Resistance to Thyroid Hormone in Graves' Disease
by Elaine Moore
RTH May Be Misdiagnosed in Conditions of Hyperthyroidism and ADHD
Resistance to thyroid hormone (RTH) may easily be confused with Graves' disease. RTH can also co-exist with Graves' disease creating a diagnostic challenge.
Thyroid hormone resistance is a condition in which the pituitary doesn’t respond to high levels of thyroid hormone, and neither do the body’s organs. Instead of becoming suppressed in the presence of elevated FT4 and FT3 levels, the TSH remains normal or only slightly suppressed. The most common cause of thyroid hormone resistance are mutations of the β (beta) form of the thyroid hormone receptor, including the MCT8 mutation. More than 100 different mutations to the thyroid hormone receptor have been documented.
The Clinical Picture in Resistance to Thyroid Hormone
Individuals with thyroid hormone resistance may have a goiter, palpitations or tachycardia or they may have no symptoms of hyperthryoidism. In RTH thyroid hormone levels are elevated, although TSH remains normal. The RAI-Uptake is elevated similar to what’s seen in Graves’ disease. Symptoms are variable even in individuals with the same mutation. Some individuals will have no symptoms and will merely be observed to have high levels of T4, FT4, T3, and FT3 during routine physicals, whereas others may have variable symptoms.
Resistance to Thyroid Hormone Can Be Confused with ADHD
Physicians at the University of Maryland School of Medicine have found a positive correlation between elevated levels of certain thyroid hormones and hyperactivity/impulsivity, a core feature of ADHD. In their study, Peter Hauser and Bruce Weintraub studied 75 individuals diagnosed with resistance to thyroid hormone and 77 of their unaffected family members. They measured levels of the thyroid hormones T3 and T4 and also TSH, a pituitary hormone that regulates thyroid function, and evaluated symptoms of both inattention and hyperactivity. The researchers found that high concentrations of T3 and T4 were significantly and positively correlated with hyperactivity/impulsivity symptoms but not with symptoms of inattention. The researchers report a case in which a child diagnosed with attention deficit hyperactivity disorder (ADHD) was found to have resistance to thyroid hormone and not ADHD (Donovan 1997).
Confusion and Co-existence of RTH with Graves Disease
In the February 2010 issue of Thyroid researchers from the Dartmouth-Hitchcock Medical Center in New Hampshire describe a case of resistance to thyroid hormone in a patient who also had Graves’ disease. The patient had symptoms of hyperthyroidism along with a low TSH, elevated thyroid hormone levels and elevated levels of thyroid stimulating immunoglobulins (TSI). In addition, the patient had an elevated RAI-uptake test with a homogeneous scan suggesting Graves’ disease. The patient was subsequently treated with RAI and became hypothyroid.
The patient needed higher doses of replacement hormone than were suggested by weight to keep his elevated TSH within range. On a dose of 325 mcg levothyroxine replacement hormone, the patient had slightly elevated T4 and T3 levels and his TSH fell into the reference range. Because of the high dose of replacement hormone needed, his physicians ordered additional tests that revealed a mutation in the thyroid hormone beta-receptor gene, a consistent finding for RTH. The researchers concluded that RTH is often misdiagnosed as Graves’ disease. There are many reports of this in the literature. The researchers noted, however, that these disorders can coexist. When they co-exist, it’s a diagnostic challenge since tests for thyroid hormone receptor mutations are not customarily performed. There has been another report of a patient having a similar medical profile but at the time gene splicing tests weren’t available to confirm the mutation (Sivakumar and Chaidarun 2010).
Resistance to thyroid hormone should be considered in patients with elevated thyroid hormone levels whose TSH levels don’t correspond with the degree of hyperthyroidism seen. In most cases of Graves’ disease, the TSH falls to less than .01 mu/L before thyroid hormone levels rise abnormally high.
© 26 Mar 2010 Copyright by Elaine Moore
Donovan, Jennifer. 1997. Hyperactivity Linked to Thyroid Hormones. Science Daily, March 12, accessed Feb 28, 2010.
Sivakumar T, Chaidarun S. 2010. Resistance to thyroid hormone in a patient with coexisting Graves' disease. Thyroid. 2010 Feb;20(2):213-6.