Recertification Refresher

Finding and treating the cause of hyperthyroidism

Christa Therese Ralph, MPAS, PA-C

Ms. Ralph practices at Des Moines Orthopaedic Surgeons in West Des Moines, Iowa. The author has indicated no relationships to disclose relating to the content of this article.

Early recognition of thyroid dysfunction is important, especially in the elderly, since treatment can improve symptoms dramatically and avert serious complications.

 

Earn Category I CME credit by reading this article and the associated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of February 2004.

Learning objectives Review normal thyroid function and the role played by disrupted hormones in the pathophysiology of the different types of hyperthyroidism Describe the clinical presentation of hyperthyroidism and how a detailed history and physical exam can identify the underlying cause Understand how routine thyroid function tests often establish the diagnosis Discuss the pharmacologic and surgical treatments of thyroid dysfunction

Disclosure of conflict of interest The author has indicated no relationships to disclose relating to the content of this article.

In 1835, Robert Graves identified a disorder that is characterized by the triad of goiter, palpitations, and exophthalmos (proptosis); the cause of these symptoms was later identified as nonthyrotropin thyroid-stimulating factor, an IgG antibody. What became known as Graves' disease is now recognized as the most prevalent autoimmune disorder in the United States, accounting for 60% to 80% of cases of thyrotoxicosis.¹ Thyrotoxicosis is the state of thyroid hormone excess, while hyperthyroidism results from thyroid overactivity.

Graves' disease is the most common type of primary hyperthyroidism and is almost always the cause of hyperthyroidism in patients younger than 50 years.² The autoimmune pathogenesis of Graves' disease differentiates it from other forms of hyperthyroidism. Hyperthyroidism due to Graves' disease, toxic multinodular goiter, which frequently occurs in patients older than 70 years, and toxic adenoma are the major causes of thyrotoxicosis.³ Secondary hyperthyroidism is caused by high levels of thyroid-stimulating hormone (TSH) or thyrotropin-releasing hormone (TRH). Although rare, TSH-secreting pituitary adenomas are the most common cause of secondary hyperthyroidism.

Anatomy and pathophysiology

A normal thyroid weighs approximately 20 to 30 g and is 2 to 2.5 cm wide and 3 to 5 cm long.⁴ Four parathyroid glands located on the posterior thyroid function separately from the thyroid itself. Thyroid follicular cells, arranged in circles with colloidal protein in the center, produce thyroglobulin, a protein involved in the synthesis and storage of thyroid hormones. Parafollicular cells (C cells) in the thyroid produce calcitonin, a calcium regulator that acts on bone and kidneys.

The thyroid gland requires dietary iodine uptake to form and release the iodine-containing hormones thyroxine (T₄) and triiodothyronine (T₃). The thyroid's ability to take in dietary iodine is unique to this gland and enables the use of radioactive iodine to assess thyroid size and activity and to treat overactive thyroids.⁴

T₃, the active form of thyroid hormone, is metabolically more potent than T₄. Although approximately 20 times more T₄ than T₃ is released, most of the T₄ is converted to active T₃. Both hormones circulate bound to thyroxine-binding globulin and albumin, but only free hormone (FT₄ and FT₃) is available to the tissues. T₃ is less tightly bound than T₄, so there is a greater amount of FT₃ available than there is of FT₄.

In Graves' disease, excessive thyroid function results from the action of thyroid-stimulating immunoglobulins on the TSH receptor,⁵ causing excess thyroid hormone production. Hypertrophy of the thyroid gland and increased follicular cells stimulate hypersecretion of thyroid hormone and lead to the diffuse goiter formation seen in Graves'. The pathogenesis of toxic multinodular goiter is not well understood. Iodine deficiency may be a contributory factor, along with genetic, autoimmune, and environmental factors.⁵ In rare pituitary adenomas, excess thyroid hormone production is usually secondary to increased TSH production by the pituitary tumor. Toxic adenomas are single, hyperfunctioning thyroid nodules, and most patients with toxic adenomas have an acquired mutation of the TSH receptor.⁵

History and physical exam

No matter what the underlying cause, the symptoms of hyperthyroidism often cause patients to feel very ill. Common complaints include unexplained weight loss despite increased appetite, nervousness, insomnia, heat intolerance, and fatigue.⁵ Tachycardia is usually present (see Table 1). Atrial fibrillation occurs in 5% to 15% of patients³ and is a serious complication that requires prompt identification of the cause and swift, appropriate treatment.

 

TABLE 1 Clinical clues to hyperthyroidism

Diarrhea Diffuse goiter Dysphagia or dyspnea Eyelid retraction or lag; periorbital edema Fatigue, weakness, exercise intolerance Heat intolerance Hyperhidrosis Hyperreflexia Menstrual irregularities Muscle weakness Nervousness, irritability Palpitations Tachycardia Tremor Warm, moist skin; localized dermopathy Weight loss despite increased appetite

Suspected hyperthyroidism warrants a general physical exam, including palpation of the thyroid for enlargement, asymmetry, irregular texture, or tenderness (see "The thyroid exam: A refresher"). Asymmetry or neck fullness also may be observed. A palpable or visible thyroid is a goiter; the goiter seen in Graves' disease is smooth, symmetric, and nontender. Both Graves' goiters and toxic nodular goiters cross the midline of the neck.⁶ Bruits, due to increased blood flow to the thyroid, may be present. A tender goiter rules out Graves' and indicates subacute thyroiditis.

 

The thyroid exam: A refresher Visual inspection First, inspect the thyroid area for any obvious enlargement. To locate the thyroid gland, start by identifying the thyroid cartilage (the Adam's apple), a midline bulge toward the top of the anterior surface of the neck. The thyroid cartilage, particularly prominent in thin men, sits atop the tracheal rings and is seen best when the patient's head is tilted back. Deviation to one side or the other may be associated with intrathoracic pathology. A pneumothorax, for example, can collapse the lung on one side, pushing mediastinal structures and the trachea toward the opposite side. Such a deviation may be visible on inspection and may be felt by gently placing your finger in the top of the thyroid cartilage and noting its position relative to the midline. The thyroid gland lies approximately 2 to 3 cm below the thyroid cartilage, on either side of the tracheal rings, which may or may not be apparent on visual inspection (see Figure 1). If you suspect an abnormality, watch this region as the patient swallows a glass of water. Thyroid tissue and the adjacent structures move up and down with swallowing. Because a normal thyroid is not visible, this swallowing exercise is unnecessary if the visual inspection is normal.   Click here to view full-size graphic   Palpation The thyroid can be palpated from in front of or behind the patient. Explain to the patient what you are going to do, that you are not going to choke him or her. To palpate the gland while standing behind the patient, place the middle three fingers of both hands along the midline of the neck, just below the chin (see Figure 2). You can also try to identify and feel the structures from the front while looking at the area before performing the exam from behind. Gently walk your fingers down the neck in the midline until you reach the top of the thyroid cartilage, the first firm structure that you encounter. The cartilage has a small notch in its top and is approximately 1.5 to 2 cm long.   Click here to view full-size graphic   Walk down the thyroid cartilage with your fingers until you come to the horizontal groove that separates it from the cricoid cartilage (the first tracheal ring). You should feel a small indentation (one that barely accepts the tip of your finger) between these two structures, directly in the midline. This is the cricothyroid membrane, the site for emergent tracheal access in the event of upper airway obstruction. Continue walking down until you reach the next well-defined tracheal ring. Now slide the three fingers of both hands to either side of the rings. The thyroid gland extends from this point downward for approximately 2 to 3 cm along each side. The two main lobes are connected by a small isthmus across the midline that is rarely palpable. Apply very gentle pressure when you palpate because the normal thyroid tissue is not very prominent and is easily compressible. To confirm the anatomy, have the patient drink water as you palpate. The gland should slide beneath your fingers while it moves upward along with the cartilaginous rings. A very soft, experienced touch is usually required to feel this structure. During the examination, note whether the gland is enlarged (a subjective determination that you will develop after many exams) and, if so, whether the enlargement is symmetric. Feel for discrete nodules in either lobe. If the gland feels firm, try to determine whether it is attached to adjacent structures (eg, fixed to underlying tissue, which would suggest malignancy) or freely mobile (eg, moves up and down with swallowing). Suspected malignancy warrants a careful examination of the nearby lymph nodes, the most common site of metastasis. Text and figures adapted with permission from Goldberg C. A practical guide to clinical medicine. The School of Medicine of the University of California, San Diego. Available at: http://medicine.ucsd.edu/clinicalmed/head.htm . Accessed January 12, 2004.

Tachycardia (a resting heart rate greater than 90 beats per minute)³ is typical, and sinus tachycardia is common. Atrial fibrillation can occur, especially in the elderly. Cardiac output may be 50 to 300 times normal.³

Exophthalmos occurs in one third of patients with Graves' disease, as well as in those with other forms of thyrotoxicosis. Exophthalmos is caused by the infiltration of cytokines and other inflammatory mediators into the extraocular muscles, resulting in fluid accumulation and edema.¹ Because Graves' disease causes other ocular symptoms including diplopia, which appears in 5% to 10% of patients, assessing visual acuity is an important part of the physical examination. Chemosis and conjunctival injection are often present. Corneal damage and blindness are serious complications, and moderate or severe active ophthalmopathy warrants referral to an ophthalmologist. Dermopathy, manifesting as inflamed, indurated deep pink or purple plaques, is usually localized over the anterolateral aspects of the shins and seen in 1% to 2% of Graves' disease patients—usually with Graves' exophthalmos.

The presentation of hyperthyroidism varies with patient age. Weight loss, decreased appetite, and atrial fibrillation are more common among elderly patients with thyrotoxicosis. Irritability and heat intolerance are less common in patients younger than 50 years. Although hyperthyroidism in children is unusual (fewer than 5% of cases occur in children), the signs and symptoms are almost the same as in younger adults, except that ophthalmopathy is rare.⁷

Female sex is the most significant risk factor for developing Graves' disease. There is a small genetic contribution, with only a 20% concordance rate in monozygotic twin studies.¹ Several HLA alleles have been associated with Graves' disease, and one HLA allele protects against it.¹ There is a strong association between smoking and ophthalmopathy. Patients taking amiodarone or lithium are at risk for developing Graves' disease. Patients can develop hyperthyroidism from taking too high a dosage of thyroid hormone for hypothyroidism. In addition, euthyroid patients who take OTC weight loss preparations that contain bovine thyroid hormone risk serious cardiac and ocular complications.

Making the diagnosis

Other diagnoses that should be included in the evaluation of a patient with suspected thyroid disorder include pheochromocytoma, anxiety states, menopause, cardiac arrhythmias not induced by excess thyroid hormone, and drug abuse or withdrawal. The presence of a goiter distinguishes hyperthyroidism from these disorders. Pheochromocytoma may be confused initially with hyperthyroidism since it causes heat intolerance, tachycardia, palpitations, sweating, and anxiety, but TSH and thyroid-hormone levels are normal for patients with these epinephrine-secreting tumors.

Signs and symptoms of hyperthyroidism, or goiter with or without symptoms, warrant laboratory evaluation for hyperthyroidism. The most sensitive, specific, and cost-effective initial laboratory test is the serum TSH level. A normal TSH value nearly rules out the diagnosis of hyperthyroidism; elevated levels of FT₄ confirm the diagnosis. Laboratory results that suggest the various etiologies of hyperthyroidism are shown in Table 2. FT₃ should be measured only if the patient has low or undetectable TSH but normal FT₄, which is seen in early Graves' disease when only FT₃ is elevated.

 

TABLE 2 TSH and free thyroid hormone values in hyperthyroid disorders
Disorder	TSH	FT4 and FT3
Graves' disease	Undetectable or low	Elevated
Toxic adenoma	Normal or elevated	Elevated
Toxic nodular goiter	Low	Elevated
Subclinical hyperthyroidism	Normal	Normal or slightly elevated
TSH-secreting pituitary adenoma	Elevated	Elevated
Key: FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyrotropin-stimulating hormone.

Laboratory results that confirm hyperthyroidism in nonpregnant patients should be followed by a radioactive iodine scan, which is usually performed with sodium iodide I 131 (¹³¹I). The scan reveals the amount and pattern of thyroid gland activity. Increased ¹³¹I uptake spread evenly over the entire thyroid gland confirms the diagnosis of Graves' disease; increased ¹³¹I uptake in a patchy distribution confirms toxic multinodular goiter.

Bone density should be measured in women with hyperthyroidism, particularly those who have a family history of osteoporosis, because bone resorption is increased, causing osteopenia in those with long-standing thyrotoxicosis.⁵ Although TSH-receptor antibody measurement is not a diagnostic tool for hyperthyroidism, it is a sensitive lab value for monitoring bone metabolism in patients with Graves' disease who are taking antithyroid medication.⁸

Managing hyperthyroidism

Hospitalization should be considered for patients who have serious weakness, anorexia and wasting, or cardiac complications, which are all more likely to occur in the elderly. Hospitalization is also warranted in thyrotoxic crisis, or thyroid storm—a sudden, drastic worsening of a patient's health due to an acute exacerbation of hyperthyroidism. Thyrotoxic crisis is usually triggered by acute illness, surgery, or radioiodine treatment in a patient with uncontrolled or incompletely treated hyperthyroidism.⁵ Mortality is approximately 30% among patients in thyrotoxic crisis.

Laboratory results that confirm hyperthyroidism warrant referral to an endocrinologist or specialist in internal medicine for the radioactive iodine scan and treatment. A head and neck surgeon should be consulted for extremely large goiters or those that cause compressive symptoms such as dysphagia or dyspnea, or if the goiter does not shrink in response to conventional treatments.

An antithyroid drug such as propylthiouracil (PTU) or methimazole (Tapazole, Thiamazole) is commonly used as the initial treatment, especially in younger patients with small goiters, active ophthalmopathy, or both. Radioiodine is also frequently used as an initial treatment for toxic multinodular or uninodular goiter. It is the preferred treatment for patients older than 50 years at the time of diagnosis and for patients who have had a relapse during or after long-term antithyroid drug therapy, who must discontinue antithyroid drug therapy because of adverse effects, or who have serious cardiac complications, such as atrial fibrillation. Radioiodine treatment is absolutely contraindicated in pregnancy and breast-feeding. Subtotal thyroidectomy is usually reserved for very large goiters that cause dyspnea or dysphagia. Thyroidectomy is the preferred treatment for pregnant women and for children who have had reactions to antithyroid drugs.² A comparison of the three treatments is given in Table 3.

 

TABLE 3 Comparing drug, radiation, and surgical therapies for hyperthyroidism
Feature	Antithyroid drugs	Radioactive iodine	Thyroidectomy
Recurrence	60%-70%	5%-20% (varies with dose)
Compliance	Lower	High	High
Cost-effectiveness	Equivalent to 131I	Equivalent to drug therapy	Most expensive
Risk for serious adverse effects	<1%	Approximately <1%	Low if done by experienced surgeon
Occurrence of hypothyroidism	Approximately 15%, 10-15 y after remission	10%-20% in first year (may be transient), 5% thereafter	Slightly lower than after 131I treatment (greater if near-total removal)
Use during pregnancy	Safe (PTU preferred)	Absolutely contraindicated	Safe after middle of second trimester
Effect on ophthalmopathy	None	Can increase periorbital edema, proptosis, or visual disturbance	None
Time to improvement	2–4 wk	4–8 wk	Days
Key:131I, sodium iodide I 131; PTU, propylthiouracil.

ß-Adrenergic-blocking agents, such as propranolol (Betachron, Inderal) or metoprolol (Lopressor, Toprol), are used to control tachycardia and palpitations. ß-Blockers may be used after starting antithyroid drugs or after ¹³¹I treatment and continued until the patient is euthyroid. The treatment goal is a resting pulse rate of 60 to 90 beats per minute.

The literature is unclear on whether subclinical hyperthyroidism should be treated. A patient who has subclinical hyperthyroidism may remain stable, develop overt hyperthyroidism, or return to a euthyroid state. In the absence of coronary artery disease, arrhythmia, or decreased bone density, it is generally best to defer treatment and observe the patient over several months.⁶ Although treatment of subclinical hyperthyroidism may prevent progression to overt hyperthyroidism, the ability of treatment to prevent atrial fibrillation and osteoporosis is unclear.⁹

Antithyroid drugs Methimazole and PTU inhibit hormone production in the thyroid, and high-dose PTU further inhibits the peripheral conversion of T₄ to active T₃, which is helpful in severe hyperthyroidism or during thyrotoxic crisis.¹ Methimazole is often preferred because it offers once-daily dosing. The starting dosage of methimazole is 10 to 30 mg once a day; for PTU, it is 100 mg three times a day. Although both PTU and methimazole are generally considered safe during pregnancy, PTU is thought to have less transplacental transfer and no teratogenic effects. Both antithyroid drugs are safe to use while breast-feeding.

As many as 5% of patients taking PTU or methimazole develop the common side effects of fever, rash, arthralgia, and pruritus, which may resolve spontaneously and do not preclude use.⁸ Fewer than 1% of patients taking an antithyroid drug develop serious adverse effects, such as liver disease, agranulocytosis, and lupuslike syndrome.² Agranulocytosis is a serious complication; patients taking an antithyroid drug should be instructed to seek medical attention if sore throat, fever, or mouth ulcers develop. Neither drug should be used in a patient who has had a serious reaction to it.² A baseline leukocyte count and liver function tests should be obtained before beginning drug treatment.

FT₄ levels should be monitored monthly until a euthyroid state is achieved. The dosage of PTU or methimazole is titrated based on these levels. A usual maintenance dosage for PTU is 50 to 100 mg/d and 2.5 to 10 mg/d for methimazole.⁵ A TSH level is not helpful initially in detecting when a euthyroid state is reached because TSH may remain undetectable months after a euthyroid state is achieved. If the TSH level becomes undetectable and FT₄ levels increase while a patient is on the drug, increase the dosage. Consider treatment with radioactive iodine or subtotal thyroidectomy if the maximum dosage (approximately 800 mg/d for PTU, 80 mg/d for methimazole) is ineffective.

Once a euthyroid state is achieved, the patient should have FT₄ levels checked every 2 to 3 months for the first year, when relapse is most likely to occur. A schedule of annual follow-up visits can begin after the first year.

Graves' disease is the hyperthyroid condition most successfully treated with antithyroid drugs. After prolonged treatment, patients may have spontaneous remission of their hyperthyroidism. For other forms of hyperthyroidism, such as toxic multinodular goiter and toxic adenoma, drug therapy may normalize thyroid function temporarily, but it is not an optimal long-term treatment and will not induce remission. Drug therapy for Graves' disease should continue for 1 to 2 years, after which it is stopped and the patient is tested to see if remission has occurred. Reported remission rates are 40% to 70%, but it is difficult to predict which patients will remit or relapse.² Once a euthyroid state is achieved, the patient should be monitored regularly for recurrence.

Radioactive iodine Treatment with ¹³¹I can be used as primary therapy or in a patient whose condition has recurred while on or after stopping antithyroid drugs, and is the treatment of choice for toxic adenoma.⁵ Taken orally, ¹³¹I is absorbed by the thyroid where it emits radiation, killing thyroid tissue. In 80% of patients, a single dose resolves hyperthyroidism and diminishes goiter size.² A lower dosage of radioactive iodine will result in a euthyroid state, and a larger dose can be given to completely ablate the thyroid. If a euthyroid state is achieved, patients must have TSH and FT₄ levels checked monthly because many patients will become hypothyroid over the next 5 to 10 years. Thyroid ablation necessitates thyroid hormone replacement therapy with levothyroxine shortly after ablation. Hyperthyroidism is commonly seen immediately after treatment with ¹³¹I, possibly a result of thyroid-hormone release with destruction of the gland.¹⁰

Active ophthalmopathy is a contraindication for ¹³¹I treatment because inflammatory mediators causing ophthalmopathy may increase after ¹³¹I treatment. It may be used, however, if patients are given a prednisone taper before receiving ¹³¹I treatment, starting with 40 mg/d and decreasing to zero over 3 months.¹

Although some recent studies show a slightly increased relative risk for bladder, kidney, stomach, and thyroid cancers with use of ¹³¹I, no definite conclusions regarding carcinogenic effects have been reached.¹⁰ The current literature suggests that ¹³¹I exposure does not affect female fertility or have teratogenic effects on pregnancies,¹⁰ but a woman who wishes to become pregnant should wait 4 to 6 months after treatment before trying to conceive.

Thyroidectomy Surgical removal of the thyroid gland is an effective and safe treatment for Graves' disease and toxic multinodular goiter. Rare postoperative complications include bleeding, hypoparathyroidism, and laryngeal nerve damage. Most patients eventually develop permanent hypothyroidism since there is little thyroid function left, and this is treated with thyroid-hormone replacement (levothyroxine). Patients who are undergoing thyroidectomy should be given methimazole or PTU that will create a euthyroid state, plus inorganic iodide (3 drops of saturated solution of potassium iodide orally three times a day)⁵ for 1 to 2 weeks before surgery to reduce thyroid function and vascularity, which minimizes the chance of postoperative thyrotoxic crisis. Thyrotoxic crisis can occur because the process of removing the thyroid can cause thyroid hormone to be released into circulation. Inorganic iodide should not be used in patients who have toxic nodular goiter since it may exacerbate the hyperthyroidism.²

Screening guidelines

The 1998 guidelines of the American College of Physicians recommend screening all women older than 50 years for thyroid disease with thyroid exam and lab tests and predict that doing so will detect an unsuspected but symptomatic case in 1 of 71 women.¹¹ An American Thyroid Association panel recommends screening of all adults with a thyroid exam and lab tests.¹² Because hypothyroidism is more prevalent, it will likely be more frequently identified. TSH is the best lab value to use for screening, but FT₄ levels may also be measured.

 

KEY POINTS in this article An undetectable or low thyrotropin-stimulating hormone value and elevated free thyroid hormones are the hallmarks of hyperthyroidism; a radioiodine uptake scan can identify the cause. The atrial fibrillation that occurs in 5% to 15% of patients with hyperthyroidism is a serious complication requiring prompt recognition of the cause and appropriate treatment. Antithyroid drugs (propylthiouracil or methimazole) are often the first-line treatment for hyperthyroidism. Radioactive iodine is also an option, especially for patients who do not respond to, or who relapse after, antithyroid drug therapy.

REFERENCES

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3. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. New Engl J Med. 2001;344:501-509.

4. Shagam JY. Thyroid disease: an overview. Radiol Technol. September-October 2001;73:25-40.

5. Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:2060-2084.

6. Bryer-Ash M. Evaluation of the patient with a suspected thyroid disorder. Obstet Gynecol Clin North Am. 2001;28:421-438.

7. Koch CA, Sarlis NJ. The spectrum of thyroid diseases in childhood and its evolution during transition to adulthood: natural history, diagnosis, differential diagnosis and management. J Endocrinol Invest. 2001;24:659-675.

8. Kumeda Y, Inaba M, Tahara H, et al. Persistent increase in bone turnover in Graves' patients with subclinical hyperthyroidism. J Clin Endocrinol Metab. 2000;85:4157-4161.

9. Pauwels EK, Smit JW, Slats A, et al. Health effects of therapeutic use of 131 I in hyperthyroidism. Q J Nucl Med. 2000;44:333-339.

10. Krassas GE. Thyroid disease and female reproduction. Fertil Steril. 2000;74:1063-1070.

11. Woeber KA. The year in review: the thyroid. Ann Intern Med. 1999;131:959-962.

12. Toft AD. Clinical practice. Subclinical hyperthyroidism. New Engl J Med. 2001;345:512-516.

 

Christa Ralph. Finding and treating the cause of hyperthyroidism. JAAPA February 2004;17:20-30.

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