Thyrotoxicosis/Graves Disease Case File

Thyrotoxicosis/Graves Disease Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 53

A 37-year-old, previously healthy woman presents to the clinic for unintentional weight loss. Over the past 3 months, she has lost approximately 15 lb without changing her diet or activity level, but she otherwise feels great. She has an excellent appetite, no gastrointestinal complaints except for occasional loose stools, and no complaints of fatigue. She denies heat or cold intolerance. On examination, her heart rate (HR) is 108 beats per minute (bpm) and blood pressure (BP) is 142/82 mm Hg, and she is afebrile. When she looks at you, she seems to stare, and her eyes are somewhat protuberant. You note a large, smooth, nontender thyroid gland and a 2/6 systolic ejection murmur on cardiac examination. Her skin is warm and dry. There is a fine resting tremor when she spreads her fingers.

▶ What is the most likely diagnosis?

▶ How could you confirm the diagnosis?

▶ What are the options for treatment?

▶ How might treatment differ if the patient were pregnant?

ANSWERS TO CASE 53:

Thyrotoxicosis/Graves Disease

Summary: A 37-year-old woman presents with

• Three months of unintentional weight loss without anorexia or increased activity level
• Tachycardia and borderline hypertension
• Exophthalmos
• A smooth, nontender goiter

Most likely diagnosis: Thyrotoxicosis/Graves disease.

Confirming the diagnosis: A low serum thyroid-stimulating hormone (TSH) level and an increased free thyroxine (T4) level with this clinical presentation would confirm the diagnosis of hyperthyroidism. However, other tests to define the etiology include thyroid-stimulating immunoglobulins (TSIs) or diffusely elevated uptake of radioactive iodine on thyroid scan.

Treatment options: Antithyroid drugs, radioactive iodine ablation, or less commonly, surgical removal of the thyroid.

Considerations in a pregnant patient: Radioactive iodine can cause spontaneous miscarriage or birth defects during pregnancy and is thus contraindicated. Methimazole (antithyroid drug) is also contraindicated in the first trimester of pregnancy.

ANALYSIS

Objectives

1. Describe the clinical presentation of thyrotoxicosis. (EPA 1)
2. Discuss the causes of hyperthyroidism, including Graves disease and toxic nodule. (EPA 1, 2)
3. List the complications of thyrotoxicosis, including thyroid storm. (EPA 10)
4. Describe the evaluation of a patient with a thyroid nodule. (EPA 1, 3)
5. Recognize the available treatment options for Graves disease and outcomes of treatment. (EPA 4)
6. Understand the considerations in management of a pregnant patient with thyrotoxicosis. (EPA 4, 10)

Considerations

This 37-year-old woman has unintentional weight loss, loose stools, and warm skin, which are all symptoms of hyperthyroidism. Her thyroid gland is diffusely enlarged and nontender, and she has exophthalmos (protuberant eyes), which is consistent with Graves disease. This is a systemic disease with many complications that affect the entire body, including osteoporosis and heart failure. Symptomatic treatments aim to eliminate the excessive thyroid hormone with antithyroid medication. Definitive therapy consists of radioactive ablative therapy or, less frequently, surgical excision.

APPROACH TO:

Hyperthyroidism

DEFINITIONS

HYPERTHYROIDISM: Hypermetabolic condition that results from the effect of excessive amounts of thyroid hormones produced by the thyroid gland itself. Because almost all cases of thyrotoxicosis are caused by thyroid overproduction, these terms are often used synonymously.

THYROID STORM: Rare but life-threatening condition caused by untreated hyperthyroidism. Can cause severe symptoms of thyrotoxicosis, such as tachycardia, fever, agitation, weakness, delirium, and most fatally, coma or death.

THYROTOXICOSIS: Usually used as a general term for the state of thyroid hormone excess from any source, for example, exogenous ingestion of thyroid hormone (factitious or iatrogenic).

CLINICAL APPROACH

Pathophysiology

Graves disease is the most common cause of hyperthyroidism (80%) and usually is seen in women, especially between the ages of 30 and 50 years. It is an autoimmune disease caused by autoantibodies that activate the TSH receptor of the thyroid follicular cell, stimulating thyroid hormone synthesis and secretion as well as thyroid gland growth. In the pregnant patient, these antibodies cross the placenta and can cause neonatal thyrotoxicosis. The disease might follow a relapsing and remitting course.

A low serum TSH will confirm the diagnosis. The degree of elevation of serum-free T4 and free T3 (triiodothyronine) levels can give an estimate of the severity of the disease. Tests that might be helpful in determining the etiology of thyrotoxicosis include the levels of TSI, which is elevated in Graves disease; thyroid peroxidase antibodies, which are markers of autoimmunity in both Graves disease and Hashimoto thyroiditis; and a thyroid uptake and scan, which will reveal diffusely elevated iodine uptake in our patient. Less common causes of thyrotoxicosis include the following:

Toxic multinodular goiter: Found mainly in elderly and middle-aged patients. Treatment consists of radioactive iodine or surgery. Radioactive iodine uptake is normal to increased, and the scan reveals irregular thyroid lobes and a heterogeneous pattern.

Autonomous hyperfunctioning adenoma (“hot nodule” or Plummer disease): Hyperthyroidism usually is not present unless the nodule is more than 3 cm. The iodine scan looks like the flag of Japan: It demonstrates the hot nodule as having increased uptake (dark) and the rest of the gland with suppressed uptake (white). Hot nodules are almost never malignant.

Thyroiditis: Caused by destruction of thyroid tissue and release of preformed hormone from the colloid space. Subacute (de Quervain) thyroiditis is an inflammatory viral illness with thyroid pain and tenderness. The hyperthyroid phase lasts for several weeks to months, followed by recovery, but some patients will then develop hypothyroidism. Treatment with nonsteroidal anti-inflammatory medications and beta-blockers usually is sufficient, but in severe cases, glucocorticoids might be used. Other forms include postradiation, postpartum, subacute (painless thyroiditis), and amiodarone-induced thyroiditis. In thyroiditis, the radioactive iodine uptake is decreased.

Pregnancy: The beta subunits of human chorionic gonadotropic (hCG) and TSH share considerable homology, and thus hCG has weak thyroid-stimulating effects. This can cause transient hyperthyroidism during peak hCG concentrations. Likewise, during normal pregnancy, there are changes in thyroid physiology to meet the increased metabolic demands. Rises in thyroid hormone-binding globulin can cause increased total T4 and total T3 concentrations without increased free T4 or free T3 concentrations.

Medications: Excessive ingestion of thyroid hormone (factitious or iatrogenic), amiodarone, and iodine load.

Diagnosis. Thyroid function tests indicating low TSH levels and increased free T4 or T3 levels are confirmatory for hyperthyroidism. Once the diagnosis has been established, the etiology should be determined. Tests to distinguish the cause of hyperthyroidism include measurement of thyrotropin (TSH) receptor antibodies, thyroid scan of radioactive iodine uptake, and measurement of thyroidal blood flow on ultrasound.

Positive thyrotropin receptor antibodies would indicate Graves disease as the most likely etiology. Thyroid scans of radioactive iodine uptake measure areas of thyroid activity. Hot nodules (areas of increased thyroid activity) are likely secondary to hyperfunctioning adenoma and are almost never malignant. Cold nodules (no demonstration of local uptake) have a 5% to 10% risk of malignancy. Fine-needle aspiration, surgical removal, or ultrasonographic follow-up is needed for these nodules.

Clinical Presentation

Hyperthyroidism is a multisystemic condition that can affect numerous body systems (Table 53–1). Weight loss is a common finding, especially in older patients who develop anorexia. Many patients develop an aversion to heat and a preference for cold temperatures. In apathetic hyperthyroidism, older patients may lack typical adrenergic features and present instead with depression or apathy, weight loss, atrial fibrillation, worsening angina pectoris, or heart failure.

Graves disease is marked by goiter (enlarged thyroid gland), thyroid bruit, hyperthyroidism, ophthalmopathy, and dermopathy. These features are variably present. Ophthalmopathy is characterized by inflammation of extraocular muscles, orbital fat, and connective tissue, resulting in proptosis (exophthalmos), sometimes with impairment of eye muscle function (diplopia), and periorbital edema. Ophthalmopathy, caused directly by the TSH receptor–directed antibodies, can progress even after treatment of thyrotoxicosis with antithyroid drugs or radioiodine ablation. Graves dermopathy is characterized by raised hyperpigmented orange peel texture papules. The most common site is the skin overlying the shins (pretibial myxedema).

Treatment

Treatment options for hyperthyroidism are medications, radioactive iodine, or surgery. Medications include beta-blockers such as propranolol (which are used for symptom relief) and antithyroid drugs such as methimazole and propylthiouracil (PTU).

The antithyroid drugs work mainly by decreasing the production of thyroid hormone. They can be used for short-term (prior to treatment with radioactive iodine or surgery) or long-term (1-2 years) treatment, after which the chance for remission is 20% to 30%. Possible side effects are rash, allergic reactions, arthritis, hepatitis, and agranulocytosis.

For nonpregnant patients, radioactive iodine is usually the treatment of choice in the United States. It is administered as an oral solution of sodium 131I that is rapidly concentrated in thyroid tissue, inducing damage that results in ablation of the thyroid within 6 to 18 weeks. At least 30% of patients will have hypothyroidism in the first year after treatment and 3% each year after that, requiring thyroid hormone supplementation. Radioactive iodine is contraindicated in pregnancy due to the risk of miscarriage or birth defects, and women of reproductive age are advised to postpone pregnancy for 6 to 12 months after treatment. Methimazole is contraindicated in the first trimester, but pregnant women with Graves disease can be managed with PTU, as it has a low transplacental transfer. Graves ophthalmopathy might be exacerbated by radioactive iodine treatment, so glucocorticoids can be used to prevent this in selected patients.

Subtotal thyroidectomy usually is reserved for large goiters with obstructive symptoms (dyspnea, dysphagia). Possible complications include recurrent laryngeal nerve injury and hypoparathyroidism (due to removal of the parathyroid glands or compromise of their vascular supply).

For our patient, treatment with radioactive iodine or antithyroid medications seems the most reasonable way to proceed, and a discussion regarding her options and our recommendations should take place after the diagnosis is confirmed and nonpregnant status is confirmed.

Complications

Thyroid storm is a dangerous condition of decompensated thyrotoxicosis. Symptoms include severe signs of hyperthyroidism such as tachycardia (> 140 bpm), fever (104 °F to 106 °F), agitation, delirium, restlessness or psychosis, vomiting, and/or diarrhea. Thyroid storms are usually due to untreated hyperthyroidism complicated by an intercurrent illness such as infection, surgery, or trauma. Treatment includes supportive care with fluids, beta-blockers to control symptoms of increased adrenergic tone, antibiotics if needed, and specific treatment directed at the hyperthyroidism.

CASE CORRELATION

• See also Case 41 (Urinary Tract Infection With Sepsis in the Elderly), Case 52 (Diabetic Ketoacidosis, Type 1 Diabetes), and Case 59 (Delirium/ Alcohol Withdrawal).

COMPREHENSION QUESTIONS

53.1 A 44-year-old woman is being seen in the office for a 2-month history of progressive anxiety, nervousness, and tremor. She also says she has heat intolerance. On exam, her HR is 110 bpm and BP is 130/80 mm Hg. Her thyroid gland is diffusely enlarged and nontender, and an audible bruit is present. Her serum TSH level is 0.01 mIU/L (normal 0.35-5.0). Which of the following is the most likely diagnosis?

A. Lymphocytic thyroiditis

B. Hashimoto thyroiditis

C. Graves disease

D. Multinodular toxic goiter

53.2 A 34-year-old woman is being seen in the urgent care center for “feeling ill.” She was diagnosed with hyperthyroidism 6 months ago, but she has not taken her medications for 5 days. After the history and physical examination, the provider is suspicious of possible thyroid storm. Which of the following features would best distinguish hyperthyroidism from thyroid storm?

A. Heart rate of 120 bpm

B. Weight loss

C. Fever and delirium

D. Large goiter

53.3 A 58-year-old woman is being seen in the office for her first evaluation of hyperthyroidism. On examination, she is found to have a diffusely slightly enlarged thyroid gland that is nontender. She has exophthalmos, tremor, and brisk deep tendon reflexes. Serum TSH is 0.03 mIU/L (normal 0.35-5.0). Which of the following is the best therapy for this patient?

A. Long-term oral propranolol

B. Lifelong oral PTU

C. Radioactive iodine ablation

D. Surgical thyroidectomy

ANSWERS

53.1 C. Graves disease is the most common cause of hyperthyroidism in the United States. It often includes the thyroid gland features described (diffusely enlarged and nontender), as well as the distinctive eye findings. The patient in this question does not have exophthalmos described, but its absence does not rule out Graves disease. The other answer choices (answer A, lymphocytic thyroiditis; answer B, Hashimoto thyroiditis; and answer D, multinodular toxic goiter) are less common causes of hyperthyroidism. Patients with multinodular toxic goiter usually have multiple irregular and variable sized nodules on thyroid palpation, and usually do not present with exophthalmos. The patient in this scenario does not have exophthalmos (thyroid stare). Only about 20-30% of patients with Graves disease have these eye findings, and therefore, their absence does not rule out Graves disease.

53.2 C. Thyroid storm is an exaggeration of hyperthyroid features with autonomic dysfunction manifesting in fever and/or central nervous system dysfunction, such as confusion or coma. It is a medical emergency with a high mortality. Although some patients may have tachycardia (answer A), mild tachycardia is very common in straightforward hyperthyroidism and not an indicator of thyroid storm. Weight loss (answer B) and a large goiter (answer D) can occur with hyperthyroidism and are not distinguishing factors. Other findings of thyroid storm include heart failure and a markedly elevated BP.

53.3 C. This patient most likely has Graves disease based on the symptoms of hyperthyroidism, mildly enlarged goiter, eye findings, and low TSH level. Radioactive iodine is a definitive treatment for Graves disease. Surgery (answer D) is indicated for obstructive symptoms or for women during pregnancy. Propranolol (answer A) is a good initial option to control tachycardia but not a long-term option. PTU (answer B) is a second-line option due to the risk of hepatocellular necrosis; long-term medical therapy with methimazole is the preferred agent in the United States and is used in many cases.

CLINICAL PEARLS

▶ The most common cause of thyrotoxicosis is Graves disease. No other diagnosis is likely if the patient has bilateral proptosis and a goiter.

▶ In patients with Graves disease, thyrotoxic symptoms may be treated with antithyroid medication or by thyroid gland ablation with radioactive iodine or surgery, but the ophthalmopathy may not improve.

▶ Graves disease may remit and relapse; in patients treated medically, one-third to half will become asymptomatic within 1–2 years.

▶ After radioactive iodine ablation, most patients with Graves disease will have hypothyroidism and require thyroid hormone supplementation.

▶ Hyperfunctioning thyroid nodules (excessive thyroid hormone pro-duction, suppressed TSH, “hot” on radionuclide scan) almost never are malignant.

▶ Most “cold” thyroid nodules are not malignant, but fine-needle aspiration should be used to evaluate the need for surgical excision.

REFERENCES

Davies DF, Larsen TF. Thyrotoxicosis. In: Wilson JD, Foster DW, Kronenberg HM, et al, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, PA: Saunders; 2003:372-421. 

Glinoer D, de Nayer P, Bourdoux P, et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab. 1990;71:276. 

Hershman JM. Hypothyroidism and hyperthyroidism. In: Lavin N, ed. Manual of Endocrinology and Metabolism. 4th ed. Boston, MA: Little Brown; 2009:435-448. 

Hyer S, Pratt B, Newbold K, Hamer C. Outcome of pregnancy after exposure to radioiodine in utero. Endocr Pract. 2011 January 17;1-10. 

Jameson LJ, Weetman AP. Disorders of the thyroid gland. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:2283-2308. 

McDermott MT. Thyroid emergencies. In: McDermott MT, ed. Endocrine Secrets. 6th ed. Philadelphia, PA: Hanley and Belfus; 2013:309-313. 

Singer PA. Thyroiditis. In: Lavin N, ed. Manual of Endocrinology and Metabolism. Boston, MA: Little Brown; 2002:386-395.

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