Thyroid Disorders Case File

Thyroid Disorders Case File

Eugene C. Toy MD, Donald Briscoe, MD, FA  AFP, Bruce Britton, MD, Joel J. Heidelbaugh, MD, FA  AFP, FACG

Case 15

A 27-year-old woman presents to your office complaining of progressing nervousness, fatigue, palpitations, and the recent development of a resting hand tremor. She also states that she is having difficulty concentrating at work and has been more irritable with her coworkers. The patient also notes that she has developed a persistent rash over her shins that has not improved with the use of topical steroid creams. All of her symptoms have come on gradually over the past few months and continue to get worse. Review of systems also reveals an unintentional weight loss of about 10 lb, insomnia, and amenorrhea for the past 2 months (the patient's menstrual cycles are usually quite regular). The patient's past medical history is unremarkable and she takes no oral medications. She is currently not sexually active and does not drink alcohol, smoke, or use any illicit drugs. On examination, she is afebrile. Her pulse varies from 70 to 110 beats/min. She appears restless and anxious. Her skin is warm and moist. Her eyes show evidence of exophthalmos and lid retraction bilaterally, although funduscopic examination is normal. Neck examination reveals symmetric thyroid enlargement, without any discrete palpable masses. Cardiac examination reveals an irregular rhythm. Her lungs are clear to auscultation. Extremity examination reveals an erythematous, thickened rash on both shins. Neurologic examination is normal except for a fine resting tremor in her hands when she attempts to hold out her outstretched arms. Initial laboratory tests include a negative pregnancy test and an undetectable level of thyroid stimulating hormone (TSH).

⯈ What is the most likely diagnosis?

⯈ What imaging study is most appropriate at this time?

⯈ What is the definitive nonsurgical treatment of this condition?

ANSWER TO CASE 15:

Thyroid Disorders

Summary: A 27-year-old woman presents with progressively worsening anxiety, palpitations, tremor, menstrual irregularities, and weight loss. Her TSH level is suppressed, confirming the presence of hyperthyroidism.

• Moat likely diagnosis: Hyperthyroidism .secondary to Graves disease
• Most appropriate imaging study: Nuclear medicine thyroid scan with uptake
• Definitive nonsurgical treatments: Thyroid ablation with radioactive iodine

ANALYSIS

Objectives

1. Know the most common conditions that cause hyper- and hypothyroidism.
2. Be able to interpret the common tests used to evaluate thyroid function.
3. Learn the modalities of treatment for disorders of the thyroid.

Considerations

This patient has symptoms and signs consistent with hyperthyroidism, including warm. moist skin caused by excessive sweating and cutaneous vasodilation; a resting tremor; an enlarged thyroid gland; weight loss; and tachycardia. Her irregular heart· beat may be a manifestation of atrial fibrillation, which occurs in approximately 10% of hyperthyroid patients. Eye abnormalities are common in hyperthyroid states. Retraction of the upper lid, resulting in the "thyroid stare" is common. Graves disease has a unique ophthalmopathy that may cau.se a prominent exophthalmos (Figure l5-1). The moat common came of noniatrogenic hyperthyroidism is Graves disease, an autoimmune thyroid disorder. Autoantibodies to the TSH receptors on the thyroid gland result in hyperfunctioning of the gland, with the result that the

Figure 15-1. Exophthalmos and proptosis of Graves disease. (Reproduced, with permission, from

Kasper DL. Braunwald E.Fauci A, et al. Harrison's Principles of Internal Medicine. 16th ed. New Yo«, NY:

McGrow-Hill; 2005:2114.)

thyroid gland functions outside the usual control of the hypothalamic-pituitary axis. Graves disease commonly occurs in reproductive-age females and is much more common in women than men. The treatment of Graves disease includes antithyroid drugs (such as propylthiouracil [PTU] and methimazole) and/or β-blockers to block some of the peripheral effects of excessive thyroxine. However, these are only temporary measures used to give patients symptomatic relief. The definitive treatment is radioactive iodine, which destroys the thyroid gland. At least 40% of patients who receive radioactive iodine eventually become hypothyroid and will need thyroid hormone replacement. Radioactive iodine therapy is contraindicated in pregnant women, as the isotope can cross the placenta and cause fetal thyroid ablation. Due to adverse effects on fetal development, methimazole is not used during first trimester of pregnancy. Most experts agree that PTU should be used in the first trimester, and methimazole can be safely used in second and third trimesters. Surgical removal of the thyroid gland is another option for the treatment of Graves disease, but it is often reserved for pregnant patients.

Approach To:

Thyroid Disease

DEFINITIONS

GRAVES DISEASE: An autoimmune thyroid disorder in which autoantibodies to the TSH receptors on the thyroid gland result in hyperfunctioning of the thyroid gland. A prominent finding is also the "stare'' due to the ophthalmic involvement.

THYROID STORM: An acute hypermetabolic state associated with the sudden release of large amounts of thyroid hormone into circulation, leading to autonomic instability and central nervous system dysfunction such as altered mental status, coma, or seizures. This condition has a significant mortality risk.

HYPERTHYROIDISM

Signs and Symptoms

Hyperthyroidism usually presents with progressive nervousness, palpitations, weight loss, fine resting tremor, dyspnea on exertion, and difficulty concentrating. Physical findings include a rapid pulse rate and elevated blood pressure, with the systolic pressure increased to a greater extent than the diastolic pressure, creating widened pulse-pressure hypertension. Examination findings can include atrial fibrillation and a fine resting tremor.

Thyroid storm is an acute hypermetabolic state associated with the sudden release of large amounts of thyroid hormone into circulation. It occurs most often in patients with Graves disease, but can also occur in acute thyroiditis conditions. Symptoms include fever, confusion, restlessness, and psychotic-like behavior. Examination may demonstrate tachycardia, elevated blood pressure, fever, and dysrhythmias. Patients can also have other signs of high-output heart failure, such as dyspnea on exertion and peripheral vasoconstriction, and may exhibit signs of cerebral or cardiac ischemia. Thyroid storm is a medical emergency that requires prompt attention and reversal of the metabolic demands of acute hyperthyroidism.

Pathogenesis

Graves disease is the most common cause of hyperthyroidism and is more commonly found in women. It is an autoimmune disorder caused by immunoglobulin (lg) G antibodies that bind to TSH receptors, initiating the production and release of thyroid hormone. In addition to the usual findings, approximately 50% of patients with Graves disease also have exophthalmos. The second most common cause of hyperthyroidism is an autonomous thyroid nodule that secretes thyroxine. These nodules do not rely on TSH stimulation and continue to excrete large amounts of thyroxine despite low or nonexistent, circulating TSH levels. Hyperthyroidism can also be caused by the acute release of thyroid hormone in the early stages of thyroiditis. In such cases, symptoms are generally transient and resolve within weeks of onset. Iatrogenic hyperthyroidism can occur secondary to the overuse of thyroxine supplementation.

Laboratory and Imaging Evaluation

Hyperthyroidism can be diagnosed by an elevated free thyroxine level, usually with a corresponding low TSH level. Once it has been identified, further testing for autoimmune antibodies and radionucleotide scanning of the thyroid can help to determine whether the problem is Graves disease, an autonomous nodule, or thyroiditis. Radionucleotide imaging provides a direct scan of the gland and an indication of its functioning. Imaging is performed using either an isotope of technetium-99 m (99mTc) or iodine-123 (1231). After the administration of one of these agents, imaging the thyroid allows visualization of active and inactive areas, as well as an indication as to the level of activity in a particular area. In patients with Graves disease, there will be diffuse hyperactivity with large amounts of uptake. In contrast, thyroiditis demonstrates patchy uptake with overall reduced activity, reflecting the release of existing hormone rather than the overproduction of new thyroxine. The detection of serum thyroid-receptor antibodies is a specific diagnostic test for Graves disease.

Treatment

Radioactive iodine is the treatment of choice for Graves disease in adult patients who are not pregnant. It should not be used in children or breast-feeding mothers. Antithyroid drugs are also well tolerated and successful at blocking the production and release of thyroid hormone in patients with Graves disease. Some examples of these drugs include PTU, methimazole, and carbimazole. These drugs work by inhibiting the organification of iodine, and PTU also prevents the peripheral conversion of thyroxine (T4) to triiodothyronine (T3), its more active form. In April, 2010, the Food and Drug Administration (FDA) added a "black box" warning to the labeling of PTU because of the risk of hepatotoxicity. For this reason, methimazole should be considered the first-line agent except when the patient is pregnant. PTU Is preferred during first trimester of pregnancy. Another serious potential side effect of these drugs is agranulocytosis, which occurs in 3 per 10,000 treated patients per year. Antithyroid drugs are especially useful in treating adolescents, in whom Graves disease may go into spontaneous remission after 6 to 18 months of therapy. Surgery is reserved for patients in whom medications and radioactive iodine ablation are unacceptable treatment modalities, or in whom a large goiter is present that is either compressing nearby structures or is disfiguring. For patients presenting with thyroid storm, aggressive initial therapy is essential to prevent complications. Treatment should include the administration of high doses of PTU or methimazole and β-blockers (to control tachycardia and other peripheral symptoms of thyrotoxicosis). Hydrocortisone is given to prevent possible adrenal crisis.

HYPOTHYROIDISM

Signs and Symptoms

Patients with hypothyroidism can present with a wide range of symptoms, including lethargy, weight gain, hair loss, dry skin, slowed mentation or forgetfulness, constipation, intolerance to cold, and a depressed effect. In older patients, hypothyroidism can be confused with .Alzheimer disease and other conditions that cause dementia. In women, it is often confused with depression. Physical findings that can present in hypothyroid patients include low blood pressure, bradycardia, nonpitting edema, hair thinning or loss, dry skin, and a diminished relaxation phase of reflexes.

Pathogenesis

Several different conditions can cause hypothyroidism. The most common noniatrogenic condition causing hypothyroidism in the United States is Hashimoto thyroiditis, an autoimmune thyroiditis. Iatrogenic causes include post-Graves disease thyroid ablation and surgical removal of the thyroid gland. Another cause is secondary hypothyroidism related to hypothalamic or pituitary dysfunction. These conditions are primarily found in patients who have received intracranial irradiation or surgical removal of a pituitary adenoma.

Laboratory and Imaging Evaluation

In primary hypothyroidism, the TSH level is elevated, indicating insufficient thyroid hormone production to meet metabolic demands. Free thyroid levels are low. In contrast, patients with secondary hypothyroidism have low or undetectable TSH levels. Once the diagnosis of primary hypothyroidism is made, further imaging or serologic testing is unnecessary if the thyroid gland is normal on physical examination. In cases of secondary hypothyroidism, however, further testing is needed to determine whether the cause is a hypothalamic or pituitary problem. This can be done by using a thyroid-releasing hormone (TRH) test. Endogenous TRH is released by the hypothalamus and stimulates the pituitary to release TSH. When TRH is injected intravenously, a normally functioning pituitary will result in an increase of TSH that can be measured in about 30 minutes. No increase in TSH after injection of TRH suggests a malfunctioning pituitary gland. In cases where pituitary dysfunction is suspected, imaging of the pituitary gland to detect microadenomas and testing of other hormones that are dependent on pituitary stimulation are indicated.

Treatment

Most healthy, nonpregnant adults with hypothyroidism require about 1.6 μg/kg of thyroid hormone replacement daily. The recommendation in patients over 50 years is to start with a dose between 25 and 50 μg daily, and increase by 25 μg every 3 to 4 weeks until optimal dose is reached. The same recommendation exists for those younger than 50 years with ischemic heart disease. In pregnancy, thyroid hormone replacement needs may increase by approximately 30%. This can be met by having the woman take nine doses of her prepregnancy dose of levothyroxine weekly. A referral to an endocrinologist may also be indicated.

Thyroxine is usually dosed once daily, although some evidence suggests that weekly dosing may also be effective. In patients with an intact hypothalamic-pituitary axis, the adequacy of thyroid replacement can be followed with serial TSH measurements. Evaluation of TSH levels should be performed 4 to 6 weeks after an adjustment in medication has been made. If TSH is greater than 5, underreplacement or nonadherence to medication should be suspected. If underreplaced, increase the levothyroxine dose by 12.5 to 25 μg per day. If TSH less than 0.35, patient is being overreplaced and a daily dose decrease by 25 μg is required. With increased age, thyroid binding decreases as a consequence of a drop in serum albumin level and the medication dosage may need to be reduced by up to 20%. Annual monitoring of the TSH level in the elderly is necessary to avoid overreplacement.

Screening

Screening asymptomatic adults for thyroid disorder is controversial. The United States Preventive Services Task Force (USPSTF) reports insufficient evidence for or against routine screening. The American Academy of Family Physicians (AAFP) does not recommend screening in asymptomatic adults. The American Thyroid Association recommends screening of all adults age 35 and more every 5 years.

NODULAR THYROID DISEASE

Thyroid nodules, both solitary and multiple, are common and are often found incidentally on physical examination, ultrasonography, or computed tomography. They are more prevalent in women and increase in frequency with age. Although their pathogenesis is not clear, nodules are known to be associated with iodine deficiency, higher gravidity, and the ingestion of goitrogens. Further workup of identified nodules is indicated, as the incidence of malignancy in solitary nodules is estimated at 5% to 6%. The incidence of malignancy is higher in children, adults younger than 30 or older than 60 years, and patients with a history of head or neck irradiation. Other historical risk factors include a family history of thyroid cancer, the presence of cervical lymphadenopathy, and the recent development of hoarseness of the voice, progressive dysphagia, or shortness of breath.

Initial assessment of thyroid nodules should include evaluation of thyroid function and ultrasonography to assess for the size of the nodule. Thyroid function can be assessed by measuring the TSH level. Ultrasonography is the imaging test of choice for assessment of the size of a thyroid nodule, its characteristics (solid or cystic), the overall size of the thyroid, and for the presence of other nodules that may not have been previously identified.

Functional adenomas that present with hyperthyroidism are rarely malignant. These represent less than 10% of all nodules. A patient who has a thyroid nodule and is found to be hyperthyroid should have a radioactive iodine uptake study to confirm functionality of the nodule. Hyperfunctioning nodules are treated with surgery or radioactive ablation therapy, depending on the level of hyperthyroidism.

Nodules measuring greater than 1 cm by ultrasonography in a person with a normal or elevated TSH require biopsy. This can be done by fine-needle aspiration (FNA), which is a highly sensitive test. Ultrasound findings suggestive of malignancy include irregular margins, intranodular vascular spots, and microcalcifications. Results of the FNA determine further management and treatment. Cytologic evaluation of FNA specimens are reported as being nondiagnostic, benign, follicular lesion of undetermined significance, follicular neoplasm, suspicious for malignancy, or malignant. Follicular cell malignancy cannot be distinguished cytologically from its benign equivalent, and thus is often read as follicular lesion of undetermined significance. These patients should be referred to surgery to obtain a definitive evaluation. Papillary, medullary, and anaplastic thyroid carcinomas can be diagnosed accurately by FNA. Patients with thyroid malignancy are treated by thyroidectomy followed by radioactive ablation. These patients will require long-term follow-up by an endocrinologist.

Thyroid nodules discovered during pregnancy are handled similarly, except that radioisotope scanning is contraindicated. FNA is safe during pregnancy, and thyroidectomy can be performed relatively safely during the second and third trimester. However, because thyroid cancer is relatively indolent, it may be wise to defer definitive diagnosis and treatment until the postpartum period in patients with indeterminate lesions on FNA.

COMPREHENSION QUESTIONS

15.1 A 28-year-old woman is noted to have had 10-lb unintended weight gain, hair loss, dry skin, and fatigue. She is diagnosed with probable hypothyroidism. Which of the following laboratory test results is most consistent with hypothyroidism?

A. Normal TSH and elevated T4 /T3 levels

B. Elevated TSH levels and low T4 /T3

C. Elevated TSH levels and normal T4 /T3

D. Low TSH and elevated T4 /T3 levels

15.2 A 35-year-old G2P1001 at 11 weeks' gestational age presents with complaint of palpitations, weight loss, nervousness and tremor. She denies prior history of thyroid problems. Laboratory studies confirm that TSH is severely suppressed. Which of the following is the best treatment for this patient at this time?

A. PTU

B. β-blockers

C. Levo thyroxine

D. Methimazole

15.3 A 24-year-old woman who is 8 weeks pregnant is found to have a thyroid nodule. Biopsy is performed and malignancy of the thyroid is diagnosed. Which of the following management options is most appropriate?

A. Confirm the diagnosis of cancer using radioisotope scanning.

B. Perform an immediate thyroidectomy.

C. Follow clinically until after delivery of child.

D. Treat with radioactive iodine ablation in the second or third trimester.

15.4 A 28-year-old man presents to his physician for a health maintenance visit. He feels well and does not report changes in his appetite, weight, energy, or bowel movements. A firm nodule is palpated in the left lobe of his thyroid. The nodule is confirmed on ultrasound and measures 0.8 cm. Which of the following is the next step in the workup of this nodule?

A. Radioactive iodine uptake study

B. Fine-needle aspiration

C. Repeat ultrasound in 6 months

D. Referral to surgeon for open biopsy

ANSWERS

15.1 B. Hypothyroidism is marked by low levels of circulating thyroid hormones. When this happens, the negative feedback to TSH is stunted, and it in turn increases. Therefore hypothyroidism presents with an increased TSH and low T3 /T4.

15.2 A. Experts agree that due to adverse effects of methimazole on fetal development, PTU should be used in first trimester of pregnancy, and methimazole in second and third trimesters.

15.3 C. Thyroid cancer detected during pregnancy can usually be observed until after the pregnancy is complete. If needed, thyroid surgery can be performed safely in the second and third trimesters. The use of radioactive iodine is contraindicated in pregnancy.

15.4 C. For thyroid nodules that are less than 1 cm, benign appearing, and no presence of positive clinical history of thyroid cancers, observation and repeat thyroid ultrasound in 6 months is appropriate. Thyroid nodules greater than 1 cm should undergo FNA, as this is a sensitive and specific test for thyroid nodules and can help to determine whether it is malignant.

CLINICAL PEARLS

⯈ The most common forms of both hyper- and hypothyroidism are autoimmune: Graves disease and Hashimoto thyroiditis causing hypothyroidism.

⯈ Once thyroid nodule is palpated on examination, the first steps are to obtain a TSH level and a thyroid ultrasound.

⯈ Thyroid disease in pregnancy needs to be evaluated and treated appropriately as both hypothyroidism and hyperthyroidism can have serious effects on fetal development.

REFERENCES

Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008;36:425. 

Davis A, Shahla N. A practical guide to thyroid disease in women. The Female patient (Primary care ed). 2005;30(9):38-47. 

Donangelo I, Braunstein GD. Update on subclinical hyperthyroidism. Am Fam Physician. 2011 Apr 15;83(8):933-938. 

Gaitonde DY, Rowley KO, Sweeney LB. Hypothyroidsm: an update. Am Fam Physician. 2012 Aug 1;86(3):244-251. 

Garber JR, Cobin RH, Hennessey JV, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18(6):988-1028. 

Jameson J, Mandel SJ, Weetman AP, et al. Disorders of the thyroid gland. In: Kasper D, Fauci A, Hauser S, Longo D,JamesonJ, Loscalzo J, eds. Harrison's Principles of Internal Medicine.19th ed. New York, NY: McGraw-Hill Education; 2015. Available at: http:/ I accessmedicine.mhmedical.com/. Accessed May 24, 2015. 

Knox MA. Thyroid nodules. Am Fam Physician. 2013 Aug 1; 88(3):193-196.

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