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Hashimoto Thyroiditis

Stephanie L Lee, MD, PhD, Fellow, Association of Clinical Endocrinology; Director of Thyroid Nodule and Cancer Center, Associate Chief, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center; Associate Professor, Department of Medicine, Boston University School of Medicine
Sylvester Odeke, MD, FACE, Clinical Assistant Professor of Medicine, Division of Endocrinology and Metabolism, The Brody School of Medicine at East Carolina University; Steven B Nagelberg, MD, Clinical Professor, Department of Medicine, Division of Endocrinology and Metabolism, Drexel University College of Medicine

Updated: Apr 10, 2009

Introduction

Background

Hashimoto thyroiditis (or Hashimoto's thyroiditis) is part of the spectrum of autoimmune thyroid diseases (AITDs). By strict criteria, it is a histologic diagnosis first described by Hakaru Hashimoto, a Japanese surgeon working in Berlin, Germany. His report was based on the examination of 4 postoperative cases that he published in 1912. He is also credited with introducing the term struma lymphomatosa in reference to the syndrome.

Pathophysiology

Hashimoto's thyroiditis is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. The initiating process is not well understood.1,2,3 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 have also been described and may contribute to further 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's 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. Nevertheless, a small percentage of patients with Hashimoto's thyroiditis (approximately 10-15%) may be antibody negative.

Other antithyroid antibodies found in AITD (including Hashimoto's thyroiditis) include thyroid-stimulating antibody and cytotoxic antibody.

Other variants of AITD include the following conditions:

  • Atrophic thyroiditis
  • Juvenile thyroiditis4
  • Postpartum thyroiditis
  • Silent thyroiditis
  • Focal thyroiditis

Frequency

United States

Hashimoto's 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, 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.

International

Worldwide, the most common cause of hypothyroidism is iodine deficiency. However, Hashimoto's thyroiditis remains the most common cause of spontaneous hypothyroidism in areas of adequate iodine intake. 

The annual incidence of Hashimoto's thyroiditis worldwide is estimated to be 0.3-1.5 cases per 1000 persons.5,6

Mortality/Morbidity

Morbidity related to Hashimoto's 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.

Race

No significant race predilection has been identified for Hashimoto's thyroiditis.

Sex

The incidence of Hashimoto's thyroiditis is estimated to be 10-15 times higher in females.

Age

The most commonly affected age range in Hashimoto's 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.

Clinical

History

  • 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.
  • The most common and 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:
    • Cold intolerance
    • Voice hoarseness and pressure symptoms in the neck from thyroid enlargement
    • Slowed movement and loss of energy
    • Decreased sweating
    • Mild nerve deafness
    • Peripheral neuropathy
    • Menstrual irregularities (typically menorrhagia, infertility, and loss of libido) - Increased prolactin secondary to increased thyrotropin-releasing hormone (TRH) leads to decreased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and to decreased response to gonadotropin-releasing hormone (GnRH). The result is anovulatory cycles with menstrual irregularities.
    • Galactorrhea - This may occur because of the increased prolactin levels.
    • Depression, dementia, and other psychiatric disturbances
    • Memory loss
    • Sleep apnea and daytime somnolence - Obstructive sleep apnea in hypothyroidism is thought to be partly caused by hypofunction of upper airway muscles and weakness of the diaphragm.
    • Joint pains and muscle cramps
    • Hair loss from an autoimmune process directed against the hair follicles

Physical

  • Findings
    • Puffy face and periorbital edema typical of hypothyroid facies
    • Cold, dry skin, which may be rough and scaly - Skin may appear yellow but does not involve the sclera, which distinguishes it from the yellowing of jaundice due to hypercarotenemia.
    • Peripheral edema of hands and feet, typically nonpitting
    • Thickened and brittle nails (may appear ridged)
    • Hair loss involving the scalp, the lateral third of the eyebrows, and possibly skin, genital, and facial hair
    • Bradycardia
    • Elevated blood pressure (typically diastolic hypertension) - Most often, blood pressure is normal or even low.
    • Diminished deep tendon reflexes and the classic prolonged relaxation phase, most notable and initially described at the Achilles tendon (although it may be present in other deep tendon reflexes as well)
    • Macroglossia
    • The thyroid gland is typically enlarged, firm, and rubbery, without any tenderness or bruit. It may be normal in size or not palpable at all.
    • Voice hoarseness
    • Slow speech
    • Impairment in memory function
    • Peripheral neuropathy - This may be a mononeuropathy (as exemplified by carpal tunnel syndrome) or a polyneuropathy resulting from the involvement of several peripheral nerves, manifesting as paresthesia
    • Ataxia from cerebellar dysfunction has been documented in hypothyroidism.

Causes

Causes of primary hypothyroidism include the following: 

  • Postradioactive iodine (I-131) therapy for hyperthyroidism
  • Total or subtotal thyroidectomy
  • Radiation therapy for head and neck cancers and lymphoma - Hypothyroidism from radiation injury to the thyroid usually manifests 2-7 years or more after therapy.
  • Iodine deficiency, which may be attributable to dietary factors or to inefficient iodine conservation due to intrathyroid and peripheral tissue deiodinase enzyme deficiency
  • Congenital disorders of thyroid hormone synthesis
  • Intrathyroid defects (eg, iodide transporter defect, thyroid peroxidase defect, thyroglobulin defect) - Other causes of congenital hypothyroidism include thyroid gland agenesis and dysgenesis.
  • Transient hypothyroid phase of subacute thyroiditis (de Quervain disease)
  • Transient hypothyroid phase of postpartum thyroiditis
  • Infiltrative diseases of the thyroid
    • Progressive systemic sclerosis (scleroderma) can cause hypothyroidism from immune and nonimmune mechanisms. The nonimmune mechanism is due to severe fibrosis involving the thyroid gland.
    • Hemochromatosis in the primary and secondary forms, amyloidosis and sarcoidosis. These conditions may also cause central (secondary) hypothyroidism from pituitary infiltration. Hypothyroidism due to sarcoidosis is rare.
    • Fibrous invasive thyroiditis (Riedel struma) is a disorder of fibrous tissue proliferation affecting multiple organs. Hypothyroidism develops in 30-40% of patients with Riedel struma because of loss of thyroid parenchyma.
  • Iodine excess, iodine-containing medications, and iodine-containing radiographic contrast agents
  • Drugs
    • Antithyroid drugs (eg, propylthiouracil, methimazole, carbimazole)
    • Lithium inhibits thyroidal iodide transport and release of T4 and T3 and may cause hypothyroidism. Lithium may also cause chronic autoimmune thyroiditis with hypothyroidism in 20-40% of patients. Up to 50% of lithium-treated patients may develop a lithium-induced goiter after 2 years of therapy.
    • Amiodarone has a large iodine content, making up nearly 40% of each 200 mg tablet, and can cause hyperthyroidism and hypothyroidism. (It most commonly causes hypothyroidism.) Amiodarone also inhibits peripheral T4-to-T3 conversion; therefore, patients may have an elevated T4 level but remain euthyroid with a normal TSH level.
    • Interferon alpha may induce thyroid autoimmunity in 10-20% of patients. It leads to production of anti-Tg, anti-TPO, and TSH receptor – blocking antibodies. Patients can present with hypothyroidism, hyperthyroidism, or a biphasic thyrotoxicosis-hypothyroidism pattern of silent thyroiditis.7
    • Aminoglutethimide is a rare cause of thyroid goiter and hypothyroidism.
    • Phenytoin, carbamazepine, and rifampin increase the hepatic clearance of levothyroxine by induction of cytochrome P-450 enzymes. This can lead to an increased levothyroxine requirement in patients on replacement therapy. Therapy with any of these medications can also precipitate hypothyroidism in patients with decreased thyroid reserve.
  • Central (secondary or tertiary) hypothyroidism
    • Diseases, surgical procedures, or irradiation of the pituitary gland can cause abnormal TSH secretion. Postpartum necrosis of the pituitary gland (Sheehan syndrome) can also lead to TSH deficiency and cause central hypothyroidism. TSH deficiency may occur in isolation, but it most commonly occurs with other tropic hormone deficiencies, such as corticotropin and gonadotropin deficiencies.
  • Diseases of the hypothalamus (eg, tumorous or granulomatous conditions) and hypothalamic destruction after cranial irradiation can cause TRH deficiency and lead to central hypothyroidism.
    • In central hypothyroidism, the TSH level is most often within the reference range, being immunologically reactive but not biologically active. The diagnosis is usually supported by the presence of symptoms of hypothyroidism, along with a low T4 level in the face of a TSH level that may be low or within the reference range.

Differential Diagnoses

Euthyroid Sick Syndrome
Hypopituitarism (Panhypopituitarism)
Goiter
Polyglandular Autoimmune Syndrome, Type I
Goiter, Diffuse Toxic
Polyglandular Autoimmune Syndrome, Type II
Goiter, Lithium-Induced
Thyroid Lymphoma
Goiter, Nontoxic
Goiter, Toxic Nodular

Other Problems to Be Considered

The following autoimmune phenomena may occur or be found in association with Hashimoto's thyroiditis:

  • Addison disease
  • Alopecia areata, totalis, and universalis
  • Autoimmune gastritis (pernicious anemia)
  • Chronic active hepatitis
  • Idiopathic hypoparathyroidism
  • Polymyalgia rheumatica and giant cell arteritis
  • Primary biliary cirrhosis
  • Primary ovarian or testicular failure
  • Rheumatoid arthritis
  • Sjögren syndrome
  • Systemic lupus erythematosus
  • Systemic sclerosis (scleroderma)
  • Type 1 diabetes mellitus8
  • Vitiligo

Workup

Laboratory Studies

  • 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's thyroiditis and in primary hypothyroidism of 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 of 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 FT4 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's thyroiditis or its variant. However, 10-15% of patients with Hashimoto's thyroiditis may be antibody negative.

Imaging Studies

  • Although features of Hashimoto's 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. 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.
  • Iodine uptake and scan usually are not indicated for the diagnosis of Hashimoto's 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.

Other Tests

  • 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.
    • Complete blood count - 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 deficient vitamin B-12 and folate intake.
    • Total and fractionated lipid profile - Total cholesterol, low-density lipoprotein (LDL), and triglyceride levels may be elevated in hypothyroidism and may be responsive to levothyroxine replacement.
    • Basic metabolic panel - Glomerular filtration rate, renal plasma flow, and renal free water clearance are all decreased in hypothyroidism and may result in hyponatremia.
    • Creatine kinase - Creatine kinase levels, predominantly the MM isoenzyme from skeletal muscle and the aldolase enzyme, are frequently elevated in severe hypothyroidism.
    • Prolactin - 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.
    • Chest radiograph may show small pleural effusions.
    • Electrocardiogram (ECG) may show low-voltage QRS tracing, nonspecific ST-wave changes, and premature ventricular contractions. Prolongation of the QT interval with torsade de pointes and ventricular tachycardia may be noted.
    • Echocardiogram may show some pericardial effusion in severe cases of hypothyroidism.

Procedures

  • Perform fine-needle aspiration of any dominant or suspicious thyroid nodules to exclude malignancy or the presence of a thyroid lymphoma in fast-growing thyroid goiters.9

Histologic Findings

Hashimoto's 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.

Treatment

Medical Care

  • The treatment of choice for Hashimoto's thyroiditis (or hypothyroidism of any cause) is thyroid hormone replacement. The drug of choice is orally administered levothyroxine sodium, usually for life.
    • Tailor and titrate the dose 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 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.
    • 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.10 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.

Surgical Care

  • Indications for surgery
    • A large goiter with obstructive symptoms, such as dysphagia, voice hoarseness, and stridor, caused by extrinsic obstruction of airflow - Evaluate patients with these symptoms with a barium swallow study and pulmonary function tests, including flow volume loops and a neck computed tomography (CT) scan.
    • Presence of a malignant nodule, as found by cytologic examination by fine-needle aspiration.
    • Presence of a lymphoma diagnosed on fine-needle aspiration - Thyroid lymphoma responds very well to radiotherapy and is the treatment modality of choice in this situation.
    • Cosmetic reasons (for large, unsightly goiters)

Consultations

Endocrinologists

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Synthetic thyroid hormones

Used as thyroid hormone replacements.


Levothyroxine sodium (Levoxyl, Synthroid)

Synthetic thyroid hormone (T4). 3,3,5,5-tetraiodothyronine. Available in 12 strengths for easy dose adjustment; 48-79% absorbed when administered orally; absorption higher in fasting state. Normal T4 levels are achieved within 24 h and normal T3 levels within a few days.

Dosing

Adult

1.6-1.8 mcg/kg lean body weight/d PO qd
When PO intake is impractical: 80% of PO dose can be administered IV.
Myxedema coma: Loading dose is 4 mcg/kg lean body weight (usually about 300-600 mcg) by IV push, followed by maintenance dose of 50-100 mcg/d; change IV maintenance dose to PO as soon as possible
Obviously judicious dosing may need to be followed in patients with compromised cardiac function

Pediatric

Children usually require a higher dose, as follows:
0-6 months: Usual dose is 8-10 mcg/kg body weight/d, equivalent to 25-50 mcg/d
6-12 months: 6-8 mcg/kg/d PO (equivalent to 50-75 mcg/d)
1-5 years: 5-6 mcg/kg/d PO (equivalent to 75-100 mcg/d)
6-12 years: 4-5 mcg/kg/d PO (equivalent to 100-150 mcg/d)

Interactions

Cholestyramine may decrease levothyroxine absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when administered with levothyroxine; activity of some beta-blockers may decrease when hypothyroid patient is converted to a euthyroid state

Contraindications

Documented hypersensitivity; uncorrected adrenal insufficiency

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Caution in angina pectoris or cardiovascular disease; monitor thyroid status periodically; caution in patients with adrenocortical insufficiency in whom steroid replacement should precede levothyroxine replacement

Follow-up

Further Outpatient Care

  • 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 sulphate, calcium supplementation, and multivitamins, which have a 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.
    • Yearly thyroid ultrasonographic evaluation is important in patients with Hashimoto's thyroiditis because of the increased risk of thyroid nodules in these patients and for follow-up of patients with existing benign thyroid nodules.

Deterrence/Prevention

  • Although it is not deemed cost-effective to screen whole populations for hypothyroidism, the following groups deserve special consideration and should be evaluated with an annual TSH screening:
    • Elderly patients - Hypothyroidism in elderly patients may be characterized by only a few subtle symptoms, which may include voice hoarseness, confusion, depression, memory changes, and dementia. Up to 15% of patients older than 65 years may have subclinical hypothyroidism or mild thyroid failure, with these individuals feeling better following treatment.
    • Patients with a history of medical or surgical treatment of thyroid disease
    • Patients with diabetes mellitus
    • Patients with other autoimmune disorders
    • Patients with dementia or depression
    • Patients with hypercholesterolemia
    • Patients with a family history of hypothyroidism or hyperthyroidism
    • Patients with Down's syndrome or Turner's syndrome

Complications

  • Complications of overreplacement with levothyroxine sodium
    • Accelerated bone loss, reduction in bone mineral density, and osteoporosis
    • Increased heart rate, increased cardiac wall thickness, and increased contractility - These problems increase the risk of cardiac arrhythmias (especially atrial fibrillation), particularly in the elderly population.
  • 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 and usually in the following settings:
    • Long-standing, undiagnosed hypothyroidism
    • Discontinuation of T4 replacement therapy
    • Failure to institute T4 replacement after radioactive iodine ablation of the thyroid in Graves disease or after total thyroidectomy
  • 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 the patients may require the following:
      • Ventilatory support for hypoventilation and carbon dioxide retention
      • Electrocardiographic monitoring and a Swan-Ganz catheter for hemodynamic monitoring
      • Judicious rewarming to avoid excessive vasodilatation, which would increase oxygen consumption and could lead to worsening of hypotension and vascular collapse
      • Steroids, preferably hydrocortisone in stress doses
      • Levothyroxine, 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 intravenous injection. The daily maintenance dose is 50-100 mcg per day, administered intravenously until the patient can take it orally.
      • Treatment of infection or any other precipitating causes
      • Fluid restriction with or without hypertonic saline and Lasix to promote water diuresis

Prognosis

  • With early diagnosis, timely institution of levothyroxine replacement therapy, informed patient follow-up care, and attention to other attendant complications, the prognosis is excellent and patients lead a normal life.
  • Untreated myxedema coma has a poor prognosis and a high mortality rate.

Patient Education

  • Patients should know that thyroid replacement therapy in Hashimoto's 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 excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

Miscellaneous

Medicolegal Pitfalls

  • Failure to recognize, diagnose, and properly treat Hashimoto's thyroiditis or hypothyroidism from any other cause
  • Failure to provide proper follow-up care
  • Failure to educate patients about their condition

Special Concerns

  • 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:
    • Cholestyramine
    • Ferrous sulfate
    • Sucralfate
    • Calcium carbonate
    • Aluminium hydroxide and other antacids
    • Iron-containing multivitamins
  • Medications that enhance the metabolism and clearance of levothyroxine may necessitate an increase in the replacement dose. These medications include phenytoin, carbamazepine, and rifampin.
  • Pregnancy induces a state of increased need for levothyroxine. In women with hypothyroidism and in women with inadequate thyroid reserve, 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 metabolism of thyroxine by the fetoplacental unit. The increase usually resolves and the patient returns to prepregnancy levothyroxine requirements 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, 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) checked every 8 weeks. Dose adjustments should be made to keep the free T4 and TSH within reference ranges. Patients who are diagnosed with Hashimoto's 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 study from Denmark found that 32% of pregnant women with type 1 diabetes had anti-TPO (compared with 8% of pregnant women who did not have diabetes).11 The presence of anti-TPO was associated with slightly higher TSH levels in these women.
  • 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.
  • Elderly patients and patients on androgens for various reasons usually require decreased levothyroxine replacement dosing.
  • Subclinical hypothyroidism (mild thyroid failure)
    • Up to 15% of patients aged 65 years or older may have subclinical hypothyroidism (as evidenced by an elevated TSH above 3.0 uIU/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 presence of thyroid autoantibodies, namely anti-TPO and antithyroglobulin (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 TSH level and increase in 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.

References

  1. Hadj-Kacem H, Rebuffat S, Mnif-Feki M, et al. Autoimmune thyroid diseases: genetic susceptibility of thyroid-specific genes and thyroid autoantigens contributions. Int J Immunogenet. Apr 2009;36(2):85-96. [Medline].

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Keywords

Hashimoto thyroiditis, Hashimoto’s thyroiditis, thyroid, hypothyroidism, TSH, hypothyroid, levothyroxine, thyroid disease, thyroid problems, goiter, goiters, low thyroid, thyroxine, thyroid hormone, thyroiditis, thyroid treatment, hypothyroidism symptoms, T3 thyroid, T4 thyroid, thyroid disorders, thyroid-stimulating hormone, triiodothyronine, myxedema coma, chronic lymphocytic thyroiditis, struma lymphomatosa, autoimmune thyroid diseases, AITD

Contributor Information and Disclosures

Author

Stephanie L Lee, MD, PhD, Fellow, Association of Clinical Endocrinology; Director of Thyroid Nodule and Cancer Center, Associate Chief, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center; Associate Professor, Department of Medicine, Boston University School of Medicine
Stephanie L Lee, MD, PhD is a member of the following medical societies: American College of Endocrinology, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Sylvester Odeke, MD, FACE, Clinical Assistant Professor of Medicine, Division of Endocrinology and Metabolism, The Brody School of Medicine at East Carolina University
Sylvester Odeke, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, and North Carolina Medical Society
Disclosure: Nothing to disclose.

Steven B Nagelberg, MD, Clinical Professor, Department of Medicine, Division of Endocrinology and Metabolism, Drexel University College of Medicine
Steven B Nagelberg, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Medical Association, Endocrine Society, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Ghassem Pourmotabbed, MD†, Former Associate Professor, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Tennessee School of Medicine and Health Science Center
Ghassem Pourmotabbed, MD† is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Further Reading

Clinical guidelines:
 American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi: Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules.
Screening for thyroid disease: recommendation statement.
Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

Clinical trials:
 Generic vs. Name-Brand Levothyroxine
Maternal Hypothyroidism in Pregnancy
Thyroid Cancer Collaborative Registry of Patients With Thyroid Cancer and/or Thyroid Nodules

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