A Root Cause Medicine Approach to Thyroid Hormone Resistance Syndrome

When someone has thyroid hormone resistance syndrome, tissues throughout the body do not respond normally to signals sent by thyroid hormones. Normally, the thyroid gland produces hormones that travel throughout the body and act on receptors in most tissues. 

In this genetically-inherited syndrome, mutations of the thyroid hormone receptor cause impaired sensitivity to the actions of thyroid hormone. This can cause symptoms of hyperthyroidism or hypothyroidism, including changes in metabolism, temperature, heart rate, and more.

Around 1 in 40,000 live births have thyroid resistance syndrome, but the condition is often missed or not diagnosed in a timely manner due to the non-specific presentation that can mimic other thyroid conditions. 

A root cause approach to thyroid hormone resistance syndrome utilizes functional medicine laboratory testing to uncover factors contributing to symptoms and imbalances. An integrative treatment approach can help restore balance to the body and improve quality of life.

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What is Thyroid Hormone Resistance Syndrome?

Your thyroid gland is located at the base of your neck. This small butterfly-shaped gland produces two main hormones, thyroxine (T4) and triiodothyronine (T3), which influence every cell in the body. When thyroid hormones bind to receptors in peripheral tissues throughout the body, they impact metabolism and how the body uses fats and carbohydrates, helps control body temperature, influences heart rate, and impacts how proteins are used. 

Normally, the hypothalamus in the brain monitors the body and releases thyroid-releasing hormone (TRH) when it detects the need for increasing metabolism and energy. This signals the pituitary gland at the base of your brain to release thyroid stimulating hormone (TSH) that acts directly on the thyroid gland to stimulate it to produce and release thyroid hormones. 

Thyroid hormone resistance syndrome most often occurs due to genetic mutations that cause peripheral tissues in the body to have a decreased response to normal stimulation with thyroid hormones. Since the thyroid hormone receptors are abnormal, they do not respond normally to the binding of thyroid hormones, and levels of thyroid-stimulating hormone (TSH) in the blood are not suppressed even with elevated thyroid hormones circulating in the blood.

In other cases, thyroid hormone resistance can occur if the feedback loop set point in the central nervous system is dysregulated so that increased thyroid hormones do not suppress TSH secretion.

Whether peripheral or central, people with thyroid hormone resistance syndrome usually have non-suppressed TSH despite elevated levels of circulating T4 and T3.

Thyroid Hormone Resistance Syndrome Signs & Symptoms

People with thyroid hormone resistance syndrome can show signs and symptoms of dysregulated thyroid function. These can overlap with symptoms that commonly occur in either hyperthyroidism or hypothyroidism, including changes in metabolism, temperature, heart rate, and more, as well as symptoms that are often seen with fibromyalgia depending on the level of expression of the mutated receptors in the target tissues. 

Common signs and symptoms of thyroid hormone resistance syndrome include:

• Growth abnormalities
• Issues with brain development and mental function like low IQ, learning disabilities, and hyperactivity
• Tachycardia or rapid heart rate
• Goiter or enlargement of the thyroid gland

Other symptoms of thyroid hormone imbalance can also occur, including those of hypothyroidism, such as:

• Fatigue 
• Weight gain
• Headaches and migraines
• Puffiness or fluid retention
• Slowed heart rate
• Fertility problems
• Thinning or dry hair, nails, and skin
• Brittle nails
• Feeling cold all the time and decreased body temperature
• Irregular periods
• Low libido
• Slow digestion and constipation
• Brain fog
• Depression 
• Aching muscles and joints
• Loss of muscle strength and tone

Alternatively, some people may show symptoms of an overactive thyroid, including:

• Anxiety or irritability
• Heart palpitations
• Increased sweating
• Weight loss despite increased appetite
• Muscle weakness, especially in the upper arms and thighs
• Difficulty sleeping
• Hair loss
• Diarrhea
• Shaking or tremors
• Irregular menstrual cycles
• Dry, thin skin

Symptoms often decrease with age, with thyroid hormone levels eventually becoming normal. 

Thyroid Hormone Resistance Underlying Causes

Thyroid hormone resistance syndrome is most commonly caused by an inherited problem with the thyroid hormone receptors. Various steps along the pathway that allows thyroid hormone to set off effects at a cellular level can result in reduced sensitivity to thyroid hormones.

The most frequent cause of resistance to thyroid hormone beta (RTHβ) is caused by a genetic mutation in the thyroid hormone receptor beta (THRβ) gene that causes receptors for thyroid hormones in cells throughout the body to not bind well to thyroid hormone. This gene mutation is generally inherited in an autosomal dominant manner. 

The abnormal receptor can be limited to the periphery (peripheral RTHβ) or pituitary gland (pituitary RTHβ) or found throughout the body (general RTHβ). People with general RTHβ may often have a lower than average IQ, but their thyroid function and skeletal development remain mostly normal. On the other hand, people with pituitary RTH often have increased levels of T4 and T3, resulting in symptoms of hyperthyroidism. Those who have peripheral RTHβ typically have normal TSH levels, but their peripheral tissues are not sensitive to thyroid hormones, leading to symptoms of hypothyroidism. 

This abnormal receptor protein makes the thyroid hormone receptor have reduced affinity for binding T3 and/or abnormal interaction with cofactors involved in thyroid hormone action at the receptor. This results in decreased responsiveness to the normal actions of thyroid hormone. Therefore, levels of thyroid-stimulating hormone (TSH) in the blood are not suppressed even in the presence of elevated thyroid hormones.

A more recently identified form of thyroid hormone insensitivity occurs due to mutations in the thyroid hormone receptor alpha (TRα), which influences the repair of damaged DNA and tissues.

In some cases, thyroid resistance can occur along with Hashimoto thyroiditis due to gene mutations located in the functional areas of the receptor which binds T3. 

Another less common cause of reduced sensitivity to thyroid hormone involves membrane transport and metabolism of thyroid hormones. One of these syndromes results from mutations in the transporter MCT8 that shuttles thyroid hormone across cell membranes and produces severe psychomotor issues.

Other people do not have a THRβ gene mutation but may develop a reduced sensitivity to thyroid hormones due to the inactivation of thyroid hormones caused by the deiodinase-3 enzyme. Some of these people have mutations in the SECISBP2 gene that is needed to make selenoproteins like thyroid hormone deiodinases. 

An increased risk of acquiring resistance to thyroid hormone is also seen with obesity, metabolic syndrome, and type 2 diabetes due to an attempt by the body to counter-regulate the energy imbalances that occur with impaired glucose and fat metabolism processing. Chronic stress, high cortisol levels, and inflammation can all contribute to acquired thyroid hormone resistance. 

No gene mutation is identified in 15% of cases of thyroid hormone resistance syndrome.

Functional Medicine Labs to Test For The Root Cause Of Thyroid Hormone Resistance Syndrome

Functional medicine laboratory testing can help to establish a diagnosis of thyroid hormone resistance, monitor thyroid hormone function, and assess the root causes contributing to the imbalance. 

Thyroid Hormone Levels

A Complete Thyroid Panel can be measured to evaluate how the thyroid is functioning. This includes thyroid-stimulating hormone (TSH), T3 (free and total), T4 (free and total), and reverse T3, which can be assessed using functional medicine ranges. Including an assessment of thyroid antibodies such as thyroid peroxidase (TPO) and anti-thyroglobulin (TG) and antibodies can help evaluate any autoimmune involvement and assess for other common causes of hypothyroidism like Hashimoto’s disease or hyperthyroidism like Grave’s disease.

In thyroid hormone resistance syndrome, the classic pattern of thyroid function laboratory results shows elevated T3 and T4 thyroid hormones with non-suppressed TSH. This pattern may also be seen with pituitary tumors that produce TSH, but patients with pituitary tumors often have symptoms of mild to severe hyperthyroidism and compression symptoms resulting from tumor growth in the brain.

Elevated serum T3 and reverse T3 (rT3) levels are also common. Although the serum T4 and T3 can be just above to several folds above the upper limit of normal in people with thyroid hormone resistance syndrome, the T3:T4 ratio is close to normal. 

Comprehensive Metabolic Profile

A Comprehensive Metabolic Profile (CMP) analyzes the body’s overall metabolic health by looking at glucose, calcium, electrolytes, proteins, kidney health markers, and liver health markers. Some people with defects in the thyroid hormone cell membrane transporter can present with abnormally elevated transaminases (alanine transaminase (ALT) and aspartate aminotransferase (AST)) in part due to to the impact of the high serum T3 levels on peripheral tissues. 

Markers of thyroid hormone action on peripheral tissues, such as alkaline phosphatase, which is included in a CMP, can be measured before and after administration of T3 to suggest thyroid hormone resistance.

Organic Acids Testing

Organic acids testing provides a comprehensive look at metabolism and nutritional status by measuring several biochemical markers, including 36 organic acids specific to mitochondrial energy production, neurotransmitter metabolism, detoxification capabilities, fatty acid and amino acid metabolism, and intestinal microbial balance health.

In addition to elevated transaminases, some people with defects in the thyroid hormone cell membrane transporter can present with abnormally elevated glycolysis metabolites lactate and pyruvate on organic acid testing. 

Micronutrient Testing

Nutrients like vitamin A improve how sensitive cells are to thyroid hormones. In addition, zinc, selenium, iodine, iron, tyrosine, magnesium, and vitamins E, B2, B3, B6, C, and D are important for the proper production of thyroid hormones, and some of these, including zinc and selenium, are also important for supporting the conversion of T4 to T3 to optimize thyroid functioning. 

Micronutrient testing measures levels of these vitamins, minerals, and other nutrients along with the performance and functional deficiencies of these micronutrients. 

Additional Lab Tests

Genomic testing can help detect mutations associated with thyroid hormone resistance syndrome, but since there are many associated gene mutation variants and others that have not been determined, testing is not always definitive.

A T3 suppression test involves giving incremental doses of thyroid hormone for three days to assess the presence and magnitude of thyroid hormone resistance. Measurements are taken to look at how the central and peripheral tissues respond to thyroid hormones.  

Similarly, a thyrotropin-releasing hormone (TRH) stimulation test can be given by administering intravenous TRH and measuring the effect on thyroid hormones. When TRH is given to people with thyroid hormone resistance syndrome, the TSH response is usually normal or exaggerated. 

To complete a radioiodine uptake scan, a small dose of radioactive iodine (I-131) is administered, and a scan is completed to look at how much iodine the thyroid takes up and in what pattern. Radioiodine uptake in the thyroid may sometimes be elevated with thyroid hormone resistance.

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Conventional Treatment for Thyroid Hormone Resistance Syndrome

Currently, there are no treatments available to target the gene mutation which causes thyroid hormone resistance syndrome in many people. Since people can present with variable levels of thyroid hormones and symptoms of either low or high thyroid hormones, treatment of thyroid resistance syndrome is tailored to the specific symptoms of thyroid hormone excess or decrease experienced by the individual patient. 

Conventional treatment generally aims to address symptoms rather than aiming to normalize thyroid hormone levels. For example, those with symptoms of hyperthyroidism like anxiety and tachycardia may be treated symptomatically with beta-blockers or anti-anxiety medications. Many patients do not require treatment as they secrete extra thyroid hormone that can overcome tissue resistance. 

Functional Medicine Treatment for Thyroid Hormone Resistance Syndrome

Although thyroid hormone resistance syndrome is usually due to various genetic mutations that each have some unique characteristics, a functional medicine approach can help manage accompanying symptoms to reduce the risk of acquired thyroid hormone resistance and improve quality of life.

Nutrition for Thyroid Hormone Resistance Syndrome

Since greater resistance to thyroid hormone is associated with obesity, metabolic syndrome, and type 2 diabetes, regulating energy and glucose balance can help reduce the risk of acquired thyroid hormone resistance. Nutrition can be utilized to keep weight and blood sugar balanced. A diet rich in fiber, vegetables, legumes, and other high-quality proteins like wild fish and grass-fed meats, which avoids processed and added sugars, helps to keep weight and fat distribution balanced, which results in improved glucose metabolism, insulin sensitivity, inflammation, and fat and sugar metabolism. 

One approach to eating in this way is the anti-inflammatory or Mediterranean diet which emphasizes citrus fruits, legumes, vegetables, and complex carbohydrates with moderate fish and olive oil. Studies show that this way of eating can help to improve blood sugar, insulin, and cholesterol levels since it balances inflammation, promotes gut health, and protects the thyroid from the effects of inflammation. 

In particular, the Mediterranean diet is rich in polyunsaturated omega-3 fatty acids found in foods like anchovies, sardines, salmon, and walnuts. Studies show that these healthy fats positively impact insulin function and can decrease inflammation that compromises thyroid function.

Supplements & Herbs

Supplements and herbs can be used to support metabolic health and keep the body in balance to reduce acquired resistance to thyroid hormones and to address common complications of this condition. 

Selenium

Selenium is an important nutrient for the activation and deactivation of thyroid hormones and also works with glutathione peroxidase to protect the thyroid gland from damage due to oxidative stress. 

Selenium can be supplemented as 200 μg of selenomethionine (l-selenomethionine) per day for a minimum of three months under the guidance of a healthcare professional. You can also incorporate Brazil nuts, eggs, sunflower seeds, chicken, mushrooms, and sardines as food sources of selenium. 

Vitamin D and Vitamin K

Thyroid hormone resistance can increase the risk of bone thinning (osteopenia and osteoporosis). Supplementing with vitamin D3 combined with vitamin K while eating calcium-rich foods like green leafy vegetables, tofu, and nuts is important for preventing fractures. 

Antioxidants

In addition to omega-3 fatty acids discussed above, antioxidants such as resveratrol and curcumin may help to counteract the excess oxidative stress associated with thyroid conditions and reduce goiters. 

Complementary and Integrative Medicine 

An integrated approach to thyroid resistance helps to balance levels of hormones in the body, reduce acquired causes of thyroid hormone resistance, and improve symptoms. 

Stress Management

Chronic stress creates excess cortisol levels in the body that contribute to thyroid and insulin resistance. Imbalanced cortisol secretion can dysregulate the hypothalamus–pituitary–thyroid (HPA) axis activity and contribute to thyroid hormone resistance as well as further imbalances in blood sugar levels. 

Utilizing regular stress management and mind-body techniques like mindfulness-based stress reduction (MBSR), meditation, and deep breathing can help keep cortisol levels stable. These relaxation practices help to promote the body's natural relaxation response.

Exercise

In addition, regular exercise and physical activity help to reduce stress, balance weight, and increase the body's capacity to handle stressors and anxiety that may occur with thyroid hormone resistance. 

Optimize Sleep

To keep the HPA axis balanced and functioning optimally, adequate sleep is also essential.

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Summary

Thyroid hormone resistance syndrome occurs when the body produces enough thyroid hormones, but the tissues do not respond appropriately. This is usually due to genetic mutations that impact the thyroid hormone receptor or the normal negative feedback loop in the brain that helps keep energy and metabolism levels stable. In other cases, thyroid resistance can develop in the presence of metabolic syndrome, obesity, or diabetes.

People with thyroid hormone resistance syndrome can experience a range of symptoms that may mimic hypothyroidism and/or hyperthyroidism. Common symptoms include growth abnormalities, issues with brain development and mental function like low IQ, tachycardia or rapid heart rate, goiter or enlargement of the thyroid gland, anxiety, and hyperactivity.

Laboratory testing usually shows elevated thyroid hormone levels with non-suppressed TSH. Functional medicine testing can also look at various metabolic markers that can be disturbed with thyroid hormone resistance to help guide an integrative management plan. 

Although thyroid hormone resistance syndrome is usually due to various genetic mutations, a functional medicine approach to treatment can help manage symptoms and reduce the risk of acquired thyroid hormone resistance. A Mediterranean diet helps reduce inflammation, balance weight, and improve insulin function to help maintain healthy blood sugar levels and reduce thyroid hormone resistance. In addition, targeted supplementation can improve thyroid function and reduce complications of thyroid disease, such as bone thinning. Managing stress and getting adequate quality sleep further helps to keep the HPA axis balanced and improves thyroid health.