Hyperthyroidism

Focus on Graves' Disease

Laurie Grubbs, ARNP, PhD, Sally Karioth, PhD

Laurie Grubbs is a Professor of Nursing at Florida State University, Tallahassee; Sally Karioth is an Associate Professor of Nursing, also at Florida State University.

A 55-year-old nurse presented to the family practitioner after noticing what she thought was ptosis of her right eyelid. She also had several vague, unrelated complaints of fatigue, depression, headache, weakness in her legs, clumsiness, hot flashes, palpitations, and hyperdefecation with 5-lb weight loss.

The patient attributed these complaints to grief over her brother's long illness and death from a brain tumor six months earlier and to a flare-up of colitis--either from stress or viral gastroenteritis contracted during a trip to England two months prior. A physician in England had prescribed a course of antibiotics and cortisone enemas for the diarrhea, but the treatment had not resulted in considerable improvement.

The patient denied chest pain, shortness of breath, dizziness, nausea or vomiting, or diplopia. She reported difficulty with her contact lenses due to "dry eyes" and had occasional blurred vision.

One year earlier, the patient had been seen by an ophthalmologist for a complaint of floaters in her right eye. She was diagnosed with a small vitreous hemorrhage that resolved spontaneously without subsequent retinal tear. Surgery was not indicated and the symptoms did not return.

The patient, an infrequent alcohol drinker and a nonsmoker, was divorced but in a stable, 15-year relationship and the mother of a 22-year-old. She had a history of colitis that had been in remission for more than 10 years. Recent medication use included hormone replacement therapy and vitamins. Her parents and sister were alive and in good health; there was no family history of autoimmune or thyroid disorders. Her job entailed extensive travel in the United States and Europe.

At physical examination, the woman's weight was measured at 126 lb; height, 5'5"; blood pressure, 180/100 mm Hg; heart rate, 98 beats/min with no murmurs; respiratory rate, 20 breaths/min. There was asymmetry of the eyelids, but rather than ptosis of the right eyelid (the patient's chief complaint), there was a scleral ring above the left eye characteristic of proptosis; the right eye was normal. Extraocular movements were conjugate and visual fields full. Corrected vision was 20/20 in both eyes.

Ophthalmoscopic examination with dilation showed no hemorrhages or papilledema. Disc margins were sharp, with no cupping or atrophy. Vessels were normal and without arteriovenous crossing changes. There was no evidence of retinal tears or macular degeneration. Ocular pressure was 18 mm Hg.

The remainder of the cranial nerve examination and the neurologic examination was normal except for deep tendon reflexes of 3+. The lungs were clear, and no carotid bruits were detected. Her thyroid was easily palpable but not enlarged or nodular. The abdomen was nontender, with active bowel sounds and no bruits; rectal examination and hemocult returned negative results. An electrocardiogram tracing showed a tachycardic sinus rhythm.

The patient's complaint of headache and the finding of unilateral exophthalmos required that tumor or aneurysm be ruled out; a CT of the head with contrast showed neither.

Laboratory findings were as follows: metabolic panel within normal limits; erythrocyte sedimentation rate (ESR), 16 mm/h; hemoglobin, 12.2 g/dL; hematocrit, 36.9%; white blood cell count (WBC), 8.0 x 10³/mL; platelets, 396,000/10³ mL; free T₄ (thyroxine), 1.74 ng/dL; thyroid-stimulating hormone (TSH [thyrotropin]), 0.011 mIU/mL. The patient was given a diagnosis of Graves' disease.

Description, Risk Factors, Presentation

Graves' disease (also called diffuse toxic goiter) is an autoimmune illness characterized by thyroid hormone hypersecretion, hypertrophy, and hyperplasia of the thyroid follicles. Specifically, thyroid-stimulating antibodies activate thyrotropin receptors, causing the thyroid to grow and the thyroid follicles to increase thyroid hormone synthesis.¹ Graves' disease is the most common cause of hyperthyroidism (except in patients older than 55, in whom toxic multinodular goiter is a more common etiology²).

Onset of this condition can occur at any age, but it is most common among women between ages 20 and 50.³ Often patients have a family history of Graves' disease or other autoimmune diseases, such as Hashimoto's disease, an autoimmune hypothyroid disorder. ⁴ Other factors that may predispose one to Graves' disease include:

• Heredity.
• Female sex.
• Recent adverse events (eg, job loss, bereavement, divorce).
• Smoking.
• Parity.
• Pregnancy.
• Viral and bacterial infections.
• Iodine supplementation or exposure to an iodine load such as those used in diagnostic tests.
• Lithium, amiodarone, or antiretroviral therapy.
• Type 1 diabetes mellitus.^1,5,6

During pregnancy, thyroid function can be disrupted, with 1% to 2% of women experiencing overt dysfunction. Symptoms of Graves' disease tend to be more severe in the first trimester, with improvements seen during the remainder of the pregnancy.⁷ Postpartum relapse is possible⁸; by the same token, diminished function of T cells and B cells during pregnancy may lead to onset of Graves' disease three to six months postpartum.^9,10

The clinical manifestations of Graves' disease include those typical for hyperthyroidism, such as nervousness and irritability, tremor, heat intolerance, and tachycardia.¹ These symptoms are far less common in patients older than 50, who often present atypically (eg, absence of thyroid changes, apathy).³ Cardiac symptoms, such as atrial fibrillation and heart failure, occur in more than 20% of elderly patients¹ (see Table 1¹ for a more complete list of manifestations of hyperthyroidism, Graves' disease, and conditions associated with Graves' disease).

Patients with symptoms of hyperthyroidism can be said to have Graves' disease if they have at least one of the following symptoms: diffuse goiter (which this patient did not have), infiltrative dermopathy (which is less common), and/or exophthalmos (which most likely accounts for this patient's difficulty wearing contact lenses; see Figure 1).

Diagnosis

Diagnosis of Graves' disease is made by clinical symptoms, physical examination, and laboratory studies. Often, clinical symptoms are vague, especially in older patients (who may present only with cardiac symptoms or weight loss¹¹), and could be attributed to anxiety or stress, particularly in cases where patients report recent adverse life events. Patients with newly diagnosed Graves' disease, when compared with patients in a control group, reported experiencing significantly greater psychological stress and a greater number of adverse life events prior to disease onset.⁵

Diffusely enlarged thyroid gland occurs in 90% of patients younger than 50 and in 75% of older patients.¹ Nodules should be investigated with ultrasound and fine-needle aspiration to rule out malignancy, particularly in older patients. Clinically evident ophthalmopathy (including exophthalmos, lid lag, periorbital edema, retrobulbar pressure or pain, extraocular muscle dysfunction, and scleral injection) is most often bilateral and occurs in 50% of patients. Approximately 90% of patients who present with ophthalmopathy have hyperthyroidism.¹

A thyroid profile with a low TSH level (< 0.1 m IU/mL) and elevated levels of T₃ (triiodothyronine) and T₄ is necessary for a diagnosis of Graves' disease.^8,11 The T₃ level, determined by radioimmunoassay, is commonly used to diagnose hyperthyroidism, because T₃ is preferentially secreted in early Grave's disease and in toxic nodular goiter, thereby causing elevated T₃ levels.¹²

Other laboratory studies to consider include an ESR (which can be elevated in Graves' disease) and a complete blood cell count to rule out anemia or an elevated WBC count (both of which are also associated with Graves' disease). A chemistry panel with special attention to calcium, glucose, and potassium can rule out pheochromocytoma and primary aldosteronism. (Pheochromocytoma may manifest with hypertension, hypermetabolism, hypercalcemia, headache, and/or hyperhidrosis; most pheochromocytoma can be detected with an assay of urinary catecholamines, metanephrines, vanillylmandelic acid, and creatinine. In primary aldosteronism, hypertension, hypernatremia, hyperkalemia, and/or elevated aldosterone levels may be evident.¹³)

For further differentiation of the etiology of the hyperthyroidism, thyroid autoantibodies (eg, TSH receptor antibodies, thyroid peroxidase autoantibodies) can be measured.^8,11 Elevated levels suggest autoimmune disease, Hashimoto's thyroiditis, or Graves' disease. Hashimoto's and Graves' diseases may have a common genetic basis, as demonstrated in one study where the two conditions were often found to occur within one family.⁴

Radioactive iodine (RAI) imaging can also help differentiate the cause of Graves' disease (increased uptake), toxic multinodular goiter (normal or slightly increased uptake), Hashimoto's disease (increased uptake), thyroiditis (decreased uptake), iodine load, or intake of excess exogenous thyroid hormone (decreased uptake). The additional benefit of RAI imaging is that it can determine whether nodules are high uptake ("hot," ie, autonomously functioning) or low uptake ("cold"). As many as 15% of low-uptake nodules have been shown on biopsy to be malignant.^8,12

Localized dermopathy, most commonly pretibial myxedema, affects approximately 4% of Graves' disease patients, including 1% to 2% of patients with ophthalmopathy.^8,14 In fact, patients with dermopathy tend to have more severe ophthalmopathy than patients without dermatologic manifestations.¹⁵ Dermopathy usually presents as nonpitting, localized edema with some raised, hyper pigmented violaceous papules. Topical steroids applied under occlusive plastic dressing film for three to 10 weeks is a common treatment.^8,16

Treatment

Although treatment options include antithyroid medications and surgery, RAI is the preferred treatment for most patients in the United States.¹⁷ It is important, however, to include patients in deciding which treatment option is best for them.¹¹

RAI therapy

Treatment goals vary, with some clinicians opting to render the patient euthyroid by giving the lowest possible doses of RAI. However, this treatment often leads to permanent hypothyroidism, which requires lifelong thyroid hormone supplementation.¹⁸ Other adverse events include transient worsening ophthalmopathy, hypoparathyroidism, and radiation thyroiditis.^1,19 Intentional full ablation of the thyroid gland, of course, also requires lifelong thyroid hormone supplementation but may be preferred to avoid trial and error. ^11,20 RAI is contraindicated in patients who are pregnant or who are contemplating becoming pregnant within six months, as it ablates the fetal thyroid.¹²

In patients with severe hyperthyroidism and in elderly patients (especially those with a history of cardiac disease), pretreatment with antithyroid drugs is recommended to deplete the gland of stored thyroid hormone.¹² However, antithyroid medication may also decrease the effectiveness of RAI.^21,22

Follow-up for patients receiving RAI treatment should be scheduled every four to six weeks until they are euthyroid and their condition is stable. Euthyroid patients who become hypothyroid usually do so within three months.¹¹

Antithyroid medications

The most commonly prescribed antithyroid medications are methimazole and propylthiouracil (PTU). Methimazole, with approximately 10 times the potency of PTU on a weight basis, has the advantage of once-a-day dosing, thus increasing compliance.²⁰ PTU, which is less likely than methimazole to cross the placenta, is the drug of choice for pregnant or lactating women.¹⁹

Minor adverse effects of both methimazole and PTU include rash, urticaria, arthralgia, fever, nausea, anorexia, and changes in taste and smell. The most serious adverse effect--agranulocytosis--is rare, but patients need close blood count monitoring for this condition.⁹ In addition, patients should be instructed to promptly report symptoms of agranulocytosis (eg, sore throat, fever) to their health care provider, who in turn should stop medication immediately until agranulocytosis is ruled out.¹⁹ Other serious adverse effects include thrombocytopenia, hepatitis, vasculitis, and insulin autoimmune syndrome.^23-25

It may take six to eight weeks to see significant effects of the antithyroid medication. Approximately 30% to 40% of patients experience remission after 18 months of antithyroid drug treatment,¹ but there are no reliable markers to predict the course and outcome of drug therapy. The likelihood of relapse--which occurs in more than half of patients after drug therapy is stopped--depends on factors such as severity of the disease (patients with subclinical hyperthyroidism may be less likely than patients with overt disease to achieve good control²), size of the goiter, and exposure to dietary and other sources of iodine.^12,19

Surgery

Total or subtotal thyroidectomy, neither of which is often used, may be appropriate for patients with a large goiter, those with coexistent thyroid nodules, and those with contraindications to RAI or antithyroid medications.³ Surgical complications include hemorrhage, hypoparathyroidism, laryngeal nerve damage, and hypothyroidism.^1,11 Many patients are treated with antithyroid medications before surgery to prevent rapid release of thyroid hormone.

In subtotal thyroidectomy, the intent is usually to leave sufficient thyroid remnant to reduce the risk of hypothyroidism--although the larger the remnant, the greater the likelihood that hyperthyroidism will recur. For patients who undergo thyroidectomy, long-term follow-up is required.¹

Adjunctive therapy

b-Adrenergic blockers may be given as adjunctive therapy. Through two mechanisms (ie, blocking the sympathetic drive from the excess thyroid hormones and blocking the conversion of inactive T₄ to active T₃), they provide rapid relief of symptoms such as palpitations, tremors, anxiety, heat intolerance, and various eyelid signs. They are also useful in preventing episodes of hypokalemic periodic paralysis in susceptible patients. Options in this class of medication include propranolol, atenolol, and metoprolol.²⁰

Iodides decrease activity of the thyroid gland by reducing thyroidal iodide uptake, oxidation, and organification, and by blocking the release of thyroid hormones. These are often administered prior to surgery because of their ability to decrease vascularity of the thyroid gland.²⁰

Resolution of the Case

The case patient was severely hyperthyroid, and pretreatment with antithyroid medications was instituted before RAI could be considered. She was placed on extended-release propranolol hydrochloride 120 mg/d (to treat symptoms of tachycardia and hypertension) and methimazole 5 mg twice daily.

Based on findings during the next four monthly follow-up visits, propranolol was discontinued and methimazole treatment was adjusted or discontinued accordingly. Severe transient hypothyroidism at the three-month follow-up necessitated a month-long course of levothyroxine sodium. At six months, it appeared that the patient's condition had stabilized, and all medications were discontinued. The patient was instructed to return in three months, or sooner if she had symptoms of hypothyroidism or hyperthyroidism. As of this writing, RAI treatment has not been indicated for this patient.

Disease Prognosis

E ven with treatment, the prognosis of Graves' disease is variable.²⁶ Often the disease worsens during the first 12 months, then gradually improves. Approximately 60% of patients show spontaneous improvement of ophthalmopathy without specific treatment for eye disease,²⁷ as was the case with this patient (see Figure 2).

For patients with untreated or poorly treated hyperthyroidism, however, ophthalmopathy is likely to progress--often leading to compromised vision or even blindness as a result of corneal lesions or compression of the optic nerve.^1,27 Smokers are at particularly high risk. Treatment-induced hypothyroidism, on the other hand, can also worsen ophthalmopathy.¹¹

Other long-term effects of untreated hyperthyroidism include osteoporosis (especially in postmenopausal women), fetal loss in pregnant women, severe weight loss, cardiac complications, and complications associated with hypertension (eg, stroke, kidney disease). ^1,11,27,28

Thyroid storm is an acute exacerbation of Graves' disease that can be triggered by concomitant illnesses (eg, bacterial infection or trauma), by discontinuation of antithyroid drugs, or (particularly in elderly or debilitated patients) by thyroid hormone release associated with RAI treatment.¹⁹ This endocrine emergency is ordinarily characterized by high fever (102F to 106F), tachycardia, nausea, vomiting, agitation, delirium, and coma; elderly patients may exhibit extreme weakness and apathy (apathetic storm).²⁹

Patients who experience thyroid storm require hospitalization and prompt referral to an endocrinologist. Treatment with steroids, PTU, b-blockers, or calcium channel blockers (with corticosteroids) is necessary.¹⁹ Currently, the mortality rate of thyroid storm is about 20%.³⁰

Conclusion

The diagnosis in this case was a challenge due to the patient's past medical history, recent stressful life events, and atypical symptoms. It is important to remember that in patients older than 50, symptoms may be atypical.

Hyperthyroidism can be difficult to manage, and it may take several months before symptoms stabilize and the correct dosing of any prescribed medication can be determined. Patients should be monitored every one to three months until thyroid functions stabilize, then every six to 12 months for repeat laboratory work-up and medication adjustments, if needed.

References

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