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Theme 2 : THYROID DISEASES

Study goals:

To recollect main points in physiology and anatomy relatively to thyroid

structure and function.

To acquaint students with aetiology, pathogenesis, clinical sighs, and specific

investigations of common thyroid diseases.

To learn general principles of treatment of thyroid diseases.

Duration of the lecture: 2 hours
Learning resources: schemes, multimedia, text books.
Plan of the lecture:
1. Core concepts in anatomy and physiology
2. Hyperthyroidism
3. Hypothyroidism
Learning resources: schemes, multimedia, text books.
1.

CORE CONCEPTS IN ANATOMY AND PHYSIOLOGY

Thyroid gland consists of two lobes (right and left) one on either side of the
trachea and isthmus which connects them together in the front of the neck
The thyroid gland produces three hormones: triiodothyronine (T 3), thyroxine
(T4) and thyrocalcitonin (calcitonin, TCT). Iodine is necessary in the thyroid hormone
synthesis. Adequate iodine intake should be 150-200 g per day.
Thyroid hormones are involved in the regulation of the following physiological
processes:
Growth and development
Thermoregulation, calorigenesis
Cardiovascular effect
Metabolism of proteins, carbohydrates, and lipids
The secretion of T3 and T4 are under the control of thyroid-stimulating hormone
(TSH), which is in turn under thyrotropin-releasing hormone (TRH).
Iodine (organic and inorganic) is absorbed in gastrointestinal tract in the form of
iodide. Iodide following active transport enters the thyroid gland. The trapped iodide
is oxidised by peroxidase system to active iodine. Active iodine iodinates the tyrosine
residue of glycoprotein and forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).
This process is called iodide organification. Two molecules of DIT form T4. whereas
MIT with DIT produces T3 (condensation process).
20 % of T3 volume comes from thyroid gland secretion. Another 80% are
derived from T4 deiodination in peripheral tissues (liver, kidneys). Normal T3 is three
to five times more potent than T4. Thats why T4 is considered as prohormone, while
T3 as hormone.

Impaired deiodination of T4 produce two types of T3: normal T3 and reverse T3

(without feedback effect).
The majority of hormones bind to thyroid-binding proteins: thyroxine-binding
globulin (TBG) and to much lesser extent thyroid-binding prealbumin (TBPA).
Thyroid diseases may be accompanied by functional derangement or/and
morphological changes. This means that certain thyroid disease may induce different
functional changes and that certain functional disorder may be caused by wide variety
of thyroid diseases. Functional state may be divided into: hypothyroidism,
hyperthyroidism, euthyroidism. Thyroid morphology can be denoted as diffuse,
nodular and mixed.
2.

HYPERTHYROIDISM

Hyperthyroidism is a common clinical condition of various diseases (Graves

disease, Plummers disease, toxic adenoma, thyroiditis, other).
GRAVES DISEASE
0.5 % of the population suffers from hyperthyroidism in adults.
Graves disease is the most common cause of hyperthyroidism.
Graves disease occurs five-eight times more often in females than in males.
Usual period of life when Graves' disease frequently appears is 4th-5th decades.
Graves disease is characterised by recidivations and remissions.
Other names of Graves disease are: Diffuse toxic goiter, Primary toxic goiter,
Basedow-Graves disease.
Definition. Graves disease is hereditary dependent an autoimmune disease,
which is usually characterised by hyperthyroidism, goiter, exophthalmos, and
pretibial myxedema.
Hyperthyroidism (thyrotoxicosis) is the syndrome resulting from the excessive
production of thyroid hormones. Goiter means thyroid enlargement. Exophthalmos is
the pathologic protrusion of the eyeballs. Pretibial myxedema is considered as
nonpitting edema of the pretibial areas.
Thyrotoxicosis is the term which mostly used to denote excessive ingestion of
thyroid hormones or iodine. Iodine-induced thyrotoxicosis appears following chronic
intake of inorganic iodine (amiodarone, potassium iodide), while iatrogenic
thyrotoxicosis is caused by hormone overdosing (levothyroxine sodium,
liothyronine). Treatment of iatrogenic hyperthyroidism should be directed toward
cancellation of hormone intake.
Aetiology
Hereditary predisposing markers in whites is HLA-B8 or -DR3, in Asians
HLA-BW35.

Defect of antigen specific T supressor.

Triggering factors: viruses and bacterial infections (Spumaviruses, Yersinia
enterocolitica, Mycoplasma), emotional crisis, pregnancy.
Pathogenesis
Thyrocytes express HLA and together with thyroid specific antigen bind T-helper
through T-cell T3 receptor complex stimulating B cells to produce antibodies against
TSH receptor.
TSH receptor antibodies, as suspected may be also originated from TSH receptor
like antigens presented in some bacteria and viruses.
Inability of antigen-specific T-suppressor to inhibit T-helper activity results in the
unregulated generation of TSH receptor antibodies.
TSH receptor antibodies bind to TSH receptors presented on the thyroid follicular
cell and stimulate thyroid hormone production.
TSH receptor antibodies is considered as thyroid-stimulating immunoglobulins
(TSI).
The higher level of TSI the more severe is hyperthyroidism.
Clinical picture
Nervous system (nervousness, anxiety, inner tension, emotional lability, poor
concentration, tremor).
Cardiac system (tachycardia).
Eyes (wide-eyed stare, angry look).
Gastrointestinal system (hunger and weight loss, hyperdefecation with
predisposition to diarrhoea).
Musculoskeletal system (lean and exhaustion appearance, reduced muscles ability
in walking, climbing, muscle weakness).
Skin (warm, sweating, moist palms).
Thyroid gland (usually enlargement).
Diagnostic approach
Inquiry of the patient (anamnesis of the disease and life).
Physical examination (visual inspection, palpation, auscultation).
Laboratory findings (TSH, T4, T3, TSI, antibodies to thyroid peroxidase).
Instrumental investigations (ultrasonography, radioisotope studies).

Treatment approach
1. Medicamentous therapy (pathogenetic and symptomatic treatment ).
2. Radioiodine therapy (radical treatment).
3. Subtotal thyroidectomy (surgery).
Medicamentous therapy
Pathogenetic treatment
Agents that inhibit iodide trapping
Potassium perchlorate and other monovalent anions such as pertechnetate, nitrate,
and thiocyanate in the different drug compositions
Monovalent anions (perchlorate, pertechnetate, nitrate, thiocyanate) in the
different drug compositions competitively inhibit accumulation of iodide. Effect of
their action is reversible. Drugs abolition causes immediate surge in T 3 and T4 with
aggravation of clinical status. These drugs are now obsolete and mostly no longer
used, except Potassium perchlorate that may be administered in the treatment of
Iodine-induced thyrotoxicosis. Cabbages contain thiocyanate and is called goitrogenic
vegetable.
Potassium perchlorate. Dosage: 0.5-1 g per day q.i.d.
Adverse effects
Aplastic anaemia which may be fatal is the main side effect. Discontinuation of
potassium perchlorate worsen thyrotoxicosis. Used only if other treatment are
contraindicated.
Agents that inhibit the synthesis of thyroid hormones
Thiamazole (Mercazolilum)
Propylthiouracil (Propacil)
In order to inhibit synthesis, thionamides (Thiamazole and Propylthiouracil)
suppress iodide organification and condensation. They decrease the synthesis of T3
and T4
blocking iodide into tyrosine incorporation and condensation of
monoiodotyrosine and diiodotyrosine. It is suggested that both of them are able to
inhibit synthesis of TSI. Propylthiouracil additionally inhibit peripheral T 4 conversion
into T3 or activate T4 transformation into inactive reverse T3. Onset of thionamides
effect takes within 3-4 weeks until the thyroid stores of T3 and T4 become depleted.
Propylthiouracil. Dosage: 300-600 mg per day q.i.d.
Thiamazole. Dosage: 30-60 mg per day t.i.d. or once a day in the morning.
Adverse effects
The usual side effects include fever, skin rash, myalgia, arthralgia, nausea,
jaundice. The most common problem is hypothyroidism as a result of long-lasting

treatment. Agranulocytosis is reported rare. Thionamides cause thyroid enlargement

because the negative feed-back effect to TSH is absent.
Drug interactions
Propylthiouracil can cause hypoprothrombinaemia.
Agents that decrease thyroid hormone release
Potassium or sodium iodide (Lugols Solution);
Sodium ipodate (Oragrafin);
Iopanoic acid (Telepaque).
High levels of iodide inhibit the synthesis of thyroid hormones while small
doses, on the contrary, are necessary in hormone synthesis. Nevertheless iodide
suppression is not beneficial for long lasting treatment (more than 10 days). Its effect
is reversible. Subsequently, the thyroid gland escapes the iodide press with large
resulting concentration of iodide. It can be used when prepare patients for surgery,
because iodine reduces thyroid vascularity. Sodium ipodate and iopanoic acid are
radiographic contrast agents. They additionally possess potent property to inhibit
peripheral conversion of T4 to T3 .
Potassium iodide. Dosage: 5 drops (by 200 mg iodide) per day.
Sodium ipodate and iopanoic acid. Dosage: 1 g per day.
Adverse effects
The most common adverse effects are: rash, hypersalivation, pruritus, sore
gums, and headache. Sudden withdrawal of iodides precipitates thyroid storm.
Symptomatic treatment
Beta-adrenergic blockers
Corticosteroids
Beta-adrenergic blockers do not cure the thyroid gland but inhibit sympathetic
reactions (tremor, anxiety, tachycardia, nervousness, sweating). As the euthyroid state
is obtained, dose should be tapered and subsequently discontinued. Besides,
nonselective beta blockers produce modest reduction in serum T 3 level by blocking
conversion T4 to T3.
Large doses of dexamethasone also inhibit peripheral conversion of T4 to T3. 2-4
weeks therapy may be indicated for severe hyperthyroidism.
Propranolol. Dosage: 80-120 mg per day t.i.d.
Dexamethasone. Dosage: 8 mg per day.
Adverse effects
Beta-adrenergic blockers mask real patient feelings thus making clinical
observation unusable.

Radioiodine therapy
Radical treatment
Radioactive iodide I131 (Iodotope)
Radioactive iodide behaves like dietary iodide and accumulates in the storage
follicles. It emits gamma (X-rays) and beta rays. X-rays alter thyroid growth and
activity, while beta-radiation destroys overactive tissue. I 131 should be given only to
people beyond their reproductive years, because of the potential carcinogenic effect
in young adults and children.
Radioiodine-131. Dosage: usually 4-10 mCi (millicurie) in the correspondence
to the following calculation 60-80 Ci/g of the thyroid estimated weight.
Adverse effects
I131 therapy causes acute release of thyroid hormones usually about 5-10 days
after ingestion as a result of ablation of thyroid tissue. Another problem is
hypothyroidism which develops at the rate of 10-15% in the first year after I 131
treatment.
Subtotal thyroidectomy
Surgery treatment should be considered in cases that suggest possible malignancy
(nodule, hoarseness, pain, rapid growth of the goiter), when Graves disease is
accompanied by advancing ophthalmopathy, in a pregnant patients with serious
contraindications to other therapy.
3.

HYPOTHYROIDISM

Hypothyroidism may occur as a result of thyroid and non-thyroid disorders.

Lack of thyroid hormones in childhood produces cretinism (mental and physical
retardation).
Thyroid hormone deficiency is presented with myxedema which denotes specific
nonpitting edema.
Definition. Hypothyroidism is the syndrome that is characterised by thyroid
hormone deficiency.
Aetiology
Hypothyroidism may develop as a result of primary, secondary, tertiary, and
peripheral causes.
Primary pathologic base includes Hashimoto disease, state after radioactive iodine
or surgical treatment of Graves disease or in the late stages without such therapy,

different thyroiditis, hereditary inability to synthesise thyroid hormones, congenital

aplasia, severe lack of iodine in environment, etc.
Secondary and tertiary causes involve congenital or acquired pathologies of
pituitary gland and hypothalamus respectively.
Peripheral hypothyroidism may be presented following peripheral tissue resistance
to effect of thyroid hormones or loss of hormones during nephritis or enterocolitis.
Pathogenesis
Pathogenesis depends on the type of hypothyroidism.
Primary hypothyroidism is characterised by decreased T4 and T3 concentration
that causes elevation of TSH and prolactin (PRL). TSH stimulates thyroid
enlargement, formation of cysts, adenomas, etc. PRL causes galactorrhea and
amenorrhea.
Secondary and tertiary hypothyroidism present with low TSH level that is usually
accompanied with deficiency of other anterior pituitary hormones results in
hypocorticism, hypogonadism, etc.
In peripheral hypothyroidism TSH, T4, and T3 levels are high. Increased levels of
peripheral hormones try to compensate tissue resistance.
Mucopolysaccharide (hyaluronic acid and chondroitin sulphate) infiltration of the
tissue is the base of specific clinical appearance of edema.
Clinical picture
Nervous system (myxedema madness, signs of intellectual and memory
impairment, drowsiness, slow speech, depression).
Cardiac system (bradycardia, cardiomegaly, reduced voltage of the ECG and flat T
waves).
Eyes (drooped eyelids, swollen periorbital tissue).
Gastrointestinal system (weight gain, predisposition to obstipation, achlorhydria,
pernicious anaemia, ascites).
Musculoskeletal system (joint effusions, arthralgia, muscle cramps, high level of
creatinine phosphokinase).
Reproductive system (amenorrhea, galactorrhea).
Skin (coarse features, dry, scaly, thick, and cool skin, nonpitting edema, yellowish
colour due to carotenaemia).
Thyroid gland (small as a result of hypoplasia or aplasia, enlargement suggests
Hashimoto thyroiditis with hypothyroid state).
Diagnostic approach

Inquiry of the patient (anamnesis of the disease and life).

Physical examination (visual inspection, palpation, auscultation).
Laboratory findings (TSH, T4, FT4 , T3, TRH tests, anaemia, hyperlipidemia).
Instrumental investigations (ultrasonography, radioisotope studies, magnetic
resonance imaging scan).
Treatment approach
Replacement therapy
1. (sodium levothyroxine)
2. Triiodthyronini hydrochloridum (Liothyronine)
3. Synthetic T4T3 combination (Liotrix)
Synthetic thyroxine (Sodium levothyroxine). Dosage: 50-200 g/day
Synthetic triiodothyronine (Liothyronine). Dosage:
Synthetic T4T3 combination (Liotrix). Dosage:

Thyroid crisis
Clinical features are delirium, fever, tachycardia, dehydration and diarrhoea. It is
a medical emergency. Treat with: rehydration, intravenous beta-blocker, potassium
iodide, carbimazole and dexamethasone.
Hypothyroidism
General
Treatment is directed at replacement of the thyroid hormone deficiency. Two
preparations are available: thyroxine (T4) and tri-iodothyronine (T3), although the
latter is rarely used.
Mechanism
These preparations provide replacement therapy by stimulation of metabolism,
growth and maturation.
Pharmacokinetics
Both T4 and T3 are adequately absorbed following oral administration. T4 has a
half-life of about a week and T3 of about 2 days. Both undergo liver conjugation and
enterohepatic circulation.
Adverse effects. These are related to physiological and pharmacological actions
of thyroid hormone.
Elderly patients or those known to have ischaemic heart disease must receive
low initial doses with slow increments since angina, infarction, tachyarrhythmias or
heart failure can be precipitated. Excess dosage produces the features of
hyperthyroidism.
Dose

Thyroxine: Starting dose is 0.05 mg/day (0.025 mg/day if old or with heart
disease) with dose increments every 2-3 weeks depending on thyroid function.
After studying this chapter you should know the following terms, meanings and
explanations given below in the order of their appearance:
CORE CONCEPTS IN ANATOMY AND PHYSIOLOGY
Thyroid gland, Adequate iodine intake, Thyroid hormones, Physiological processes,
TSH, TRH, Organification, Condensation, Deiodination in peripheral tissues,
Prohormone, TBG.
HYPERTHYROIDISM
Graves disease, Goiter, Exophthalmos, Pretibial myxedema, Thyrotoxicosis,
Iatrogenic hyperthyroidism, Iodine-induced thyrotoxicosis, Aetiology, Pathogenesis,
Clinical picture, Diagnosis, Medicamentous therapy, Pathogenetic treatment, Agents
that inhibit iodide trapping, Agents that inhibit the synthesis of thyroid hormones,
Agents that decrease thyroid hormone release, Symptomatic treatment, Radioiodine
therapy, Radical treatment, Subtotal thyroidectomy.
HYPOTHYROIDISM
Cretinism, Myxedema, Hypothyroidism, Aetiology, Pathogenesis, Clinical picture,
Diagnosis,