
least 140 μg, and dietary supplementation of salt
and bread has reduced the number of areas
where ‘endemic goitre’ still occurs.
CLINICAL EVALUATION
 During clinical examination the exact dimensions of
the thyroid gland can be documented, while in
epidemiological studies goitre can be graded as
follows:
 Grade 0: No visual or palpable goitre.
 Grade 1: A goitre that is palpable, but not visible when
the neck is in the normal position. Thyroid nodules in
a thyroid which is otherwise not enlarged are included
in grade 1.
 Grade 2: A swelling in the neck that is clearly visible
when the neck is in normal position and is consistent
with an enlarged thyroid when the neck is palpated.
 Goitre is said to be present when each lateral lobe has
a volume greater than the terminal phalanx of the
thumb of the subject being examined.
Thyroid function tests
 Immunoassays for free T4, free T3 and TSH are widely available. There are
only minor circadian rhythms, and measurements may be made at any time.
Particular uses of the tests are summarized in Table 19.13, with typical
findings in common disorders.
 TSH measurement
 In most circumstances, TSH levels can discriminate between hyperthyroidism,
hypothyroidism and euthyroidism (normal thyroid gland function). Exceptions
are hypopituitarism, and the ‘sick euthyroid’ syndrome where low levels
(which normally imply hyperthyroidism) occur in the presence of low or
normal T4 and T3 levels. As a single test of thyroid function TSH is the most
sensitive in most circumstances, but accurate diagnosis requires at least two
tests, e.g. TSH plus free T4 or free T3 where hyperthyroidism is suspected,
TSH plus serum free T4 where hypothyroidism is likely.
 TRH test
 This has been rendered almost obsolete by modern sensitive TSH assays
except for investigation of hypothalamic-pituitary dysfunction. TRH
(protirelin) is occasionally used to differentiate between thyroid hormone
resistance and TSHoma in the context of raised fT4 and TSH levels. Typically,
after TRH administration there is a rise in TSH in thyroid hormone resistance,
whilst in TSHoma there is a flat response due to continued autonomous TSH
secretion which does not respond to TRH.