Thyroid Patho and Pharm

Question 1

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

Answer 1

foramen cecum

Question 2

T3 and T4 are peptide hormones which circulate in the plasma bound to _____ and _____

Answer 2

thyroxine-binding globulin and transthyretin

Question 3

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?

Answer 3

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)

Question 4

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?

Answer 4

cretinism - hypothyroidism due to iodine deficiency (in utero)

more common in mountainous areas, where iodine runs off in the water (Himalayas, inland China, Africa)

Question 5

myxedema

Answer 5

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

Question 6

what histological changes occur with Hashimoto’s thyroiditis?

Answer 6

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)

Question 7

patients with _____ thyroiditis are at an increased risk of developing extranodal marginal zone B cell lymphoma (MALT) within the thyroid gland

Answer 7

Hashimoto’s thyroiditis (autoimmune mediated fibrosis)

Question 8

granulomatous (De Quervain’s) thyroiditis is usually triggered by…

Answer 8

viral infection (usually upper respiratory)

most common cause of thyroid pain with fever and malaise

Question 9

what histological changes occur with granulomatous (De Quervain’s) thyroiditis?

Answer 9

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

Question 10

most common cause of thyroid pain with fever and malaise

Answer 10

granulomatous (De Quervain’s) thyroiditis: triggered by viral infection, causes inflammation of the thyroid

causes transient hyperthyroidism (2-6 weeks)

Question 11

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

Answer 11

Riedel thyroiditis

Question 12

what autoantibodies are produced in Grave’s disease?

Answer 12

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

Question 13

what histological changes occur with Grave’s disease?

Answer 13

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

Question 14

Plummer syndrome

Answer 14

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)

Question 15

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

Answer 15

c. nodules in males are more likely to be neoplastic than nodules in females

all other statements are true as stated

Question 16

what type of mutations are associated with toxic adenomas of the thyroid?

Answer 16

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

Question 17

Conventional papillary thyroid carcinoma’s have what 2 defining genetic abnormalities?

Answer 17

1. gene fusions of RET: GOF, encodes receptor tyrosine kinase (RTK) that is normally not expressed in thyroid follicular cells
2. point mutations in BRAF: GOF, encodes serine/threonine kinase that lies downstream of RTK in growth factor signaling pathways

Question 18

follicular neoplasm of the thyroid are often associated with gain of function mutations in what gene?

Answer 18

RAS GOF mutations - cause expression of thyroid differentiation factors (thyroglobulin, thyroid peroxidase)

Question 19

What are the three recurrent genetic “hits” associated with poorly differentiated and anaplastic thyroid carcinoma?

Answer 19

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)

Question 20

mutations in what gene are associated with medullary thyroid carcinoma?

Answer 20

RET mutations seen in both familial medullary thyroid carcinoma (as part of MEN-2) and also non-familial (sporadic) cancer

Question 21

papillary thyroid carcinomas are associated with mutation of which of the following?
a. RAS
b. RET
c. TP53
d. TERT

Answer 21

b. RET gene fusion (and also point mutation in BRAF)

a. RAS - follicular neoplasm
c. TP53 and d. TERT - anaplastic carcinoma

Question 22

follicular thyroid neoplasms are associated with mutation of which of the following?
a. BRAF
b. TP53
c. beta-catenin
d. RAS
e. RET

Answer 22

d. RAS

a. BRAF - papillary carcinoma
b. TP53 and c. beta-catenin - anaplstic carcinoma
e. RET - papillary and medullary carcinomas

Question 23

gene fusions of RET are associated with which of the following thyroid cancers?
a. follicular neoplasms
b. anaplastic carcinomas
c. papillary carcinomas

Answer 23

c. papillary carcinomas (and also point mutations in BRAF)

Question 24

GOF RAS mutations are associated with which of the following thyroid cancers?
a. follicular neoplasms
b. anaplastic carcinomas
c. papillary carcinomas
d. medullary carcinoma

Answer 24

a. follicular neoplasms

Question 25

why is levothyroxine preferred over liothyronine?

Answer 25

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

Question 26

name the 2 major thioamides used in the treatment of thyrotoxicosis - which one is “drug of choice”?

Answer 26

1. methimazole - 10x more potent, DOC
2. 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

Question 27

propylthiouracil (PTU) should only be used for… (3)

Answer 27

PTU = thioamide, treats thyrotoxicosis

1. first trimester of pregnancy (crosses placenta less readily than methimazole)
2. thyroid storm (blocks both TPO and 5-deiodinase)
3. in patients with severe adverse reactions to methimazole

Question 28

what adverse reactions are associated with thioamides (methimazole and propylthiouracil)? (3)

Answer 28

1. maculopapular pruritic rash - most common, accompanied by systemic signs like fever
2. severe hepatitis - reported with PTU (black box warning)
3. agranulocytosis - most dangerous complication, but reversible with drug discontinuation

Question 29

which would improve thyrotoxic symptoms quicker, a thioamide or an iodide?

Answer 29

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)

Question 30

why can’t iodides be used alone for treatment of thyrotoxicosis?

Answer 30

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