1 Overview

Suggested citation: Endocrine Society. Endocrine Facts and Figures: Thyroid. First Edition. 2015.

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The thyroid is a component of the hypothalamic-pituitary-thyroid axis, which is responsible for maintaining normal levels of thyroid hormones.1 Thyroid hormones, T3 and T4, play an essential role in the regulation of many aspects of metabolism2,3,4, with T4 being the predominant thyroid hormone in circulation and T3 being the most active form.5 Interestingly, approximately 80% of T4 is converted to T3 in liver and other target organs, whereas 20% of T3 is synthesized in the thyroid.1

Thyroid disease or dysfunction may result from structural or functional abnormalities along any part of this complex network. This chapter presents epidemiological data on the following thyroid conditions: thyroid nodules and goiter; hypothyroidism; hyperthyroidism; thyroiditis; autoimmune thyroiditis (Hashimoto’s thyroiditis); and iodine deficiency— hereinafter collectively referred to as thyroid disease.

1.1 Epidemiology

Table 1 summarizes recently published data on the prevalence of thyroid disease, by condition, conducted in United States (US) and international-based studies.

Table 1. Estimated prevalence of thyroid disease by condition 
CONDITION METHOD DATA SOURCE POPULATION PREVALENCE REFERENCE
Thyroid nodules Autopsy Review article International population 13% – 60% Stanicic et al, 2009.6
Palpation Whickham Survey (1972) Adults, Whickham, UK 0.5% – 26% Vanderpump et al, 19957
Ultrasonography Review article International population 13.4% – 46% Stanicic et al, 2009.6
Enhanced chest radiography Johns Hopkins Hospital Adult outpatients, US 25.1% Ahmed et al, 20128
Hyperthyroidism Overt NHANES III (1988–1994) Subjects age 12 years and older, US (n=17,353) 0.1% – 0.5% Hollowell et al, 20029
Subclinical NHANES III (1988–1994) Subjects age 12 years and older, US (n = 17,353) 0.75% – 4.3% Hollowell et al, 20029
Graves’ disease Literature review US population 0.63% – 1.49% Hayter et al, 2012 10
Hypothyroidism Overt NHANES III (1988–1994) Subjects age  12 years and older, US (n = 17,353) 0.3% – 0.8% Hollowell et al, 20029
Subclinical NHANESIII (1988–1994) Subjects age 12 years and older, US (n = 17,353) 0.7% – 13% Hollowell et al, 20029
Gestational Quest diagnostics data (2005–2008) Pregnant women, US (n=117,892) 15.5% Blatt et al, 201211
Congenital (incidence) NNSGRC dataset (1991–2000) Newborns, US 0.04% Hinton et al, 201012
Autoimmune thyroiditis Hashimoto’s thyroiditis Thyroid Multidisciplinary Clinic, Wisconsin (2006 -2008) 811 consecutive patients who received fine needle application  biopsies, US 4.6% – 13.4% Staii et al, 201013
Goiter Sporadic diffuse Literature review International population 1% – 10% Lind et al, 199814
Sporadic nodular Literature review International population 5% – 9% Lind et al, 199814
School-aged children Research study Children age 9–16 years, US (n=7,785) 6.8% Trowbridge et al, 197515
Iodine deficiency Low urinary iodine concentrations ( <50 mcg/L) NHANES (2001 – 2006) Non-pregnant, non-lactating women age 15–44 years, US 17% Perrine et al, 201016

Note: Differences in diagnostic criteria and analytical techniques account for ranges of prevalence of thyroid disease reported in the literature.

There are significant differences in the prevalence of thyroid disease based on factors that include sex, race and ethnicity. Differences in thyroid disease prevalence among major ethnic/racial groups in the US are summarized below (Table 2).

 Table 2. Prevalence of thyroid disease by race/ethnicity in the US.
RACE/ETHNICITY HYPOTHYROIDISM HYPERTHYROIDISM
OVERALL OVERT SUBCLINICAL OVERALL OVERT SUBCLINICAL
All 4.6% 0.3% 4.3% 1.3% 0.55% 0.75%
White, non-Hispanic 5.1% 0.4% 4.8% 1.4% 0.6% 0.8%
Black, non-Hispanic 1.7% 0.1% 1.6% 1.1% 0.5% 0.6%
Mexican American 4.1% 0.2% 3.9% 0.7% 0.2% 0.5%
All other races/ethnicities 4.2% 0.2% 4.0% 0.7% 0.4% 0.3%

Source: Hollowell et al. 20029

As a group, thyroid conditions affect 5–10 times more females than males.17,18 Table 3 provides an example of this sex difference as observed in the incidence of Graves’ disease and Hashimoto’s thyroiditis.

 Table 3. Sex differences in incidence of thyroid disease (per 1000 person-years).
DATA SOURCE POPULATION CONDITION MALES FEMALES
Comprehensive analysis of medical diagnoses of  active US Military Personnel (1997 – 2011) US adults age 20 – 57 years Hashimoto’s thyroiditis 0.03 0.26
Graves’ disease 0.08 0.47

Source: McLeod et al. 201419

1.2 Cost Burden of Disease

National surveillance data report a steady rise in case volume of endocrine procedures in the US over the last decade, mainly attributable to new and improved imaging and surgical techniques.20 It is estimated that the number of endocrine procedures performed in the US in 2020 may be as high as 173,509.20

In 2008, overall thyroid disease treatment costs in the US for females over age 18 totaled $4.3 billion, including $2.2 billion for ambulatory visits, and $1.4 billion for prescription medications. In 2008, among females with any expenses for thyroid disease treatment, the average expenditure per female for the treatment of thyroid disease was $343; the mean expenditure for ambulatory care visits was $409, and the mean expenditure for prescription medications was $116.21

 Table 4. Estimated cost of inpatient thyroidectomies in US adults.
DATA SOURCE POPULATION MEASURE 1996 2006
Nationwide Inpatient Sample (NIS) and National Survey of Ambulatory Surgery (NSAS) 52,062 hospital patients with ICD-9 code undergoing thyroidectomies Inflation-adjusted per capita charges $9,934 $22,537
Aggregate national inpatient charges $464 Million $1.37 Billion

Source: Sun et al. 201322

Importantly, in the time period reported in Table 4 (1996 to 2006), there was only a 19.5% increase in inpatient thyroidectomies, whereas outpatient thyroidectomies increased 60.9%. In 2006, the difference in unit charge between inpatient and outpatient (i.e. length of stay in hospital < 24 hours) thyroidectomy ($15,315) yielded estimated yearly savings of $63.6 million by reducing length of stay to less than 24 hours.22

In addition to costs related to treatment expenses and hospitalization, costs also involve work absence, and unemployment. Indeed, certain forms of disease have a higher cost in terms of work disability. For example, a recent Danish study found that patients with Graves’ orbitopathy had the highest risk of work disability, with this being most pronounced in the first year after diagnosis.23

 

1.3    Scientific Breakthroughs

 1.3.1        Epigenetics

The pathophysiology of Graves’ disease involves genetic and environmental factors that interact in as-yet-unknown ways to trigger the disease. Recent research reports a previously unidentified genetic–epigenetic interaction. Using human thyroid cells exposed to interferon-alpha, meant to mimic the immune response produced by exposure to a virus (environmental trigger), researchers found that a noncoding single-nucleotide polymorphism in the thyroid stimulating hormone receptor (TSHR) gene interacts epigenetically with the transcriptional repressor PLZF. This interaction resulted in decreased thymic expression of TSHR, enabling TSH receptor-reactive T cells to escape central tolerance mechanisms, thereby triggering thyroid autoimmunity and Graves’ disease.24

 1.3.2        Selenium supplementation

Given its pivotal role in the thyroid, selenium supplementation is being evaluated in several clinical trials in patients with thyroid disorders. The Danish GRASS study (NCT01611896) is currently investigating whether adding dietary selenium supplementation to the standard treatment regimen of antithyroid drugs (ATDs) for 24–30 months—with ATD withdrawn and selenium continued 12–18 months after randomization—may lead to fewer treatment failures and faster and longer-lasting remissions in patients with Graves’ disease.25 Similarly, the CATALYST trial (NCT02013479) aims to compare selenium supplementation versus placebo, both adjuvant to the standard treatment with T4, in patients with chronic autoimmune thyroiditis.26 A 2013 Cochrane review concluded that studies published to date are highly heterogeneous and had little clinical relevance. Indeed, they have failed to confirm or refute the efficacy of selenium supplementation for symptom management in patients with Hashimoto’s thyroiditis.27 Results of ongoing trials for the aforementioned thyroid conditions may provide further insight into the value of selenium supplementation in thyroid condition-specific cases.

 1.3.3        Use of genetic/genomic markers to assess risk of thyroid nodules prior to surgery

Since its inception as a diagnostic technique about 35-40 years ago, fine-needle aspiration (FNA) has become the gold standard for determining the malignancy of thyroid nodules.28 However, in cases where FNA yields indeterminate results, the use of molecular markers may be an effective diagnostic strategy. In 265 lesions shown to be cytologically indeterminate by FNA, the negative predictive values for “atypia (or follicular lesion) of undetermined clinical significance,” “follicular neoplasm or lesion suspicious for follicular neoplasm,” or “suspicious cytologic findings” were 95%, 94%, and 85%, respectively.29 In a recent study, Eszlinger and colleagues assessed the presence of point mutations and rearrangements in samples extracted by FNA as predictors of follicular thyroid carcinoma. In this study, BRAF mutations and RET/PTC rearrangements mutations were associated with thyroid cancer in 100% of the samples, while RAS and PAX8/PPARG rearrangements were a positive indicator of malignancy in 12% and 50% of samples, respectively.30

Similarly, Rossi and colleagues evaluated the diagnostic utility of molecular screening, specifically the presence of BRAF and RAS mutations, as well as RET/PTC1 and RET/PTC2 rearrangements, in the pre-surgical assessment of thyroid nodules. Parallel cytological examination and molecular testing in 940 specimens collected by FNA showed that BRAF mutations were the best molecular marker for cancer diagnosis, including cytologically indeterminate lesions, whereas RAS and RET/PTC analysis did not improve diagnostic sensitivity.31 In addition, the biomolecular analysis of the BRAF V600E mutation has been reported to increase the accuracy of FNA diagnosis for papillary thyroid carcinoma from 43.9% to 73.25%.32 To date, the presence of the aforementioned markers has not been unanimously correlated to specific prognostic values.33

 1.3.4        TSH receptor antagonist for Graves’ disease

Graves’ disease is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor. In recent years, TSH receptor antagonists and reverse agonists have been pursued as a way of reversing this pathogenic process. Researchers from the National Institute of Diabetes and Digestive and Kidney Diseases synthesized a small-molecule antagonist of TSH receptor signaling and demonstrated its efficacy in decreasing serum free T4 levels and thyroid gene expression in female mice.34 Although not the first compound with this mechanism of action,35 this is the first TSH receptor antagonist to be successfully tested in vivo.

1.3.5        Effect of low maternal thyroid hormone on childhood cognitive function

Low maternal thyroid hormone levels during pregnancy have been linked to poor cognitive function in offspring,36 contributing to the opinion that timely diagnosis and treatment of maternal hypothyroidism may improve infant outcomes. An antenatal screening program was conducted in the United Kingdom (UK) and Italy to identify women with thyrotropin levels above the 97.5th percentile, free T4 levels below the 2.5th percentile, or both, in blood samples obtained during the first 16 weeks of gestation.37 Blood samples were obtained, but not tested until after delivery, for a control group. Women in the screening group who tested positive for hypothyroidism and received T4 supplementation throughout their pregnancy, and offspring from both the screening and control groups were followed for the first 3 years of life. At the end of this period, there was no difference in cognitive function (measured as IQ levels) in children born to mothers diagnosed with and treated for hypothyroidism, as compared to those born to mothers in the control group with untreated hypothyroidism.37 A trial comparing 390 children of women treated for isolated high TSH or isolated low free T4, with 404 children of untreated mothers showed no improvement in the cognitive ability of the former group of children. Currently, a trial is being conducted to further clarify this issue (NCT00388297); however, at present there is no consensus regarding the need for routine screening for subclinical thyroid dysfunction during pregnancy. In addition, the threshold level of TSH used as an indicator of possible fetal damage is a topic of ongoing discussion.38

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