Thyroid Patho and Pharm Flashcards
the thyroid develops embryologically from an evagination of the pharyngeal epithelium that descends from the ______ at the base of the tongue to its normal position in the anterior neck
foramen cecum
T3 and T4 are peptide hormones which circulate in the plasma bound to _____ and _____
thyroxine-binding globulin and transthyretin
Pt is a 51yo F presenting with a goitrous (enlarge) thyroid. Blood labs are positive for anti-thyroid peroxidase and anti-thyroglobulin antibodies. What is the diagnosis?
Hashimoto’s thyroiditis: most common cause of hypothyroidism, due to autoimmune attack of thyroid
can occur in isolation or in conjunction with MEN 1/2 (multiple endocrine neoplasia)
An immigrant child presents for the first time to a pediatrician in the US. PE is significant for severe intellectual disability, short stature, coarse facial features, protruding tongue, and umbilical hernia. What deficiency caused this condition?
cretinism - hypothyroidism due to iodine deficiency (in utero)
more common in mountainous areas, where iodine runs off in the water (Himalayas, inland China, Africa)
myxedema
hypothyroidism developing in the older child or adult, marked by slowing of physical and mental activity
decrease in cardiac output, increase in total cholesterol and LDL, non-pitting edema, coursing of facial features, macroglossia, deepening of voice
what histological changes occur with Hashimoto’s thyroiditis?
Type IV hypersensitivity (CD8-T cell cytotoxicity), thyroglobulin and thyroid peroxidase autoantibodies
—> diffusely enlarged thyroid
—> lymphocytic infiltration and fibrosis
—> well-developed germinal centers
—> atrophic thyroid follicles, lined by Hurthle cells (metaplastic response to chronic injury)
patients with _____ thyroiditis are at an increased risk of developing extranodal marginal zone B cell lymphoma (MALT) within the thyroid gland
Hashimoto’s thyroiditis (autoimmune mediated fibrosis)
granulomatous (De Quervain’s) thyroiditis is usually triggered by…
viral infection (usually upper respiratory)
most common cause of thyroid pain with fever and malaise
what histological changes occur with granulomatous (De Quervain’s) thyroiditis?
gland is enlarged and firm, early on scattered follicles are replaced by neutrophils forming micro-abscesses
later, lymphocytes/macrophages/plasma cells form aggregates in collapsed follicles
multinucleated giant cells enclose pools of colloid —> granulomas
most common cause of thyroid pain with fever and malaise
granulomatous (De Quervain’s) thyroiditis: triggered by viral infection, causes inflammation of the thyroid
causes transient hyperthyroidism (2-6 weeks)
rare disorder characterized by extensive fibrosis involving the thyroid and contiguous neck structures, which may be mistaken for thyroid carcinoma, manifested by tissue infiltration by IgG4 plasma cells
Riedel thyroiditis
what autoantibodies are produced in Grave’s disease?
anti-TSH receptor, most common subtype is thyroid stimulating immunoglobulin (TSI), only seen in Grave’s disease
TSI binds TSH receptor and activates it, stimulating adenyl cyclase and thyroid hormone production
what histological changes occur with Grave’s disease?
diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells - tall/more crowded than usual
crowding results in formation of small papillae (finger like projections) which encroach on colloid within follicle lumen —> lumen is pale with scalloped margins
Plummer syndrome
aka toxic multinodular goiter: occurs when thyroid goiters start autonomously producing thyroid hormone independent of TSH
concern for malignancy arises when goiters change in size or associated symptoms (ex, hoarseness)
Which of these is INCORRECT?
a. solitary thyroid nodules are more likely to be malignant than multiple nodules
b. nodules in very young (<20) and very old are more likely to be neoplastic
c. nodules in females are more likely to be neoplastic than nodules in males
d. a history of radiation treatment/exposure to the head and neck region is associated with increased incidence of thyroid malignancy
e. nodules that are “cold” (do not take up radioactive iodine in imaging studies) are more likely to be malignant
c. nodules in males are more likely to be neoplastic than nodules in females
all other statements are true as stated
what type of mutations are associated with toxic adenomas of the thyroid?
toxic adenomas: adenomas (benign neoplasms) that produce thyroid hormone, causing thyrotoxicosis
associated with GOF somatic mutations leading to constitutive activation of TSH receptor (TSHR gene) or alpha subunit of Gs protein (GNAS gene)
—> hyperthyroidism and “hot” nodule on imaging
Conventional papillary thyroid carcinoma’s have what 2 defining genetic abnormalities?
- gene fusions of RET: GOF, encodes receptor tyrosine kinase (RTK) that is normally not expressed in thyroid follicular cells
- point mutations in BRAF: GOF, encodes serine/threonine kinase that lies downstream of RTK in growth factor signaling pathways
follicular neoplasm of the thyroid are often associated with gain of function mutations in what gene?
RAS GOF mutations - cause expression of thyroid differentiation factors (thyroglobulin, thyroid peroxidase)
What are the three recurrent genetic “hits” associated with poorly differentiated and anaplastic thyroid carcinoma?
anaplastic thyroid carcinomas usually arise via papillary or follicular thyroid carcinomas gaining more mutations, associated with point mutations in:
1. TP53
2. beta-catenin
3. TERT (encodes catalytic portion of telomerase)
mutations in what gene are associated with medullary thyroid carcinoma?
RET mutations seen in both familial medullary thyroid carcinoma (as part of MEN-2) and also non-familial (sporadic) cancer
papillary thyroid carcinomas are associated with mutation of which of the following?
a. RAS
b. RET
c. TP53
d. TERT
b. RET gene fusion (and also point mutation in BRAF)
a. RAS - follicular neoplasm
c. TP53 and d. TERT - anaplastic carcinoma
follicular thyroid neoplasms are associated with mutation of which of the following?
a. BRAF
b. TP53
c. beta-catenin
d. RAS
e. RET
d. RAS
a. BRAF - papillary carcinoma
b. TP53 and c. beta-catenin - anaplstic carcinoma
e. RET - papillary and medullary carcinomas
gene fusions of RET are associated with which of the following thyroid cancers?
a. follicular neoplasms
b. anaplastic carcinomas
c. papillary carcinomas
c. papillary carcinomas (and also point mutations in BRAF)
GOF RAS mutations are associated with which of the following thyroid cancers?
a. follicular neoplasms
b. anaplastic carcinomas
c. papillary carcinomas
d. medullary carcinoma
a. follicular neoplasms
why is levothyroxine preferred over liothyronine?
levothyroxine (synthetic T4) - long half-life allows 1x/day to weekly administration
liothyronine (synthetic T3) - shorter half life (24 hours) requires multiple daily doses, should be avoided in patients with cardiac disease due to risk of cardiotoxicity, reserved for short-term TSH suppression
name the 2 major thioamides used in the treatment of thyrotoxicosis - which one is “drug of choice”?
- methimazole - 10x more potent, DOC
- propylthiouracil (PTU) - risk of severe hepatitis, only used in first trimester of pregnancy (crosses placenta less readily), thyroid storm, or in patients with severe adverse reactions to methimazole
propylthiouracil (PTU) should only be used for… (3)
PTU = thioamide, treats thyrotoxicosis
- first trimester of pregnancy (crosses placenta less readily than methimazole)
- thyroid storm (blocks both TPO and 5-deiodinase)
- in patients with severe adverse reactions to methimazole
what adverse reactions are associated with thioamides (methimazole and propylthiouracil)? (3)
- maculopapular pruritic rash - most common, accompanied by systemic signs like fever
- severe hepatitis - reported with PTU (black box warning)
- agranulocytosis - most dangerous complication, but reversible with drug discontinuation
which would improve thyrotoxic symptoms quicker, a thioamide or an iodide?
iodides work faster - inhibit hormone release, improvement in thyrotoxic symptoms within 2-7 days
thioamides require 3+ weeks before stores of T4 are depleted (inhibit TPO/ 5-deiodinase)
why can’t iodides be used alone for treatment of thyrotoxicosis?
iodides inhibit hormone release (via Wolff-Chaikoff effect) and also decrease vascularity/size of a hyper-plastic gland (good for pre-surgery)
however, thyroid can escape the iodide block in 2-8 weeks and withdraw may produce severe exacerbation of thyrotoxicosis in an iodine-enriched gland
