Endocrinology: Thyroid Gland Anatomy & Function

Endocrinology - Thyroid Gland

Anatomy of the Thyroid Gland

• The thyroid is a bilobular, butterfly-shaped gland located in the neck, wrapped around the trachea
• It is made up of two main types of cells: follicular and parafollicular

Follicular Cells

• Form the walls of the follicles

Parafollicular Cells (C cells)

• Found between the follicles, in the connective tissue

Follicles (Structure & Function)

• Each follicle is a hollow ball made of a single layer of follicular cells
• The inside contains a colloid (gel-like substance) that stores thyroglobulin, a glycoprotein produced by the follicular cells
• Thyroglobulin is essential for making thyroid hormones
• The connective tissue around follicles contains C cells, which secrete calcitonin, which aids in calcium regulation

Function of Thyroid Hormones

• Thyroid hormones have many roles in the body, including boosting metabolism
• They increase energy use and heat production to keep the body warm
• Supporting growth, development, and sexual maturation
• They stimulate protein synthesis and break down carbohydrates and fats
• Promote fat burning (lipolysis and fatty acid oxidation)
• They influence heart rate and force of contractions
• They are essential for brain and nerve development, especially in infants

Synthesis of Thyroid Hormones

• The thyroid makes thyroxine (T4), which is the main hormone released
• It also makes triiodothyronine (T3), which is a more active form, and small amounts of reverse T3 (rT3), an inactive form
• Iodide (I-) from the diet is required to make these hormones
• Iodine is key in hormone synthesis and is usually taken in via iodized salt or food

Triiodothyronine (T3)

• T3 is more active than T4, even though there's less T3 in the blood, it's more potent in terms of its biological effects
• T4 is more abundant in the bloodstream than T3
• T3 testing is less common than other thyroid tests
• T3 testing is used for subclinical hyperthyroidism particularly if T4 is normal
• Elevated T3 is present in hyperthyroidism
• T3 levels drop in chronic illness (like stress or severe non-thyroid illnesses) making it less reliable for diagnosing hypothyroidism

Thyroid-Stimulating Hormone (TSH)

• TSH is a glycoprotein hormone made and secreted by the anterior pituitary gland
• TSH stimulates the thyroid gland to grow (hyperplasia) by increasing the number and size of follicular cells
• TSH helps trap more iodide, which is needed to make thyroid hormones
• TSH breaks down thyroglobulin in the colloid so thyroid hormones (T3 and T4) can be released into the blood
• High TSH usually indicates low thyroid hormone levels (hypothyroidism)
• Low TSH usually indicates high thyroid hormone levels (hyperthyroidism)

Thyroxine (T4) Synthesis -- Step-by-Step

• Follicular cells in the thyroid make a protein called thyroglobulin, which is rich in tyrosine amino acids, essential for making thyroid hormones
• The process starts by trapping iodide (I-) from the blood
• Iodide is pulled into the thyroid follicle cells using active transport, which means energy (ATP) is used to pump iodide against its concentration gradient
• Inside the follicular cell, iodide is enzymatically "activated" and converted to a reactive form
• An enzyme called thyroid peroxidase adds iodine atoms (one at a time) to tyrosine residues on thyroglobulin

Steps In Iodination of Tyrosine

• One iodine → MIT (Monoiodotyrosine)
• Two iodines → DIT (Diiodotyrosine)
• These iodinated tyrosines are then combined enzymatically:
  • MIT + DIT → T3 (Triiodothyronine)
  • DIT + DIT → T4 (Thyroxine)
• The T3 and T4 formed remain attached to thyroglobulin and are stored in the colloid (the central part of the follicle) until needed, remaining inactive in storage until the body signals for their release
• When the pituitary gland releases TSH, it signals the thyroid and TSH triggers enzymes to break the bonds between tyrosines and the rest of thyroglobulin
• Thyroglobulin with T3 and T4 is taken back into follicular cells and inside the cell, it is broken down (hydrolyzed), freeing T3 and T4, which are then released into the bloodstream

T4 Conversion in Peripheral Tissues

• When T4 enters the bloodstream, it travels to peripheral tissues (like the liver, kidneys, and others)
• In these tissues, enzymes remove one iodine atom from T4 to convert it into T3, which called deiodination, and the primary way T3 is made in the body
• This T4→ T3 conversion is crucial because T3 is far more biologically active than T4, and the liver is the primary site for this conversion
• T4 can also be converted into reverse T3 (rT3), an inactive form that does not stimulate metabolism, typically during illness or stress and is part of the body's way of conserving energy

Protein Binding of Thyroid Hormones

• Once T3 and T4 are in the bloodstream, they bind to plasma proteins
• Main binding proteins:
  • Thyroxine-Binding Globulin (TBG) is the main transport protein
  • TBG binds the majority of circulating T3 and T4 and is made by the liver
  • Liver disease decreases TBG, which decreases total T4 (less protein-bound T4)
  • Pregnancy or high estrogen increases TBG, which increases total T3 and T4 (but free hormone stays normal)
  • Thyroxine-Binding Prealbumin (TBPA or transthyretin)
  • Albumin binds thyroid hormones loosely

Additional Information

• 99% of T4 and T3 are bound to proteins
• Less than 1% is free, and only the free form is biologically active (~0.04% Free T4, ~0.4% Free T3)
• Measuring total T4 includes both bound and free and can be misleading in liver disease or pregnancy
• Free T4 tests are accurate to assess thyroid function

Regulation of Thyroid Hormone Secretion

• The Hypothalamus and the anterior pituitary continually monitor levels of T4 in the blood to maintain metabolism
• When free T4 levels are low:
  • the Hypothalamus secretes TRH (Thyrotropin-Releasing Hormone)
  • TRH travels to the anterior pituitary, which secretes TSH (Thyroid-Stimulating Hormone, aka thyrotropin)
  • TSH stimulates the thyroid gland to produce and release more T3 and T4
• When T4 levels are high:
  • The increase in T4 (and T3) is detected by the hypothalamus and pituitary.
  • This inhibits further release of TRH and TSH completing the negative feedback loop

Primary Hyperthyroidism

• A condition where the thyroid gland itself is overactive, producing too much T3 and T4 independently of control signals from the hypothalamus and pituitary
• The thyroid produces excess T3 and T4, which should signal the hypothalamus and pituitary to slow down TRH and TSH production
• the thyroid ignores this feedback loop and continues to overproduce hormones

Common Causes

• Most commonly Graves disease (autoimmune)
• Toxic adenoma: single overactive nodule
• Toxic multinodular goiter (Plummer disease)
• Thyroiditis (inflammatory types)
• Taking too much thyroid hormone (exogenous thyroxine)
• Rarely: pituitary adenoma or thyroid cancer

Symptoms of Hyperthyroidism

• Symptoms include hypermetabolic state:
  • Weight loss
  • Sweating
  • Anxiety
  • Tremors

Lab Findings for Hyperthyroidism

• Decreased TSH
• Increased Free T4
• Very decreased TSH
• Increased Total T4 and T3
• Increased Free T3
• Decreased TRH
• Sometimes, free T4 is normal, but TSH is still low suggesting T3 thyrotoxicosis and necessitating an fT3 check

Graves Disease

• Graves disease is the most common cause of thyrotoxicosis which is a condition with excess thyroid hormone in the blood.
• It's an autoimmune disorder where the immune system mistakenly attacks healthy tissue

How does it work?

• The body produces an autoantibody that mimics TSH, stimulating the thyroid which is called:
  • Thyroid-Stimulating Immunoglobulin (TSI) or Thyroid-Stimulating Antibody (TSAb)
• These antibodies bind to the TSH receptors on the thyroid gland and falsely stimulate it, causing an overproduction of T3 and T4, and ignoring feedback controls

Lab Markers In Graves Disease

• Decreased TSH
• Increased TSI
• Other antibodies can be present:
  • Antimicrosomal antibodies
  • Antithyroglobulin antibodies

Signs of Hyperthyroidism

• Classic signs = goiter, exophthalmos, tremors, weight loss, fast heart rate
• Graves = autoimmune mimicry of TSH → overstimulated thyroid → ↑ T3/T4, ↓ TSH, ↑ TSI, symptoms of high metabolism

Primary Hypothyroidism

• A condition where the thyroid gland doesn't make enough T3 and T4, despite stimulation from the pituitary gland
• The problem is in the thyroid itself and the gland fails to respond to TSH appropriately

Causes

• Most commonly: Hashimoto thyroiditis (an autoimmune destruction of the thyroid)
• Others include:
  • Thyroidectomy
  • Thyroiditis
  • De Quervain, lymphocytic
  • I-131 therapy or radiation
  • Certain drugs like iodine excess, lithium, interferons, interleukin-2

Lab Results for Hypothyroidism

• Increased TSH
• Decreased Free T4
• Decreased Total & Free T3/T4
• Increased TRH

Symptoms Of Hypothyroidism

• Slowed metabolism
  • Weight gain
  • Cold intolerance
  • Fatigue / lethargy
  • Mental slowing
  • Dry skin, constipation, depression

Congenital Hypothyroidism

• Hypothyroidism presents at birth
• Causes include defective hormone synthesis, absence of thyroid tissue, or a problem in the hypothalamus or pituitary
• Without treatment, leads to intellectual and physical disability or cretinism
• All newborns are screened by measuring free T4 from a blood spot
• If fT4 is low, then TSH is measured to confirm the diagnosis
• If confirmed, infants must be given oral T4 for life to prevent mental retardation because early diagnoses = normal development
• Newborns normally have higher T4 levels than adults because of metabolism and brain development

Myxedema

• A severe form of hypothyroidism, occurring from long-standing or untreated hypothyroidism
• Features include goiter, thickening of the skin due to deposits giving a doughy appearance, hoarseness due to swollen vocal cords, and weight gain from slowed metabolism

Hashimoto Thyroiditis

• The most common cause of primary hypothyroidism
• An autoimmune disease in which the immune system attacks the thyroid

Autoantibodies involved

• Anti-thyroid peroxidase (TPO) antibodies
• Anti-thyroglobulin antibodies
• TSI is not present

Lab Results for Hashimoto Thyroiditis

• In the early phase it may show only thyroglobulin antibodies
• The thyroid is heavily infiltrated by lymphocytes
• Patients usually require lifelong thyroid hormone replacement to suppress elevated TSH levels

Secondary Thyroid Disease

• Caused by problems in the pituitary gland
• The pituitary fails to produce enough TSH, so the thyroid doesn't get the signal to make T3 and T4
• The symptoms are the same as primary hypothyroidism, but the origin is different

Lab Results

• Decreased TSH
• Decreased T4/T3

Causes

• Often due to hypopituitarism (low pituitary function)

Tertiary Thyroid Disease

• Caused by a problem in the hypothalamus, which fails to produce TRH
• Without TRH → no TSH from pituitary → no T4/T3 from thyroid
• Also leads to hypothyroidism, but due to a higher-level control failure

Euthyroid Sick Syndrome

• Euthyroid means the thyroid gland itself is functioning normally
• In serious non-thyroid illnesses, thyroid function tests may appear abnormal, even though the thyroid gland is not diseased
• In critical illness, the body uses up thyroid hormones faster for tissue repair and immune responses
• This leads to low levels of free T4 and T3, and high reverse T3 (rT3)
• The thyroid and pituitary gland are normal and feedback regulation is intact
• If lab results show low T4 and T3, but TSH is normal in a critically ill patient → suspect ESS, not true hypothyroidism
• Don't perform thyroid function tests during acute serious illness because the results might mimic hypothyroidism, but they are not accurate reflections of thyroid function

Goiter

• A goiter is simply an enlargement of the thyroid gland, which causes swelling in the front of the neck
• The thyroid gland grows in response to increased TSH due to iodine deficiency.
• low T4 levels cause pituitary TSH secretions and then it tells thyroid to grow

Thyroid Cancer

• Exposure to radioactive iodine from incidents increases this risk
• The thyroid absorbs iodine very efficiently, and can't tell the difference between normal iodine and radioactive iodine
• To Protect the Thyroid from Radiation, Potassium iodide (KI) tablets can saturate the thyroid with non-radioactive iodine, preventing it from taking up radioactive iodine if taken before or within 3-4 hours after exposure

Diagnosis of Thyroid Disorder

Initial Steps

• Start testing only if symptoms or signs suggest a thyroid problem, such as changes in weight, mood, temperature tolerance, heart rate, etc
• The first lab test to order is TSH
• Don't test total T4 in healthy people without symptoms
• Screening starts at age 35, and should be repeated every 5 years

Abnormal Results

• if TSH and/or T4 levels are outside age- and sex-adjusted reference ranges, thyroid disease is likely

When to Add fT4 Testing

• Free T4 (fT4) or the fT4 index can be added if:
  • TSH is abnormal
  • Symptoms don't match TSH findings
  • To distinguish between subclinical and overt thyroid disease
• High thyroid hormone levels in labs can cause changes like increased body temperature, increased BMR, cardiac output and heart rate, and mood and behavior fluctuations

Diagnosis of Neonatal Thyroid Disorders

• Most commonly due to thyroid dysgenesis
• Screening of newborns involves a test for Free T4, followed by TSH to confirm

Other Causes of Abnormal Thyroid Tests

• Conditions where thyroid function appears abnormal, but the thyroid gland is actually normal and the abnormality lies in hormone transport proteins like TBG

TSH (Thyrotropin)

• TSH is the best diagnostic test for both hyper- and hypothyroidism, it reflects the pituitary's response to circulating thyroid hormone levels
• In hypothyroidism, TSH is elevated
• In hyperthyroidism, TSH is low
• This said, it's important to note that it's not used when diagnosing central hypothyroidism

Total T4 (Thyroxine)

• Most of it is bound to proteins, notably TBG
• Remember too that levels can be affected by TBG

Special Considerations

• ~5% of hyperthyroid patients may have normal total T4, but elevated T3, called T3 toxicosis
• Since they are highly protein-bound, their levels can be affected by Changes in TBG even if thyroid function is normal (making fT4 and fT3 levels more useful than total hormone levels)

Thyroid-Binding Globulin (TBG)

• TBG is the main protein in the blood that binds to thyroid hormones, where they stay inactive
• Only free T4 and T3 are biologically active
• Increased TBG increases total T4 and T3, but free T4 and TSH stay normal

Causes of Increased TBG

• Pregnancy
• Oral contraceptives
• Estrogen therapy
• Active hepatitis
• Hypothyroidism
• A decreased TBG lowers total T4 and T3, but free hormone and TSH remain normal
• Hypoproteinemia, androgen therapy and cortisol excess can lower TBG levels

If total T4 or T3 is abnormal, but free hormone and TSH are normal, think about non-thyroid causes like TBG changes due to pregnancy, liver disease, or inherited conditions

Reverse T3 (rT3)

• rT3 is an inactive byproduct made when T4 is metabolized in peripheral tissues
• It competes with T3 for cellular receptors but has no hormonal activity
• Is elevated in Euthyroid Sick Syndrome (ESS)

TRH Stimulation Test

• A diagnostic test that helps evaluate which part of the thyroid axis may be involved in hypothyroidism
• It's helpful when it's unclear whether the issue is in the thyroid, pituitary, or hypothalamus
• If there's an elevated THS, there thyroid is likely responsible for the imbalance
• If there's no rise in TSH, hyperthyroidism is likely because T4/T3 is already suppressing it
• If there's blunted/no TSH, its likely a pituitary issue

Anti-TSH Receptor Antibody

• It is a blood test used to detect autoimmune hyperthyroidism, most commonly Graves disease by detecting antibody mimicking TSH Useful when labs suggest primary hyperthyroidism, and for differentiating Graves disease from other causes of hyperthyroidism, like thyroid nodules or thyroiditis

How is thyroxine (T4) measured?

• The most common techniques are: Enzyme immunoassay and Fluorescent immunoassay
• These are done on plasma or serum samples

Total T4 Assay Process (step-by-step)

• To measure Total T4, which is mostly bound to TBG, you must displace T4 from its binding proteins and compete T4 with an antibody, where unbound materials are washed away the rest are tested using immunoassay

Medications Affecting Thyroid Function

• Amiodarone -Contains alot of Iodine, so it can impact thyroid function. May cause hypothyroidism or hyperthyroidism based on local iodine levels
• Lithium
  • Inhibits T4 Release leading to Hypothyroidism