Thyroid hormone resistance is a rare genetic disorder that impacts how the body’s tissues respond to thyroid hormones. The pituitary gland, which regulates the thyroid, is not correctly signaled by thyroid hormone, leading to an overproduction that can cause the thyroid gland to enlarge, a condition known as a goiter. This results in elevated levels of thyroid hormones in the blood.
Genetic Origins of Resistance
The root cause of thyroid hormone resistance lies in genetic mutations that affect how cells receive hormonal signals. Thyroid hormones function by binding to specific proteins called receptors inside cells, which are widespread throughout the body in tissues like the liver, heart, and muscles. In approximately 85% of cases, the condition is linked to mutations in the thyroid hormone receptor beta (THRB) gene, which provides the instructions for building one of the main receptors for thyroid hormone.
When a mutation occurs in the THRB gene, the resulting receptor protein can have an altered structure or function, making it less responsive to the circulating thyroid hormones so the cells cannot properly utilize them. The body attempts to compensate for this lack of response by producing even higher levels of thyroid hormones, but the underlying resistance in the tissues remains.
This genetic condition is passed down in an autosomal dominant pattern, meaning an individual needs to inherit only one copy of the mutated gene from one parent to be affected. A person with the condition has a 50% chance of passing the mutation on to each of their children. The syndrome affects both males and females equally and is estimated to occur in about 1 in every 40,000 live births.
Recognizing the Contradictory Symptoms
The clinical presentation of thyroid hormone resistance is variable and can differ even among members of the same family who share the identical genetic mutation. A defining feature is a mix of symptoms associated with both an underactive thyroid (hypothyroidism) and an overactive thyroid (hyperthyroidism). This occurs because the degree of hormone resistance can vary between different tissues in the body.
For instance, some tissues may be highly resistant, leading to hypothyroid-like symptoms. In contrast, other tissues might remain more sensitive to the high circulating levels of thyroid hormone, resulting in hyperthyroid symptoms. One common sign of this overstimulation is a persistently fast heart rate, or tachycardia. An enlarged thyroid gland (goiter) is a frequent physical finding that leads individuals to seek medical evaluation.
Hypothyroid symptoms can include:
- Fatigue
- Unexplained weight gain or difficulty losing it
- A feeling of being cold
- Developmental delays in children
Other reported symptoms can include irregular menstrual periods and, in some cases, an association with attention deficit hyperactivity disorder (ADHD). Despite the abnormal hormone levels, many individuals may not experience any obvious symptoms and appear to have normal thyroid function, a state referred to as being clinically euthyroid.
The Diagnostic Pathway
Diagnosing thyroid hormone resistance begins with identifying an unusual pattern in thyroid function blood tests. Lab results will characteristically show elevated levels of circulating free thyroid hormones (T4 and T3). However, unlike in typical cases of hyperthyroidism where high hormone levels would suppress it, the thyroid-stimulating hormone (TSH) level remains normal or even slightly elevated.
In primary hyperthyroidism, TSH would be very low, as the pituitary gland reduces its production in response to the excess thyroid hormone. Conversely, in primary hypothyroidism, TSH would be high as the pituitary tries to stimulate a failing thyroid gland. The lab results in resistance syndrome do not fit either of these common patterns.
Because these distinct blood test results can also be found in other rare conditions, such as a TSH-producing pituitary tumor (TSH-oma), further confirmation is required. The definitive diagnosis is established through genetic testing. This analysis can identify a mutation in one of the thyroid hormone receptor genes.
Strategies for Treatment and Management
Managing thyroid hormone resistance is individualized and focuses on alleviating symptoms rather than normalizing blood test results. For many individuals who are asymptomatic, no treatment may be necessary, as their bodies have adequately compensated for the hormone resistance. These patients are monitored to ensure they remain symptom-free and that children are growing and developing normally.
When treatment is required for symptoms of an underactive thyroid, the strategy often involves administering levothyroxine, a synthetic version of the T4 hormone. The goal is to provide a high enough dose to overcome cellular resistance and reduce symptoms. This requires careful monitoring by an endocrinologist to find the right balance, as dosages may need to be significantly higher than those used for standard hypothyroidism.
For patients experiencing symptoms of an overactive thyroid, such as a rapid heart rate, medications like beta-blockers may be prescribed. These drugs help control the effects of excess hormone stimulation on sensitive tissues like the heart. Management is a lifelong process that requires regular follow-up with a specialist to adjust therapies based on the patient’s changing symptoms.