Hyperthyroidism 

  • Author: Stephanie L Lee, MD, PhD; Chief Editor: George T Griffing, MD   more...
 
Updated: Oct 27, 2011
 

Background

Hyperthyroidism includes diseases that are a subset of thyrotoxicosis that are caused by excess synthesis and secretion of thyroid hormone by the thyroid. These diseases are not associated with exogenous thyroid hormone intake or subacute thyroiditis. (See Etiology.)

Thyrotoxicosis is the hypermetabolic condition associated with elevated levels of free thyroxine (FT4) and/or free triiodothyronine (FT3). Most clinicians, exclusive of endocrinologists, use the terms hyperthyroidism and thyrotoxicosis interchangeably. This article discusses the causes of thyrotoxicosis associated with hyperthyroidism (excess synthesis and release of thyroid hormone) and the surreptitious use of thyroid hormone. (See also Subacute Thyroiditis.)

The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma. Together with subacute thyroiditis, these conditions constitute 85-90% of all causes of thyrotoxicosis. Table 1 contains a list of hyperthyroid conditions associated with thyrotoxicosis. For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems. (See Etiology, Clinical, Treatment, and Medications.)

Table 1. Common, Less Common, and Uncommon Forms of Thyrotoxicosis and Hyperthyroidism (Open Table in a new window)

Common Forms (85-90% of cases)Radioactive iodine uptake over neck
Diffuse toxic goiter (Graves disease)Increased
Toxic multinodular goiter (Plummer disease)Increased
Thyrotoxic phase of subacute thyroiditisDecreased
Toxic adenomaIncreased
Less Common Forms
Iodide-induced thyrotoxicosisVariable
Thyrotoxicosis factitiaDecreased
Uncommon Forms
Pituitary tumors producing thyroid-stimulating hormoneIncreased
Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma)Increased
Pituitary resistance to thyroid hormoneIncreased
Metastatic thyroid carcinomaDecreased
Struma ovarii with thyrotoxicosisDecreased
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Pathophysiology

The hypermetabolic effect of thyrotoxicosis affects every organ system. The pituitary gland stimulates the thyroid to make thyroid hormone, which is released into the circulation to reach every cell in the body. Thyroid hormone is necessary for normal growth and development, and it regulates cellular metabolism. Excess thyroid hormone causes an increase in the metabolic rate that is associated with increased total body heat production and cardiovascular activity (increased heart contractility, heart rate, vasodilation).

Ophthalmopathy

The pathogenesis of Graves ophthalmopathy lies in the deposition of glycosaminoglycans (GAG) in the extraocular muscles and adipose and connective tissue of the retro-orbit, leading to T-cell activation. The TSH receptor antigen is thought to be a key mediator in the process of T-cell activation. Cigarette smoking is a significant risk factor for ophthalmopathy, increasing the odds of it approximately 7-fold. Patients who are treated with radioactive iodine are more likely to experience worsening of their ophthalmopathy than are patients treated with antithyroid medications or surgery. (See the image below.)

Severe proptosis and eyelid retraction from thyroiSevere proptosis and eyelid retraction from thyroid-related orbitopathy. This patient also had optic nerve dysfunction from thyroid related orbitopathy.
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Etiology

Genetics appears to influence the incidence of thyrotoxicosis. Observing autoimmune thyroid disease, including Hashimoto hypothyroidism and Graves disease, in multiple members of a patient's family is common.

Autoimmune thyroid disease has a higher prevalence in patients with human leukocyte antigen (HLA)-DRw3 and HLA-B89. Graves disease is felt to be an HLA-related, organ-specific defect in suppressor T-lymphocyte function. Similarly, subacute painful or granulomatous thyroiditis occurs more frequently in patients with HLA-Bw35. Similar to other immune diseases, these thyroid conditions occur more frequently in women than in men.

Iodine intake also appears to influence the occurrence of thyrotoxicosis. Clearly, patients in borderline iodine-deficient areas of the world develop nodular goiter, often with areas of autonomy. When this population is moved to areas of sufficient iodine intake, thyrotoxicosis occurs. Evidence that iodine can act as an immune stimulator exists, precipitating autoimmune thyroid disease and acting as a substrate for additional thyroid hormone synthesis.

Graves disease

The most common cause of thyrotoxicosis is Graves disease (50-60% of cases). Graves disease is an organ-specific autoimmune disorder characterized by a variety of circulating antibodies, including common autoimmune antibodies, as well as anti ̶ thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibodies.

The most important autoantibody is thyroid-stimulating immunoglobulin (TSI). TSI is directed toward epitopes of the thyroid-stimulating hormone (TSH) receptor and acts as a TSH-receptor agonist. Similar to TSH, TSI binds to the TSH receptor on the thyroid follicular cells to activate thyroid hormone synthesis and release and thyroid growth (hypertrophy). This results in the characteristic picture of Graves thyrotoxicosis, with a diffusely enlarged thyroid, very high radioactive iodine uptake, and excessive thyroid hormone levels compared with a healthy thyroid. (See the images below.)

Color flow ultrasonogram in a patient with Graves Color flow ultrasonogram in a patient with Graves disease. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope. Iodine 123 (123I) nuclear scintigraphy: 123I scansIodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

Thyroid hormone levels can be extremely elevated in this condition. Clinical findings specific to Graves disease include thyroid ophthalmopathy (periorbital edema, chemosis [conjunctival edema], injection, proptosis) and, rarely, dermopathy over the lower extremities. This autoimmune condition may be associated with other autoimmune diseases, such as pernicious anemia, myasthenia gravis, vitiligo, adrenal insufficiency, and type 1 diabetes mellitus.

Subacute thyroiditis

The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 15-20% of cases), a destructive release of preformed thyroid hormone. A typical nuclear scintigraphy scan shows no radioactive iodine uptake in the thyrotoxic phase of the disease. (See the images below.) Thyroid hormone levels can be extremely elevated in this condition.

Absence of iodine 123 (123I) radioactive iodine upAbsence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis. Three multinuclear giant cell granulomas observed Three multinuclear giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis.

Toxic multinodular goiter

Toxic multinodular goiter (Plummer disease) occurs in 15-20% of patients with thyrotoxicosis. It occurs more commonly in elderly individuals, especially in patients with a long-standing goiter. Thyroid hormone excess develops very slowly over time and often is only mildly elevated at the time of diagnosis.

As discussed below, very high thyroid hormone levels may occur in this condition after high iodine intake, ie, with contrast or amiodarone exposure. Symptoms of thyrotoxicosis are mild, often because only a slight elevation of thyroid hormone levels is present, and the signs and symptoms of thyrotoxicosis often are blunted (apathetic hyperthyroidism) in older patients. (See the image below.)

Scan in a patient with a toxic multinodular goiterScan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake.

Toxic adenoma

Toxic adenoma is caused by a single hyperfunctioning follicular thyroid adenoma. Patients with a toxic thyroid adenoma account for approximately 3-5% of patients who are thyrotoxic. The excess secretion of thyroid hormone occurs from a benign monoclonal tumor that usually is larger than 2.5 cm in diameter. The excess thyroid hormone suppresses TSH levels. Radioactive iodine uptake usually is normal, and the radioactive iodine scan shows only the hot nodule, with the remainder of the normal thyroid gland suppressed because the TSH level is low.

Other causes of thyrotoxicosis

Several rare causes of thyrotoxicosis exist that deserve mention. Struma ovarii is ectopic thyroid tissue associated with dermoid tumors or ovarian teratomas that can secrete excessive amounts of thyroid hormone and produce thyrotoxicosis.[1]

Iodide-induced thyrotoxicosis (Jod-Basedow syndrome) occurs in patients with excessive iodine intake, such as after an iodinated radiocontrast study. It also occurs in patients with areas of thyroid autonomy, such as a multinodular goiter or autonomous nodule. The thyrotoxicosis appears to be a result of loss of the normal adaptation of the thyroid to iodide excess. It is treated with cessation of the excess iodine intake and with administration of antithyroid medication. Usually, after depletion of the excess iodine, thyroid functions return to preexposure levels.

Patients with a molar hydatidiform pregnancy or choriocarcinoma have extremely high levels of beta human chorionic gonadotropin (β-hCG), which can weakly activate the TSH receptor. At very high levels of β-hCG, activation of the TSH receptors is sufficient to cause thyrotoxicosis. Physiologic maximum elevation of β-hCG at the end of the first trimester of pregnancy is associated with a mirror-image temporary reduction in TSH. Despite the reduction in TSH, the FT4 levels usually remain normal or only slightly above the reference range. As the pregnancy progresses and the β-hCG plateaus at a lower level, TSH levels decrease back to normal levels.

In cases of metastatic follicular thyroid carcinoma, the lesions maintain the ability to make thyroid hormone and can cause thyrotoxicosis in patients with bulky tumors.

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Epidemiology

Occurrence in the United States

Graves disease is the most common form of hyperthyroidism. Approximately 60-80% of cases of thyrotoxicosis are due to Graves disease. The annual incidence of Graves disease was found to be 0.5 cases per 1000 persons during a 20-year period, with the peak occurrence in people aged 20-40 years.

Toxic multinodular goiter (15-20% of thyrotoxicosis) occurs more frequently in regions of iodine deficiency. Most persons in the United States receive sufficient iodine, and the incidence of toxic multinodular goiter is less than the incidence in areas of the world with iodine deficiency. Toxic adenoma is the cause of 3-5% of cases of thyrotoxicosis.

International occurrence

The incidences of Graves disease and toxic multinodular goiter change with iodine intake. Compared with regions of the world with less iodine intake, the United States has more cases of Graves disease and fewer cases of toxic multinodular goiters.

Race-, sex-, and age-related demographics

Autoimmune thyroid disease occurs with the same frequency in Caucasians, Hispanics, and Asians and with less frequency in the black population.

All thyroid diseases occur more frequently in women than in men. Graves autoimmune disease has a male-to-female ratio of 1:5-10. The male-to-female ratio for toxic multinodular goiter and toxic adenoma is 1:2-4. Graves ophthalmopathy is more common in women than in men.

Autoimmune thyroid diseases have a peak incidence in people aged 20-40 years. Toxic multinodular goiters occur in patients who usually have a long history of nontoxic goiter and who therefore typically present when they are older than age 50 years. Patients with toxic adenomas present at a younger age than do patients with toxic multinodular goiter.

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Prognosis

Hyperthyroidism from toxic multinodular goiter and toxic adenoma is permanent and usually occurs in adults. After normalization of thyroid function with antithyroid medications, radioactive iodine ablation usually is recommended as the definitive therapy. Long-term, high-dose antithyroid medication is not recommended. Toxic multinodular goiters and toxic adenomas probably will continue to grow slowly in size during antithyroid medication therapy. The prognosis is good after radioactive iodine therapy.

Generally, the thyrotoxic areas are ablated, and patients may remain euthyroid. Those who become hypothyroid after radioactive iodine therapy are easily maintained on thyroid hormone replacement therapy, with T4 taken once daily.

Patients with Graves disease often become hypothyroid in the natural course of their disease. Whether treatment is radioactive iodine or surgery, the outcome usually is hypothyroidism. The development of an eye disease can happen at a time distant from the initial diagnosis and therapy. Generally, after the diagnosis, the ophthalmopathy slowly improves over years.

Morbidity and mortality

The clinical manifestations of thyrotoxicosis can be divided into those associated with any form of thyrotoxicosis and those associated specifically with Graves disease.

Nonspecific changes due to excessive thyroid hormone include weight loss, nervousness, fatigue, heat intolerance, and rapid heartbeat or palpitations sometimes associated with atrial fibrillation and high-output congestive heart failure (CHF).[2, 3]

Thyroid hormone excess causes left ventricular thickening, which is associated with an increased risk of CHF. Thyrotoxicosis has been associated with dilated cardiomyopathy, right heart failure with pulmonary hypertension, and diastolic dysfunction.[2]

An increase in the rate of bone resorption occurs, but bone loss measured by bone mineral densitometry has been convincingly shown to occur only in postmenopausal women with hyperthyroidism.

Ophthalmopathy associated with Graves disease includes periorbital edema, chemosis, and proptosis with extraocular muscle dysfunction and diplopia. Dermopathy, a painless swelling of the pretibial area, may occur in patients with Graves disease who have severe ophthalmopathy.

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Contributor Information and Disclosures
Author

Stephanie L Lee, MD, PhD  Associate Professor, Department of Medicine, Boston University School of Medicine; Director of Thyroid Health Center, Associate Chief, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center; Fellow, Association of Clinical Endocrinology

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)

Sonia Ananthakrishnan, MD  Assistant Professor of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Frederick H Ziel, MD  Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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.

References
  1. Mittra ES, Niederkohr RD, Rodriguez C, El-Maghraby T, McDougall IR. Uncommon causes of thyrotoxicosis. J Nucl Med. Feb 2008;49(2):265-78. [Medline].

  2. Dahl P, Danzi S, Klein I. Thyrotoxic cardiac disease. Curr Heart Fail Rep. Sep 2008;5(3):170-6. [Medline].

  3. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med. Aug 9-23 2004;164(15):1675-8. [Medline].

  4. [Best Evidence] Heeringa J, Hoogendoorn EH, van der Deure WM, et al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam study. Arch Intern Med. Nov 10 2008;168(20):2219-24. [Medline].

  5. Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. Jun 2011;21(6):593-646. [Medline].

  6. FDA MedWatch Safety Alerts for Human Medical Products. Propylthiouracil (PTU). US Food and Drug Administration. Accessed: June 3, 2009. [Full Text].

  7. Stalberg P, Svensson A, Hessman O, et al. Surgical treatment of Graves' disease: evidence-based approach. World J Surg. Jul 2008;32(7):1269-77. [Medline].

  8. Sisson JC, Freitas J, McDougall IR, Dauer LT, Hurley JR, Brierley JD, et al. Radiation safety in the treatment of patients with thyroid diseases by radioiodine ¹³¹i: practice recommendations of the american thyroid association. Thyroid. Apr 2011;21(4):335-46. [Medline].

  9. Shindo M. Surgery for hyperthyroidism. ORL J Otorhinolaryngol Relat Spec. 2008;70(5):298-304. [Medline].

  10. [Best Evidence] Worni M, Schudel HH, Seifert E, Inglin R, Hagemann M, Vorburger SA, et al. Randomized controlled trial on single dose steroid before thyroidectomy for benign disease to improve postoperative nausea, pain, and vocal function. Ann Surg. Dec 2008;248(6):1060-6. [Medline].

  11. Porterfield JR Jr, Thompson GB, Farley DR, Grant CS, Richards ML. Evidence-based management of toxic multinodular goiter (Plummer's Disease). World J Surg. Jul 2008;32(7):1278-84. [Medline].

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Severe proptosis and eyelid retraction from thyroid-related orbitopathy. This patient also had optic nerve dysfunction from thyroid related orbitopathy.
Color flow ultrasonogram in a patient with Graves disease. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope.
Absence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis.
Three multinuclear giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis.
Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake.
Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).
Table 1. Common, Less Common, and Uncommon Forms of Thyrotoxicosis and Hyperthyroidism
Common Forms (85-90% of cases)Radioactive iodine uptake over neck
Diffuse toxic goiter (Graves disease)Increased
Toxic multinodular goiter (Plummer disease)Increased
Thyrotoxic phase of subacute thyroiditisDecreased
Toxic adenomaIncreased
Less Common Forms
Iodide-induced thyrotoxicosisVariable
Thyrotoxicosis factitiaDecreased
Uncommon Forms
Pituitary tumors producing thyroid-stimulating hormoneIncreased
Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma)Increased
Pituitary resistance to thyroid hormoneIncreased
Metastatic thyroid carcinomaDecreased
Struma ovarii with thyrotoxicosisDecreased
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