Once the diagnosis of hyperthyroidism has been established, the cause of the hyperthyroidism should be determined.


 

Anti-thyroid medications

Radioactive iodine to slow the production of thyroid hormones.

Surgery to remove all or part of your thyroid gland.

Treatment is often with PTU (blocks peroxidase activity), iodine (inhibits the iodine pump), radioactive iodine (ablates the thyroid), or surgery (thyroidectomy). Beta-blocker medications often are used when tachycardia is present.

Without nodular thyroid disease — For a nonpregnant, hyperthyroid patient without a nodular thyroid and without obvious clinical manifestations of Graves' disease (eg, without ophthalmopathy), measurement of TRAb, determination of radioactive iodine uptake, or assessment of thyroidal blood flow on ultrasonography are acceptable options to distinguish Graves' disease from other causes of hyperthyroidism. We typically measure TRAb first (see 'Thyrotropin receptor antibodies' below). If the antibodies are positive, it confirms the diagnosis of Graves' disease. If negative, it does not distinguish among the etiologies, as TRAb may not be elevated in patients with mild Graves' disease [25,26]. In this setting, we proceed with a radioactive iodine uptake. An alternative is to assess thyroidal blood flow on ultrasound in those centers where expertise is available. (See 'Other tests' below.)

With nodular thyroid disease — For nonpregnant, hyperthyroid patients with physical examination findings consistent with or suspicious for nodular thyroid disease, we obtain a radioactive iodine uptake and scan as our initial test to distinguish toxic multinodular goiter (multiple areas of focal increased and suppressed uptake) and toxic adenoma (focal increased uptake) from Graves' disease (diffuse increased uptake) or to assess the functionality of nodules that may coexist with Graves' disease. (See 'Radioiodine uptake' below.)

Radioactive iodine is contraindicated during pregnancy. Thus, for pregnant, hyperthyroid women, we measure TRAb or assess thyroidal blood flow on ultrasonography (where expertise is available). Hyperthyroidism during pregnancy is reviewed in detail separately. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Establishing the cause'.)

Thyroid tests — Sometimes the pattern of thyroid function test abnormalities suggests a specific diagnosis. As examples:

●If TSH is low and only serum T3 is high (normal free T4 concentration), the patient most likely has Graves' disease or an autonomously functioning thyroid adenoma. This pattern is more common in regions of marginal iodine intake than in the United States. Another possibility is exogenous T3 (liothyronine) ingestion. T3-hyperthyroidism can also be seen in patients taking antithyroid drugs [27]. A radioiodine scan can differentiate between Graves' disease or autonomy and exogenous intake of T3. (See 'Radioiodine uptake' below.)

●If TSH is low, free T4 is high, and T3 is normal, the patient may have hyperthyroidism with concurrent nonthyroidal illness, amiodarone-induced thyroid dysfunction, or exogenous T4 ingestion. Patients who ingest exogenous T4 (levothyroxine) may have high serum T4 and T3 concentrations, but the T3/T4 ratio is lower than that in most patients with Graves' hyperthyroidism and toxic adenoma(s) whose T3/T4 ratio usually exceeds 20 (ng/mcg) [28]. (See "Thyroid function in nonthyroidal illness" and "Amiodarone and thyroid dysfunction".)

●If free T4 and T3 are elevated and serum TSH is normal or elevated, serum alpha subunit and a pituitary magnetic resonance imaging (MRI) should be obtained to assess the possibility of a TSH-producing pituitary tumor (see "TSH-secreting pituitary adenomas"). Patients with resistance to thyroid hormone have variable degrees of end-organ evidence of hyperthyroidism and a family history of "hyperthyroidism" or genetic abnormalities in the T3 receptor; commercial assays for genetic testing for thyroid hormone resistance are now available. (See "Impaired sensitivity to thyroid hormone".)

The various causes of hyperthyroidism and the tests used to identify them are discussed in more detail elsewhere. (See "Disorders that cause hyperthyroidism" and "Painless thyroiditis" and "Subacute thyroiditis" and "Exogenous hyperthyroidism" and "Diagnostic approach to and treatment of thyroid nodules" and "Clinical presentation and evaluation of goiter in adults".)

Radioiodine uptake — For nonpregnant, hyperthyroid patients with physical examination suggesting nodular thyroid disease, we obtain a radioactive iodine uptake as our initial test to determine the etiology of hyperthyroidism. Pregnancy and breastfeeding are absolute contraindications to radionuclide imaging. However, in the unusual instance where radioiodine uptake measurement is felt to be essential for a definitive diagnosis in a lactating woman, breast milk can be pumped and discarded for five days after ingestion of iodine-123 (123I), then breastfeeding may be resumed [23]; breastfeeding should not be resumed if the iodine-131 (131I) isotope is used for determining the uptake.

From a pathogenetic viewpoint, hyperthyroidism results from two different mechanisms that can be distinguished by the findings on the 24-hour radioiodine uptake (table 1):

●Hyperthyroidism with a high (or normal) radioiodine uptake indicates de novo synthesis of hormone.

●Hyperthyroidism with a low (nearly absent) radioiodine uptake indicates either inflammation and destruction of thyroid tissue with release of preformed hormone into the circulation or an extrathyroidal source of thyroid hormone, such as in patients with factitious thyrotoxicosis and in patients with struma ovarii, where the functioning thyroid tissue is in the pelvis rather than the neck. Patients who have been exposed to large amounts of iodine (eg, intravenous radiographic contrast, amiodarone) may also have a misleading low radioiodine uptake, although a nearly absent level of uptake after iodine exposure is common only with amiodarone. (See "Overview of thyroiditis" and "Exogenous hyperthyroidism" and "Struma ovarii" and "Amiodarone and thyroid dysfunction".)

A radioiodine uptake and scan may be indeterminate in a patient with subclinical hyperthyroidism due to an autonomous nodule. A suppression scan may better demonstrate an area of focal autonomy (image 1). Suppression scans are reviewed in more detail separately. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Thyroid scintigraphy'.)

Thyrotropin receptor antibodies — For pregnant, hyperthyroid patients and for nonpregnant, hyperthyroid patients without nodular goiter and without obvious clinical manifestations of Graves' disease (eg, without ophthalmopathy), we measure TRAb to determine the etiology of hyperthyroidism. Graves' disease is caused by autoantibodies to the TSH (thyrotropin) receptor that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter). The presence of TRAb in serum distinguishes the disorder from other causes of hyperthyroidism.

In such situations where the clinical diagnosis is uncertain, TRAb, using third-generation assays, have a sensitivity and specificity of 97 and 99 percent for diagnosing Graves' disease [26]. Therefore, in the presence of TRAb, it is reasonable to assume the diagnosis of Graves' hyperthyroidism [25,29].

Note that there are two methods for measuring TRAb, and commercial labs in the United States may refer to these assays as TBI (thyrotropin-binding inhibiting) immunoglobulin, TBII (thyrotropin-binding inhibitory immunoglobulin), and thyroid-stimulating immunoglobulin (TSI) assays [26]. Third-generation TBI/TBII assays are competition-based assays that measure inhibition of binding of a labeled, monoclonal, anti-human TRAb (or labeled TSH) to recombinant TSH receptor. In contrast, TSI assays measure immunoglobulin-stimulated increased cAMP production, eg, from Chinese hamster ovary cells transfected with human TSH (hTSH) receptor.

When TRAb measurement is negative, we then obtain a radioiodine uptake and scan to determine the etiology of the hyperthyroidism. Assessment of thyroid blood flow by ultrasonography is an alternative approach, if expertise is available.

Other tests — Other measurements that help differentiate Graves' hyperthyroidism from destruction-induced hyperthyroidism when a radioiodine uptake is contraindicated include a serum T3/T4 ratio >20 (in standard units ng/mcg) [28] and a serum free T3/free T4 ratio >0.3 (SI units) [30]. Additionally, assessment of quantitative thyroid blood flow by ultrasonography may be helpful to differentiate Graves' hyperthyroidism from painless thyroiditis [31]. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Establishing the cause' and "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Autoimmune thyroid disease'.)

 

During pregnancy, the hormone HCG (human chorionic gonadotropin) is produced. HCG increases to a peak at around 12 weeks. It has mild thyroid stimulating effects and, as a result, can cause some symptoms of hyperthyroidism.1

 

Sixty percent of these women have either subclinical (no apparent symptoms) or mildly clinical (mild symptoms) hyperthyroidism, which also usually resolves after the first trimester.

There are other rare conditions associated with abnormal pregnancies that result in hyperthyroidism that are beyond the scope of this discussion.

While the conditions mentioned above are self-limited and associated with changes in the first trimester of pregnancy, women who have hyperthyroidism and become pregnant present another issue.

Pregnancies complicated by uncontrolled hyperthyroidism may result in higher incidences of:

Although any form of uncontrolled hyperthyroidism can complicate pregnancies, the most common form is Graves' disease.

The diagnosis of hyperthyroidism in pregnancy can be complicated since some of the blood tests used for the diagnosis are altered because of the pregnancy. The diagnosis is based on high levels of thyroid hormones, T3 and T4, and a low level of thyroid stimulating hormone (TSH).

The treatment of hyperthyroidism in pregnancy is limited because the safety of the baby must also be considered. Usually, drugs such as propylthiouracil (PTU) and methimazole (MMI) are used. While both of these drugs do cross the placenta and can enter the baby's system, treatment is still preferred because of the poor outcomes associated with not treating these women. PTU is preferred because MMI has been associated with a rare scalpcondition in the fetus known as "aplasia cutis."

Medications to slow the mother's heart rate down may also be necessary. The class of drugs recommended is called beta-blockers (metoprolol, propranolol). While these drugs are not thought to be dangerous to the fetus (teratogenic), there have been associations with growth retardation. Low blood sugars at birth and some respiratory problems have also been reported.

Since radiation therapy is not safe for the baby in pregnancy, surgery may be the only other option for women who cannot tolerate medicine treatments. Surgery itself is associated with an increased risk of premature delivery and spontaneous abortion (miscarriage).

Of the babies born to women with Graves' disease, about 1% will have hyperthyroidism at birth. The cause is the transfer of antibodies that stimulate the TSH receptor across the placenta to the baby. These antibodies then stimulate the baby's thyroid gland. These antibodies should be measured in the mother during her second trimester of pregnancy, because values that are greater than five times normal have been associated with hyperthyroidism in the baby at birth. Before the baby is born, a high fetal heart rate (greater than 160 beats/min), a goiter in the fetus noted during ultrasound, poor growth, and bony abnormalities are indications of hyperthyroidism in the baby. If these are noticed, the mother may be given medications (PTU or MMI) to help treat the fetus. At birth, hyperthyroidism may be detected by a blood test. On physical examination, a low birth weight, enlarged liver or spleen, and abnormalities in the shape of the skull (smallish head, triangular face) can be clues to hyperthyroidism in the newborn.

Hyperthyroid women who want to nurse their babies should be able to safely nurse on PTU and MMI medications. Although the older literature discouraged breastfeeding, newer studies indicated that it is safe since the concentration of drug that enters the breast milk is quite low. PTU is preferred since it has lower concentrations in breast milk.


 

In summary, hyperthyroid states can occur due to the hormonal changes of pregnancy and these cases are usually self-limited. In women who have underlying hyperthyroidism, in particular Graves' disease, uncontrolled disease may have detrimental effects on the pregnancy for both more and child. The best way to avoid the complications of hyperthyroidism in pregnancy is to be sure the disease is controlled before conception occurs.

If you have hyperthyroidism and are considering a family in the near future, it may be worthwhile to discuss the options of surgery and radiation with your doctor while you are still in the stages of planning for a family. Remember that with pregnancy, there are really two patients - the mother and child. Close follow-up with your doctor before and during pregnancy can help assure the best possible outcome for the both of you.

 

 

Content 2

Content 3

 

 

 

This disease results from stimulation of the thyroid gland by the binding of antibodies to the TSH receptor. The normal negative feedback mechanism does not stop the thyroid because antibody levels, unlike TSH levels, are not modulated by T3 and T4 levels.

 

Content 9

 

History

 
 
 
 

 

Physical Exam

 

Laboratory Tests

X-ray

 

Essentail Criteria to Establish Diagnosis

 

 

Content 4

Content 3

A 41-year-old woman presents to her primary care physician with weight and hair loss, diarrhea, nervousness, and eye pressure. She has no medical problems, but some of her family members have similar symptoms and require medication. On examination, she is noted to have exophthalmos, an enlarged nontender goiter, hyperreflexia, and a tremor when her arms are outstretched. The patient has a decreased thyroid-stimulating hormone (TSH) level and an increased free thyroxine (T4) level and is diagnosed with Graves disease (hyperthyroidism).

Summary: A 41-year-old woman has weight and hair loss, diarrhea, nervousness, eye pressure, nontender goiter, exophthalmos, and laboratory evidence of hyperthyroidism.

 

What is the mechanism by which high levels of iodine inhibit thyroid production?

How does propylthiouracil (PTU) inhibit thyroid synthesis?

 

 

  • High levels of iodine: Inhibit the iodine pump (Wolff-Chaikoff effect).

  • Mechanism of action of PTU: Inhibits peroxidase enzyme activity in the follicular cell membrane, resulting in an inability to oxidize iodine.

Clinical Correlation

Patients with abnormalities of the thyroid may present with many different clinical symptoms. Patients with hyperthyroidism may present with weight loss, tremor, weakness, diarrhea, hair and nail changes, heat intolerance, goiters, exophthalmos, and/or tachycardia. The most common cause of hyperthyroidism is Graves disease. This disease results from stimulation of the thyroid gland by the binding of antibodies to the TSH receptor. The normal negative feedback mechanism does not stop the thyroid because antibody levels, unlike TSH levels, are not modulated by T3 and T4 levels. Laboratory findings suggestive of hyperthyroidism include a decreased TSH and an elevated T4 or T3 count. Treatment is often with PTU (blocks peroxidase activity), iodine (inhibits the iodine pump), radioactive iodine (ablates the thyroid), or surgery (thyroidectomy). Beta-blocker medications often are used when tachycardia is present.

What is the mechanism by which high levels of iodine inhibit thyroid production?

How does propylthiouracil (PTU) inhibit thyroid synthesis?

What affect does pregnancy have on the free thyroid hormone level?

Answers to Case 34: Thyroid Disease

Summary: A 41-year-old woman has weight and hair loss, diarrhea, nervousness, eye pressure, nontender goiter, exophthalmos, and laboratory evidence of hyperthyroidism.

  • High levels of iodine: Inhibit the iodine pump (Wolff-Chaikoff effect).

  • Mechanism of action of PTU: Inhibits peroxidase enzyme activity in the follicular cell membrane, resulting in an inability to oxidize iodine.

  • Effect of pregnancy on free thyroid levels: No change in free levels. The total level would be elevated because of an increase in thyroxine-binding globulin. Because the free levels remain the same, the patient is euthyroid.

Clinical Correlation

Patients with abnormalities of the thyroid may present with many different clinical symptoms. Patients with hyperthyroidism may present with weight loss, tremor, weakness, diarrhea, hair and nail changes, heat intolerance, goiters, exophthalmos, and/or tachycardia. The most common cause of hyperthyroidism is Graves disease. This disease results from stimulation of the thyroid gland by the binding of antibodies to the TSH receptor. The normal negative feedback mechanism does not stop the thyroid because antibody levels, unlike TSH levels, are not modulated by T3 and T4 levels. Laboratory findings suggestive of hyperthyroidism include a decreased TSH and an elevated T4 or T3 count. Treatment is often with PTU (blocks peroxidase activity), iodine (inhibits the iodine pump), radioactive iodine (ablates the thyroid), or surgery (thyroidectomy). Beta-blocker medications often are used when tachycardia is present.