Introduction
Background
The term thyrotoxicosis refers to the hypermetabolic clinical syndrome resulting from serum elevations in thyroid hormone levels, specifically free thyroxine (T4), triiodothyronine (T3), or both. Hyperthyroidism is a type of thyrotoxicosis in which accelerated thyroid hormone biosynthesis and secretion by the thyroid gland produce thyrotoxicosis. However, hyperthyroidism and thyrotoxicosis are not synonymous.
Although many patients have thyrotoxicosis caused by hyperthyroidism, other patients may have thyrotoxicosis caused by inflammation of the thyroid gland, which causes release of stored thyroid hormone but not accelerated synthesis, or thyrotoxicosis, which is caused by ingestion of exogenous thyroid hormone. Differentiating between thyrotoxicosis caused by hyperthyroidism and thyrotoxicosis not caused by hyperthyroidism is important because disease management and therapy differ for each form. Thyroid imaging and radiotracer thyroid uptake measurements combined with serologic data enable specific diagnosis and appropriate patient treatment.
Pathophysiology
The thyroid gland actively transports iodide from circulating blood into the thyroid follicular cells. Subsequently, iodide is organified into tyrosyl residues of thyroglobulin and stored within the thyroid follicles. When required, thyroglobulin undergoes proteolysis with the release of T3 and T4 as the principle active forms of thyroid hormone. In extrathyroidal tissues, some of the T4 is deiodinated to the more metabolically potent T3 hormone.
The process of synthesis, storage, and release of T3 and T4 by the thyroid is normally controlled by the pituitary gland through its release of thyrotropin. This process involves a negative feedback loop wherein increasing blood levels of T3 and/or T4 inhibit release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin from the pituitary (see Image 1). In thyrotoxicosis, the high blood levels of T3 and/or T4 inhibit the hypothalamic-pituitary release of thyrotropin; therefore, serum levels of thyrotropin are markedly reduced or undetectable. Therefore, the measurement of thyrotropin serum levels is the primary test in the diagnosis of thyrotoxicosis.
Causes
The common causes of thyrotoxicosis have different pathophysiologic features, which include autoimmune disease, functioning thyroid adenoma, and infection. Common causes of thyrotoxicosis include (1) autoimmune disease; Graves disease, lymphocytic thyroiditis with hyperthyroidism (ie, silent thyroiditis), and postpartum thyrotoxicosis (PPT); (2) neoplasm, toxic nodule, and toxic multinodular goiter (autonomously functioning nodules); and (3) infection, subacute thyroiditis (SAT), and, very rarely, acute suppurative thyroiditis.
Graves disease
Named for the Irish physician, Robert Graves, who described the disease in 1835, Graves disease is caused by circulating thyroid receptor autoantibodies (TRab). The antibodies not only displace thyrotropin from the thyroid receptors but also mimic thyrotropin by activating the receptor to stimulate the synthesis and release T3 and T4. Because autoantibody production is not linked to the normal pituitary negative feedback loop, thyroid gland function becomes autonomous, and serum T4 and T3 levels become abnormally high and lead to clinical thyrotoxicosis.
Because hormone synthesis is accelerated and thyroid gland radioiodine uptake is elevated, radionuclide scans demonstrate a diffuse increase in iodine uptake by the gland (see Images 2-4). The natural clinical course of Graves disease usually is interrupted by specific therapy; left untreated, Graves disease may be lethal.
Graves disease is closely associated with Hashimoto disease (chronic lymphocytic thyroiditis) in which thyrotoxic/cytotoxic antithyroid antibodies attack the gland. Hashimoto disease is the leading natural cause of thyroid failure and hypothyroidism. The 2 diseases may coexist, and their clinical features may overlap. Graves ophthalmopathy also appears to share a similar immune basis and may occur with or without associated thyroid disease.
Disseminated autonomy
Disseminated autonomy (DISA) is a disease that is addressed less frequently. DISA can be established only by the exclusion of Graves disease. DISA and Graves disease can be distinguished from each other only with clinical findings, such as the presence of endocrine ophthalmopathy or thyrotropin-binding immunoglobulins. (See further discussion of thyroid autonomy under nodular disease below.)
Lymphocytic thyroiditis
In the spectrum of autoimmune thyroid diseases, variants that cause thyrotoxicosis exist. These diseases occur by mean of an inflammatory process unassociated with thyroid pain or tenderness, not the production of stimulating antibodies. This process has been termed painless thyroiditis with hyperthyroidism to distinguish it from subacute or "viral" thyroiditis in which the thyroid is painful or tender (see Subacute thyroiditis, below).
Lymphocytic thyroiditis more commonly is termed silent thyroiditis. A similar condition that occurs in 5-10% of postpartum women is called postpartum thyroiditis (PPT). During the acute phase, silent thyroiditis may be clinically indistinguishable from Graves disease. However, because iodine clearance and hormone synthesis by the thyroid is turned off by the decrease in serum thyrotropin levels, radioiodine uptake is low, generally less than 3%, which allows its differentiation from Graves disease. The low uptake usually precludes diagnostic radionuclide scanning of the thyroid.
The natural course of silent thyroiditis most frequently is spontaneous resolution; therefore, symptomatic treatment usually suffices. Acute flares may be followed by a period of hypofunctionality. The hypothyroid phase is usually transient; therefore, the physician should time for spontaneous recovery before initiating lifelong hormone replacement therapy.
Occasionally, silent thyroiditis is a recurring process, and patients may benefit from anti-inflammatory drugs, surgery, or iodine 131, which is administered in the asymptomatic phase when iodine uptake is adequate. PPT occurs at a time of great physiologic and emotional challenge to the patient. Symptoms can be mistaken for anxiety or depression; therefore, clinical awareness of the potential for thyroiditis is important at this time.
Toxic nodules and thyroid autonomy
Thyroid autonomy is the state wherein a single nodule, several nodules, or the entire gland function autonomously in the absence of circulating thyrotropin or thyroid-stimulating immunoglobulins (TSIs). Somatic thyrotropin receptor mutation is the most prevalent etiology of autonomously functioning thyroid nodules.
Thyroid autonomy is most frequently found in toxic multinodular goiters, a group of clinical presentations in which autonomously functioning nodules are present in a goiter with or without additional nodules. The nonautonomous nodules may show normal or suppressed radioiodine uptake on scintigraphy.
The 3 distinct categories of thyroid autonomy are (1) benign adenomas (encapsulated tumor) and adenomatous nodules (not encapsulated but circumscribed), (2) malignant thyroid tumors with hyperthyroidism, and (3) microscopic areas in euthyroid goiters, perhaps the histological equivalent of disseminated autonomy.
An autonomously functioning thyroid nodule (AFTN) is a focus of functioning thyroid cells wherein thyroid hormone production has been uncoupled from the normal pituitary-thyroid negative feedback loop. When the nodule's level of thyroid hormone production has reached a level at which serum thyrotropin levels are depressed, the nodule is termed toxic. In one US study, 94% of AFTNs treated with surgical excision were adenomas and the remainder were more heterogeneous lesions. Functioning thyroid carcinomas that cause thyrotoxicosis are exceedingly rare. Usually, they should not be included in the differential diagnosis.
Thyroid iodine uptake is normal or high, and thyroid scans reveal a hyperfunctional (ie, hot) nodule with depressed or absent tracer uptake in the remainder of the gland (see Image 5). A toxic nodule rarely resolves spontaneously, and the use of antithyroid drugs is a commitment to lifelong therapy. Therefore, specific curative treatment with131 I treatment or surgical excision is performed. Ablation of the nodule with percutaneous alcohol injection is proven effective, but it has not become commonplace therapy in most practices.
Toxic multinodular goiter
Usually, toxic multinodular goiter (TMNG) is the end result of a slow process that occurs over many years, and patients often are older than those with other conditions. In contrast to most cases of Graves disease, TMNG is subtler and/or more likely to be overlooked because of its insidious onset. TMNG occurs in a patient with multinodular goiter whenever newly generated follicles with some degree of autonomous capability reach sufficient size and functionality to cause thyrotoxicosis (ie, Plummer disease).
Similar to toxic adenomas and adenomatous nodules, toxic multinodular goiters may have somatic mutations of the thyrotropin receptor, but this is not uniform and different or overlapping pathophysiologic processes may be present. This is a clinical disorder rather than a specific disease entity.
Iodine uptake is normal or elevated, and radionuclide scans demonstrate multiple nodules or a markedly heterogeneous distribution of tracer (see Image 6).
As in AFTN, successful treatment of TMNG with131 I may require a dose that is larger than the usual effective dose for Graves disease. The use of131 I may be somewhat more hazardous in an elderly patient with coexisting cardiovascular disease, and pretreatment with antithyroid drugs may reduce the risk. Surgery can be effective immediately. Treatment with antithyroid drugs is effective in the short term, but it is not recommended as definitive therapy because it must be lifelong.
Subacute thyroiditisThe cause of subacute thyroiditis (de Quervain thyroiditis, granulomatous giant cell thyroiditis) may be multifactorial; however, indirect but strong evidence suggests that viral infection is the precipitating event. Half the patients have a history of antecedent viral upper respiratory tract illness. When a patient with clinical signs and symptoms of thyrotoxicosis also has substantial thyroid pain and tenderness, a diagnosis of SAT is almost always correct. The diagnosis is confirmed with elevated T3 and/or T4 levels, low thyrotropin levels, and low ( <3%) thyroid radioiodine uptake. The sedimentation rate is consistently elevated. However, if the patient presents late in the course of the illness, the clinical and laboratory findings may be confusing.
SAT seldom is occurs very young or elderly patients. The hyperthyroid phase usually lasts 4-10 weeks; frequently, this phase is followed by a hypothyroid phase of similar duration. The illness may last for 1 year or longer, but ultimately, the patient almost always returns to a euthyroid state; therefore, treatment is aimed at the symptoms. Beta-blocking drugs and nonsteroidal anti-inflammatory agents often are beneficial. Occasionally, steroid anti-inflammatory therapy is necessary. Correct diagnosis minimizes inappropriate therapeutic attempts with antithyroid drugs,131 I, or surgery. In addition, care must be taken not to initiate long-term thyroid hormone replacement therapy in the hypothyroid phase of the illness because thyroid function returns to normal in more than 90% of patients.
Uncommon causes of thyrotoxicosis include the following: acute or suppurative thyroiditis, factitious or iatrogenic thyrotoxicosis, struma ovarii, follicular carcinoma, thyrotoxicosis induced by excess pituitary production of thyrotropin, and thyrotoxicosis secondary to high circulating levels of human chorionic gonadotropin.
Frequency
United States
On a survey, as many as 27 women per 1000 provide a history of current or past hyperthyroidism. At any time, the risk for Graves disease is approximately 1.4 cases per 1000 persons. The rate of SAT is approximately 20% of the rate for Graves disease. AFTN and TMNG are somewhat less common than SAT, but the incidence varies considerably in separate series. Silent thyroiditis is less common than Graves disease or SAT, but PPT may affect 5-10% of new mothers.
International
Graves disease appears to be distributed equally worldwide. Also, nodular thyrotoxicosis and silent or PPT also are commonly reported commonly. SAT is rare in the tropics.
Mortality/Morbidity
Thyroid storm occurs only rarely, but it is potentially lethal and must be recognized and treated with urgency (see Hyperthyroidism, Thyroid Storm, and Graves Disease).
Untreated chronic hyperthyroidism that results from cardiac decompensation or metabolic complications is rarely fatal, but permanent or long-term states of hyperthyroidism require specific treatment to control or cure the disease. Usually, associated complications, such as muscle deterioration and infertility, fully resolve after successful treatment.
Graves ophthalmopathy is a chronic orbital inflammatory process that occurs with or without associated autoimmune thyroid disease. Its pathogenesis remains controversial, but a theory states the thyroid and orbit share antigens. The course of the disease may be innocuous or aggressive, with a loss of vision.
TSI levels correlate with activity and the severity of ophthalmopathy, and high TSI levels in combination with low thyroid peroxidase antibodies (TSO) are associated with a marked increase in the occurrence of ophthalmopathy.
Reports state that Graves ophthalmopathy may be exacerbated by131 I treatment of Graves thyrotoxicosis. At least 1 report suggests that concurrent corticosteroid treatment with131 I prevents exacerbation of the ophthalmopathy. Prednisone with131 I has been shown to prevent an exacerbation of exophthalmos at a dose of 30 mg/d for 1 month, with tapering over 2-3 months. Individual risk-benefit assessment is necessary before such treatment.
Race
Thyrotoxicosis affects all races. Differences in the reported rates appear to be based on geographic factors rather than ethnicity; they may partly result from dietary influences.
Sex
With most forms of thyrotoxicosis, women are affected approximately 4 times as frequently as men. This difference is true even for SAT, which is believed to be viral induced. X-linked genetic transmission is probably a factor, and it may responsible for sex and familial prevalences.
Age
In Graves disease, the incidence is fairly consistent in persons aged 20 years and older. Increasing incidence is noted in TMNG in those older than 30 years. In AFTN, silent thyroiditis, and SAT, disease predominately occurs in patients aged 20-60 years.
Anatomy
The normal location of the thyroid in the superficial anterior neck facilitates clinical examination and evaluation with ultrasonography (US) and scintigraphy. The normal thyroid is bilobed, with a connecting isthmus. The shape often is described as that of the H of the Honda car symbol. Commonly, the right lobe is larger than the left; occasionally, the extreme of the absence or agenesis of the left lobe is observed. A pyramidal lobe of variable size projects cephalad from the isthmus in many people. Neoplastic or hyperplastic growth may extend inferiorly (retrosternal), and adjustments in the imaging technique may be required. The adjacent anatomy of the laryngeal nerves and parathyroid glands is an important surgical consideration.
Presentation
Clinical features of thyrotoxicosis are largely independent of its cause, although clues (eg, tender thyroid gland or palpable nodule) may suggest SAT or AFTN. The presence of a fast pulse, tremor, eyelid lag, and warm moist skin in a patient with weight loss, difficulty climbing stairs, palpitations, and intolerance for warm rooms or weather is the pathognomonic clinical presentation of thyrotoxicosis. However, the clinical features are variable. Elderly patients may have few symptoms and limited signs of disease; they may have only atrial fibrillation, lethargy, or weight loss. A profound acute presentation or exacerbation of the signs or symptoms may herald the onset of thyroid storm, a potentially fatal state that requires immediate recognition and treatment see Hyperthyroidism, Thyroid Storm, and Graves Disease).
Subclinical thyroid disease
In countries in which screening thyrotropin assays are commonly used, patients with only a low thyrotropin level but no other signs or symptoms of thyrotoxicosis are identified with greater frequency. The causes include excess thyroid hormone therapy, early or mild Graves disease, autonomous nodule(s), or mild cases of silent, postpartum or viral thyroiditis.
A few patients will be encountered who (1) have persistently low thyrotropin levels but are otherwise clinically normal and have normal T3 and T4 levels and are negative for TRab, (2) have normal responses to thyroid feedback homeostasis tests (eg, T3 suppression), and (3) do not become hyperthyroid during many years of monitoring.
Many of these patients have preclinical or asymptomatic early Graves disease, and they must be distinguished from those without disease but just a low thyrotropin level because the former are at risk for complications such as atrial fibrillation and left ventricular dysfunction. Such patients usually have elevated TRab and/or TSI values.
Other than proper adjustment of dose in those patients on thyroid hormone therapy, no uniform recommendations for management of subclinical hyperthyroidism have been established. Fifty percent of patients with an isolated suppressed (but measurable) sensitive thyrotropin level return to normal levels without intervention, and observation and repeat testing is appropriate in those without symptoms.
Those with an undetectable sensitive thyrotropin or those who are symptomatic should be considered for intervention after the cause has been determined.
Preferred Examination
The diagnosis of thyrotoxicosis is predominately based on laboratory results, including an elevated free T3/T4 level and suppressed thyrotropin level; however, the clinical examination may reveal the etiology. If the thyroid gland is normal or diffusely enlarged on physical examination, the most likely diagnosis is Graves disease. If one or more thyroid nodules are palpated, the patient probably has AFTN or TMNG. If the thyroid gland is markedly tender, subacute thyroiditis is likely. However, silent thyroiditis is almost always in the differential diagnosis with Graves disease. In addition, some patients with silent thyroiditis may have a tender thyroid gland, and some patients with subacute thyroiditis have only mild thyroid tenderness.
As a result of the clinical overlap, knowledge of thyroid iodine uptake is necessary for specific diagnosis and appropriate therapy in most patients. Also, thyroid radionuclide scintigraphy can help distinguish Graves disease from a toxic nodule and toxic multinodular goiter. The Table contains a summary of the laboratory, thyroid uptake, and scanning findings in the various common forms of thyrotoxicosis.
Summary of Laboratory, Thyroid Uptake, and Scanning Findings
Open table in new window
Limitations of Techniques
Thyroid uptake testing, thyroid scintigraphy, and thyroid US are not the primary testing modalities for diagnosis of thyrotoxicosis, but their findings can be critical in the differential diagnosis and in selecting treatment once thyrotoxicosis is established with serologic test results.
Scintigraphy
Open table in new window
Table
| Graves disease | Elevated to highly elevated | Elevated | Low to absent | Normal to very high | Diffuse increased uptake |
| Autonomous nodule | Elevated to highly elevated | Normal | Low to absent | Normal to very high | Hot nodule |
| Toxic mulitnodular goiter | Elevated to highly elevated | Normal | Low to absent | Normal to very high | Hot nodules |
| Subacute thyroiditis | Elevated to highly elevated | Normal | Low to absent | Very low (0-2%) | Depressed uptake |
| Silent thyroiditis or PPT | Elevated to highly elevated | Normal | Elevated | Very low (0-2%) | Depressed uptake |
| Graves disease | Elevated to highly elevated | Elevated | Low to absent | Normal to very high | Diffuse increased uptake |
| Autonomous nodule | Elevated to highly elevated | Normal | Low to absent | Normal to very high | Hot nodule |
| Toxic mulitnodular goiter | Elevated to highly elevated | Normal | Low to absent | Normal to very high | Hot nodules |
| Subacute thyroiditis | Elevated to highly elevated | Normal | Low to absent | Very low (0-2%) | Depressed uptake |
| Silent thyroiditis or PPT | Elevated to highly elevated | Normal | Elevated | Very low (0-2%) | Depressed uptake |
Establishing the presence of thyrotoxicosis
Currently, the measurement of free thyroid hormone is considered the appropriate test. A total T3 or T4 level has less diagnostic accuracy compared with other measure because of the variability of binding protein levels.
At present, most thyrotropin assays are performed with sensitive methods. The measurement of thyrotropin levels is unique as a screening test for hyperthyroidism.
Regarding other laboratory tests, T3-suppression and TRH-stimulation tests are seldom needed to establish the autonomy of the gland or nodule. The measurement of free T3 and T4 levels and the sensitive thyrotropin assay usually suffice for diagnosis and therapeutic decision making. In truly borderline cases, short-term observation and repeat testing may be helpful. TRab and TSI measurement may be helpful in borderline or confusing cases.
Establishing the cause of thyrotoxicosis
In the thyroid radioiodine tracer uptake test, a measured dose of radiotracer, usually iodine 123 or131 I is administered to the patient. After 4-24 hours, activity in the thyroid (ie, neck activity corrected for background levels) is imaged, and the percentage of the administered dose within the thyroid is calculated. Each laboratory should establish their normal values, but generally, normal values are in the range of 5-25%. Thyrotoxicosis (ie, Graves disease, AFTN, TMNG) caused by hyperfunctional thyroid tissue is associated with normal-to–markedly increased uptake.
Thyrotoxicosis (ie, SAT, silent thyroiditis) caused by inflammation of the thyroid gland has low-to-absent uptake. Thyroid scintigraphy after the oral administration of123 I or intravenous administration of technetium 99m is helpful in demonstrating diffuse tracer uptake (Graves disease) versus nodular tracer concentration (AFTN, TMNG). The image can also be used distinguish low thyroid uptake from a high thyroid uptake, but the findings are not as quantitative as those of the thyroid uptake test.
The common antithyroid antibody (ie, antimicrosomal/peroxidase, antithyroglobulin) levels are somewhat variable and inconsistent but are elevated in most cases. High levels are usually seen in persons with Hashimoto disease. Antibody assays are not required for the clinical diagnosis and treatment of thyroid disease in most patients.
Differential Diagnoses
More on Thyrotoxicosis |
 Overview: Thyrotoxicosis |
| Imaging: Thyrotoxicosis |
| Follow-up: Thyrotoxicosis |
| Multimedia: Thyrotoxicosis |
| References |
| Next Page » |
References
Bajnok L, Mezosi E, Nagy E, et al. Calculation of the radioiodine dose for the treatment of Graves'' hyperthyroidism: is more than seven-thousand rad target dose necessary?. Thyroid. Sep 1999;9(9):865-9. [Medline].
DeGroot LJ, Mangklabruks A, McCormick M. Comparison of RA 131I treatment protocols for Graves'' disease. J Endocrinol Invest. Feb 1990;13(2):111-8. [Medline].
Floyd JL, Rosen PR, Borchert RD, et al. Thyroid uptake and imaging with iodine-123 at 4-5 hours: replacement of the 24-hour iodine-131 standard. J Nucl Med. Aug 1985;26(8):884-7. [Medline].
Franklyn JA. The management of hyperthyroidism. N Engl J Med. Jun 16 1994;330(24):1731-8. [Medline].
Franklyn JA, Maisonneuve P, Sheppard M, et al. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet. Jun 19 1999;353(9170):2111-5. [Medline].
Gluck FB, Nusynowitz ML, Plymate S. Chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake. Report of four cases. N Engl J Med. Sep 25 1975;293(13):624-8. [Medline].
Graves RJ. Clinical lectures. London Med Surg J. 1835;(Pt2):516.
Hagen GA, Ouellette RP, Chapman EM. Comparison of high and low dosage levels of 131-I in the treatment of thyrotoxicosis. N Engl J Med. Sep 14 1967;277(11):559-62. [Medline].
Hamburger JI, Hamburger SW. Diagnosis and management of large toxic multinodular goiters. J Nucl Med. Aug 1985;26(8):888-92. [Medline].
Hayek A, Chapman EM, Crawford JD. Long-term results of treatment of thyrotoxicosis in children and adolescents with radioactive iodine. N Engl J Med. Oct 29 1970;283(18):949-53. [Medline].
Hedley AJ, Young RE, Jones SJ, et al. Antithyroid drugs in the treatment of hyperthyroidism of Graves'' disease: long-term follow-up of 434 patients. Scottish Automated Follow- Up Register Group. Clin Endocrinol (Oxf). Aug 1989;31(2):209-18. [Medline].
Kasagi K, Kousaka T, Higuchi K, et al. Clinical significance of measurements of antithyroid antibodies in the diagnosis of Hashimoto''s thyroiditis: comparison with histological findings. Thyroid. Oct 1996;6(5):445-50. [Medline].
Miles J, Charles P, Riches P. A review of methods available for the identification of both organ- specific and non-organ-specific autoantibodies. Ann Clin Biochem. Jan 1998;35 ( Pt 1):19-47. [Medline].
Palit TK, Miller CC 3rd, Miltenburg DM. The efficacy of thyroidectomy for Graves'' disease: A meta-analysis. J Surg Res. May 15 2000;90(2):161-5. [Medline].
Roti E, Emerson CH. Clinical review 29: Postpartum thyroiditis. J Clin Endocrinol Metab. Jan 1992;74(1):3-5. [Medline].
Roti E, Braverman LE, DeGroot LJ. TCH Receptor Antibody Measurement in the Diagnosis and Management of Graves' Disease Is Rarely Necessary. The Journal of Clinical Endocrinology & Metabolism. 1998;11:3781-3784. [Full Text].
Singer PA. Thyroiditis. Acute, subacute, and chronic. Med Clin North Am. Jan 1991;75(1):61-77. [Medline].
Torring O, Tallstedt L, Wallin G, et al. Graves'' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group. J Clin Endocrinol Metab. Aug 1996;81(8):2986-93. [Medline].
Volpe R. The management of subacute (DeQuervain''s) thyroiditis. Thyroid. Fall 1993;3(3):253-5. [Medline].
Further Reading
Keywords
Graves disease, Grave's disease, toxic nodule, toxic multinodular goiter, TMNG, thyroiditis, free thyroxine, T4, triiodothyronine, T3, hyperthyroidism
