4 Hyperthyroidism

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

Hyperthyroidism, also called overactive thyroid, is a condition in which the thyroid produces too much of the thyroid hormones T4 and/or T3.2

4.1    Prevalence and Incidence

4.1.1        Overt hyperthyroidism

The estimated prevalence of overt hyperthyroidism ranges from 0.1% to 0.5%, and is higher among females than males.9 Based on data from the NHANES III, the prevalence of overt hyperthyroidism among persons age 12 years and older was 0.5%.9 Examinations of 3,121 adults ages 31-38 years between 1985-1986, in a 3-state area of the southwestern US where nuclear testing had been carried out, indicated a hyperthyroidism prevalence of 0.39%.70

In 1992, the Cardiovascular Health Study found that the prevalence of overt hyperthyroidism in persons 65 years and older was 0.33%.72 In a review article examining studies published from 1990-2013, the relative incidence of overt hyperthyroidism in pregnancy was estimated to range from 0.1% to 0.4%.108

In the UK the 20-year follow-up of the Whickham Survey found that the annual incidence of hyperthyroidism was 0.008% among females and undetectable among males.7 The prevalence of previously unsuspected hyperthyroidism was 0.5% in females, and undetectable in males.7

An increase in primary hyperthyroidism between 1994 and 2001 was documented in a population-based study of patients in Tayside, Scotland. Among participants in this study, the overall prevalence of hyperthyroidism increased from 0.86% to 1.26% in females and 0.17% to 0.24% in males. The standardized incidence of hyperthyroidism increased from 0.68 to 0.87 per 1000 females per year, representing a 6.3% annual increase.69

A recent study found 1682 new cases of overt hyperthyroidism in a large cohort from two cities in Denmark, one with moderate iodine deficiency (Aalborg, population 311,102 ) and another with only mild iodine deficiency (Copenhagen, population 227,632). The overall standardized incidence rate (SIR) per 100,000 person-years was 81.6, and was higher in Aalborg compared with Copenhagen (96.7 vs. 60.0). The SIR ratio between moderate versus mild iodine-deficient areas was 1.6.109

Whereas there are limited incidence data for hyperthyroidism in the US, based on the number of new prescriptions of thionamide antithyroid drugs, incidence per 1000 subjects by age group and data from the 2008 US census is presented in Table 21.

Table 21. Incidence per 1000 of overt hyperthyroidism by age.
AGE INCIDENCE PER 1000 SUBJECTS
     4–11 years 0.44
     12–17 years 0.26
     18–44 years 0.59
     56–64 years 0.78
     65 years and older 1.01

Source:  Emiliano et al. 2010110

 The prevalence of hyperthyroidism during pregnancy, according to one study, has been found in 0.1%-0.4% of pregnancies.108 Another study quotes a higher range: 0.4%-1.7%.111 The latter study notes that thyroid disorders during pregnancy can be missed because of nonspecific symptoms and normal changes in thyroid gland that accompany pregnancy. As mentioned earlier, thyroid function tests need to be interpreted properly with trimester specific TSH reference ranges.

 4.1.2       Subclinical Hyperthyroidism

The clinical consequences of subclinical hyperthyroidism, such as atrial dysrhythmia, accelerated bone loss, increased fracture rate, and higher rates of cardiovascular mortality, are dependent on age and severity.112 NHANES III reports the prevalence of subclinical hyperthyroidism among people age 12 years and older as 0.7%.9 According to the CHS, in 1992 the prevalence of subclinical hyperthyroidism was 1.2% among adults age 65 years and older.72

 4.1.3       Graves’ Disease

The Defense Medical Surveillance System reported that in US active-duty military personnel age 20-54 years (1997–2011), compared with whites, the incidence rate ratio (IRR) for Graves’ disease was significantly elevated in black women (IRR, 1.92) and men (IRR, 2.53), as well as Asian/Pacific Islander women (IRR, 1.78) and men (IRR, 3.36).19  Table 22 summarizes data on the epidemiology of Graves’ disease.

Table 22. Epidemiology of Graves’ disease.
POPULATION METHOD INCIDENCE PER 100,000/YEAR PREVALENCE REFERENCE
Rochester, Minnesota, US (1935­–1967) Hospital records 36.8 (F) Furszyfer et al. 1972113
Nurses’ Health Study, US (1989–2001) 724 supplemental questionnaires 40.9 (F) Holm et al. 2005114
Specialized clinic, UK Estimate from population studies in literature 0.65% (F, 2.3%; M, 0.145%) Boelaert et al. 2010115
US active-duty military personnel, age 20–54 years, (1997–­2011) Data analysis of records of patients with ICD-9 code 242.0 47.9 (F); 8.0 (M) McLeod et al. 201419

Abbreviations: F, females; M, males

 

 4.2    Demographic Differences

 4.2.1        Overt Hyperthyrodism

NHANES III data for patients age 12 years and older indicate that prevalence of hyperthyroidism differs only slightly by ethnicity (Table 23).9

Table 23. Prevalence of overt and subclinical hyperthyroidism by race/ethnicity in the US.
RACE/ETHNICITY HYPERTHYROIDISM
OVERALL OVERT SUBCLINICAL
All 1.3% 0.5% 0.7%
White, non-Hispanic 1.4% 0.6% 0.8%
Black, non-Hispanic 1.1% 0.5% 0.6%
Mexican American 0.7% 0.2% 0.5%
Other races/ethnicities 0.7% 0.4% 0.3%

Source: Hollowell et al. 20029

4.3    Life Expectancy and Mortality

A prospective, observational study of British patients presenting with a first episode of hyperthyroidism between 1989-2003, and followed until 2012, found that over time, 32% of the initial cohort of 1036 patients (age 40 years and older) died. This was 15% higher for all-cause mortality than the expected deaths for this population. However, comorbidity was high in the population. Cardiovascular and cerebrovascular causes were 20% higher than expected, and in study subjects presenting with atrial fibrillation the risk of death was 59% higher. Excess mortality was not observed in the subgroup having no preceding comorbidities. Among subjects with Graves’ disease, all-cause mortality increased by 16%. However, excess mortality was not observed in subjects rendered hypothyroid by RAI.116

A recent meta-analysis selected 8 (seven cohort, one case–control) studies for analysis by stringent criteria. Most of the studies were performed in Europe, with only 2 from the US. Six of the 8 studies found a higher mortality in hyperthyroid patients compared with controls. As in the British study mentioned above, cardiovascular disease imposed an increased risk: 19% higher than in the general population. As a whole, the studies found an overall relative mortality risk of 1.21 among patients with overt hyperthyroidism, indicating an increased mortality risk of about 21%.117  Subsequent analysis of data from the Thyroid Studies Collaboration reached similar conclusions for subclinical hypothyroidism, including an association with increased risk of total mortality, coronary heart disease mortality, and incident atrial fibrillation.118

Data from the OPENTHYRO database regarding thyroid-stimulating hormone (TSH) levels show that thyroid dysfunction, including both hypo- and hyperthyroidism, is associated with an increased risk of comorbidities. Hyperthyroidism was linked to a higher burden of comorbidity and increased mortality; subclinical hyperthyroidism was associated with a 9% excess mortality per year of age, and 12% with overt hyperthyroidism.119 The Nijmegen Biomedical Study found an association between increased mortality for subjects under 65 years of age, but not those older than 65 years. In a cohort of community-dwelling men age 70-89 years, free T4 levels in euthyroid men were associated with all-cause mortality independently of conventional risk factors and medical comorbidities.120

A 2013 review cited long-term adverse effects resulting from subclinical hyperthyroidism, including an increased 24 hour heart rate and increased frequency of atrial and ventricular ectopic beats. Large studies of older adults showed a 13% increase in the frequency of atrial fibrillation. Some studies show an increase in all-cause mortality; the highest risk of coronary heart disease mortality and atrial fibrillation is found in patients with serum TSH is under 0.10 mIU/L.74

 

4.4    Diagnosis, Treatment, and Prescription Trends

In 2011, a survey of members of the Endocrine Society (ES), American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) found that most members’ initial treatment of choice for uncomplicated Graves’ disease was antithyroid drugs. Initial treatment preferences are outlined in Table 24.121

 Table 24. Initial treatment preferences for patients with Graves’ disease.
INITIAL TREATMENT PREFERENCE
Antithyroid drugs 53.9%
Radioactive iodine therapy (RAI) 45.0%
Thyroid surgery 0.7%

Source: Burch et al. 2012121

Moreover, the majority of respondents cited methimazole as the preferred antithyroid drug (Table 25).

 Table 25. Preferred antithyroid medication for patients with Graves’ disease.
ANTITHYROID DRUG PREFERENCE
Methimazole 83.5%
Carbimazole (not available in US) 13.8%
Propylthiouracil 2.7%

Source: Burch et al. 2012121

Compared to findings from a similar survey conducted in 1991, fewer respondents opted for RAI during treatment (59.7% in 2011 vs. 69% in 1991).121

A retrospective evaluation of data from patients with Graves’ disease treated with RAI, found that the 1- and 5-year recurrence rate was 5%. In addition, after 5 years, 78% of patients developed hypothyroidism and 17% showed euthyroid state. 122

The aforementioned survey of endocrinologists found that patients with Graves’ ophthalmology were treated with antithyroid drugs or surgery most frequently (Table 26).121

 Table 26. Treatment preferences for patients with Graves’ ophthalmology.
TREATMENT PREFERENCE
Antithyroid drugs 62.9%
Thyroid surgery 18.5%
RAI + corticosteroids 16.9%
RAI alone 1.9%

Abbreviation: RAI, radioactive iodine

Source: Burch et al. 2012121

4.5    Health Outcomes Measures

4.5.1        Graves’ disease

Three treatment modalities for Graves’ disease— RAI, anti-thyroid drug therapy, and surgery—are largely focused on controlling hyperthyroidism.123

In the case of RAI, a critical step is determining the appropriate dosage to achieve optimal efficacy. Interestingly, Bakos and colleagues presented data of 326 patients with a mean follow-up of 5.7 years, in which Graves’ disease patients had a hyperthyroidism recurrence rate of 5% after 5 years. In those with toxic goiter, the 5-year recurrence rate was 7%. In the Graves’ disease population, subsequent recurrence of hyperthyroidism and hypothyroidism is not unusual.122

A systematic review of trials related to radioactive iodine administration due to hyperthyroidism caused by toxic nodular goiter found that patients who received calculated dosimetry treatment had a 9.6% higher cure rate and 0.3% more permanent hypothyroidism than those treated with the fixed dose method.124

A retrospective analysis of 384 patients in northern Italy presented varying results in the 249 patients who were treated with the anti-thyroid drug methimazole (MMI). After excluding those with inadequate response to MMI at low doses, 138 patients maintained euthyroidism beyond 20 to 24 months.125

The European Multicentre Trial Group randomized two patient groups to treatment with 10 or 40 mg of MMI. The overall relapse rate a mean observation period of 4.3 years was 58%, and did not differ between patients treated with the higher or lower dose. The conclusion was that the dose of MMI in Graves’ disease therapy can be kept to the minimal required dose to provide the best balance of risk and benefit.126

In a trial designed to investigate the 6-year outcome of MMI treatment with or without exogenous T4 in Chinese patients with Graves’ disease, the conclusion was that the addition of T4 to methimazole treatment neither improved or prevented the remission or recurrence of Graves’ disease.126

A review of 31 cohort studies found adverse effects reported in 13% of patients. These were more common with MMI and were typically dermatological, whereas hepatic effects were more common with propylthiouracil. Drug therapy yielded higher relapse rates than surgery or RAI.127

Additional therapeutic approaches are in the development pipeline. Among biological agents, rituximab is a humanized chimeric monoclonal antibody targeting CD20, an antigen expressed on lymphocytes. A high affinity antibody, termed 5C9, blocks the effects not only of the monoclonal stimulatory TRAb and thyroid stimulating hormone, but also the polyclonal TRAb found in the sera of Graves’ disease patients.128 Also, newly developed drug-like small molecule ligands antagonize TSHR signaling.129

A recent meta-analysis reached similar conclusions, but indicated that total thyroidectomy was associated with an increase in both temporary and permanent hypoparathyroidism.130

The potential risk of damage to the recurrent laryngeal nerve (RLN) is a consideration to be kept when opting for surgery as treatment.  In 844 thyroidectomies for benign thyroid diseases in Japan between 2008 and 2010, 1,372 nerves were at risk during the surgery. The RLN was involuntarily transected in 5 patients during the operation and the incidence of RLN palsy was 5.3% per patient and 3.3% per nerve.131 Conversely, a cohort study of 780 patients, of whom 203 had Graves’ disease, found no permanent laryngeal damage among the Graves’ disease patients. In addition, 80% of the reported thyroidectomies were performed as outpatient procedures.132

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