3. Robbins: Thyroid Flashcards
Describe the morphology of the thyroid

What is the mechanism of T3/T4 release from the thyroid?

Where is thyroglobulin made and stored?
Colloid
What is thyroglobulin converted into?
T4 (thyroxine) and lesser amounts, into T3 (triidothyronine).
Which thyroid hormones binds to [thyroid hormone nuclear receptors] in target cells with greater affinity and have greater activity?
T3
Actions of thyroid hormone
- Increase in the basal metabolic rate (MAIN)
- Carb/lipid catabolism
- Protein synthesis
_________ = chemicals that inhibit the function of the thyroid gland
Goitrogens: [↓ T3/T4 —> ↑ TSH —> enlargement of the thyroid].
What is the MOA of the antithyroid agent, propylthiouracil?
Decreases TH production
- Inhibits the oxidation of iodide by TPO => thus, blocks production of TH
- Inhibits the peripheral conversion/deiodination of T4 => T3
What occurs when large doses of iodide are given?
- Acts as a goitrogen: Blocks release of thyroid hormones by inhibiting the proteolysis of thyroglobulin.
- Thyroid hormone is made and incorperated into colloid, but not released into blood.
Hyperthyroidism is also called _______.
Thyrotoxicosis
Hyperthyroidism/Thyrotoxicosis
- What is it?
- Types and MCC
- Hypermetabolic state d/t increase levels of free T3/4
- Primary hyperparathyroidism (MC) and secondary hyperparathyroidism.
Types of Primary Hyperparathyroidism
Which is the MC?
- Diffuse hyperplasia (Graves disease) of thyroid => MC
- Hyperfunctioning mulinodular goiter
- Hyperfunctioning thyroid adenoma
Types of Secondary Hyperparathyroidism
- Pituitary thyrotroph adenoma
How does the clinical presentation of hyperthyroidism vary?
Symptoms exist on a continuum
- 1. Apathetic hyperthyroidism
- 2. Regular hyperthyroidism
- 3. Thyroid storm
Symptoms of Regular Hyperthyroidism
-
Hypermetabolic state due to too much T3/T4 and overactive sympathetic NS
- Increase in BMR => perspiration, flushing and heat intolerance
- Cardiac manifestations: tachycardia, palpitatio, sinus tachycardia (NL rhythm, but increase rate: a-fib)
- Exophthalmos
- Overative sympathetic NS: nervousness, excited, restless, insomnia, emotionally unstable

Thyroid Storm
What is it?
Symptoms
If left untreated what is a common cause of death?
Thyroid storm = abrupt onset of SEVERE hyperthyroidism that occurs MC in patients with Graves disease and most likely due to acute elevation of catecholamines
- Febrile
- Cardiac manifestation: tachycardia and CHF
- GI symptoms: diarrhea and jaundic
- Death: due to cardiac arrhythmia
Who is more likely to get thyroid storm?
- Ppl with Graves disease who are/have
- Pregnancy/postpartum
- Hemithyroidectomy
- Take amiodarone
Apathetic hyperthyroidism
What is it?
- Thyrotoxicosis that occurs in older adults who have co-morbidities that mask symptoms. Present with
- Unexplained WL
- Worsening CV disease
T3/T4 & TSH levels
Primary and secondary hyperthyroidism
- Primary: ↑ T3/T4 and ↓ TSH levels
- Secondary: ↑ T3/T4 and ↑ TSH levels
TRH stimulation test
- NL rise in TSH =______
excludes secondary hyperthyroidism
Once a diagnosis of thyrotoxicosis is made, how can we determine etiology?
- Measure radioative iodine uptake by thyroid gland
- ↑ uptake by whole gland = Graves
- ↑ uptake by 1 nodule = Toxic adenoma
- ↓ uptake = thyroiditis
Treatment of Hyperthyroidism
- Treat manifestations with B-blocksrs or NSAIDS
-
Treat underlying disease with:
- High doses of iodide (Wolf-Chaikoff effect)
- Thionamide
- Radiodine ablation
- Surgery
MC etiology of Hyperthyroidism
Graves disease
What is Graves Disease?
AI disorder caused by (+) of thyroid epithelial cells by TSI (thyroid stimulating immunoglobulins) autoAb to the TSH-receptor that mimic TSHs action.
Graves Disease
- Triad of symptoms
- Hyperthyroidism with gland enlargment
- Infiltrative ophthalmopathy –> exophthalmos
- Pretibial myxedema/dermopathy = scaly/indurated skin on shins
Graves Disease
- MC in:
- Most common antibody subtype
- HLA subtypes associated with Graves disease:
- Lab findings
- W 20-40 YO
- Thyroid stimulating immunoglobulin (TSI)
- HLA-DR3 and B8
- ↑ free T3/4; ↓ TSH; ↑ uptake of radioactive iodine (bc thyroid follicles are STILL being stimulated by TSI)
The exopthalmos associated with Graves Disease is caused by what underlying process?
- CD4-helper T cells infiltration of retroorbital space and release TSI =>
- TSI Ab bind to TSH-receptor on fibroblasts => proliferate
- EOM begin to swell due to edema + inflammation
- Accumulation of EC matrix components (GAG and chondroitin sulfate)
- ↑ number and expansion of adipocytes
- Eyeball pushes forward.
The exopthalmos associated w/ Graves disease appears to stem from activation of which cells in the orbit and via which receptor?
Orbital preadipocyte fibroblasts, which have TSH receptors
Gross morphology of Graves Disease
- Soft, symmetrical enlargement of thyroid due to diffuse hypertrophy and hyperplasia of follicular epithelial cells
Histology of the thyroid in untreated Graves Disease
- Follicular epithelial cells are taller and more crowded –> formation of small papillae WITHOUT fibrovascular cores that project into the lumen and encroach on the colloid
- Colloid has scalloped margins with resorption droplets (colloid in endocytotic vesicles made by pseudopodial extensions of cytoplasm at the lumen)
- Lymphiod infiltrates + germinal centers

How do the papillae seen in graves disease differ histologically from those of papillary carcinoma?
Lack fibrovascular cores
Hypothyroidism
- MC in whom?
- Due to?
- Increases with age; W
- Primary hypothyroidism *** vs. Secondary hypothyroidism
Primary hypothyroidism can be _______, _______, _____
Congenital vs Autoimmune vs Iatrogenic
Congenital hypothyroidism is most often due to _________
Endemic iodine deficiency in the diet during pregnancy.
Inborn errors of thyroid metabolism causing congenital hypothyroidism is known as what?
Dyshormonogenetic goiter: where one of multiple steps leading to thyroid hormone synthesis is defective:
- Iodide transport into thyrocyte
- Organification of iodine (binding of iodine to tyrosine resides of the storage protein, thyroglobulin)
- Iodotyrosine coupling to form active T3/4
Other causes of hypothyroidism
- Thyroid agenesis (complete absence of thyroid parenchyma)
- Thyroid hyopplasia (gland is reduced in size)
Cretinism
- What is it?
- Sx
- Possible causes
Congenital hypothyroidism that develops in infancy or early childhood
Symptoms:
- Mental retardation
- Short stature
- Coarse facial features and a protruding tongue
- Umbilical hernia
Possible causes:
- Areas w/o iodine supplementation
- Result of genetic alterations in normal thyroid metabolic pathways i.e., dyshormonogenetic goiter
Myxedema
- What is it
- Symptoms
- Possible causes
- Hypothyroidism that occurs in older child/adult
- Symptoms:
- Mental and physical slowing (sluggish)
- Weight gain
- Cold intolerance
- Decrease cardiac output and hypercholesterolemia
- Facial edema and yellow skin

Histologically, there is an accumulation of what in Myxedema; leads to what clinical findings?
- Matrix substances, such as glycosaminoglycans and hyaluronic acid in skin, subcutaneous tissue, and some visceral sites
- Leads to nonpitting edema, broad/coarse facial features, enlarged tongue, and deepening of the voice
What is the most common cause of hypothyroidism in iodine-sufficient areas of the world?
Autoimmune hypothyroidism i.e., Hashimoto thyroiditis
What will levels of TSH be like in pt with primary hypothyroidism and primary hyperthyroidism?
- Primary hypothyroidism = ↑↑↑ TSH
- Primary hyperthyroidism = ↓↓↓ TSH
Polymorphisms in which immune-regulation associated genes are implicated in Hashimoto Thyroiditis?
CTLA4 and PTPN22
What Ig4-related diseases is someone with Reidals thyroididtis more likely to get?
- AI pancreatitis
- Sclerosing mediastinitis
- Idiopathic retroperitoneal fibrosis
Goiters
- Goiters (enlargement of the thyroid gland) is caused by _________.
- Most often hypo/hyperthyroidism/euthyroid
- Degree of enlargement = __________\_
- Impaired synthesis of thyroid hormone, which is most often due to dietary iodine deficiency => rise in TSH levels => hypertrophy and hyperplasia of follicular cells.
- Euthyroid: increase in mass overcomes hormone deficiency. If enlargement is not enough => goitrous hypothyroidism.
- Level and duration of hormone deficiency
Diffuse nontoxic (simple) goiter causes enlargement of the entire gland without producing ______.
Nodularity
Causes of Diffuse Nontoxic Goiter
-
Endemic due to iodine deficiency or goitrogens
- Cassava root/thiocyanate or brassicaceae veggies (broccoli, caulifloer, cabbage and radish)
- Sporadic, with unknown etiology, but more common in females
The clinical manifestations of diffuse nontoxic (simple) goiters are most often due to what?
Mass effect bc most pt’s are clinically euthyroid (normal T3 and T4; TSH is high or upper range of NL):
- Dysphagia
- Hoarseness
- Stridor
- SVC syndrome (flushed face)
What are the 2 phases identified in the evolution of diffuse nontoxic goiter?
-
Hyperplastic phase: Thyroid is diffusely and symetrically mildly enlarged
- Follicular epithelium can crowd and form papillary projections.
- Colloid involution: occurs when dietary iodine increases or demand of thyroid hormone increases => stimulated follicular epithelium involtes to form a large colloid goiter.
Virtually all long-standing simple goiters convert into what?
Multinodular goiters via recurrent episodes of hyperplasia and involution.
Which type of goiter produces the most extreme enlargements and are more frequently mistaken for neoplasms than any other thyroid disease?
Multinodular goiters
What morphological feature is missing from multinodular goiters which is distinct from follicular neoplasms?
There is NOT a prominent capsule between hyperplastic nodule and compressed thyroid parenchyma.
Older lesions of multinodular goiter show what histological change?
Areas of hemorrhage, fibrosis, calcification, and cystic change
Morphology of Multinodular Goiters
- Multilobulated and assymetrically enlarged.
- Cut: nodules have brown, gelatinous colloid.
- Older masses: hemorrage, fibrosis, calcifcation and cystic changes.
Microscopy of Multinodular Goiters
- Colloid-rich follicles lined with flat, inactive epithelium
- Follicular hyperplasia with degenerative changes due to stress.
When an autonomous nodule develops within a long-standing multinodular goiter and produced hyperthyroidism this is known as what?
Toxic multinodular goiter (aka Plummer syndrome)
Clincal presentation of Multinodular Goiter
Indicence of malignancy
- Euthyroid or subclinical hyperthyroidism (low TSH), so present with mass effect (same sx as diffuse)
- Low, but not 0, malignant potential.
What are the levels of T3/ T4 + TSH like in older pt (>55 y/o) with multinodular goiter?
- ↑ T3 and T4
- ↓ TSH
What is the purpose of radioisotope scanning?
- Determines whether a specific nodule is hyperfunctioning. If so, excise or ablate.
-
Low serum TSH => perform a radioactive scan (determines if nodule is hot or cold)
- Hot —> I or surgery
- Cold —> US and FNA to confirm
- NL/High serum TSH => perform a US
Which type of nodule is more likely to be neoplastic (cold or hot)?
Overall, hot and cold nodules are benign.
However, cold nodules have a BETTER chance at being malignant.
____ can be used to determine cellular constituents of a nodule.
FNA
Benign neoplasms of the Thyroid
- Hyperplastic (adenomatoid) nodules
- Follicular adenomas
Solitary Thyroid Nodule
- What is it?
- MC in?
- Majority are:
- Palpable discrete swelling in a NL thyroid gland
- W; incidence increases with age.
- Localized non-neoplastic lesions (dominant nodule in a multinodular goiter, simple cyst or foci of thyroiditis) or benign neoplasm (follicular adenoma)
Nodules are more likely to be neoplastic if:
- Solitary nodules (not multiple)
- Pt is younger
- Males
Nodules are more likely to be malignant if:
- Hx of radiation to head and neck
- Functional nodule that take up radioactive iodine (hot nodules) = more likely to be benign
What is the BEST way to tell the nature of a nodule?
Look at morphology by FNA and surgical resection.
Follicular Adenomas
- What are they?
- Nonfunctional or functional?
- Clonal proliferation of follicular epithelium that forms a BENIGN discrete, encapsulated, solitary masses with “thyroid autonomy”.
- Majority are non-functional, but some can be functional and make thyroid hormone, causing thyrotoxicosis.
Follicular Adenomas
- Gross morphology
- Microscopic morphology
-
Gross
- Solitary, well-defined, encapsulated mass that ranges in color from [grey-white => red-brown].
- Hemorrage, fibrosis, calcification and cysts are common.
-
Microscopic
- Proliferation of uniformly looking follicles + colloid (easily ID’d from nearby non-neoplastic thyroid)
- Hurthle cells metaplasia/oxyphil: cytoplasm of neoplastic cells become eosinophilic

Differentiate [follicular adenomas] from [follicular carcinomas]?
Intact, well-formed capsule surrounds the tumor, so it does NOT invade.
What mutations are found in [toxic adenomas] and [toxic multinodular goiters], but RARE in follicular carcinomas?
Somatic mutations in TSH-receptor signaling pathway: GOF of TSH-R or a-subunit of Gs (GNAS)
=> hyperthyroidism and produces a functional “hot” nodule on imaging.
Evaluation of ________ is CRITICAL to distinguish follicular adenoma from follicular carcinoma?
Integrity of the capsule
Clinical presentation of follicular adenomas
- Present as a [unilateral, painless mass] discovered during PE. If large => problem swallowing.
- If non-functioning = take up less radioactive iodine than NL parenchyma and look like “cold nodules”.
How is definitive diagnosis of adenomas made?
Remove surgically => look at integrity of capsule so that follicular adenoma can be differentiated from follicular cancer.
Thyroid Cancer
- MC in:
- Most thyroid cancers are derived from ________ epithelium and of these, the majority are ____-differentiated.
- W: early –> middle adult years
- Follicular epithelium (except medullary carcinoma); well-differentiated
Types of Thyroid Cancer and which is the most common?
- 1. Papillary cancer (>85%)*
- 2. Follicular cancer
- 3. Anaplastic undifferentiated cancer
- 4. Medullary cancer
In the 3 cancers that are derived from the follicular epithelium, genetic mutations are present in what pathways?
GOF mutations in the growth-factor receptor signaling pathway.
The diffuse slcerosing variant of papillary carcinoma is often associated with a prominent lymphocytic infiltrate, simulating what other disease of the thyroid?
Hashimoto thyroiditis
What are the 2 characteristics of follicular carcinoma?
- Angioinvasion => spreads hematogenously
- Invasion of capsule => forming a mushroom.
How is the distinction between follicular adenomas and minimally invasive follicular carcinomas made?
Invasion of capsule and vascular invasion
Serum levels of what are used for monitoring follicular carcinoma recurrence?
Serum thyroglobulin; as should be barely detectable
Which cancer is recognized based on nuclear features (ground-glass nuclei and pseudoinclusions)
Papillary carcinomas of thyroid
High aggressive, uniformly lethal cancers
Anaplastic cancers
Cancers that arise from parafollicular C cells occur sporadically (70%) or famial (30%)
Medullary cancers
Features of familial medullary cancers
1. Multicentricity
2. C-cell hyperplasia
What is Reidels Thyroiditis?
Chronic inflammation (lymphocytes + IgG4 plasma cells) that causes extensive fibrosis of the thyroid gland (euthyroid), which can extend to nearby structures (parathyroid gland, recurrent laryngeal nerve and trachea)
=> produces a “rock hard” thyroid w involvement of adjacent structures in a younger patient that can be confused wiht anaplastic carcinoma.
Young W has rock hard thyroid with hoarness, hypoparathyroidism and difficulty breathing. What does she have?
Reidal thyroiditis
70-80YO W has rock hard thyroid with hoarness, hypoparathyroidism and difficulty breathing. What does she have?
Anaplastic carcinoma: can be hard and extend beyond thyroid
What HLA is assx with Hashimoto thyroiditis?
DR5
What is DeQuarvians Thyroiditis?
Painful goiter followed by a period of [transient hyperthyroidism] that lasts for 2-6 weeks; returning back to NL fx in 6- 8 weeks after a URI/virus causes granulmatous inflammation. (NO HYPO),
What is Subacute lymphocytic/painless thyroitidits?
AI-destruction by antiTPOab that causes lymphocytic infiltrate (lympho, plasma cells + germinal centers) of the thyroid gland, commnly afte rpregnany => tramsient mild hyperthyroidim => 1/3 get permant hypothyroidism => painless goiter (no hurthlr crll metaplasia or firbosis.
- thyroid is enlarged. but looks NL