Thyroid Hormone Physiology

• Thyroid disorders impact thyroid hormone production or secretion, which results metabolic instability.

Thyroid Hormone Physiology

• Thyroxine (T4) and triiodothyronine (T3) are thyroid hormones that are formed inside thyroglobulin, a large glycoprotein synthesized in the thyroid cell.
• Inorganic iodide enters the thyroid follicular cell, thyroid peroxidase oxidizes it, and then it covalently binds to tryrosine residues of thyroglobulin.
• Mono-iodo-tyrosine (MIT) and diiodotyrosine (DIT), which are iodinated tyrosine residues, combine to form iodothyronines, catalyzed by thyroid peroxidase.
• Two molecules of DIT combine to form T4, while MIT and DIT combine to form T3.
• Proteolysis in thyroid cells releases T4 and T3 into the bloodstream where they're transported by thyroid binding globulin (TBG), transthyretin, and albumin.
• Only unbound thyroid hormones can diffuse into cells, produce biologic effects, and regulate thyroid stimulating hormone (TSH) secretion from the pituitary.
• The thyroid solely secretes T4, but less than 20% of T3 is produced there, most T3 is formed by the breakdown of T4 catalyzed by 5'-mono deiodinase in peripheral tissues.
• T3 is five times more active than T4 and T4 may also be acted on by 5'-monodeiodinase to form reverse T3, which lacks significant biologic activity.
• TSH secreted by the anterior pituitary regulates thyroid hormone production, and this is controlled by negative feedback from the circulating level of free thyroid hormone and positive influence of hypothalamic thyrotropin releasing hormone (TRH).
• Extrathyroidal deiodination of T4 to T3, which can be affected by nutrition, nonthyroidal hormones, drugs, and illness, regulates thyroid hormone production.

Thyrotoxicosis (Hyperthyroidism) Pathophysiology

• Thyrotoxicosis results from tissues' exposure to excessive levels of T4, T3, or both.
• Hyperthyroidism is a cause of thyrotoxicosis and refers to thyroid gland overproduction of thyroid hormones.
• TSH-secreting pituitary tumors sporadically release biologically active hormone that does not respond to normal feedback control that may cosecrete prolactin or growth hormone.
• Patients may have amenorrhea, galactorrhea, or signs of acromegaly.
• Resistance to thyroid hormone occurs rarely and it can be due to molecular defects, including mutations in the TRβ gene.
• Pituitary resistance to thyroid hormone (PRTH) is selective resistance of the pituitary thyrotrophs to thyroid hormone.
• Graves' disease is the most common cause of hyperthyroidism, resulting in thyroid stimulating antibodies (TSAb) act against the thyrotropin receptor on the surface of thyroid cells.
• These immunoglobulins bind to the receptor and activate adenylate cyclase like TSH does.
• An autonomous thyroid nodule is a benign thyroid mass that produces thyroid hormones regardless of pituitary and TSH control.
• Hyperthyroidism usually occurs with nodules greater than 3 cm in diameter.
• In multinodular goiter, follicles with autonomous function coexist with normal or nonfunctioning follicles and thyrotoxicosis occurs when autonomous follicles generate more thyroid hormone than is required.
• Painful subacute thyroiditis often develop after a viral syndrome.
• Painless thyroiditis is cause of thyrotoxicosis and autoimmunity may underlie most cases.
• Thyrotoxicosis factitia is hyperthyroidism due to ingesting exogenous thyroid hormones.
• This may occur when thyroid hormone is inappropriately indicated, used surreptitiously, excessive doses are used/accidental ingestion.
• Amiodarone can induce thyrotoxicosis in 2–3% of patients, overt hypothyroidism in 5% of patients, subclinical hypothyroidism in 25% of patients, or euthyroid hyperthyroxinemia.
• Amiodarone's iodine content (37%I by weight) increases thyroid hormone production and exacerbates thyroid dysfunction in patients with preexisting thyroid disease, and causes destructive thyroiditis.
• Destructive thyroiditis causes leakage of thyroglobulin and thyroid hormones.

Clinical Presentation

• Symptoms of thyrotoxicosis: nervousness, anxiety, palpitations, emotional lability, easy fatigability, heat intolerance, weight loss, increased appetite and bowel movement frequency, proximal muscle weakness, and scanty or irregular menses.
• Physical signs: warm, smooth, moist skin, fine hair, separation of fingernails and beds, retraction of eyelids, tachycardia, widened pulse pressure, systolic ejection murmur, gynecomastia, fine tremor, and hyperactive deep tendon reflexes.
• Thyromegaly is usually present.
• Graves' disease is manifested by hyperthyroidism, diffuse thyroid enlargement, and extrathyroidal findings of exophthalmos, pretibial myxedema, and thyroid acropachy.
• Severe disease may cause a thrill to be felt and a systolic bruit to be heard over the gland.
• Subacute thyroiditis: patients have thyroid region pain that extends to the ear along with systemic symptoms including fever, malaise, myalgia and firm and exquisitely tender thyroid gland.
• Painless thyroiditis presents with mild thyrotoxic symptoms, lid-retraction and lid lag, and diffuse thyroid gland enlargement
• Exophthalmos is absent.
• Thyroid storm is a life-threatening medical emergency characterized by decompensated thyrotoxicosis, high fever (often >39.4°C [103°F]), tachycardia, tachypnea, dehydration, delirium, coma, nausea, vomiting, and diarrhea.
• Precipitating factors include infection, trauma, surgery, radioactive iodine (RAI) treatment, and withdrawal from antithyroid drugs.

Diagnosis

• Elevated 24 hour radioactive iodine uptake (RAIU) indicates true hyperthyroidism with overproduction of T4, T3, or both (normal RAIU 10%–30%).
• Low RAIU indicates that excess thyroid hormone does not result from thyroid gland hyperfunction, instead it is likely caused by thyroiditis, struma ovarii, follicular cancer, or exogenous thyroid hormone ingestion.
• Thyrotoxic Graves' disease has an increased hormone production rate with a disproportionate increase in T3 relative to T4.
• TBG saturation is increased due to elevated T4 and T3 serum levels, which results in increased T3 resin uptake.
• Concentrations of free T4, free T3, and the free T4 and T3 indicies are increased to a greater extent than the measured serum total T4 and T3 concentrations.
• TSH level is undetectable due to negative feedback by elevated levels of thyroid hormone at the pituitary.
• Measurement of serum free T4, total T4, total T3, and TSH will confirm thyrotoxicosis diagnosis in symptomatic patients.
• Increased 24 hour RAIU indicates inappropriate iodine usage by the thyroid gland to produce more thyroid hormone (if patient is not pregnant or lactating).
• Toxic adenomas can cause isolated serum T3 elevation with autonomously functioning nodules, thus, measure T3 levels to rule out T3 toxicosis if the T4 level is normal.
• Autonomous function can be confirmed if TSH is normal, but test fails to decrease iodine uptake during T3 administration sufficient to suppress TSH.
• In miltinodular goiters, thyroid scan shows patchy areas of autonomously functioning thyroid tissue.
• TSH iduced hyperthyroidism is diagnosed by peripheral hypermetabolism, diffuse thyroid gland enlargement, elevated free thyroid hormone levels, that indicate inappropriate TSH production.
• Elevated serum immunoreactive TSH concentrations with a normal or elevated TSH level in a thyrotoxic patient.
• TSH secreting pituitary adenomas are diagnosed by a lack of TSH response to TRH stimulation and elevated TSH α subunit levels, along with radiologic imaging.
• Subacute thryoiditis shows triphasic course in thyroid function tests, specifically.
• Serum T4 is initially elevated due to release of preformed thyroid hormone, then 24 hour RAIU during this time is