Hypothyroidism results from an underactive thyroid gland. Overt hypothyroidism is defined as elevated serum TSH levels with low-serum free T4, while subclinical hypothyroidism, or mild thyroid failure, is defined as elevated serum TSH with a serum free T4 level in the normal range. In rare cases, hypothyroidism may be due to pituitary disease causing a deficient secretion of TSH, in such cases both TSH and free T4 are expected to be low.68
3.1.1 Overt Hypothyroidism
A study conducted in Whickham, UK in 1972 became the model for later epidemiological studies; it reported a prevalence of overt hypothyroidism in 1.4% (14/1000) of females and less than <0.1% (<1/1000) of males, and overall, 0.8% in a population of 2779 persons (1494 women, 1285 men).48 The 20-year follow-up study of 1877 survivors (1051 women, 826 men) of the original Whickham cohort found a prevalence of 7.7% among women and 1.3% among men, and 9.3% overall. The incidence among survivors per year was 3.5/1000 among women and 0.6/1000 among men.7
A study in Tayside, Scotland with a much larger population (390,000) between 1994 and 2001 found that the overall prevalence of thyroid dysfunction increased from 2.3% to 3.8% over that period. The prevalence of hypothyroidism among females increased from 3.18% to 5.46%, and among males from 0.51% to 0.95%. The incidence of hypothyroidism also showed significant increases: from 4.23/1000 to 4.57/1000, and among males from 0.65/1000 to 1.01/1000.69
There are few US-based data regarding incidence of hypothyroidism. In a study of children age 11–18 years in southwestern Nevada and Utah, the prevalence of overt hypothyroidism was 0.19% (1965–1968); in follow-up examinations of two-thirds of the original cohort (1985-1986), it was 1.59%.70 Although the impetus for the study was in part to discern whether fallout from nuclear testing in the region might have increased thyroid disorders, the authors could only conclude that these disorders are dynamic and changeable in form, function, appearance, and disappearance.
Analysis of NHANES III (1988–1994) data for patients age 12 years and older found a prevalence of 0.3% for overt hypothyroidism.9 A cross-sectional study of 70- to 79-year-olds in Memphis, Tennessee and Pittsburgh, Pennsylvania reported the incidence of overt hypothyroidism to be 0.54% in males and 1.3% in females.71 Interestingly, the Cardiovascular Health Study (CHS), a population-based longitudinal study of adults age 65 years and older throughout the US, found that in 1992 the prevalence of untreated overt hypothyroidism was 0.61%.72
Table 18 summarizes US inpatient, outpatient and physician office visits for ICD-9 code 244.9 (unspecified acquired hypothyroidism) between 2008 and 2010.
|HOSPITAL INPATIENT 73|
|HOSPITAL OUTPATIENT 50|
|PHYSICIAN OFFICE VISITS 50|
Sources: National Ambulatory Medical Care Survey 201050; National Hospital Discharge Survey 201073
3.1.2 Subclinical Hypothyrodism
Subclinical hypothyroidism is more prevalent than overt hypothyroidism. NHANES III data for patients age 12 years and older indicated a prevalence of 4.3% for subclinical hypothyroidism.9
Observational data indicate that pregnant women with subclinical hypothyroidism have demonstrated an increased risk of adverse pregnancy outcomes. Subclinical hypothyroidism may increase the odds of pregnancy complications, including preeclampsia, placental abruption, preterm birth and neonatal mortality.74
Shields and colleagues reported the presence of subclinical hypothyroidism in 12.4% of pregnant healthy women (n=523) with no known thyroid disorders. Of these, 75.4% had normal thyroid function after pregnancy and 24.6% showed persistent high TSH.75
Among US adults age 70-79 years, in Memphis and Pittsburgh, the prevalence of subclinical hypothyroidism was 3.1%.71 Interestingly, the 1992 Cardiovascular Health Study (CHS) reported the prevalence of subclinical hypothyroidism to be 12.8% among adults age 65 years and older.72 In addition, data collected from adults aged 18 years and older at the Colorado Heath Fair in 1995 revealed a prevalence of 9.0% for subclinical hypothyroidism.76
3.1.3 Congenital Hypothyroidism
Congenital hypothyroidism occurs in approximately 1:2000 to 1:4000 newborns. Universal neonatal screening for this condition is carried out in the US and most developed countries. The symptomatology includes decreased activity, increased sleep, feeding difficulty, constipation, and prolonged jaundice.77
The incidence of congenital hypothyroidism has increased since the early 1990s, resulting in part from changes in testing protocols that enhanced detection of mild disease.78
In 2010, a study examining data from 11 states’ newborn screening databases reported congenital hypothyroidism incidence to be 0.04%.12 Moreover, this study indicated an increase in incidence from 0.029% to 0.04% between 1991 and 2000, as well as an overall increase of 30.4% across the decade.12 Importantly, congenital hypothyroidism is more frequent in iodine-deficient regions. Indeed, the prevalence of neonatal TSH levels above 5 mIU/L may be greater than 40% in severely iodine-deficient regions, but should be below 3% in iodine-sufficient populations.79
According to data collected on all newborn infants in Rhode Island, US from 2000-2006, the incidence of congenital hypothyroidism with a delayed TSH elevation was higher among lower birth weight infants (Table 19).80
|BIRTH WEIGHT||INCIDENCE OF HYPOTHYROIDISM|
Source: Woo et al. 201180
3.1.4 Gestational Hypothyroidism
For information related to gestational hypothyroidism, refer to section 3.2.3 of this chapter.
NHANES III data for patients aged 12 and older indicated that mean TSH levels and antithyroid antibody (TPOAb and TgAb) prevalence were greater in whites and Mexican Americans than in blacks. Prevalence of overt and subclinical hypothyroidism was highest among whites and lowest among blacks (Table 20).9
Source: Hollowell et al. 20029
3.2.1 Subclinical Hypothyroidism
Among adults age 70-79 years in Memphis and Pittsburgh, older black adults had a lower prevalence of subclinical hypothyroidism than older white adults. In blacks, the prevalence was 2% in males and 3% in females compared to 4% and 6% in whites.71 The prevalence of subclinical hypothyroidism by race and ethnicity is summarized in Table 20.
3.2.2 Congenital Hypothyroidism
In 2010, a study reported that the incidence of congenital hypothyroidism was 100% higher in Hispanic newborns compared with whites, and 44% higher in Asian and Native Hawaiian/Other Pacific Islanders. However, the incidence was 30% lower in black newborns than in whites.12
3.2.3 Gestational Hypothyroidism
There is currently insufficient evidence to recommend universal thyroid function testing for all women considering pregnancy or who are newly pregnant. However, there is general agreement in favor of screening in women who are at high risk for thyroid dysfunction or in those with a history of thyroid dysfunction and/or thyroid hormone use. Guidelines for the assessment and management of thyroid dysfunction in pregnancy have been issued by a variety of professional associations, including the Endocrine Society;81-84 notable differences between these guidelines have been discussed elsewhere.85-87
In unselected iodine-sufficient populations, the prevalence of subclinical hypothyroidism in pregnant women is about 2.5%, and the prevalence of overt hypothyroidism is 0.5%.88,89 As mentioned earlier, a study of 523 pregnant healthy women with no known thyroid disorders found subclinical hypothyroidism in 12.4% of the population, with 75.4% presenting normal thyroid function after pregnancy, and 24.6% exhibiting persistently high TSH.75
An evaluation of data collected between 2005 and 2008 from the Quest Diagnostic Informatics Data Warehouse, including results from TSH tests for pregnant women aged 18 to 40 years, reported a 15.5% prevalence of gestational hypothyroidism (overt and subclinical).11 The Quest data indicated that Asian women were 1.8 times more likely than African-American women to be tested for gestational hypothyroidism and almost 5 times as likely to develop this condition.
According to the aforementioned Quest data, only 23% of pregnant women (18-40 years) were tested for gestational hypothyroidism between 2005 and 2008. However, the study estimated that an additional 483,000 pregnant women in the US may have gestational hypothyroidism.11 While this study offers important insights on the prevalence of gestational hypothyroidism, it is critical to note that the study did not report the indicators used for thyroid function testing during gestation nor whether women taking thyroid hormone preparations or antithyroid drugs were excluded.
Hypothyroidism has been linked to many conditions limiting life expectancy, including cardiac dysfunction, atherosclerosis, hypertension, and coagulopathy.90 A review of available studies on hypothyroidism-related morbidity found varying and inconsistent data supporting the increased mortality related to either subclinical or overt hypothyroidism.90 Conversely, data from NHANES III indicate that hypothyroidism is associated with greater mortality than euthyroidism in blacks, but not in non-blacks.91
Whereas US-based data is limited, a British study analyzing death registration data between 1979-2010 found that mortality rates for acquired hypothyroidism decreased significantly during this period as a result of improved care.92 Average annual percentage change was 2.6%, with the highest decrease observed during the 1980’s. Both overt and subclinical hypothyroidism have been associated with increased risk of coronary heart disease, congestive heart failure, and cardiovascular mortality.93,94,95
Data from NHANES III indicated that mortality rates were higher in congestive heart failure patients with subclinical hypothyroidism compared with euthyroid heart failure patients.91 In fact, studies have linked the risk for coronary heart disease (CHD) events and a rise in CHD mortality with both elevated and reduced TSH levels.95 A meta-analysis of studies from 11 prospective cohorts in the US, Europe, Australia, Brazil, and Japan found subclinical hypothyroidism in 6.2% among a cohort of 55,287 adults. The risk of CHD events rose with TSH level, from a hazard ratio of 1.00 for TSH level of 4.5 to 6.9 mIU/L, to 1.17 for a TSH level of 7.0 to 9.9 mIU/L, and to 1.89 for a TSH level of 10.0 to 19.9 mIU/L. The corresponding hazard ratios for CHD mortality were 1.09 for euthyroid participants, 1.42, and 1.58.95
Importantly, total mortality was not elevated among patients with subclinical hypothyroidism.95 Similarly, a more recent study also failed to demonstrate a link between subclinical thyroid dysfunction and increased mortality risk in heart failure patients.96 In 5816 randomly selected Dutch participants, age 80 years or older, free T4 levels even within the high-normal range (18.5–22 pmol/L) were associated with 70% higher mortality as compared with those whose T4 levels were within the middle range. In those elderly persons, TSH levels within the high-normal range (3.0–4.0 mIU/L) were also associated with an 80% higher mortality in comparison with those persons having TSH levels within the middle range (1.0–2.0 mIU/L).98
In a study based on the NHANES III, the authors affirmed that TSH distribution progressively shifts toward higher concentrations with age. Without thyroid disease, 10.6% of patients age 20-29 years had TSH greater than 2.5 mIU/liter, increasing to 40% in the >80 group, 14.5% of whom had TSH greater than 4.5 mIU/liter. When TSH was greater than 4.5 mIU/liter, the percentage with antibodies was 67.4% (age 40-49 years) and progressively decreased to 40.5% in the >80 group. The prevalence of subclinical hypothyroidism may be significantly overestimated unless an age-specific range for TSH is used.99
Following an extensive evidence review, the American Thyroid Association recently concluded that levothyroxine (LT4) monotherapy is the standard of care for hypothyroidism, and found insufficient evidence to recommend alternative preparations such as T4/T3 combination therapy or thyroid extract therapy.100 Others have concluded that while there may be a role for T4/T3 combination therapy in selected patients, there remains a lack of well-conducted trials examining the effectiveness and health outcomes associated with such therapies.101
There remains some controversy regarding the treatment of subclinical hypothyroidism,82,83,102 though patients with this condition have an increased risk of progression to overt hypothyroidism and may also be at risk of cardiovascular disease.103 It has been suggested that treatment of subclinical hypothyroidism (TSH values 10 mIU/L or lower) should be avoided in patients over age 85 years. There is insufficient evidence regarding an association between subclinical hypothyroidism and adverse cardiac events and other systemic symptoms of hypothyroidism in patients with TSH values <10 mIU/L, suggesting treatment of this patient group may be unnecessary. In addition, there is evidence that suggests that subclinical hypothyroidism in persons over 85 years of age is associated with longevity.104
Among hypothyroid patients treated with T4 for at least 12 months between 2006 and 2011, normal TSH was found in 75% of those with spontaneous hypothyroidism and 68% of those with hypothyroidism following surgery or RAI therapy. T4 overtreatment was observed in 4% and 6% of patients respectively.105
There are few studies that have evaluated the incidence and progression of thyroid dysfunction in a single older population-based cohort. The Blue Mountains Eye Study (New South Wales, Australia) offered this opportunity by evaluating the 5-year incidence, progression, and risk factors for thyroid dysfunction. During this 5-year period progression from subclinical to overt hypothyroidism, associated with obesity, was observed in 17.9% of 1768 subjects with subclinical hypothyroidism.106
Subclinical hypothyroidism during pregnancy can persist postpartum. Among 523 pregnant healthy women with no known thyroid disorders, blood samples were taken at 28 weeks of pregnancy and at a mean of 4.9 years postpregnancy. Subclinical hypothyroidism (TSH 3 mIU/L) was present in 12.4%. Postpregnancy, 24.6% had persistent high TSH (>4.5 mIU/L). Of the women with subclinical hypothyroidism in pregnancy for whom antibody measurements were available, those with thyroid peroxidase antibodies in pregnancy were more likely to have persistently elevated TSH or to be receiving T4 replacement after pregnancy) 86% vs 18%).75
In addition, thyroid dysfunction during pregnancy has been associated with pregnancy complications and negative effects on pregnancy outcomes. Among 17,298 pregnant women screened for TSH and free T4 levels at a US hospital during 2000-2003, 404 (2.3%) were considered to have subclinical hypothyroidism. These women had a 3-times higher risk of placental abruption and a 1.8-fold risk of preterm birth.88 In a later evaluation of 6,985 women identified among those previously screened at the same hospital, 230 (3.3%) were found to have subclinical hypothyroidism after a subsequent delivery. In subsequent pregnancies, subclinical hypothyroidism was associated with diabetes (adjusted odds ratio, aOR 1.58) and stillbirth (aOR 3.41).107