Thyroglobulin

Walter Reed Medical Army Center

A 20-year-old active duty male presented with palpitations, tachycardia, and a nontender, diffusely enlarged thyroid. The differential diagnosis and appropriate management of this patient's symptoms and physical examination findings are reviewed. Various diagnostic modalities are highlighted and effective treatment strategies as well as their risks and benefits are discussed.

Introduction

A 20-year-old active duty male presented in Kuwait with complaints of palpitations. His symptoms worsened over a month, from having palpitations at rest to developing dyspnea on exertion, anxiety, tremors, increased perspiration, and heat intolerance. The patient had an unintentional 15-pound weight loss over the previous 6 months. The patient denied any visual changes, chest pain, or lightheadedness. He was medically evacuated from the theater to Landstuhl Regional Medical Center and then transferred to Walter Reed Army Medical Center for further evaluation. Vital signs were significant for a relative tachycardia at 96 beats per minute. His skin was warm and moist and a mild tremor was visible in both hands. He had no lid lag or periorbital edema but palpation of the neck revealed a nontender, diffusely enlarged thyroid gland. Cardiovascular examination revealed tachycardia with no murmurs or extra heart sounds. Electrocardiography demonstrated sinus tachycardia.

1. What is the most likely diagnosis in this patient?

a. thyrotoxicosis

b. hyperthyroidism

c. excess caffeine ingestion

d. pheochromocytoma

e. Post-traumatic stress disorder

Nervousness, irritability, heat intolerance, increased sweating, tremor, weight loss or gain, diarrhea, dependent lower extremity edema, dyspnea, exertional intolerance, impaired fertility, sleep disturbances, changes in vision, fatigue, muscle weakness, and thyroid enlargement best characterize the thyrotoxic patient.1-3 Although the terms "thyrotoxicosis" and "hyperthyroidism" are often used interchangeably, they have different meanings. Thyrotoxicosis refers to the syndrome caused by excess thyroid hormone, irrespective of the source, whereas hyperthyroidism refers to an overactive thyroid gland. With the information provided, the patient described above can only be diagnosed with thyrotoxicosis. Caffeine is a potent central nervous stimulant and in excess amounts can cause anxiety, restlessness, insomnia, tremor, tingling sensations, and can acutely raise the systolic and diastolic blood pressure but is not usually associated with a goiter. Pheochromocytoma is a rare catecholamine-secreting tumor and patients will classically experience spells characterized by headaches, palpitations, and diaphoresis, in association with severe hypertension. Many manifestations of thyrotoxicosis are due to increased adrenergic tone and may be confused with an anxiety disorder, especially post-traumatic stress disorder (PTSD). PTSD is common in soldiers or veterans who were exposed to the psychological stresses associated with being in a combat area. Specifically, PTSD can be characterized by persistent symptoms of increased arousal, hypervigilance, difficulty concentrating, irritability, outbursts of anger, difficulty falling or staying asleep, and an exaggerated startle response with an increase in heart rate, respiration, sweating, and muscle tension. Symptoms last longer than a month and develop after a person sees, is involved in, or hears of an "extreme traumatic stressor," accompanied by intense fear, helplessness, or horror. When an active duty soldier or veteran presents with some or all of these symptoms, PTSD should be considered when other organic causes have been ruled out.

The diagnosis was confirmed based on the patient's signs and symptoms and laboratory values revealing a low serum thyroid-stimulating hormone (TSH) of

2. Which of the following is the most reasonable next step in the evaluation of this patient?

a. radioactive iodine uptake (RAID)

b. serum thyroid antibodies

c. Fine-needle aspiration biopsy (FNAB) of the thyroid

d. Computed tomography (CT) of the neck

e. Magnetic resonance imaging of the neck

The patient's elevated levels of free thyroxine (free T4 and T3) correspond with a decrease in TSH because of the intact feedback inhibition of the hypothalamic/pituitary axis. The differential diagnosis includes Graves' disease, subacute thyroiditis, toxic adenoma, toxic multinodular goiter, and exogenous thyroid hormone. Unless the source of thyrotoxicosis can be clearly determined by history (e.g., the patient reports taking exogenous thyroid hormone and has no goiter), a RAIU is the next step to help differentiate the different thyrotoxic states in nonpregnant patients. A high uptake indicates de novo synthesis of thyroid hormone and can be caused by Graves' disease, toxic multinodular goiter, Hashimoto's thyroiditis, iodine deficiency, and toxic adenoma. Conversely, a low uptake indicates little activity and can be caused by inflammation and destruction of thyroid tissue with release of preformed hormone into the circulation (e.g., subacute thyroiditis, silent thyroiditis) or in patients on excessive levothyroxine therapy. A recent administration of a large amount of iodine, such as in a contrast CT study, can saturate the iodine receptors and cause the uptake to appear erroneously low. Although TSH receptor antibodies are present in the sera of almost all patients with Graves' disease, their measurement is available only in some settings and is not the favored diagnostic test in patients who can undergo a RAIU. Antibodies to thyroglobulin and thyroid peroxidase may also be present but are not diagnostic. Thus, thyroid antibody levels need not be obtained unless the cause of the hyperthyroidism is unclear from the history, physical examination, and other laboratory tests. Currently, thyroid FNAB is an essential step in the work-up of thyroid nodules but not thyrotoxicosis. CT and magnetic resonance imaging become important when evaluating substernal goiters and their impingement on adjacent tissues.

The RAIU showed a 24-hour radioiodine uptake of ^sup 131^I of 79.1% (normal, 5% to 25%).

3. Which one of the following is the most reasonable next step in the evaluation of this patient?

a. thyroid ultrasound

b. thyroid scintiscan

c. fine-needle aspiration

d. subtotal thyroidectomy

e. total thyroidectomy

The increased RAIU most likely confirms de novo synthesis of thyroid hormone from the thyroid gland, and the most common cause of hyperthyroidism is Graves' disease. Several studies have shown that the prevalence of thyroid nodules in patients with Graves' disease to be at least twice that of the general population.4 Because thyroid nodules associated with Graves' disease have a higher likelihood of malignancy and aggressiveness, with malignancy rates ranging from 1% to 9%,5 it is important to perform an anatomical study of the thyroid for cancer, once Graves' disease is suspected. The sensitivity of thyroid palpation for malignancy is poor.6 One-third of patients diagnosed with thyroid cancer in Graves' disease have been found not to have a palpable nodule on examination.5 Not only may nodules be too small to palpate, the nodules may be nonpalpable if they are deeply located in a large goiter. However, screening all Graves' patients with thyroid ultrasound leads to an unacceptably high rate of false positive nodules, leading to unnecessary FNABs.7 We advocate the use of thyroid scintiscan in addition to palpation in screening for thyroid cancer in patients with Graves' disease.5 Scintiscans are easily obtainable at the time of the thyroid uptake study and yield important information on underactive or "cold" nodules, which can be indicative of malignancy. Thyroid scintigraphy is also helpful in demonstrating diffuse tracer uptake (Graves' disease) versus nodular tracer concentration (toxic adenoma, toxic multinodular goiter). Any significant cold defects discovered can then undergo further evaluation, to include a thyroid ultrasound to confirm the presence and size of a nodule. Nodules confirmed by ultrasound should undergo FNAB to rule out malignancy.6 Patients should be referred for subtotal or total thyroidectomy if FNAB results suggest thyroid cancer or if clinical suspicion of a malignancy is high irrespective of pathology results.

The patient had a thyroid scintiscan that showed an unusual scintigraphic pattern with an asymmetric and or heterogeneous distribution within the right lobe of his thyroid. This heterogeneous pattern was indicative of a cold nodule. Thyroid ultrasound was performed to better characterize the right thyroid and did not reveal a discrete nodule or mass.

4. Which of the following treatments can be initiated at presentation before completion of diagnostic testing?

a. salicydates and nonsteroidal anti-inflammatory agents

b. steroids

c. levothyroxine

d. β blocker therapy

e. surgery

For patients with subacute or silent thyroiditis, salicydates or nonsteroidal anti-inflammatory agents may be effective in controlling the neck pain seen in these disorders. In severe cases of thyroiditis, the use of steroids may be indicated for short-term therapy. Prednisone started at 40 to 60 mg/day for 1 week should provide prompt results within a day or two. Levothyroxine is thyroid replacement therapy and is indicated for the treatment of "hypothyroidism." β-adrenergic blocking agents are useful for ameliorating the symptoms of thyrotoxicosis regardless of the etiology. In many tissues, thyrotoxicosis increases the number of β-adrenergic receptors.7 The resulting increase in adrenergic activity is responsible for many of the symptoms of thyrotoxicosis and explains the ability of β blockers to ease palpitations, tachycardia, tremulousness, anxiety, and heat intolerance.1 Although all β blockers are effective in relieving the symptoms of thyrotoxicosis, either sustained release propranolol or a long-acting β-1 selective antagonist such as atenolol or metoprolol is recommended.1 Propranolol may be started at a dose of 10 mg three times a day. The starting dose of atenolol or metoprolol is 25 to 50 mg/day, but can be increased up to 100 mg/day as required. Objective demonstration of effective β blockade may be demonstrated by a resting heart rate less than 80 beats/minute. Treatment with β blockers may be initiated before completion of diagnostic testing. Surgical thyroidectomy treats thyrotoxicosis by reducing overall hormone output. Surgery is infrequently recommended but is appropriate in certain situations. Typical candidates are those with large goiters, patients intolerant to antithyroid drugs, and patients who refuse radioiodine therapy, pregnant women who cannot take antithyroid medications, and patients with thyroid cancer. Because of the risk of removing too much or too little thyroid tissue, the potential complications associated with general anesthesia and the possibility of hypoparathyroisim and recurrent laryngeal nerve damage, surgery is not the preferred method of treatment in the United States.

Propranolol at a dose of 10 mg three times a day was initiated at Landstuhl Regional Medical Center and was changed to metoprolol at a dose of 50 mg once a day at Walter Reed Army Medical Center with a noticeable decrease in the patient's tremors and resolution of the patient's tachycardia and palpitations.

5. What physical limitations are necessary for military personnel with thyrotoxicosis?

a. restrict patient to quarters

b. all duties at own pace with no prolonged exposure to excessive heat

c. running at training heart rate for up to 60 minutes daily

d. no mandatory physical training, but soldier must be able to pass physical training test and height/weight standards

e. strict record of daily body weight but otherwise no physical limitations

Symptoms of thyrotoxicosis, such as tremors, heart palpitations, and gastrointestinal disturbances, can impair exercise. Thus, it is important to make the correct diagnosis and provide proper treatment so that patients can safely and comfortably resume their activities. In the meantime, active duty soldiers presenting with these symptoms should be air-evacuated from the theater and worked up immediately. Referral to a Medical Evaluation Board is not required because their condition is generally treatable. These soldiers should be placed on a physical profile that details the level of their physical duties. In thyrotoxicosis, the patient is hypermetabolic at baseline and starts at a higher metabolic rate, temperature, and heart rate at rest. It takes little or even no exertion to push these patients to a physical maximum, even to the risk of a cardiac event. For these reasons, it is inappropriate for these patients to participate in any organized physical training. However, mild activity performed at the individual's own pace is appropriate. Also, the thyrotoxicosis will interfere with temperature regulation and volume status; therefore, duty in hot environments, such as a desert in summer, should be restricted. Finally, weights should not be recorded formally because these weights are influenced by this systemic illness and are not representative of the patient's baseline. Patients should be permitted to wait until their clinical symptoms have improved, become euthyroid, and are tolerating a stable treatment plan before resuming regular activities. Military record physical fitness tests and body weight measurements should be postponed until after the disease has been treated definitively and thyroid function tests have normalized and demonstrated stability on repeated assessments.

The patient was given the appropriate profile and treated with radioactive iodine therapy for definitive therapy. Thyroid function tests were checked every 4 to 6 weeks and, after 2 months, the patient became hypothyroid. Levothyroxine at a dose of 125 µg once a day was initiated and metoprolol was discontinued. Thyroid function tests were checked again every 4 to 6 weeks until a goal TSH of 1 to 2 UIU/mL was achieved, and then were checked annually. Following normalization of TSH, no further work or duty restrictions were necessary.

Discussion

Robert Graves first identified the association of goiter, palpitations, and exophthalmos in 1835.1 Graves' hyperthyroidism is caused by thyroid-stimulating antibodies that bind to and activate the thyrotropin receptor on thyroid cells.8,9 Although thyroid-stimulating antibodies cause Graves' hyperthyroidism, the serum antibody concentrations are very low and are even undetectable in some patients.10 The most common symptoms of Graves' disease are nervousness, fatigue, a rapid heartbeat or palpitations, heat intolerance, and weight loss. A combination of these symptoms is present in more than one-half of all patients. The physical examination may reveal tremor, anxiety, brisk reflexes, palmar erythema, and tachycardia. The patient's thyroid gland is usually diffusely enlarged and nontender. Clinically evident ophthalmopathy occurs in approximately 50% of patients with a lower prevalence in Asians than in Caucasians. Older men and smokers are at highest risk of severe ophthalmopathy.

The diagnosis of Graves' hyperthyroidism is based on the clinical and biochemical manifestations of hyperthyroidism. Laboratory studies include a TSH, a free T4, and a free T3. In Graves' disease, the patient's free T4 or T3 levels are elevated with a corresponding decrease in TSH because of the intact feedback inhibition of the hypothalamic/pituitary axis. In more than 90% of patients with hyperthyroidism, the T4 and T3 are both elevated. In 5 to 10% of patients in the United States, T3 is exclusively elevated and the T4 is normal or even low.9 Therefore, the failure to obtain a T3 could result in missing the diagnosis. Although Graves' disease is the most common cause of hyperthyroidism, other causes should be ruled out when the diagnosis is in doubt. The differential diagnosis includes subacute thyroiditis, toxic adenoma, toxic multinodular goiter, and exogenous thyroid hormone. The RAIU and scan can help differentiate Graves' disease (diffusely increased uptake), toxic nodules (focal uptake) and subacute, chronic, or postpartum thyroiditis (low uptake). The RAIU is a safe and painless test that reflects the activity level of the gland. In this test, a set dose of radioactive iodine is orally administered after an overnight fast. The dose can be given either by capsule or in a liquid form. Once the radioactive iodine has been administered, the uptake into the thyroid is determined 4 to 24 hours later when the uptake has reached a plateau. The uptake is determined by using a radiation detector that is placed over the thyroid to determine the percentage of the dose that was taken up by the thyroid. Thyroid nodules associated with Graves' disease have a higher likelihood of malignancy and may be more aggressive if cancerous; therefore, a thyroid scan at the time of the radioactive uptake study is recommended for all patients.5 Then, patients whose scans reveal a photopenic ("cold") defect should have an ultrasound to confirm whether a nodule is present and, if so, whether it should undergo a fine-needle aspiration biopsy of the nodule.5

The treatment goals of Graves' disease are to control symptoms and restore euthyroidism. β blockers can decrease distressing adrenergic symptoms until the patient becomes euthyroid. Antithyroid drugs, radioiodine, and surgery have all be shown to restore euthyroidism but have potentially serious side effects. The antithyroid medications propylthiouracil and methimazole inhibit thyroid hormone synthesis. Studies reveal that methimazole is more effective than propylthiouracil at equivalent doses, decreases thyroid hormone levels more rapidly, and achieves euthyroidism sooner. Side effects of antithyroid medications include leucopenia, rash, pruritus, arthralgias, and rarely agranulocytosis (0.3%). A white blood cell count should be obtained if there is any sign of fever, infection, or sore throat, given the risk of agranulocytosis. Radioactive iodine ablation is a common, safe treatment. It is rapidly incorporated into the thyroid, and via its β emissions, produces radiation thyroiditis and fibrosis resulting in euthyroidism or hypothyroidism. The main contraindication is pregnancy, although radioactive iodine should be used with great caution in patients with severe Graves' ophthalmopathy because it can worsen the ophthalmopathy. Successful treatments will often cause patients to become slightly hypothyroid, and lifelong thyroid supplementation may be required. Thyroidectomy is infrequently used in this country, but may be indicated for patients who have large goiters, thyroid nodules, and patients who are pregnant and allergic to antithyroid medications. Surgery should also be performed on all patients with Graves' disease with a coexisting discrete nodule responsible for a cold area on thyroid scan if the biopsy result of the nodule causes concern.6 Reported complications of surgery include hypoparathyroidism and vocal cord paresis attributable to damage of the recurrent laryngeal nerve. Because all available treatments have serious drawbacks, discussion of the risks and benefits of each option with the patient is important.

Answers

1. a; 2. a; 3. b; 4. d; 5. b

References

1. Geffner DL, Hershman JM: β-Adrenergic blockade for the treatment of hyperthyroidism. Am J Med 1992; 93: 61-8.

2. Pacini F, Elisei R. Di Coscio GC. Anelli S, et al: Thyroid carcinoma in thyrotoxic patients treated by surgery. J Endocrinol Invest 1988; 11: 107-12.

3. Cantalamessa L, Baldini M. Orsatti A. Meroni L. Amodei V. Castagnone D: Thyroid nodules in Graves's disease and the risk of thyroid carcinoma. Arch Intern Med 1999; 159: 1705-8.

4. Stocker DJ. Foster SS. Solomon BL. Shriver CD. Burch HB: Thyroid cancer yield in patients with Graves' disease. Thyroid 2002; 12: 305-11.

5. Bilezikian JP. Loeb JN: The influence of hyperthyroidism and hypothyroidism on α and β adrenergic receptor systems and adrenergic responsiveness. Endocr Rev 1983; 4: 378-88.

6. Rapoport B. Chazenbalk GD, Jaune JC. McLachlan SM: The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocrine 1998; 19: 673-716.

7. Mazzaferri EL: Thyroid cancer and Graves' disease: the controversy ten years later. Endocr Pract 2000; 6: 221-5.

8. Chazenbalk GD, Wang Y, Guo J, et al: A mouse monoclonal antibody to a thyrotropin receptor ectodomain variant provides insight into the exquisite antigenic conformational requirement, epitopes and in vivo concentration of human autoantibodies to the TSH autoantibodies. J Clin Endocrinol Metab 1999; 84: 702-10.

9. Perros P, Crombie AL. Matthews JNS. Kendall-Taylor P: Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol 1993; 38: 367-72.

10. Singer PA, Cooper DS. Lew EG, et al: Treatment guidelines for patients with hyperthyroidism and hypothyroidism: standards of care committee, American Thyroid Association. JAMA 1995; 273: 808-12.

Guarantor: CPT Suyoung Tina Chang, MC

Contributors: CPT Suyoung Tina Chang, MC; MAJ Derek J. Stocker, MC

Copyright Association of Military Surgeons of the United States Jun 2005
Provided by ProQuest Information and Learning Company. All rights Reserved