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Anatomy of the Thyroid The thyroid gland is a highly vascularized organ located anteriorly in the neck, deep to the

platysma, sternothyroid and sternohyoid muscles, and extending from the 5th cervical (C5) to the 1st thoracic (T1) vertebrae. The gland consists of two lobes (left and right) connected by a thin, median isthmus overlying the 2nd to 4th tracheal rings, typically forming an "H" or "U" shape. Occasionally the isthmus is absent and the thyroid exists as two distinct lobes. Embryologically, the thyroid gland develops as a thickening in the pharyngeal floor that elongates inferiorly as the thyroglossal duct, dividing into two lobes as it descends through the neck. Beneath the visceral layer of the pretracheal, deep cervical fascia, the thyroid gland is surrounded by a true inner capsule, which is thin and adheres closely to the gland. The capsule sends projections into the thyroid forming septae and dividing it into lobes and lobules. Dense connective tissue attachments secure the capsule of the thyroid to both the cricoid cartilage and the superior tracheal rings. The lobules of the gland are composed of follicles, the structural unit of the thyroid. Each follicle is lined by a simple layer of epithelium surrounding a colloid-filled core. This colloid contains iodothyroglobulin, the precursor to thyroid hormones. Blood Supply and Nerves Because the thyroid gland is a hormone secreting organ, it is highly vascularized. It receives its blood supply from the superior and inferior thyroid arteries. These arteries lie between the fibrous capsule and the pretracheal layer of deep cervical fascia. The superior thyroid artery is the first branch of the external carotid artery and supplies the top half of the thyroid gland. It divides into anterior and posterior branches supplying respective sides of the thyroid. On the anterior side, the right and left branches anastomose with each other. On the posterior side, the right and left branches anastomose with their respective inferior thyroid arteries. The inferior thyroid artery supplies the lower half of the thyroid and is the major branch of the thyrocervical trunk, which comes off the subclavian artery. It too divides into several branches, supplying the inferior portion of the thyroid and anastomosing posteriorly with the superior thyroid branches. There are three main veins that drain the venous plexus on the anterior surface of the thyroid. They include the superior, middle, and inferior thyroid veins, and each drains its respective portion of the thyroid. The superior and middle thyroid veins drain into the internal jugular veins, whereas the inferior thyroid vein drains into the brachiocephalic veins, behind the manubrium of the sternum. Lymphatic drainage of the thyroid gland is quite extensive and flows multidirectionally. Immediate drainage flows first to the periglandular nodes, then to the prelaryngeal (Delphian), pretracheal, and paratracheal nodes along the recurrent laryngeal nerve, and then to mediastinal lymph nodes. The principal innervation of the thyroid gland is derived from the superior, middle, and inferior cervical sympathetic ganglia of the autonomic nervous system and parasympathetic fibersfrom the vagus nerves. These nerves reach the thyroid gland by coursing with the blood vessels (superior and inferior thyroid periarterial plexuses). Dissection Considerations Cephalad to the superior pole of the thyroid gland, the external branch of the superior laryngeal nerve runs alongside the superior thyroid artery before turning medially to supply the cricothyroid muscle. High ligation of the superior thyroid artery during thyroidectomy places this nerve at risk of inadvertent injury, which would produce dysphonia by altering pitch regulation. The cricothyroid artery is a potentially bothersome branch of the superior thyroid artery, which runs cephalad to the upper pole of the thyroid gland and runs toward the midline on the cricothyroid ligament. This vessel can be lacerated during emergent cricothyroidotomy. The inferior thyroid artery is closely associated with the recurrent laryngeal nerve. This nerve can be found after it emerges from the superior thoracic outlet, in a triangle bounded laterally by the common carotid artery, medially by the trachea, and superiorly by the thyroid lobe. The relationship of the recurrent laryngeal nerve and the inferior thyroid artery is highly variable in that the nerve can lie deep to the artery, superficial to the artery, or between the branches of the artery, and be different on either side of the neck. Consideration of this nerve and its branches must be given during dissection and thyroidectomy.

follicular cells - are almost columnar in appearance in some regions, whilst elsewhere they have a low cuboidal appearance. This is because in active glands, the follicles are smaller, and have reduced colloid - the cuboidal lining cells are relatively tall because they are actively making and secreting hormones - so packed full of ER and golgi.

The thyroid gland is unusual, in that the hormones are stored in cavities, surrounded by secretory cells, which make up a 'follicle'. To secrete the hormone, the hormone is re-absorbed from the cavity, and then released into the surrounding interstitial spaces. The stored hormone is bound to a glycoprotein, and this stored hormone is called 'colloid'. This gland secretes iodine containing hormones called Tri-iodo thyronine (T3) andthyroxine (T4) of which T3 is more active. It regulates the basal metabolic rate, and it is regulated by the pituitary hormone TSH. It also secretes calcitonin which regulates blood calcium levels. Secretion of calcitonin causes blood calcium levels to drop, and its secretion is directly dependent on blood calcium levels. Colloid is an inactive precursor of T3 and T4. It is made up of a glycoprotein called thyroglobulin, made by the epithelial cells, which is bound to iodine. The iodine binds to the tyrosine residues of thyroglobulin. The clear cells are parafollicular cells that are scattered among the follicular cells. As you might guess from their name, they have a pale cytoplasm. They are only found in the middle third or lateral lobes of the thyroid, and they have a different embryological origin to the follicular cells. These cells secrete calcitonin in response to increased levels of blood calcium. In the condition known as hyperthyroidism, the thyroid becomes enlarged, and hyperactive, and the follicles look smaller.

DEVELOPMENT OF THYROID The thyroid gland is the first endocrine gland to develop in the embryo. It begins to form, under the influence of FGF signaling pathways, approximately 24 days after fertilization from a median endodermal thickening in the floor of the primordial pharynx. This thickening soon forms a small outpouchingthethyroid primordium. As the embryo and tongue grow, the developing thyroid gland descends in the neck, passing ventral to the developing hyoid bone and laryngeal cartilages. For a short time, the thyroid gland is connected to the tongue by a narrow tube, the thyroglossal duct. At first the thyroid primordium is hollow, but it soon becomes a solid mass of cells and divides into right and left lobes that are connected by the isthmus of the thyroid gland, which lies anterior to the developing second and third tracheal rings. By 7 weeks, the thyroid gland has assumed its definitive shape and is usually located in its final site in the neck. By this time, the thyroglossal duct has normally degenerated and disappeared. The proximal opening of the thyroglossal duct persists as a small pit in the dorsum (posterosuperior surface) of the tonguethe foramen cecum. A pyramidal lobe of the thyroid gland extends superiorly from the isthmus in approximately 50% of people. Hyperthyroidism General Hyperthyroidism and thyrotoxicosis are terms often used interchangeably, however each refers to slightly different conditions. Hyperthyroidism refers to overactivity of the thyroid gland, with resultant excessive secretion of thyroid

hormones and accelerated metabolism in the periphery. Thyrotoxicosis refers to the clinical effects of an unbound thyroid hormone, regardless of whether or not the thyroid is the primary source. Thus, while the surreptitious use of exogenous thyroid hormone could cause a thyrotoxicosis, it would not be classified as a primary hyperthyroidism. There are a number of pathologic causes of hyperthyroidism in children and adults. These include Grave's disease, toxic adenoma, toxic multinodular goiter, and thyroiditis. Of these, Grave's disease accounts for approximately 95% of cases of hyperthyroidism. To understand the pathophysiology of hyperthyroidism, it is necessary to understand the normal physiology of the thyroid gland. Like the other endocrine glands of the body, the thyroid is controlled by a complex feedback mechanism. The release of thyroid-stimulating hormone (TSH) from the anterior pituitary is stimulated by low circulating levels of thyroid hormones and is under the influence of thyrotropin-releasing hormone (TRH) from the hypothalamus. When released, TSH binds to TSH receptors on the thyroid gland setting off a cascade of events within the gland, leading to the release of thyroid hormones (mainly T4 and, to a lesser degree, T3). Elevated levels of these hormones, in turn, act back on the hypothalamus and anterior pituitary to decrease the synthesis of TRH and TSH, thereby (under normal physiologic conditions) maintaining a tightly regulated level of circulating free hormones. A systematic approach to narrowing the differential of hyperthyroidism is shown below. What causes hyperthyroidism? Hyperthyroidism has several causes, including Graves disease thyroid nodules thyroiditis, or inflammation of the thyroid consuming too much iodine overmedicating with synthetic thyroid hormone, which is used to treat underactive thyroid Rarely, hyperthyroidism is caused by a pituitary adenoma, which is a noncancerous tumor of the pituitary gland. In this case, hyperthyroidism is due to too much TSH.

Grave's Disease
Named after Dr. Robert Graves (1797-1853), Grave's disease is the most common cause of hyperthyroidism today. In this autoimmune disease, elevated levels of thyroid hormone are the result of circulating thyroid-stimulating immunoglobulins (TSI's) of the IgG1 subclass. These antibodies bind to the extracellular domain of the TSH receptor and activate it, causing follicular growth and the release of thyroid hormones. The initial stimulus for the formation of the autoantibodies is unknown, but some have implicated bacterial or viral infections of the thyroid gland, which produce cross-reacting antibodies to the TSH receptor. As such, the thyroid gland, in effect, becomes "ramped up" and no longer maintains its tight regulation under the influence of the pituitary. Subsequently, circulating levels of TSH by the pituitary decline in response to negative feedback by an abundance of thyroid hormone. Risk factors for the development of Grave's disease include: Female Gender: The reported female to male ratio is about 3 - 6 to 1, however the frequency of neonatal Grave's disease is about 1 to 1 Family History: Risk increases with a family history of Grave's Stress: Appears to have a role Other Autoimmune Disorders: Increases the risk of having Grave's Clinical Presentation Patients with Grave's disease typically present with a diffuse, non-tender, symmetric enlargement of the thyroid gland, although a goiter is rarely the presenting complaint. Patient's often complain of the symptoms associated with the hypermetabolic state that is induced by the excessive production of thyroid hormones. Nervousness, restlessness, heat intolerance, tachycardia, palpitations, anxiety, increased sweating, hair loss, leg swelling, and pretibial myxedema are among the most common complaints. In addition, patient's may present with a wide range of eye findings such as exophthalmos (or proptosis), lid lag, lid retraction, stare,

conjunctival injection, periorbital edema, optic atrophy, and even complete blindness. Although not well understood, the pathogenesis of eye involvement is thought to be multifactorial. Some symptoms such as lid lag and lid retraction can be explained by the sympathomimetic effects of the induced thyrotoxicosis. Other effects, such as exophthalmos or proptosis may be the result of an autoimmune reaction against the muscles or fibroblasts of the eye. The dermopathy of Grave's disease, pretibial myxedema, consists of thickening of the skin, usually over the lower tibia, such that the skin cannot be picked between the examiner's fingers. Although relatively rare, it usually occurs in association with ophthalmopathy. Treatment There are currently three possible treatments available for Grave's hyperthyroidism. They include medical blockade of thyroid hormone and its effects (with the use of thionamides which interfere with thyroid hormone synthesis), radioiodine ablation of active thyroid tissue, and surgical resection of the thyroid gland. As this tutorial deals with the surgical aspects of therapy (as opposed to medical management), the surgical options of total and subtotal thyroidectomy will be discussed. The following link discusses the surgical therapies currently in use. Thyroid Nodules Thyroid nodules, also called adenomas, are lumps in the thyroid. Thyroid nodules are common and usually noncancerous. About 3 to 7 percent of the U.S. population has them.2 However, nodules may become overactive and produce too much hormone. A single overactive nodule is called a toxic adenoma. Multiple overactive nodules are called toxic multinodular goiter. Often found in older adults, toxic multinodular goiter can produce a large amount of excess thyroid hormone. Thyroiditis Thyroiditis is an inflammation of the thyroid that causes stored thyroid hormone to leak out of the thyroid gland. At first, the leakage raises hormone levels in the blood, leading to hyperthyroidism that lasts for 1 or 2 months. Most people then develop hypothyroidismwhen thyroid hormone levels are too lowbefore the thyroid is completely healed. Several types of thyroiditis can cause hyperthyroidism followed by hypothyroidism: Subacute thyroiditis. This condition involves painful inflammation and enlargement of the thyroid. Experts are not sure what causes subacute thyroiditis, but it may be related to a viral or bacterial infection. The condition usually goes away on its own in a few months. Postpartum thyroiditis. This type of thyroiditis develops after a woman gives birth. For more information, see the section titled What happens with pregnancy and thyroid conditions? Silent thyroiditis. This type of thyroiditis is called silent because it is painless, as is postpartum thyroiditis, even though the thyroid may be enlarged. Like postpartum thyroiditis, silent thyroiditis is probably an autoimmune condition and sometimes develops into permanent hypothyroidism. Consuming Too Much Iodine The thyroid uses iodine to make thyroid hormone, so the amount of iodine consumed influences the amount of thyroid hormone the thyroid makes. In some people, consuming large amounts of iodine may cause the thyroid to make excess thyroid hormone. Sometimes significant amounts of iodine are contained in medicationssuch as amiodarone, which is used to treat heart problemsor in supplements containing seaweed. Some cough syrups also contain large amounts of iodine. See Eating, Diet, and Nutrition for more information on iodine. Overmedicating with Synthetic Thyroid Hormone Some people who take synthetic thyroid hormone for hypothyroidism may take too much. People who take synthetic thyroid hormone should see their health care provider at least once a year to have their thyroid hormone levels checked and follow the health care providers instructions about the dosage. Some other medications may also interact with synthetic thyroid hormone to raise hormone levels in the blood. People who take synthetic thyroid hormone should ask their health care provider about interactions when starting new medications. Symptoms

Signs

Weight loss despite an increased appetite. Weight gain. Increased or decreased appetite. Irritability. Weakness and fatigue.

Palmar erythema. Sweaty and warm palms. Fine tremor. Tachycardia - may be atrial fibrillation and/or heart failure (common in the elderly). Hair thinning or diffuse alopecia.

Diarrhoea steatorrhoea. Sweating. Tremor. Mental illness: may range from anxiety to psychosis. Heat intolerance. Loss of libido. Oligomenorrhoea or amenorrhoea.

Urticaria, pruritus. Brisk reflexes. Goitre. Proximal myopathy (muscle weakness wasting). Gynaecomastia. Lid lag (may be present in any cause of hyperthyroidism).

Defect of hypothalamus and pituitary gland can be hyper-secreting of hormone which can induce excessive secretion of thyroid hormone causing hyperthyroidism. But this is rare. Hyper-secretion may be due to certain tumor or any other defects. On investigation, this defect can increase level of tri-iodothyronine (T3) and level of thyroxine (T4) in plasma. Level of Thyroid Releasing Hormone (TRH) and/or level of Thyroid Stimulating Hormone (TSH) also may be increased. Goiter that is enlargement of thyroid gland may be present. Defect also can be originated from the thyroid gland itself. Hyper-secreting of thyroid hormone may be one of the causes with absent of goitre. Other than that, is Gravess Disease which is the common cause of hyperthyroidism. Gravess Disease is an autoimmune disease in which the body abnormally produces thyroid-stimulating immunoglobulin (TSI), an antibody whose targeting the TSH receptor on the thyroid cells. TSI will stimulates both secretion and growth of the thyroid in a manner similar to TSH. Unlike TSH, TSI is not subjected for negative feedback inhibition by thyroid hormone, so thyroid secretion and growth continued unchecked. On investigation, level of T3 and T4 may be high while level of TSH remains normal or low. Goiter may be present. Last causes of hyperthyroidism are Apathetic Hyperthyroidism which refers to thyrotoxicosis occurring in elderly, in whom old age and various co-morbidities may blunt typical features of thyroid hormone excess seen in younger patients. The diagnoses of thyrotoxicosis in these individual are often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease. Clinical manifestations of hyperthyroidism are induced by abnormal increased in thyroid hormone. Thyroid hormone can cause three major effects that is hyper metabolic state, over stimulation of sympathetic nervous system and cardiac effect as compensatory mechanism of certain condition caused by increased thyroid hormone.

Thyroid hormone can lead to hyper metabolic state by increasing general metabolic rate. Normally, thyroid hormone participated in inducing synthesis and degradation of carbohydrate, fat and protein. However, overall metabolic effects of thyroid hormone at normal physiologic level are to favor the consumption rather than storage of body fuel. So, when thyroid hormone becomes abnormally high, it will increase the overall basal metabolic rate by increasing rate of degradation. Skin of patient may be soft, warm and flushed. Heat intolerance and excessive sweating also can be noted. Thyroid hormones has sympathomimetic action which the actions are similar to one produced by sympathetic nervous system. Normally, thyroid hormone stimulates proliferation of specific cathecholamines target cell receptors which can induce sympathomimetic effect. Increased in thyroid hormone can induce overstimulation of sympathetic effects which can lead to condition known as Thyroid Storm which is an abrupt onset of acute hyperthyroidism. Thyroid Storm is a medical emergency situation which significant number of untreated patients led to cardiac arrhythmias. Overstimulation of gut will induce hypermotility which led to diarrhea and eventually malabsoption. Overstimulation of levator palpebrae superioris of the eye will result in ocular manifestation of wide, gaze, starring and lid lag of the eyes. Overstimulation of neuromuscular will lead to nervousness, irritability and tremor. Nearly 50% develop proximal muscle weakness called thyroid myopathy. Increasing thyroid hormone also can lead to thyroid effects. Heart rate and contractility of heart muscle will be increase due to increase in hearts responsiveness towards circulating cathecolamines. In addition, in response to heat load generated by cholinergic effect of thyroid hormone as discussed above, peripheral vasodilatation occurs to carry extra heat to body surface for elimination to the environment. Palpitation that is conscious of increasing heart beat and tachycardia that is abnormally rapid heartbeat is commonly seen in patient with hyperthroidosis. What is Graves ophthalmopathy? Graves ophthalmopathy is a condition associated with Graves disease that occurs when cells from the immune system attack the muscles and other tissues around the eyes. The result is inflammation and a buildup of tissue and fat behind the eye socket, causing the eyeballs to bulge out. Rarely, inflammation is severe enough to compress the optic nerve that leads to the eye, causing vision loss. Other GO symptoms are dry, gritty, and irritated eyes, puffy eyelids, double vision, light sensitivity, pressure or pain in the eyes and trouble moving the eyes. GO can occur before, at the same time as, or after other symptoms of hyperthyroidism develop and may even occur in people whose thyroid function is normal. Smoking makes GO worse. Who is likely to develop Graves disease? Graves disease usually occurs seven to eight times more common in women than men. Women are most often affected between ages 30 and 60. And a persons chance of developing Graves disease increases if other family members have the disease. Scientists know some people inherit an immune system that can make antibodies against healthy cells, predicting who will be affected is difficult. People with other autoimmune diseases have an increased chance of developing Graves disease. Conditions associated with Graves disease include type 1 diabetes, rheumatoid arthritis, and vitiligoa disorder in which some parts of the skin are not pigmented. How is Graves disease diagnosed? Health care providers can sometimes diagnose Graves disease based only on a physical examination and a medical history. Blood tests and other diagnostic tests, such as the following, then confirm the diagnosis. TSH test. The ultrasensitive TSH test is usually the first test performed. This test detects even tiny amounts of TSH in the blood and is the most accurate measure of thyroid activity available. T3 and T4 test. Another blood test used to diagnose Graves disease measures T3 and T4 levels. In making a diagnosis, health care providers look for below-normal levels of TSH, normal to elevated levels of T4, and elevated levels of T3. Because the combination of low TSH and high T3 and T4 can occur with other thyroid problems, health care providers may order other tests to finalize the diagnosis. The following two tests use small, safe doses of radioactive iodine because the thyroid uses iodine to make thyroid hormone. Radioactive iodine uptake test. This test measures the amount of iodine the thyroid collects from the bloodstream. High levels of iodine uptake can indicate Graves disease. Thyroid scan. This scan shows how and where iodine is distributed in the thyroid. With Graves disease the entire thyroid is involved, so the iodine shows up throughout the gland. Other causes of hyperthyroidism such as nodules small lumps in the glandshow a different pattern of iodine distribution. TSI test. Health care providers may also recommend the TSI test, although this test usually isnt necessary to diagnose Graves disease. This test, also called a TSH antibody test, measures the level of TSI in the blood. Most people with Graves disease have this antibody, but people whose hyperthyroidism is caused by other conditions do not. Thyroid function tests (TFTs): serum TSH can exclude primary thyrotoxicosis. Confirm the diagnosis with free T4 levels. If TSH is suppressed but free T4 levels are normal, then if not previously supplied, free T3 level is needed (T3 toxicosis occurs in 5% of patients).

Autoantibodies - these are most commonly seen in Graves' disease:


Antimicrosomal antibodies - against thyroid peroxidase. Antithyroglobulin antibodies. TSH-receptor antibodies which are commonly present in Graves' disease but are not routinely measured. TSI if elevated helps to establish a diagnosis of Graves' disease.

Imaging:

Thyroid ultrasound scan. Thyroid uptake scans: to locate hot (overactivity) and cold (no activity) spots.

Management Refer to a specialist for treatment. Beta-blockers can be used for rapid symptom control whilst waiting for thyroid function to normalise. Calcium-channel blockers may be used if patients are intolerant of beta-blockers. There are three kinds of definitive treatment:[1][12]

Antithyroid drugs: carbimazole (methimazole) or propylthiouracil (Class:thionamides):


These drugs act very quickly and inhibit the production of thyroid hormones. Full benefit may take 2-3 weeks to become apparent. Recent reports from America about liver damage with propylthiouracil are currently being evaluated. Until these reports can be further evaluated propylthiouracil should be reserved for specific situations in which it is considered first-line (eg, pregnancy).[13] The aim is to avoid drug-induced hypothyroidism which occurs in 40-60% cases. There are two potential methods of treating hyperthyroid patients: 'block and replace' - where antithyroid drugs are given with thyroxine replacement, and 'dose titration' - where only antithyroid drugs are used and doses are adjusted to achieve normalisation of thyroid hormone production. A systematic review and meta-analysis suggest that both types of methods are equally effective. Furthermore, the dose titration method was associated with a lower rate of side-effects.[14] Carbimazole is most commonly used to begin with, in a dose of 10 mg twice or three times daily initially (depending on the weight of the patient), adjusting or stepping down according to response and TFT results. TFTs usually normalise in a few weeks to months. TFTs are repeated every month and the dose altered according to the T4 level. TSH may remain suppressed for months despite the T4 coming into the normal range and is, thus, unreliable. Once the patient is euthyroid the dose of carbimazole is reduced until the patient is on the lowest amount necessary to maintain the T4 and T3 within the normal range. Remission is usually achieved at 18-24 months, after which attempts may be made to stop antithyroid drugs. But monitoring for recurrence is needed. One study recommends that block and replace therapy should be continued in patients with Graves' orbitopathy until the orbitopathy has resolved.[15] Minor side-effects include: nausea and a bitter taste after taking medication.Warn patients to come for FBC if they develop a sore throat, etc (as anti-thyroid drugs can cause bone marrow suppression). This is seen in less than 0.5% of patients.

Radio-iodine - is increasingly the first-line treatment in teenagers:[16]

Radioactive iodine is given to the patient as a drink and is taken up by the thyroid gland, leading to destruction of the gland. It is given as 200-600 MBq and some may need a second treatment. It can take 3-4 months to take effect. Radio-iodine has the advantages that it is relatively inexpensive and a definitive method of treating hyperthyroidism.

It cannot be given to pregnant or breast-feeding females and females must be advised not to get pregnant for at least four months. Radioactive iodine may also worsen eye disease in Graves' thyrotoxicosis: this is more marked in smokers. The patient does have to be informed that the radioactive iodine is cleared via the urine and thus can be passed on. They are usually advised to avoid close contact with children and pregnant women. It also requires patients to sleep alone for a week. Hypothyroidism is also a potential and common complication. Estimates suggest that between 50% to 80% of patients can develop hypothyroidism.[17] Therefore, there is a need for long-term follow-up of the TFTs. Radio-iodine is the treatment of choice for toxic adenoma.[18] Toxic multinodular goitre is usually treated by radio-iodine; anti-thyroid drugs will work but relapse always occurs when the drugs are discontinued.

Surgical:

Subtotal or near total thyroidectomy achieves a 98% cure rate. It is indicated if there is suboptimal response to anti-thyroid medication or radio-iodine, especially in patients who are pregnant or who have Graves' orbitopathy. Complications include: haemorrhage, hypoparathyroidism and vocal cord paralysis. Patients who undergo surgery will need to be followed up over a number of years, as they may develop hypothyroidism. Toxic adenoma or toxic multinodular goitre which is resistant to conservative treatment or causing compression symptoms is best treated with surgical excision.[18]