The thyroid gland is a butterfly-shaped organ composed of bulbous right and left lobes connected in the midline by a thin structure called the isthmus. Located in the neck, the thyroid wraps around the anterior trachea directly inferior to the larynx, at the level of the C5 through T1 vertebrae. On average, it measures 5 cm in height, and 5 cm in width, and weighs 20-30 g in adults, with slightly heavier thyroids seen in women. A richly vascular structure, the thyroid receives its blood supply predominantly from two sources. The superior thyroid artery, which is the first branch of the external carotid artery, supplies the upper half of the thyroid in over 95% of people. The lower portion of the thyroid is most commonly supplied by the inferior thyroid artery, branching from the thyrocervical trunk, itself a branch of the subclavian artery; in a subset of the population, the inferior thyroid artery may be absent or duplicated. In addition, the thyroid has extensive lymphatic drainage involving multiple levels of lymph nodes, including but not limited to the laryngeal (or Delphian), pre-and paratracheal, retropharyngeal, gastroesophageal, and internal jugular lymph nodes. This becomes very important in the staging of thyroid carcinoma, during which careful lymph node dissection may be necessary in the search for metastases. Embryology The thyroid gland is the first endocrine organ to form during fetal development. It begins to develop at four weeks gestation as an epithelial diverticulum arising from the foregut endoderm near the base of the primitive tongue, which extends progressively inferiorly starting at week five as the fetus develops. It reaches its final shape and relative size by seven weeks of gestation. The connection between the thyroid and the foregut called the thyroglossal duct, later regresses in normal development; if this regression does not occur, a thyroglossal duct cyst may form. The most common congenital anomaly of the thyroid, thyroglossal duct cysts is seen in 7% of adults, appearing as 2-3 cm fusiform or spherical nodules in the midline neck, which move upon swallowing. Histologically, the cyst lining varies based on location; superiorly, the lining is stratified squamous, and inferiorly, it is thyroid epithelium. On occasion, thyroglossal duct cysts may become infected, and, rarely, squamous cell and/or thyroid carcinoma may arise from the cyst lining. The thyroglossal duct may also leave behind an anatomic remnant known as the pyramidal lobe, which is a third, narrow thyroid lobe extending superiorly from the isthmus in 18-60% of people. Finally, due to the thyroid’s intimate association with branchial structures during development, several clinically insignificant anatomic variations can occur, including intrathyroidal ectopic thymus, parathyroid gland, salivary gland, and cartilage. Normal Histology The normal thyroid is comprised of numerous follicles surrounded by a fibrous capsule, which forms septae that divide the parenchyma into multiple lobules. The septae also contain the nerves and blood vessels supplying each lobule. Each lobule contains 20-40 round follicles, 200 μm in average diameter and lined by simple, flat to low columnar epithelium, depending on the state of functional activity; the more active the follicle, the taller the follicular epithelium. Follicular cells have uniform dark, small nuclei that are centrally located, and some have abundant granular cytoplasm, a variant known as Hürthle cells. Sanderson polsters, which are small follicles extending into the central spaces of larger follicles, can be seen scattered throughout the thyroid, and should not be mistaken for papillary structures. Follicles contain colloid, a viscous material composed predominantly of the thyroid hormone precursor protein thyroglobulin. The normal thyroid gland contains up to three months’ worth of thyroglobulin stored within colloid. The final cell type of the thyroid is the parafollicular, or C cell, a derivative of the neural crest by way of the ultimobranchial body. Parafollicular cells form clusters – as the name suggests – within and in between follicles, and are found in the highest concentration within the mid-and upper portions of the lobes. These cells form and secrete calcitonin, thereby participating in calcium homeostasis, which is a subject not included in this review. Hyper- and Hypothyroidism Hyper- and hypothyroidism are two of the most common disorders of the endocrine system worldwide. Approximately 4-5% of the population of the United States is affected, and the number is even higher in iodine-deficient countries. Most importantly, both symptomatic and silent versions of these two conditions are associated with increased mortality – in particular, due to cardiovascular disease. Normal Physiology In order to discuss hyper- and hypothyroidism and their sequelae, one must first recall the normal physiology of the thyroid gland. The primary function of thyroid follicular cells is the synthesis of thyroid hormones, of which there are predominantly two: tetraiodothyronine (T4), more commonly known as thyroxine, and triiodothyronine (T3). These hormones are extremely important for a significant variety of functions throughout the body, including development, growth, and basal metabolic rate (BMR) control, which will be discussed further below. Thyroid hormone production and release are stimulated through the hypothalamic-pituitary axis. Thyrotropin-releasing hormone (TRH) from the hypothalamus causes the anterior pituitary to release thyrotropin, also called thyroid-stimulating hormone (TSH). In response to TSH, thyroid follicular cells produce thyroglobulin, an inactive protein, which is then released from the apical surface into the follicle as a colloid. Sodium-iodide cotransporters on the basal surface of follicular cells take up iodide from the bloodstream, which is then released via transport protein, pendrin, into the follicle and oxidized by thyroid peroxidase into iodine. Next, tyrosine residues on thyroglobulin are iodinated and then conjugated via oxidative coupling, forming T3 and T4. Iodinated thyroglobulin is taken back into the follicular cell, where lysosomal protease degradation releases the T3 and T4 to exit into capillaries. Thyroid hormones travel in the bloodstream bound predominantly to thyroxine-binding protein. T4 is significantly more abundant, making up 90% of the total thyroid hormone; however, T3 is two to ten times more bioactive. To combat this problem, the target tissues contain 5′-iodine, which can convert T4 into T3. The activity of thyroid hormone is very broad, as it can act by essentially three main mechanisms: 1) directly at the cellular level, 2) via the sympathetic nervous system, and 3) through changing metabolism and affecting circulation. Thyroid hormone increases BMR, body temperature, gluconeogenesis, lipolysis, proteolysis, and glucose absorption. It increases stroke volume and heart rate, leading to increased cardiac output. In the young, it promotes growth and leads to bone maturation and fusion of growth plates. It is essential for central nervous system (CNS) maturation during fetal development. This series of biochemical events leading to thyroid hormone formation is controlled by a negative feedback loop whereby increased levels of thyroid hormone, especially T3, inhibit the release of TSH from the anterior pituitary. The opposing forces of TRH and T3 allow for the maintenance of a relatively steady thyroid state in the normal individual. However, when derangements occur within this delicate system, serious and potentially fatal conditions may result. Hyperthyroidism Increased concentration of thyroid hormone has many causes, the most common of which is Graves disease, which will be discussed in detail below. Less common causes of hyperthyroidism include hyperfunctional (or toxic) adenoma, toxic multinodular goiter, thyroid malignancy, increased TSH from pituitary adenoma (secondary hyperparathyroidism), increased TRH (tertiary hyperparathyroidism), exogenous thyroid hormone ingestion, or thyroid damage from amiodarone toxicity, radiation, or trauma. No matter the inciting factor, for the most part, the signs and symptoms of hyperthyroidism are the same, related to the previously described activity of thyroid hormone. These include weight loss despite adequate or increased caloric intake, heat intolerance, tremors, hyperreflexia, sweating, skin flushing, weakness, irritability, and nervousness. Most important to the discussion of thyroid-related mortality, however, are the substantial cardiac manifestations of hyperthyroidism. Indeed, symptoms related to effects on the heart are a consistent feature, and often the presenting complaint, of a hyperthyroid patient. These include tachycardia, palpitations, and arrhythmias, notably atrial fibrillation, which is not only the most common cardiac arrhythmia in this population but also a substantial contributor to cardiovascular disease-related morbidity and mortality, particularly cerebrovascular events (CVE) or stroke. Many other arrhythmias can occur as well, including sinus tachycardia, supraventricular tachycardia (SVT), premature atrial contractions, and complete heart block. The atria are more sensitive to the effects of thyroid hormone than the ventricles, and as such, ventricular arrhythmias are very rarely caused by hyperthyroidism. Other cardiac manifestations of hyperthyroidism that have been reported include coronary spasm, mild interstitial fibrosis, and mild lymphocytic and eosinophilic myocarditis. In more severe cases, thyrotoxic cardiomyopathy, myocardial infarction (MI), CVE, and congestive heart failure (CHF) can occur. Congestive heart failure may be the sole symptom of so-called “apathetic” hyperthyroidism in a subset of elderly patients. Almost 6% of patients with hyperthyroidism present with CHF and atrial fibrillation. Thyrotoxic cardiomyopathy often presents as acute heart failure in young patients without cardiovascular risk factors and may be fatal if not treated properly. Stabilization of thyroid function status may reverse the process; however, chronic dilated cardiomyopathy can also result. Graves Disease Causing approximately 85% of clinically apparent hyperthyroidism, Graves disease was first reported by Caleb Hillier Parry in 1786. It presents most commonly in Caucasian and Asian women between the ages of 20-40 years and affects 1.5-2% of women in the United States. The pathophysiology is autoimmune in nature; specifically, autoantibodies to the TSH receptors of the follicular cells lead to stimulation of thyroid hormone production. Because of the negative feedback effect of thyroid hormone on the anterior pituitary gland, TSH levels will be low in this disease. Along with the signs and symptoms of hyperthyroidism discussed previously, Graves disease has several unique characteristics due to autoimmunity, including thyroid ophthalmopathy (or proptosis), which occurs in 50% of patients, exophthalmos from hypertrophy of the extraocular adipose tissue, generalized lymphadenopathy, and late findings including pretibial myxedema (thickened, indurated, and scaled skin overlying the shins), which occurs in only 1-2% of patients, and acropachy (clubbing of all digits from new bone formation. However, at the time of autopsy, clinical history may be unavailable, the decedent may not have a diagnosis of Graves disease, and the above findings may not be present; therefore, diagnosing Graves disease in the forensic setting requires examination of the thyroid gland. Grossly, the thyroid gland of Graves disease is symmetrical, with mild-to-moderate, diffuse enlargement. It is firm on palpation, and the cut surface is uniform, solid, and grey-to-red; to some, it resembles the pancreas. Histologic examination reveals severely hyperplastic follicles with papillae extending into the follicles, which contain pale colloids with somewhat characteristic scalloped edges. Within the interstitium may be lymphoid aggregates and/or mild fibrosis. Graves disease is often treated with radioactive iodine ablation (RIA), which changes the thyroid histology significantly. Soon following RIA, thyroid histology shows nuclear atypia, follicle dropout, and alterations of the vasculature. When these changes subside, the thyroid becomes atrophic and fibrotic…
