Thyroid disorders

Hadi Rabee’, MD
Internal Medicine Specialist
Arab and Palestinian Boards
 Outline
• Introduction.
• Laboratory tests.
• Hyperthyroidism and Grave’s disease
• Hypothyroidism and Hashimoto thyroiditis.
 Introduction
Physiology and Biochemistry
• Production of thyroid hormones is regulated by the hypothalamic–pituitary–thyroid axis.
• Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and induces thyroid-
stimulating hormone (TSH or thyrotropin) production in the anterior pituitary.
• TSH, in turn, stimulates thyroid hormone production and release by the thyroid gland.
• TSH production is inversely related to plasma thyroxine (T4) and triiodothyronine (T3) concentrations.
• The 2 primary hormones synthesized and secreted by the thyroid gland are T4 and, in lesser
quantities, T3.
• They are transported by plasma proteins—notably thyroid-binding globulin (TBG), transthyretin, and
albumin—to various tissue sites where T4 is deiodinated to the active form, T3, and the inactive form
known as reverse T3 (rT3).
• Thyroid hormones act through nuclear hormone receptors that are transcription factors for numerous
genes.
• These genes regulate a number of critical physiologic functions in development and metabolism.
 Laboratory tests
TSH:
• A “generational” classification has been applied for TSH immunoassays
based on the assay sensitivity.
• Third-generation assays can accurately measure TSH as low as 0.01 mU/L.
• This allows the physician to distinguish mildly subnormal TSH values from
the low values of overt hyperthyroid patients.
• The third-generation tests are also useful for evaluating the effectiveness
of the thyroid hormone replacement in hypothyroid patients.
• Third-generation assays are essential for monitoring TSH suppression
therapy in patients with a TSH-responsive thyroid tumor.
 Cont ..
• The relationship between TSH and the thyroid hormones, particularly free T4, is
an inverse log-linear one, such that very small changes in free T4 result in large
changes in TSH.

• Thus, TSH is the most sensitive first-line screening test for suspected thyroid
abnormalities.

• If the TSH is within the normal reference range, no further testing is performed.

• If the TSH is outside of the reference range, a free T4 is obtained.

 Cont ..
Total Thyroid Hormone Measurements:
• Assays are available for both total T4 and total T3 measurements.
• These assays are quite specific and suffer little interference. However, transient changes in serum
thyroid hormone-binding protein concentrations may affect total T4 and T3 concentrations.
• Therefore, an assessment for free T4 is usually more helpful in evaluating thyroid function.
• The concentration of T4 in the blood is usually 100 to 200 times greater than the T3 level.
• In hyperthyroidism, total T3 and T4 concentrations correlate in all but a small subset of patients
who have an elevation only in T3. For that reason, T3 should be measured in the serum of
patients clinically suspected to be hyperthyroid and who have normal concentrations of serum
T4.
• Measurement of T3 concentrations has limited clinical utility in assessment of hypothyroidism.
• Significant decreases in total T3 are seen in euthyroid sick syndrome (ETS).
 Cont ..
Free Thyroid Hormones and Thyroid Hormone-binding Capacity
• “Direct” free thyroid hormone assays, without the need for a preliminary step to separate free
hormones from hormones bound to protein carriers, are available for measurement of free T4
and free T3.
• Only a small fraction of T4 (<0.1%) circulates unbound to proteins, and this has made the
accurate quantitation of free T4 analytically difficult.
• Free T4 is a better indicator of thyroid status than total T4 because, as noted above, the total T4
is altered by changes in the amounts of TBG, albumin, and other thyroid hormone-binding
proteins.

• About 0.3% of T3 circulates as free T3.

• In general, free T3 concentrations correlate well with total T3, but as with T4, the
concentrations of thyroid hormone-binding proteins influence the total T3 level
 Cont ..
Reverse Triiodothyronine (rT3):
• Under acute stress or in illness, there is a shift in the T4 deiodination
in favor of the inactive rT3 form rather than the active T3.
• rT3 is markedly increased in euthyroid sick syndrome (ETS
syndrome)?, but its measurement is rarely required for this diagnosis
because its increase is proportional to the decrease in T3.
 Cont ..
Antithyroid Antibodies
• Antithyroid antibodies are present in approximately 15% of the general population and are the
most common cause of thyroid disease in iodine-replete societies.
• They are also present in selected autoimmune diseases not usually associated with thyroid
dysfunction.
• Descriptions of 3 types of antithyroid antibodies follow:
• Antimicrosomal/antithyroid peroxidase antibodies (anti-TPO)—These antibodies are directed
against a protein component of thyroid microsomes, the enzyme TPO.
• They are present in almost all patients with Hashimoto thyroiditis, in about 85% of patients with
Graves disease, and in some patients with type 1 insulin-dependent diabetes mellitus, celiac
disease, and Addison disease.
• An elevated titer of anti-TPO antibodies in the context of clinical symptoms of thyroid dysfunction
and abnormal TSH and free T4 results is diagnostic for autoimmune thyroid disease. y test is
 Cont ..
• The presence of TPO antibodies before or during pregnancy is a good predictor of those
women who will develop postpartum thyroid disease.
• Normal concentrations are not well established because the antibodies may be found in
healthy people (up to 12% of the population), and the reference range depends on the
method used to perform the test.

• Antithyroglobulin antibodies—These are also called colloidal antibodies. They are present in
more than 85% of patients with Hashimoto thyroiditis and in more than 30% of patients with
Graves disease.
• Like anti-TPO, antithyroglobulin antibodies also may be found in other autoimmune diseases.
• In iodine-sufficient areas, the antithyroglobulin antibodies used less often, in favor of anti-
TPO.
 Cont ..
• TSH receptor antibodies—These are a diverse group of immunoglobulins that bind to TSH
receptors and influence their action.
• They are found in most patients with Graves disease and in patients with selected other
autoimmune disorders involving the thyroid.
• The biological functions of these antibodies vary from thyroid stimulation to thyroid inhibition
(by blocking stimulation induced by TSH).
• Antibodies referred to as thyroid-stimulating immunoglobulins are present in 95% of patients
with untreated Graves disease.
• In vitro bioassays can assess the ability of stimulatory antibodies to induce functional responses
in cultured cells by measuring cyclic adenosine monophosphate increases or adenylate cyclase
activity.
• Assays are available that measure the capability of the inhibitory antibodies, called thyrotropin-
binding inhibitory immunoglobulins, to block the binding of labeled TSH to its receptors
 Hyperthyroidism
• Also known as thyrotoxicosis, is a collection of disorders associated with excess thyroid hormone.
• There are 4 main causes of hyperthyroidism:
• 1) overstimulation of the thyroid (elevated TSH, [hCG], and/or TSH receptor autoantibodies [TRAbs]).
• 2) genetic mutations leading to increased synthesis and secretion of thyroid hormone (germline, sporadic, or
tumor induced).
• 3) release of excess hormone from the thyroid (inflammation, infection, injury).
• 4) extrathyroidal sources of thyroid hormone (ectopic thyroid tissue or exogenous hormone).

• Patients with hyperthyroidism demonstrate a spectrum of hypermetabolic features, including

nervousness, palpitations, muscle weakness, increased appetite, diarrhea, heat intolerance, warm
skin, weight loss, and perspiration.
• Affected patients may have exophthalmos, emotional changes, menstrual changes, and a fine
tremor of the hands
 Cont ..
• In the presence of a clinical history and physical examination
consistent with hyperthyroidism, a diagnosis of hyperthyroidism
(but not necessarily its cause) can be established by the
demonstration of a low TSH level and a high free T4.
• In uncommon situations, only the total T3 level is elevated and the
serum free T4 is normal (T3 thyrotoxicosis).
• To determine the etiology of the hyperthyroidism, additional
testing is usually necessary.
• Graves disease, toxic multinodular goiter (TMNG), and toxic
adenoma account for the vast majority (>95%) of cases of
hyperthyroidism.
• It should be noted that diffuse or focal enlargement of the thyroid
gland, also known as goiter, can be associated with hyperfunction,
normal function, and hypofunction of the gland.
 Graves disease
• Graves disease is a relatively common hyperthyroid disorder occurring
more frequently in women.
• It has a familial predisposition.
• It is an autoimmune disease caused by TSH receptor antibodies
(TRAbs) that bind to and stimulate TSH receptors resulting in the
autonomous production of thyroid hormone.
• While many patients have the classic signs and symptoms of
thyrotoxicosis, in elderly patients with Graves disease, apathy, muscle
weakness, and cardiovascular abnormalities occur more often than
hypermetabolic symptoms.
 Cont ..
• Laboratory tests show undetectable TSH and increased free T4.
• In some cases, the T3 is elevated and the T4 is normal.
• The differential diagnosis includes TMNG, toxic adenoma, painless
and subacute thyroiditis, ectopic thyroid tissue.
• Detection of TRAbs along with the results from radioactive iodine
uptake and nuclear thyroid scans are helpful in distinguishing among
these possibilities.
• There is usually diffuse increased radioactive iodine uptake in Graves
disease.
 Hypothyroidism
• When hypothyroidism occurs during development and in infancy, it results in a condition
known as cretinism, which is marked by retardation of physical and intellectual growth.
• In 95% of cases, hypothyroidism originates in the thyroid gland itself.
• If a patient has an increased serum TSH and a decreased free T4—together with
appropriate clinical symptoms—a diagnosis of hypothyroidism is confirmed.
• In asymptomatic patients, increased TSH, accompanied by a normal free T4, is known as
subclinical hypothyroidism and may be indicative of the early stages of primary
hypothyroidism.
• High titers of anti-TPO antibodies suggest Hashimoto thyroiditis or postpartum thyroid
dysfunction in a postpartum woman.
• In the United States, autoimmunity is the main cause of hypothyroidism,but iodine
deficiency is the primary cause worldwide.
 Cont ..
• Hypothyroidism also may be a result of inadequate stimulation of the
thyroid by TSH. This is known as secondary hypothyroidism.
• A subnormal free T4 with a decreased or inappropriately normal TSH
is suggestive of secondary hypothyroidism from decreased TSH
production.

• Clinical pictures of hypothyroidism differ, depending on the age:

• Congenital hypothyroidism is characterized by low production of thyroid
hormones and can result in growth and intellectual delay if untreated. In the
United States, all states screen for congenital hypothyroidism.
 Cont ..
• In adults, hypothyroidism can have an
insidious onset, especially in the elderly.
• Symptoms are usually nonspecific in the early
stage and then progress to more definitive
characteristics of hypothyroidism with dry
hair, dry skin, periorbital puffiness, dull
expression, large tongue, and enlarged heart.
• If untreated, myxedema coma with
respiratory failure may occur.
• Treatment involves hormone replacement.
 Hashimoto Thyroiditis
• Hashimoto thyroiditis is a common chronic inflammatory disease of the thyroid that
accounts for as many as 90% of all cases of hypothyroidism in areas of iodine sufficiency.
• Autoimmune factors are thought to be the cause.
• Hashimoto thyroiditis is often associated with other autoimmune diseases such as
Sjögren syndrome and pernicious anemia.
• Patients with Hashimoto thyroiditis carry anti-TPO and antithyroglobulin antibodies.
• Firm thyroid enlargement and goiter is characteristic.
• Patients typically have an increased TSH and may have a normal free T4 and an elevated
radioactive iodine uptake in the early stage of the disease.
• Over time, serum T4 declines first, followed by a decline in T3 as hypothyroid symptoms
become predominant.