Hashimoto thyroiditis is part of the spectrum of autoimmune thyroid diseases (AITDs) and is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. This condition is the most common cause of hypothyroidism in the United States in individuals older than 6 years.[1] The treatment of choice for Hashimoto thyroiditis (or hypothyroidism from any cause) is thyroid hormone replacement. The drug of choice is orally administered levothyroxine sodium, usually for life.
Hypothyroidism typically has an insidious onset with subtle signs and symptoms that may progress to more advanced or even florid signs and symptoms over months to years. The presentation of patients with hypothyroidism may also be subclinical, diagnosed based on routine screening of thyroid function. Such patients may have nonspecific symptoms that are difficult to attribute to thyroid dysfunction. They frequently do not improve with thyroid hormone supplementation..
Early nonspecific symptoms may include the following:
More advanced/florid symptoms may include the following:
See Autoimmune Disorders: Making Sense of Nonspecific Symptoms, a Critical Images slideshow, to help identify several diseases that can cause a variety of nonspecific symptoms.
See Clinical Presentation for more detail.
Physical findings are variable and depend on the extent of the hypothyroidism and other factors, such as age. Examination findings may include the following:
Testing
Laboratory studies and potential results for patients with suspected Hashimoto thyroiditis include the following:
The following tests are not necessary for the diagnosis of primary hypothyroidism but may be used to evaluate complications of hypothyroidism in some patients, as indicated:
Imaging tests
Features of Hashimoto thyroiditis are usually identifiable on an ultrasonogram; however, a thyroid ultrasonogram is usually not necessary for diagnosing the condition. This imaging modality is useful for assessing thyroid size, echotexture, and, most importantly, whether thyroid nodules are present.
Chest radiography and echocardiography are not usually performed and are not necessary in routine diagnosis or evaluation of hypothyroid patients.
Procedures
Hashimoto thyroiditis is a histologic diagnosis. Therefore, perform fine-needle aspiration of any dominant or suspicious thyroid nodules to exclude malignancy or the presence of a thyroid lymphoma in fast-growing goiters.[2]
See Workup for more detail.
Pharmacotherapy
The treatment of choice for Hashimoto thyroiditis (or hypothyroidism from any cause) is thyroid hormone replacement. The drug of choice is individually tailored and titrated levothyroxine sodium administered orally, usually for life.
Surgery
Indications for surgery include the following:
See Treatment and Medication for more detail.
Hashimoto thyroiditis (or Hashimoto’s thyroiditis) is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. It is the most common cause of hypothyroidism in the United States after age 6 years. Hashimoto thyroiditis is part of the spectrum of autoimmune thyroid diseases (AITDs).[1] (See Etiology, Presentation, and Workup.)
By strict criteria, Hashimoto thyroiditis is a histologic diagnosis first described by Hakaru Hashimoto, a Japanese surgeon working in Berlin, Germany. His report, published in 1912, was based on the examination of 4 postoperative cases. He is also credited with introducing the term struma lymphomatosa in reference to the syndrome.
Other variants of AITD include the following conditions:
The initiating process in Hashimoto thyroiditis is not well understood.[4, 5, 6, 7] The thyroid gland is typically goitrous but may be atrophic or normal in size. Antibodies binding to and blocking the thyroid-stimulating hormone (TSH) receptor, thyrotropin receptor blocking antibodies (TBII) have also been described and may contribute to impairment in thyroid function. The result is inadequate thyroid hormone production and secretion, although initially, preformed thyroxine (T4) and triiodothyronine (T3) may "leak" into the circulation from damaged cells.
Patients with Hashimoto thyroiditis have antibodies to various thyroid antigens, the most frequently detected of which include anti-thyroid peroxidase (anti-TPO), antithyroglobulin (anti-Tg), and to a lesser extent, TSH receptor-blocking antibodies (TBII). Nevertheless, a small percentage of patients with Hashimoto thyroiditis (approximately 10-15%) may be serum antibody negative.
Other antithyroid antibodies found in AITD (including Hashimoto thyroiditis) include thyroid-stimulating antibody and cytotoxic antibody.
Hashimoto thyroiditis has a markedly higher clustering of other autoimmune diseases, including pernicious anemia, adrenal insufficiency, celiac disease, and type 1 diabetes mellitus.[8, 9] A study by Ruggeri et al of patients with Hashimoto thyroiditis indicated that the disease is associated with different nonthyroidal autoimmune diseases (NTADs) at different ages. Associated NTADs were significantly more prevalent in adults than children/adolescents in the study, and more adults than children/adolescents suffered from two or more associated NTADs, with the frequency of arthropathies and connective tissue diseases being greater in adults and the frequency of type 1 diabetes and celiac disease being higher in children/adolescents.[10]
A study by Mazokopakis et al indicated that an association may exist between vitamin D deficiency and the development of Hashimoto thyroiditis. The study, which included 218 patients with Hashimoto thyroiditis, found serum 25-hydroxy vitamin D levels to be negatively correlated with anti-TPO levels in all patients, with the anti-TPO levels being significantly greater in the 186 patients who were vitamin D deficient. After receiving oral vitamin D3 supplementation of 1200-4000 IU daily for 4 months, serum anti-TPO levels in the vitamin D deficient patients were determined to be significantly reduced.[11, 12]
In a study of 830 patients with Hashimoto thyroiditis, Tagami et al reported slight, but significant, increases in TSH serum levels and decreases in free T4 serum levels, with increasing patient age. In addition, TSH levels were positively correlated with levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and non-HDL, as well as with the ratio of LDL to HDL. Free T4 levels, on the other hand, were negatively correlated with these lipid parameters.[13]
A study by Bothra et al reported that, compared with the general population, first-degree relatives of persons with Hashimoto thyroiditis have a nine-fold greater risk of developing the disease.[14]
Hashimoto thyroiditis is the most common cause of hypothyroidism in the United States after age 6 years, with the incidence estimated to be 1.3% in a series of 5000 children aged 11-18 years. In adults, the incidence is estimated to be 3.5 per 1000 per year in women and 0.8 per 1000 per year in men. Incidence may be as high as 6% in the Appalachian region.
In the Colorado Thyroid Disease Prevalence Study, involving 25,862 adults, the prevalence of elevated TSH in symptomatic and asymptomatic adults was 9.5%, with a greater percentage of those involved being women. The prevalence of hypothyroidism and of thyroid disease in general increases with age.
Worldwide, the most common cause of hypothyroidism is iodine deficiency. However, Hashimoto thyroiditis remains the most common cause of spontaneous hypothyroidism in areas of adequate iodine intake. The annual incidence of Hashimoto thyroiditis worldwide is estimated to be 0.3-1.5 cases per 1000 persons.[15, 16, 12]
The incidence of Hashimoto thyroiditis is estimated to be 10-15 times higher in females. The most commonly affected age range in Hashimoto thyroiditis is 30-50 years, with the peak incidence in men occurring 10-15 years later. The overall incidence of hypothyroidism increases with age in men and women.
With early diagnosis, timely institution of levothyroxine replacement therapy, informed patient follow-up care, and attention to other attendant complications, the prognosis in Hashimoto thyroiditis is excellent, with patients leading a normal life. Untreated myxedema coma has a poor prognosis and a high mortality rate.
Morbidity related to Hashimoto thyroiditis typically results from failure to make the diagnosis of hypothyroidism or to institute L-thyroxine replacement therapy in adequate doses, or from failure on the part of the patient to take the replacement medication.
The increased prevalence of lipid disorders in association with untreated hypothyroidism has the potential to increase morbidity from coronary artery disease.
The risk for papillary thyroid carcinoma is increased in patients with Hashimoto thyroiditis.[17, 18, 19] (Indeed, a prospective study by Silva de Morais et al indicated that any patient with Hashimoto thyroiditis presenting for thyroid nodule evaluation has a greater risk of malignancy than do patients without Hashimoto thyroiditis who present with nodules [23.3% vs 15.9%, respectively].)[20] These cancers are not clearly more aggressive than other papillary thyroid carcinomas. In fact, a study by Liang et al suggested that in patients with papillary thyroid carcinoma, those with concurrent Hashimoto thyroiditis have a better prognosis than do patients without it. Subjects with both papillary thyroid carcinoma and Hashimoto thyroiditis tended to have a smaller tumor size, a less advanced TNM stage, and a decreased lymph node metastasis rate.[21]
A study by Kahaly et al indicated that a strong link exists between the presence of TSH receptor-stimulating antibodies (TSAbs) in patients with Hashimoto thyroiditis and the development of thyroid-associated orbitopathy (TAO). The study, which included 700 patients with Hashimoto thyroiditis, found higher serum levels of TSAbs in those with TAO than in those without this condition, while patients with active and severe TAO had higher TSAb levels than did patients with mild and inactive TAO. Healthy controls were negative for TSAbs.[22]
Complications of overreplacement with levothyroxine sodium Include the following:
The last three problems above increase the risk of cardiac arrhythmias (especially atrial fibrillation), particularly in the elderly population.
Patients should know that thyroid replacement therapy in Hashimoto thyroiditis is, except in very rare cases, lifelong. Patients must be informed about the importance of compliance with their replacement therapy and must be instructed to report any symptoms suggestive of hyperthyroidism caused by overreplacement.
Patients must be instructed to separate—by at least 4 hours—ingestion of levothyroxine from ingestion of cholestyramine, ferrous sulfate, sucralfate, calcium carbonate, aluminum hydroxide (and other antacids), and iron-containing multivitamins, all of which impair the absorption of levothyroxine.
For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems.
Hypothyroidism is usually insidious in onset, with signs and symptoms slowly progressing over months to years. Most commonly, patients do not relate a history suggestive of transient hyperthyroidism secondary to increased T4 and T3 levels resulting from thyrocyte destruction. The time course is influenced by the rapidity of onset and the severity of the clinical state of hypothyroidism. The history may be suggestive of other autoimmune associations.
The presentation of patients with hypothyroidism may be subclinical, without any symptoms, and may be found simply from routine screening of thyroid function. The usual finding is an elevated TSH level. The early compensatory increase in TSH tends to maintain a nearly normal thyroid function and keeps the patient in a euthyroid state.
Patients most commonly present with nonspecific symptoms suggestive of overt hypothyroidism. Patients with long-standing, severe hypothyroidism could present in myxedema coma, precipitated by some major stress or infection.
Common, early presenting symptoms of hypothyroidism, such as fatigue, constipation, dry skin, and weight gain, are nonspecific. Weight gain due to hypothyroidism is usually no greater than 10% of the baseline euthyroid weight and is mostly attributable to fluid accumulation in interstitial tissues.
Other symptoms of hypothyroidism include the following:
Physical findings are variable and depend on the extent of hypothyroidism and other factors such as age. Findings include the following:
Up to 15% of patients aged 65 years or older may have subclinical hypothyroidism (mild thyroid failure, as evidenced by an elevated TSH above 4.0 μ IU/mL and normal free T4 levels), with few if any symptoms suggestive of hypothyroidism. These patients have a decreased thyroid reserve.
The best marker of progression to overt hypothyroidism is a combination of an elevated TSH level with the presence of thyroid autoantibodies, namely anti-TPO and anti-Tg antibodies. The rate of progression to overt hypothyroidism is estimated to be about 5% per year.
Patients with positive thyroid autoantibodies but a normal TSH level should be followed up periodically to monitor for symptoms of hypothyroidism and to detect any rise in their TSH or cholesterol levels. Checks can usually be performed every 6-12 months. These patients should be treated if the TSH level continues to rise, even if the level is at the upper limit of the reference range.
Iodine uptake and scan usually are not indicated for the diagnosis of Hashimoto thyroiditis. The usefulness of radioactive iodine and scan is in classifying a nodule as either hot or cold. A cold thyroid nodule would indicate a higher risk for malignancy and therefore a need for fine-needle aspiration.
Perform fine-needle aspiration of any dominant or suspicious thyroid nodules to exclude malignancy or the presence of a thyroid lymphoma in fast-growing goiters.[2]
A literature review by Travaglino et al found that with regard to evidence of the presence of Hashimoto thyroiditis, the pooled prevalence was 78.9% in patients with primary thyroid lymphoma. A significantly higher prevalence of Hashimoto thyroiditis was found in patients with mucosa-associated lymphoid tissue (MALT) lymphoma or with mixed MALT/diffuse large B-cell lymphoma (DLBCL) than in those with DLBCL alone.[25]
Hashimoto thyroiditis is a histologic diagnosis. Typically, the thyroid gland shows diffuse lymphocytic and plasma cell infiltration with formation of lymphoid follicles from follicular hyperplasia and damage to the follicular basement membrane. Atrophy of the thyroid parenchyma is usually evident. Correlation with the presence of thyroid autoantibodies, namely anti-TPO and anti-Tg, is helpful in confirming the diagnosis.
In the presence of suggestive symptoms and physical findings, a serum TSH test is needed for the diagnosis of primary hypothyroidism, and it serves to assess the functional status of the thyroid.
This is a sensitive test of thyroid function; levels are invariably raised in hypothyroidism due to Hashimoto thyroiditis and in primary hypothyroidism from any cause.
The TSH level is also elevated in subclinical hypothyroidism and is usually the initial laboratory abnormality detected as the pituitary gland attempts to increase thyroid hormone production from the failing thyroid gland. The total T4 or free T4 usually remain within reference ranges in subclinical hypothyroidism. The TSH level may also be elevated in the recovery phase of euthyroid sick syndrome.
In the outpatient setting, when there is no cause to suspect hypothalamic or pituitary disease and in the absence of nonthyroidal illness and of medications that suppress TSH production in the inpatient setting, a normal TSH level excludes primary hypothyroidism from any cause.
Medications that suppress TSH production include steroids, dopamine, dobutamine, and octreotide.
A free T4 is usually needed to correctly interpret the TSH in some clinical settings. A low total T4 or free T4 level in the presence of an elevated TSH level further confirms the diagnosis of primary hypothyroidism.
When a total T4 study, rather than a free T4 study, is performed, a T3 resin uptake helps to correct the total T4 and T3 values for protein binding, especially thyroid hormone–binding globulin (TBG) abnormalities, but the free T4 is typically the test of choice.
When the serum TSH and the free T4 levels are low in the outpatient setting, the case for central hypothyroidism is strengthened. However, in the acutely ill patient, nonthyroidal illness (euthyroid sick syndrome) is the more likely possibility. The TSH level cannot be reliably used in some clinical settings to distinguish central hypothyroidism from nonthyroidal illness. Physical findings suggestive of thyroid disease, as well as the presence of obvious or subtle clinical features of hypothyroidism, become pivotal in establishing the correct diagnosis.
A low T3 level and a high reverse T3 level may be of additional help in the diagnosis of nonthyroidal illness.
T3 levels are most often maintained within reference ranges (even in the very late stages of hypothyroidism), and T3 measurement has little value in the diagnosis of hypothyroidism. Furthermore, T3 levels may be low in up to 70% of hospitalized patients without hypothyroidism or any thyroid disease, as is the case with nonthyroidal illness.
The presence of thyroid autoantibodies, typically anti-TPO and also anti-Tg antibodies, delineates the cause of hypothyroidism as Hashimoto thyroiditis or its variant. However, 10-15% of patients with Hashimoto thyroiditis may be antibody negative.
Although features of Hashimoto thyroiditis are usually identifiable on an ultrasonogram, a thyroid ultrasonogram is usually not necessary for diagnosing the condition. However, it is useful for assessing thyroid size, echotexture, and, most importantly, whether thyroid nodules are present.[26] Ultrasonographic study aids in confirming the presence of a thyroid nodule, in defining a nodule as solid or cystic, and in defining features suggestive of malignancy, such as irregular margins, a poorly defined halo, microcalcification, and increased vascularity on Doppler interrogation.
Ultrasonography is useful in facilitating fine-needle aspiration of nodules in general and, in particular, small or poorly defined nodules when indicated and in patients with distorted neck anatomy. A definite diagnosis of benign versus malignant thyroid lesion can be confirmed only by cytologic or histologic examination of thyroid tissue.
The following tests are not necessary for the diagnosis of primary hypothyroidism but may be performed to evaluate complications of hypothyroidism in some patients, when clearly indicated.
Up to 30-40% of patients with hypothyroidism have anemia, usually from decreased erythropoiesis. In 15% of patients, the anemia is of the iron deficiency type, with microcytosis and hypochromia. Although this can be a normocytic normochromic anemia, the most common morphologic abnormality is a macrocytic anemia that may be partially due to insufficient vitamin B-12 and folate intake.
Total cholesterol, LDL, and triglyceride levels may be elevated in hypothyroidism and may be responsive to levothyroxine replacement.
Glomerular filtration rate, renal plasma flow, and renal free water clearance are all decreased in hypothyroidism and may result in hyponatremia.
Creatine kinase levels, predominantly the MM isoenzyme from skeletal muscle and the aldolase enzyme, are frequently elevated in severe hypothyroidism.
Prolactin may be elevated in primary hypothyroidism. This is thought to be caused by overlap secretion due to stimulation of the lactotroph by the elevated TRH level. The decreased clearance of prolactin in hypothyroidism may also play a contributory role. The elevated prolactin level leads to decreased gonadotropin secretion and decreased responsiveness to GnRH. The result of this is anovulatory cycles with menstrual abnormalities, galactorrhea, and infertility in some patients.
Other studies may be performed in the evaluation of complications of primary hypothyroidism (when indicated). These tests are usually not performed and are not necessary in routine diagnosis or evaluation of hypothyroid patients.
The treatment of choice for Hashimoto thyroiditis (or hypothyroidism from any cause) is thyroid hormone replacement. The drug of choice is orally administered levothyroxine sodium, usually for life.
Tailor and titrate the dose of levothyroxine sodium to meet the individual patient's requirements. The goal of therapy is to restore a clinically and biochemically euthyroid state. The standard dose is 1.6-1.8 mcg/kg lean body weight per day, but the dose is patient dependent. The free T4 and TSH levels are within reference ranges in the biochemically euthyroid state, with the TSH level in the lower half of the reference range.
Patients younger than 50 years who have no history or evidence of cardiac disease can usually be started on full replacement doses.
Start patients older than age 50 years and younger patients with cardiac disease on a low dose of 25 mcg (0.025 mg) per day, with clinical and biochemical reevaluation in 6-8 weeks. Carefully titrate the dose upward to achieve a clinical and biochemical euthyroid state. Rarely, it may not be possible to achieve a euthyroid state in a patient with baseline cardiac dysrhythmic disease without worsening his or her cardiac status. In such cases, the astute clinician is content to achieve the clinically euthyroid state and to accept a slightly elevated TSH level.
Elderly patients usually require a smaller replacement dose of levothyroxine, sometimes less than 1 mcg/kg lean body weight per day.
Elderly patients and patients on androgens for various reasons usually require decreased levothyroxine replacement dosing.
Patients who have undergone bowel resection and have short-bowel syndrome (or malabsorption for any reason) often require increased doses of levothyroxine to maintain the euthyroid state.
In their previously described study of 830 patients with Hashimoto thyroiditis, Tagami et al found that, following treatment with small doses of levothyroxine in 32 of the study's patients with subclinical hypothyroidism, significant decreases occurred in the patients' total cholesterol, LDL, and non-HDL levels, as well as in their LDL/HDL ratios.[13]
One popular treatment, more so among patients than physicians, is the combined use of liothyronine (T3) and levothyroxine in an effort to mimic more closely thyroid hormone physiology. However, a literature review found that out of 9 controlled clinical trials, only 1 indicated that combined therapy seemed to improve the mood, quality of life, and psychometric performance of patients more than did levothyroxine alone.[27]
Until investigators can demonstrate a definite advantage to the administration of levothyroxine plus liothyronine, the use of levothyroxine alone should remain the treatment of choice for replacement therapy in hypothyroidism.
Consultation with an endocrinologist is recommended
Pregnancy induces a state of increased need for levothyroxine. In women with hypothyroidism and in women with inadequate thyroid reserve from Hashimoto thyroiditis or partial thyroidectomy, this is manifested by an increase in the level of TSH and a decrease in the level of free T4.
The increase in the levothyroxine requirement is thought to be due to increased levels of thyroid hormone–binding protein, increased use by the fetus, and increased metabolism of thyroxine by the fetoplacental unit. The increase usually resolves and levothyroxine requirements return to prepregnancy levels 6-8 weeks postpartum.
Note that total T4 and T3 levels may actually be increased in pregnancy. This phenomenon is thought to be due to the estrogen-induced sialylation (increased sialic acid content) of the thyroxine-binding globulin (TBG). This leads to decreased clearance of the TBG by the liver and to increased levels and binding capacity of the TBG. Increased TBG synthesis is also thought to play a contributory role. The pregnancy-induced increased need for T4 occurs in the first trimester, usually within the first 8 weeks, and persists throughout pregnancy. Patients with hypothyroidism may require up to a 45-50% increase in the levothyroxine dose.
Patients with hypothyroidism are best followed up by monitoring the TSH and free T4 levels. Upon becoming pregnant, patients should have the TSH and free T4 levels checked within 4-8 weeks and then every 6-8 weeks while dose adjustments are being made. Patients who are adequately dosed and who are in a clinically and biochemically euthyroid state should have thyroid function tests (TSH and free T4) every 8 weeks. Dose adjustments should be made to keep the free T4 and TSH within reference ranges.
Patients who are diagnosed with Hashimoto thyroiditis or hypothyroidism from any cause during pregnancy should be started on a levothyroxine dose close to their replacement requirement, and the TSH level should be normalized as soon as possible. Untreated hypothyroidism carries increased maternal and fetal complications.
A transient reduction in serum TSH levels occurs toward the end of the first trimester, owing to high circulating levels of human chorionic gonadotropin (hCG); this phenomenon is often confused with hyperthyroidism.
The incidence of fetal loss is increased in patients who are TPO antibody positive.
Myxedema coma is a state of extreme hypothyroidism with a very high mortality rate (approaching 60%). Patients with this condition usually present with an acute precipitating condition, most often in the following settings:
Myxedema coma typically manifests in winter (or during extremely cold weather) in an elderly woman who has long-standing hypothyroidism. Hospitalized patients may have a history of sedating medication use. Typical clinical findings include hypothermia, obtundation or coma, hypoventilation, bradycardia, hyponatremia, hypoglycemia, and hypotension. Besides having an elevated TSH level, these patients may have undetectable free T4 levels.
The usual precipitating causes include infection, cardiovascular accident, pulmonary infection, congestive cardiac failure, and drugs, such as narcotics, sedatives, anesthetic agents, antidepressants, and tranquilizers (all of which depress the respiratory drive).
Therapy should be conducted in an acute care unit, where patients may require the following:
Levothyroxine is administered intravenously in a loading dose of 4 mcg/kg of lean body weight; this is about 300-600 mcg, which should be administered by rapid IV injection. The daily maintenance dose is 50-100 mcg/d, administered intravenously until the patient can take it orally.
Indications for surgery include the following:
Upon the initiation of the levothyroxine replacement therapy, check thyroid function tests, specifically TSH, initially every 6-8 weeks as dose adjustments are made. After the attainment of the clinical euthyroid state and a normal TSH level, patients and the TSH levels may be checked every 6-12 months.
More frequent follow-up and TSH checks may need to be performed when patients start taking medications, such as ferrous sulfate, calcium supplementation, and multivitamins, that have the potential to impair the absorption of levothyroxine and therefore to affect the TSH level. Patients need to be advised to separate these medications from levothyroxine by at least 4 hours.
Follow-up care should include clinical evaluation for symptoms of hypothyroidism or iatrogenic hyperthyroidism.
Physical examination should routinely include weight measurement, pulse and blood pressure determinations, and thyroid examination for the presence of nodules.
As previously discussed, the treatment of choice for Hashimoto thyroiditis (or hypothyroidism from any cause) is thyroid hormone replacement. The drug of choice is orally administered levothyroxine sodium, usually for life.
Tailor and titrate the dose of levothyroxine sodium to meet the individual patient's requirements. The goal of therapy is to restore a clinically and biochemically euthyroid state.
The following medications interfere with the absorption of levothyroxine from the gastrointestinal tract, and patients should be advised to separate ingestion of these compounds from ingestion of levothyroxine by at least 4 hours:
Medications that enhance the metabolism and clearance of levothyroxine may necessitate an increase in the replacement dose. These medications include phenytoin, carbamazepine, and rifampin.
Clinical Context: This is a synthetic thyroid hormone (T4). It is available in 12 strengths for easy dose adjustment. Absorption of levothyroxine sodium is 48-79% when it is administered orally; absorption is higher in persons in a fasting state. Normal T4 levels are achieved within 24 hours and normal T3 levels are reached within a few days. Thyroid hormone is involved in normal metabolism, growth, and development.