Detecting Graves' Disease: Presentations in Young Athletes
David H. Wang, MD, MS; Scott M. Koehler, MD; Cary N. Mariash, MDTHE PHYSICIAN AND SPORTSMEDICINE - VOL 24 - NO. 12 - DECEMBER 96
In Brief: Graves' disease has a multitude of presentations, and certain symptoms can mimic sports-related concerns such as overtraining. A review of three cases of Graves' disease in young athletes illustrates the spectrum of symptoms and the pathophysiology. Diagnosis involves a detailed patient history, physical exam, and appropriate lab studies, including a thyroid radioactive iodine uptake scan. Treatment consists of symptom management and antithyroid medication, radioactive iodine thyroid ablation, or, rarely, thyroidectomy.
Graves' disease is relatively common in the general population, so the condition is not unusual in active people. Though the symptoms vary widely, they can mimic overtraining syndrome or chronic fatigue, making it important to consider Graves' disease in the workup of patients who report fatigue, depression, muscle weakness, or menstrual irregularity.
Some symptoms of Graves' disease, such as tremors, heart palpitations, and gastrointestinal disturbances, can impair exercise. Thus it's important to make the correct diagnosis and provide proper treatment so that patients can safely and comfortably resume their activities. The following cases illustrate the impact of Graves' disease on activity and demonstrate the diagnostic workup.
A 21-year-old female college golfer complained of shaky legs when addressing the golf ball and of periodic hot flushes. She denied tremors at any other time. Her history revealed that she might have had a recent 5- to 10-lb weight gain; she denied menstrual or visual changes. Her family history was not significant for thyroid disease.
The physical exam demonstrated a prominent stare (figure 1). Her vital signs were significant for tachycardia; her heart rate was 110 beats per minute. There was no evidence of mental status changes. The thyroid gland was nontender and diffusely enlarged to three times the normal size. The ophthalmologic exam revealed bilateral proptosis and eyelid retraction without lid lag. There was no obvious eyelid or conjunctival edema. The cardiac exam revealed a grade 2/6 systolic flow murmur. Electrocardiography demonstrated sinus tachycardia and a regular rhythm.
The patient was diagnosed as having presumed Graves' disease and treated with propranolol hydrochloride to control the tachycardia. The laboratory evaluation demonstrated a thyroid-stimulating hormone (TSH) level of under 0.05 microunits/mL (normal range, 0.3 to 0.5 microunits/mL), a free thyroxine (T4) index of 18.8 micrograms/dL (5 to 12 micrograms/dL), and a free triiodothyronine (T3) index of 2,519 ng/dL (260 to 480 ng/dL). The antithyroid peroxidase level was 34 U/mL (0 to 0.4 U/mL), thyroid stimulating antibodies were 6.4 (0 to 1.3), and the antithyroglobulin antibody level was 12 U/mL (0 to 0.9 U/mL). A thyroid radioactive iodine uptake (RAIU) scan (figure 2) demonstrated a diffuse increased uptake consistent with Graves' disease.
Following an extensive discussion with the patient and family, it was decided to proceed with pharmacologic management for Graves' disease. The patient was started on methimazole, and her symptoms rapidly improved, allowing her to discontinue the beta blocker after 3 weeks. After 7 weeks, her T4 level was normal, and she was started on levothyroxine sodium. She was asymptomatic during her final year of competitive golf.
A 22-year-old female college track athlete presented with a complaint of fatigue for more than 1 month. She said she was very tired before starting her workout, feeling as though she'd already finished a difficult workout. She denied visual changes, palpitations, tremor, constipation, and diarrhea. Her appetite was good, with no recent weight change. She had no changes in her menstrual cycle or sleep patterns. She denied myalgia, joint pain, fever, sweats, and chills. Her family history was significant for thyroid disease in a grandmother.
On physical exam her vital signs were normal. On palpation, her thyroid was twice its normal size, symmetric, smooth, and without nodules. There was no ophthalmopathy. The laboratory evaluation revealed a TSH level of 0.02 microunits/mL, a T4 of 17.3 micrograms/dL, and T4 index of 25.4 micrograms/dL with antithyroglobulin antibodies of 6.5 U/mL and antithyroid peroxidase of 188 U/mL.
The thyroid RAIU scan showed diffusely increased uptake consistent with Graves' disease.
Treatment options were discussed with the patient, and it was agreed to proceed with antithyroid medications.
The patient's symptoms were worse at her 3-week follow-up. She complained of worsening fatigue, heat intolerance, feelings of increased heart rate, and amenorrhea. Because thyroid hormone levels were decreasing and she was tolerating the medication well, she was reassured that clinical improvement would take some time.
At the 6-week follow-up, the patient said she felt better than she had in the previous 4 months. She was started on a small dosage of levothyroxine. At the 3-month follow-up, the patient was doing well and said her menses had returned. She became euthyroid within 1 year, and levothyroxine was stopped. The patient successfully trained for and completed her senior track season.
A 17-year-old female high school volleyball and basketball player presented with increasing fatigue and difficulty concentrating in school. She also reported years of fluctuating weight and inconsistent menses.
The patient history revealed that she was being followed at another office for hyperthyroidism. Review of her records revealed that at age 14 she had presented to her local clinic with secondary amenorrhea and a 40-lb weight loss. That exam did not reveal any abnormalities. Thyroid function testing at that time revealed a TSH level of less than 0.01 microunits/mL, T4 of 13.1 micrograms/dL, T4 index of 20.7 micrograms/dL, plus antithyroid peroxidase of 4.9 U/mL, and antithyroglobulin antibodies of less than 1.0 U/mL. No further evaluation was performed, and the patient was followed for "hyperthyroidism." The patient was seen 13 times over the ensuing 3 years for various complaints including fatigue, decreased exercise tolerance, oligomenorrhea, palpitations, lightheadedness, chest discomfort, and abdominal discomfort. She was given the tentative diagnosis of infectious mononucleosis at one point despite the abnormal thyroid function tests.
Four months before presenting to our clinic, she had been seen at her local clinic with fatigue and tremors. Her thyroid was noted to be five times the normal size and was described as diffusely enlarged, soft, and nontender. Thyroid function testing again revealed hyperthyroidism, and the diagnosis of probable Graves' disease was made. Antithyroid medication was initiated. The patient did not tolerate the dosages of the medication and asked about other options. At this point she was referred to our clinic for further evaluation and treatment.
After the disease course and treatment options with the patient were discussed, she and her family elected for radioactive iodine treatment. She responded rapidly to the treatment. The patient stabilized and is now maintained asymptomatically on levothyroxine. She went on to play college basketball.
About Graves' Disease
Graves' disease is a common autoimmune disorder that is up to seven times more prevalent in females. The most common age of onset is in the third and fourth decades (1). The etiology of Graves' disease is not precisely known, but antibodies to the thyroid TSH receptors are usually present. Graves' disease also has a familial predisposition; abnormal immune response genes apparently err in allowing autoantibody formation. Specifically, an increased frequency of the haplotypes HLA-DRw3 and HLA-B8 has been found in white patients, while there is an increase of HLA-Bw36 in Japanese patients, and an increase of HLA-Bw46 in Chinese patients who have Graves' disease (1-3).
The implicated autoantibody—thyroid stimulating immunoglobulin (TSI)—appears to stimulate hyperthyroidism by binding to the TSH receptor on thyroid cells. In fact, current bioassays for TSI are 95% sensitive for Graves' disease (4).
The diagnosis of Graves' disease is made by the history, physical examination, and appropriate laboratory tests. If a patient presents with overt hyperthyroidism and orbital inflammation, Graves' disease is very likely. If there is no orbital involvement, a workup to determine the cause of the hyperthyroidism is indicated.
History. The typical history for patients who have Graves' disease consists of nervousness, depression, insomnia, tremors, frequent bowel movements, heat intolerance, sweating, weight loss despite a good appetite, weakness of the proximal muscles, and oligomenorrhea or amenorrhea in females (5-7). Dyspnea and palpitations are common, and older patients may present with only these complaints, making the diagnosis more difficult.
Physical exam. The physical exam may reveal tremor, anxiety, palmar erythema, brisk reflexes, and tachycardia. The patient's thyroid gland is usually diffusely enlarged and nontender. A bruit may be heard over the gland because of increased blood flow. Cardiac manifestations can include tachycardia and atrial arrhythmias such as atrial fibrillation.
The classic eye findings were present in the patient in case 1, but are not found in most patients who have Graves' disease. Ophthalmologic manifestations vary and can be classified as noninfiltrative and infiltrative. Lid lag and widened palpebral fissures are attributed to noninfiltrative sympathetic stimulation of the levator muscle of the upper eyelid. Exophthalmos results from pressure buildup behind the globe. The increased pressure is due to infiltration of the orbital tissues, especially the extraocular muscles, and from edema caused by the immunologic reaction. Increased pressure compromises venous drainage, which can lead to edema of the globe and conjunctiva (8,9). Blurred vision is an occasional complaint, while diplopia may be seen secondary to infiltration and weakness of the extraocular muscles (6,9,10).
Patients who have hyperthyroidism commonly develop characteristic soft, smooth skin. The skin is warm and moist from peripheral vasodilation. Some patients who have Graves' disease (0.5% to 4%) may develop infiltrative dermopathy over the dorsum of the legs and feet (5). This pretibial myxedema is characterized by hyperpigmented patches and plaques that are indurated to the touch. Dermopathy is seen only in patients who have infiltrative eye findings, which links dermopathy to the autoimmune process (6,10). As with ophthalmopathy, dermopathy may develop years into the course of the disease.
Lab tests. Lab studies for hyperthyroidism include a TSH, a free T4 index, and a free T3 index. In Graves' disease, the patient's T3 level is elevated with a corresponding decrease in TSH because of the intact feedback inhibition of the hypothalamic/pituitary axis. The thyroid RAIU scan should be performed and shows diffusely increased uptake in Graves' disease. T4, thyroid stimulating immunoglobulin, antithyroid peroxidase, and antithyroglobulin antibody levels are frequently elevated in Graves' disease. Antibody levels need not be obtained unless the cause of hyperthyroidism is unclear from the history, physical examination, and other laboratory tests.
Differential diagnosis. Though 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. An elevated TSH level suggests thyroid hormone resistance or, rarely, a tumor, while thyroid nodules suggest an adenoma or toxic multinodular goiter. The RAIU scan can help differentiate Graves' disease (diffusely increased uptake) from toxic nodules (focal uptake) and from subacute, chronic, or postpartum thyroiditis (low uptake). The differential diagnosis may also include anxiety, myasthenia gravis, or other diseases, depending on the patient's symptoms.
Two Goals for Treatment
Treatment for Graves' disease involves relieving the patient's symptoms and managing the overactive thyroid gland. Beta blockers can decrease distressing adrenergic symptoms (tremor, tachycardia) until the patient becomes euthyroid. The infiltrative changes in patients who have Graves' ophthalmopathy may or may not improve with thyroid treatment, and corticosteroids occasionally help reduce the edema and infiltration (8). Symptomatic corneal exposure can be treated by taping the eyelid closed at night. Other mild eye symptoms can be treated with sunglasses and artificial tears, but an ophthalmologist should be consulted for more serious symptoms. Orbital decompression may be indicated for severe proptosis, orbital inflammation, or optic neuropathy (8).
There are three established means for managing hyperthyroidism that exhibits increased iodine uptake: antithyroid medications, radioactive iodine ablation, and thyroidectomy.
The antithyroid medications propylthiouracil and methimazole inhibit thyroid hormone synthesis. Studies have suggested that 2 years of treatment with the addition of thyroid hormone replacement can lead to a remission in 40% to 65% of patients (7). The addition of thyroxine prevents elevations of TSH and therefore minimizes the immunologic stimulation from the thyroid gland. A more recent study (11) has questioned the validity of this strategy.
Side effects of antithyroid medications include leukopenia, rash, pruritus, arthralgias, and, rarely (0.3%), agranulocytosis (12). A white blood cell count should be obtained if there is any sign of infection, fever, or sore throat. These patients should be followed every 4 to 12 weeks until they are euthyroid, then every 3 to 4 months. T3 and T4 indexes should be followed because patients' TSH levels may remain suppressed for many months. After the medications are discontinued, patients should be seen at 4- to 6-week intervals for 3 to 4 months, after which the interval length may be increased.
Radioactive iodine ablation is a common, safe treatment (12). The main contraindication is pregnancy, so this must be ruled out before administering radioactive iodine. Successful treatment will often cause patients to become slightly hypothyroid, and lifelong thyroid supplementation may be required. Antithyroid medications may still be needed the first several months after radioactive ablation. Patients' thyroid state usually stabilizes 6 to 12 months after treatment, and they can be followed every 3 to 4 months, or as needed, with a T4 index and TSH tests. Once euthyroid, these patients should be followed yearly with a serum TSH test.13
Thyroidectomy is rarely used in this country, but may be indicated for patients who have large goiters or thyroid nodules, or for those who are pregnant and allergic to antithyroid medications (12). Surgical complications include hypoparathyroidism and recurrent laryngeal nerve injury (6). After surgery patients may be hypothyroid and require supplemental thyroid hormone. Usual follow-up is at 2 months to assess the thyroid status. A yearly TSH test should be performed regardless of whether patients require thyroid replacement or are euthyroid postoperatively.
The variability of presenting symptoms in patients who have Graves' disease was demonstrated by these three cases. In the golfer, the tremor was unusual because it was present only when the patient addressed the golf ball. Fatigue was the only prominent complaint in the case of the college runner, making Graves' disease difficult to differentiate from other potential causes of her fatigue, such as overtraining, anemia, illness, and depression. The more common symptoms of weight loss and menstrual changes were seen in the high school basketball player. This third case demonstrated how the symptoms of hyperthyroidism can be mistakenly attributed to other causes (such as infectious mononucleosis), and the diagnosis can be overlooked.
Dr Wang is director of general medicine and sports medicine clinics at Boynton Health Service and team physician at the University of Minnesota in Minneapolis. He is on the clinical faculty in the Department of Family Practice at the University of Minnesota Medical School. Dr Koehler is a first-year family practice resident at Oregon Health Sciences University in Portland, Oregon. Dr Mariash is a professor of medicine and cell biology at the University of Minnesota. Address correspondence to David H. Wang, MD, MS, University of Minnesota, Boynton Health Service, 410 Church St SE, Minneapolis, MN 55455; send e-mail to [email protected].
The authors thank Gerry Vuchetich for his photographic assistance.