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Thyroid Physiology

The thyroid gland consists of two lobes connected by an isthmus and is located in the lower neck.

Follicular cells synthesize, store, and release two major metabolically active hormones: tetra-iodothyronine (Thyroxine, T4) and tri-iodothyronine (T3), which are primarily responsible for regulating metabolism.

Most T4 is converted to T3 outside the thyroid.

Thyroid hormones are essential for proper fetal growth and development, especially of the central nervous system (CNS).

After delivery, thyroid hormones mainly regulate energy metabolism.

Thyroid hormones affect the function of virtually every body organ, and the parafollicular cells of the thyroid gland produce calcitonin.

T4 and T3 are produced through the organification of iodine in the thyroid gland, where iodine is actively transported into follicular cells.

Inorganic iodine is oxidized by thyroid peroxidase and covalently bound to tyrosine residues of thyroglobulin; iodinated tyrosine residues, monoiodotyrosine, and diiodotyrosine combine to form T4 and T3.

Around eighty percent of thyroid hormone is synthesized as T4.

Thyroid hormones are released from the gland as needed, primarily under the influence of TSH.

T4 and T3 are transported in the blood by three proteins: albumin, thyroid-binding globulin, and transthyretin.

T4 is 99.97% protein bound, and T3 is 99.7% protein bound, with only the unbound fractions being physiologically active.

The high degree of protein binding results in a long half-life, approximately 7 to 10 days for T4 and 24 hours for T3.

Most of the physiologic activity of thyroid hormones comes from the action of T3.

T4 can be considered a prohormone.

Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases.

Deiodinases allow end organs to produce the amount of T3 needed to control the local metabolic functions.

Regulation of Thyroid Hormone Synthesis

The hypothalamic-pituitary-thyroid axis regulates the production and release of thyroid hormones.

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the release of thyrotropin or thyroid-stimulating hormone (TSH) when thyroid hormone levels are physiologically inadequate.

TSH promotes the production and release of thyroid hormones.

As circulating thyroid hormone levels rise to needed levels, negative feedback results in decreased release of TSH and TRH.

Function of Thyroid Gland Hormones

Thyroid hormones increase the rate of energy from carbohydrates, increase the rate of protein synthesis, and stimulate activity in the nervous system.

The source of control for thyroid hormones is TSH (thyroid-stimulating hormone).

Calcitonin lowers blood calcium and phosphate concentration by inhibiting bone resorption and increasing excretion of these ions by the kidney.

The source of control for calcitonin is blood calcium concentration.

Thyroid Disorders

Include: Hypothyroidism, Hyperthyroidism, Goiter, Thyroid nodules, and Thyroid cancer.

Goiter

It is a swelling in the neck resulting from an enlarged thyroid gland, which may or may not be functioning properly.

Goiter can be associated with hypothyroidism, hyperthyroidism, or normal thyroid function.

Causes of Goiter

Simple goiters develop when the thyroid gland does not make enough hormones.

Endemic goiters occur in people in certain parts of the world who do not get enough iodine.

Sporadic goiters, in most cases, have no known cause but can be caused by certain drugs like lithium.

Graves' disease is an autoimmune disease where the immune system attacks the thyroid gland, causing it to grow larger.

Hashimoto's disease is another autoimmune disease that causes inflammation of the thyroid gland, resulting in fewer thyroid hormones and leading to goiter.

Nodular goiter involves growths called nodules on one or both sides of the thyroid gland.

Thyroid cancer can cause enlargement of the thyroid.

Pregnancy: Human chorionic gonadotropin produced during pregnancy can cause the thyroid to grow.

Thyroiditis involves inflammation of the thyroid gland itself.

Other Risk Factors for Goiter

Hereditary factors

Being female

Age over 40

Thyroid Nodules

Refers to an abnormal growth of thyroid cells that may be solid or fluid-filled lumps within the thyroid.

Most thyroid nodules are benign and asymptomatic, but a small proportion contain thyroid cancer.

Evaluation is necessary to diagnose and treat thyroid cancer early.

Thyroid Cancer

More common among women than men.

About 2/3 of cases occur in people under age 55.

Most cases have a good prognosis and high survival rates, especially when diagnosed early

Hypothyroidism Etiology

Primary hypothyroidism is gland-related.

Secondary hypothyroidism is related to hypopituitarism.

Tertiary hypothyroidism occurs due to hypothalamic dysfunction, which is rare.

Primary hypothyroidism is the most common type, caused by disease in the thyroid, resulting in high TSH levels.

Causes of primary hypothyroidism include autoimmune thyroiditis (Hashimoto disease), iatrogenic causes (irradiation, surgery), certain drugs (amiodarone, radiocontrast media, lithium, interferon-α, tyrosine kinase inhibitors), silent thyroiditis (including postpartum), and iodine deficiency.

Secondary hypothyroidism is less common, due to pituitary disease, leading to low TSH levels.

Tertiary hypothyroidism occurs when insufficient TRH from the hypothalamus leads to insufficient release of TSH, causing inadequate thyroid stimulation.

Risk Factors for Hypothyroidism

Age (older than 50)

Female gender

Obesity

Thyroid surgery

X-ray or radiation treatments to the neck

Clinical Features of Hypothyroidism

Cardiovascular signs consist of Bradycardia, Pericardial effusion and Cardiomegaly.

Renal Function is impaired.

Anemia include, Impaired Hb synthesis, Fe deficiency due to menorrhagia and impaired intestinal absorption, Folate deficiency due to impaired intestinal absorption and Pernicious anemia..

Neuromuscular signs consist of Muscle cramps, Slow reflexes, and Carpal tunnel syndrome.

CNS symptoms include Fatigue, lethargy, depression, and inability to concentrate.

Other clinical features include Hyperlipidemia, Constipation, ascites, Weight gain, Cold intolerance, Rough/dry skin, Puffy face and hands, Hoarse voice, Respiratory failure and Menorrhagia, infertility, hyperprolactinemia.

Hashimoto's Thyroiditis

It's an autoimmune disease where the thyroid gland is gradually destroyed, potentially leading to the enlargement of the thyroid gland, forming a goiter.

Early cases may be present without symptoms.

It is thought to result from a combination of genetic and environmental factors.

Risk factors include family history and having another autoimmune disease.

Hashimoto's thyroiditis is about seven times more common in women than in men

The immune system attacks the thyroid gland, causing it to stop producing hormones, leading to hypothyroidism.

The autoimmune inflammatory response results in lymphocytic filtration of the thyroid gland and its eventual destruction.

Patients with autoimmune thyroiditis (Hashimoto disease) have circulating antithyroid peroxidase antibody (anti-TPOAbs) and elevated blood TSH level.

Diagnosed with with elevated blood TSH level, decreased T4 level and elevated anti-thyroid autoantibodies titres.

Common cause of hypothyroidism and goiter, especially in teens and young women.

Related Complications

Myxedema coma is a rare, life-threatening clinical condition representing severe hypothyroidism, typically in patients with long-standing, undiagnosed hypothyroidism.

Myxedema also describes dermatologic changes in hypothyroidism and occasionally hyperthyroidism, referring to mucopolysaccharides deposition in the dermis, causing swelling of the affected area.

Symptoms of myxedema coma include Weakness, Confusion or non-responsiveness, feeling cold, low body temperature, swelling of the body (especially the face, tongue, and lower legs), Difficulty breathing,Low blood pressure, and Low blood sugar.

Management of Myxedema Coma

Medical treatment includes supporting ventilation as respiratory failure is the major cause of death, intravenous fluids, electrolyte replacement, and intravenous thyroid hormones to quickly correct low thyroid hormone levels.

L-thyroxine 0.2-0.5 mg IV bolus, followed by 0.1 mg IV until oral therapy is tolerated, results in clinical response in hours.

Additional treatments include:

IV glucose if the blood sugar level is low

Antibiotics if an infection is present.

Monitoring in an ICU setting

Screening/Diagnosis

Normal TSH level is 0.4-4.5 mIU/L.

TSH level of 4.5 to 10 mIU/L may indicate mild or subclinical hypothyroidism.

TSH level greater than 10 mIU/L signifies overt hypothyroidism.

Normal free T4 level is 0.7-1.9 ng/dL and level less than 0.7 ng/dL indicates hypothyroidism.

Low free T4 and high TSH is diagnostic of primary hypothyroidism.

A positive test for thyroid autoantibodies (anti-TPOAbs) plus an enlarged thyroid gland suggests Hashimoto's thyroiditis.

TRH test may be done to differentiate pituitary from hypothalamic disease. Absence of TSH response to TRH indicates pituitary deficiency, but in tertiary hypothyroidism, TRH administration produces an increase in TSH.

MRI of brain is indicated if pituitary or hypothalamic disease is suspected to look for other pituitary deficiencies.

Treatment of Hypothyroidism

Has three major goals:

Replace missing hormones, for example, treatment to ensure patients receive a dose of thyroxine that will restore well-being, which usually returns the persons TSH level to the lower end of the normal range..

Relieve signs and symptoms

Achieve a stable biochemical euthyroid state.

The preferred treatment is synthetic Levothyroxine (LT4), which mimics the normal thyroid gland physiology by secreting mostly T4 as a prohormone.

Peripheral tissues convert T4 to T3 as needed based on metabolic demands. Using T3 can cause the peripheral tissues to lose their ability to control local metabolic rates.

The initial dose of L-thyroxine depends on the patient's age, severity, and duration of the disease.

For young, healthy patients with a short disease duration, L-thyroxine may be started at 50-100 mcg daily; given its long half-life, administration is once daily.

The most convenient time for treament is in the morning.

Thyroid function tests should be checked after 6 weeks on the same dose to allow TSH to stabilize after a dose change.

TSH concentration is the best indicator of the thyroid state for further dosage adjustment.

A raised TSH concentration indicates inadequate treatment.

Majority of patients will be controlled with doses of 100-200 mcg daily, with few patients requiring more than 200 mcg.

The thyroxine dosage must be increased by 25-50% to maintain normal TSH levels during pregnancy.

TSH concentration should be checked every month during pregnancy as L-thyroxine dose requirement tends to go up as the pregnancy progresses.