Thyroid and You
By Anil Kumar, PhD
Article’s theme: Thyroid hormones, hypothyroidism, hyperthyroidism, and key risk factors.
What is Thyroid?
Thyroid is one of the most critical glands for human well-being, particularly during pregnancy and childhood. Today, thyroid disease is a global health problem that impacts a significant population—including those in advanced economies despite widespread testing and continuous lowering of treatment thresholds that has brought significant awareness. Even in iodine-sufficient areas thyroid dysfunction is fairly common due to thyroid autoimmune diseases.
The key role of thyroid hormones is metabolism control. They are also critical for neurological development of newborns, growth in childhood, and reproduction.
Iodine is key to maintaining thyroid health as almost 75% of the iodine in body is used by thyroid gland. Iodine supplementation in human diet remains a hot issue despite salt-fortification across the globe. Resurgence of thyroid diseases in many previously declared iodine sufficient regions has been alarming.
More from our blogs: Thyroid and Pregnancy – how thyroid impacts pregnancy | Thyroid and Iodine – understand the role of iodine in thyroid health | All About Thyroid – brief summary of thyroid disorder, deficiency symptoms, and more | At Home Thyroid Test – a test that measures TSH, free T4, free T3, and TPO.
Both high and low iodine supplies negatively impact health, however, two-third of the world is naturally iodine-deficient. That’s why almost 120 countries mandate iodine fortification of dietary salt to ensure adequate supply. In general, coastal areas with marine food supply seem to have adequate or high iodine supply in their food.
The role of thyroid in every day health is well recognized across the world. Despite a high degree of awareness, thyroid disease is a global health problem, particularly during pregnancy and childhood. In US alone, it is estimated that approximately 6% or 18 million people have some form of mild or serious thyroid disorder (NHANES III 2002).
About 80% of these cases are due to low thyroid hormones, or hypothyroidism. The remaining cases are due to hyperthyroidism, a condition of high thyroid hormones.
How does thyroid work?
The hypothalamus-pituitary-thyroid (HPT) axis controls thyroid health. Hypothalamus senses the thyroid hormones and releases TRH (thyrotropin-releasing hormone). Pituitary gland senses TRH and releases the thyroid stimulating hormone (TSH) which directs the thyroid gland to release two hormones: thyroxine (also called T4 due to four iodine atoms in it), and tri-iodo-thyronine (also called T3, converted from thyroxine after loosing one iodine atom). Any issues with this closed loop will result in thyroid problems.
Hypothyroidism (underactive thyroid) and hyperthyroidism (overactive thyroid) commonly arise from pathological processes in the thyroid gland (and therefore termed primary thyroid disease), although in rare cases, they can arise from disorders of the hypothalamus or pituitary (called secondary or central hypothyroidism) or other from peripheral causes, such as ovarian tumor (struma ovarii), or thyroid cancer.
Since the T4 and T3 release is triggered by TSH, first step in diagnosis is checking the TSH levels. Insufficient hormone release by the thyroid gland triggers hypothalamus to oversupply TSH to boost T4 release. TSH levels above 4.5 mIU/L (milli-international-unit-per-liter) are termed as hypothyroid. In contrast, excess T4 will underdrive the TSH levels, and levels below 0.1 mIU/L result in hyperthyroid.
The low or elevated TSH levels are warning signs of a potential thyroid problem. As long as the T4 levels are within healthy range, the conditions remain sub-clinical and may not be a full blown thyroid problem.
When the thyroid gland can not keep up with TSH levels and still underproduces or overproduces, the potentially serious conditions are called clinical or overt stage of thyroid diseases. T4 levels below 57.9 nMol/L (nano-moles-per-liter) with high TSH is termed clinical hypothyroidism. On the other hand, levels above 169.9 nMol/L are termed clinical hyperthyroidism.
What is Thyroiditis?
The clinical state that results from too much thyroid hormone in the body. In the overwhelming majority of cases, this is due to excess production from the thyroid gland (hyperthyroidism).
- Self-limiting and returns to normal in few weeks to months
- 50% higher occurrence in women
- In 10-20% cases result in permanent hypothyroidism
- Painful form occurs often after throat infection; silent form occurs after pregnancy is about 9% cases
- Iodine rich compound amiodarone is a known cause, with a 3x high occurrence in men
- Other drugs that are known to cause thyrotoxicosis: IFN-α, lithium, tyrosine kinase inhibitors, highly active antiretroviral therapies, immune checkpoint mediators, the humanized monoclonal antibodies used in the treatment of multiple sclerosis
As of 2016, 110 countries are now classified to have an optimal iodine supply in diet, while insufficient iodine intake persists in only 19 countries (as per Iodine Global Network Annual Report 2016. http://www.ign.org/). Iodine fortification of all food-grade salt is now mandated in ~120 countries (Dasgupta 2010). However, a growing number of countries, ten as of 2016, are now classified as have excessive iodine supply in diet. In some areas, fortification or jump in iodine intake has seen increases in cases of toxic nodular goiters, after a certain period post-iodization, with fatalities resulting from cardiovascular complications in some areas.
Individuals on thyroid hormone replacement medication often remain hypothyroid or become hyperthyroid which underscores the importance of monitoring.
Thyroid disease: Key Risk Factors
- Everybody: prevalence in general population is reasonably high at 3.7% for hypothyroidism (TSH > 4.5 mIU/L) and 0.5% for hyperthyroidism (TSH < 0.1 mIU/L)
- Gender: Women are at much higher risk than men, and pregnancy causes fluctuations in thyroid levels; women of reproductive age (12-49 years) are at much higher risk
- Age: those 80+ years older have 5x higher odds than those 12-49 years
- Race: African-Americans have lower TSH levels and higher rates of hyperthyroidism than Hispanic and White populations
- Geography: one-third of the world is iodine deficient with high rates of hypothyroidism; coastal regions are more iodine-rich with higher rates of hyperthyroidism than hypothyroidism
- Medication or supplementation: certain medications, e.g. levothyroxine, lithium, amiodarone are known modulators of thyroid levels; sudden iodine supplementation can negatively affect thyroid health
Thyroid in General Population
Even if you are doing everything right, thyroid disorder can affect anyone
- High TSH and low thyroid hormones are observed in approximately 3.7% of US population (data from 1999-2002); in today’s population that corresponds to 12M people with some form of potential hypothyroidism problem (Aoki 2008)
- Low TSH and high thyroid hormones are observed in about 0.5% of US population (1999-2002); that corresponds to 1.5M people today with potential hyperthyroidism problem (Aoki 2008)
- In regions with sufficient iodine in diet, thyroid autoimmunity is the most common dysfunction. This is confirmed through the presence of thyroid-specific autoreactive antibodies. The two well known dysfunctions are Graves disease (an overactive thyroid when immune system attacks the gland), Hashimoto thyroiditis (an underactive thyroid when immune system attacks the gland), and post-partum thyroiditis (an abnormal thyroid hormone levels after pregnancy).
- Presence of nodules in the thyroid causing gland inflammation or thyroiditis (high and low fluctuations of T4, T4)
- Those taking certain medications can have adverse effects, e.g., from amiodarone and lithium
- Thyroid treatment itself can sometimes cause both hypothyroidism and hyperthyroidism
Grave’s disease: hyperthyroid with an overactive thyroid in which immune system attacks the gland. Key symptoms include a much diffused and swollen goiter, thyroid red eye disease in 20-30% cases, and rare cases localized thickening of skin and thyroid acropachy that manifests as swollen hands and clubbed fingers.
Thyroid and Gender
Thyroid dysfunction has a gender asymmetry with women at much higher risk
- Women are more susceptibility to thyroid problems and have increased rate of dysfunction with age
- Data suggest hypothyroidism is approximately ten times more prevalent in women than men (Vanderpump, 2011)
- Women also tend to have higher occurrence of mild or subclinical hyperthyroidism (Taylor 2018)
- In US, women of reproductive age (12-49 years) have a 3.1% rate of hypothyroidism
- Graves disease (an overactive thyroid when immune system attacks the gland) is known to predominantly affect women with an 8-fold rate compared to men, with highest impact in the age group of 30s-to-50s (De Leo, 2016)
- Solitary toxic thyroid nodules, the relatively benign lesions, are more common in women than in men, and some studies have reported a 5x higher occurrence
- Thyrotoxicosis, excessive thyroid hormones, from the iodine-rich compound amiodarone is more common in iodine-deficient areas but have a 3x higher prevalence among men.
Thyroid and Pregnancy
Pregnancy is a time period of large fluctuation in thyroid hormones
- In pregnant women, an increased iodine demand and the urinary excretion result iodine deficiency
- Thyrotoxicosis or excess thyroid hormone occurrence during pregnancy is significantly high; data show an estimated incidence of 0.2% for overt or clinical thyrotoxicosis and 2.5% for subclinical thyrotoxicosis (Cooper 2013; Korevaar 2017)
- In US, studies estimate the incidence of hyperthyroidism to be 5.9 per 1000 pregnant women per year (Korelitz, 2013)
- Greatest risk of hyperthyroidism is pregnant women seems to be in the first trimester
- Graves disease is the most common cause of thyrotoxicosis in pregnancy, although other causes, such as toxic nodules and goiters, are known to occur during pregnancy.
- Subclinical hypothyroidism before 20 weeks of pregnancy is associated with an increased risk of miscarriage (Zhang 2017)
- However, occurrence of hyperthyroidism during pregnancy might be overestimated mostly due to inclusion of cases of gestational thyrotoxicosis—a benign and transient disorder of pregnancy that typically occurs in the first trimester
- Thyrotoxicosis management in pregnancy is highly complex and needs to address the risk of mother’s hyperthyroidism without fetal harm from transplacental transfer of maternal antibodies and thionamide drugs
- Globally, in iodine-sufficient areas of developed countries, the prevalence of hypothyroidism during pregnancy is approximately 2% (Korevaar 2017; Medici 2015)
- Isolated hypothyroxinaemia (which is defined as free T4 in lowest 2.5% of population but with normal TSH) is associated with adverse pregnancy results, including premature birth (Korevaar 2013)
- Congenital hypothyroidism—the thyroid deficiency in newborns—nearly doubled in US in a 15-year period from 1987 at 1 in 3,985 to 1 in 2,273 in 2002 (in part due to increased ethnic diversity and lowering of TSH cut-off limit)
Thyroid and Age
Thyroid risk increases with age but those in 20-to-40 year age group are surprisingly at higher risk for hyperthyroidsm
- Those 80+ years older have 5x higher odds than those 12-49 years (Hollowell 2002)
- Elderly patients are more susceptible to thyroid nodules and hyperthyroidism, especially in iodine-deficient regions
- Graves disease (an overactive thyroid when immune system attacks the gland) is more common in younger population and they tend to have higher thyroid hormone levels with more likely overt or clinical hyperthyroidism than mild or subclinical hyperthyroidism
- Graves disease (an overactive thyroid when immune system attacks the gland) has highest impact in the age group of 30s-to-50s and predominantly affects women with an 8-fold impact compared to men (De Leo, 2016)
- Surprisingly, mild or subclinical hyperthyroidism is more common in two age groups: 20-40 years old and those 80+ years old (NHANES III, Hollowell 2002); that’s why many people experience thyroid problem in youth
- Older population with well known nodular goiter in areas of chronic iodine deficiency and trying iodine supplementation is at higher risk of iodine-induced hyperthyroid (also known as the Jod–Basedow phenomenon)
- Elderly patients with potential cardiac disease and limited access to health care are potentially at risk of iodine-induced hyperthyroid
- In elderly patients, toxic nodular goiter is the most frequent cause of thyrotoxicosis—a condition with too much thyroid hormones
- Data suggests that in iodine-sufficient countries, the prevalence of hypothyroidism ranges from 1% to 2% , rising to 7% in individuals aged between 85 and 89 years (Gussekloo, 2004)
Thyroid and Race
A significant variation in TSH levels is observed across various ethnic groups
- Ethnicity has strong correlation to subclinical hyperthyroidism with African-Americans having the highest prevalence at 0.4%, Mexican Americans, 0.3% and white Americans, 0.1% (Hollowell, 2002); in Asia, subclinical hyperthyroidism prevalence ranges between 0.43% to 3.9% of the overall population
- Similar trend is observed in data obtained for people of mixed races: Compared to non-Hispanic whites, non-Hispanic African-Americans had a 54% lower risk for hypothyroidism and 3.2-times higher risk for hyperthyroidism, while Mexican Americans had the same risk as non-Hispanic whites for hypothyroidism, but a 2-fold higher risk for hyperthyroidism (Aoki 2008); similar data from Brazil show same pattern, with black individuals having the lowest prevalence of hypothyroidism and those of dual heritage and white individuals having a higher prevalence
- Ethnicity seems to influence the risk of developing certain thyroid disease complications, e.g., risk of Graves ophthalmopathy (or thyroid eye disease) is six times more common in white populations than in Asian populations (Tellez and Cooper, 1992)
- The rare but serious complication of hyperthyroidism called thyrotoxic periodic paralysis is much more common among Asian men; studies from China and Japan (Okinaka, 1957) show periodic paralysis occurs in 2% of population compared to 0.2% in North America (Kelley, 1989); genetic studies show variations in certain HLA haplotypes, such as DRw8, A2, Bw22, Aw19 and B17, have been identified in patients of Chinese or Japanese origin (Tamai, 1987)
Thyroid and Geography
Thyroid dysfunction correlates to iodine intake which strongly depends on geography
- Almost one-third of the world’s population lives in iodine-deficient areas that face severe iodine deficiency and the devastating consequences of neurological development to fetuses and children
- Thyroid nodules are more prevalent in regions with iodine deficiency; on the other hand, Graves disease (an overactive thyroid when immune system attacks the gland), Hashimoto thyroiditis (an underactive thyroid when immune system attacks the gland) occur in regions with adequate or excess iodine
- Nodular thyroid disorders are more prevalent in areas where iodine deficiency is more common, while autoimmune thyroid disorders, including Hashimoto thyroiditis and Graves disease, occur more frequently in iodine-rich populations.
- Higher rates of hyperthyroidism occur in iodine-deficient regions, mainly due to thyroid nodules in elderly patients
- In iodine-sufficient regions, Graves disease can account for 70–80% of patients with hyperthyroidism
- In iodine deficient areas, Graves disease constitutes almost 50% of all cases of hyperthyroidism, while other half is attributed to nodular thyroid disease (e.g., a high prevalence of Graves disease in Iceland, an iodine-rich region, compared to a predominance of toxic multinodular goiter in Denmark with a lower iodine intake)
- Thyrotoxicosis from the iodine-rich compound amiodarone is more common in iodine-deficient areas as more patients supplement iodine using this compound.
- Regions with low iodine in diet have up to 12x higher occurrence of toxic nodular goiter compared to regions with higher iodine; they also have up to 2x higher incidence of solitary toxic nodules that are relatively benign lesion but potential risks in rare cases
Thyroid Medication and Other Special Circumstances
Certain medications and lifestyle play key role in thyroid health
- Thyroid problem can arise more frequently in those taking thyroid-related medications, e.g., levothyroxine/thyroid, estrogen, androgen, amiodarone; others, e.g., lithium, monoclonal antibodies, sodium valproate (anti-epileptic), tyrosine kinase inhibitors and immune checkpoint inhibitors can cause hypothyroidism
- Tyrosine kinase inhibitors are well known drugs causing hypothyroidism; the immune checkpoint inhibitors used by advanced cancer patients are well known to cause hypothyroidism, including drugs called ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab
- Among those taking levothyroxine or desiccated thyroid, the adjusted risk for hypothyroidism was 4x and hyperthyroidism was 11.4x (Aoki 2008)
- Borderline or mild cases of thyroid disorders have risen in past few decades due to increase in lower cost sensitive testing; the treatment threshold are also becoming progressively lower
- Levothyroxine prescription has been on rise, often as part of fertility treatment and other reproduction issues
- Genetic mutations into specific tissues can also cause hypothyroidism (e.g., THRα, THRβ and MCT8 (also known as SLC16A2))
- Radiographic contrast agents used during X-ray imaging and CT scan can also cause iodine-induced hyperthyroidism
- Smoking status, alcohol consumption, presence of other autoimmune conditions, syndromic conditions and exposure to some therapeutic drugs also influence thyroid disease in the population
Significant awareness and low cost high sensitivity testing has brought more awareness
- A common question to ask is: why am I always cold? Or hot? Because thyroid hormones control body temperature, this will be first signs of thyroid dysfunction
- A first step is to check TSH levels; however, checking for T4 and TPO antibodies should be included in the test for full diagnosis
- Not all testing is equal and may not be always necessary despite increased awareness, lower cost and easy access; e.g., 2017 trial of thyroid hormone therapy for elderly patients with subclinical hypothyroidism (the TRUST trial, Scott 2017), found that up to 60% of potentially eligible elderly individuals with an elevated TSH had returned to normal euthyroidism with healthy hormone levels when reassessed for the trial.
- Screening during pregnancy is fairly common although large fluctuations in thyroid levels during pregnancy requires careful assessment of the test timing
- Up to 50% cases of mild or subclinical hyperthyroidism is now attributed to the rise in levothyroxine treatment, especially because the treatment threshold has fallen over past two decades (Taylor 2014, Eligar 2016)
Why a TSH test alone is not enough?
Since TSH is only one part of the HPT axis, full cycle of thyroid hormone circulation can not be completely understood with TSH alone. It is a first step to identify potential issues. But to understand the subclinical or mild form of hypothyroidism or hyperthyroidism, testing for T4 levels is necessary. Similarly, an immune attack on thyroid glands can be proactively assessed by checking the TPO antibody levels.
Be informed, read more:
- Peter N Taylor, John H Lazarus, et. al. “Global epidemiology of hyperthyroidism and hypothyroidism“, Nature Reviews Endocrinology (Mar 2018)
- Joseph G. Hollowell et. al. “Serum TSH, T4, and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III)”, Journal of Clinical Endocrinology & Metabolism, 87(2):489 (2002)
- For monitoring latest research and literature on thyroid, visit: www.thyroid.org
- Learn about hypothyroidism, hyperthyroidism, and their symptoms at All About Thyroid
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