Approach to a low TSH level: Patience is a virtue

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If the free T4 level is high, the free T3 level is usually high as well. Patients should undergo iodine 123 nuclear imaging.

If iodine 123 uptake is high

Graves disease vs toxic nodular goiter. If iodine 123 uptake is high, a low (suppressed) TSH level, in conjunction with elevations of the free thyroid hormones, is consistent with overt hyperthyroidism secondary to autonomous (TSH-independent) thyroid function.

Graves patients usually test positive for TRAB, and they may have related ophthalmopathy, whereas patients with toxic nodular goiter are TRAB-negative and do not have Graves ophthalmopathy.24–27

Patients with either Graves disease or toxic nodular goiter have increased iodine 123 uptake; however, the pattern of uptake in Graves disease is diffuse, whereas it is patchy or nodular when toxic nodular goiter is the underlying etiology (Figure 3).24,27 Complicating matters, the pattern of uptake in Graves disease may be patchy if the patient has been pretreated with antithyroid drugs such as propylthiouracil or methimazole (Tapazole).

Review of the patient’s history is important, as a recent iodine load (eg, intravenous contrast medium that contains iodine) can transiently worsen thyrotoxicosis while causing the iodine 123 uptake to be low. The reason for the low uptake is that the gland becomes saturated with “cold” (nonradiolabeled) iodine from the contrast medium and cannot take up more iodine (radiolabeled) for the radionuclide scan. For this reason, iodine 123 imaging should not be performed for 6 to 8 weeks after an exogenous load of iodine. In this circumstance, the history and physical examination, as well as laboratory testing (for TRAB), must be relied on to make the correct diagnosis.

Elevated human chorionic gonadotropin. Iodine 123 nuclear imaging studies are forbidden during pregnancy. Therefore, all women of childbearing age should have a pregnancy test before undergoing radioisotope imaging. If thyrotoxicosis from hCG is suspected (eg, in cases of hydatidiform mole or choriocarcinoma), ultrasonography of the uterus should be done to rule out a viable pregnancy before pursuing radioisotope imaging.

Treatment options for the usual causes of hyperthyroidism (toxic nodular goiter or Graves disease) include radioactive iodine ablation (unless the patient was exposed to a recent cold iodine load), antithyroid drugs (methimazole or propylthiouracil), or surgical resection (partial or complete thyroidectomy).27

Patients with overt hyperthyroidism should be referred to an endocrinologist for a thorough evaluation and discussion of the diagnosis and the treatments that are available. Beta-blockers can be used to ameliorate the symptoms of thyrotoxicosis such as palpitations, anxiety, and tremor.

If iodine 123 uptake is low

A low (suppressed) TSH level, in conjunction with elevations of the free thyroid hormones and low uptake of iodine 123, is consistent with overt hyperthyroidism secondary to:

  • Thyroiditis
  • Ectopic hyperthyroidism due to T4-T3 therapy, struma ovarii (very rare), or large deposits of functioning thyroid cancer metastases (very rare)
  • Iodine-induced hyperthyroidism (Jod-Basedow effect)
  • Amiodarone-induced thyrotoxicosis.27,28

Thyroiditis, ie, destruction or inflammation of thyroid tissue with subsequent release of preformed thyroid hormones into the circulation, results in thyrotoxicosis. The severity and duration of thyrotoxicosis depends not only on the size of the injured thyroid gland and the store of preformed thyroid hormones, but also on the extent and duration of the thyroid destruction and injury.

Subacute thyroiditis usually lasts several weeks to a few months, and typically follows a pattern of:

  • Transient hyperthyroidism due to release of thyroid hormone stores
  • A brief period of euthyroidism
  • Hypothyroidism, as the store of preformed thyroid hormone is exhausted and thyroid inflammation and destruction subside, and then
  • Recovery (usually, unless the thyroid is not capable of recovery), during which the TSH level rises in response to low levels of thyroid hormones in the circulation, and the recovering thyroid begins to resume thyroid hormone synthesis.28

There is a brief period during the hypothyroid phase of thyroiditis during which the TSH level remains low (or inappropriately normal), even though the free thyroid hormone levels are also low; this period is commonly called the “disequilibrium state” (Figure 2). This state is due to the slow recovery of the pituitary thyrotrophs as they escape tonic suppression by excess thyroid hormones.

The classic entity of de Quervain thyroiditis (subacute granulomatous thyroiditis) is painful, whereas other forms are painless (eg, autoimmune lymphocytic thyroiditis, postpartum, or related to cytokine [interferon] or lithium therapy).28 Other forms of thyroiditis, which may or may not be painful, include those induced by amiodarone, radiation, or trauma.

Regardless of the cause, watchful waiting is warranted while monitoring thyroid function tests to ensure that recovery takes place.28 Beta-blockers are often used to decrease symptoms during the transient hyperthyroid state observed early in the course of thyroiditis.

Ectopic hyperthyroidism. Ingestion of exogenous T4, T3, or both can suppress thyroid function. This can occur with supratherapeutic T4 and T3 (usually for hypothyroidism) and also factitiously or in patients abusing the drugs to lose weight. A useful way to differentiate exogenous from endogenous causes of thyrotoxicosis is to measure serum thyroglobulin, which would be decreased in the former and elevated in the latter.

Ectopic production of T4 and T3 can occur, albeit rarely, as in cases of struma ovarii or in patients with large deposits of functioning thyroid cancer metastases.29–31 Struma ovarii is a very rare ovarian teratoma (accounting for 1% of all ovarian tumors), and even when present it does not usually result in thyrotoxicosis. 29,30 However, the diagnosis should be considered in the appropriate clinical context, ie, in the setting of thyrotoxicosis and a pelvic mass; radioiodine uptake would be elevated in the pelvis in those cases.

Likewise, thyrotoxicosis secondary to functioning thyroid cancer metastases is also rare but should be considered in the right clinical context (iodine-avid tissue throughout the body noted on radioiodine whole-body imaging).

Iodine-induced hyperthyroidism develops in patients with underlying thyroid disease (toxic nodular goiter or Graves disease) and is caused by an exacerbation of autonomous (TSH-independent) thyroid function by an iodine load (eg, intravenous contrast medium that contains iodine, or amiodarone therapy [see below]).

Amiodarone-induced thyrotoxicosis. In various reports, the incidence of amiodaroneinduced thyrotoxicosis ranged from 1% to 23%.32 There are two types.

Type 1 is a form of iodine-induced hyperthyroidism. It can occur in patients with autonomous thyroid function when they are exposed to amiodarone, which contains 37% iodine by weight.

Type 2 occurs in patients with no underlying thyroid disease and is probably a consequence of a drug-induced destructive thyroiditis. Mixed or indeterminate forms of amiodarone-induced thyrotoxicosis encompassing several features of both type 1 and type 2 may also be observed.20

The treatment varies by type: antithyroid drugs (thionamides) in type 1 and corticosteroids in type 2.20 It can be difficult to discern between the two entities, and combination therapy with antithyroid drugs and prednisone may be needed. One of the drugs is then withdrawn, and the effect on the levels of free thyroid hormones is monitored. This helps determine which drug is working, pointing to the correct diagnosis and treatment.


Our patient’s thyroid function tests were repeated at the time of her endocrinology consult, 2 weeks after she was noted to have a low TSH in the setting of low free T4, which suggested central hypothyroidism. Her TSH level was now 3.5 μIU/mL, and her free T4 level was 0.8. Thus, her low TSH in the setting of the low free T4 noted 2 weeks earlier reflected a disequilibrium state, which occurs during the hypothyroid phase of thyroiditis (Figure 2).

Repeated measurements of her thyroid function tests verified complete recovery and resolution of her thyroiditis. No levothyroxine therapy was required, and no further investigation was performed.

Acknowledgments: We thank Nada Johnson from the Department of Endocrinology, Cleveland Clinic, for her skillful help with the preparation of the figures.

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