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Flashcards in Thyroid Dysfunction Deck (36):
1

Thyroid

a. The thyroid lies caudal to the cricoid cartilage (which is the prominent tracheal ring just caudal to the thyroid cartilage - your adams apple) and superior to the suprasternal notch

b. The isthmus (horizontal connection of the two thyroid lobes) is just below the cricoid cartilage

2

T4 and T3 Hormone

a. T4
3,5,3’,5’ - Tetraiodothyronine
(thyroxine)
i. has 4 Iodine attached

b. T3 --> the active form
3,5,3’ - Triiodothyronine
i. has 3 iodine form

c. T4 is turned into T3 via Type 1 or 2 Deiodinase
i. this happens at every cell that has receptors for thyroid hormone

d. rT3---> Inactive T3 hormone
i. Type 3 Deiodinase
ii. Conditions of starvation, stress, severe illness, turn down activity of T3 (want less catabolism)

3

Loss of T3 conversion

rT3---> Inactive T3 hormone
i. Type 3 Deiodinase

Conditions of starvation, stress, severe illness, turn down activity of T3 (want less catabolism)
i. want to lower basal metabolic rate as body may need energy

Starvation
Severe illness
Severe stress
Neonatal period
Glucocorticoids
Propranolol
Amiodarone
Radiocontrast dyes

4

Serum Total T4
Bound plus Free

a. 99.98% of T4 is bound
i. TBG (thyroxine-binding globulin)
ii. TBPA (thyroxine-binding prealbumin)
iii. Albumin

Half life = 7 days
Total T4 = 4-12 μg/dL

Free T4 = 0.02%
= 0.8-1.8 ng/dL

5

Serum Total T3
Bound plus Free

99.8% of T3 is bound
TBG (thyroxine-binding globulin)
Albumin

Half life = 1 day
Total T3 = 80-180 ng/dL

6

Causes of Increased Total T4 and Total T3

*notice that total means bound and unbound thyroid hormone

a. Hyperthyroidism/Thyrotoxicosis

b. Increased binding proteins
i. Estrogen--> will lead to greater amounts of binding proteins

c. Thyroid hormone resistance
i. body will try to create more T3 and T4 to overcome resistance

7

Causes of Increased Free T4 and Free T3

a. Hyperthyroidism/Thyrotoxicosis

b. Thyroid hormone resistance

*binding proteins not important here

8

Causes of Decreased Total or Free T4 and T3

a. Hypothyroidism

b. Decreased serum protein binding

c. Euthyroid sick syndrome (nonthyroidal illness)

d. Drugs

e. Liver or kidney disease (total T4, total T3)

9

Thyroid Stimulating Hormone (TSH)

a. The single best test to screen for thyroid dysfunction

b. Indicates an individual’s thyroid hormone “set point”

c. TSH Elevated in primary hypothyroidism
i. Lack of negative feedback by thyroid hormone

d. TSH Suppressed in primary hyperthyroidism
i. Excess negative feedback by thyroid hormone

e. When can one not rely on a TSH?
i. Abnormal pituitary gland
ii. Ex. panhypopituitarism, TSHoma, idiopathic central hypothyroidism

10

TSH stimulates iodine uptake into thyroid follicular cells and thyroid hormone production

1. The Na+/I− symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion.
i. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I− against its concentration gradient.

2. I− is moved across the apical membrane into the colloid of the follicle.

3. Thyroperoxidase oxidises two I− to form I2. Iodide is non-reactive, and only the more reactive iodine is required for the next step.

4. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid.
i. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.

5. Iodinated Thyroglobulin binds megalin for endocytosis back into cell.

6. Thyroid-stimulating hormone (TSH) released from the adenohypophysis binds the TSH receptor (a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.

7. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin.
i. The thyroid hormones cross the follicular cell membrane towards the blood vessels by an unknown mechanism

11

Symptoms of Thyroid Disease

Hyperthyroidism

Nervousness 84%
Weight Loss 51%
Increased Appetite 57%
Decreased Appetite 4%
Fatigue 84%
Tremor 84%
Heat Intolerance 92%

Other signs/symptoms:
Palpitations
Hyperdefecation
Trouble sleeping
Diaphoresis

12

Biochemical Diagnosis- Hyperthyroidism or Thyrotoxicosis

1. Overt:
i. decreased TSH (primary hyper-thyroid)
ii. Increased Free T4
iii. Increased Free T3

2. Subclinical: not as severe as overt hyperthyroidism
i. decreased TSH
ii. nl Free T4
iii. nl Free T3


*T3 not a reliable assay

13

What would you do next?


TSH

Serum is low
She is “euthyroid.”

Exceptions (RARE):
TSH-producing tumor
Thyroid hormone resistance

14

What would you do next?

She has Goiter--->enlarged throat

TSH

a. Serum TSH is low.
i. Free T4 and total T3 are elevated.

b. She has thyrotoxicosis.
i. This is suggestive of “hyperthyroidism.”
ii. this means there are high levels of Thyroid going through body



15

Thyrotoxicosis
(high levels of circulating thyroid hormone)

Thyrotoxicosis
(high levels of circulating thyroid hormone)

High thyroid hormone can be:

1. Overproduction of T4 and T3
i. HYPERTHYROIDISM

2. No Overproduction
i. High Release of preformed/stored T4 and T3

16

Radioactive iodine uptake and scan

*important slide

a. TSH stimulates the thyroid to take up iodine and synthesize T4 and T3.

b. In thyrotoxicosis, TSH should be low .
i. The hypothalamus and pituitary “sense” elevated T4 and T3 levels, and secretion of TRH and TSH is suppressed.

c. If TSH is suppressed, there should be no uptake of iodine.

d. A “normal” or elevated iodine uptake in the setting of a low TSH is abnormal and indicates autonomous production of thyroid hormone.
i. This is a true hyperthyroid state.

e. If uptake is low (appropriately so, in the setting of a low TSH), then thyroid hormone excess is due to high release of preformed thyroid hormone

17

Diagnostic evaluation

1. TSH measure
i. Normal/high – not hyperthyroid
(with rare exceptions)
ii. Low – check FT4
(for baseline values)

2. If low TSH--> Thyroid uptake – gives info on category of hyperthyroidism/ thyrotoxicosis (radiolabeled iodine – I radiolabeled
i. High Thyroid uptake--> Thyroid scan – pattern gives info on etiology of high uptake
(Graves’ vs. hot nodule vs. multinodular goiter)
ii. Low thyroid uptake

18

Etiology of Hyperthyroidism

High Uptake Hyperthyroidism
1) Thyrotropin receptor antibody
i. Graves’ disease
ii. Hashitoxicosis
2)Thyroid autonomy
i. Toxic adenoma
ii. Toxic multinodular goiter (MNG)
3) HCG
i. Hydatidiform mole
ii. Choriocarcinoma
4) TSH
i. TSH-oma (pituitary tumor)
ii. Thyroid hormone resistance

Low Uptake “Hyperthyroidism”
1) Subacute thyroiditis
i. Granulomatous thyroiditis (viral); de Quervain’s
2) Chronic lymphocytic thyroiditis (Hashimoto’s)
i. Postpartum thyroiditis
3) Radiation-induced thyroiditis
4) Infectious thyroiditis
5) Drug-induced thyroiditis
6) Ectopic thyrotoxicosis
i. Factitious
ii. Struma ovarii


19

Does this Woman Have A Functional Thyroid Problem?

-Goiter (enlarged throat/thyroid)

*Great slide

1. Check her TSH--> it is low

2. Her T4 and T3 are high

3. Iodine scan---> See high amount of Iodine uptake

Diagnosis: Grave's disease
i. antibodies are causing high uptake of iodide across the entire thyroid
-if it was a nodule or tumor, it would be taking ioddie at one spot
ii. will see low TSH

20

TSH Receptor

*Grave disease will bind to these

GPCR

a. The thyroid-stimulating hormone (TSH), autoantibodies (TSAbs), and small molecule drug-like ligands (SMLs) bind to the TSH receptor at different sites.

b. TSH and TSAbs bind primarily to the large ectodomain, whereas SMLs bind to a pocket within the transmembrane domain.

c. Ectodomain is in red while the Transmembrane domain’s individual helices are ribbons in different colors

21

Grave's Disease

a. Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (TSH receptor) which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3).

b. Thyroxine receptors in the pituitary gland are activated by the surplus hormone suppressing additional release of TSH in a negative feedback loop.

c. The result is very high levels of circulating thyroid hormones and a low TSH level.

Clinical:

Grave's disease
i. antibodies are causing high uptake of iodide across the entire thyroid
-if it was a nodule or tumor, it would be taking ioddie at one spot
ii. will see low TSH

22

Graves’ Ophthalmopathy (Thyroid Eye Disease)

a. Thyroid-associated ophthalmopathy is one of the most typical symptoms of Graves' disease.
i. Thyroid eye disease is an inflammatory condition, which affects the orbital contents including the extraocular muscles and orbital fat.

b. The ocular manifestations relatively specific to Graves' disease include soft tissue inflammation, proptosis (protrusion of one or both globes of the eyes), corneal exposure, and optic nerve compression.

c. Also seen, if the patient is hyperthyroid, are more general manifestations, which are due to hyperthyroidism itself and which may be seen in any conditions that cause hyperthyroidism (such as toxic multinodular goitre or even thyroid poisoning).
i. These more general symptoms include lid retraction, lid lag, and a delay in the downward excursion of the upper eyelid, during downward gaze.

d. Fibroblasts in the orbital tissues may express the thyroid stimulating hormone receptor (TSHr).
i. This may explain why one autoantibody to the TSHr can cause disease in both the thyroid and the eyes

23

Pretibial Myxedema
(Graves’ disease)

a. Pretibial Myxedema is an infiltrative dermopathy, resulting as a rare complication of Graves' disease, with an incidence rate of about 1-5% in patients.

b/ It usually presents itself as a waxy, discolored induration of the skin—classically described as having a so-called peau d'orange (orange peel) appearance—on the anterior aspect of the lower legs, spreading to the dorsum of the feet, or as a non-localised, non-pitting edema of the skin in the same areas

24

Treatment- Graves’ Disease

a. Medications
1) Antithyroid drugs (methimazole, propylthiouracil)- Inhibit synthesis of thyroid hormone

2). Beta blockers- Reduce systemic hyperadrenergic symptoms and effects (primarily tremor, palpitations, etc.)

b. Radioactive Iodine (131-I)
i. this I-131 is damaging to the overproducing thyroid cells and recpetors

c. Surgery

25

Destructive Thyroiditis
Clinical Course

a. Over months, has a varying course:
1. Will see drastic rise T4 of the first few months, and lowered TSH by negative feedback
2. After a few months, will normal out briefly
3. Now the Thyroid gland is damaged/sick, cannot produce enough T4
i. needs time to heal itself

b. Can develop permanent damage from the high T4 production in the first few months

26

Biochemical Diagnosis- Hypothyroidism

a. Overt:
i. Increased TSH
ii. Decreased Free T4

Subclinical:
i. Increased TSH
ii. nl Free T4

27

Subclinical Hypothyroidism
Small Decrease in Free T4 = Large Increase in TSH

1. Free T4
i. is typically kept within a very maintained rangle
ii. lowered amounts below range can lead to STRONG affect on TSH amont

2. TSH
i. with lowered T4 = NO negative feedback
ii. will see very high TSH

28

Symptoms of Thyroid Disease

Hypothyroidism

Mental Slowness 68%
Weight Gain 58%
Increased Appetite 2%
Decreased Appetite 50%
Fatigue 83%
Muscle Cramps 55%
Cold Intolerance 65%

Other signs/symptoms:
Bradycardia
Constipation
Hypersomnia
Dry skin

29

Etiology of Hypothyroidism

a. Primary Hypothyroidism
i.* Chronic autoimmune (Hashimoto’s) thyroiditis
ii. *Transient hypothyroidism
-Silent or postpartum thyroiditis
-Subacute or granulomatous thyroiditis
iii. *Iatrogenic
-Thyroid surgery/thyroidectomy
-Radioactive iodine
-External neck irradiation
iv. Iodine deficiency or excess
v. Drugs
-Antithyroid drugs, lithium, amiodarone, tyrosine kinase inhibitors, iron, cholestyramine, phenytoin, carbamazepine

vi. Infiltrative diseases
-Hemochromatosis, sarcoidosis, amyloidosis, fibrous (Reidel’s) thyroiditis, scleroderma
vii. Infections
-M. tuberculosis, P. carinii
Congenital


b. Central Hypothyroidism (2˚/3˚)
i. *Pituitary tumor
ii. Trauma
iii. Postpartum pituitary necrosis (Sheehan’s syndrome)
iv. Hypophysitis
v. Craniopharyngiomas
vi. Radiation therapy
vii. Infiltrative disease
viii. TSH or TRH resistance

30

Hashimoto’s Thyroiditis

a. Thyroid Autoantibodies:
i. TPO (thyroid peroxidase)
ii. Tg (thyroglobulin)

b. These are targeting the gland for destruction (Unlike grave for activating receptors)

c. Destruction leads to low T4 and high TSH

31

Risk of developing hypothyroidism

a. In general – patients with elevated TSH and positive thyroid antibodies develop hypothyroidism at a rate of ~ 5%/year
TPO Abs alone ~ 2%/year

b. Very likely to develop Hashimoto’s Thyroiditis

32

When to treat Hypothyroidism

a. Almost all thyroidologists would treat with a TSH > 10 mIU/L
i. Normal TSH range 0.4-4.0

b. Whether to treat with a TSH between 5-10 mIU/L is very controversial

c. Much of the objective data to suggest therapeutic benefit is based on cardiovascular risk

d. Treat with Levothyroxine---> synthetic T4

33

Treatment Goal

a. Normal TSH range 0.4-4.0
i. Almost all thyroidologists would treat with a TSH > 10 mIU/L

b. Treat with Levothyroxine---> synthetic T4

34

Myxedema Coma

a. “An extreme form of hypothyroidism, so severe as to readily progress to death unless diagnosed promptly and treated vigorously.”

b. True Endocrine Emergency
i. Decreased cardiac output, bradycardia, respiratory depression, edema, altered mental status, hypothermia, metabolic derangements

c. High mortality rate

35

TSH in primary hyperthyroidism and hypothyroidism

1. TSH Elevated in primary hypothyroidism
i. Lack of negative feedback by thyroid hormone

2. TSH Suppressed in primary hyperthyroidism
i. Excess negative feedback by thyroid hormone

36

Radioactive iodine uptake and scan test

a. Will see the activity of TSH on the thyroid gland

b. High TSH activity will see high Iodide uptake---> can see radiolabeled 123-I get taken up
i. means there is a true hyperthyroid state, something is causing high TSH or other high activity

c. Low TSH, but high T3 or T4---> means there is thyroid hormone excess due to high release of Stored thyroid hormone (already made T3 or T4)