[B] How should clinically or incidentally discovered thyrotoxicosis be evaluated and initially managed?

[B1] Assessment of disease severity

The assessment of thyrotoxic manifestations, and especially potential cardiovascular and neuromuscular complications, is essential to formulating an appropriate treatment plan. While it might be anticipated that the severity of thyrotoxic symptoms is proportional to the elevation in the serum levels of free T4 and T3 estimates, in one study of 25 patients with GD, the Hyperthyroid Symptom Scale did not strongly correlate with free T4 or T3 estimates and was inversely correlated with age (24). The importance of age as a determinant of the prevalence and severity of hyperthyroid symptoms has been recently confirmed (25). Cardiac evaluation may be necessary, especially in the older patient, and may require an echocardiogram, electrocardiogram, Holter monitor, or myocardial perfusion studies. In addition to the administration of beta-blockers (26), specific cardiovascular treatment may be directed toward concomitant myocardial ischemia, congestive heart failure, or atrial arrhythmias (20), and anticoagulation may be necessary in patients in atrial fibrillation (27). Goiter size, obstructive symptoms, and the severity of Graves’ ophthalmopathy (GO; the inflammatory disease that develops in the orbit in association with autoimmune thyroid disorders can be discordant with the degree of hyperthyroidism or hyperthyroid symptoms.

All patients with known or suspected hyperthyroidism should undergo a comprehensive history and physical examination, including measurement of pulse rate, blood pressure, respiratory rate, and body weight. In addition, thyroid size; presence or absence of thyroid tenderness, symmetry, and nodularity; pulmonary, cardiac, and neuromuscular function (23,26,28); and presence or absence of peripheral edema, eye signs, or pretibial myxedema should be assessed.

[B2] Biochemical evaluation

Serum TSH measurement has the highest sensitivity and specificity of any single blood test used in the evaluation of suspected hyperthyroidism and should be used as an initial screening test (29). However, when hyperthyroidism is strongly suspected, diagnostic accuracy improves when both a serum TSH and free T4 are assessed at the time of the initial evaluation. The relationship between free T4 and TSH (when the pituitary-thyroid axis is intact) is an inverse log-linear relationship; therefore, small changes in free T4 result in large changes in serum TSH concentrations. Serum TSH levels are considerably more sensitive than direct thyroid hormone measurements for assessing thyroid hormone excess (30). In overt hyperthyroidism, usually both serum free T4 and T3 estimates are elevated, and serum TSH is undetectable; however, in milder hyperthyroidism, serum T4 and free T4 estimates can be normal, only serum T3 may be elevated, and serum TSH will be <0.01mU/L (or undectable). These laboratory findings have been called ”T3-toxicosis” and may represent the earliest stages of disease or that caused by an autonomously functioning thyroid nodule. As is the case with T4, total T3 measurements are impacted by protein binding. Assays for estimating free T3 are less widely validated than those for free T4, and therefore measurement of total T3 is frequently preferred in clinical practice. Subclincial hyperthyroidism is defined as a normal serum-free T4 estimate and normal total T3 or free T3 estimate, with subnormal serum TSH concentration. Laboratory protocols that automatically add free T4 estimate and T3 measurements when screening serum TSH concentrations are low avoid the need for subsequent blood draws.

In the absence of a TSH-producing pituitary adenoma or thyroid hormone resistance, if the serum TSH is normal, the patient is almost never hyperthyroid. The term ”euthyroid hyperthyroxinemia” has been used to describe a number of entities, mostly thyroid hormone-binding protein disorders, that cause elevated total serum T4 concentrations (and frequently elevated total serum T3 concentrations) in the absence of hyperthyroidism (31). These conditions include elevations in T4 binding globulin (TBG) or transthyretin (TTR) (32), the presence of an abnormal albumin which binds T4 with high capacity (familial hyperthyroxinemic dysalbuminia), a similarly abnormal TTR, and, rarely, immunoglobulins which directly bind T4 or T3. TBG excess may occur as a hereditary Xlinked trait, or be acquired as a result of pregnancy or estrogen administration, hepatitis, acute intermittent porphyuria, or during treatment with 5-flourouracil, perphenazine, or some narcotics. Other causes of euthyroid hyperthyroxinemia include those drugs that inhibit T4 to T3 conversion, such as amiodarone (18) or high-dose propranolol (26), acute psychosis, extreme high altitude, and amphetamine abuse. Estimates of free thyroid hormone concentrations frequently also give erroneous results in these disorders. Spurious free T4 elevations may occur in the setting of heparin therapy. When free thyroid hormone concentrations are elevated and TSH is normal or elevated, further evaluation is necessary.

After excluding euthyroid hyperthyroxinemia, TSH-mediated hyperthyroidism should be considered. A pituitary lesion on MRI and a disproportionately high serum level of the alpha-subunit of the pituitary glycoprotein hormones support the diagnosis of a TSH-producing pituitary adenoma (33). A family history and positive result of genetic testing for mutations in the T3-receptor support a diagnosis of thyroid hormone resistance (34). Rare problems with TSH assays caused by heterophilic antibodies can cause spuriously high TSH values.

[B3] Determination of etiology

  • RECOMMENDATION 1

    A radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD; a thyroid scan should be added in the presence of thyroid nodularity. 1/+00

In a patient with a symmetrically enlarged thyroid, recent onset of ophthalmopathy, and moderate to severe hyperthyroidism, the diagnosis of GD is sufficiently likely that further evaluation of hyperthyroidism causation is unnecessary. A radioactive iodine uptake (RAIU) is indicated when the diagnosis is in question (except during pregnancy) and distinguishes causes of thyrotoxicosis having elevated or normal uptake over the thyroid gland from those with near-absent uptake (Table 3). It is usually elevated in patients with GD and normal or high in toxic nodular goiter, unless there has been a recent exposure to iodine (e.g., radiocontrast). The pattern of RAIU in GD is diffuse unless there are coexistent nodules or fibrosis. The pattern of uptake in a patient with a single TA generally shows focal uptake in the adenoma with suppressed uptake in the surrounding and contralateral thyroid tissue. The image in TMNG demonstrates multiple areas of focal increased and suppressed uptake, and if autonomy is extensive, the image may be difficult to distinguish from that of GD (35).

The RAIU will be near zero in patients with painless, postpartum, or subacute thyroiditis, or in those with factitious ingestion of thyroid hormone or recent excess iodine intake. The radioiodine uptake may be low after exposure to iodinated contrast in the preceeding 1–2 months or with ingestion of a diet unusually rich in iodine such as seaweed soup or kelp. However, it is rarely zero unless the iodine exposure is reoccurring as during treatment with amiodarone. When exposure to excess iodine is suspected (e.g., when the RAIU is lower than expected), but not well established from the history, assessment of urinary iodine concentration may be helpful.

TABLE 3. CAUSES OF THYROTOXICOSIS

Thyrotoxicosis associated with a normal or elevated radioiodine uptake over the necka

            GD

            TA or TMNG

            Trophoblastic disease

            TSH-producing pituitary adenomas

            Resistance to thyroid hormone (T3 receptor mutation)b

Thyrotoxicosis associated with a near-absent radioiodine uptake over the neck

            Painless (silent) thyroiditis

            Amiodarone-induced thyroiditis

            Subacute (granulomatous, de Quervain’s) thyroiditis

            Iatrogenic thyrotoxicosis

            Factitious ingestion of thyroid hormone

            Struma ovarii

            Acute thyroiditis

            Extensive metastases from follicular thyroid cancer

aIn iodine-induced or iodine-exposed hyperthyroidism (including amiodarone type 1), the uptake may be low.

bPatients are not uniformly clinically hyperthyroid.

T3, triiodothyronine.

Technetium scintigraphy (TcO4) utilizes pertechnetate that is trapped by the thyroid, but not organified. While this results in a low range of normal uptake and high background activity, total body radiation exposure is less than for 123I scintiscans; either type of scan can be useful in determining the etiology of hyperthyroidism in the presence of thyroid nodularity. Ultrasonography does not generally contribute to the differential diagnosis of thyrotoxicosis. When radioactive iodine is contraindicated, such as during pregnancy or breastfeeding, or not useful, such as following recent iodine exposure, ultrasound showing increased color Doppler flow may be helpful in confirming a diagnosis of thyroid hyperactivity (36). Doppler flow has also been used to distinguish between subtypes of amiodarone-induced thyrotoxicosis (see Section[U3], and between GD and destructive thyroiditis (see Section [V1]).

An alternative way to diagnose GD is by measurement of TRAb. This approach is utilized when a thyroid scan and uptake are unavailable or contraindicated (e.g., during pregnancy and nursing). The ratio of total T3 to total T4 can also be useful in assessing the etiology of thyrotoxicosis when scintigraphy is contraindicated. Since relatively more T3 is synthesized than T4 in a hyperactive gland, the ratio (ng/mcg) is usually >20 in GD and toxic nodular goiter, and <20 in painless or postpartum thyroiditis (37).

In most patients, the distinction between subacute and painless thyroiditis is not difficult. Subacute thyroiditis is generally painful, the gland is firm to hard on palpation, and the erythrocyte sedimentation rate (ESR) is almost always >50 and sometimes over 100 mm/h. Patients with painless thyroiditis may present in the postpartum period, often have a personal or family history of autoimmune thyroid disease, and typically have low to moderate concentrations of antithyroid peroxidase antibodies (38).

Thyroglobulin is released along with thyroid hormone in subacute, painless, and palpation thyroiditis, whereas its release is suppressed in the setting of exogenous thyroid hormone administration. Therefore, if not elucidated by the history, factitious ingestion of thyroid hormone can be distinguished from other causes of thyrotoxicosis by a low serum thyroglobulin level and a near-zero RAIU (39). In patients with antithyroglobulin antibodies, which interfere with thyroglobulin measurement, an alternative but not widely available approach is measurement of fecal T4 (40).

Technical remarks: Most TRAb assays are specific for GD, but thyroid-stimulating immunoglobulins (TSI) and first-generation thyrotropin-binding inhibitor immunoglobulin (TBII) assays are less sensitive (41,42). For example, one study found a second-generation TBII assay, which utilizes human recombinant TSH receptors, to have a specificity of 99%and a sensitivity of 95%compared to a sensitivity of 68% for a first-generation assay (43).

[B4] Symptomatic management

  • RECOMMENDATION 2

    Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease. 1/++0

  • RECOMMENDATION 3

    Beta-adrenergic blockade should be considered in all patients with symptomatic thyrotoxicosis. 1/+00

In patients in whom the diagnosis of thyrotoxicosis is strongly suspected or confirmed, treatment with propranolol, atenolol, metoprolol, or other beta-blockers leads to a decrease in heart rate, systolic blood pressure, muscle weakness, and tremor, as well as improvement in the degree of irritability, emotional lability, and exercise intolerance (24).

Technical remarks: Since there is not sufficient beta-1 selectivity of the available beta-blockers at the recommended doses, these drugs are generally contraindicated in patients with bronchospastic asthma. However, in patients with quiescent bronchospastic asthma in whom heart rate control is essential, or in patients with mild obstructive airway disease or symptomatic Raynaud’s phenomenon, a nonselective beta-blocker such as nadolol can be used cautiously,with careful monitoring of pulmonary status. Occasionally, very high doses of beta-blockers are required to manage symptoms of thyrotoxicosis and to reduce the heart rate to near the upper limit of normal (Table 4) (26). Calcium channel blockers, both verapamil and diltiazem, when administered orally and not intravenously, have been shown to effect rate control in patients who do not tolerate or are not candidates for beta-adrenergic blocking agents.

TABLE 4. BETA-ADRENERGIC RECEPTOR BLOCKADE IN THE TREATMENT OF THYROTOXICOSIS

Drug

Dosage

Frequency

Considerations

Propanolola

10–40 mg

TID-QID

Nonselective beta-adrenergic receptor blockade

Longest experience

May block T4 to T3 conversion at high doses

Preferred agent for nursing mothers

Atenolol

25–100 mg

QD or BID

Relative beta – 1 selectivity

Increased compliance

Metoprolola

25–50 mg

QID

Relative beta – 1 selectivity

Nadolol

40–160 mg

QD

Nonselective beta-adrenergic receptor blockade

Once daily

Least experience to date

May block T4 to T3 conversion at high doses

Esmolol

IV pump 50–100 µg/kg/min

 

In intensive care unit setting of severe thyrotoxicosis or storm

Each of these drugs has been approved for treatment of cardiovascular diseases, but to date none has been approved for the treatment of thyrotoxicosis.

aAlso available in once daily preparations.

T4, thyroxine.