The following discussion of hypothyroidism is intended to be understandable and practical. I’ll first present a glossary of terms and then a description of hypothyroidism in adults: symptoms, causes, testing, and treatment. Then I have sections on special groups with hypothyroidism: pregnant women, newborn infants, and children. I first published this online as a Google “Knol”.
Thyroid gland refers to the endocrine organ located in the low anterior (front) of the neck. The thyroid gland secretes two forms of thyroid hormone (T4 and T3) to regulate the body’s metabolism. The thyroid gland weighs only about 15 grams (0.5 ounces) and is shaped something like a butterfly, with wings (lobes) flanking the trachea (windpipe) and connected to each other in front of the trachea. Figure1: http://www.med.umich.edu/1libr/aha/aha_thyroidg_art.htm
T4, thyroxine, levothyroxine (synonyms) refers to the form of thyroid hormone that has 4 atoms of iodine in each molecule. T4 is the main hormone secreted by the thyroid gland. Over 99% of T4 circulates in the bloodstream attached to proteins (eg, thyroid binding globulin, TBG). The unattached T4 is known as free T4 (FT4, free thyroxine) and only that tiny portion of T4 can leave the circulating blood to enter cells.
T3, triiodothyronine (synonyms) refers to the form of thyroid hormone that has 3 atoms of iodine in each molecule. T3 is secreted by the thyroid gland and also made from T4 in other cells that can convert T4 to T3. Over 99% of T3 circulates in the bloodstream attached to proteins (eg, thyroid binding globulin, TBG). The unattached T3 is known as free T3 (FT3) and only that tiny portion of T3 can leave the circulating blood to enter cells. FT3 is active thyroid hormone and works by entering a cell’s nucleus (center) and binding to certain receptors (like a key in a lock) to regulate the activity of genes. T3 receptors are found in nearly every cell of the body, from the brain to the skin, such that thyroid hormone’s effect is extremely widespread and profound.
TSH (Thyroid Stimulating Hormone) refers to a hormone that is produced by the pituitary, a small endocrine gland that lies at the base of the brain. TSH stimulates the thyroid gland to produce T4 and T3. The normal pituitary gland secretes more TSH when thyroid hormone levels are too low (hypothyroidism).Â The TSH level is elevated when the thyroid gland fails.
Symptoms of Hypothyroidism in Adults
Most adults with hypothyroidism complain of fatigue, weight gain, and feeling cold. There are many symptoms of hypothyroidism that vary considerably among individuals and most people with hypothyroidism will have only a few of them.
Common Symptoms of Hypothyroidism: slow heart rate (bradycardia), high blood pressure, cold intolerance, fatigue, depression, mental dullness, puffiness in face or extremities, thyroid enlargement (goiter), headache, slow speech, hoarse voice, heavy menstrual periods, joint and muscle pains, tingling feeling (paresthesia), carpal tunnel syndrome, hair breakage and thinning, brittle nails, decreased perspiration and dry skin, skin pallor or yellowing, weight gain.
Uncommon Symptoms of Hypothyroidism in Adults:
Trouble swallowing (dysphagia), breast milk secretion when not nursing (galactorrhea), shortness of breath, pneumonia, weight loss from decreased appetite, absent menstrual periods (amenorrhea), psychosis, sensitivity to narcotics and reduced consciousness. and coma.
Causes of Hypothyroidism in Adults
Hashimoto thyroiditis (autoimmune thyroiditis) is the most common cause of hypothyroidism. Dr. Hakaru Hashimoto, a Japanese surgeon, first described the condition in 1912. It’s an autoimmune condition in which the body’s immune system is turned against the thyroid. White blood cells (B lymphocytes) invade the thyroid gland, such that the condition is also known as chronic lymphocytic thyroiditis. The thyroid gland may enlarge and develop a rather firm, rubbery texture. The blood contains antibodies (immune proteins) that are directed against the thyroid gland. Such antithyroid antibodies are found in about 10% of most adult populations. Hashimoto thyroiditis is usually a chronic condition that can eventually damage the thyroid to cause hypothyroidism.
Painless thyroiditis,also known as Hashitoxicosis, is an acute autoimmune inflammation of the thyroid gland that releases stored thyroid hormone and initially causes hyperthyroidism, followed by hypothyroidism, due to thyroid damage. Frequently, the thyroid recovers normal function. The condition is termed postpartum thyroiditis when it occurs in women within 6 months after delivery.
There is a very strong genetic predisposition to autoimmune thyroiditis. http://www.jautoimdis.com/content/2/1/1Â Hashimoto thyroiditis can also occur during treatment with lithium, amiodarone, interferon therapy, and immuno-chemotherapy with immune checkpoint inhibitors. Dietary iodine supplementation also appears to increase the risk of autoimmune thyroiditis. http://www.ncbi.nlm.nih.gov/pubmed/12849065?dopt=Abstract
When Hashimoto thyroiditis causes hypothyroidism, it is usually permanent. However, up to 11% of patients with hypothyroidism may experience a remission after several years.
Rarely, hypothyroidism can resolve and may even go on to hyperthyroidism due to Graves disease. Graves disease is an autoimmune thyroiditis in which antibodies stimulate the thyroid’s TSH receptors, causing the thyroid to produce excessive amounts of thyroid hormone. In Graves disease, there is usually concurrent Hashimoto thyroiditis. Rarely, hypothyroidism may alternate with hyperthyroidism.
Although autoimmune thyroiditis can occur at any age and in either sex, it typically affects women. The sexual disparity is striking, with a female: male ratio of 10:1. Other autoimmune conditions also tend to be more common in women and the reason for this is not understood. One debated theory is that, during pregnancy, fetal cells enter the mother and might cause an autoimmune reaction, but autoimmune disease occurs even in women who have never been pregnant.
Usually, autoimmune thyroiditis is an isolated condition. However, individuals with autoimmune thyroiditis are somewhat prone to develop other autoimmune conditions. Some degree of Sjoegren syndrome (dry eyes & mouth) is fairly common. Celiac disease, an autoimmunity against the intestine provoked by gluten (wheat), is also more common. Vitiligo (patches of white skin) can also occur. In polyglandular autoimmune syndromes, patients with autoimmune thyroiditis have other autoimmune endocrine deficiencies, such as adrenal insufficiency, hypoparathyroidism (low serum calcium), or type 1 diabetes mellitus,
Other causes of hypothyroidism include surgery, radioiodine treatment or exposure (nuclear fallout), chronic hepatitis C, Reidel thyroiditis, and certain drugs: lithium, propylthiouracil, methimazole, sulfonamides, amiodarone, interferon alpha, interferon beta, interleukin-2. Iodine deficiency can cause hypothyroidism and goiter. Certain foods (turnips, cassava) can aggravate iodine deficiency and are known as goitrogens. Hypopituitarism can cause hypothyroidism, due to a deficiency of TSH.
Tests for Hypothyroidism
When the thyroid gland fail, lower levels of thyroid hormone are sensed by the pituitary gland, which secretes more Thyroid Stimulating Hormone (TSH). An elevated serum TSH level is the most sensitive test for hypothyroidism (except with hypopituitarism) In hypothyroidism, the serum free T4 (FT4) level is usually low or low-normal.
To screen for Hashimoto (autoimmune) thyroiditis, blood is assayed for antithyroid antibodies: anti-thyroperoxidase (TPO) antibodies and anti-thyroglobulin (TG) antibodies.
Factors that can cause misleading testing for hypothyroidism:
When a serum TSH level is elevated, the test should be repeated before embarking on long-term thyroid hormone replacement. Certain factors can cause a misleadingly elevated serum TSH that may be mistaken for hypothyroidism: recovery from an illness, acute psychiatric crises, sleep deprivation, and strenuous exercise just before testing. Heroin or amphetamines can also elevate serum TSH.Â Misleadingly elevated serum TSH levels may also be caused by spurious test results resulting from laboratory error or from circulating antibodies that interfere with the TSH antibody assay method or block the TSH receptor.
Misleadingly low serum total T4 levels occur with malnourishment and factors that reduce serum protein levels, such as cirrhosis and nephrotic syndrome. Other conditions that can lower TBG and result in a misleadingly low serum total T4 include anabolic steroid abuse and familial TBG deficiency. Serum free T4 (FT4) levels are normal in these conditions and the FT4 assay is superior to the total T4 assay.
However, misleadingly low serum FT4 levels can also occur and can result from laboratory error or can be seen in severe illness, particularly congestive heart failure. Certain drugs also cause low FT4 levels without hypothyroidism: high-dose corticosteroids (eg, prednisone, dexamethasone), anti-seizure drugs (eg, carbamazepine, phenytoin, phenobarbitol), and therapy with T3 (Cytomel). In these conditions, the serum TSH is not elevated.
Â Other Laboratory Findings in Hypothyroidism:
Certain other laboratory tests can also be abnormal in patients with hypothyroidism: hyponatremia (low serum sodium), elevated liver enzymes, elevated serum prolactin levels, and anemia. High serum lipids are commonly sen: high LDL cholesterol, high triglycerides, and high lipoprotein(a). In patients with autoimmune thyroiditis, serum ANA levels are usually elevated and are nonspecific, i.e., not usually indicating systemic lupus erythematosis.
Treatment of Adults with HypothyroidismÂ
History: Treatment for hypothyroidism first became available in 1892, when sheep’s thyroid was fried and eaten to treat this condition. This was not particularly palatable. In 1900, a thyroid preparation was first introduced in the United States as dessicated (dried) sheepâ€™s thyroid that had been freed from fat, cleaned, dried, and powdered.Â It could be made into tablets whose dosage was measured as weight in an old measurement called grains, where 1 grain (not to me confused with the word gram) is equivalent to 60 milligrams (mg). However, the original desiccated thyroid preparations differed in potency from batch to batch, although it has become more reliable and continues to be available.Â Synthetic thyroxine was developed to be a more reliable thyroid medication and that is the type of thyroid preparation in greatest use today.
Synthetic thyroxine (T4) is thyroid medication that is preferred by most clinicians for treating patients with hypothyroidism. There are several thyroxine formulations and many dosage strengths. Most formulations have accurate amounts of thyroxine in their tablets. However, the bioavalability (absorption) of the different manufacturer’s thyroxine formulations can differ slightly. Therefore, it’s best for hypothyroid patients to be consistent and to take the same brand name of thyroxine or the same manufacturer’s generic thyroxine.
Beginning therapy with thyroxine: There is no mandatory starting dosage of thyroxine.Â Generally, for pregnant women, or patients with severe hypothyroidism, a full replacement dosage of thyroxine is given immediately. For children and otherwise healthy younger adults, near-replacement doses are begun from the outset. However, for older patients with suspected coronary disease, the replacement dosage should be lower and increased as tolerated. If angina occurs, the dosage is reduced until coronary intervention can restore coronary artery perfusion.
Monitoring Treatment of Hypothyroidism:
Serum TSH (thyroid stimulating hormone) levels are used to monitor the adequacy of thyroxine replacement. While receiving optimal thyroxine replacement therapy, most people’s symptoms of hypothyroidism resolve fully. Serum TSH levels are generally kept between 0.4 – 2.0 mcg/dL. Although serum TSH levels are very useful to determine the optimal replacement dosage of thyroxine, it is important not to rely entirely on this test.
Some hypothyroid individuals who receive thyroxine replacement continue to have symptoms typical of hypothyroidism (particularly fatigue), despite having serum levels of TSH and FT4 that are solidly normal. In such cases, it is important to screen for other conditions, such as concurrent illness (eg, anemia, diabetes, hypercalcemia, electrolyte abnormalities, celiac disease, adrenal insufficiency, hypogonadism, depression). Medications can cause fatigue (eg, oral statin drugs for treatment of high cholesterol, oral beta blockers, beta blocker eye drops for glaucoma, etc). In the absence of such conditions, a serum T3 or FT3 can be checked. If the serum T3 or FT3 level is low or low-normal and there are no contraindications (eg, angina, atrial fibrillation), a careful increase in thyroxine replacement is reasonable and may be continued if symptomatic relief is obtained. But if thyroxine is given such that serum TSH levels are suppressed, the serum T3 or FT3 levels should be monitored, keeping them in the lower half of the normal reference range. Careful clinical monitoring is also required for symptoms or signs of hyperthyroidism. Periodic bone mineral densitometry may be followed, thyroid hormone replacement does not cause osteoporosis as long as they are clinically euthyroid (no signs of excess thyroid). Individuals receiving doses of thyroxine that suppress serum TSH below 0.1 mIU/L, as a group, have been found to be at an increased risk for clinical hyperthyroidism (eg, atrial fibrillation), particularly with menopause or withdrawal of oral estrogen therapy.
Since the normal thyroid secretes both T4 and T3, there have been studies comparing T4 to combined T4/T3 thyroid preparations, which have yielded conflicting results. Such combined T4/T3 preparations include Armour Thyroid (desiccated animal thyroid), Nature-Throid, and Liotrix (synthetic, unavailable in USA). The main problem with giving combined T4/T3 preparations is that the T3 component peaks a few hours after taking the pill, with transiently elevated serum T3 levels. Nevertheless, some patients subjectively prefer the T4/T3 preparations. A Dutch double-blind study of 141 hypothyroid individuals found that their patients often preferred the T4/T3 preparation, and during such treatment, the serum TSH levels were often suppressed.
Medications that Interact with Thyroid Hormone Therapy:
Certain medications can interact with thyroid hormone replacement treatment for hypothyroidism. Care must be taken when thyroid hormone is taken with the following medications:
Amiodarone: inhibits conversion of T4 to T3; rely on serum TSH levels.
Antacids (aluminum or calcium): reduces thyroxine intestinal absorption.
Anti-tuberculous antibiotics: increase liver break-down of thyroxine.
Rifampin (Rifadin, Rimactane)
Anti-sex hormone chemotherapy for breast cancer or prostate cancer: Â reduces estrogen and liver TBG production, reducing thyroxine dosage requirement:
Leuprolide (Lupron, Lupron Depot):Â reduces estrogen and liver TBG production, reducing thyroxine dosage requirement:
Anti-seizure medications: increase liver break-down of thyroxine
Chemotherapy: may cause ovarian failure, reducing estrogen levels and liverÂ TBG production, reducing thyroxine dosage requirement.
Cholesterol-lowering bile acid-binding drugs: reduces thyroxine absorption
Didanosine (ddi, Videx anti-HIV therapy): reduces thyroxine absorption
Digoxin (Lanoxin): thyroxine increases thyroxine clearance.
Estrogens (oral): increases liver production of Thyroid Binding Globulin
Oral contraceptives and oral estrogen replacement therapy: increase in hepatic production of thyroid binding globulin (TGB) may increase thyroxine dose requirement.
Imatinib chemotherapy (Gleevec): increases liver metabolism of thyroxine
Iron supplements: reduce thyroxine absorption
Proton Pump Inhibitors (PPIs): may cause atrophic gastritis and reduce the absorption of thyroxine (omeprazole, lansoprazole, pantoprazole, etc)
Raloxifene (Evista): reduces thyroxine absorption
Sucralfate (Carafate): reduces thyroxine absorption
Warfarin (Coumadin): dosage requirement may change (usually drops), due to changes in hepatic metabolism and Â clotting factors caused by thyroxine therapy.
Pregnant Women with Hypothyroidism:
Hypothyroidism is a very common condition and unsuspected maternal hypothyroidism appears to cause a 3.8% increase in miscarriage rate. http://www.ncbi.nlm.nih.gov/pubmed/11126160?ordinalpos=25&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
During pregnancy, the developing baby receives the motherâ€™s thyroid hormones, which cross the placenta.Â The baby is particularly dependent upon maternal thyroid during the first trimester when the fetal thyroid has not fully developed.Â Maternal hypothyroidism can adversely affect the intellectual development of the baby. http://www.ncbi.nlm.nih.gov/pubmed/10451459?ordinalpos=69&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Therefore, screening for hypothyroidism is reasonable for all women who are planning to become pregnant or who have become pregnant. Screening is mandatory for women with symptoms of hypothyroidism (see above) or who have a personal or family history of thyroid or autoimmune disorders. Screening for hypothyroidism is done with a blood test for TSH.
Iodine deficiency is surprisingly common and can cause hypothyroidism during pregnancy. This can be prevented by ensuring adequate dietary iodine with iodized salt and tea or by taking one prenatal multivitamin daily. The multivitamin should contain 150 mcg iodine, the recommended daily requirement during pregnancy. Excessive iodine supplements should be avoided, as this can cause the baby to develop a goiter.
Women with known hypothyroidism should have prenatal thyroid function testing to ensure they are euthyroid (normal thyroid levels) before becoming pregnant. During pregnancy womenâ€™s thyroxine requirements predictably increase by as much as 50%. Therefore, at the diagnosis of pregnancy the dosage of thyroxine is increased empirically by 20-30%. It is prudent to monitor TSH levels every 6 weeks and adjust the thyroxine replacement to ensure that they are doing well clinically and to keep the TSH level below 2.0 mIU/L Following delivery, the thyroxine dosage may be tapered back gradually over several weeks to the prenatal dosage.
Newborns with Hypothyroidism:
About 1 in 3000 newborn infants are born with hypothyroidism, which is known as congenital hypothyroidism. Hypothyroid infants may appear lethargic and have a hoarse cry. They may nurse poorly and have abdominal bloating, constipation, and vomiting.Â They may also have hypothermia, a large posterior fontanelle and neonatal jaundice that persists for more than 3 days. They may develop a large tongue and a bulging around the belly button (omphalocele). However, hypothyroidism is often not clinically recognized at birth, so a mandated screening process tests all newborns for congenital hypothyroidism, usually with blood obtained from a heel stick and absorbed onto filter paper. The blood specimen is sent to a central laboratory to assess for inborn errors of metabolism and for TSH and/or T4. TSH levels fluctuate a great deal during the first few days of life, so there may be false positive and false negative results.
Transiently low T4 levels (with normal TSH) are commonly seen in babies who are not hypothyroid, but who are premature, low birth weight, or who are sick from other causes. Such babies’ low T4 levels usually rise into the normal range after their recovery and there are no adverse sequelae. However, repeat testing is advisable, since permanently low FT4 with low or normal TSH levels can be seen with congenital hypopituitarism, which is rare but must be suspected in babies with an abnormally slow growth.
Low neonatal T4 with a high TSH usually indicates hypothyroidism. About 10% of such babies have temporary hypothyroidism; when this is suspected, at age 3-4 years, thyroxine replacement may be held for 3-4 weeks and the FT4 and TSH repeated to see if they are now normal.
Most babies with hypothyroidism have a permanent condition. The causes of this include an absent thyroid (thyroid aplasia), an underdeveloped thyroid (thyroid hypoplasia), or an abnormally located (ectopic) thyroid under the tongue (lingual thyroid) or on the side of the neck. Congenital hypothyroidism can also be caused by thyroid enzyme defects.
When screening tests (T4 and TSH) indicate hypothyroidism, confirmatory blood tests are drawn immediately and the baby is treated with thyroxine while the test results are pending. Frequent monitoring of the FT4 and TSH levels is important and the FT4 level should be kept in the upper range of normal. Thyroxine may be not be properly absorbed by the intestines of babies who receive concurrent soy formula or iron preparations.
When babies are diagnosed with hypothyroidism by newborn thyroid screening testing and treated with thyroxine, their growth and intellectual development will be entirely normal. However, when congenital hypothyroidism is untreated, the baby’s brain gradually suffers irreversible damage that results in a condition known as cretinism.
Children with Hypothyroidism:
Children who develop hypothyroidism typically have a diminished growth velocity and become shorter relative to peers of their age. The eruption of adult teeth may be delayed. Hypothyroid children may be somewhat overweight but often do not look particularly sick or have physical complaints. When hypothyroidism develops after age 2 years, permanent mental deficiency does not typically occur. In fact, hypothyroid children may sometimes be good students because they lack some of the normal hyperactivity of childhood and pay attention in class. However, with more severe hypothyroidism, children can develop problems with cognitive and attention deficits that may seem like a new learning disability. They may complain of feeling fatigued and cold and may appear depressed and lethargic. Their skin may be dry and they may be constipated. Girls may develop the onset of menstrual periods before age 10 years (precocious puberty) and may have heavy, painful, and irregular periods. These symptoms reverse with treatment of their hypothyroidism.
Thyroxine replacement therapy is given to children with hypothyoidism. Because of their increased metabolic rate, children and adolescents with hypothyroidism often require a higher relative doses (mcg/kg body weight) of thyroxine than do adults. Autonomous adolescents may neglect to take their thyroxine medication regularly and some supervision may be required.