Diseases of the Thyroid
Describe the symptoms and histologic features associated with Hashimoto thyroiditis.
Autoimmune response to the thyroid. Most common cause of hypothyroid in areas where iodine intake is sufficient. Affects middle aged to older women. Antibodies against TSH receptor, thyroglobulin, and thyroid peroxidase Presence of chronic inflammation with well-developed germinal centers in the thyroid under microscope. Atrophic follicles. Hypothyroid: cold intolerance, mental sluggishness, fatigue, weight gain
Discuss three features that distinguish follicular carcinomas, anaplastic carcinomas, and medullary carcinomas from papillary thyroid carcinomas.
Features of papillary thyroid carcinomas are discussed in #7. Follicular carcinoma: cells do not display the nuclear features of papillary thyroid carcinomas. Tumors invade the vasculature, have distant mets, or invade the tumor capsule. Anaplastic carcinoma: nuclei are very large, are abnormal and there are many mitotic figures. The features characteristic of papillary thyroid carcinomas are not present. Medullary carcinoma: rare tumor of parafollicular (C) cells. Amyloid deposits are seen in the stroma. Associated with MEN 2A or 2B.
3. Define goiter, list different subtypes of goiters, and explain the pathogenesis of goiters.
Goiter is enlargement of the thyroid. Diffuse type has uniform enlargement throughout the thyroid (Grave's disease) Multinodular type has areas of enlargement that are not uniform repeated episodes of hyperplasia and involution) Occurs due to dietary factors (not enough iodine: endemic) or because of some other cause (sporadic)
Describe the pathogenesis of Grave's disease and explain how to distinguish it from other forms of hyperthyroidism.
Graves disease occurs due to the presence of a thyroid-stimulating immunoglobulin (TSI) that activates the TSH receptor. Primary hyperthyroidism. Symptoms include tachycardia, weight loss, exophthalmos, pretibial myxedema, diffuse toxic goiter (hyperplastic thyroid with excessive production of thyroid hormone). This activation causes increased production and secretion of T3 and T4. Under the microscope, the follicles have a scalloped edge appearance due to follicular cells sucking in the thyroglobulin to quickly produce thyroid hormone; leaves behind a white space Autoimmune. Lymphocytic infiltrate in the interstitium.
Compare and contrast the symptoms of hypothyroidism and hyperthyroidism.
Hypothyroidism Very slow BMR. Cold intolerance, weight gain, swelling of eye, fatigue, mental slowness, decreased sweating, constipation, shortness of breath and poor exercise tolerance Myxedema (in adulthood) Cretinism (in infancy or early childhood), characterized by severe mental retardation, short stature, large tongue, coarse facial features, umbilical hernia Hyperthyroidism Very fast BMR. Heat intolerance, weight loss, palpitations, arrhythmias, increased cardiac output, cardiomegaly, tachycardia, tremor, anxiety, insomnia, gut hypermotility/diarrhea, increased sweating, increased appetite, osteoporosis.
Describe the key diagnostic features of papillary thyroid carcinoma.
Most common primary carcinoma of the thyroid. Oval nuclei with nuclear grooves; "Orphan Annie eye" nuclei; intranuclear inclusions Nuclear changes are the most specific features Often has papillary architecture. Psammoma bodies (concentric calcifications) are sometimes seen.
Explain the laboratory evaluation of thyroid function and the difference between primary and secondary hyper- and hypothyroidism.
TSH is the main evaluator of thyroid function in relation to symptoms. T3 and T4 can also be measured (usually free T4). Elevated TSH and low T3/T4: primary hypothyroidism Low TSH and low T3/T4: secondary hypothyroidism Low TSH and elevated T3/T4: primary hyperthyroidism Elevated TSH and elevated T3/T4: secondary hyperthyroidism Primary hyper (or hypo) thyroidism is due to a problem in the thyroid itself that is causing under or oversecretion of hormone. For example, Hashimoto's thyroiditis destroys the thyroid and results in hypothyroidism, and Graves disease is characterized by antibodies that bind and activate the TSH receptor, causing excess T3 and T4 secretion (hyperthyroidism). Both of these examples are primary causes. Secondary hyper or hypo thyroidism is due to a problem outside of the thyroid (problem is with the pituitary). For example, if the pituitary thyrotrophs have an adenoma that secretes TSH, then the thyroid will be constantly stimulated to secrete T3 and T4. If the pituitary is absent, ischemic, removed, etc, then there will be no TSH to stimulate the thyroid, and no T3 or T4 released (secondary hypothyroidism).
5. Characterize the pathogenesis of Grave's disease and distinguish it from other forms of hyperthyroidism
a. A disease that consists of a series of different clinical findings. These include toxic goiter, opthalmopathy (bulging eyes because of hypertrophy of the fat pads behind the eyes) and dermopath (the most common cause of hyperthyroidism). Graves disease is an auto-immune disease specifically targeting TSH receptors. Graves disease is associated with an abundance of thyroid-stimulating immunoglobulin (TSI) which will mimic the actions of TSH and bind to TSH receptor which stimulate proliferation of the follicular epithelium. This is distinguished from other forms of hyperthyroidism in that it is antibody mediated and not do to an increased release of thyroid hormone or increased release of TSH from the pituitary. b. The most distinct clinical finding on physical exam Is exophthalmos which is a protrusion of the eyeballs. Pretibial myxedema which is characterized by scaly indurations of the skin are also present. c. Pathology of graves disease: Thyroid is enlarged with diffuse hypertrophy and hyperplasia of the follicular cells. There is additional lymphoid infiltrate in the intersititum with frequent germinal centers.
4. Relate the symptoms and histologic features associated with Hashimoto thyroiditis
a. Also known as chronic lymphocytic thyroiditis. An auto immune disease linked to destruction of the thyroid gland. Most common cause of hypothyroidism where there is adequate dietary intake of iodide. Common in middle aged or older women. b. Mechanism: CD4+ T helper cells are sensitized to thyroid antigens in hashimoto thyroiditis which leads to the destruction of the thyroid follicular cells. c. Clinical presentation: Goiters disease (thyroid enlargement) and hypothyroidism. Goiters could be an initial compensatory mechanism for the destruction of the follicular cells. The hypothyroidism is gradual and progressive as the gland is gradually destroyed over time. d. Histology: Extensive mononuclear cell infiltrate with well developed germinal centers. The thyroid follicles are atrophic. Metaplastic follicular cells with granular eosinophilic cytoplasm are common (Hurthle cells) Fibrosis may also be present and form dense bands.
6. Compare the key diagnostic features of papillary thyroid carcinoma.
a. Diagnostic features of papillary thyroid carcinoma i. Most common primary carcinoma of the thyroid (75-85% of thyroid carcinomas) ii. Most common in women from young to middle adulthood. iii. Patients present with a thyroid mass but some patients present with a single cervical lymph node metastasis at presentation. iv. Histology: Papillary architecture with the neoplastic cells frequently growing along papillary fibrovascular cores. Psammoma bodies are sometimes seen. The characteristic nuclear changes are the most specific feature to papillary carcinoma, not the papillary architecture
7. Distinguish features of follicular carcinomas, anaplastic carcinomas, and medullary carcinomas from papillary thyroid carcinomas. ( MK PC )
a. Follicular carcinoma: Less common than papillary thyroid carcinoma but still accounts for 10-20% of thyroid carcinomas. Present as painless masses of the thyroid. Features include capsular invasion, vascular invasion or distant metastases. The follicular structure of the follicular carcinoma may be present within papillary thyroid carcinoma so distinguishing between the two is based upon identifying characteristic nuclear findings of papillary thyroid carcinoma b. Anaplastic carcinoma: Aggressive malignancy with no therapy. All patients usually die within the first year of diagnosis. The disease presents as a rapidly growing neck mass which adheres to adjacent neck structures. Histologically, the tumor is composed of highly abnormal anaplastic cells. c. Medullary carcinoma: differ from other thyroid carcinomas in that they do not arise from thyroid follicular cells. They arise from Parafollicular cells (C cells) that normally secrete calcitonin. A small group of patients with medullary carcinoma occur in the setting of MEN syndrome 2A or 2B. mutations in the RET proto-oncogene are important in the development of both familial and sporadic medullary carcinomas. Histologically, the presence of amyloid deposits are the most distinctive feature which occur because of altered calcitonin secreted by the tumor cells. Likewise, foci of C cells may undergo hyperplasia within the background thyroid tissue. The presence of multiple foci of C-cell hyperplasia suggests a familial syndrome.
1. Compare and contrast the symptoms of hypothyroidism and hyperthyroidism
a. Hyperthyroidism is associated with enhanced metabolic activity, enhanced protein generation and metabolism (greater degredation compared to synthesis), clinical presentations such as increased sweating, tremors, tachycardia. Cardiac findings are the first indication of hyperthyroidism. Cardiomegaly, thyrotoxic dilated cardiomyopathy, palpitations and arrhythmias, emotional lability, anxiety, insomnia, gut hypermotility and chronic diarrhea are also common findings. Increased metabolic activity via hyperthyroidism is accompanied by heat intolerance, increased sweating, weight loss, increased appetite and osteoporosis. The two forms of hyperthyroidism include primary and secondary hyperthyroidism i. Primary hyperthyroidism: Dysfunction of the thyroid gland itself with low levels of TSH. The thyroid is essentially ignoring orders from the pituitary to reduce the release of thyroid hormone. You will have an elevated T4/T3 but will have low TSH ii. Secondary hyperthyroidism: The pituitary is dysfunctional and produces excess TSH. The thyroid will thus increase the release of thyroid hormone based on the increased release signaling from the anterior pituitary. This may be without stimulation from the hypothalamus to produce thyroid releasing hormone. iii. The most common causes of hyperthyroidism include grave's disease (antibody targeting TSH leading to activation of hypertrophy of follicular cells), toxic multinodular goiter (multinodular) and toxic adenoma. Diffuse goiter is usually attributable to an inflammatory process since the entire gland is affected. b. Hypothyroidism: a state characterized by inadequate thyroid hormone. Similar to hyperthyroidism, dysfunction of the thyroid deal with reduced sensitivity to TSH (primary hypo) or reduced activity of the pituitary gland (TSH)leading to insufficient release of thyroid hormone from the thyroid gland. There are many different kinds of hypothyroidism based upon the age of presentation. Primary always is associated with the gland itself. i. Cretinism: Hypothyroidism in infancy or early childhood. Usually always attributable to inadequate dietary iodine. Consequences of absent thyroid hormone in infants results in severe mental retardation, short stature, coarse facial features, protruding tongue and umbilical hernia. Mothers need to have an abundance of T4 to be converted to T3 for the developing child. ii. Myxedema: Hypothyroidism that develops in later childhood or in adulthood. Features of hypothyroidism roughly the polar opposite to features commonly seen in hyperthyroidism. These include fatigue, mental sluggishness, cold intolerance, obesity, shortness of breath and poor exercise tolerance, decreased sweating, constipation. Edema of the skin, subcutaneous tissues and some visceral sites due to increased accumulation of matrix substances such as glycosaminoglycans and hyaluronic acid. iii. Hypothyroidism is treated with hormone replacement therapy
2. Interpret laboratory evaluation of thyroid function and the difference between primary and secondary hyperthyroidism and hypothyroidism. ( MK PC )
a. Measurement of serum TSH levels is the most useful single screening test for both hyperthyroidism and hypothyroidism. It is an easy serum marker to evaluate relate to other factors such as TRH (difficult anatomic location) In hyperthyroidism, low TSH values are accompanied with an increased free T4 measurement. Secondary hyperthyroidism (overactive pituitary signal) is rare and leads to elevated or normal TSH levels with elevated T4 levels at the same time. b. TSH are increased in primary hypothyroidism. This is because the gland itself may have reduced sensitivity to TSH which in turn will increase the amount of TSH being released in order to illicit a response. In secondary hypothyroidism TSH levels are normal or low. Free T4 is low in all forms of hypothyroidism. This may be because of reduced TRH from the hypothalamus to the anterior pituitary. c. Primary vs. Secondary hyperthyroidism: for primary hyperthyroidism, there is dysfunction of the thyroid gland itself, and the thyroid is ignoring orders from the pituitary to slow down and is thus producing excess thyroid hormone. T4 will be high and TSH will be low in primary. In secondary hyperthyroidism, the pituitary is secreting too much TSH which will be accompanied by increased circulating levels of T4. d. Primary vs. Secondary hypothyroidism: In primary hypothyroidism, the thyroid is not responding to signals from the pituitary to release thyroid hormone, thus resulting in lower than normal circulating thyroid hormone. This will show and elevated levels of serum TSH and a reduced T4. For secondary hypothyroidism, the pituitary is not receiving signals from the pituitary (low TSH) which in turn will lead to an overall reduction in the release of T4.
3. Characterize different subtypes of goiters, and their pathogenesis
i. Endemic goiter: Caused by a dietary issue. Low dietary intake of iodine is associated with endemic goiters. Low iodine will lead to low circulating T4 which will upregulate TRH and TSH to increase activity of the thyroid leading to gland hypertrophy. ii. Sporadic goiters: Not endemic and more common in females than males. Gioters results from stimulation of the TSH receptor found on thyroid follicular cells initially causing diffuse hypertrophy and hyperplasia of the follicular cells, leading to enlargement of the gland. Impaired thyroid hormone synthesis can cause an increased secretion of TSH by the pituitary to compensate. If the patient is unable to compensate than hypothyroidism will occur. Most have no known cause but some sporadic goiters occur as a reaction to drugs. iii. Multinodular goiter: May develop after repeated episodes of hyperplasia and involution. The multinodular goiters can become very large and have dominant nodules that simulate neoplasia. A hyperfunctioning nodule may aris leading to hyperthyroidism. The goiter is then called a toxic multinodular goiter. Usually benign and a diagnosis if follicular adenoma (singular nodule) is not present. iv. Diffuse goiters vs. multinodular goiter: Histologic appearance of both Is very similar. Diffuse goiter rarely exceeds 100g, multinodular goiters weigh up to 2000g. Fibrosis, hemorrhage, calcification and cystic change may also be seen in multinodular goiters.
