1. Thyroid hormones 2

2. Introduction TSH glycoproteins consisting of alpha and beta subunits, the alpha subunit is similar to that found in three glycoproteins hormones LH, FSH, HCG is in turn regulated by thyrotropin releasing hormone TRH from hypothalamus. TRH is a tripeptide which has been synthesized and is available for exogenous administration. A 200 microgram bolus of TRH given intravenously produces a rise in TSH with a peak at 20 minutes (4- 25mU/L) which falls but does not reach baseline by 60 minutes after injection

3. The levels of circulating T4 and T3 exert a feedback effect on the secretion of TSH and possibly TRH. A fall in T4 and T3 stimulates TSH release and increase of T4 and T3 suppresses TSH.

4. Thyroid hormones Hormones (T4, T3, and RT3), once released into the bloodstream, exist either as protein bound or in a free form. The T3 and T4 hormones help regulate the body's metabolic rate (the rate at which the various processes in the body work, such as how quickly calories are burnt). An excess of T3 and T4 will make you feel overactive and you may lose weight. If you don't have enough of these hormones, you'll feel sluggish and you may gain weight.

5. Measurement of total thyroid hormones includes protein-bound and free fractions. Alterations in the concentration of serum proteins will affect total T4 and total T3 levels. Such changes in proteins may result in misleading elevation or reduction of total thyroxine and tri- iodothyronine. This can be recognized either by direct measurement TBG, to arrive at a T4/TGB ratio, or by an indirect method of estimating the available binding sites for thyroid hormone.

6. Because over 99% of released thyroid hormone is attached to proteins in the blood, it is believed that measuring the amount not attached to proteins (i.e., free thyroid hormone) is a more accurate measurement of thyroid hormone levels. Measuring the total hormone level is generally less reliable.

7. Techniques which measure free fractions of T4 or T3 are not usually influenced by the amount of TBG present. Whilst T4 is produced entirely by the thyroid, T3 is also produced by peripheral conversion from T4 in cells of the kidney, liver, heart, anterior pituitary and other tissue. T4 is deiodinated to the active metabolite T3 or an inactive metabolite reverse T3(rT3). The mechanism controlling these conversions is poorly understood

8. Note that high levels of estrogens (birth control pills, non- bio-identical hormone replacement, or pregnancy) or estrogen dominance can increase the amount of the protein that binds T4. This will produce misleading elevated Total T4 and T3 values which can look like ‘hyperthyroidism’ when it is not. But free T3 or free T4 not affected with these conditions

9. In healthy individuals, T4 is largely converted to T3 but in severely ill people suffering from a variety of acute or chronic illnesses, less T3 and more reverse T3 is produced.

10. Triiodothyronine (T3) T3 is typically only measured in cases of hyperthyroidism where the T4 levels are normal. hyperthyroidism

11. RT3: Reflects the level of Reverse T3. It is used to measure often but found little need for it once. It is realized the approximate value can be estimated from knowing T4 and T3 values since we know that T4 will become either T3 or RT3. For example, if the T4 is elevated and the T3 is low, we know that RT3 (what the rest of the T4 becomes) will be relatively elevated. Cortisol decreases TSH, lowering thyroid hormone production.. Cortisol inhibits the conversion of T4 to active T3, and increases the conversion of T4 to reverse T3.

12. Hypothyroidism In overt primary hypothyroidism, serum total T4 is low and serum TSH raised. Serum T3 levels are of no diagnostic value as they are frequently in the normal range even when T4 is low. In primary hypothyroidism the ECG may reveal bradycardia, low voltage complexes, ST segment depression and T wave inversion, but such changes are not invariably present and are not specific.

13. In hypothyroidism secondary to pituitary disease, T4 values and FTI are low and there is no TSH response to TRH, but with lesser degrees of pituitary impairment the pattern of the TSH response to TRH is variable. In hypothalamic disease, TSH response to TRH is typically delayed.

14. Hyperthyroidis The clinical diagnosis of hyperthyroidism is confirmed by finding an elevated serum T4. if T4 is normal but thyrotoxicosis is still suspected, then T3 should be measured. T3 is often elevated before T4 in hyperthyroidism (T3 toxicosis), but other evidence of thyroid autonomy, such as a flat TSH response to TRH or failure of T3 suppression of radio-iodine uptake, should be sought. Misleading high total T4 value are found in pregnancy or oral contraceptive therapy due to the effect of estrogens on TBG capacity and in rare condition of familial increased TBG. Such patients are clinically euthyroid and the high t4 levels can be corrected by direct measurement of TBG or free thyroxine index, and free T4 levels are normal.

15. Antithyroid antibodies Antithyroid antibodies are created when the body's immune system attacks parts of the thyroid with antibodies. There are several different types of antithyroid antibodies. TSH-R Ab is a TSH receptor antibody, and is present in most of patients who have Graves' disease. The antibodies stimulate the TSH-receptor which causes the thyroid to make more thyroid hormone (T4 and T3).TSH-R AbTSHGraves' diseaseT4 Antithyroglobulin antibodies (Anti-TG Ab) are present in patients with Hashimoto's thyroiditis. Antibodies against the protein thyroglobulin can result in destruction of thyroid cells. This destruction can lead to hypothyroidism.Anti-TG Ab hypothyroidism Antithyroid peroxidase antibodies (Anti-TPO Ab) are similar to antithyroglobulin antibodies. They are found in high levels in patients with Hashimoto's thyroiditis, and can lead to destruction of thyroid cells.Anti-TPO Ab Hashimoto's thyroiditis

16. * Antibodies: Autoimmune thyroid disease falls into two main categories: Hashimoto’s Thyroiditis and Grave’s Disease. Hashimoto’s Thyroiditis is typically identified by checking antibodies that attach the thyroid tissue. Grave’s Disease is typically diagnosed using Thyroid-Stimulating Immunoglobulin (TSI), Long Acting Thyroid Stimulator (LATS) and TSH-Binding Inhibiting Immunoglobulin (TBII). These are different names for the same test.

17. Hashimoto’s patient Hashimoto’s patient who is taking replacement hormones but still suffers from hypothyroid symptoms – often in spite of repeated changes in the dose and type of medication. In these patients, inflammation is depressing thyroid receptor site sensitivity and producing hypothyroid symptoms, even though lab markers like TSH, T4 and T3 may be normal.

18. Confounding factor When exogenous T4 is ingested, the T4 (or free T4) measurements can become discordant from the TSH measurements. For example, suppose a patient has primary hypothyroidism with a low FT4 level and an elevated TSH level. With oral administration of thyroxine, the FT4 can return to the reference interval far more quickly than can the TSH, which may not return to the reference interval for several weeks

19. Tumor in thyroid gland The important points to remember are that cancers arising in thyroid nodules generally do not cause symptoms, thyroid tests are typically normal even when cancer is present, and the best way to find a thyroid nodule is to make sure your doctor checks your neck! The primary therapy for all forms of thyroid cancer is surgery. After surgery, patients need to be on thyroid hormone for the rest of their life. If your doctor recommends radioactive iodine therapy, your TSH will need to be elevated prior to the treatment.

20. Thyroid cancer that spreads (metastasizes) to distant locations in the body occurs rarely but can be a serious problem. Surgery and radioactive iodine remain the best way to treat such cancers as long as these treatments continue to work. However, for more advanced cancers, or when radioactive iodine therapy is no longer effective, other means of treatment are needed

21. Thyroid tumor Example 2: * George had a thyroidectomy to remove a cancerous tumor. He was healthy otherwise. His thyroid hormone replacement of 75mcg Synthroid is not enough to meet his needs. He is hypothyroid. * Thyroid lab values show are: TSH = 5 (high), FT4 = 0.7 (low), FT3 = 280 (lower than optimal but relatively higher than T4) What does this mean: The pituitary gland is sensing insufficient thyroid energy and is therefore sending a strong signal to the (absent) thyroid gland telling it to make more T4. Because there is insufficient T4, the body can compensate by converting T4 to T3 at a higher than usual rate, hence we see a T3 that is higher than T4 on a relative scale.

22. All patients who have undergone thyroidectomy require thyroid hormone replacement with levothyroxine once the thyroid is removed. The dose of levothyroxine prescribed by your doctor will in part be determined by the extent of your thyroid cancer. More extensive cancers require higher doses of levothyroxine to suppress TSH. In cases of minimal or very low risk cancers, it’s safe to keep TSH in the normal range. The TSH level is the most sensitive indicator of whether the levothyroxine dose is correctly adjusted and should be followed regularly by your doctor.

23. Thyroglobulin Thyroglobulin is a protein produced by thyroid tissue and most types of thyroid cancer and is usually checked at least once annually. Following thyroidectomy and radioactive iodine ablation, thyroglobulin levels should be undetectable for life. Therefore, a detectable thyroglobulin level should raise a suspicion for possible cancer recurrence. Detectable thyroglobulin levels may require additional tests and possible further treatment with radioactive iodine and surgery. Thyroglobulin is generally measured either when you’re on thyroid hormone with a low or normal TSH, or after TSH is elevated either by stopping thyroid hormone for 3-6 weeks, or after injection of Thyrogen®. Measurement of thyroglobulin may not be possible in up to 25% of patients who have interfering thyroglobulin antibodies present in their blood. In these patients, other means of follow up are often used.

24. In addition to routine blood tests, your doctor may want to periodically repeat a whole-body iodine scan to determine if any thyroid cells remain. Whole body scanning is also done after your TSH level is raised, either by stopping your thyroid hormone or by administering Thyrogen® injections. Increasingly, these scans are only done for high risk patients and have been largely replaced by routine neck ultrasound and thyroglobulin measurements that have a higher diagnostic sensitivity especially when done together.

25. Follow up the thyroid cancer treatment People treated for thyroid cancer are typically asked to return to the doctor’s office every six months to a year. At a follow-up care visit, the doctor will conduct a physical examination and blood tests to watch the level of TSH suppression and to test for Tg. If the thyroid gland has been removed, there should be little or no Tg in the blood; an elevated level may indicate the cancer has returned. Other blood tests may be done depending on the specific type of thyroid cancer treated. Blood tests also help the doctor determine the correct dosage of the patient’s thyroid replacement medication (if needed), which may be adjusted over time as the patient gets older.

26. Thyroid cancer  acromegaly – a rare condition where the body produces too much growth hormone can be considered as risk factor for thyroid cancer. acromegaly  The thyroid gland is the only organ which makes Tg. Therefore, Tg is a good test to tell if there are thyroid cells in the body. Once the whole thyroid is taken out, the thyroglobulin level should go down to close to zero.Tg Thyroglobulin levels can then be measured, by a simple blood test, after thyroidectomy. Thyroglobulin is used as a tumor marker (i.e. test to see how much cancer is in the body) for thyroid cancer. If thyroglobulin levels go up after removing the whole thyroid, there is concern that the cancer may have come back (i.e. recurred) or spread (i.e. metastasized).

27. Calcitionin Calcitonin helps control blood calcium levels. Calcium is a mineral that performs a number of important functions, such as building strong bones.Calcium Calcitonin isn't essential for maintaining good health because your body also has other ways of controlling calcium.

28. Calcitonin is produced by the parafollicular, or C cells, found in the thyroid gland.Calcitonin This test is used as a tumor marker for a rare type of thyroid cancer known as medullary thyroid cancer.

29. Appropriate use of thyroid tests commentTest Most sensitive test for primary hypothyroidism and hyperthyroidism Excellent test serum TSH FT4 Screening High in primary and low in secondary hypothyroidism Elevated in Hashimoto thyroiditis Serum TSH Anti-thyroglobulin and anti-thyroperoxidase antibodies For hypothyroidism Suppressed except in TSH-secrting pitutary tumor or pituitary hyperplasia(rare) Elevated Increase uptake; diffuse versus (hot) foci on scan Elevated in Graves disease Ususally (65%) positive in Graves disease Serum TSH T3 or FT3 I123 uptake and scan Antithyroperoxidase and antithyroglobulin antibodies TSI, TSH-R-Ab (stim) For hyperthyroidism

30. Best diagnostic method for thyroid cancer. Cancer is usually (cold); less reliable than FNA biopsy Vascular versus avascular Useful to assist FNA biopsy. Useful in assessing the risk of malignancy(multinodular goiter or pure cysts are less likey to be malignant). Useful to mointor nodules and patients after thyroid surgery for carcinoma Fine-needle aspiration biopsy I123 uptake and scan 99mTC scan ultrasonography For thyroid nodules

31. Note: In states of thyroid hormone resistance, the concentrations of the thyroid hormones and thyroid-stimulating hormone TSH are typically elevated, but the affected patients are usually euthyroid or even possibly hypothyroid.