Exogenous hyperthyroidism

INTRODUCTION — Exogenous hyperthyroidism is the term used to describe hyperthyroidism caused by ingestion of excessive amounts of thyroid hormone. It may be intentional (ie, suppressive doses of thyroxine to treat thyroid cancer) or inadvertent (ie, contamination of dietary supplements). When exogenous hyperthyroidism is due to the surreptitious ingestion of thyroid hormone, it is termed thyrotoxicosis factitia.

The clinical manifestations, diagnosis, and treatment of exogenous hyperthyroidism will be reviewed here. An overview of disorders that cause hyperthyroidism is found elsewhere. (See "Disorders that cause hyperthyroidism".)

CAUSES — Exogenous hyperthyroidism is caused by the ingestion of excessive amounts of thyroid hormone. Levothyroxine (T4) is the most widely used thyroid hormone preparation, but the hormone is also available as liothyronine (T3) and thyroid extract (desiccated thyroid). Symptoms from exogenous hyperthyroidism frequently occur at doses in excess of 200 mcg for T4, 50 mcg for T3, and 120 mg for desiccated thyroid. However, most patients are taking considerably higher doses.

Exogenous hyperthyroidism can occur in several clinical settings [1]. As examples:

●Patients with thyroid cancer prescribed suppressive doses of thyroxine to minimize potential thyroid-stimulating hormone (TSH) stimulation of tumor growth.

●Patients with goiter prescribed excessive doses in an attempt to shrink the thyroid gland.

●Patients with a psychiatric disorder who may intentionally be prescribed excessive doses of thyroid hormone.

●Other patients, with or without the help of a clinician, may take excessive doses to treat obesity, menstrual disorders, depression, or infertility.

●Patients who intentionally or accidentally (particularly children) take an overdose of thyroid hormone. Accidental overdose has been reported due to errors made by compounding pharmacies [2].

Accidental overdose has also been described in adults taking weight-reducing dietary supplements (purchased over the internet) that claimed to contain only herbs but also contained significant amounts of both T3 and T4 or animal thyroid tissue [3-7]. Eleven of 19 glandular thyroid products purchased on the internet had up to 210 mcg T4 or 32 mcg T3 [6]. In one report, two individuals taking a Mexican weight loss supplement, Redotex (consumed at the recommended dose), developed T3 thyrotoxicosis; the supplement contained 75 mcg T3 per tablet [7].

A novel form of exogenous hyperthyroidism is the ingestion of thyroid tissue inadvertently removed and ground up with neck muscle in slaughterhouses to prepare hamburger; this has resulted in at least two community outbreaks of thyrotoxicosis [8,9]. The terms hamburger thyroiditis and hamburger hyperthyroidism were applied to these outbreaks because the clinical presentation mimicked that of painless thyroiditis (see "Painless thyroiditis"). Patients who ate large quantities of "thyroid burgers" became thyrotoxic for several weeks to months until their freezers were depleted, after which they had transient hypothyroidism. Subsequent case reports have described similar findings after ingestion of beef or sausage [10,11].

CLINICAL FEATURES

Clinical manifestations — The symptoms and signs in patients who take excessive doses of thyroid hormone are similar to those in patients with hyperthyroidism from other causes, such as Graves' disease. The classic symptoms include weight loss, heat intolerance, tremor, palpitations, anxiety, increased frequency of bowel movements, and shortness of breath. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

There are, however, two important exceptions:

●Exophthalmos (ophthalmopathy) occurs only in patients with Graves' hyperthyroidism because it is not caused by thyroid hormone per se. However, lid lag and lid retraction, signs of catecholamine excess, do occur. (See "Clinical features and diagnosis of thyroid eye disease".)

●There is usually no goiter because exogenous thyroid hormone in amounts sufficient to cause hyperthyroidism inhibits TSH secretion, resulting in thyroid atrophy. In patients with goiter given thyroid hormone in an attempt to reduce goiter size, however, the goiter may persist despite exogenous hyperthyroidism.

Acute levothyroxine (T4) overdose can cause acute hyperthyroidism. Myocardial infarction also can occur, especially in older adult patients, and seizures have rarely been described in children [12-14]. In most cases, however, particularly in children (who ingested a parent's medication), accidental ingestion of many milligrams of T4 and the accompanying transient marked elevation in serum thyroxine (T4) concentrations cause few symptoms and signs of hyperthyroidism [14].

Chronic T4 overdose can cause chronic overt (low serum TSH, high free thyroxine [T4] and/or triiodothyronine [T3]) or subclinical (low serum TSH with normal free T4) hyperthyroidism. The skeleton and the cardiovascular system are the major target tissues adversely affected by chronic overt and subclinical hyperthyroidism, although abnormalities in other systems have been reported (table 1). Overt hyperthyroidism is most clearly associated with accelerated bone remodeling, reduced bone density, osteoporosis, and an increase in fracture rate, especially in postmenopausal women. In some, but not all studies, even subclinical hyperthyroidism is also associated with low bone density in postmenopausal women. In addition, the frequency of atrial fibrillation is increased in older patients with subclinical hyperthyroidism, as it is in patients with overt hyperthyroidism. These topics are reviewed in detail elsewhere. (See "Bone disease with hyperthyroidism and thyroid hormone therapy", section on 'Exogenous thyroid hormone therapy' and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.)

Laboratory and imaging — All patients with exogenous hyperthyroidism have low serum TSH concentrations. Serum T4 and/or T3 may be elevated or normal, depending upon the degree of hyperthyroidism and which thyroid hormone preparation was ingested. Serum thyroglobulin (Tg) is suppressed and 24-hour radioiodine uptake is low due to suppression of TSH secretion. Thyroidal artery blood flow on Doppler is also reduced.

DIAGNOSIS — The diagnosis of exogenous hyperthyroidism is based upon the clinical features, laboratory findings, and 24-hour radioiodine uptake. Patients with exogenous hyperthyroidism have classic biochemical findings (low TSH, elevated or normal free T4 and/or T3). The absence of goiter, a low serum thyroglobulin (Tg) concentration, and a low or undetectable 24-hour radioiodine uptake differentiate exogenous hyperthyroidism from other causes of hyperthyroidism.

The serum concentrations of T4 and T3 may be useful in identifying the type of thyroid hormone ingestion [1,2]. As an example, patients taking excessive amounts of liothyronine (T3) have high serum T3 and low serum T4 concentrations. Those taking levothyroxine (T4) have high serum T4 and T3 concentrations, but the T4/T3 ratio is higher than that in most patients with spontaneously occurring hyperthyroidism. Conversely, patients taking thyroid extract have higher than normal serum T3/T4 ratios, like most patients with Graves' hyperthyroidism, toxic nodules, and toxic nodular goiter, since thyroid extracts contain a higher ratio of T3 to T4 than is present in euthyroid patient blood.

Diagnostic evaluation — In the setting of thyroid cancer or goiter, intentional intake of exogenous thyroid hormone is easily identified. A careful history may also reveal intentional intake of excessive doses of thyroid hormone to treat psychiatric disorders. In such cases, further evaluation is not necessary to diagnose exogenous hyperthyroidism. (See "Differentiated thyroid cancer: Overview of management", section on 'Thyroid hormone suppression' and "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter" and "Unipolar depression in adults: Augmentation of antidepressants with thyroid hormone", section on 'Long-term treatment'.)

Accidental ingestion of thyroid hormone (diet pills, contaminated meat) or surreptitious use of thyroid hormone (thyrotoxicosis factitia) is usually more difficult to detect. In these cases, further evaluation is needed to confirm the cause of hyperthyroidism. The initial evaluation typically includes measurement of radioiodine uptake. The findings on 24-hour radioiodine uptake can distinguish hyperthyroidism due to de novo synthesis of thyroid hormone (normal or high uptake) from either inflammation and destruction of thyroid tissue with release of preformed hormone into the circulation or an extrathyroidal source of thyroid hormone (nearly absent uptake). For patients with nearly absent uptake, we measure serum Tg to distinguish exogenous hyperthyroidism (low Tg) from all other causes of hyperthyroidism with nearly absent uptake (high Tg). Whenever serum Tg is measured, a test for anti-Tg antibodies should be performed at the same time (good laboratories do the latter first) because serum Tg measurements are falsely low in immunometric assays in the presence of anti-Tg antibodies.

●Nearly absent radioiodine uptake – The 24-hour radioiodine uptake in the thyroid is less than 1 percent in patients with exogenous hyperthyroidism due to the suppression of TSH secretion, except in patients with some autonomously functioning thyroid tissue. In addition to exogenous hyperthyroidism, other causes of hyperthyroidism with low or nearly absent 24-hour radioiodine uptake values include any of the different types of thyroiditis associated with release of preformed hormone from an inflamed gland, struma ovarii, and sometimes iodine-induced hyperthyroidism. (See "Overview of thyroiditis" and "Struma ovarii" and "Iodine-induced thyroid dysfunction", section on 'Iodine-induced hyperthyroidism'.)

●Tg – Serum Tg concentrations are low in patients with exogenous hyperthyroidism in the absence of goiter or thyroid cancer [15]. In contrast, they are high in hyperthyroid patients with endogenous hyperthyroidism, including functional metastatic thyroid cancer, struma ovarii, thyroiditis, and iodine-induced hyperthyroidism.

In difficult cases where thyrotoxicosis factitia is suspected and Tg is either not suppressed potentially because of a goiter, or Tg is undetectable potentially because of anti-Tg antibodies, fecal T4 measurement may be useful. In one study, fecal T4 values were approximately 0.8 mcg/g (1 nmol/g) in normal subjects and were increased twofold in patients with Graves' hyperthyroidism and 12- to 24-fold in patients with exogenous hyperthyroidism [16].

TREATMENT — Discontinuation or reduction in the dose of thyroid hormone is usually the only treatment needed. When therapy is stopped in patients taking levothyroxine (T4), serum T4 concentrations fall approximately 50 percent in seven days. T3 is cleared more rapidly (serum half-life approximately one day). However, very symptomatic patients may benefit from additional therapy.

●Beta-adrenergic antagonist drugs will relieve many of the symptoms of hyperthyroidism promptly. (See "Beta blockers in the treatment of hyperthyroidism".)

●In patients taking T4 (or thyroid extract), the radiographic contrast agents ipodate or iopanoic acid can be given to inhibit T4 conversion to T3 (these drugs are presently not available in the United States) [1]. The usual dose is 500 mg once daily; treatment is rarely needed for longer than seven days. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".)

●Cholestyramine can be given to bind T4 and T3 in the intestine, thereby interrupting the normal enterohepatic circulation of the two hormones [17]. The usual dose is 4 g four times a day.

●Patients (usually children) seen shortly after accidental ingestion of very large doses of thyroid hormone may be treated by induced emesis, gastric lavage, and intragastric instillation of charcoal.

●While plasmapheresis and exchange transfusion have been used to treat massive thyroid hormone overdose [1,2,18], most patients, especially children, have few symptoms and signs of hyperthyroidism, and conservative management is usually satisfactory [14].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

SUMMARY AND RECOMMENDATIONS

●Causes – Exogenous hyperthyroidism is the term used to describe hyperthyroidism caused by ingestion of excessive amounts of thyroid hormone. It may be intentional or inadvertent. It can occur in several clinical settings, including ingestion of excessive doses to treat thyroid cancer or to shrink the thyroid gland in patients with goiter, or through ingestion of weight-reducing dietary supplements containing levothyroxine (T4), liothyronine (T3), or animal thyroid tissue. (See 'Causes' above.)

●Clinical features – The symptoms and signs in patients who take excessive doses of thyroid hormone are similar to those in patients with hyperthyroidism from other causes and include weight loss, heat intolerance, tremor, palpitations, anxiety, increased frequency of bowel movements, and shortness of breath. Unless underlying thyroid disease is present, there is no goiter or ophthalmopathy. (See 'Clinical features' above and "Overview of the clinical manifestations of hyperthyroidism in adults".)

●Diagnosis – The diagnosis of exogenous hyperthyroidism is based upon clinical manifestations (presence of hyperthyroid symptoms, absence of goiter), abnormal thyroid function tests (low TSH, elevated or normal free thyroxine [T4] and/or triiodothyronine [T3]), a low serum thyroglobulin (Tg) concentration, and a low or undetectable 24-hour radioiodine uptake. (See 'Diagnosis' above.)

●Treatment – Discontinuation or reduction in the dose of thyroid hormone is usually the only treatment needed for most patients. When therapy is stopped in patients taking thyroxine, serum T4 concentrations fall approximately 50 percent in seven days. T3 is cleared more rapidly (serum half-life approximately one day). (See 'Treatment' above.)

Beta-adrenergic antagonist drugs can be used briefly to immediately relieve many of the symptoms of hyperthyroidism. (See "Beta blockers in the treatment of hyperthyroidism".)