Thyroid Disease

By
Dr.Bushra Mahmood Hussein
F.I.C.M Path
Learning objectives
• To understand
The mechanisms that regulate the hypothalamic-pituitary-thyroid
axis;
 The causes and features of thyroid dysfunction and the
investigations that should be performed when thyroid disease is
suspected;
 How to interpret the results of thyroid function tests for both
diagnosis and in monitoring treatment;
 The concept of subclinical thyroid disease and when treatment
should be implemented in such patients;
Introduction
• Thyroid hormones are essential for normal growth, development and
metabolism, and their production is tightly regulated through the
hypothalamic– pituitary–thyroid axis.
• Thyroid disease is common, particularly in women, and the
prevalence rises with age such that around 10% of the population
over 65 years of age may have some abnormality in thyroid function.
• Although primary diseases of the thyroid gland are the most
common, pituitary disease and the use of certain drugs can also give
rise to thyroid dysfunction. Once diagnosed, thyroid disease is easily
treated, with an excellent long-term outcome for most patients.
Thyroid hormone synthesis, action and
metabolism
• Synthesis and metabolism
• Thyroxine (T4) and small amounts of tri-iodothyronine (T3) and
reverse T3 (rT3) are all synthesized in the thyroid gland by a process
involving:
• Trapping of iodide from plasma by a sodium iodine symporter in the
thyroid.
• Oxidation of iodide to iodine by thyroid peroxidase.
• Incorporation of iodine into tyrosylresidues on thyroglobulin in the
colloid of the thyroid follicle. Mono-iodotyrosine (MIT) and di-
iodotyrosine (DIT) are formed.
• Production of T3 and T4 by coupling iodotyrosyl residues in the
thyroglobulin molecule.
• Splitting off of T4 and T3 from thyroglobulin following its
reabsorption from the colloid.
• Release of T4 and T3 into the circulation. These stages are shown
diagrammatically in Figure 1.1.
Figure 1.1 The synthesis of T3 and T4 in the
thyroid gland.
Hypothyroidism
Introduction

• Hypothyroidism is the most common disease in our country and

is caused by suboptimal circulating concentrations of thyroid
hormones.
• It becomes more prevalent with age, affecting about 6 per cent
of people over 60 years, and is more common in women.
• The condition may develop insidiously and in its early stages
may cause only vague symptoms.
Symptoms of hypothyroidism

• There is a generalized slowing down of metabolism, with lethargy,

bradycardia, depression and weakness.
• If the hormone deficiency is caused by a primary disorder of the
thyroid gland, the patient may present with weight gain, myopathy,
menstrual disturbances, such as menorrhagia, and constipation.
• The skin may be dry, the hair may fall out and the voice may be
hoarse.
• In severe cases, coma with profound hypothermia may develop.
Figure 2: Hypothyroidism women with depression
 Pathophysiology:
• As primary hypothyroidism develops, TSH secretion from the anterior pituitary gland
increases as the negative feedback (associated with the falling plasma T4 or fT4
concentration) decreases.
• Plasma T3 or fT3 concentrations may be normal and thus not usually useful in making
the diagnosis.
• Generally, in primary hypothyroidism the plasma TSH concentration is high, but it is low
in secondary hypothyroidism due to pituitary or hypothalamic disease.
• Initially, the plasma T4 or fT4 concentration may be within the population reference
range, although abnormally low for the individual. For this reason, the plasma TSH
concentration is the most sensitive index of early hypothyroidism. If the patient is very ill,
investigations should be deferred.
Figure 3: Hypothalamic–pituitary–thyroid axis (pathophysiology).

• Thyrotropin releasing hormone (TRH)

Stimulates the production and release
of thyrotropin (TSH). TSH stimulates the
thyroid gland to synthesize and secrete
thyroid hormone. T4 that is released by
the thyroid gland is mostly converted to
T3 by the liver and kidney. T3 and T4
feedback inhibit TSH release directly
through action at the pituitary and
indirectly by decreasing TRH release from
the hypothalamus.
Pregnancy and neonatal hypothyroidism:

• In about 0.3 per cent of pregnancies the mother has Hashimoto’s

disease. Thyroid hormones are essential for fetal development, hence
the importance of treating the mother with thyroxine.
• In neonatal hypothyroidism ,The head is broad, the eyes wide apart,
the tongue protrudes from the mouth and all movements and
responses are slow and sluggish; as seen in figure 3.
 Figure4:Congenital hypothyroidism. The head is broad,
the eyes wide apart, the tongue protrudes from the
mouth and all movements and responses are slow and
sluggish.
What is the causes of Hypothyroidism
 Multiple factors may contribute to
hypothyroidism, including:
• Iodine deficiency is the most common causes of hypothyroidism.
• Hashimoto's thyroiditis: This autoimmune disease is the most common cause of
hypothyroidism.
• Medications: Certain medications, such as lithium, can cause hypothyroidism.
• Pregnancy: Hypothyroidism can develop during or after pregnancy.
• Treatment for hyperthyroidism: People who have hyperthyroidism (overactive
thyroid) are treated with radioactive iodine therapy, which impairs thyroid
function and can cause hypothyroidism.
• Thyroid surgery: If your thyroid gland is removed, you can’t make thyroid
hormone, so you’ll need to take thyroid hormone replacement.
Diagnosis of Hypothyroidism
 Diagnosis
• A careful history should be taken and an examination performed, checking for a goiter.
The plasma TSH and total T4 or fT4 concentrations should be measured.
Slightly elevated plasma TSH and normal fT4 concentrations suggest compensated
hypothyroidism.
Measuring circulating thyroid antibodies may be useful, that is, anti-TPO. Tests should be
repeated after 3–6 months as some patients may develop full blown hypothyroidism.
Raised plasma TSH and low fT4 concentrations suggest primary hypothyroidism.
Low plasma TSH and low fT4 concentrations may indicate that the hypothyroidism is caused
by a hypothalamic or pituitary disorder.
Raised plasma TSH and raised/normal plasma fT4 concentrations in the presence of
hypothyroid symptoms may indicate thyroid hormone resistance.
Thyroid Hormone Replacement Therapy for
Hypothyroidism
 Treatment of hypothyroidism:
• This is usually with T4, which can be titrated until the plasma TSH is within
the reference range.
• On rare occasions, such as in hypothyroid comas, T3 is given instead, as its
action is more immediate.
• The response to T4 therapy can be checked every 2–3 months until the
patient is stable, after which 6- to 12-month blood checks may be useful.
• Thyroxine should be used with caution in patients with ischemic heart
disease for fear of worsening angina pectoris, and low doses initially plus b-
blockers may be indicated.
• Overtreatment with T4 can evoke atrial fibrillation and osteoporosis; in
such cases, plasma TSH concentrations are often low or suppressed.
 Subclinical hypothyroidism:
• Subclinical (compensated hypothyroidism) is the state in which
plasma TSH concentration is raised but the total or fT4 concentration
still falls within the reference range.
• In individuals over the age of 60 years, the prevalence may be as
high as 10 per cent. Some of these patients have positive thyroid
antibodies, for example anti-TPO or anti-Tg, and each year about 2–
5 per cent of thyroid antibody-positive patients go on to develop
hypothyroidism.
• Some patients may be asymptomatic, whereas others have symptoms
suggestive of hypothyroidism.
Hyperthyroidism
Hyperthyroidism (thyrotoxicosis)

• Hyperthyroidism causes sustained high plasma concentrations of T4 and T3.

There is often generalized increase in the metabolic rate, evidenced clinically by,
for example, heat intolerance, a fine tremor, tachycardia including atrial
fibrillation, weight loss, tiredness, anxiety, sweating and diarrhea.
• The following biochemical features may be associated with hyperthyroidism:
• Hypercalcaemia is occasionally found in patients with severe thyrotoxicosis.
There is an increased turnover of bone cells, probably due to a direct action of
thyroid hormone.
• Hypocholesterolaemia can occur, due to increased LDL clearance.
• Hypokalemia may also occur, associated with hyperthyrotoxic periodic
paralysis.
• Plasma SHBG is increased.
• Plasma creatine kinase may be increased with thyrotoxic myopathy.
Causes of hyperthyroidism
• Autonomous secretion
• Graves’ disease
• Toxic multinodular goitre (Plummer’s disease) or a single functioning
nodule (occasionally an adenoma)
• Subacute thyroiditis
• Some metastatic thyroid carcinomas
• Excessive ingestion of thyroid hormones or iodine
• Amiodarone
• Thyrotoxicosis factitia (self-administration of thyroid hormones)
• Administration of iodine to a subject with iodine deficiency goiter ,Jod–
Basedow syndrome
Rare causes
• Thyroid-stimulating hormone secretion by tumours, including
pituitary tumours or those of trophoblastic origin.
• Struma ovarii (thyroid tissue in an ovarian teratoma).
• Excess human chorionic gonadotrophin, e.g. molar pregnancy or
choriocarcinoma.
• Pituitary resistance to thyroid hormone.
Graves’ disease
• This is the most common form of thyrotoxicosis and occurs more
often in females than in males. It may be caused by relatively
autonomous secretion from a diffuse goitre and is characterized by:
• exophthalmos, due to lymphocytic infiltration and swelling of retro-
orbital tissues of the eyes (Fig. 4),
• localized thickening of the subcutaneous tissue over the shin
(pretibial myxoedema).
Figure 4. A patient with primary hyperthyroidism.
Note exophthalmos and diffuse thyroid swelling.
Subacute thyroiditis
• This is a destructive thyroiditis resulting in the release of preformed
thyroid hormones.
• There are three subtypes: granulomatous or painful, lymphocytic or
silent and painless, and post-partum.
• This condition is associated with extremely elevated thyroid
hormones and no radioactive iodine uptake by the thyroid gland.
• The clinical course progresses through 6–8 weeks of thyrotoxicosis,
2–4 months of hypothyroidism and a return to euthyroidism in about
90 per cent of patients.
Toxic nodules
• Toxic nodules, either single or multiple, in a nodular goitre may secrete
thyroid hormones autonomously.
• The secretion of TSH is suppressed by negative feedback, as in Graves’
disease.
• The nodules may be detected by their uptake of radioactive iodine or
technetium, with suppression of uptake in the rest of the thyroid tissue
(‘hot nodules’).
• Toxic nodules are found most commonly in older patients, who may
present with only one of the features of hyperactivity, usually
cardiovascular symptoms such as atrial fibrillation.
• Toxic multinodular goitre is also called Plummer’s disease.
Pathophysiology of hyperthyroidism
• Plasma T or fT and T and fT concentrations are usually increased in
4 4 3 3

hyperthyroidism.
• Much of the T is secreted directly by the thyroid gland, and the
3

increase in plasma T concentrations is greater, and usually evident

3

earlier, than that of T .

4

• Rarely, only plasma T and fT concentrations are elevated (T

3 3 3

toxicosis).
• In both situations, TSH secretion is suppressed by negative feedback,
and plasma TSH concentrations are either very low or undetectable.
Treatment
• The aetiology of hyperthyroidism must be fully investigated and treatment
started. Various forms of treatment are available, the selection of which depends
on the cause, the clinical presentation and the age of the patient.
• b-blocker drugs such as propranolol, which inhibit the peripheral conversion of
T4 to T3, may be used initially. Additional treatment includes the use of such
drugs as carbimazole or propylthiouracil. Carbimazole inhibits the synthesis of
T3 and T4; propylthiouracil additionally inhibits T4 to T3 conversion. Some
clinicians use block-and-replace regimens:
• Carbimazole is used to ‘block’ thyroid secretion, and simultaneous exogenous T4
maintains and replaces T4 concentrations.
• It is important to remember that carbimazole can have the potentially lethal side
effect of bone marrow suppression, and patients should be warned about
infections such as sore throats and about the need to have their full blood count
monitored.
• Radioactive iodine can be used in resistant or relapsing cases; surgery
is rarely indicated, but may have a place if there is a large toxic
goitre that is exerting pressure or if drug therapy fails but radioactive
iodine is contraindicated.
• Thyroid function must be checked regularly, as some patients may
become hypothyroid or may relapse after radioiodine or surgery.
• The progress of a patient being treated for hyperthyroidism is usually
monitored by estimating plasma TSH, fT and fT concentrations, and
4 3

trying to restore these to normal (although TSH concentration may

be slow to normalize).
• Overtreatment may induce hypothyroidism, with a rise in plasma TSH
concentrations and low plasma T4/fT4 and T3/fT3 concentrations. In some
patients with severe prolonged hyperthyroidism, such a rise in plasma TSH may
be delayed because of the effects of prolonged feedback suppression of T4 on the
pituitary.
• Subclinical hyperthyroidism
• Subclinical hyperthyroidism may occur with a low or suppressed TSH
concentration but normal (usually high-normal) plasma fT4 and fT3
concentrations.
• The condition may progress to full-blown hyperthyroidism with suppressed
plasma TSH and raised plasma fT4 and fT3 concentrations.
• Subclinical hyperthyroidism may be associated with atrial fibrillation, decreased
bone mineral density and other features of hyperthyroidism.
• Plasma TSI may be raised.
Laboratory investigation of suspected hyperthyroidism

• A careful history (including drugs) should be taken and examination

performed, checking for a goitre.
• The plasma TSH, fT3 and fT4 concentrations should be measured.
• The plasma fT4 and fT3 concentrations are clearly high and the TSH
concentration is suppressed in clinically thyrotoxic patients.
• In the face of suppressed plasma TSH, a clearly elevated plasma fT3
concentration confirms the diagnosis of hyperthyroidism.
• Remember that in T3 thyrotoxicosis the plasma fT4 may be normal.
• If the plasma fT4 concentration is raised and the TSH concentration is
normal, this is suggestive of biochemical euthyroid hyperthyroxaemia (see
below for causes).
• Measurement of thyroid antibodies is useful, particularly if the
concentration of TSIs is raised, which supports a diagnosis of Graves’
disease.
• The rare TSH-secreting pituitary tumours need pituitary assessment . a-
subunit concentrations may be useful, as they are usually raised in such
circumstances.
• In difficult cases, determination of plasma SHBG concentration can help
decide whether the patient is hyperthyroid, as it is lowered in
hypothyroidism and raised in hyperthyroidism.
• Radioiodine uptake studies of the thyroid can be useful to distinguish some
of the causes of hyperthyroidism.
• The TRH test is sometimes useful in the diagnosis of unclear cases.
Thank you