What is Thyroid?
Thyroid is one of the most important glands for our well-being.
It plays critical roles in pregnancy and during childhood. A relatively small, butterfly-shaped gland, that sits next to the throat.
Thyroxine (T4) and tri-iodo-thyronine (T3) are released by this gland depending on thyroid-stimulating-hormone (TSH) levels from the pituitary –another small glad located below the brain.
The key role of thyroid hormones is in controlling metabolism. They are also important for neurological development of newborns, normal growth in childhood, and for reproduction.
Thyroid disease is a global health problem that impacts a significant population—including those in advanced economies—despite significant awareness, widespread testing and low cut-off for treatment threshold.
Iodine is necessary for healthy thyroid: almost 75% of the iodine in our body is used by this gland alone.
Even in iodine-sufficient areas thyroid dysfunction is fairly common due to autoimmune diseases.
Still, supplementation of human diet with iodine remains a hot issue.
For decades, salt has been fortified with iodine across the globe. However, frequent resurgence of thyroid diseases in many previously iodine-sufficient regions is a constant problem. Therefore, the constant need for monitoring and testing is important for public health.
How common is thyroid disease?
Both low and high levels of iodine impact health negatively.
Alas, 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.
Across the world, role of thyroid hormones in every day health is well recognized. Despite this 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% of population (or over 18 million people) have some form of mild or serious thyroid disorder (Reference: 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.
Our risk of hypothyroidism is highest under 20-years and over 60-years of age.
Source: National Health and Nutrition Examination Survey (NHANES III): Serum TSH, T4, and Thyroid Antibodies in the United States Population (1988 to 1994) in The Journal of Clinical Endocrinology & Metabolism, Volume 87, Issue 2, 1 February 2002, Page 489.
The risk of hyperthyroidism is highest for the elderly, and somewhat surprisingly, during the child bearing years.
Source:National Health and Nutrition Examination Survey (NHANES III): Serum TSH, T4, and Thyroid Antibodies in the United States Population (1988 to 1994) in The Journal of Clinical Endocrinology & Metabolism, Volume 87, Issue 2, 1 February 2002, Page 489.
How does thyroid work?
The hypothalamus-pituitary-thyroid (HPT) axis controls thyroid function.
First, hypothalamus senses the thyroid hormones and releases TRH (thyrotropin-releasing hormone). The pituitary gland detects this TRH and releases the thyroid stimulating hormone (or TSH).
Next, TSH 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). T3 is a simple conversion from thyroxine after loosing one iodine atom. Finally, hypothalamus senses these hormones and the
closed-loop cycle continues.
Any issues with this closed loop result in thyroid problems.
THE HPT AXIS AND CLOSED LOOP FUNCTIONING
As TSH levels reduce, free-T4 levels increase. The following graph shows ranges for healthy, mild (sub-clinical), and severe (clinical) conditions for these two hormones.
Hypothyroidism (an under-active thyroid) and hyperthyroidism (an over-active thyroid) commonly arise from pathological processes in the thyroid gland (primary thyroid disease). In rare cases, they can arise from disorders of the hypothalamus or pituitary (secondary or central
hypothyroidism). Peripheral causes such as ovarian tumor (struma ovarii), or thyroid cancer may arise.
Since TSH triggers T4 and T3 release, diagnosis starts with checking TSH levels. They modulate to boost or curb T3, T4.
When TSH levels rise above 4.5 mIU/L (milli-international-unit-per-liter) they reach the clinical definition of hypothyroidism. In contrast, excess T4 will under-drive TSH release, and levels below 0.1 mIU/L result in hyperthyroidism.
The abnormally low or high 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 not result into a full blown thyroid problem.
What if it’s not possible to keep up with abnormal TSH levels, and underproduction or overproduction continues? That’s clinical or overt stage of thyroid disease with potentially serious consequences.
T4 levels below 57.9 nMol/L (nano-moles-per-liter) or 4.5 ng/dL (nano-gram-per-deci-liter) combined with high TSH (above 4.5 mIU/L) is clinical or overt hypothyroidism. On the other hand, levels above 169.9 nMol/L or 13.2 ng/dL in combination with low TSH (below 0.1 mIU/L) is clinical
hyperthyroidism. Both have serious health impact.
What’s the global status of iodization?
As of 2016, 110 countries classify as optimal for iodine supply in the diet. Still, 19 countries have persistently insufficient iodine intake, according to a 2016 report by the Iodine Global Network, a non-profit advocacy group. Iodine fortification of all
food-grade salt is now mandatory in ~120 countries (Dasgupta 2008).
On the other hand, a growing number of countries–ten as of 2016–classify as having excessive iodine supply in diet. In some parts of the world, fortification or jump in iodine intake has seen increases in cases of toxic nodular goiters. Levels jump post-iodization, causing fatalities as a
result of cardiovascular complications.
Individuals on thyroid hormone replacement medication often remain hypothyroid or become hyperthyroid which underscores the importance of monitoring.
What are the key risk factors in thyroid disease?
The list of risk factors is long, as the following table shows (Taylor 2018).
What’s the status of thyroid hormones 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, based on data from 1999-2002. At this rate, today, it corresponds to 12 million 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 (again, 1999-2002 data). That corresponds to 1.5M people today, with potential hyperthyroidism problem.
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).
- The presence of nodules in the thyroid can cause inflammation in the gland or thyroiditis (the high and low fluctuations of T4, T3 as shown in chart above).
- Those taking certain medications can have adverse effects, e.g., from amiodarone and lithium.
- Thyroid treatment itself can sometimes cause both hypothyroidism and hyperthyroidism.
Hyperthyroidism with an overactive gland, such that the immune system attacks the gland itself, is called Grave’s disease.
Key symptoms include
- a much diffused and swollen goiter
- thyroid red eye disease (in 20-30% cases)
- in rare cases, localized thickening of skin and thyroid acropachy that manifests as swollen hands and clubbed fingers
Are women at higher risk of problems with thyroid hormones?
Thyroid dysfunction has a gender asymmetry with women at much higher risk, and rate of dysfunction increases 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. The highest impact is in the age group of 30s-to-50s (De Leo, 2018).
- 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, i.e., excessive thyroid hormones, from the iodine-rich compound amiodarone is more common in iodine-deficient areas but have a 3x higher prevalence among men.
What roles thyroid hormones play during pregnancy?
Pregnancy is a time period of large fluctuation in thyroid hormones.
In pregnant women, an increase in demand and relatively higher urinary excretion result in iodine deficiency.
Thyrotoxicosis or occurrence of excess thyroid hormone, is significantly high during pregnancy. Estimates of incidence are 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).
The 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. It is necessary to address the risk of mother’s hyperthyroidism without fetal harm from transfer of maternal antibodies through placenta and thionamide drugs.
Globally, in iodine-sufficient areas of developed countries, the prevalence of hypothyroidism during pregnancy is approximately 2% (Korevaar 2017;
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. This is in part due to increased ethnic diversity and lowering of TSH cut-off limit.
How age affects thyroid hormones?
Thyroid risk increases with age but those in 20-to-40 year age group are surprisingly at higher risk for hyperthyroidsm.
- Those 80 years or older have 5-times 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. They also tend to have higher thyroid hormone levels, with more likelihood of overt or clinical hyperthyroidism than mild or subclinical hyperthyroidism.
- Graves disease has the highest impact in 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. The condition is also known as the Jod–Basedow phenomenon.
- Elderly patients with potential cardiac disease and limited access to health care are potentially at the 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).
What is the role of race and ethnicity on thyroid hormones?
A significant variation in TSH levels is common across various ethnic groups.
Ethnicity has strong correlation to subclinical hyperthyroidism with highest prevalence of 0.4% among African-Americans, 0.3% in Mexican Americans, and 0.1% in white Americans (Hollowell, 2002). In Asia, subclinical
hyperthyroidism prevalence ranges between 0.43% to 3.9% of the overall population.
Similar trend is exists for people of mixed races: compared to non-Hispanic whites, non-Hispanic African-Americans had a 54% lower risk of hypothyroidism and 3.2-times higher risk of hyperthyroidism. Mexican Americans had the same risk as non-Hispanic whites for hypothyroidism, but a
2-fold higher risk for hyperthyroidism (Aoki 2008). Data from Brazil show same pattern: black individuals have the lowest prevalence of hypothyroidism and those of dual heritage and white individuals have a higher
Ethnicity seems to influence the risk of developing certain thyroid disease complications. For example, 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).
How geography affects prevalence of thyroid disease?
Thyroid dysfunction correlates to iodine intake which strongly depends on geography.
- Almost one-third of the world’s population lives in iodine-deficient areas. They live with 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
- Nodular thyroid disorders are more prevalent in areas where iodine deficiency is more common. But 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 remaining half are due to nodular thyroid disease. As an example, Graves disease has higher prevalence in Iceland, an iodine-rich region, in comparison to a predominance of toxic
multinodular goiter in Denmark that has 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 12-times higher occurrence of toxic nodular goiter compared to regions with higher iodine. They also have up to two-fold higher incidence of solitary toxic nodules–relatively benign lesion with potential risks in rare cases.
What’s the effect of medication on thyroid disease?
Certain medications and lifestyle play key role in thyroid health.
Thyroid problem can arise more frequently in those taking thyroid-related medications. These include levothyroxine, estrogen, androgen, amiodarone. Additionally, lithium, monoclonal antibodies, sodium valproate (anti-epileptic), tyrosine kinase inhibitors and immune checkpoint inhibitors
can cause hypothyroidism.
- Tyrosine kinase inhibitors are drugs that often cause hypothyroidism. The immune checkpoint inhibitors given to advanced cancer patients are well known to cause hypothyroidism. Few of these drugs are: ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab.
- Among those taking levothyroxine or desiccated thyroid, the adjusted risk for hypothyroidism was 4-times and hyperthyroidism was 11.4-times (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.
How to test for disorders related to thyroid hormones?
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. Or, testing may not always be necessary despite an increase in awareness, easy access and falling cost. A 2017 trial of thyroid hormone therapy for elderly patients with subclinical hypothyroidism (the TRUST trial,
Stott 2017) highlights how testing might be wasteful. They found that up to 60% of potentially eligible elderly individuals with an elevated TSH had returned back to normal euthyroidism and 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 because treatment threshold has fallen over past two decades (Taylor 2014,
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.
- Global epidemiology of hyperthyroidism and hypothyroidism by Taylor et. al. in Nature Reviews Endocrinology, 2018.
Serum TSH, T4, and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III) by Hollowell et. al. in Journal of Clinical Endocrinology & Metabolism, 2002.
- Iodine Nutrition: Iodine Content of Iodized Salt in the United States by Dasgupta, Liu & Dyke in Environ. Sci. Technol. 2008.
Serum TSH and Total T4 in the United States Population and Their Association With Participant Characteristics: National Health and Nutrition Examination Survey (NHANES 1999–2002) by Aoki et. al. in
- The epidemiology of thyroid disease by Vanderpump in British Medical Bulletin, 2011.
- Hyperthyroidism in pregnancy by Cooper and Laurberg in Lancet: Diabetes & Endocrinology, 2013.
- Thyroid disease in pregnancy: new insights in diagnosis and clinical management by Korevaar et. al. in Nature Reviews Endocrinology, 2017.
Thyroid Function in Pregnancy: What is Normal? by Medici et al. Clin. Chem., 2015.
- Thyroid Status, Disability and Cognitive Function, and Survival in Old Age by Gussekloo et. al. in Journal of American Medical Association, 2004.
- Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism by Stott et. al. in New England Journal of Medicine, 2017.
Falling Threshold for Treatment of Borderline Elevated Thyrotropin Levels—Balancing Benefits and Risks: Evidence From a Large Community-Based Study by Taylor et. al. in
JAMA Internal Medicine, 2014.
- For monitoring latest research and literature on thyroid, visit: www.thyroid.org
- Learn about hypothyroidism, hyperthyroidism, and their symptoms at All About Thyroid