lab dx II: thyroid function tests

a review of the thyroid in the context of lab diagnosis in the context of cramming for finals.

the synthesis of thyroid hormones begins in the follicles of the thyroid, filled with a protein rich colloid where iodine is incorporated into thyroglobulin molecules to form mostly T4 (90%) and T3 (10%, the biologically active form). the thyroid is stimulated to release T4/T3 by TSH, which is released by the pituitary via stimulation by TRH, which is released by the hypothalamus. once released, T4 is converted to T3 in the periphery and mediate cellular growth, differentiation and metabolism.

in the periphery T4 and T3 are either free or bound; if bound they are most likely bound to TBG, or TBPA (20% of T4), or albumin (10% T4, 30% T3). T4 is converted to T3 mainly in the liver and skeletal muscle, which then has a ten times greater affinity for nuclear receptors within cells which mediate metabolic activity. only about 40% of T4 is converted directly to T3; the remaining T4 can be converted either to reverse T3 or T3AC, both of which are inactive isomers of T3 that can be activated by intestinal sulfatases.

more detail on T4: when in the blood, T4 is mostly bound (99.98%) rather than free. thus when levels of the main carrier for T4 goes up, TBG (as can happen in pregnancy), T4 levels may appear to be falsely elevated- however free, unbound T4 levels will remain normal. T4 levels less than 2.0 ug/mL are equivalent to "myxedema hypothyroidism" and can be caused by primary, secondary, or tertiary hypothryoidism-- lack of production at the level of the thyroid, pituitary, or hypothalamus, respectively. T4 greater than 20 ug/ml is considered a "thyroid storm" and can be from primary hyperthyroid (most commonly grave's disease), acute thyroiditis, struma ovarii, or a TBG increase.

a test that can provide an indirect measurement of T4 is the T3 resin uptake test, which measures relative saturation of TBG- because the T4 in the blood is nearly all bound to TBG. if T4 levels are elevated in hyperthyroidism or struma ovarii, TBG will be more saturated and not able to accommodate much T3, which will result in higher levels of T3 bound to resin rather than TBG-- leading to a high T3RU. conversely, hypothyroid states will leave TBG less saturated, allowing T3 to bind to it rather than to the resin-- leading to a low T3RU.

testing TSH levels is useful for differentiating between different types of hypothyroidism-- primary hypothyroid would present with high TSH levels and would not be responsive to exogenous TSH, whereas secondary or tertiary hypothyroid would have near zero TSH levels and would be responsive to exogenous TSH.

some more lab markers and what they indicate: total T3 levels (bound plus free) are useful for measuring hyperthyroidism. free T4 or T3 useful for patients with protein abnormalities. reverse T3 levels high in hyperthyroidism and with stressed physiology. autoantibodies can also be measured, to the thyroid gland (results in hyperthyroid), or TPO and thyroglobulin (hypothyroid).

primary hypo and hyperthyroid and most commonly caused by antibodies to the thyroid; in primary hyperthyroid, this results from defective suppressor genes which ultimately allow b cells to create anti TPO and TGLB antibodies. grave's can manifest with marked exophthalmos due to the targeting of TSH receptors in the retro orbital area by the anti thyroid antibodies. on the other end of the spectrum, hashimoto's is the result of an anti TPO antibody, and might initially present as hyperthyroidism, then progress to hypothyroidism with low T4, T3RU, and high TSH. compared to grave's, hashimoto's has a higher level of anti TPO antibodies.


questions
thyroid hormone synthesis...
1. what type of cell in the thyroid produces thyroid hormone?
2. what is contained inside the follicles?
3. what do the parafollicular cells produce?
4. what is the role of the hypothalamus and pituitary in thyroid function?
5. what form is thyroid hormone secreted in and which form is biologically active?
6. what is the role of TPO in the colloid of the follicles?
7. what is the T4:T3 ratio in the colloid?
8. what are the three fundamental physiological processes that thyroid hormones affect?

thyroid hormones in the wilderness...
9. which protein binds most T3 and T4 in the blood?
10. what does TBPA carry?
11. what does albumin carry?
12. which tissues does T4 conversion generally take place in?
13. compare the biological potency of T4 vs. T3.
14. under normal circumstances, what is T4 converted into besides T3?
15. are T3s and T3AC biologically active?

T4...
16. what percentage of T4 is protein bound?
17. what conditions might show falsely elevated T4 levels? how does this appear as a lab result?
18. what are congenital defects that can result from low T4 levels?
19. what are the critical high and low values for T4?
20. what are the most common factors for increased T4 levels?
21. what are the most common causes for decreased T4 levels?

T3RU...
22. what is T3RU a measure of?
23. what would be the T3RU for hyperthyroidism and why?
24. what would be the T3RU for hypothyroidism and why?
25. is T3RU better for assessing hyper or hypothyroidism?
26. what else can cause increased T3RU besides hyperthyroidism?
27. what else can cause decreased T3RU besides hypothyroidism?
28. what is the formula for FTI and what does it represent?

TSH...
29. TSH aids in the diagnosis of...
30. what are TSH levels in primary, secondary, tertiary hypothyroidism?
31. describe the diurnal variation seen in TSH levels.
32. what causes increased TSH levels?
33. what causes decreased TSH levels?
34. what does TRH assess?

total T3, free T4/T3, reverse T3, thyroid antibodies...
35. are total T3 levels better for diagnosing hyper or hypothyroidism?
36. what is T3 toxicosis and how does it present?
37. when are free T4 or T3 levels useful to measure?
38. when are reverse T3 levels high?
39. what did Dr. Dennis Wilson, MD propose in relation to reverse T3?
40. what are some examples of autoantibodies to the thyroid gland?

grave's and hashimoto's...
41. what is grave's disease?
42. what is the "suppressor defect" in the context of grave's disease?
43. what are the autoantibodies that are commonly seen in grave's?
44. why does grave's disease manifest with exophthalmos?
45. what is hashimoto's?
46. which gender is more likely to get hashimoto's?
47. early stages of hashimotos might present as...
48. early labs of hashimotos might show...
49. compare the antibody titer levels in grave's vs. hashimotos.

euthyroid sick syndrome...
50. what is ESS?
51. what are three specific physiogical processes that can cause ESS?

answers
1. follicular epithelium.
2. protein rich colloid, high in thyroglobulin.
3. calcitonin.
4. hypothalamus releases TRH, which stimulates release of TSH from pituitary, which is the main mediator of thyroid gland function.
5. 90% secreted as T4, then converted to biologically active T3 in cells.
6. thyroid peroxidases oxidize iodide to iodine for use in T3/T4.
7. 5:1.
8. cellular growth, differentiation, metabolism.

9. TBG, 70%.
10. 20% of T4 and no T3.
11. 10% of T4, 30% T3.
12. liver and skeletal muscle.
13. T3 has a 10 times greater affinity for DNA transcription factor receptors than T4.
14. 40% T3, 20% reverse T3, 20%T3S.
15. not unless they encounter sulfatases in the GI tract.

16. 99.98%.
17. pregnancy and oral contraceptives. high TBG but normal free T4.
18. cretinism, mental retardation.
19. less than 2.0 ug/ml- myxedema coma
more than 20 ug/ml- thyroid storm
20. primary hyperthyroid (grave's disease)
acute thyroiditis
struma ovarii
TBG increase
21. primary hypothyroid (hashimoto's)
secondary hypothyroid (pituitary dysfx)
tertiary hypothyroid (hypothalamus dysfx)
protein malnutrition

22. an indirect measurement of the amount of free binding sites on TBG and TBPA.
23. hyperthyroidism -> high T4 levels -> more saturated TBG -> more T3 bound to resin instead of TBG -> higher T3RU.
24. hypothyroidism -> low T4 -> more unsaturated TBG -> more T3 bound to TBG -> lower T3RU.
25. better for hyperthyroidism-- only 60% accurate for hypo.
26. hypoproteinemia, struma ovarii.
27. any factor that increases TBG like pregnancy, hepatitis / cirrhosis.
28. FTI=(T4*T3RU)/100, is an estimate for total T4 levels.

29. hypothyroidism.
30. primary- high TSH. secondary + tertiary: TSH almost 0.
31. lowest at 10AM, highest at 10PM.
32. primary hypothyroid
thyroiditis
thyroid agenesis
congenital cretinism
excess iodine intake
33. secondary, tertiary hypothyroid
hyperthyroid
self medication with T4
34. responsiveness of anterior pituitary to secrete TSH upon injection of TRH.

35. hyperthyroid.
36. normal T4 and high T3.
37. useful to measure thyroid functioning in patients who have protein abnormalities.
38. hyperthyroidism.
39. a stressed body might have a predisposition to converting T4 to rT3 instead of T3.
40. thyroid stimulating antibodies, resulting in hyperthyroidism. anti TPO antibody, inhibits thyroid peroxidase. anti TGLB, inhibits thyroglobulin.

41. most common form of hyperthyroid that results from TSI's stimulating TSHR's.
42. a defect in a suppressor gene allows t helper cells to interact with thyroid antigens, which then stimulate b cells to create thyroid stimulating immunoglobulin.
43. anti TPO, anti TGLB.
44. the TSH antibodies produced in grave's bind to TSH receptors in the retroorbital tissues which produces inflammation and swelling.
45. the most common cause of acquired hypothyroid.
46. females 8:1.
47. hyperthyroid.
48. normal T4 and TSH + anti TPO ab.
49. much higher in hashimotos.

50. thyroid dysfunction secondary to nonthyroidal systemic illness.
51. decreased peripheral conversion of T4 to T3,
decreased clearance of reverse T3
decreased binding of thyroid hormones to TBG
[conversion, clearance, binding]