Thyroid Disorders Flashcards
What is colloid composed of?
Thyroglobulin, which is made of tyrosine residues that serve as sites for TH synthesis
3 things that inhibit TRH
Glucocorticoids, DA, somatostatin
4 steps of TH synthesis
- 1) Iodide transport (trapping) through Na-iodide symporter (NIS)
- 2) Oxidation / incorporation into TG (organification). Regulated by thyroid peroxidase (TPO). TPO is upregulated by TSH.
- 3) Coupling of MIT (monoiodotyrosine) and DIT to form T3 and T4
- 4) TSH stimulates TPO and transcription of TG
What 2 things inhibit proteolysis / release of TH?
Excessive iodine and lithium
3 TH binding proteins
Thyroid binding globulin, transthyretin, and albumin
What increases thyroid binding globulin concentration?
Hyperestrogenic states: pregnancy, exogenous estrogens
What decreases thyroid binding globulin? (5)
Androgens, glucocorticoids, protein malnutrition, nephrotic syndrome, cirrhosis.
What inhibits 5’MDI? (6)
Illness, caloric deprivation, malnutrition, glucocorticoids, beta-blockers, amiodarone, and PTU
Half life for T4/3
T4 is 7 days
T3 is 1 day
Wolff-Chaikoff Effect
Protects against iodine excess. Thyroid peroxidase (TPO) is shut down so TH isn’t made in excess. Normally, a subsequent decrease in I → escape from this effect and resumption of normal TH synthesis. However, if there is no escape from this effect, I-induced hypothyroidism may occur.
Jod-Basedow Phenomenon
When pxs who have accommodated to chronic iodine deficiency are exposed to high doses of iodine → hyperthyroidism.
TH effects Neurogenesis Metabolism Weight Cholesterol Heart Bone Childhood growth GI GU Renal
- Neurogenesis: absence during early life → irreversible MR (cretinism). TH regulates transcription of myeline basic protein.
- Metabolism: increases metabolic rate, O2 consumption, heat production, glucose absorption, GNG, glycogenolysis, hepatic LDL receptors, lipolysis, and metabolism of cholesterol to bile acids.
- Hyperthyroidism doesn’t cause universal weight loss b/c it stimulates appetite. Also causes muscle wasting.
- Hypothyroidism may involve weight gain of 10-20 lbs (not obese)
- Hypercholesterolemia occurs w/ hypothyroidism
- Heart – stimulates contractility, increases O2 consumption, enhances sensitivity to catecholamines. Hyperthyroid causes tachycardia and increased contraction force.
- Bone – stimulation of bone formation and resorption (increased urine / serum Ca), but overall resorption prevails. Hyperthyroid → osteoporosis.
- Hypothyroidism may blunt growth in childhood.
- GI – stimulates gut motility. Hyperthyroid → hyperdefecation. Hypothyroid → constipation.
- GU – TH affects ovulation, so excess / deficiency → menstrual irregularities / infertility. High TRH stimulates hyperprolactinemia → anovulation
- Renal – necessary for normal renal free water excretion
T3/4 levels in primary hypothyroidism
T4 is low. T3 often remains normal.
Indications for TSH screening (10)
Women > 60 y/o (older women have highest rates of thyroid disease), family hx, sxs of hyper / hypothyroidism, goiter, hyperprolactinemia, hypercholesterolemia, infertility / menstrual irregularity, cardiomyopathy / arrhythmia, osteoporosis, before getting pregnant.
Apathetic thyrotoxicosis
Population
2 main sxs
More common in older pxs. Usually involves cardiac problems (A fib, CHF), and / or osteoprosis
Thyroid storm
3 main characteristics
Causes (5)
Treatment (5)
- Severe thyrotoxicosis + mental status changes + fever.
- Caused by underling hyperthyroidism plus acute precipitant: not taking meds, surgery, MI, CVA, infection.
- Treatment
- PTU – decreases production and blocks T4 → T3
- Propranolol – treats hyperadrenergic sxs and blocks T4 → T3
- Potassium iodide AFTER PTU – blocks TH release
- Glucocorticoids – blocks T4 → T3 conversion
- Supportive care
Does hyper stimulation of TSH receptor cause high or low iodine uptake?
High
Does leak of TH cause high or low iodine uptake?
Low
What percentage of iodine is normally taken up by the gut?
25%
Graves' Disease I uptake Population Which cells make TSI? What increases risk of orbitopathy? Signs / sxs of orbitopathy (8) Risk if untreated Treating dermopathy
- High I uptake
- More common in younger people. 9x more common in women.
- TSI is made in B lymphocytes.
- Smoking increases risk of orbitopathy.
- Sxs / signs include proptosis / exophthalmos, eye irritation / pain, dryness, photosensitivity, periorbital edema, exposure keratopathy, diplopia / gaze paralysis, loss of color vision
- If untreated, risk of A fib, bone loss, and thyroid storm.
- Treat dermopathy w/ corticosteroids
Toxic multinodular goiter (TMNG) / Solitary hyperfuctioning nodules I uptake level Population Presentation Cause
- High I uptake
- More often seen in older pxs.
- May present as “apathetic hyperthyroid”. Hot and cold areas seen on nuclear imaging.
- May be due to activating mutations of TSH receptor.
TSH secreting tumors I uptake level Elevated levels of what? Sx Treatment (2)
- High iodine uptake.
- Normal / high TSH, high T4, high alpha subunit.
- May have visual field defects.
- Tx w/ tumor resection and somatostatin analogs.
Thyroid hormone resistance
I uptake level
Inheritance
Treatment
High I uptake
Autosomal dominant.
Tx usually not necessary. May use BB’s to control HTN.
Excess hCG
I uptake level
Effect on thyroid function
High I uptake if from tumor.
Stimulates TSH receptor.
3 main strategies for treating high I uptake hyperthyroidism
Anti-thyroid drugs (PTU, MMI), radioactive I, and total thyroidectomy
2 anti-thyroid drugs Mechanism / Use Timing of onset, and why Which acts faster? Which is used for thyroid storm? Which is used during pregnancy?
- Propylthiouracil, methimazole
- Mechanism / Use
- PTU and MMI interfere w/ hormone synthesis (inhibit iodination of tyrosyl groups in thyroglobulin and coupling to form T4/3).
- Does not impact release, explaining delayed onset of action, b/c stores have to be depleted first.
- PTU also blocks peripheral conversion of T4 → T3. Acts faster than methimazole and is preferred tx for thyroid storm. Also tx of choice during 1st trimester of pregnancy b/c MMI may result in aplasia cutis (lack of scalp). After 1st trimester, MMI is used due to lower risk of hepatotoxicity.
Side effects of PTU and MMI (4)
- Agranulocytosis – most severe side effect. Check CBC routinely if px has fever or sore throat.
- PTU has risk of liver failure. Check LFTs routinely
- Urticaria / rash – most common side effect
- Arthralgias
Radioactive Iondine Uses (5) Mechanism Timing of onset Requirements (2) Side effects (3)
- Uses – Graves’, toxic multinodular goiter, toxic adenoma, thyroid cancer, and diagnosis
- Mechanism – emits beta (short range / destructive) and gamma rays (longer range, detected by nuclear camera).
- Cytotoxic effect is delayed for 1-2 months. Peaks at 2 months.
- Anti-thyroid drugs must be stopped for 3 weeks prior to administration. Low I diet for 1-2 weeks prior to tx.
- Side effects – dry mouth (acts on salivary gland), altered taste, dry eyes (lacrimal glands)
What should be done before a total thyroidectomy?
Pre-treatment w/ anti-thyroid drugs may reduce surgical risk
3 things that cause low I uptake hyperthyroidism
Thyroiditis, struma ovarii, meds
Thyroiditis I uptake level Pathogenesis Presentation Treatment (4)
- Low I uptake.
- Involves increased TH release, not increased production.
- Presents w/ neck pain after URI.
- SELF-LIMITED. May have transient phase of hypothyroidism. Supportive tx w/ NSAIDs / prednisone for pain control and BB’s to control HR.
Silent thyroiditis
No neck pain, but still inflammation of thyroid
Treatment of post-partum thyroiditis
Self-limited
Struma ovarii
Description
I uptake level
Rare ovarian tumor that produces TH. I uptake is low in neck but high in ovaries.
3 meds that induce hyperthyroidism
I uptake level
Low I uptake
•High I levels –> Jod-Basedow phenomenon
•Amiodarone – rich in iodine
•Thyroid hormone (levothyroxine)
Myxedema coma Population Features (6) Cause (4) Treatment (4)
- Life-threatening hypothyroidism. Most common in older women.
- Main features: mental status changes, hypothermia, respiratory failure. May have associated hypotension, bradycardia, and hyponatremia
- Precipitated by omission of T4 replacement therapy, MI, CVA, or sepsis
- Treatment – glucocorticoids (prophylaxis in case of adrenal insufficiency, must be given prior to thyroid hormone), levothyroxine, liothyronine (beware in cardiac pxs), supportive care
5 drugs that cause hypothyroidism
- Lithium – impairs release of T4/3
- Amiodarone – Wolff-Chaikoff effect
- PTU, methimazole
- Interferon – causes presentation similar to Hashimoto’s
Liothyronine
What is it?
When is it used?
Liothyronine = T3 – rarely used. Used when a faster onset of action is required and in rare cases of impaired T4 → T3 conversion (defect in 5’ deiodinase)
Side effects of Levothyroxine / Liothyronine (3)
Changes in estrogen status or weight. Hyperthyroidism sxs (arrhythmia, bone loss)
6 things that decrease absorption of exogenous TH
Iron, Ca, soy, sucralfate (antacid), chromium, coffee
4 things not related to the thyroid that cause low TSH
Acute illness, exogenous / endogenous glucocorticoids, exogenous DA, or catecholamines.
What has a poor prognosis during acute illness?
Low T4
What is common during non-thyroidal illness?
Low T3
Why is rT3 high during illness?
Mainly due to decreased clearance.
Partly due to increased production
Evaluation of thyroid nodules (5)
- First check TSH level. If TSH is normal or high (indicates a cold nodule), then do FNA.
- FNA – Initial diagnostic study for euthyroid pxs w/ thyroid nodules. Can diagnose papillary, medullary, and anaplastic cancer, but cannot differentiate follicular adenoma from follicular carcinoma.
- Thyroid scan w/ Tc99 obtained if TSH is low or if FNA shows evidence of follicular neoplasia.
- US – determines size of nodules and helps guide FNA. Differentiate b/w solid and cystic nodules.
- I-131 uptake (only used in presence of low TSH and hyperthyroidism)
What percentage of thyroid nodules are malignant?
10%
Warning signs for thyroid cancer (8)
Under age 20 or >60, rapid growth, hard / fixed mass, cold nodule in setting of Graves’, hoarseness (laryngeal nerve invasion), hx of childhood head / neck radiation, family hx of thyroid cancer, cervical LAD.
Indications for biopsy
> 1cm, solid / hypoechoic on US, microcalcifications, irregular borders, central blood flow, hx of radiation
Papillary thyroid carcinoma How common? Poor prognostic factors Mutations Where is it found? Histology Metastases Treatment (3) Tumor marker
- Accounts for 75%
- Poor prognosis: >4 foci, age >45, tall cell variant, BRAF mutation
- Caused by mutations in NTRK, RET, and BRAF
- BRAF mutation → decreased expression of NIS and TPO → decreased I trapping and organification → less responsive to radioactive iodine. Bad prognosis.
- RET rearrangements are associated w/ younger age and radiation-induced tumors. May cause constitutive activity of a tyrosine kinase.
- Multifocal: often found in both lobes.
- Histology: Papillary architecture, hypercellular, overlapping nuclei, cleaved / grooved nuclei, NUCLEAR CLEARING (GROUND GLASS, ORPHAN ANNIE EYES [WHITE IN MIDDLE]), intranuclear cytoplasmic inclusions (represent cytoplasmic invagination), prominent nucleoli, fibrovascular floors, PSAMMOMA BODIES (laminated calcifications; large purple things).
- Metastasizes via lymphatics, but this does not increase mortality rate.
- Treat w/ thyroidectomy, I-131, and T4 suppression. I-131 and T4 suppression (levothyroxine) not required for low grade cancers.
- Use thyroglobulin as tumor marker.
Follicular carcinoma Histology requirements Other histo findings Diagnosis Which variant is more aggressive? Metastases Treatment (3) Tumor marker
- MUST have capsular invasion and / or vascular invasion.
- Small follicles w/ a thick fibrous capsule.
- May have cytologic atypia: enlarged nuclei, prominent nucleoli.
- FNA is not capable of differentiating follicular adenoma from carcinoma
- Hurthle cell variant is more aggressive.
- Metastasizes hematogenously → more likely to spread to lungs / liver / bone / brain.
- Treatment is similar to papillary: thyroidectomy, I-131, T4 suppression
- Follow thyroglobulin.
Anaplastic carcinoma Population Presentation Histology Mutation Treatment
- More common in elderly
- Presents as rapidly expanding, fixed, and hard thyroid mass. Often doubles in size in 1 week.
- Sheets of pleomorphic giant cells, look similar to osteoclasts. Many mitoses. Necrosis. Very dedifferentiated
- BRAF mutations are found in 50%
- Treatment is palliative
Medullary carcinoma Always preceded by what? Tumor markers Doubling rate Mutation Prophylaxis Diagnosis Histology Treatment
- Always preceded by C-cell hyperplasia.
- Tumor markers: calcitonin or CEA
- Doubling rate: Calcitonin doubling w/in 6 months is a bad sign. If it does not double w/in 2 years, pxs often live at least 10 years (good prognosis).
- Mutation in RET oncogene. Genetic screening for germline mutation recommended for ALL pxs diagnosed w/ medullary cancer. If positive, screen 1st deg relatives. If catch early (familial screening), then prophylactic thyroidectomy may be done.
- Diagnosed w/ FNA
- Histology - Monotonous cells: polygonal, PLASMACYTOID (eccentric nucleus; look similar to plasma cells) or spindle-shaped cells in nests, cords, or follicles. Round / oval nuclei w/ “salt and pepper chromatin”. Granular cytoplasm. AMYLOID DEPOSITION – seen w/ congo red stain.
- Treat w/ thyroidectomy. No I-131 tx b/c C cells do not produce TH.
What does MEN stand for?
Multiple endocrine neoplasia
MEN 1
Gene
Inheritance
Mnemonic
- Loss of function mutation in MENIN gene (tumor suppressor).
- Autosomal dominant.
- Mnemonic PPP: Parathyroid hyperplasia (most common feature), pancreatic islet cell tumors / neuroendocrine tumors, pituitary tumors.
- If you see parathyroid disease in a young patient, think of MEN1
MEN 2a
Mutation
Inheritance
3 characteristics
- Gain of function mutation in RET oncogene. Autosomal dominant.
- Medullary thyroid cancer (100%), bilateral pheochromocytoma (50%), parathyroid hyperplasia (40%)
MEN 2b Mutation Inheritance 4 characteristics Prognosis
- Also a gain of function mutation in RET oncogene. Autosomal dominant.
- Medullary thyroid cancer (100%), pheochromocytoma (50%), NOT parathyroid hyperplasia, Marfanoid habitus (tall / lanky), mucosal neuromas (often 1st sign)
- Poor prognosis. 50% are de novo mutations so hard to identify.
