Pregnancy and Hyperthyroidism

B.Thyroid Hormones

Concentrations of circulating thyroid hormones, thyroxine and triiodothyronine, are increased in pregnancy largely due to the increase in TBG (4). Despite the maintenance of a euthyroid condition, TT4 and TT3 concentrations often exceed the normal reference intervals. Reflecting the increase in TBG, concentrations of TT4 and TT3 rise substantially in the first trimester, reach a plateau around midgestation, and remain constant throughout the remainder of the pregnancy (4). It has been proposed that increases in total thyroid hormones could also be due to the increased production of type III deiodinase. Maternal hormones cross the placenta and are converted from T4 and T3 to rT3 and T2, respectively, by placenta type III deiodinase, which has extremely high activity during pregnancy (6). It has been suggested that high turnover rates create an increase in demand for total thyroid hormones during pregnancy (7,8).

It is generally accepted that concentrations of circulating free hormones are lower, albeit still within normal limits, than concentrations in nonpregnant women (9). There is some controversy about this in the literature (10–15); however, most recent publications suggest that the differences among published reports are likely due to the assays used to measure free hormones (16,17). It is important to note that this trend of lower concentrations of free hormones is more notable among women in iodine-deficient areas (18).

C.Thyroglobulin

Thyroid hormones are synthesized and stored in the colloid matrix of the thyroid follicles known as thyroglobulin (TG) (1). TG concentrations represent the activity and volume of the thyroid gland despite having no known hormonal function (19). In pregnancy, TG concentrations are often elevated, typically in the second and third trimesters, demonstrating increased thyroid stimulation (4). Increasing concentrations of TG are often associated with increases in thyroid volume (4). Although goiter is observed in fewer than 15% of pregnant women in the United States, women in iodine-deficient areas have significant increases in thyroid volume and hence elevations of TG (20,21).

D.Iodine Clearance

Circulating iodine concentrations are maintained in equilibrium with the iodine present in the thyroid and kidneys (4). In pregnancy, the glomerular filtration rate is considerably increased over nonpregnant patients, thereby resulting in lower concentrations of circulating iodine (22). The thyroid gland counteracts renal losses by increasing thyroidal iodine clearance, sometimes as much as twoto threefold over nonpregnant patients (23). Renal loss of iodine in areas of inadequate dietary supplies can rapidly lead to hypothyroidism and goiter, especially in the second and third trimesters of pregnancy when maternal iodine crosses the placenta in response to fetal demands (24).

E.Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH) belong to a family of heterodimeric glycoproteins that share a common α-subunit and differ only by a hormone-specific β-subunit (1). Extensive homology exists between TSH and hCG in the β-subunit and several conserved cysteine residues suggest similar three-dimensional structures (25). In addition, the luteinizing hormone (LH)/hCG and TSH receptors also share structural homology (25). Kosugi et al. demonstrated cross-reactivity of hCG to

Figure 1 Serum TSH and hCG as a function of gestational age. Serum hCG was determined at initial evaluation and during late gestation. The data points represent the mean values ( SE) for samples pooled for 2 weeks of 33 determinations for hCG and 49 for TSH. (From Ref. 21.)

TSH receptors that induces cellular responses leading to TSH suppression (26). Various reports indicate that the hCG in blood is a heterogeneous mixture and that certain oligosaccharide side chain modifications can affect the thyrotropic effect of hCG. For instance, removal of the sialic acid residues on hCG can increase its thyrotropic activity (27,28).

Numerous studies have documented the thyrotropic effect of hCG (9,25,29–34). Approaching the end of the first trimester, when hCG concentrations are highest, hCG stimulates the thyroid to release thyroid hormones resulting in a transient suppression of TSH (Fig. 1) (21). In normal pregnancy TSH suppression is a transient phenomena that typically remains within normal reference limits. Abnormal values are only observed in cases when the hCG concentration exceeds 50,000 IU/L (4,9). In certain pathological conditions such as molar pregnancies and trophoblastic disease, circulating concentrations of hCG are extremely elevated for extended periods of time, and the thyroid stimulatory effects of hCG are more severe, often inducing thyroid hyperfunction (4).

II. THYROID HYPERFUNCTION IN PREGNANCY

A. Causes

Graves’ disease, toxic multinodular goiter, subacute thyroiditis, toxic adenoma, TSH hypersecretion, and hormone overreplacement are just a few of the causes of hyperthyroidism occurring in the general population, although all of these can be observed in pregnant patients as well (35–38). Graves’ disease is by far the most common cause of hyperthyroidism in pregnancy (39,40). Hyperemesis gravidarum and hydatiform mole are pregnancy-specific associations that can induce hyperthyroidism and will be discussed

below. The prevalence of hyperthyroidism complicating pregnancy has been estimated to be 0.1–0.4% and is presumed to be increasing (35,38). This rise has in part been due to increased physician awareness and increased sensitivity of assays in detecting mild forms of the disease.

Although most pregnant women can tolerate mild hyperthyroidism, it is critical to monitor hyperthyroid patients. Poorly controlled hyperthyroidism in pregnancy can lead to deleterious effects in the mother and fetus (4). Some of these complications include congestive heart failure, thyroid storm, infection, spontaneous abortions, increased rate of stillbirths, low birth weights, preterm delivery, fetal or neonatal hyperthyroidism, and intrauterine growth retardation (37,39,40). Euthyroid pregnant women can exhibit tachycardia, wide pulse pressures, and mild heat intolerance that may make the diagnosis of hyperthyroidism difficult (39,41). However, a careful clinical interpretation of observed symptoms, medical history, and laboratory measurements can lead to the appropriate assessment of thyroid status.

B.Diagnosis and Laboratory Assessment

Differentiating between symptoms of hyperthyroidism and the hypermetabolic state of pregnancy can be particularly challenging. If symptoms such as weight loss or inappropriate weight gain, the presence of goiter, lid lag, fatigue, heart rate 100 beats/min (bpm), onycholysis, and ophthalmopathy are observed, the clinical suspicion of hyperthyroidism should be evaluated (20). Laboratory testing is similar to that in nonpregnant patients and should include measurement of TSH and free, not total, hormone levels. As discussed earlier, total T4 and T3 measurements are influenced by fluctuations in serum TBG concentrations during pregnancy and therefore should not be used (2,4,41). Measurements of free concentrations can be determined either directly or by a calculated index. In spite of increases in TBG during pregnancy, calculated indices are useful in determining free concentrations. In addition, hyperthyroid patients may exhibit mild increases in certain routine laboratory tests including white blood count, calcium, bone alkaline phosphatase, and liver enzymes (42). Table 1 summarizes thyroid-related changes that occur during pregnancy (5).

C.Graves’ Disease and Pregnancy

Graves’ disease is the most common cause of hyperthyroidism in pregnant women, accounting for 85% of all cases (20,43,44). Typically, a history of Graves’ disease or at least thyrotoxic symptoms predates the pregnancy. It is important to obtain a complete medical history and carefully evaluate clinical symptoms because a missed diagnosis can pose serious threats to the mother and fetus. Graves’ disease is characterized by the presence of goiter, tachycardia, warm moist skin, and mild heat intolerance (1). Ophthalmic findings suggestive of Graves’ include proptosis and diplopia resulting from eye muscle dysfunction (40). Exophthalmos is absent or mild, with one eye appearing slightly more prominent than the other in most cases. Stare is common, as is edema of the conjuctiva. However, pretibial myxedema is rare (35). Swollen eye muscles of Graves’ ophthalmopathy may be detected by ultrasonography when clinical symptoms are inconclusive upon routine examination (40). Unfortunately, the literature offers only a limited number of cases that discuss treatment and intervention methods for endocrine orbitopathy in pregnancy (45).

The natural course of Graves’ disease is altered during pregnancy. There is an aggra-

↑ Goiter in I2-deficient areas

↑, elevated; ↓, reduced. Source: Modified from Ref. 25.

vation in the first trimester due to increased thyroid activity, amelioration in the second and third trimesters of pregnancy because of immunosuppression, and exacerbation of symptoms in the postpartum period as the immune system rebounds (46). Additional laboratory tests to differentiate Graves’ disease from other causes of hyperthyroidism include measurement of thyroid peroxidase antibodies (TPO) and thyroid hormone receptor antibodies (TSHR-abs) (5,47). TPO antibodies suggest an autoimmune cause and TSHR-abs are specific for Graves’ disease. Therefore, measurement of these antibodies can be useful in establishing a diagnosis of Graves’ disease. Furthermore, the TSHR-abs have prognostic implications for fetal and neonatal hyperthyroidism (39,42,48). TSHR-abs can cross the placenta and, at high concentrations, bind to TSH receptors and stimulate the fetal thyroid (49). High titers of TSHR-abs ( 500% over normal) in maternal serum are predictive of fetal or neonatal dysfunction (20). It is important to note that a patient may be clinically euthyroid during pregnancy, but a previous history of Graves’ disease can result in a persistence of high concentrations of TSHR-abs (50). The fetus should be closely monitored for signs of TSHR-abs-stimulating activity.

Ideally, women should have their hyperthyroidism under control prior to conception. Antithyroid drugs (ATDs) are the treatment of choice during pregnancy (37). The dosage should be titrated to achieve the minimum drug required to maintain the free thyroid hormone levels in the upper third of the normal range (38,51). ATDs can cross the placenta and therefore, their administration should be reduced or stopped whenever possible, for example, during the second and third trimesters when the symptoms of Graves’ disease begin to lessen (39,52). Subtotal thyroidectomy should only be performed if there is an allergic reaction to ATDs or if there is sufficient evidence for drug resistance (20). If surgery is deemed necessary, it should be postponed until after the first trimester (38). 131I treatment is contraindicated in pregnancy (52).

D. Thyroid Antibodies and Spontaneous Miscarriage

One percent of women experience recurrent (three or more) spontaneous miscarriages (53,54). Only within the last decade has there been shown to be a strong association

Figure 2 The percentage of miscarriages in unselected pregnancies in women who were thyroid antibody positive (TAb ) and thyroid antibody negative (TAb ). (From Ref. 53.)

between thyroid antibodies and recurrent abortions (54–59). Stagnaro-Green et al. were the first to recognize the correlation in their study that was initially designed to determine the prevalence and causes of postpartum thyroiditis (55). During the study, it was discovered that patients who were thyroid antibody positive (TPO and/or Tg) experienced a significantly greater number of miscarriages than women who were thyroid antibody negative. Four additional studies have confirmed this report (56–59). These findings are reviewed by Abramson et al. and summarized in Figure 2 (53). All of these studies demonstrate an association with positive thyroid antibodies and spontaneous miscarriage, although there was not a correlation with thyroid antibody titers and pregnancy loss. At this time the mechanism of pregnancy loss and its relationship to the presence of thyroid antibodies remains elusive. Research aimed at treatment intervention in at-risk patients is currently being evaluated.

E.Gestational Transient Thyrotoxicosis

Gestational transient thyrotoxicosis (GTT) is a broad term that encompasses a number of nonimmune causes for transient hyperthyroidism associated with pregnancy (4). Although the majority of cases of transient hyperthyroidism in pregnancy are affiliated with hyperemesis gravidarum, other conditions of pregnancy such as multiple gestation and gestational trophoblastic disease can result in transient hyperthyroidism with or without symptoms of hyperemesis. Therefore, some researchers have adopted the term transient hyperthyroidism of hyperemesis gravidarum (THHG) to define the most common syndrome of transient hyperthyroidism in pregnancy (60).

Hyperemesis gravidarum occurs in about 0.2% of pregnant women and symptoms of hyperthyroidism manifest in more than half of those patients (60,61). These patients generally have no history of thyroid illness prior to pregnancy, goiter is usually absent, and thyroid antibodies are absent (4). Laboratory evaluation generally finds elevated concentrations of free T4, often over free T3 concentrations (5). Studies suggest that hyperemesis gravidarum is associated with extreme elevated concentrations of hCG in early pregnancy (62). In addition, desialylated forms of hCG have been isolated from serum of patients experiencing hyperemesis gravidarum (27,63). Although these patients frequently have more severe symptoms, there is not always a correlation between increased concentrations of hCG and symptoms of hyperemesis gravidarum (20). The symptoms associated with THHG typically disappear upon resolution of the hyperemesis.

Gestational trophoblastic disease (GTD) is another nonimmune condition associated with transient hyperthyroidism of pregnancy (63,64). GTD is a general term that includes benign and malignant conditions of hydatidiform mole and choirocarcinomas. Goiter is rare or lacking in these patients and ophthalmopathy is absent (43). Hyperthyroidism in these patients is attributed to significant and sustained elevations in serum hCG concentrations, which in some cases exceed the upper limit of normal by 1000 times. Laboratory examination finds increases in free hormone concentrations and marked elevation in serum hCG levels (4). As is the case with hCG-induced stimulation, T4 to T3 ratio is commonly increased over ratios observed in patients with Graves’ disease (25). Treatment involves complete removal of the GTD and this rapidly cures the hyperthyroidism.

F. Postpartum Thyroid Disease

Postpartum thyroid disease (PPTD) is believed to be an autoimmune destruction of thyroid follicles that results in transient hyperthyroidism (1–3 months postpartum) followed by hypothyroidism (3–8 months postpartum) (65,66). PPTD occurs with a prevalence of approximately 5–9% in unselected postpartum women (66–68). The release of preformed T4 and T3 from the damaged thyroid makes this condition characteristically distinct from Graves’ disease (69). PPTD can be differentiated from Graves’ disease on the basis of low radioactive iodine or technetium uptake in the thyroid during the thyrotoxic phase. Serum TSH is a good screening test. If results are abnormal, measurement of free T4 should be performed. Despite the strong association of TPO antibodies with PPTD, 50% of TPO-antibody-positive women do not develop PPTD (66,67). Occasionally, antithyroglobulin (TG) antibodies are present and, in rare cases, anti-TG antibodies are the only antithyroid antibodies found (70). Although PPTD is a transient state of thyroid dysfunction, there is an increased risk for permanent hypothyroidism (71). Treatment is usually not required because symptoms of PPTD generally are mild and nonspecific. In fact, PPTD is often underdiagnosed (72). Patients with a history of unstable thyroid function should be monitored yearly to assess thyroid status for subsequent pregnancies and for the development of permanent thyroid dysfunction.

III. SUMMARY

Correct assessment of thyroid function during pregnancy is critical to avoid both fetal and maternal complications. It is also important to keep in mind that thyroid activity undergoes many changes during normal pregnancy including significant increases in serum TBG, thyroglobulin, total T4, and total T3; an increase in renal iodine clearance; and hCG stimu-

lation. However, measurement of these values is not useful in the investigation of thyroid disease during pregnancy. Assessment of both hyperand hypothyroidism should be done with a careful evaluation of the patient’s symptoms as well as measurement of TSH and free thyroid hormones. Measurement of thyroid autoantibodies may also be useful to diagnose maternal Graves’ disease, recurrent spontaneous miscarriages, and postpartum disease. Knowing the patient’s history, clinical symptoms, and, moreover, realizing the changes associated with thyroid function in pregnancy, the physician can properly determine thyroid status.

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many subjective biases must be fully discussed and priority given to patient preferences over individual physician experience and interpretation of the literature (2,3; Table 1). Practice guidelines for the management of Graves’ disease by the American Association of Clinical Endocrinologists (AACE), the American Thyroid Association (ATA), the American College of Physicians (ACP), and the Royal College of Physicians (RCP) were reviewed by Arbelle and Porath (4): both AACE and ATA prefer radioiodine therapy, RCP does not specify a preference, and ACP does not discuss a preference. Results from surveys of the ATA and European Thyroid Association (ETA) demonstrate a preference by European thyroidologists for the use of medical therapy and American thyroidologists for the use of radioiodine therapy (5–8). In a recent review on the subject, Weetman (2) advocates ATDs for patients under age 50 and RAI if the patient is age 50 or over, since recurrent hyperthyroidism is associated with a higher risk of atrial fibrillation in this age group; or if there has been a recurrence after ATD therapy, provided there is no indication for surgery.

If ATDs are chosen for definitive therapy, there are still several decisions to be made: duration of therapy, high-dose (so-called block–replace) or low-dose (titration) therapy, choice of specific ATD, use of adjunctive therapy, and use of adjunctive diagnostic tests. Other questions include whether or not ATDs should be administered prior to RAI therapy and whether ATDs are safe for children and adolescents.

II. MEDICAL ARMAMENTARIUM

A. Antithyroid Drugs

The endocrinologist may individualize therapy using one or more drugs that influence thyroid pathophysiology (Table 2). The regimen will depend on symptom severity, medical comorbidities, patient’s age, and child-bearing status. The mainstays of treatment are the thionamides propylthiouracil (PTU) and methimazole (MMI). Carbimazole is principally used in Europe; 10 mg is rapidly converted to roughly 6 mg MMI in the serum. Since their pharmacological properties are virtually the same, they may be considered the same. Following the clinical studies by Astwood in 1943 (9) and Gabrilove et al. in 1945 (10) with thiouracil that demonstrated not only benefit but also a high frequency of agranulocytosis, PTU was synthesized and accepted. MMI was developed later and differs from PTU in several ways. Both drugs essentially inhibit the organification process, coupling reaction, thyroglobulin immunoreactivity, thyroidal autoimmunity, and thyroid cell growth. PTU, but not MMI, inhibits peripheral deiodination of T4 to T3, which may add benefit to the management of accelerated hyperthyroidism. However, a greater percentage of patients have disease that is controlled with a single daily dose of MMI than with PTU, favoring the use of MMI in patients with difficulty adhering to their regimen (11). Even though MMI has far greater lipid solubility than PTU, recent studies have demonstrated comparable fetal hypothyroidism and thus transplacental passage between PTU and MMI (12). However, excretion of MMI into breast milk exceeds that of PTU and the latter is generally recommended in nursing mothers when thionamide use is indicated (13). Adverse effects are comparable with PTU and MMI.

If a hypersensitivity reaction occurs, generally after 3 weeks of therapy, it is reasonable to switch to the other thionamide before abandoning antithyroid medication. Agranulocytosis represents the major risk of this therapy and may be more frequent with higher doses and in older patients. To be eligible for ATD treatment, patients must understand

the importance of contacting their physician if they experience sore throat, unexplained fever, other signs of infection, generalized aching or malaise, rash, or pruritus. If these symptoms or signs occur, a complete blood count should be obtained immediately. Since agranulocytosis can occur suddenly, and many patients with Graves’ disease are leukopenic at presentation, it is not cost-effective to monitor the blood count routinely. If the leukocyte count is less than 1500–2000/mm3 or the granulocyte count less than 1000/ mm3, the patient should be admitted to the hospital for intravenous (IV) fluids and broadspectrum antibiotics; the ATD should be stopped and not restarted. The use of rh granulocyte colony-stimulating factor (GCSF) has been supported by several clinical studies (14– 16) but also refuted by a recent report by Fukata et al. (17) using prolonged doses. Until these negative findings are confirmed, a brief ambulatory course of rhGCSF is warranted since hospitalization may be avoided if the granulocyte count significantly rises hours after administration. Last, cholestatic hepatitis with MMI, and fulminant hepatic failure with PTU requiring liver transplant, have been reported. Hyperthyroidism itself is associated with abnormal liver function tests, but routine liver function monitoring for deteriorating function seems prudent.

Once a particular ATD has been selected, a decision should be made whether to treat briefly to render the patient euthyroid and then administer radioiodine, or to continue the ATD as definitive therapy for 6–18 months. Several studies have reported higher overall remission rates with ATD (40–70%) (18–22) compared with beta blockers alone (14–30%); (23–26). In 1983, Romaldini et al. (27) demonstrated a relationship between daily doses of ATD (MMI and PTU) and remission rates in a retrospective, nonrandomized cohort study. In a prospective, randomized study in 1990, Allannic et al. (28) demonstrated a higher recurrence rate with a 6 month MMI course (58%) than with an 18 month MMI course (38%).

Two prospective trials taken together suggest, but do not prove, a role for dietary iodine in recurrence rates following ATD therapy. In 104 patients from an iodine-deficient region, Meng et al. (29) found a relatively low 1 year recurrence rate: 31% and 33% following 40 mg or 5–10 mg MMI daily, respectively. In contrast, in patients from an iodine-rich region, Jorde et al. (30) found a relatively high 2 year recurrence rate: 72.4% and 81.5% following 60 mg or titrated low-dose MMI daily, respectively. Overall, retrospective studies have identified the following as good prognosticators for treatment with ATD: female male, older age, smaller goiter or from an iodine-deficient region (decreased intrathyroidal iodine content), milder thyrotoxicosis, and lower TRAb levels (8,31–33). In fact, it is argued that monitoring TRAb titers may allow for an abbreviated (6 month) course of ATD by predicting long-term remissions (34).

If used as definitive therapy, should high doses of ATD be used to ensure intrathyroidal levels necessary for immunosuppression? If so, supplemental L-thyroxine may need to be added to maintain euthyroidism and a low-normal TSH, thus avoiding physiological stimulation of thyroid cell growth and possible antigen expression. The recent literature has clarified some of these points. If the titration method is used (low-dose ATD), there is no benefit extending the treatment duration past 18 months (35). As an alternative, if the block–replace method is used (high-dose ATD), there may be no benefit beyond 6 months (36). A review of prospective, randomized controlled clinical trials comparing lowand high-dose ATD is given in Table 3. A critical review of these reports, heavily biased by the recent European Multicenter Trial (43), would conclude that there are insufficient data to justify routine use of the block–replace method.

B.Adjunctive Medical Therapy

The goal of early-phase therapy in Graves’ disease is twofold: to decrease synthesis and release of thyroid hormone, and to lessen the impact of thyrotoxicosis on peripheral tissues. Antithyroid drugs act to decrease synthesis and, in the particular case of PTU, to decrease peripheral T4 to T3 conversion. However, several other classes of drugs can potentiate the effects of ATD. In cases in which ATD cannot be used because of adverse effects, these adjuvant agents can control thyrotoxicosis sufficiently until definitive therapy with radioiodine or surgery can be undertaken.

1. Adrenergic Antagonists and Calcium Channel Blockers

Nonspecific clinical findings in thyrotoxicosis thought to derive from hyperadrenergic tone and improve with beta-blockade include fine tremor, palpitations, amenorrhea, stare, lid lag, heat intolerance, and anxiety (44). Clinical studies have failed to demonstrate conclusively any increased adrenergic sensitivity, adrenomedullary activity, or increased catecholamine levels with thyrotoxicosis. Therefore, the utility of beta-blockade is simply to inhibit native sympathetic tone on the heart and peripheral tissues. An additional favorable pharmacological effect of beta-blockers is the inhibition of 5′-monodeiodinase activity, which converts T4 to T3. Miscellaneous actions of beta-blockers are improvement in nitrogen balance, correction of hypercalcemia, reversal of bulbar dysfunction and proximal myopathy, and treatment of periodic paralysis.

The usual starting dosage of propranolol is 10–40 mg orally four times daily, depending on the severity of the thyrotoxicosis. The dosage is titrated to achieve a heart rate in the 70–80 beats/min range and is gradually decreased as thyroid hormone levels normalize with ATD. Patients with a history of asthma may be treated with a calciumchannel blocker such as diltiazem.

2. Stable Iodine

Even though iodine can cause hyperthyroidism in patients with nodular goiters, it can temporarily control hyperthyroidism in patients with Graves’ disease. The spectrum of action of iodides includes inhibition of trapping with prolonged exposure, inhibition of organification (Wolff-Chaikoff effect), inhibition of thyroid hormone release via TSH action on adenyl cyclase and thyroglobulin endocytosis, direct cytotoxicity, and inhibition of cellular proliferation and γ-interferon-induced major histocompatibility complex (MHC) class II expression. Overt improvement in the thyrotoxic patient occurs within days: 50% reduction in T4 by 4 days, and 47% reduction in T3 by 11 days (45,46). Escape occurs by 3–4 weeks as the trapping mechanism recovers and intrathyroidal iodine accumulation enhances total thyroid hormone secretion.

One drop of saturated solution of potassium iodide (SSKI) equals 6 drops of compound solution of iodine (Lugol’s solution) and 38 mg iodine. The daily requirement is 75–200 µg (250 µg in pregnancy) and total body stores are 20–50 mg. Only a few drops per day are required for therapeutic action. Because of the very unpalatable taste, iodine should be diluted in 50–100 ml water prior to ingestion. Adverse effects range from acute hypersensitivity reactions (angioedema, hemorrhagic skin lesions, and serum sickness) to chronic iodism (brassy taste, burning mouth, parotid/salivary gland swelling, rhinitis, conjunctivitis, headache, cough, gastritis, bloody diarrhea, anorexia, depression, acneiform rash, and severe skin eruptions). Urinary iodine excretion can be promoted by administration of loop diuretics if a severe reaction occurs.

3. Glucocorticoids

These drugs are very effective in the management of thyrotoxicosis because of their multiplicity of effects. Glucocorticoids inhibit peripheral monodeiodination of T4 into T3 as well as possibly decreasing thyroidal T4 output. If steroids with mineralocorticoid action are used, the plasma volume expands, which further reduces thyroid hormone concentrations. The use of dexamethasone 1–2 mg two to four times daily, or equivalent doses of prednisone or methylprednisolone, should be reserved for rapid biochemical control during early-phase therapy. H2-blockers, antacids, or proton-pump inhibitors might be useful to control the dyspepsia that may result from steroid use. If acute behavioral changes occur, the steroid should be discontinued. Fluid retention, alkalosis, and hypokalemia may result when steroids with intrinsic mineralocorticoid activity are used. Moreover, the possibility of hyperglycemia should be anticipated and treated if it develops.

4. Oral Cholecystographic Agents

Ipodate is the most potent oral cholecystographic agent used to manage acute thyrotoxicosis. It is 63% iodine by weight, which explains part of its action. The liberated iodine acts to inhibit thyroid hormone release. An additional effect is inhibition of peripheral monodeiodinase activity. In hyperthyroid patients, the serum T3 level is reduced by 50– 62% in 24 h following a single 0.5, 1, or 3 g dose; after 6 h, there is a 30% reduction in serum T3 following a 3 g dose (47). This compares with a 65% reduction in serum T3 in 24 h following large and repeated doses of PTU, SSKI, and dexamethasone (48).

Ipodate improves the biochemical response when added to an ATD regimen (49). It is superior to stable iodine due to the additional inhibitory effect on peripheral monodeiodination (75% reduction in T3 by day 5 for ipodate compared with 64% by day 9 for stable iodine; [50]). However, there is a rebound effect in serum T4 (23%) and T3 (50%) levels with ipodate discontinuation that is not seen with stable iodine discontinuation (50). Ipodate therapy may be considered for acute management of accelerated Graves’ hyperthyroidism. However, it should only be used for a brief period of time since iodine stores in fat can persist up to a year, compromise the efficacy of ATD, and therefore increase recurrence rates after ATD treatment is stopped (51). Adverse effects of ipodate include nausea, vomiting, and diarrhea as well as iodine-induced hyperthyroidism (Jod-Basedow phenomenon), which can also be observed with stable iodine treatment.

5. Lithium

In 1968, Schou et al. (52) noted that patients treated with lithium for 5 months to 2 years developed goiter. Unlike stable iodine or ipodate, the use of lithium during early-phase management does not mitigate the efficacy of radioiodine therapy. When lithium levels are maintained at 0.5–1.0 mEq/L, with a usual daily dosage of 900–1500 mg, colloidal droplet formation and thyroglobulin hydrolysis, in response to TSH and cAMP, are inhibited. Following 2 weeks of lithium therapy, 8 of 11 Graves’ disease patients were rendered euthyroid; this was associated with a 35% reduction in serum T4 and T3 levels (53). During 6 months of treatment there was no escape, but after 1–4 weeks following discontinuation of the lithium, seven of the eight responders relapsed. This relapse can be prevented by concomitant use of ATD, which would inhibit thyroid hormone synthesis.

Lithium is rapidly absorbed by the gastrointestinal tract and attains peak levels by 4 h, with a serum half-life of 24–36 h. There is 80% resorption in the proximal nephron and toxicity is dose-dependent. A three times daily regimen is preferred to produce an

even plateau. Nevertheless, levels must be meticulously monitored and maintained in the 0.5–1.5 mEq/L range (60 years old and under) or 0.1–0.5 mEq/L (over 60 years old). Adverse effects of lithium are significant and account for the relative infrequency of its use in the management of thyrotoxicosis. Common side effects include nausea, diarrhea, anorexia, and malaise. Of interest, lithium therapy has been associated with progression of orbitopathy requiring surgical decompression, with lithium withdrawal inducing a dramatic improvement in the exophthalmos (54). Endocrinopathies associated with lithium use include hypothyroidism, hyperthyroidism (TSH receptor mediated in susceptible individuals), nephrogenic diabetes insipidus (managed with thiazides or amiloride), and hypercalcemia.

6. Bile Acid Sequestrants

This class of drugs represents the newest addition to the armamentarium used to combat endogenous thyrotoxicosis. Both cholestyramine and colestipol bind iodothyronine from the enterohepatic circulation, thereby increasing their fecal excretion. They were first used to treat factitious or iatrogenic thyrotoxicosis due to inadvertent or surreptitious ingestion of excessive thyroid hormone. In a small controlled trial, cholestyramine, 4 g orally administered four times daily, improved the biochemical response to treatment with MMI (55). Similarly, but in a large, controlled trial of 92 patients, colestipol, 5 g orally four times daily, improved the biochemical response to treatment with MMI; the data indicated that MMI dosing could be reduced with colestipol, thus decreasing the risk of MMI-dependent side effects (56). These agents are generally safe but require that the patient can tolerate oral or enteric tube administration. Since the absorption of other drugs may be compromised if they are administered with the bile acid sequestrant, it is recommended that all other medications be taken approximately 2 h before or after cholestyramine or colestipol.

III. SPECIAL CLINICAL SITUATIONS

A. Pediatric Graves’ Disease

Children and adolescents with Graves’ disease, in contrast to adults, present with weight loss, increased bowel movements, polyuria and polydipsia, palpitations, impaired skeletal mineralization, behavioral disturbances, and poor academic performance. In children treated with ATD, long-term remission rates range from 30 to 60%, with a longer time to remission in prepubertal children than in pubertal children (57). The initial PTU dosage in children is 5–10 mg/kg/day and 0.5–1.0 mg/kg/day MMI. Adverse effects of ATD are more common in children than adults: overall 35%; prepubertal 71%, pubertal 28%, postpubertal 25% (57). In a study of more than 500 children, the most common complication of ATD was mild liver function test elevation (28%), followed by mild leukopenia (25%), skin rash (9%), granulocytopenia (4.5%), arthritis (2.4%), nausea (1.1%), and agranulocytosis and hepatitis (0.4% each) (58).

Surgery affords a rapid and definitive cure but, in addition to the infrequent risks of damage to the recurrent laryngeal nerve, hypoparathyroidism, and hypothyroidism, cosmesis is a concern. On ther other hand, radioiodine, despite being convenient and effective, is associated with a higher risk of thyroid cancer, especially in children under 5 years of age (58). Based on the available evidence, antithyroid drugs are a reasonable first-line choice for definitive therapy in older children and adolescents, and may be considered in younger children. The best approach involves a thorough discussion of the risks

164 Mechanick

and benefits of these three efficacious modalities with the patient (if old enough) and parents.

B.Pregnancy, Postpartum, and Breast Feeding

Graves’ hyperthyroidism is the most common cause of thyrotoxicosis among pregnant women (see Ref. 59 for a review). Not infrequently, the diagnostic differentiation between physiological suppression of TSH and true hyperthyroidism is confusing. In fact, over half the patients with hyperemesis gravidarum in early pregnancy will have biochemical hyperthyroidism which will resolve by 18 weeks of gestation. Radioiodine scanning and treatment are absolutely contraindicated during pregnancy.

Antithyroid drugs are used in early-phase therapy: PTU is generally preferred over MMI due to demonstration of less transplacental passage, although this concept has been challenged. In fact, in a retrospective study of 185 pregnant patients with Graves’ disease treated with ATD, PTU and MMI were equivalent with respect to percentage still hyperthyroid at delivery, time to euthyroidism, and incidence of major congenital anomalies (60). ATD are generally administered in smaller amounts in pregnancy. Initial dosages of PTU may be 100–200 mg daily and MMI 10–20 mg daily. Block–replace regimens of ATD therapy are contraindicated since they require higher dosages that can cause fetal hypothyroidism. If the patient’s disease cannot be controlled due to adverse effects of ATD or nonadherence to the medical regimen, surgery is indicated and generally performed in the second trimester when the hyperthyroidism ameliorates transiently.

Beta-blockers may be safely used preoperatively or to control maternal symptoms of thyrotoxicosis, if severe, but there are controversial associations with placental insufficiency, intrauterine growth retardation, excessive uterine irritability, fetal bradycardia, hypoglycemia, hyperbilirubinemia, and polycythemia. Stable iodine can be used preoperatively, generally for less than 7–10 days to avoid fetal goiter. If accelerated hyperthyroidism occurs, especially during the onset of labor, dexamethasone, 2 mg every 6 h, may be added to the regimen.

Up to 60% of women of reproductive age with Graves’ disease identify a postpartum onset (see 61 for review). This condition is associated with recurrent TSH-receptor antibodies and the appearance of symptoms 3–6 months after delivery. If ATD are chosen, low-dose PTU ( 100–150 mg daily) is preferred because of its lower concentration in milk compared with MMI. If PTU allergy occurs, MMI can be used at dosages less than 10 mg daily. In any case, the baby should have thyroid function tests regularly to determine whether there is fetal hypothyroidism from ATD use, or fetal hyperthyroidism from transplacental passage of stimulating TSH-receptor antibodies (1–5% incidence).

C.Adjunctive Medical Therapy with Radioiodine Therapy or Surgery

Pretreatment with ATD may render the patient euthyroid more rapidly and decrease the risk of toxic radiation thyroiditis and accelerated hyperthyroidism. There has been little controversy surrounding the benefit of stopping ATD therapy during RAI therapy (62). However, the general practice of pretreating with PTU or MMI, discontinuing ATD at least 3 days prior to RAI, restarting ATD no sooner than 3 days following RAI, and then stopping ATD approximately 2 months after RAI, has recently been challenged. Tuttle et al. (63) demonstrated a higher failure rate when PTU was used as a pretreatment. In a prospective, randomized, controlled study of 51 patients with Graves’ disease, patients pretreated with MMI experienced higher post-RAI thyroid hormone levels due to with-

drawal of the ATD than patients not pretreated at all (64). In a commentary by Perros (65), it is argued that pretreatment with ATD as early-phase therapy should only be reserved for those with severe thyrotoxicosis or heart disease.

If early-phase medical therapy is required prior to RAI therapy, other drugs can be added to ATD to improve clinical and biochemical control. Administration of stable iodine initiated 7 days after RAI renders a euthyroid state earlier but with a more likely transient (60%), but not permanent (58%), post-RAI hypothyroid state (66). If the thyroid gland is small with rapid turnover, or if the patient is young and a lower radioiodine dosage is preferred, pretreatment for 7 days and posttreatment for 7 days with lithium can increase RAI dose retention (54). Propranolol and glucocorticoids can also provide additional control of severe thyrotoxicosis prior to RAI therapy. Prednisone, 0.4–0.5 mg/kg/day, or dexamethasone at equivalent dosages, initiated at the time of RAI therapy, continued for 1 month, and then weaned over a 2 month period, can attenuate the mild transient worsening of orbitopathy observed following RAI therapy (67).

Subtotal thyroidectomy by an experienced thyroid surgeon is indicated for patients with Graves’ disease in whom immediate biochemical control is desired, the goiter is very large, or when there is a coexistent thyroid nodule that has a higher risk of malignancy than in patients without Graves’ disease. Contrary to destructive therapy with RAI, neartotal thyroidectomy is not associated with progression of orbitopathy (68). Preoperative therapy with ATD is recommended to render the patient euthyroid. Stable iodine may also be used for 1–2 weeks preoperatively to decrease blood flow and induce involution, firmness and mobility of the gland, thus technically facilitating the resection. If ATD or stable iodine cannot be used, an alternative would be lithium therapy. Propranolol is used preand postoperatively; shorter acting beta-blockers such as esmolol may be used intraoperatively.

IV. CONCLUSION

The medical management of systemic Graves’ disease includes a host of drugs with specific and sometimes overlapping modes of action that allow for a tailoring of therapy. Antithyroid drugs are the mainstay of medical treatment and may be used as definitive therapy or in short courses prior to surgery or administration of radioiodine. Many disturbing controversies are being clarified by recent, well-designed clinical trials allowing an evidence-based approach. Future interventions will no doubt involve immunological methods directed at the autoimmune causes of Graves’ disease.

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