All You Ever Wanted to Know About Thyroid
Thyroid anatomy and physiology
Thyroid gland is a butterfly shaped organ located in front of the throat. The follicular cells of the thyroid gland secrete tetraiodothyronine (T4) and triiodothyronine (T3), which are synthesized by attaching iodine atoms to the amino acid tyrosine. T3 and T4 combine with tyrosine-binding globulin (TBG), a transport protein in the blood, which carries the hormones throughout the body. Approximately 75 percent of the thyroid hormone is bound to TBG, and only the free/unbound portion of the hormone can act in the body.
More than 90 to 95 percent of the hormone the thyroid secretes directly is the inactive form of T4. Under normal circumstances, this T4 then gets converted into four different hormones:
- ~60 percent is converted into active T3 by the removal of one iodine atom by the 5’ deiodinase enzyme and 80 percent of this conversion occurs in the liver;
- ~20 percent is converted into reverse T3 (rT3), which is completely inactive and cannot be reactivated; and
- ~20 percent is converted into T3 sulfate (T3S) and triiodothroacetic acid (T3AC). These are inactive until an enzyme in the intestines converts them into active T3. This process requires healthy intestinal bacteria.
T3 is four times as potent as T4, but lasts a much shorter time. Therefore T4 acts as a reserve for thyroid activity because it can be converted to T3 as needed. There are also specialized cells within the thyroid that secrete calcitonin, which helps regulate calcium levels.
Thyroid hormone secretion is controlled by feedback systems with the pituitary and hypothalamus glands as well as the body’s iodine level. Low levels of T3 and T4 or a lower metabolic rate will trigger the hypothalamus to secrete thyrotropin releasing hormone (TRH). TRH then stimulates the pituitary to secrete thyroid stimulating hormone (TSH), which stimulates the production and release of T3 and T4 from the thyroid gland. So as T3/T4 levels begin to decrease in the body, TRH from the hypothalamus and TSH from the pituitary begin to increase, stimulating the thyroid gland to produce more T4. Production of thyroid hormone will also be stimulated by any situation that increases energy demand, including a cold environment, low blood sugar, pregnancy, and high altitude.
Thyroid functions in body
Thyroid hormones have a wide variety of functions in the body, including:
- regulating the basal metabolic rate to produce energy and heat;
- stimulating protein synthesis;
- enhancing triglyceride breakdown and cholesterol excretion;
- promoting normal growth and development of bone;
- affecting production and function of other hormones, including cortisol, testosterone, estrogen, progesterone, insulin, and growth hormone;
- supporting normal liver and gallbladder function, especially phase 2 detoxification;
- regulating brain inflammation and brain autoimmunity, especially through effects on microglial cells in the brain;
- influencing the actions of and receptors for neurotransmitters, including serotonin, dopamine, GABA, acetylcholine, adrenaline and noradrenaline;
- affecting methylation pathways, and therefore, estrogen metabolism and activity of B12 and folate; and
- accelerating body growth in children, especially in the nervous system.
Symptoms relating to thyroid disorders
Thyroid disorders can be generally divided into low (hypo-) or high (hyper-) thyroid, and in general, hypothyroid conditions are more common than hyperthyroid conditions. Patients with hypothyroid disorders may present with:
- weight gain even with reduced calories due to reduced overall metabolic rate;
- decreased mobilization of free fatty acids from fat tissue;
- slow degradation of lipids;
- delayed insulin response to glucose;
- slow glucose uptake by tissues and decreased glucose absorption in the intestines; and
- slower degradation of insulin, which may present clinically as hypoglycemia.
- morning headaches that wear off through the day;
- bone development delay; and
- muscle cramps and body pain.
- poor brain function;
- depression, and sometimes anxiety; and
- high need for sleep.
- sensitivity to cold/cold weather and poor circulation in extremities;
- low body temperature;
- facial swelling;
- loss of the outer third of the eyebrows;
- difficulty recovering from infections/ healing wounds;
- dry or brittle skin/hair/nails; and
- hair falling out.
- chronic low stomach acid/poor digestion;
- decreased intestinal transit time;
- altered intestinal absorption rates;
- reduced liver clearance with possible AST/ALT elevations on bloodwork;
- sluggish gallbladder contraction;
- abnormal phase II detoxification in the liver;
- decreased B12, folate, and iron absorption; and
- increased intestinal permeability to proteins.
- difficult menstrual periods and/or infertility;
- altered metabolism of androgens and estrogens;
- altered estrogen metabolism toward forms which increases risk for estrogen-related cell growth;
- reduced sensitivity at progesterone receptors (progesterone resistance); and
- increased sex-hormone binding globulin, which affects the free portions of sex hormones.
- atrial fibrillation
There may also be a painless swelling of the thyroid or a sensation of fullness in the throat. Low levels of thyroid hormone can also affect other hormones, such as estrogen or progesterone, which can then cause their own set of symptoms.
Patients with hyperthyroid disorders may present with hypermetabolism, rapid heart rate, and fatigue, weight loss despite normal to increased calories, excess heat, osteoporosis and bone demineralization, nervousness, and tremors.
Testing thyroid and what results mean
There are many tests of thyroid function and it is important to know the information that each of these tests does and does not provide.
- TSH is a direct measure of the amount of TSH produced by the pituitary. Many doctors feel this is best means of determining thyroid dysfunction because they feel normal results essentially rule out hyperthyroidism or hypothyroidism. However, using TSH to evaluate thyroid function doesn’t consider abnormal thyroid-pituitary feedback loops, peripheral thyroid metabolism/conversion issues, or autoimmune thyroid conditions.
- Total T4 (TT4) is a measure of bound and free T4 hormone. Changes in levels of TBG will produce corresponding changes in TT4.
- Free T4 (fT4) is a direct measure of the unbound T4 hormone. This can appear elevated if the TBG levels are decreased.
- Total T3 (TT3) is a measure of bound and free T3 hormone. It tightly bound to TBG (although 10 times less so than T4) and like TT4, TT3 levels are influenced by alterations in serum TBG level and by drugs that affect binding to TBG.
- Free T3 (fT3) is a direct measure of the unbound T3 hormone. This test is usually done to evaluate thyrotoxicosis or when a hyperthyroid patient has normal FT4 levels.
- Reverse T3 (rT3) is a direct measure of the reverse T3 levels. This will be higher primarily under conditions of elevated cortisol and an inability to clear rT3.
- T3 Uptake (T3U) is used to estimate protein binding and measures the number of sites for fT3 to bind with thyroxine binding proteins.
- Free Thyroxine Index (FTI) is a calculated value that corrects TT4 for the effects of varying amounts of thyroid hormone–binding serum proteins and thus gives an estimate of fT4 when TT4 is measured. While it is an older tests, the FTI is readily available and compares well with direct measurement of fT4.
- Thyroid antibodies are measurements of immune activity against different portions of the thyroid. The most common tests are thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies. These tests are used to identify cases where hypothyroidism (Hashimoto’s thyroiditis) or hyperthyroidism (Grave’s disease) is caused by autoimmune activity, and positive results indicate that treatment must be based on treating autoimmunity in addition to appropriate thyroid support.
TPO antibodies target the thyroid peroxidase enzyme, which is important in the synthesis of thyroid hormone inside the thyroid follicular cells. The TPO antibody test is the most sensitive test for detecting any autoimmune thyroid disease and are highest in patients with Hashimoto’s thyroiditis. Tg antibodies bind thyroglobulin, the major thyroid-specific protein that is crucial to thyroid hormone synthesis, storage, and release; these antibodies can interfere with thyroid hormone production. Tg is not released into circulation under normal conditions. However, inflammation, bleeding, or rapid growth of thyroid tumors can cause destruction of the thyroid follicular cells, causing Tg to leak into the blood. This process can cause the formation of Tg antibodies and the exposure of other thyroid proteins to the immune system, especially TPO.
TPO antibodies are positive in 90-100% of cases of Hashimoto’s thyroiditis and 50-80% of cases of Graves’ disease and Tg antibodies are positive in 80-90% of cases of Hashimoto’s thyroiditis and 50-70% of cases of Graves’ disease. TPO and/or Tg antiobdies may also be present in other autoimmune diseases (40% of cases), pregnancy (14% of cases) and sporadic multinodular goiter, isolated thyroid nodule, and thyroid cancer. Elevated levels of TPO or Tg antibodies may be present in 40-50% of relatives of patients with an autoimmune thyroid disorder.
TPO antibody tests are more sensitive than but equally specific to Tg antibody tests for diagnosing autoimmune thyroid conditions. However, for some patients, only the Tg antibodies are positive and anti-Tg levels should be evaluated if TPO antibodies are negative, but clinical suspicion of autoimmune thyroid disease is high. According to the Mayo Clinic, “in patients with subclinical hypothyroidism, the presence of TPO antibodies is associated with an increased risk of developing overt hypothyroidism. Many clinical endocrinologists use the TPO antibody test as a diagnostic tool in deciding whether to treat a patient with subclinical hypothyroidism.”
- Radioactive iodine uptake testing is used to help diagnose hyperthyroidism. A trace amount of radioiodine is given orally or IV and a scanner then detects the amount of radioiodine taken up by the thyroid.
It is important to know that there are medications that can affect both thyroid functioning as well as thyroid test results. Medications can:
- decrease TSH secretion;
- decrease or increase thyroid hormone production;
- decrease T4 absorption;
- increase or decrease TBG, thereby increasing or decreasing the free hormone levels;
- displace T3 and T4 from the transport proteins;
- increase liver metabolism; and
- decrease the 5’deiodinase activity.
Lab Findings with Thyroid Disorders
Lab test results will vary with different types of thyroid disorders.
With hypothyroidism, there will be a high TSH; low-normal TT4, FT4, TT3, FT3, FTI, and T3U; and normal rT3. Antibodies may be negative or positive depending if the cause is autoimmune. If hypothyroidism is caused by low pituitary functioning, the labs will be the same except that the TSH will be low instead of high. In that case, the thyroid itself may be able to function normally, but it is not getting the correct stimulation (TSH) from the pituitary. Other things to consider then include adrenal dysregulation, post-partum, thyroid receptor site resistance, and heavy metal toxicity, all of which will affect pituitary functioning.
Subclinical hypothyroidism occurs when the patient has hypothyroid symptoms and the TSH is mildly elevated but FT4 is within lab reference range; over 80% of patients have a TSH of less than 10 mIU/L. This condition is fairly common and the diagnosis can be supported by positive TPO antibodies. It may be considered a very early stage of an autoimmune condition because the majority of patients diagnosed do go on to develop full hypothyroidism, especially if those patients have positive TPO antibodies.
With hyperthyroidism, there will be a low TSH; high-normal TT4, FT4, TT3, FT3, and FTI; and normal T3U and rT3. Antibodies are almost always positive for hyperthyroidism because almost all cases are due to autoimmunity (Grave’s disease).
Thyroid underconversion is a very common pattern and occurs when the thyroid is producing T4 normally, but the T4 is not being converted to T3 correctly in the body. In this case, labs will show a normal TSH; high-normal TT4, FT4, and FTI; and low t3U, TT3, FT3, and rT3. In this case, current or past causes of downregulation of the 5’deiodinase enzyme need be investigated.
Thyroid overconversion occurs when too much T4 is converted to T3, and the chronic high T3 can lead to thyroid resistance. This is typically caused by elevated testosterone and insulin. In this case, TSH is normal with low-normal TT4, FT4, FTI; high-normal T3U, TT3 and FT3; and normal rT3.
Excess estrogen (e.g., oral contraceptives, hormone replacement therapy, pregnancy) can cause elevations of TBG. In this case, labs will show normal TSH, TT4, TT3, and rT3; low FT4, FT3, and T3U; and low-normal FTI. In this case, patients often do not respond to nutritional thyroid support or thyroid replacement and eliminating exposure to outside estrogens and balancing estrogen levels needs to be considered.
In thyroid resistance, all labs may be within normal ranges or FT4 and FT3 may be elevated. Patients may have no symptoms, or symptoms of either low or high thyroid function. This is may be caused by a fairly rare genetic condition or by functional issues, typically high cortisol, which down-regulates some of the thyroid receptor sites, making them unable to respond to thyroid hormone. For these non-genetic cases, there may also be issues with methylation (high homocysteine), vitamin A deficiency, or insulin resistance.
In Wilson’s syndrome, all lab tests are normal except a persistently elevated rT3 and the patient has hypothyroid symptoms. This is most commonly due to chronically elevated cortisol.
Euthyroid Sick Syndrome most commonly occurs when a patient has another chronic illness that begins to affect the thyroid function test results. The actual results may vary depending on the underlying condition, and for most of these patients, treatment focuses on the underlying illness and thyroid replacement is not recommended.
Autoimmune thyroid conditions can be difficult to assess because antibody levels and their resultant impact on thyroid function can fluctuate depending on factors affecting immune activity. Early cases of Hashimoto’s thyroiditis, patients may present with a high or even normal TSH, hypothyroid and/or hyperthyroid symptoms but no thyroid Abs; in this case there is an autoimmune reaction, but the thyroid tissue has not been attacked enough to cause a change in thyroid test levels. Without intervention, this patient would very likely continue on to develop Hashimoto’s thyroiditis with hypothyroid lab results. For a patient with a low TSH, hyperthyroid symptoms and positive antibodies, it could be Grave’s disease or Hashimoto’s thyroiditis in a hyperthyroid state.
Treatments for Thyroid Disorders
Treatments for thyroid disorders vary greatly and depend on the specific type of imbalance. Thyroid hormone replacement can include synthetic T4 (levothyroxine or synthroid), synthetic T3 (cytomel), synthetic combination (thyrolar) and natural thyroid sources, which include both T4 and T3 (e.g., Armour thyroid, Nature-throid, Westhyroid). Dosing goals should include both achieving optimum lab test results and resolution of patient symptoms.
Thyroid supports include nutrients, herbs, and remedies that support normal thyroid function. These may be helpful in addition to thyroid replacement or in cases where a patient’s lab values are not at optimum, but are still within the laboratory reference ranges. Supports need to be tailored to each patient, and there are some cautions in using thyroid supports. For example, while tyrosine and iodine are necessary to produce T3 and T4, excess levels can be suppressive to thyroid function. If thyroid support is needed, functioning of other hormones should also be addressed.
Autoimmune thyroid conditions require broader treatment to include both support for thyroid function as well as addressing the immune dysfunction, the underlying causes for that dysfunction, and other concurrent health issues. For example, some patients with Hashimoto’s thyroiditis have a defect in the vitamin D receptor which means these patients will require more vitamin D than a “normal” patient. Additionally, patients with Hashimoto’s thyroiditis may also have other concurrent autoimmune conditions, especially celiac disease, and have a higher risk of developing thyroid cancer or pernicious anemia, type I diabetes, or rheumatoid arthritis. It is also important to remember that patients with Hashimoto’s thyroiditis can have periods of episodes of hyperthyroidism if there are periods of greater immune activity and thus increased destruction of thyroid tissue and release of stored thyroid hormone. Autoimmune hyperthyroidism often requires surgical removal or irradiation of the thyroid or pharmaceuticals to significantly suppress thyroid function.
There can also be many other influences on thyroid function, and in some cases, abnormal thyroid labs or thyroid-related symptoms are due to a non-thyroid cause. Thyroid underconversion is most often caused by one or more of the following:
- High cortisol (due to chronic stress, low blood sugar, insulin resistance, anemia, acute or chronic infections, toxicity, surgery, accidents, chronic pain);
- Hepatic dysfunction;
- Imbalances in normal intestinal bacteria;
- Viral infections;
- Low selenium, zinc, and/or iodine;
- Heavy metals;
- Inflammation; and
- Low glutathione.
All of these factors can affect thyroid functioning in general, and any treatment plan needs to investigate these other factors, and provide thyroid support while addressing the underlying cause(s). This will also be true for the hormone imbalances that lead to thyroid overconversion or elevations of TBG. Gluten sensitivity, celiac disease, and gut inflammation can also have a negative effect on thyroid function, as can overconsumption of soy, especially the more highly processed forms. Many of the factors leading to thyroid underconversion may also result in thyroid resistance, and should be investigated when that condition is suspected.
The Merck Manual
Kharrazian, Datis. Functional Blood Chemistry Analysis Seminar.
Thom, Dick. Practical Endocrinology Seminar.