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1. Be familiar with specific thyroid hormone synthesis: feedback/role of TRH, TSH, tyrosine, iodine, percentage of T4 & T3 released by the gland.

--T3 and T4 negative feedback to hypothalamus to stop TRH-->less TSH-->less T3 & T4
--thyroid releases T3 (7%) and T4 (93%), both can enter tissues
--tyrosine incorporates iodine into moniiodotyrosine (MIT) then adds another iodine to form diiodotyrosine (DIT). Two DIT makes L-thyroxine (T4) and a DIT & MIT makes T3

MORE
--TRH = thyrotropin releasing hormone from the hypothalamus
--TRH travels to anterior pituitary (via hypophyseal portal) --> stimulates release of TSH
--TSH = thyrotropin stimulating hormone, major modulator of thyroid activity
--somatostatin acts opposite of TRH, inhibiting production of TSH
--TSH stimulates production of T3 and T4 by the thyroid, using iodine and tyrosine raw material
--TSH screening 85% or more sensitive and specific for thyroid dz
--iodide is absorbed by GI, thyroid removes from circ and stores
--iodide converted to iodine via thyroid peroxidase = TPO, in colloid
--iodide concentration ratios of thyroid:plasma ranges 25:1 to 500:1
--tyrosine incorporates iodine into moniiodotyrosine (MIT) then adds another iodine to form diiodotyrosine (DIT). Two DIT makes L-thyroxine (T4) and a DIT & MIT makes T3
--large portion of T3 formed in liver by conversion of T4
--if secondary hypothyroidism is suspected --> test TRH
--thyroid releases T3 (7%) and T4 (93%), both can enter tissues
--T3 and T4 bound to proteins in blood
--T3 and T4 negative feedback to hypothalamus to stop TRH-->less TSH-->less T3 & T4
--T4 converted to T3 in peripheral tissues, esp liver and also skeletal muscle
--T3 and T4 target receptors in nucleus and stimulate RNA synthesis
--nuclear receptor 10X more affinity for T3 than T4
--T4 can be converted to reverse T3, rT3, which is hormonally inactive
--normally 40% of T4 converted --> T3, 20% --> 4T3,
--normally 20% of T4 --> T3S (sulfate) and 20% --> T3AC iodothyroacetic acid
--T4 usu increased in hyperthyroidism, and TBG increased too
--T3 mb decreased or normal in hypothyroidism
--T3 may help distinguish euthyroid from hypothyroid cases
--sx of Wilson's syndrome = hypothyroid secondary to low T3
--free T4 94% specific for thyroid dz, not quite so sensitive
--T4 levels affected by estrogen

REVERSE T3
--rT3 usu increased in hypERthyroid cases
--may help dx "sick thyroid" pts (euthyroid) from hypOthryoid cases
--Dennis Wilson, MD, proposed that in a body under stress more T4 is diodinized to rT3 instead of T3
--enzyme responsible for conversion: 5'-deiodinase
--normally 40% of T4-->T3
--decreased T3 results in lover basal body temp (BBT)
--treat with ramped dosing of T3

TSH
--TSH aids in dx of primary hypothyroidism
--TSH best screening test for abn fx of thyroid gland
--TSH helps differentiate primary hypo from secondary and tertiary
--low T3 and T4 (mainly) stimulate TRH from hypothalamus --> increased TSH from ant pit
--routine screening is usu TSH and free T4
--TSH shows diurnal variation, basal at 10am, highest ~10pm (2-3x basal levels)
--NORMAL TSH levels in mU/ml: adult 2-10, newborn 3-18, naturopath optimal .5-2.0
--increased TSH etio: primary hypo, thryoiditis, thyroid agenesis, congenital cretinism, excess iodine intake, thyroid ablation
--decreased: secondary & tertiary hypothyroidism, hypERthyroidism, medication with T4
--TSH stimulation test used to differentiate primary and secondary hypothyroidism
--pts with secondary or pituitary hypo will increase T3 and T4 output with exogenous TSH
--pts with primary hypo can't increase T3 & T4 no matter how much TSH you give them

BBT
--basal body temperature controlled by thyroid hormones
--Broda Barnes, MD did research
--normal axial BBT = 97.6-98.2 F
--menstruating females take BBT on days 2-4
--low BBT may reflect hypothyroid
--high BBT less common, mb evidence of hypERthryoid
--correlate either finding with other sx of thyroid dz

2. Know what proteins function as thyroid hormones carriers?

--TBG = thyroxine binding globin, specialized for thyroid, highest affinity, carries 70%
--TBPA = thyroid binding pre-albumin carries 20% of T4 and NO T3
--albumin has low affinity, binds 10% of T4 and 30% of T3
--so T3 carried 70% by TBG and 30% by albumin
--T4 carried 70% by TBG, 20% by TBPA, and 10% by albumin, 99.98% is bound, .02% is free

3. How might changes in TBG affect Total T4 & T3 levels? What can alter TBG levels?

--lowered TBG-->high T3RU, low TT4, normal FTI
--etio of low TBG: protein loss, androgen excess

4. Why is total T4 NOT the best test to evaluate thyroid function?

--because lots of things can cause elevated or decreased T4 (besides primary thryoid issue)
--affected by TBG levels
--increase etio: thyroiditis, T4 meds, struma ovarii, TBG increase, familial dysalbuminemic hyperthyroxinemia, also in pregnancy, OCP's
--decrease etio: pituitary insufficiency (secondary hypo), hypothalamic failure (tertiary hypo), protein malnutrit, iodine insuff, drugs
--T4 is tested in newborns to screen for hypothyroidism, prevent cretinism
--T4 is increased after use of iodinated X-ray contrast
--T4 is increased in pregnancy due to increased TBG
--normal T4 (thyroxine) levels in micrograms/mil are: male 4-12, female 5-12, over 60 5-11, children: variable
--critical T4 levels: <2.0 (myxedema coma) or >20 (thyroid storm)

5. Know the normal percentages of Free T4 & free T3 and their biologic activity?

--thyroid releases T3 (7%) and T4 (93%), both can enter tissues
--nuclear receptor 10X more affinity for T3 than T4
--T4 converted to T3 in peripheral tissues, esp liver and also skeletal muscle
--T3 and T4 target receptors in nucleus and stimulate RNA synthesis

6. Know how variations in TBG levels influence T3RU [See the TBG bus diagram. Be sure you understand what the T3RU uptake test actually measures!]

--TBG = "the bus"
--T3RU = T3 resin uptake, measures any T3's bound to resin after marked T3 is added
--FTI = total T4 x T3RU
--T3RU is indirect measure of T4, does not measure T3 in any way
--T3RU is an indirect measure of the amount of unsaturated binding sites on TBG and TBPA
--high TBG --> low T3RU because T4 will all be "on the bus"
--low TBG --> high T3RU (no room on the bus) (unless there's a deficiency of T3 also)
--drugs (dilantin, lasix) can bind TBG "seats"
--TBG can be low dt protein loss or androgen excess
--TBG can be elevated dt OCP, pregnancy
--T3RU increase: hypoerthyroid, hypoprotein, nonthyroid illness, T4 med, stuma avoii, familial dysalbuminemic hyperthyroxeinmia
--T3RU decrease: increased TBG (preg, OCP), hypothyroid, hepatitis, cirrhosis

7. What does the FTI test measure?

--free T4 index
--a mathematical computation that tells us how much thyroid H is free and able to act
--FTI = total T4 x T3RU
--aka T7
--mathematically accounts for reciprocal effects of T4 and T3 uptake
--a single figure that correlates with free T4
--FTI increased in hyperthyroidism
--FTI decreased in hypothyroidism
--remains normal in early stages of hypo or hyper
--FTI corrects for changes in thyroid binding proteins that affect T4 level
--interfering factors: recent radioisotope scans using labeled T3, drugs
--FIT helpful to dx hyper and hypo thyroid
--is it a calculated estimate of total T4
--FTI = (T4)(T3RU)/100
--increased FTI: primary hyperthyroid, acute thyroiditis, T4 med, struma ovarii
--decreased FTI: hypothyroid states, pituitary insuff, hypothal failure, iodine insuff

8. Recognize hypErthyroidism vs hypOthyroidism (1o, 2o & 3o) from data provided. When would you want to use the TRH stimulation test?

hypERthyroidism
--TSH low, T4 high
--negative feedback loop not working
--rT3 usu incrased

primary hypOthyroidism
--gland not working no matter how much TRH and TSH released
--TSH levels high, trying to get it to work
--T4 level low

secondary hypothyroidism
--mb anterior pituitary problem
--TSH and T4 low

tertiary hypOthyroidism
--hypothalamus problem

TSH stimulation test
--TSH stimulation test used to differentiate primary and secondary hypothyroidism
--pts with secondary or pituitary hypo will increase T3 and T4 output with exogenous TSH
--pts with primary hypo can't increase T3 & T4 no matter how much TSH you give them

TRH stimulation test
--assess responsiveness of anterior pituitary
--if primary hypo, TSH level increases 2-3x N
--if secondar, no TSH response
--if tertiary, delayed TSH increase, or need multiple injections of TRH to increase TSH (have to wake up anterior pituitary because it has been sleeping, the alarm clock doesn't go off)

9. Know how to use the FT4 or FTI to sort out TSH abnormalities.

--free hormone levels used to eval thyroid fx in pts w/ prot abn affecting tot hormones
--.02-.03% of T4 is unbound "free" and metabolically active
--.03% of T4 is unbound
--NORMALS in ng/dL: FT4 .7-2.0, FT3 260-480 (in non-medicated pts)

10. What test would confirm a diagnosis of T3 toxicosis?

--T3 toxicosis = rare form of hypER with normal T4 and elevated T3
--use test of triiodothyronine, aka T3 (total)
--total T3 aka T3 by RIA, measures bound and unbound
--used to dx hypERthyroidism
--may be used to monitor thyroid replacement or suppression
--no good for dx hypo
--severe non-thyroid dz decreases T3
--overlap between hypothyroid and euthyroid levels (seems normal)
--this test not same as T3 uptake

assimilate Mamie's answers below:
11. Why might patients with “Euthyroid Sick Syndrome” have hypothyroidism symptoms & what test would confirm your suspicion? Hypothyroidism secondary to decreased peripheral conversion of T4→T3, decreased clearance of rT3, & decreased binding of thryroid hormones to TBG; see slide 26; thyroid function test (T4, free T4, T3, free T3, TSH)
12. When would you want to order a radioactive iodine uptake test (T3RU), or a thyroglobulin level (T3/T4)? Suspected hyper or hypothyroidism. What other test do you need to order simultaneously? TSH to differentiate between primary, secondary & tertiary hypo; single best test to screen for abN function of thyroid gland, see #9

11. Why might patients with “Euthyroid Sick Syndrome” have hypothyroidism symptoms & what test would confirm your suspicion?

--Why? because they're sick? Because sick pts make more rT3 and less T3??
--test rT3, levels will be elevated

EUTHYROID SICK SYNDROME
--low thyroid function due to systemic illness, thyroid gland is fine
-- = abnormal findings on thyroid function tests w/ nonthyroidal illness (NTI) and no preexisting hypothalamic-pituitary and thyroid gland dysfunction
--recover from NTI and thyroid function resumes
--most common: low T3 and high rT3
--TSH, T4, fT4, FTI also mb affected
--liver failure-->decreased conversion of T4 to T3-->decreased binding to TBG
--liver fail-->decreased clearance of rT3
--what kind of illness can cause: acute or chronic, fasting, starvation, protein-calorie malnutrition, general surgical trauma, MI, chronic renal failure, pulmonary and digestive dz
--most pts show TSH >0.05 µIU/mL
--severe, critical illness-->reduced T4 levels
--10% of pts hospitalized for NTI have low TSH, they are the most ill

12. When would you want to order a radioactive iodine uptake test, or a thyroglobulin level? What other test do you need to order simultaneously?

--RIU to determine why thyroid hormone levels are elevated, or why the gland is enlarged
--DX hypERthyroidism or hashimoto's or cancer
--thyroglobulin level will inform about deficiency and suggest testing for anti-TBG Ab's
--also order anti-TPO, anti-thyroid peroxidase test

THYROGLOBULIN TEST
--primarily used as a tumor marker
--evaluate Tx effectiveness for thyroid cancer, monitor for recurrence
--not all thyroid cancer produce TBG
--the most common types (papillary and follicular) frequently do
--order TSH too
--order several over time to watch change
--anti-TBG Ab's (aka TgAb) interfere with the test, so check for them too
--occasionally ordered to help determine the cause of hyperthyroidism and to monitor the effectiveness of treatment for conditions such as Grave’s disease

THYROID ANTIBODIES
--risk factors: type I DM, pernicious anemia, age
--"stimulating" antibodies against thyroid receptor are called thyroid stimulating immunoglobulins (TSI), -->hyperthyroid, GRAVES DZ
--"blocking" autoantibodies against thyroperoxidase are called anti-thryoid peroxidase antibodies, aka anti-TPO, aka anti-microsomal AB's
--"blocking" AB's against thyroglobin are called antithyroglobulin AB's
--GRAVES DZ caused by stim of thyroid stimulating hormone receptors (TSHR) by thyroid stimulating immunoglobulins (TSI)
--often see anti-peroxidase and anti-thyroglobuin antibodies too
--antibodies arise due to defect in T-suppressor cells
--suppressor defect permits clone of T-helper to interact with thyroid antigens
--T-helpers stim B-lymps to produce TSI
--IgG AB's can cross placenta
--Dx of GRAVES: high T3, T4, low TSH, gland nonpalpable or smooth symmetric goiter

13. What TSH & FT4 levels and antibodies are typically present in Graves Disease & Hashimoto’s thyroiditis?

--Graves: low TSH and high T4
--Hashimoto's: early may have normal TSH and T4, late T4 will be low and TSH will be high

HASHIMOTO'S THYROIDITIS
--most common cause of acquired primary hypothyroidism
--8:1 more females get it
--onset usu age 30-50
--family Hx common
--early stages may present as hypERthyroid
--early labs may show normal T4 and TSH, high titer anti-TPO, possible antithryoglobulin Ab's
--radioactive iodine uptake mb increased
--later in dz pt develops hypOthyroid with low T4, low T3RU, high TSH, decreased iodide uptake due to gland destruction
--antibody titers higher in thyroiditis than in Graves (anti-TPO and anti-TBG)
--gland mb tender to palpation dt inflam

NEONATAL SCREENING
--T4 normal at birth, increases up to 6x over next 4 hours
--T4 returns to normal in first week
--T4 tested in newborns (heel stick)
--1:4000 have low thyroid fx, if not treated-->cretinism (mental retardation)
--TBG slighter higher than adults
--TSH rises rapidly and peaks 30 minutes after birth

Comments

( 1 comment — Leave a comment )
thomaskruger281
Nov. 4th, 2009 02:46 pm (UTC)
Great Post! Great Help
Whoa! Thanks for the post...It will be a great help for me especially for my mother who is having a thyroid problem. But she is now going well cause she used some elisa test kit as prescribe by her private doctor.
( 1 comment — Leave a comment )

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