Thyroid Gland Anatomy and Function

• Thyroid cells are solely responsible for iodine absorption
• Iodine combines with tyrosine, an amino acid
• This combination produces triiodothyronine (T3) and thyroxine (T4)
• T3 and T4 are discharged into the bloodstream to regulate metabolism

Normal Thyroid Gland

• A small, butterfly-shaped gland
• Composed of two lobes that are connected by an isthmus
• Located in the anterior neck, hugging the trachea around the 2nd to 3rd tracheal rings or C5-C7 vertebrae
• Produces 80% T4 and 20% T3
• Function units are called follicles, which can vary in size and are lined by epithelial cells surrounding a colloid space
• Function is to uptake iodine and convert it into thyroid hormones like thyroxine (T4) and triiodothyronine (T3)
• Follicle cells are lined by epithelial cells ranging from simple cuboidal to simple columnar
• Weighs 15 to 25 g
• Consists of two lobes connected by a narrow isthmus
• Divided into lobules, each composed of 20 to 40 follicles separated by connective tissue
• Follicles are ring-shaped structures where a single cell band of follicular cells surrounds a closed cavity that contains colloid, thyroid hormone, thyroglobulin (Tg), and glycoproteins
• Follicular cells have microvilli that extend into the colloid, for iodination, exocytosis, and the initial phase of hormone secretion
• Parafollicular or C cells synthesize and secrete calcitonin, a hormone important for calcium metabolism
• Under the control of the pituitary gland

Regulators of Thyroid Gland Function

• Thyrotropin-Releasing Hormone (TRH) is regulated by the Hypothalamus
• Is a modified tripeptide derived from a large prepro-TRH molecule
• Acts on the production of pituitary hormones, especially prolactin
• Found in the hypothalamus, brain, C cells of the thyroid gland, β cells of the pancreas, myocardium, prostate, testis and spinal cord
• Neuron bodies producing TRH are innervated by catecholamine
• Leptin plays a significant role in the regulation of the TRH regulating appetite
• Somatostatin-containing axons

Thyroid-Stimulating Hormone (TSH)

• Pituitary Hormone
• Glycoprotein consisting of two monocovalently linked α and β subunits
• α subunit has the same amino acid sequences as LH, FSH, and human chorionic gonadotropin (hCG)
• β subunit carries specific information to the binding receptors for expression of hormonal activities
• Radioimmunoassay for measuring TSH was first developed in 1965

First Generation Assay

• Did not have sufficient sensitivity to distinguish normal TSH levels from suppressed levels in Primary Hyperthyroidism

Second Generation Immunomeric TSH Method

• Used in the mid 1980s
• Uses monoclonal or polyclonal antibodies
• Improved sensitivity to 0.1 to 0.2 mU/L

Third Generation Assay

• Now in common use.
• Allows measurement down to about 0.005 mU/L
• Provides sufficient sensitivity for the vast majority of clinical applications
• The ATA recommends this assay be able to quantitate TSH in the 0.010 to 0.020 mU/L range on an interassay results

Fourth Generation Assay

• Developed recently
• Sensitivity of 0.0004 mU/L
• Not widely available
• Serum TSH is <0.004 mIU/L in patients with severe hyperthyroidism

Functional Sensitivity

• Defined by ATA as the point at which the interassay precision has a coefficient of variation equal to less than 20%

TSH Assay

• Can identify virtually all instances of hyperthyroidism and hypothyroidism
• Exceptions are damage to the hypothalamus or pituitary gland, thyroid hormone resistance, or interference with normal functioning of the HPT axis due to medication

TSH Normal Results

• Approximately 0.5 and 5.0 mIU/L in most laboratories

Hyperthyroid Patients

• Have suppressed TSH values, except for individuals who have hyperthyroidism caused by TSH-producing tumors or other diseases such as pituitary resistance to thyroid hormone

Subclinical Hyperthyroidism

• Defined by the presence of low TSH with normal levels of T4 and T3

Subclinical Hypothyroidism

• Describe patients with elevated TSH but with normal levels of T4, T3 and FT4

Nonthyroidal Illness (NTI)

• Patients tend to have low TSH results during their acute illness
• TSH rises to within or above the reference range with resolution of the underlying illness
• TSH levels turn to normal once the acute illness has resolved
• These medications suppress TSH: glucagon, opioids, glucocorticoids and dopamine

TSH-Centered Strategy Limitations

• Assumes hypothalamic-pituitary function is intact and normal
• Assumes patient is stable without recent hyperthyroidism or hypothyroidism therapy
• The serum TSH result can be misleading if the above criteria are not met.

Confirming Thyroid Dysfunction

• Measure FT4 with or without total T4, in addition to TSH

Serum Free T3 and TSH

• Are appropriate to patients suspected of hyperthyroidism with a normal to low-normal T4 (T3 thyrotoxicosis)

Free T4 and Free T3

• Serum

Pituitary Gland

• Regulated by the hypothalamus
• Produces TRH to stimulate pituitary gland to release TSH
• Under control of the Pituitary Gland:
• When thyroid hormone level is low, the pituitary gland produces TSH
• TSH stimulates the thyroid gland to produce more hormones
• This raises the level in the blood, and the pituitary senses this, causing decreased TSH production

Commonly Used Thyroid Tests

• Measurement of serum thyroid hormones by radioimunoassay (RIA)

Serum T4

• Most used thyroid test
• Reflects the amount of thyroxine in the blood
• Thyroxine (T4) represents 80% of thyroid hormone and generally represent overall function of the gland
• Good measure of thyroid function if patient does not take any type of thyroid medication

Thyroxine (T4)

• After release from thyroid follicles, Thyroxine will bind to proteins in the blood
• The thyroid-binding globulin, albumin or thyretin
• Can be measured by immunoassay
• Reference Range: 5 to 12.5 ug/dL in adults (slightly lower results in certain pediatric age groups)
• Thyroxine measurements are often used along with TSH (can be important in interpreting TSH results)

Primary Hypothyroidism

• Low T4, Increased TSH

Primary Hyperthyroidism

• Elevated T4 and T3, Decreased TSH

T4 Thyrotoxicosis

• Elevated Serum T4, Serum T3 within reference range or low
• Can occur in patients with iodine-induced thyrotoxicosis or patients in beta blockers

Factors Affecting Thyroid Tests

• Amiodarone
• Large doses of steroids
• Thyrotoxic patients with NTI

T3 Thyrotoxicosis

• Suppressed TSH, Normal to low-normal T4 and High T3
• More common in a toxic nodule

Low T4 and T3 Syndrome

• Low T4, Low T3
• Severe nonthyroidal illness
• Associated with poor prognosis
• Adaptive response to reduce metabolic demands and conserve protein stores
• Thought to arise from a maladjusted central inhibition of TRH

Euthyroid Hyperthyroxinemia

• Increased Serum T4, Normal TSH
• Increased binding proteins as may be seen with certain drugs (e.g., estrogen)
• Medical conditions (e.g., liver disease)
• Hospitalized for psychiatric illness and in patients with familial dysalbuminemia

T3 Uptake (T3-UP) Test

• Assess T4 measurement by checking binding sites
• Measure unoccupied binding sites of all proteins
• Saturate available binding sites with 3 and measure the unbound 3

Free Thyroxine Index (FTI)

Patient’s Total T4) X (T3-UP of the Patient)/(Mean T3-UP of the Reference Population)

• Reference Range: 5.4 to 9.7
• Estimate of the free T4 concentration
• Largely replaced by the direct measurement of Free T4 by immunoassay, dialysis or ultrafiltration

Serum T3

• Represent 20%
• Sometimes the diseased thyroid gland will start producing very high levels of T3 but still produce normal level of T4
• Measurement of both hormones provide an even more accurate evaluation of thyroid function

Triiodothyronine (T3)

• Generally measured by immunoassay
• Reference Interval: 60 to 160 ug/dL (0.9 to 2.46 nmol/L)
• T3 is much less bound to serum protein than T4; thus, a relatively greater proportion of T3 than T3 exists in the free, diffusible state
• Elevated TBG will cause elevated T3
• Measurement of Serum T3 is not useful in evaluating patients suspected of having hypothyroidism because serum T3 levels are within the reference interval in 15% to 30% of hypothyroid patients
• Serum T3 concentrations are low in cord blood but increase rapidly during the first hours of life
• Administration of T3 results in a peak within 2 to 4 hours
• Serum T3 levels do not show a peak in patients treated daily with T4
• Total T3 concentrations are measured by competitive immunoassay methods that are now mostly nonisotopic and use enzymes, fluorescence, or chemiluminescence molecules as signals

Total T3 Measurement

• Is helpful in confirming the diagnosis of hyperthyroidism, especially in patients with no or minimally elevated T4 or ambiguous clinical manifestation

Serum T3 Levels

• Can be in the reference range or low in patients with hyperthyroidism if there is coexistent NTI
• Or if patients are on drugs that decrease the conversion of T4 to T3 (e.g., propranolol, amiodarone)

T3 Thyrotoxicosis

• Elevated Serum T3 but normal T4 and free T4
• Heterogenous group with no distinctive signs or symptoms
• Most patients have Graves' disease
• May also occur in patients with other causes of hyperthyroidism such as: Toxic nodular goiter or Toxic adenoma
• About 1% to 4% of thyrotoxic patients have T3 thyrotoxicosis, except in regions of iodine deficiency, where it is more common

Thyroid Binding Globulin (TBG)

• Most of the thyroid hormones in blood are attached to TBG
• If there is excess or deficiency, it alters T3 or T4 measurement
• Does not affect action of hormone
• If with normal thyroid function + unexplained high or low T4 or T3 → may be due to an increase/decrease of TBG
• Causes no problem except falsely elevating/lowering the T4 level → misdiagnosed as hyperthyroid/hypothyroid

Thyroxine-Binding Globulin (TBG)

• The main serum carrier protein for both T4 and T3
• Measurement may be helpful in patients who have serum T4 and T3 levels that do not agree with other laboratory parameters of thyroid function
• Measured by immunoassay
• Range: 13 to 39 ug/dL (150 to 360 nmol/L) in healthy individuals
• Inherited abnormalities include: complete of partial deficiency

Pituitary Production of TSH

• Measured by immunoradiometric Assay (IRMA)
• Normally: Low level of TSH are sufficient to keep normal thyroid gland functioning properly
• Early Hypothyroidism – TSH become elevated even though T3 and T4 may still be within "normal" range
• Rise in TSH represent the Pituitary response to a drop in circulating thyroid hormone and can be a first indication of Thyroid Gland failure
• TSH is usually used in combination with T4 and T3

TRH Stimulation Test

• Helpful in the diagnosis of patients with confusing Thyroid function test
• Involves determining basal TSH level administer bolus of TRH and measures TSH 15 to 30 minutes after
• Normal is:
• Baseline TSH (5 or less)
• Give TRH to increase TSH up to 10-20

Primary Hyperthyroidism

• TS are low. TRH causes little to no rise in TSH

Primary Hypothyroidism

• TRH causes a prompt increase in TSH to compensate

Secondary Hypothyroidism

• TRH causes no increase in TSH

Tertiary Hypothyroidism

• TRH causes delayed (1-2 hours) increase in TSH

Iodine Uptake Scan

• Measure how much iodine is taken up by the thyroid gland (RAI uptake)
• The test is performed by giving a dose of radioactive iodine, the iodine is concentrated in the thyroid gland and the amount of iodine that goes into the thyroid gland that can be measured is by a "thyroid uptake"
• Hypothyroid patients take up too little iodine
• Hyperthyroid patients take up too much iodine

Thyroid Scan

• Measure how well the thyroid gland is functioning
• Require giving a radioisotope to the thyroid gland

Technetium (Radioisotope)

• Will be concentrated by the thyroid gland
• Will not measure iodine uptake
• Usually done at the same time that the iodine uptake test is performed
• Used for identifying nodules, measure the size of the goiter prior to treatment, in the follow-up of thyroid cancer patients after surgery and for locating thyroid tissue outside the neck
• Identify where nodules are hot or cold. Increased hormone uptake is hot nodule. Decreased uptake is cold nodule. A malignant 1 nodules is 1 in10 chance to be malignent.

Thyroid Ultrasound

• Obtain images of the thyroid gland and identify nodules
• Cannot tell if a nodule is benign or malignant
• Allows accurate measurement of the nodule size
• Aids in performing Thyroid Needle Biopsy

Thyroid Needle Biopsy

• Provide definitive information

Thyroid Function Test Recommendations

• Commonly ordered tests are TSH, FT4, and FT3
• Asymptomatic patients are not screened for thyroid dysfunction because there is low likelihood of thyroid disease, but may still be tested if there are symptoms and risk factors
• TSH is used as the sole test of thyroid function in most situations as a more sensitive indicator

When to Test

• Clinical assessment and judgment remain paramount
• Initial testing for thyroid dysfunction should be based on clinical suspicion

Signs and Symptoms of Thyroid Disease

• Hypothyroidism includes Goiter, Delayed reflexes, Fatigue, Family History, Weight gain, and intolerance to cold
• Hyperthyroidism includes Goiter, Thyroid bruit, lid lag, Proptosis, Fatigue, Family History, Weight loss, and intolerance to heat

Study by Bandolier in 1997

• Showed that in patients with high suspicion, 78% had thyroid disease and in patients with intermediate symptoms, 2.9% suffered from thyroid disease

Appropriate to Test only TSH?

• There are conditions wherein it is inappropriate to test for TSH only

Central (Secondary) Hypothyroidism

• Pituitary failure:
• Request TSH and FT4
• Result will be a normal TSH with decreased FT4

Non-Compliance with Replacement Therapy

• Elevated TSH. Request TSH and FT4
• Result will be a discordant serum value (high TSH/ high FT4)

Early Stages of Therapy

• During early stages of therapy, testing TSH alone is inappropriate
• During the first 2 months of treatment, the thyroid is still unstable
• TSH has not reached equilibrium and measuring FT4 becomes a more reliable test

Combination Results

• High Irregular /SubclinicalPrimary TSH use ofthyroxine hypothyroidism hypothyroidism
• Normal Amiodarone/T4 under (problem inNormalto slight Thyroiditselft TSH pituitaryhypothyroidism replacement increased hypothyroidism
• Drugs Severe, Drugs. Pituitary to slight thyroiditis Hypothyroidism.
• TSH and FT 4 should be normal and the range is broad and this does not include non-thyroidal cases
• Non - Thyroidal illnesses

FT3 (non-thyroidal illness) is high

• Non - thyroidal cases

Thyroxine administration

1 month will make the test accurate

8 week testing period

8 week period after thyroxine

Anti-thyroids

May stay suppressed for approximately 3 to 6 months

Pregnancy tests recommendable

Because the hormones are already functioning

Thyroid cancers - Intentionally

• To cause the TSH to function less because TSH has more tumor reoccurrences

Pregnant Tests non recommends

• As they already may be suppressed

Hypothyroidism in pregnant tests, treat even at a slight increase to prevent miscarriage

Low:

• Irregularly/subclinical, primary High: -Amiordarone
• T4: administration errors
• Hypothryoid

TSH :

1st for line: assess thyroid function- More sensible primary test- A4 metabolic activity

FT4 with FT3 with little testing specificity

If on thyroxine treatment is needed:

6.8 weeks as to what to 8. Long is not what the lab has to test to 6. Every change in the dose requires 6-8 weeks 7. If dose is the result

TSH administration should be followed after 2-48 weeks for stability in results

• Monitor TSH with thyroid anti-medication medication (3-6) -Recheck the TSH every 1-2 weeks till stabilization -Then recheck again every 8 weeks for stability

If TSh is under 0.5 with hyper-thyroidism suspected

• Test or retest will show a normal result
• A follow up test is given for the FT3 because an abnormality might be located there with the F4 test with show it normal

Hypo FT4

-If low, replace thyroid and let retest

• Is an elevated increase after with hypo due to TSH

FT4

Thyroid tests in the first trimeters of pregnancy are not recommended due to the effects of chorionic administration stimulating hormone stimulation

-Nonthyroid

• Test: for acute illnesses as well
• Measure Thyroid : Cancer

Cancer from hormones

• Cause more sensitivity than needed -So treatment in the long run happens TSH measures : - Metablollic and free

To high with thyroxine T3-FT: