Hyperthyroidism due to Graves Disease Case File

Hyperthyroidism due to Graves Disease Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 21

A 25-year-old G1P0 woman is seen in your office for a new obstetrical visit. Her last normal menstrual period was 8 weeks ago. She is currently on no medications other than prenatal vitamins. She has noted over the past 3 months weight loss, heat intolerance, and an increase in the number of daily bowel movements. Occasionally, she notices that her heart races. She has a personal history of vitiligo as well as a family history of thyroid disease.

Physical examination reveals her height is 5 ft 3 in, weight is 100 lb (45.3 kg), blood pressure is 133/84 mm Hg, and pulse is 109 bpm. She appears nervous and slightly diaphoretic. She does not exhibit exophthalmos. Her thyroid gland is diffusely enlarged and nontender. Her lungs are clear, and her heart exhibits a 3/6 systolic ejection murmur heard best over the second left intercostal space. The remainder of her examination is unremarkable.

Her initial lab studies are normal except for her TSH which is 0.004 mIU/L (normal 0.5-4.7 mIU/L), and her free T4 which is reported as 5.4 ng/dL (normal 1.2-1.8 ng/dL).

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 21:

Hyperthyroidism due to Graves Disease

Summary: This is a 25-year-old G1P0 with newly diagnosed hyperthyroidism most likely due to Graves disease who now presents in the first trimester with a hypermetabolic state.

➤ Most likely diagnosis: Hyperthyroidism due to Graves disease.

➤ Next step: Evaluate patient for Graves disease and thyroid-stimulating immunoglobulins.

➤ Potential complications: Maternal thyroid storm; congestive heart failure; spontaneous pregnancy loss; IUGR; preterm labor; fetal demise; preeclampsia; fetal or neonatal hyperthyroidism.

ANALYSIS

Objectives

1. Recognize signs and symptoms consistent with hyperthyroidism.
2. Be able to confirm thyroid disease with laboratory studies.
3. Be able to treat hypo- and hyperthyroidism during pregnancy.
4. Be able to manage acute symptoms of hyperthyroidism during pregnancy.
5. Be able to describe the effects of pregnancy on thyroid disease and of thyroid disease on pregnancy.

Considerations

This is a 25-year-old Caucasian woman G1P0 presenting at 8 weeks’ gestation with overt hyperthyroidism. The first priority for the physician is to treat the hypermetabolic state of the patient. Thioamides are the treatment of choice during pregnancy as they have minor side effects and can induce remission in up to 30% of patients. There is a small risk of fetal goiter and hypothyroidism when given during pregnancy. Surgery is reserved for those pregnant women allergic to thioamides. Radioactive iodine is contraindicated during pregnancy.

APPROACH TO

Thyroid Disease in Pregnancy

HYPERTHYROIDISM

Recognition of hyperthyroidism in pregnancy is sometimes difficult due to the hyperdynamic physiological changes in pregnancy. However, unintended weight loss, nervousness, palpitations, tachycardia, or tremor are clinical manifestations that bear evaluation. The diagnosis is established by thyroid function tests, such as TSH and free T4 levels. The immediate treatment includes beta-blocking agents and thioamides.

Thioamides inhibit thyroid hormone synthesis by reduction of iodine organification and iodotyrosine coupling. Both propylthiouracil (PTU) and methimazole have been used during pregnancy (see Table 21-1), but PTU has been traditionally preferred because of concern regarding reduced transplacental transfer of PTU compared to methimazole. However, recent studies do not confirm this finding. Teratogenic patterns associated with methimazole include aplasia cutis and choanal/esophageal atresia; however, these anomalies do not occur at a higher rate in women on thioamides compared to the general population.

Side effects of thioamides include transient leukopenia (10%); agranulocytosis (0.1%-0.4%); thrombocytopenia, hepatitis, and vasculitis (< 1%) as well as rash, nausea, arthritis, anorexia, fever, and loss of taste or smell (5%). Agranulocytosis usually presents with a fever and sore throat. If a CBC indicates agranulocytosis, the medication should be discontinued. Treatment with another thioamide carries a significant risk of cross-reaction as well.

Initiation of thioamides in a patient with a new diagnosis during pregnancy requires a dose of PTU 100 to 150 mg three times daily or methimazole 10 to 20 mg twice daily. Free T4 levels are used to monitor response to therapy in hyperthyroid patients and should be checked in 4 to 6 weeks. The PTU or methimazole can be adjusted in 50 mg or 10 mg increments, respectively, with a therapeutic range for free T4 of 1.2 to 1.8 ng/dL. The goal of treatment is to maintain the free T4 in the upper normal range using the lowest possible dose in order to protect the fetus from hypothyroidism. The required dose of thioamide during pregnancy can increase up to 50% for patients with a history of hyperthyroidism prior to conception. The patient’s TSH should be checked at the initial prenatal visit and every trimester. Medication adjustments, testing intervals, and therapeutic goals for the free T4 are the same as for patients with new-onset disease.

Beta-blockers initially can be used to relieve the adrenergic symptoms of tachycardia, tremor, anxiety, and heat sensitivity by decreasing the maternal heart rate, cardiac output, and myocardial oxygen consumption. Longer-acting agents, such as atenolol and metoprolol 50 to 200 mg/d, are recommended. Beta-blockers are contraindicated in patients with asthma and congestive heart failure and should not be used at the time of delivery due to possible neonatal bradycardia and hypoglycemia.

The most common cause of hyperthyroidism is Graves disease, which occurs in 95% of all cases at all ages. The diagnosis of Graves disease is usually made by the presence of elevated free T4 level or free thyroid index with a suppressed TSH in the absence of a nodular goiter or thyroid mass. The differential diagnosis of hyperthyroidism, in the order of decreasing frequency, includes subacute thyroiditis, painless (silent or postpartum) thyroiditis, toxic multinodular goiter, toxic adenoma (solitary autonomous hot nodule), iodine-induced (iodinated contrast or amiodarone), iatrogenic overreplacement of thyroid hormone, factitious thyrotoxicosis, struma ovarii (ovarian teratoma), and gestational trophoblastic disease. The general symptoms of hyperthyroidism include palpitations, weight loss with increased appetite, nervousness, heat intolerance, oligomenorrhea, eye irritation or edema, and frequent stools. The general signs include diffuse goiter, tachycardia, tremor, warm, moist skin, and new-onset atrial fibrillation. Diagnosis during pregnancy is even more difficult because the signs and symptoms of hyperthyroidism may overlap with the hypermetabolic symptoms of pregnancy. Discrete findings with Graves disease include a diffuse, toxic goiter (common in most young women), ophthalmopathy (periorbital edema, proptosis, and lid retraction in only 30%), dermopathy (pretibial myxedema in < 1%), and acropachy (digital clubbing).

The pathogenesis of Graves disease is characterized by an autoimmune process with production of thyroid-stimulating immunoglobins (TSIs) and TSH-binding inhibitory immunoglobulin (TBIIs) that act on the TSH receptor on the thyroid gland to mediate thyroid stimulation or inhibition, respectively. These antibodies, in effect, act as TSH agonists or antagonists, to stimulate or inhibit thyroid growth, iodine trapping, and T4/T3 synthesis. Maternal Graves disease complicates 1 out of every 500 to 1000 pregnancies. The frequency of poor outcomes depends on the severity of maternal thyrotoxicosis with a risk of preterm delivery of 88%, stillbirth of 50%, and risk of congestive heart failure of over 60% in untreated mothers. As a result of transplacental transfer of the TSIs, 1% to 5% of neonates born to mothers with Graves disease have hyperthyroidism, or neonatal Graves disease. Although fetal hyperthyroidism requiring treatment is rare because of these antibodies (< 0.01% of pregnancies), it is possible in any woman with a past or current history of Graves disease. Fetal hyperthyroidism can be associated with IUGR, fetal tachycardia, fetal goiter, fetal hydrops, preterm delivery, and fetal demise. Because TSIs freely cross the placenta and can stimulate the fetal thyroid, these antibodies should be measured by the end of the second trimester in mothers with a current or past history of Graves disease, including those who have undergone treatment with surgery or I131 or who have had a prior infant with neonatal Graves disease. Close observation of pregnancies with elevated TSI levels or antithyroid drug treatment is recommended with monthly ultrasound after 20 weeks. Those women with negative TSI levels and no medication are not at increased risk of fetal goiter or thyroid disease.

Maternal thyroid storm is a medical emergency characterized by a hypermetabolic state in a woman with uncontrolled hyperthyroidism. Thyroid storm occurs in less than 1% of pregnancies but has a high risk of maternal heart failure. Usually, there is an inciting event, such as infection, cesarean delivery, or labor, which leads to acute onset of fever, tachycardia, altered mental status (restlessness, nervousness, confusion), seizures, nausea, vomiting, diarrhea, and cardiac arrhythmias. Shock, stupor, and coma can ensue without prompt intervention, which includes OB-ICU admission, supportive measures, and acute medical management (see Table 21-2). Therapy includes a standard series of drugs, each of which has a specific role in suppression of thyroid function: PTU or methimazole blocks additional synthesis of thyroid hormone, and PTU also blocks peripheral conversion of T4 to T3. Saturated solutions of potassium iodide or sodium iodide block the release of T4 and T3 from the gland. Dexamethasone decreases thyroid hormone release and peripheral conversion of T4 to T3. Propranolol inhibits the adrenergic effects of excessive thyroid hormone. Phenobarbital can reduce extreme agitation or restlessness and may increase catabolism of thyroid hormone. Fetal surveillance is performed throughout, but intervention for fetal indications should not occur until the mother is stabilized.

Other complications of hyperthyroidism during pregnancy include severe preeclampsia, congestive heart failure, thyroid storm, early pregnancy failure, preterm delivery, fetal growth restriction, intrauterine fetal demise, and fetal thyrotoxicosis due to TSI antibodies in women with Graves disease.

Data from Thyroid Disease in Pregnancy. ACOG Practice Bulletin No. 37. Washington DC: American

College of Obstetricians and Gynecologists; August, 2002.

Hypothyroidism in Pregnancy

Overt hypothyroidism occurs in 1 to 3 out of every 1000 pregnancies. Transient hypothyroidism occurs in up to 6% of postpartum women while congenital hypothyroidism, or cretinism, affects 1 out of 4000 newborns. Most causes of hypothyroidism result from a primary thyroid defect. Hypothalamic dysfunction is a much less frequent etiology. The most common causes in pregnancy and postpartum are Hashimoto thyroiditis (chronic thyroiditis or chronic autoimmune thyroiditis), subacute thyroiditis, thyroidectomy, radioactive iodine ablation, and iodine deficiency. In developed countries Hashimoto thyroiditis is the most common etiology and is characterized by the production of antithyroid antibodies, including antimicrosomal, antithyroglobulin, and antiperoxidase (TPO) antibodies. Worldwide, iodine deficiency is the leading cause of primary hypothyroidism. Secondary, or central, hypothyroidism results from defects at the level of the pituitary (TSH deficiency) or hypothalamus (TRH deficiency) as well as generalized thyroid hormone resistance. Types of pituitary disease include Sheehan syndrome, pituitary macroadenoma, or pituitary surgery. Hypothalamic disease includes lymphocytic hypophysitis or history of hypophysectomy.

The clinical manifestations of hypothyroidism include somatic changes (fatigue, dry skin, alopecia, cold intolerance, constipation, myalgias, carpel tunnel syndrome, weight gain of 5 to 10 kg, prolonged relaxation phase of the deep tendon reflexes); cognitive and mood changes (impaired memory, depression, slowed thinking, irritability); and reproductive changes or issues (menorrhagia, amenorrhea, infertility, precocious or delayed puberty). Hypothyroidism is characterized by vague, nonspecific signs and symptoms with insidious onset, which can be confused with the normal complaints of pregnancy. Maternal complications of hypothyroidism include early pregnancy failure, preeclampsia, abruptio placenta, nonreassuring fetal heart rate tracing, low birth weight due to prematurity, an increased rate of cesarean delivery, and postpartum hemorrhage. However, adequate treatment greatly reduces the risk of a poor obstetrical outcome. Congenital complications include cretinism due to iodine deficiency, which can lead to IUGR, mental retardation, and neuropsychologic deficits.

The diagnosis of overt hypothyroidism is based on serum TSH elevation. The serum-free T4 level distinguishes between overt and subclinical hypothyroidism as the free T4 should be low, or suppressed, in overt disease while the free T4 level remains normal in subclinical hypothyroidism. The diagnosis of overt secondary hypothyroidism is made in the presence of low serum TSH and low serum-free T4.

Treatment for overt hypothyroidism in pregnancy is levothyroxine, the prohormone of thyroxine (T4), which is converted to active T3 in the peripheral tissues. Levothyroxine has a long half-life of 1 week, which allows once-a-day dosing. Average dose requirements are 1.6 to 1.8 μg/kg/d. Initiation of levothyroxine in a patient with a new diagnosis during pregnancy requires a dose of 0.1 to 0.2 mg/kg/d or 100 to 125 μg per day. Serum TSH levels are used to monitor response to therapy in hypothyroid patients and should be checked in 4 to 6 weeks. Levothyroxine can be adjusted in 25 to 50 μg increments with a therapeutic range for TSH of 0.5 to 2.5 mU/L. The goal of treatment is to maintain the TSH in the upper normal range using the lowest possible dose in order to protect the fetus from hypothyroidism. The required dose of levothyroxine can increase up to 50% for patients with a history of hypothyroidism prior to conception. The patient’s TSH should be checked at the initial prenatal visit and every trimester. Medication adjustments, testing intervals, and therapeutic goals for TSH are the same as for patients with new-onset disease.

Physiologic Changes in Thyroid Function during Pregnancy

Multiple physiologic changes occur in thyroid function during pregnancy. Moderate thyroid enlargement develops due to pregnancy, hormone-induced glandular hyperplasia, and hypervascularity (see Table 21-3). Major changes in thyroid function tests are the result of an estrogen-mediated increase in thyroid-binding globulin (TBG), the major transport protein for thyroid hormone. As TBG increases, total T4, total T3, and free thyroid index increase as more thyroid hormone is bound to TBG. However, the serum levels of free T4 and free T3, the unbound active thyroid hormones, remain the same during pregnancy as do serum TSH levels. The resin T3 uptake (RT3U) decreases during pregnancy. In addition, thyroid stimulation occurs due to a “spillover” effect by hCG, especially in the first trimester. Iodine availability declines as maternal renal clearance increases and with additional losses to the fetus and placenta.

Pregnancy also affects thyroid function test results in disease states. In pregnant patients with hyperthyroidism, serum TSH decreases, free T4 increases, free thyroid index increases, total T4 increases, total T3 increases or remains unchanged, and the resin T3 uptake increases. In pregnant patients with hypothyroidism, serum TSH increases, free T4 decreases, free thyroid index decreases, total T4 decreases, total T3 decreases or remains unchanged, and the resin T3 uptake decreases.

Thyroid Function and the Fetus

The fetal thyroid begins to concentrate iodine at 10 to 12 weeks’ gestation with control by fetal pituitary TSH at 20 weeks’ gestation. Fetal serum TSH, TBG, free T4, and free T3 reach adult levels at 36 weeks gestation. The placenta does not allow transfer of TSH, but TRH, iodine, and TSI do cross the placental barrier. Small amounts of PTU and methimazole also cross, as well as T4 and T3, which prevent the stigmata of congenital hypothyroidism at birth.

aFindings as compared to nonpregnant state

bFindings as compared to pregnancy euthyroid state

TSH—thyroid stimulating hormone

Total T4—total thyroxine

Total T3—total triiodothyronine (T3)

RT3U—resin T3 uptake

FT4—free thyroxine (T4)

Comprehension Questions

21.1 During pregnancy, the preferred method of assessing the dosage of antithyroid drug needed to keep a patient with Graves disease in remission is to monitor which of the following?

A. TSH level

B. TSI level

C. Total T4 levels

D. Free T4 levels

E. The fetal thyroid with ultrasonography

21.2 A 30-year-old patient at 32 weeks’ gestation presents to labor and delivery with onset of preterm contractions. Her cervical examination is 3 cm and 80% effaced with bulging membranes, and she is contracting every 2 to 3 minutes on external tocometry. She has a history of Graves disease and is on PTU 200 mg t.i.d, but it is uncertain if she has been compliant with therapy. She becomes febrile with a temperature of 103°C and tachycardic with heart rate of 124 beats per minute. She seems very anxious and agitated and wants to walk around her room. Thyroid function studies are obtained but the results won’t be available for several hours. The next most appropriate step in management includes all of the following EXCEPT:

A. Amniocentesis

B. Betamethasone administration

C. Emergent cesarean delivery

D. Propylthiouracil 600 to 800 mg orally stat

E. ICU admission

21.3 Neonatal Graves disease is associated with which maternal autoimmune antibody production?

A. Thyroid-stimulating immunoglobin (TSI)

B. Antimicrosomal antibodies

C. Antithyroglobulin antibodies

D. Antiperoxidase (TPO) antibodies

E. Antinuclear antibodies

21.4 Hyperthyroidism in pregnancy is associated with all of the following maternal and fetal complications EXCEPT:

A. Preeclampsia

B. IUGR

C. Thyroid storm

D. IUFD

E. Venothromboembolic events

ANSWERS

21.1 D. During pregnancy, the preferred method of assessing the dosage of antithyroid drug needed to keep a patient with Graves disease in remission is to monitor the free T4 levels. Free T4 levels are used to monitor response to therapy in hyperthyroid patients and should be checked in 4 to 6 weeks. The PTU or methimazole can be adjusted in 50 mg or 10 mg increments, respectively, with a therapeutic range for free T4 of 1.2 to 1.8 ng/dL. The goal of treatment is to maintain the free T4 in the upper normal range using the lowest possible dose in order to protect the fetus from hypothyroidism. TSH levels are used to measure response to levothyroxine therapy in hypothyroidism. Thyroid-stimulating immunoglobin (TSI) levels are measured in women with Graves disease to determine possible risk for fetal or neonatal Graves disease. Total T4 levels increase during pregnancy due to estrogen-mediated increases in thyroglobulin binding protein (TBG), but the free T4 levels remain unchanged in normal pregnancy. Fetal thyroid surveillance with ultrasonography is not recommended for detection of fetal goiter in gravid women with Graves disease, and it is not used for monitoring drug therapy response in hyperthyroidism.

21.2 C. This patient with hyperthyroidism appears to be in preterm labor. It is not clear if she has concomitant chorioamnionitis and/or maternal thyroid storm given her fever and tachycardia. Her altered mental status points toward the diagnosis of thyroid storm, but both diagnoses are possible. Given the fact that her thyroid function studies won’t be resulted immediately, the presumption is uncontrolled thyrotoxicosis and PTU administration would be indicated. Intrauterine infection would be ruled out with amniocentesis. Betamethasone for fetal pulmonary lung maturation is reasonable given prematurity less than 34 weeks’ gestation. Even ICU admission could be indicated given the catastrophic nature of possible thyroid storm and need for high-acuity care. However, maternal stabilization is necessitated before delivery unless fetal indications outweigh the maternal risks.

21.3 A. In developed countries Hashimoto thyroiditis is the most common etiology of primary hypothyroidism and is characterized by the production of antithyroid antibodies, including antimicrosomal, antithyroglobulin, and antiperoxidase (TPO) antibodies. While these antibodies may be detected in maternal Graves disease, it is the production of thyroid-stimulating immunoglobin (TSI), which crosses the placenta and impacts the fetus. Specifically, thyroid-stimulating immunoglobin (TSI) and TSH-binding inhibitory immunoglobulin (TBII) act as TSH agonists or antagonists on the TSH receptor on the thyroid gland and mediate thyroid stimulation or inhibition, respectively, of thyroid growth, iodine trapping, and T4/T3 synthesis. Maternal Graves disease complicates 1 out of every 500 to 1000 pregnancies. One to 5% of neonates born to mothers with Graves disease have hyperthyroidism, or neonatal Graves disease, as a result of transplacental transfer of TSI. Although fetal hyperthyroidism requiring treatment is rare (< 0.01% of pregnancies), it is possible in any woman with a past or current history of Graves disease.

21.4 E. Untreated hyperthyroidism in pregnancy is associated with many maternal and fetal complications; however, hypercoagulability is not one of them. Women with hyperthyroidism in pregnancy are not at increased risk for deep venous thrombosis or pulmonary embolism.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ An increase in thyroid-binding globulin early in pregnancy causes a rise in total T3 and total T4 but does not affect free T3 or T4 levels (Level II-3).

➤ hCG levels in early pregnancy may transiently decrease maternal TSH levels (Level II-3).

➤ Signs of hypo- and hyperthyroidism may be confused with normal changes occurring in pregnancy (Level III).

➤ Women with a history of Graves disease (treated or untreated) should have TSI levels measured in the second trimester so those with positive levels may have more intense fetal monitoring (Level III).

REFERENCES

1. Thyroid Disease in Pregnancy. ACOG Practice Bulletin No. 37. Washington DC: American College of Obstetricians and Gynecologists; August, 2002. 

2. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Clinical expert series. Obstet Gynecol. 2006;108:1238-1292. 

3. Neal DM, Cootauco AC, Burrow G. Thyroid disease in pregnancy. Clin Perinatol. 2007;34: 543-557.

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