THE EPIDEMIOLOGY OF THYROID DISEASE AND IMPLICATIONS FOR SCREENING

EPIDEMIOLOGY AND CLINICAL DECISION MAKING

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THE EPIDEMIOLOGY OF THYROID DISEASE AND IMPLICATIONS FOR SCREENING Clifford Wang, MD, and Lawrence M. Crapo, MD, PhD

Strictly speaking, the term epidemiology means the study of epidemics; however, the word often is used in a broader sense to mean the examination of the prevalence and incidence of a disease in the community and, when possible, the determinant factors which underlie the observed distributions. An excellent review of the epidemiology of thyroid disease has recently been published by the principal investigators of the renowned Whickham survey and its 20-year follow-up study.'" In this review, we make an attempt to extend these important insights by providing a somewhat more detailed analysis of the epidemiologic data, including that on thyroid cancer. The Whickham survey in northeastern England'2Kis, to date, the only study that has surveyed a representative sample of the entire adult population of a large community for thyroid disease by employing detailed medical histories, rigorous physical examination, and sophisticated laboratory testing including serum levels of T,, free T4, T3, thyroid-stimulating hormone (TSH), and antithyroid antibodies. The Whickham survey and its follow-up conducted over a 20-year period from 1972 to 1993, have permitted the calculation of the prevalence and incidence of overt hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism, and goiter in a community of about 21,000 adult inhabitants. The adult Whickham population has been shown to reflect closely the entire adult population of Great Britain which, in turn, is probably a reflection of the population of northern Europe. Other studies, narrower in scope from around the world (including Europe, the United States, and Japan) have corroborated the findings of the Whickham survey, suggesting that the results from Whickham may have a broad application except for regions of the world

From the Department of Medicine, Stanford University School of Medicine, Stanford; and the Divisions of Primary Care (CW) and Endocrinology (LMC), Department of Medicine, Santa Clara Valley Medical Center, San Jose, California

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA -~~~~

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that have obvious environmental disturbances that are known to cause thyroid disease, such as iodine deficiency, water-borne goitrogens, and excessive radiation. The Whickham Survey is discussed in considerable detail in this article because of its central importance in the epidemiology of thyroid disease. However, we also examine other studies in comparison with the Whickham survey for the prevalence of overt and subclinical hypothyroidism, overt hyperthyroidism, and goiter. The prevalence of low serum TSH levels and its association with a clinical condition called subclinical hyperthyroidism is explored. Awareness of this disorder is a direct result of the increased sensitivity of the new secondand third-generation TSH assays, just as awareness of subclinical hypothyroidism arose out of the first-generation TSH assays. In addition to hypothyroidism, hyperthyroidism, and goiter, a discussion of the epidemiology of thyroid disease should consider estimates of the prevalence and incidence of thyroid nodules and thyroid cancer. Because these disorders were not thoroughly studied in the Whickham survey, we turn to other sources of information, including studies that include physical examination, ultrasound, other scans, and autopsy reports. It is not surprising that the prevalence of thyroid nodules and thyroid cancer turns out to depend dramatically on the means of detection that is chosen. The problem of screening adult populations for thyroid disease is considered based on the underlying epidemiology. Although a detailed cost-effective analysis of adult thyroid screening is beyond the scope of this review, we will attempt to answer the following questions: who should be screened, what should they be screened for, what screening test should be used, and where should the screening take place? In pediatrics, these four questions have been answered definitively. All neonates should be screened for congenital hypothyroidism using a total T4 or TSH assay on a heelstick blood sample obtained shortly after birth in the hospital. Even though congenital hypothyroidism is rare, occurring in approximately 1 per 4000 live births, this screening strategy has been proven to be cost-effective when blood sampling is coordinated with screening for other neonatal diseases such as phenylketonuria. A screening strategy for adults is more elusive, and, currently, no major task force or medical agency recommends that adults be screened for any of the thyroid diseases. In the future, the answer to the four questions posed previously may be that we should screen older women for hypothyroidism or subclinical hypothyroidism using a serum TSH assay in the clinic. THE WHICKHAM SURVEY Initial Survey

Between July 1972 and June 1974, an initial survey of the adult population of the Whickham district in northeast England was conducted.12R This district is a mixed rural and urban area near Newcastle-Upon-Tyne. The purpose of the survey was to determine the prevalence of hypothyroidism, hyperthyroidism, autoimmune thyroiditis, and goiter in the community. The survey sample was drawn randomly by selecting every sixth name on the electoral register of adult subjects who were aged 18 years or older. In this way, a representative sample of 3538 persons was identified. Of these, 2779 persons (SOY0)became participants in the study (168 died or moved from the area and 591 refused to participate). Approximately 89% of the participants and 80% of their parents were born in the study region. The age, sex, and social class of the participants were similar to that of the population of Great Britain as a whole. No details about the 595

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persons who refused to participate were obtained. The sample included 1285 men (46%) and 1494 women (56%), with a mean age of 47 years. All participants were examined carefully for evidence of hypothyroidism, hyperthyroidism, and goiter, including detailed personal and family histories. Fasting blood samples were obtained for serum TSH by radioimmunoassay, total T,, total T , T, Sephadex uptake to derive a free thyroxine index (FTI), antithyroid thyroglobulin antibodies, and antithyroid microsomal antibodies, glucose, cholesterol, and triglyceride. In addition, subjects were evaluated for evidence of diabetes mellitus, hypertension, and atherosclerotic vascular disease. Prevalence of Hypothyroidism and Hyperthyroidism

The prevalence of abnormal thyroid function tests in the survey population is summarized in Table 1. Several important observations are highlighted by these results. First, virtually all of the cases of unsuspected overt hyperthyroidism and hypothyroidism were in women. In the 1285 men in the study, there were no cases of unsuspected overt hypothyroidism or unsuspected hyperthyroidism, only one case of previously known hypothyroidism, and three cases of known hyperthyroidism. This is a small amount of thyroid disease to uncover from a community base of 21,000 adults. Second, although 57 of 1494 women (4.6%) had either overt hypothyroidism or hyperthyroidism, only 12 of these subjects (0.8%) had unsuspected disease. Thus, even in women, the level of unsuspected overt disease was low. Finally, the number of individuals in the community with elevated serum TSH levels ( 1 6 mU/L in this study) was substantial (7.5% of the women and 2.8% of the men), suggesting that TSH screening in the community would pick up mostly persons with subclinical hypothyroidism. This implies that TSH screening in an adult population would only be useful if the detection and treatment of subclinical disease could be demonstrated to be cost-effective. An interesting feature of the data from the Whickham survey (not shown in Table 1) is that TSH levels showed a progressive increase with age in women but not in men. The increase was almost entirely seen in women with positive serum antithyroid antibodies. For example, 5.9% of the women aged less than 45 years had an elevated TSH level, whereas 10.4% aged more than 45 years and 17.4% aged more than 75 years had an

Table 1. THE PREVALENCE OF THYROID DYSFUNCTION PER 1000 WHICKHAM SURVEY PARTICIPANTS

Group

Unsuspected Overt Hypothyroidism

Known Overt Hypothyroidism

Total Overt Hypothyroidism

Elevated TSH (TSH > 6 mUIL)

Women Men

3 0

15 1

18 1

75 28

Group

Unsuspected Overt Hyperthyroidism

Known Overt Hyperthyroidism

Total Overt Hyperthyroidism

Undetectable TSH (TSH < 0.5 mUIL)

Women Men

5 0

23 2

28 2

100

-

Data from Tunbridge WMG, Evered DC, Hall R, et at: The spectrum of thyroid disease in a community: The Whickham Survey. Clin Endocrinol 7:481, 1977; with permission.

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increase in serum TSH. Serum TSH levels were undetectable (< 0.5 mU/L) in 10% of the survey population, suggesting that a substantial number of persons in the community may have subclinical hyperthyroidism. However, the TSH assay used in the initial Whickham survey was not sensitive enough to allow an accurate estimate of the true prevalence of very low TSH levels. Subsequent studies employing second- and third-generation TSH assays have estimated the prevalence of subclinical hyperthyroidism to be approximately 1%. Prevalence of Goiter

The prevalence of autoimmune thyroiditis and goiter in the Whickham survey population is shown in Table 2. Again, it is clear that thyroid disease is much more common in women than in men. Overall, 10.3%of all women in the survey had positive antithyroid microsomal antibodies. This rose to 67% of women with an elevated TSH level greater than 6 mU/L, whereas only 8% of women with a normal TSH level had positive antibodies. There was a strong association between positive antithyroid antibody titers and elevated TSH levels in both women and men; 60% of all participants in the survey with an elevated TSH (> 6 mU/L) and 80% of those with a high TSH (> 10 mU/L) had positive antithyroid antibody titers. Goiters were observed in 15.5%of Whickham survey participants, including 8.6% with small goiters and 6.9% with obvious large goiters. There was a much higher prevalence of goiter in women as shown in Table 2; in particular, large goiter showed a 13 to 1 female-to-male prevalence ratio. There was no association between goiter and positive antithyroid antibody titers in men and only a small association in women. The 84.5% of Whickham survey participants without goiter had daily urinary iodine outputs similar to that in the 15.5% with goiter, thus it is unlikely that iodine deficiency explains the difference between the groups. Thyroid nodules were estimated to be present in 5.3% of women and 0.8% of men, but these observations were mentioned only briefly. No details were given about nodule size or their association with goiter. No data were presented on thyroid cancer. Follow-up Survey Approximately 20 years after the original Whickham survey of 2779 representative persons from the adult community, a follow-up survey was conducted from March 1992 to August 1993 to evaluate the incidence and natural history of thyroid disease.I3*The outcome of the follow-up survey can be viewed in Table 2. THE PREVALENCE OF ANTITHYROID ANTIBODIES AND GOITER PER 1000 WHICKHAM SURVEY PARTICIPANTS

Group Women Men

Antithyroid Microsomal Antibodies

Antithyroid Thyroglobulin Antibodies

103

30 9

27

Small Goiter

Large Goiter

121

123

45

9

Small goiters were palpable but not visible, whereas large goiters were both palpable and obvious to inspection. Data from Tunbridge WMG, Evered DC, Hall R, et al: The spectrum of thyroid disease in a community: The Whickham Survey. Clin Endocrinol 7:481, 1977; with permission.

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terms of the survivors and the deceased. Of the original 2779 participants, 1877 (67%) were known to be living at the time of follow-up, 825 (30%) were known to have died, and 77 (3%)were of unknown outcome (52 untraced, 20 emigrated, and 5 did not respond). Of the 1877 living subjects, 1801 (96%) provided direct follow-up information in the study clinic, by home visit, or by questionnaire. Blood samples were obtained from 1704 (91%) of the living subjects. There were 824 death certificates available for the 825 deceased subjects, and, in addition, 530 subjects (64%) had further information available from general practitioner or hospital notes and post-mortem reports. Thus, of the original 2779 survey participants, some type of follow-up information was available on 2625 (95%), whether from direct survey of living subjects or post-mortem records of deceased subjects. Prevalence of Hypothyroidism and Hyperthyroidism

The data in Table 3 describe the prevalence of abnormal thyroid function tests in 1051 female and 826 male survivors from the original Whickham survey including 1704 women and men who gave blood samples for thyroid testing. Once again, the prevalence of overt hypothyroidism and hyperthyroidism in the community is much higher in women than in men by roughly an order of magnitude. As the survey population aged by about 20 years (the median duration of follow-up was 19 years, with a range of 18 to 21 years), there was a marked increase in the prevalence of hypothyroidism in both male and female survivors, whereas the prevalence of hyperthyroidism remained about the same. Similar to the finding in the 2779 subjects in the initial survey, 91 of 1704 (5.3%) of the survivors in the follow-up survey had an elevated TSH level as shown in Table 3. Of these 91 survivors, 31 (1.8%) had a TSH level above 10 mU/L, and 27 (87%) of these subjects were clinically hypothyroid (23 with a low free T, level and 4 with a low-normal free T4level). Most of the 31 survivors with a TSH level above 10 mU/L also had positive antithyroid antibody titers (antimicrosomal or antithyroglobulin antibody titers or both 2 1:lOO). The re-

Table 3. THE PREVALENCE OF THYROID DYSFUNCTION PER 1000 WHICKHAM SURVEY SURVIVORS Group

Overt Hypothyroidism

Women Men

93 13

Group

Overt Hyperthyroidism

Women Men

39 2

Elevated TSH* (> 5.2 rnUIL)

High TSH* (> 10 mUIL)

53

18

Low TSHt (< 0.17 mU/L)

Undetectable TSHt (< 0.01 mUIL)

31

12

'TSH levels were determined in 1704 surviving women and men using a second-generation TSH assay with a normal range of 0.5 to 5.2 mU/L and a lower detection limit of 0.05 mU/L. tTSH levels were determined using a third-generation TSH assay with a normal range of 0.17 to 2.89 mU/L and a lower detection limit of 0.01 mU/L in all patients in whom the TSH level using the second-generation assay was low or undetectable. Data from Vanderpump MPJ, Tunbridge WMG, French JM, et al: The incidence of thyroid disorders in the Community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol 43:55, 1995; with permission.

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maining 60 survivors with slightly elevated TSH levels between 5.2 and 10.0 mU/L had a 68% prevalence of positive antithyroid antibody titers; 8 (13%) of these survivors had a low free T4 estimate. When a highly sensitive thirdgeneration TSH assay was employed, 3.1% of the survivors had a low TSH level below 0.17 mU/L, and 1.2% of the survivors had a TSH level below 0.05 mU/L (the limit of detectability). Of the 52 survivors with a low TSH, approximately 36% were taking levothyroxine, and 10% were newly diagnosed with hyperthyroidism. The remaining 54% would be classified as having subclinical hyperthyroidism, a disorder that can only be detected with a highly sensitive TSH assay. Of course, some of these subjects could be truly euthyroid but in the third standard deviation of normal. Incidence of Hypothyroidism and Hyperthyroidism

Incidence data for hypothyroidism and hyperthyroidism are presented in Table 4. As expected, women had a much higher incidence of both disorders, about four cases of hypothyroidism and one case of hyperthyroidism per 1000 women per year. In contrast, there was only one case of hypothyroidism and no cases of hyperthyroidism per 1000 men per year. From a total of 1051 women survivors, 97 with overt hypothyroidism and 44 with overt hyperthyroidism were identified. Of the 97 women with overt hypothyroidism, 16 were previously known from the first survey, 59 were subjects in whom hypothyroidism developed since the first survey, and 22 were unsuspected cases discovered during the follow-up survey. Thus, 81 cases of new overt hypothyroidism developed during the 19-year median follow-up period after the first survey, resulting in an incidence of 81 per 1.051 per 19 or 4.1 cases per 1000 women survivors per year. Of these 81 cases of new overt hypothyroidism, 69 occurred spontaneously and 12 resulted from the treatment of hyperthyroidism, giving an incidence of spontaneous hypothyroidism of 69 per 1.051 per 19 or 3.5 cases per 1000 survivors per year. In this way, all of the data in Table 4 have been calculated. The incidence of spontaneous hypothyroidism showed a dramatic increase with age in women. The probability that overt hypothyroidism would develop in a woman increased from 1.4 per 1000 per year at ages 20 to 25 years to 14 per 1000 per year at ages 75 to 80 years, an order of magnitude change in risk. The risk of hyperthyroidism developing in women did not change with age and remained at about 1 case per 1000 women per year across the entire adult age range. Among the men, overt hypothyroidism developed in 10 of 826

Table 4. INCIDENCE OF HYPOTHYROIDISM AND HYPERTHYROIDISM PER 1000 SUBJECTS PER YEAR DURING WHICKHAM SURVEY FOLLOW-UP ~~~~~~~~~~~~~~~~~~~

Group

Women Men

Overt Hypothyroidism in the Survivors

Overt Hypothyroidism in the Deceased

4.1

3.6 0.8

0.6

Overt Hyperthyroidism in the Survivors

Overt Hyperthyroidism in the Deceased

0.8

1.2 0

0

The incidence of thyroid disease is calculated as the number of new cases discovered since the initial survey per 1000 subjects divided by the mean duration of follow-up (19 years for the survivors and 10 years for the deceased). Data from Vanderpump MPJ, Tunbridge WMG, French JM, et al: The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol4355, 1995; with permission.

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Table 5. PERCENTAGE OF SURVIVORS WITH OR WITHOUT A PALPABLE GOITER AT THE TIME OF THE INITIAL AND FOLLOW-UP WHICKHAM SURVEYS

No Goiter at Second Survey

Goiter Present at Second Survey

Women (n = 892) No goiter at first survey Goiter present at first survey

70% 20%

4%

Men (n = 722) No goiter at first survey Goiter present at first survey

93% 5%

2% 0%

Group

6%

Data from Vanderpump MPJ, Tunbridge WMG, French JM, et al: The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol 43:55, 1995; with permission.

survivors and overt hyperthyroidism in one survivor during the 19-year followup period, leading to incidence estimates of 10 per 0.826 per 19 or 0.6 and 1 per 0.826 per 19 or 0.06, respectively. Natural History of Goiter

As is true for hypothyroidism and hyperthyroidism, goiter is much more prevalent in women than men. As demonstrated in Table 5, 93% of 722 male survivors and 70% of 892 female survivors had no palpable goiters in the first and second surveys. Twenty percent of the women and 5%of the men who had goiters in the initial survey had no goiter in the follow-up survey, whereas only 4% of the women and none of the men acquired a goiter between the two surveys. Thus, the natural history of goiter is to disappear over time. Of the 182 women (80%) who lost a goiter following the first survey, 100 had small goiters and 82 larger goiters; nine of the women lost the goiter following the treatment of hyperthyroidism. There was no significant association between the presence of goiter in the follow-up survey and initial or follow-up serum TSH levels in women or men, but there was a significant association between goiter at the initial survey and serum antithyroid antibody titers at the initial and follow-up surveys for woman. Risk Factors for Hypothyroidism

Because the incidence and prevalence of unsuspected spontaneous hypothyroidism in the general community are low in women and rare in men, a search for this disorder in the community may not be cost-effective. However, if risk factors associated with an increased incidence of disease could be identified, clinicians could be alerted to this possibility by evaluating such factors. Table 6 presents data on the development of spontaneous hypothyroidism in female survivors by the time of the second survey in whom no or a minor degree of thyroid failure was present at the time of the initial survey. Whereas the incidence of hypothyroidism is low in women with a normal TSH level and negative antithyroid antibodies (4% in 20 years), it rises dramatically to 55% in women with an elevated TSH level and positive antibodies. The presence of either an increased TSH level or positive antibodies alone confers an increased risk of about eightfold. If the probability of hypothyroidism developing in female

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Table 6. PERCENTAGE OF FEMALE SURVIVORS IN WHOM SPONTANEOUS HYPOTHYROIDISM DEVELOPED OVER 20 YEARS IN THE FOLLOW-UP WHICKHAM SURVEY Initial TSH Level

Normal Elevated

Initial Antithyroid Antibodies Negative

Initial Antithyroid Antibodies Positive

4%

27%

33%

55%

Data from Vanderpump MPJ, Tunbridge WMG, French JM, et al: The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol 4355, 1995; with permission.

survivors is plotted against the serum TSH level measured at the time of the initial survey, an interesting curve results. The probability of hypothyroidism is nearly flat at approximately 0.1% per year for TSH levels in the low-normal range from 0.5 to 2 mU/L and then bends sharply upward on a logarithmic scale so that at a TSH of 5 mU/L the probability of hypothyroidism is 0.5% per year and at 10 mU/L, as much as 2.5% per year. Thus, there is increased risk of hypothyroidism even when the TSH level is in the high-normal range of 2 to 5 mU/L and, as the TSH level increases linearly above 2 mU/L, there is an exponential increase in the probability of hypothyroidism. Men demonstrate an increased risk of hypothyroidism with elevation of the serum TSH level and positive antithyroid antibodies that is even more pronounced than the increased risk in women. Summary of the Whickham Survey

Beginning in 1972 and ending approximately 20 years later in 1993, the Whickham survey has firmly established certain epidemiologic characteristics of thyroid disease in a sizeable northern European community.12*,132 The prevalences of elevated TSH levels, overt hypothyroidism, overt hyperthyroidism, and elevated antithyroid antibody titers are much higher in women than in men. This observation is of considerable importance for the planning of programs to screen for thyroid disease in the community. The incidence of spontaneous hypothyroidism in women is low at 3.5 cases per 1000 subjects per year and, in men, is much lower at 0.6 cases per 1000 subjects per year. The incidence of hyperthyroidism is very low in women at 0.8 per 1000 per year and undetectable in men (none of 826 male survivors surveyed over 20 years had a new case of hyperthyroidism). Goiters are common in women, uncommon in men, and tend to disappear over time. The risk for hypothyroidism is increased substantially when the serum TSH level is elevated and serum antithyroid antibodies are positive, either alone or together. Importantly, the survey demonstrated that as the serum TSH level rises above 2 mU/L, there is a sharp increase in the probability of hypothyroidism independent of age or antithyroid antibody status. OTHER SURVEYS Prevalence of Hypothyroidism and Hyperthyroidism

Since the publication of the results of the initial Whickham survey in 1977, numerous studies of the prevalence of thyroid dysfunction in the community

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and in the clinic have been reported. Studies that have reported the prevalence of unsuspected overt hypothyroidism and hyperthyroidism in women and in which sampling has been representative of the general community or a general outpatient clinic setting are presented in Table 7. Only studies enrolling more than 1000 subjects are included. Most of the studies were conducted in Sweden, Japan, and the United States. These three countries represent very different patient populations. Seven of the twelve studies in Table 7 include women aged 18 years and over, whereas the other five studies include women aged more than 40 years. All of the reports except for three estimate the prevalence of unsuspected overt hypothyroidism in women to be 0.6% or less, similar to the Whickham survey; all of the reports except for two estimate the prevalence of unsuspected overt hyperthyroidism to be the same, 0.6% or less. Not included in Table 7 are prevalence estimates for men which, similar to estimates in the Whickham survey, are generally much lower than in women. The data in Table 7 suggest that older women may have a higher prevalence of overt thyroid disease. The highest rates reported were 1.9% for overt hyperthyroidism" and 1.3% for overt hypothyroidism,gOboth in populations of Swedish women in the higher age range. In a study from the United States, adult women aged more than 18 years had a prevalence of unsuspected overt thyroid disease of 1.1%, whereas in the same study women aged more than 40 years had a prevalence of 1.7%. The prevalence of thyroid disease has been studied in many different Io6, Iz6 acute hospital medical clinical settings, including geriatric 44, 114 and psychiatric wards,Z3,6b, 'IR and in postpartum women.3,41, 52, sfl, 67 These are very specialized settings associated with an increased frequency of abnormal thyroid tests, thyroid dysfunction, or both and, consequently, are not relevant to an inquiry into the prevalence of thyroid disease in the general community. However, alertness for the presence of thyroid disease in these settings is warranted, and some investigators advocate screening the elderly'"h,IZ4 and postpartum womenlZ4for thyroid dysfunction. Prevalence of Abnormal TSH Levels The original Whickham survey demonstrated that a substantial number of men and women had elevated serum TSH levels.12xIn the adult population as a whole, 2.8% of men and 7.5% of women had TSH levels above normal (6 mU/ L) using a first-generation TSH assay. Older women (but not older men) had an even higher prevalence, 10.4% for women aged more than 45 years and 17.5"/0 for women aged more than 75 years. Since the initial Whickham survey, a large number of studies including the follow-up to the Whickham survey132have measured serum TSH in the community employing second- and third-generation TSH assays. These studies from many different countries are summarized in Tables 8 and 9. In the studies listed in Table 8, as much as 5.7% of men and 13.6% of women in the community demonstrated an elevated level of serum TSH, corroborating the observations of the initial Whickham survey. Overall, there is a 1.3% to 10.3% prevalence of TSH levels above normal in the community. Furthermore, older women show a higher prevalence of elevated TSH levels, ranging from 11.6% to 13.6% in women older than 60 years, similar to the findings in the Whickham survey. A substantial number of men and women in the community have low serum TSH levels as shown in Table 9. The prevalence of TSH levels below the normal range is only slightly higher in women than in men, and the overall

1977 1978 1980 1981 1983 1984 1985 1986 1988 1989 1991 1993

Tunbridge Baldwin Remedios Kugedal Fa1kenberg Nystrornt Nolan Fukazawa Eggertsen 0kamura Petersen Konno

Japan Sweden Japan Sweden Japan

us

Sweden Sweden Sweden

us us

UK

Location

Community Clinic Clinic Community Community Community Clinic Clinic Clinic Community Community Clinic 2779 1554 2704 3885 1442 1283 5002 1114 2000 2421 1154 1179

Number of Subjects

+

18+ 18+ 18+ 39-60 60 44-66 18+ 18+ 18+ 40 + 50-72 18+

Age of Subjects (years)

3 5 6 6 6 0 5 5 12 6 13 9

Prevalence of Hypothyroidism

5 8 5 6 19 6 2 2 5 2 2 5

Prevalence of Hyperthyroidism

*Screening in the community means evaluating a group of subjects for thyroid disease who are representative of the community as a whole. Screening in the clinic is primarily case-finding, that is, evaluating patients for thyroid disease who are enrolled in a health plan or who are seen in an outpatient clinic for other medical reasons. tSee also Nystrom 1981.84

Year

Study

Screening Population*

Table 7. PREVALENCE OF UNSUSPECTED OVERT HYPOTHYROIDISM AND HYPERTHYROIDISM PER 1000 WOMEN IN THE COMMUNITY OR CLINIC

Year

1977 1985 1988 1989 1990 1991 1991 1993 1995 1995

Study

Tunbridge Sawin Eggertsen Okarnura Bagchi Parle Sundbeck Konno Manciet Vanderpump

Great Britain Sweden Japan France Great Britain

us

Sweden Japan

us

Great Britain

Country 2779 2139 2000 2421 968 1193 844 4111 420 1704

Number of Subjects

+ +

+ + + +

18+ 60 18+ 40 55 60 85 25 + 65 40

Age of Subjects (YW

Table 8. PREVALENCE OF ELEVATED TSH LEVELS IN THE COMMUNITY

-

-

3.0

-

6.2 8.5 11.6

-

0.7

3.6 4.4 3.0

7.5 13.6

5.3 10.3 5.8 5.0 7.3 7.9 6.5 1.3 5.7 5.3

(“4

(”/.I

(W 2.8 5.7

Total with Elevated TSH

Elevated TSH in Women

Elevated TSH in Men

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WANG & CRAPO

Table 9. PREVALENCE OF LOW TSH LEVELS IN THE COMMUNITY

Study

Year

Number of Subjects

Eggertsen Okarnura Bagchi Parle Sawin Sundbeck Konno Manciet Vanderpump

1988 1989 1990 1991 1991 1991 1993 1995 1995

2000 242 1 968 1193 2575 844 4111 420 1704

Age of Subjects (yrs) 18+ 40 55 60 60 + 85 25 + 65 + 40 +

+ + +

Low TSH in Men

Low TSH in Women

(“/I

(%I

-

-

2.2 5.5

4.4 6.3

-

-

0.5

0.9

-

-

Total With Low TSH (%.) 3.7 5.0 3.8 6.0 3.9 2.2 0.6 4.1 4.3

prevalence ranges from 0.6% to 6.0%. It is instructive to evaluate in closer detail those studies in which the TSH assays employed could distinguish undetectable TSH levels (generally below 0.1 mU/L) from low but detectable TSH levels (generally below 0.4 or 0.5 mU/L) and also to evaluate the characteristics of the subjects with regard to their free T, estimates and whether they were taking thyroxine. 73 of 1704 survivors (4.3%) had a low In the follow-up Whickham serum TSH level less than 0.5 mU/L using a second-generation TSH assay with a detection limit of 0.05 mU/L, a coefficient of variation (CV) of 9% at 0.6 mU/ L, and a normal range of 0.5 to 5.2 mU/L. When these 73 subjects were further analyzed by employing a third-generation TSH assay with a detection limit of 0.01 mU/L, a CV of 10% at 0.08 mU/L, and a normal range of 0.17 to 2.89 mU/ L, 21 (29%) subjects were determined to actually have a normal TSH level. A total of 31 (42%) had a low but detectable TSH level ( 2 0.01 < 0.17 mU/L), including a patient with unsuspected overt hyperthyroidism, and 21 (29%) had an undetectable TSH level (< 0.01 mU/L), including four patients with newly diagnosed hyperthyroidism and approximately seven patients taking thyroxine. Thus, 21 of the 73 subjects with a low TSH by a second-generation assay had an undetectable TSH by a third-generation assay. Of these 21 subjects, 17 had a normal free T4 and total T, level with no chemical evidence of overt hyperthyroidism and therefore would be good candidates for the diagnosis of subclinical hyperthyroidism with a prevalence of 17 per 1704 x 100 or 1.0%. Nearly half of the patients with subclinical hyperthyroidism in the community were taking thyroxine. Those not taking thyroxine had a prevalence of spontaneous subclinical hyperthyroidism of 10 per 1704 X 100 or 0.60%. Nearly 30% of the 73 subjects with a low TSH level initially had a normal TSH on a subsequent assay, suggesting that transient decreases in TSH are common. only 25 of 4110 (0.16%) subjects surveyed had a low In another TSH assay with a detection limit of 0.08 mU/L and a CV of 11% at 0.36 mU/L. However, 14 of these subjects had an elevated serum free T4 estimate, leaving 11 of 4110 subjects as candidates for unsuspected subclinical hyperthyroidism or a prevalence of 11 per 4110 X 100 or 0.27%. Several other studies have shown comparable prevalence rates for spontaneous subclinical hyperthyroidism when the disorder is defined as a clinically euthyroid state in subjects not taking thyroxine, with an undetectable TSH level and normal levels of free T, and total T3. These prevalence rates are 13 per 1193 X 100 or 1.09Y0,6~ 8 per 968 X 100 or 0.83%: and 6 per 886 X 100 or Q.68’/0.’~*

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Thus, the prevalence of subclinical hyperthyroidism ranges from 0.3'x to 1.O%, roughly an order of magnitude less than the prevalence of subclinical hypothyroidism, which is characterized by a clinically euthyroid state in patients with an elevated TSH level and normal free T, estimate. Subjects with slightly low but not undetectable TSH levels and who have no evidence of thyroid disease are difficult to classify, Some are simply in the third standard deviation of the normal range, some have transient decreases, and others may have nonthyroidal illness or may be receiving medications that suppress TSH. Of 73 subjects surveyed by Vanderpump and c o - w o r k e r ~ only , ~ ~ ~1 had a low but detectable TSH level and was overtly hyperthyroid. Thus, low TSH levels are common in the community, undetectable TSH levels are less common, and subclinical hyperthyroidism is uncommon with a prevalence of less than 1%.In contrast, subclinical hypothyroidism is a common disorder present in approximately 5% of the adult population and 10% to 20% of elderly women. If the data in Tables 8 and 9 are combined, approximately 10%of all subjects in the community aged more than 40 years will have an abnormal TSH level, and the vast majority of these individuals will be clinically euthyroid.

Incidence of Hypothyroidism and Hyperthyroidism

In a longitudinal study of 320 women aged 70 to 79 years,'23the incidence of spontaneous hypothyroidism was 2.4 per 1000 women per year, similar to the incidence of 3.5 obtained in the follow-up Whickham survey of women survivors. Numerous studies have estimated the incidence of hyperthyroidism in women and men in the entire adult community. The results of these studies, including the follow-up Whickham survey,'32are presented in Table 10. Four of the studies give surprisingly similar incidence results of 0.36 to 0.47 per 1000 women per year and 0.087 to 0.101 per 1000 men per year, comparable with the findings in the Whickham survey. One study from South Africa gives very low incidence estimates of 0.09 for women and 0.007 for men.m This study in blacks from the Johannesburg area suggests that African blacks may have a much lower incidence of hyperthyroidism than among European whites. The data in Table 10 also demonstrate that the incidence of hyperthyroidism is greater in women than in men by a factor of 4 to 13.

Table 10. INCIDENCE OF HYPERTHYROIDISM PER 1000 WOMEN OR M E N PER YEAR Study

Year

Country

Morgensen Barker Haraldsson Kalk Berglund Vanderpump

1980 1984 1985 1989 1990 1995

Denmark Great Britain Iceland South Africa Sweden Great Britain

Female Overt Hyperthyroidism

Male Overt Hyperthyroidism

0.47 0.36 0.38 0.09

0.087 0.092 0.089

0.41

0.007 0.101

0.80

<0.100

The Progression of Autoimmune Thyroid Disease

The follow-up Whickham survey showed that women with an initially elevated serum TSH level or a positive antithyroid antibody titer or both had a high incidence of subsequent overt hypothyroidism as presented in Table 6. Several other studies have supported this observation. In 1981 Gordin and Lamberg46reported that 22 euthyroid women with an initial high titer of antithyroid antibodies demonstrated an annual progression to overt hypothyroidism of 7.5'10. In 1987 Rosenthal and co-workerslOO reported that 13% of 258 euthyroid subjects aged more than 60 years had an elevated TSH. Over the course of 4 years, overt hypothyroidism developed in 33% of those with an initially elevated TSH level and in 80% of those who had both an initially elevated TSH and a high titer of antithyroid microsomal antibodies. Geul and colleagues42published a study in 1993 in which 423 women aged 40 to 60 years were randomly selected from a population survey in the city of Zoetermeer, the Netherlands. Serum samples for TSH and thyroid microsomal antibodies were obtained initially and then again after 10 years from all of the women. The results of this study are summarized in Table 11, which is analogous in structure to Table 6 listing data from the Whickham survey. Two important observations presented in Table 11 confirm results from the followup Whickham survey. First, serum thyroid microsomal antibody is predictive of thyroid failure with an annual incidence of 5.8% in subjects with an initial TSH level in the upper-normal range (2.0 to 4.2 mU/L). Second, serum TSH is also predictive of thyroid failure. Only 2 of 317 women (0.6%) with a low-normal TSH level (0.2 to 2.0 mU/L) and negative thyroid microsomal antibody titer at the outset of the study demonstrated an elevated TSH level (>4.2 mU/L) 10 years later, whereas 8 of 26 women (30.8%) with a high-normal TSH level (2.0 to 4.2 mU/L) and negative thyroid microsomal antibody titer ultimately had an elevated TSH level. Thus, studies from Great Britain ( W h i ~ k h a m )and ' ~ ~the Netherlands (Zoete ~ m e e r ) independently ~* confirm that initial serum TSH levels and antithyroid antibody titers are both predictive of minor and major degrees of subsequent thyroid gland failure. These observations, and the observation by many investigators that the prevalence of elevated TSH levels in older women is high, lead ultimately to the question of whether screening for thyroid disease should be performed in adult women in the community.

Table 11. PERCENTAGE OF FEMALES ( n AFTER 10 YEARS

=

423) WITH AN ELEVATED TSH LEVEL

Initial TSH Level

Initial TMA' Negative ( n = 375)

Initial TMAt Positive ( n = 48)

<2.0mU/L 2.0-4.2 mU/L >4.2 mU/L

0.6 30.8 33.3

8.0 58.3 90.9

'TMA is the serum thyroid rnicrosornal antibody titer. tThe TSH assay used in this study is a second-generation IRMA assay with a normal range of 0.2 to 4.2 mU/L. Data from Geul KW, van Sluisveld KL, Grobbee DE, et al: The importance of thyroid rnicrosomal antibodies in the development of elevated serum TSH in middle-aged women: Associations with serum lipids. Clin Endocrinol 39:275, 1993; with permission.

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THYROID NODULES

Thyroid nodules are commonly seen in the general population. The prevalence of this disorder depends on the modality of screening and the population being evaluated. Individuals who receive head and neck irradiation at a young age have a higher than average rate of thyroid nodules.'h Age and gender are also important factors in the prevalence of nodules. Previous studies have addressed the management of thyroid nodules once they are detected.lh,72-74. y8, 134,139 The following sections in this article evaluate data on the prevalence and incidence of thyroid nodules in unselected populations with respect to different diagnostic methods. The prevalence and incidence of thyroid cancer are discussed along with the mortality rate to determine the risk for thyroid cancer. Prevalence of Thyroid Nodules by Palpation

Physical examination of the thyroid by palpation is the easiest and least expensive modality. To evaluate the prevalence of thyroid nodules by this method of detection, we reviewed studies from nonendemic goiter areas and unselected populations. The prevalence of thyroid nodules detected by palpation ranges from 4.7 to 51 per 1000 subjects in adults and from 2.2 to 14 per 1000 subjects in children (Table 12).12,7n, 93, lZ7,Iz8, I3l Other studies with smaller sample sizes or some selection bias report prevalences ranging from 13 to 210 per 1000 persons.22,3z,76,79 The two studies that give the best estimate of the prevalence of thyroid nodules by palpation in the general population are described in the reports by V a n d e ~ '131 ~ ~and , Tunbridgelz8and their colleagues. Vander's group conducted an investigation of the thyroid using subjects enrolled in the FramingTable 12. PREVALENCE OF THYROID NODULES PER 1000 SUBJECTS IN THE COMMUNITY YearIMethod of Detection Palpation 1965 1968 1975 1975 1977 1991 Ultrasound 1985 1991 1994 Autopsy* 1932 1935 1938 1954 1955 1965

Subjects

Prevalence

Matovinovic Vander Rallison Trowbridge Tunbridge Brander

8641 5127 2271 7785 2979 253

4.7 42.0 15.0 32.0 51.O

England Finland

0-70 30-59 11-18 9-1 6 18-75 19-50

Woestyn Brander Bruneton

300 253 1000

190.0 273.0 347.0

Belgium Finland France

0-90 19-50 Adults

Rice Hellwig Schlesinger Hull Mortensen Oertel

390 100 1373 221 821 137

570.0 513.0 82.0 646.0 495.5 130.0

us us us us us us

11-75 5-85 0-89 20-1 00 0-99 18-39

2.2

Country

Ages (yrs)

Investigator

us us us us

'Autopsy series report all nodules seen by microscopic examination except for the study by Schlesinger who reports only nodules 1 cm in size or larger.

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ham study, an epidemiologic survey of cardiovascular disease begun in 1948. At that time, Framingham was a community of 28,000 located in Massachusetts. A random sample of 6507 individuals between the ages of 30 and 59 years was drawn. Of these, 4469 (69%) participated. An additional 740 volunteers outside of the sample but with similar characteristics were also recruited. Individuals with known coronary heart disease were excluded, bringing the total number of subjects in the study to 5127. This group of subjects was an unbiased representation of the population in this community with respect to the age range studied and serves as one of the few population-based studies available. Each of the subjects in the Framingham study underwent a complete history and physical examination including a thyroid evaluation for nodules. The majority of subjects had at least two evaluations of the thyroid. A total of 218 individuals had evidence of thyroid nodules which provided an overall prevalence of 42 per 1000 persons in this population. Tunbridge and co-workers128likewise investigated a randomly sampled population in Whickham, England of 2779 subjects and found a prevalence of 32 per 1000. In a community study performed in Michigan, M a t o v i n o v i ~noted ~~ a prevalence of 4.7 per 1000. The variation in these studies may be related to differences in the populations being studied, in the thoroughness of the examinations, or in the sensitivity of detecting thyroid nodules by palpation. More recently, Ezzat and c o - w o r k e r ~studied ~~ 100 normal healthy volunteers; 21% of subjects had palpable nodules. This high percentage was most likely the result of having a greater proportion of female subjects in the study and an increased prevalence of antithyroid microsomal antibodies among the participants in comparison with other studies. The prevalence of nodules increases with age, and women generally have a higher prevalence than men.94,I3O In the Whickham survey, the prevalence of thyroid nodules increased from 2% in the second decade to 5% in the seventh decade.lz8Single thyroid nodules are palpated more often than are multiple nodules in some studies, whereas in other studies the opposite is true.z2,30,32, 70, 7(r Investigations performed in other countries report similar prevalences.22A Finnish study with a randomly selected population noted a prevalence of palpable thyroid nodules of 51 per 1000.12 Palpation is not a good method to distinguish benign from malignant nodules. A palpable thyroid nodule represents a wide spectrum of pathology, including cysts, adenomas, colloid nodules, or malignant growths. Although nodules that are single, firm, and enlarging tend to have a higher probability of malignancy, this is not always the case. Many single nodules on palpation are multiple on ultrasound or at surgery.74Data are limited on the natural history of nodules detected by routine palpation, thus their clinical significance is unclear. Prevalence of Thyroid Nodules by Imaging Imaging of thyroid nodules can be performed by several different modalities, including radionuclide scan, MR imaging, CT scan, and ultrasound. Radionuclide scanning offers some functional information but is not as sensitive or specific as the other modalities?’, 50, ‘I7 Most cold nodules on scans are benign, and, as a consequence, scans cannot distinguish effectively between benign and malignant MR imaging and CT are both excellent in detecting thyroid nodules but have about the same or slightly lower sensitivity associated with u l t r a ~ o u n d .83, ~~, 120 They are useful in the evaluation of substernal or retrosternal thyroid masses and regional or distant metastasis. Given the higher

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cost of MR imaging and CT and the ease of performing ultrasound, ultrasound is the modality of choice for evaluating thyroid nodules. Ultrasound classifies nodules as solid, cystic, or mixed. High-resolution ultrasound can detect nodules as small as 1 mm. Several ultrasound investigations in nonendemic goiter populations have estimated the prevalence of thyroid nodules in the general population. The prevalence estimates from the three best studies range from 190 to 347 per 1000 subjects (Table 12).12,Is, 14" The study by Brander and co-workers,'2 reporting a prevalence of 27.3%, is the one in which patients were randomly selected from a general community. Other studies with smaller sample sizes or selection biases report prevalence estimates ranging from 134 to 670 per 1000.19,32,ss~7h The overall prevalence obtained by pooling data from all of these studies is 280 per 1000.'y As in the palpation studies, the prevalence of nodules by ultrasound was higher in women than in men and increased with age.12, ly, 32, 76, 14" The range of prevalence in men was 79 to 195 per 1000 and in females, 206 to 720 per 1000. Both BranderI2and W~etsyn'~" found a significant rise in prevalence starting at around age 30 years in women, whereas Bruneton and co-workersIs noted that patients aged less than 50 years had a prevalence of 250 per 1000 in comparison with those aged more than 50 years for whom the prevalence was 420 per 1000. From this information, it is clear that thyroid nodules detected by ultrasound are prevalent in the general population, particularly in women aged more than 30 years. However, the significance of these findings is unclear. Most thyroid nodules are benign when discovered routinely, and the term thyroid incidentalorna is befitting.32Ultrasound cannot distinguish between benign and malignant nodules definitively," h2, 9s, 134 thus it has a high sensitivity in picking up thyroid nodules but a low specificity. Prevalence of Thyroid Nodules on Autopsy

Autopsy data provide the gold standard for determining the true prevalence of thyroid nodules. Several autopsy studies have been performed in nonendemic and endemic areas of goiter. The prevalence of thyroid nodules in these studies s6, 79, 86, 97, lnR The variability ranges from 82 to 650 per 1000 autopsies (Table 12).54, of the rates may be a result in part, of the thoroughness of the examinations. Mortensen and c o - ~ o r k e r ssystematically ~~ studied 821 thyroid glands during routine consecutive autopsies at the Mayo Clinic in patients with no previous history of thyroid disease. Each of the glands was sectioned into slices 2-cm thick and then evaluated for macroscopic lesions. The prevalence from this study was 495 per 1000. Schlesinger and co-workersIoRevaluated autopsy specimens from three teaching hospitals in the Boston area and noted a prevalence of 82 per 1000. They only tallied nodules measuring 1 cm or greater and thus may have underestimated the true prevalence. The studies by Ricey7and HulP were performed in goitrous areas, which may explain the higher prevalence estimates. OerteP performed autopsies on men in the military who died unexpectedly between the ages of 18 and 39 years. The prevalence rate of thyroid nodules in these previously healthy men was 130 per 1000. As in the palpation and ultrasound studies, autopsy studies reveal a higher prevalence of thyroid nodules in women than in men and an increased prevalence with age. The increased prevalence in the Mortensen began between the ages of 30 and 39 years and in the Schlesinger study'DRbetween 40 and 49 years. The prevalence by palpation of thyroid nodules in the general population

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is approximately 3% to 5%. By ultrasound, the prevalence increases to approximately 30% to 40%. Autopsies provide prevalence estimates of 40% to 50%. Thus, depending on the modality of screening, different prevalence estimates are observed. Incidence of Thyroid Nodules by Palpation

There is little information regarding the incidence rate of thyroid nodules. The best information comes from the Framingham study by Vander and cow o r k e r ~ in ' ~ which ~ subjects initially free of thyroid nodules by physical examination were followed up approximately every 2 years for 15 years. In the original cohort, 4909 subjects were without evidence of thyroid nodules. New nodules developed in 67 of these 4909 subjects, providing an annual incidence rate of 0.09%. Women had an incidence rate of 0.11% and men a rate of 0.06%. The number lost to follow-up was 0.4%, making the likelihood of a bias small. From the Framingham study we may infer that the occurrence of new thyroid nodules in the group aged 30 to 59 years is rare. Rallison and c o - ~ o r k e r evaluated s~~ school-aged children from 1965 to 1968 and noted a yearly incidence rate of 0.07% to 0.2%. Maxon and colleagues71 pooled prevalence data from five studies and fitted a linear regression line from which an annual incidence rate for thyroid nodules of 0.08% was estimated. The prevalence rate of thyroid nodules is much higher than the incidence rate, suggesting that thyroid nodules once formed tend to remain present for long periods of time. In support of this is the finding that 74% of the thyroid nodules present initially in the Framingham study remained unchanged at 15 years. Other investigators have suggested that thyroid nodules may be under constant ~hange.9~ Although the true incidence rate of thyroid nodules is unknown, it is clear that palpation is a relatively insensitive method for detecting thyroid nodules, and that the incidence rate would be higher if ultrasound were used. However, there are no reported incidence studies on thyroid nodules in the community by ultrasound. THYROID CANCER Prevalence of Occult Thyroid Cancer From Autopsies

Occult thyroid cancer was originally defined by Woolner and colleagues141 as any tumor less than or equal to 1.5 cm in diameter. Currently, it is defined as any inapparent tumor found on a specimen by a p a t h o l o g i ~ tThe . ~ ~ majority of these are papillary carcinomas. A series of nine autopsy studies performed in the United States revealed a mean prevalence of 36 per 1000 among 3744 cases with a range between 4.5 and 130 per 1000 (Table 13). In each of these studies, 1- to 3-mm slices of thyroid were evaluated for the presence of microscopic thyroid malignancies. Other autopsy studies evaluating the thyroid gland by a routine protocol have generated lower prevalence rates ranging from 0 to 4.4 per 1000.108In 5636 consecutive autopsies performed at Memorial Hospital in New York, a prevalence rate of 6 per 1000 was found. In that study, the peak prevalence in women occurred at 20 to 29 years of age and in men at 30 to 39 years of age.'09 In other studies the peak prevalence was between 51 and 60 years of age.'3,38, 78, 7y, jo2, There was no increase in the prevalence with age as seen with incidence rates.3*,1w Sampson102noted a similar finding in adults and

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Table 13. PREVALENCE OF OCCULT THYROID CARCINOMA IN THE UNITED STATES PER 1000 AUTOPSIES Investigator

Year

Hazard Mortensen Queen Hull Brierre Silverberg Farooki Sampson Nishyama Total

1952 1954 1954 1955 1964 1966 1969 1973 1977

Number of Cases

Prevalence

("/.I

Location of Study

429

9 28 16 14 40 27 5 57 130

Cleveland, OH Rochester, MN Portland, OR Denver, CO Bethesda, MD New Haven, CT Philadelphia, PA Olmstead County, M N Ann Arbor, MI

1000

1217 22 1 100 300 220 157 100 3744

36 (mean)

suggested that some of the tumors seem to involute. The data for individuals less than 40 years of age are scarce. In a study of men aged 15 to 39 years by Oertel and KlinckFh a prevalence of 7 per 1000 was noted. In other countries in which the subjects are without prior exposure to ionizing irradiation, the prevalence by autopsy ranges from 45 to 356 per 1000.72A study in Japan of 408 autopsies noted a prevalence rate of 113 per 1000 with no significant difference by age.142In contrast to the increased incidence of clinically apparent thyroid cancer in women compared with men, there seems to be little difference by gender among occult cancers.38, One of the difficulties in determining the natural history of thyroid nodules and thyroid cancer is that not all thyroid cancers arise from thyroid adenomas. Some investigators believe that most thyroid carcinomas arise de novo.25,56 However, Silverberg"* noted that five of eight carcinomas discovered at autopsy may have arisen from an adenoma. Warren has shown experimentally that adenomas can be transformed into carcinomas.137 Schlesinger1"8 noted an overall prevalence of thyroid cancer of 0.4%, but 4.5% of the nodular thyroid glands were carcinomatous. In a series of 821 clinically normal glands, Mortensen and c o - w o r k e r ~reported ~~ a prevalence of occult thyroid carcinoma of 2.1%. When only the nodular glands were included, the prevalence increased to 4.270.~'Thus, some thyroid nodules may begin as low-grade malignancies and grow to nodular size, whereas others are adenomas that transform into carcinomas. The correlation between the prevalence of occult thyroid cancer and mortality is poor. Many countries, most notably Japan, have a high prevalence but a low mortality rate of thyroid cancer, whereas other countries have both low prevalence and mortality.102The stable prevalence of occult thyroid cancers suggests that most tumors originate early in life and remain quiet, or that there is constant turnover of tumors with ongoing development of new ones and death of old ones during adult life.3s Franssila and H a r a ~ hsuggest ~~ that the first hypothesis is true on the basis of an increasing tumor size after young adulthood. The prevalence of occult thyroid cancers in the majority of studies indicates a difference of two logarithms in comparison with clinical thyroid cancer incidence rates. Thus, although the prevalence of occult thyroid carcinoma is high, the majority of these tumors never become clinically apparent. The factors that induce these carcinomas to become clinically apparent are unclear.

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Prevalence of Thyroid Cancer in Thyroid Nodules Among Surgical Series

The prevalence of thyroid cancer in patients with thyroid nodules who are referred to surgery ranges from 5% to 24%.14,21, 22, 75, 141 This variation in frequency is a result of differences in the pretest probability of cancer determined by the referring physician or the referral center. In a study of 296 patients, Sokal”6 noted that those patients clinically selected for minimal or more extensive surgery had a higher prevalence of thyroid malignancy than those who were just observed. In a study of 712 patients in Boston, attributed an increased prevalence of malignancy from 9% to 19% between 1948 and 1972 to more careful selection of patients using 1-131 scanning and thyroid function tests. With the use of fine-needle aspiration (FNA), the frequency of thyroid cancer in one surgical study approached 5oY0.~ Lever and co-workersa reviewed a series of 14 studies on patients with hyperparathyroidism who underwent parathyroidectomy and found a prevalence of thyroid cancer that ranged from 1%to 15%, with a mean of 6.3%. Caruso and MazzaferriZoreviewed ten studies to evaluate the frequency of thyroid cancer in FNAs among patients referred for surgery. The prevalence of malignancy by FNA in more than 9119 patients was 4%, with a range of 0% to 18%. If we include the suspicious FNAs and assume that approximately 10% to 30% of nodules excised with a suspicious FNA are malignant, the overall prevalence ranges from 5% to 7%.” Giuffrida and Gharib43combined a series of FNA studies from the Mayo Medical Center and the University of Catania in Italy involving a total of 16,576 cases and calculated a prevalence of malignancy by FNA of 4%. Belfiore and co-workers9 studied 5637 cold thyroid nodules by FNA and discovered a prevalence of 4.6%. The cancer prevalence was higher in men than in women by twofold. The risk of malignancy was lowest in the fourth decade and higher before age 30 years or after age 60 years. Unlike previous studies, the prevalence of thyroid cancer was similar among patients with solitary nodules when compared with those with multiple nodule^.^, 98 In children, the prevalence of thyroid cancer in thyroid nodules ranges from ~~ 2% to 50%.50,93 In a surgical series of 35 children, Hung and c o - w ~ r k e r snoted a 14% prevalence of carcinoma. A recent study by Raab and colleagues9*using FNA in 66 patients aged 1 to 18 years reported an 18% incidence rate of malignancy in thyroid nodules. In each of these investigations, there is most likely a bias toward the selection of cases with thyroid cancer. Thus, rates probably overestimate the prevalence of thyroid cancer in thyroid nodules in the general population. Incidence of Clinical Thyroid Cancer

Clinical thyroid cancer accounts for 1%to 2% of all cancers in most populations. The annual incidence of thyroid cancer is approximately 0.5 to 10 per 100,000 in the w0rld.3~For 1996, The American Cancer Society estimated a total of 15,600 new cases of thyroid cancer in the United States, with 11,600 in women and 4000 in menTg The age-adjusted annual incidence rate of thyroid cancer in the United States from 1986 to 1990 based on Surveillance, Epidemiology, and End Results (SEER) data was 4.5 per 100,000. There is a difference in the incidence rates seen by gender and age. For females, the annual rate is 6.4 per 100,000 and for males, 2.5 per 100,000. For males younger than 65 years, the annual rate is 2.0 per 100,000 and increases to 7.1 per 100,000 after the age of 65

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209

0

0

20

40

60

80

Age (Y) Figure 1. Age-adjusted annual incidence and mortality rates of thyroid cancer per 100,000 persons. = Incidence; m = mortality. (USA data from Surveillance, Epidemiology, and End Results program [SEER] 1986-1 990. Miller BA, et al: SEER Cancer Statistics Review: 1973-1 990. National Cancer Institute NIH Pub No. 93-2789, 1993.)

+

years. For females, the annual rate for ages less than 65 years is 6.0 per 100,000 compared with 9.4 per 100,000 after 65 years. The peak rate in women occurs at age 35 to 39 years and in men at age 75 to 79 years. In Figure 1, the incidence of thyroid cancer gradually increases for the combined sexes until age 50 and then plateaus. Temporal trends for incidence rates in the United States from the late 1940s to 1984 reveal increases in both sexes up until the late 1970s and then stabilization. In men, the increases occurred for the most part at greater than 60 years of age and in women at age 20 to 39 years.35The Connecticut Tumor Registry noted a relative threefold increase in the incidence of thyroid cancer between the periods 1940 to 1949 and 1970 to 1973 in women and a 2.5-fold increase in men. The increased incidence in this population was the result of increased numbers of cancers in individuals aged less than 50 years. A similar increase is seen in New York State from 1941 to 1962.'09The increases in incidence rates have been attributed to changes in diagnostic criteria, the completeness of reporting, and histology patterns. A review of thyroid cancer in Olmstead County, Minnesota, from 1935 to 1965 suggested that an increased recognition of occult papillary carcinomas was responsible for the increased incidence during this period.'36 An evaluation of thyroid cancer by histology in Connecticut attributed the fivefold increase in age-adjusted incidence rates between 1935 and 1975 to an increase in papillary and follicular carcinoma^.^' From 1958 to 1987, a few areas in the world had increasing incidence rates of thyroid cancer, including Iceland, Finland, Norway, Israel, and the United States (Hawaii and Connecticut), but, for the most part, the rates were stable. There has been no predilection for developed or underdeveloped countries.35In contrast to the general population, individuals exposed to significant irradiation of the neck have a rate of thyroid cancer of approximately 0.5% per year increasing to as much as 5% within 20 years.'O Mortality of Thyroid Cancer

The annual death rate adjusted for age in the United States from 1985 to 1989 was 0.3 per 100,000 in females and 0.2 per 100,000 in males. Similar rates

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are found in Canada.35Mortality rates have steadily been coming down over the past 35 years and have remained fairly stable over the last 10 to 15 years. From 1986 to 1990, there was a difference in mortality by age. Those persons aged less than 65 years had an annual mortality rate of about 0.1% and those older than 65, a mortality rate of about 2% to 2.5%. As shown in Figure 1, the mortality rate of cancer does not start to increase significantly until age 65 years and then increases nonlinearly with a peak annual mortality rate of 4.8 per 100,000 at age 85 years or older. The mortality rates are much lower than the incidence rates, particularly in the younger ages. The increasing mortality seen in the older age groups is probably related to the increasing frequency of anaplastic carcinomas which are more lethal. It has been estimated from 1988 to 1990 SEER data that the lifetime risk of being diagnosed with thyroid cancer starting at age zero is 0.22% in males and 0.6% in females. The lifetime risk of dying of thyroid cancer starting at age zero is 0.03% in males and 0.06Oh in females. Five-year survival rates from 1960 to 1991 as reported by the American Cancer Society increased from 83% to 95YiSsThis is probably the result of earlier detection and treatment. A study by Akslen and co-workers] of 2479 persons with thyroid cancer in the entire Norwegian population and followed up until death reported very little risk of dying associated with papillary thyroid cancer until after age 55 years. Thus, there is very low risk of developing cancer and an even lower risk of dying of cancer. The mortality rate from thyroid cancer is low despite the fact that the prevalence of occult thyroid cancer is high. Therefore, we do not recommend screening for thyroid cancer in the general population. Incidence of Benign Thyroid Nodules Becoming Malignant

The natural history of thyroid nodules is important in determining risk. An understanding of the biologic nature of thyroid nodules helps the physician to understand their potential for malignant transformation. This, in turn, can help him or her decide if and when it might be appropriate to intervene at an earlier time in the hope of changing the outcome. From the Framingham study, after a 15-year follow-up period, of the nodules noted initially none showed any clinical change suggesting malignancy. Of the 45 lesions surgically removed in these patients, all were benign. In addition, none of the new nodules detected showed any evidence of malignancy. Several more recent studies have evaluated the false-negativity of FNA in benign nodules. Grant and c o - ~ o r k e r sevaluated ~~ 439 nodules (diagnosed by FNA as benign 6 years earlier) with a repeat FNA and found thyroid carcinoma in about 0.7%. In a similar fashion, Kuma and colleaguesM,65 followed up benign nodules by FNA 10 years later and noted a less than 1%incidence of thyroid cancer. Thus, if we assume that most of these nodules are benign to begin with, transformation of benign thyroid nodules to thyroid carcinomas is a slow and rare occurrence. SCREENING FOR THYROID DISEASE

The data on the epidemiology of thyroid disease in the community presented herein should serve as a basis for the consideration of screening for thyroid disease in adults, keeping in mind that, currently, no major medical organization recommends routine screening for thyroid dysfunction in the general c~mrnunity.'~, The issues surrounding a screening program to detect

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thyroid disease in adults are exceedingly complex and have been thoroughly reviewed in the recent 1iterafu1-e.~~. 52, 53, The following sections present a brief summary of the major results of these detailed reviews as they pertain to epidemiologic data. We use the word screening to mean the employment of a test designed to detect thyroid disease in a population of subjects who have no clinical evidence of disease. Screening can be carried out in different patient populations with entirely different probabilities of disease. Mass screening may be defined as the search for thyroid disease in the general community, case-finding as screening in clinics or health centers where patients are seen for other reasons, and surveillance as screening in subjects who have a high risk of thyroid disease, such as those with a family history of thyroid disease. As discussed previously, there is a substantial amount of unsuspected thyroid disease and dysfunction in the adult community, particularly in women. The critical question is whether a screening program to detect thyroid disease in adults would be worth the investment. Once we consider conducting a screening program, a host of other questions emerge. Who should be screened and in what clinical setting? Would the detection and treatment of clinical or preclinical thyroid dysfunction result in clear benefits to patients? What is the cost of such a program and is it affordable? What tests should be used and is their accuracy sufficient to minimize the harm and costs of false-positive and false-negative tests? To begin the discussion of screening for thyroid disease we briefly consider a screening program that is widely considered to be cost-effective and that is currently employed in numerous countries throughout the world, namely, screening for congenital hypothyroidism in neonates. Screening in Neonates

Congenital hypothyroidism occurs in about 1 in 4000 live births and has a female-to-male ratio of about 2 to 1.*This prevalence is an order of magnitude lower than the prevalence of unsuspected overt hypothyroidism in adult women (about 1 in 200). Screening programs for congenital hypothyroidism in neonates are now conducted on a worldwide basis and result in the annual detection of more than 2500 cases in 10 million neonates screened.28To improve cost-benefit, screening for congenital hypothyroidism is combined with screening for phenylketonuria. The programs have effectively eliminated mental retardation resulting from congenital hypothyroidism in detected neonates. There is no question that the programs are cost-effective and well-organized. Two screening strategies are employed to detect congenital hypothyroidism. The first strategy, used primarily in Canada and the United States, initially measures a total T4 level with a high cut-off near the tenth percentile and then measures a TSH level as a confirmatory test in those neonates with a low total T4. The second strategy, employed primarily in Europe and Japan, measures the TSH level as the initial screening test and then uses a total T, level as a confirmatory test. In both of these strategies the initial screening is conducted before neonates leave the nursery, and both strategies are comparable in their ability to detect congenital hypothyroidism. A third strategy employing both a total T, and TSH assay simultaneously in the initial screening may eventually replace the other two strategies when it becomes technically and financially feasible.

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In neonatal screening, all of the questions posed previously have been answered. Neonates should be screened before leaving the hospital. The detection and treatment of congenital hypothyroidism results in clear benefit for patients. A total T4 or TSH assay should be used as the initial test, and their accuracy is sufficient to minimize false-positive and false-negative tests. The costs of screening programs are affordable when combined with screening for other neonatal disorders such as phenylketonuria. There is virtually no debate about the efficacy and importance of screening for congenital hypothyroidism in neonates. Screening in Adults Data from the Whickham survey and other studies indicate that the prevalences and incidences of unsuspected overt hypothyroidism and hyperthyroidism in men are extremely low, and thus it is unlikely that screening for overt thyroid disease in men would be cost-effective. As shown in Table 7, the prevalence of unsuspected overt thyroid disease is low (less than 1%) in women in general, although it is probably somewhat higher in older women. Thus, it is unlikely that screening for overt disease in healthy women of any age would be cost-effective, although screening elderly women in the clinic or in geriatric centers may have some merit? Screening adults in the community with a TSH assay will yield a large percentage of subjects with an abnormal TSH level as demonstrated in Tables 8 and 9. Approximately 5% to 10% of adults will have an elevated serum TSH, and 1% to 5% will have a low TSH. Elderly women have a 10% to 20% prevalence of an elevated TSH. The vast majority of subjects with an abnormal serum TSH level are clinically euthyroid and have a normal serum free T, estimate and total T, level. Given the fact that most of the screened adults in the community who have an abnormal sensitive serum TSH assay turn out to have subclinical hypothyroidism and subclinical hyperthyroidism, is such screening cost-effective? The answer to this question depends on several factors, including whether the early detection and treatment of subclinical thyroid disease leads to clear clinical benefit for patients.lZ5,13R Subclinical hypothyroidism may be associated with unfavorable serum lipid profiles and cardiovascular abn~rmalities?~ whereas subclinical hyperthyroidism is definitely associated with an increased incidence of atrial fibrillation in older subjects and may be associated with an increased rate of bone loss.'01,'07,129 It is beyond the scope of this review to present a detailed cost-effectiveness analysis of a screening program for subclinical thyroid disease in the community. Such an analysis employing a computer decision model has recently been published and concludes that it is comparatively cost-effective to screen persons in the general community for mild thyroid failure with a serum TSH level combined with a serum cholesterol level every 5 years beginning at age 35 years.*saThe analysis further concludes that screening elderly women is especially cost-effective, and that physicians in practice should consider screening their patients with a TSH measurement during the periodic health examination. References 1. Akslen LA. Haldorsen T. Thoresen SO, et al: Survival and causes of death in thvroid cancer. A population-based study of 2479 cases from Norway. Cancer Res 51.r1234, 1991

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2. American Academy of Pediatrics and American Thyroid Association: Newborn screening for congenital hypothyroidism: Recommended guidelines. Pediatrics 80: 745, 1987 3. Amino N, Mori H, Iwatani Y, et al: High prevalence of transient postpartum thyrotoxicosis and hypothyroidism. N Engl J Med 306:849, 1982 4. Ashcraft MW, Van Herle AJ: Management of thyroid nodules. I. History and physical examination, blood tests, x-ray tests and ultrasonography. Head Neck Surg 3:216, 1981 5. Ashcraft MW, Van Herle AJ: Management of thyroid nodules. 11. Scanning techniques, thyroid suppressive therapy and fine-needle aspiration. Head Neck Surg 3:297, 1981 6. Bagchi N, Brown TR, Parish RF Thyroid dysfunction in adults over age 55 years: A study in an urban US community. Arch Intern Med 150:785, 1990 7. Baldwin DB, Rowett D. Incidence of thyroid disorders in Connecticut. JAMA 239:742, 1978 8. Barker DJP, Phillips DIW: Current incidence of thyrotoxicosis and prevalence of goiter in 12 British towns. Lancet 2:567, 1984 9. Belfiore A, La Rosa GL, La Porta GA, et al: Cancer risk in patients with cold thyroid nodules: Relevance of iodine intake, sex, age and multi-nodularity. Am J Med 93:393,1992 10. Berglund J, Christensen SB, Hallengren B: Total and age-specific incidence of Graves' thyrotoxicosis, toxic nodular goiter and solitary toxic adenoma in Malmo 1970-74. J Intern Med 227137, 1990 11. Brander A, Viikinkoski P, Nickels J, et a1 Thyroid gland: US screening in middleaged women with no previous thyroid disease. Radiology 173:507, 1989 12. Brander A, Viikinkoski P, Nickels J, et a1 Thyroid gland: US screening in a random adult population. Radiology 181:683, 1991 13. Brierre JT Jr, Dickson LG: Clinically unsuspected thyroid disease. Gen Pract 30:94, 1964 14. Brooks JR: The solitary thyroid nodule. Am J Surg 125:477, 1973 15. Bruneton JN, Balu-Maestro C, Maray PY, et al: Very high frequency (13 MH,) ultrasonographic examination of the normal neck: Detection of normal lymph nodes and thyroid nodules. J Ultrasound Med 13237, 1994 16. Burch HB: Evaluation and management of the solid thyroid nodule. Endocrinol Metab Clin North Am 24663, 1995 17. Canadian Task Force on the Periodic Health Examination: The periodic health examination. Can Med Assoc J 121:1193, 1979, and Canadian Guide to Clinical Preventive Health Care. Ottawa, Canada Communication Group, 1994, p 611 18. Carcangiu ML, Steeper T, Zampi G, et al: Anaplastic thyroid carcinoma: A study of 70 cases. Am J Clin Pathol 83:135, 1985 19. Carrol BA: Asymptomatic thyroid nodules: Incidental sonographic detection. AJR Am J Roentgenol 133:499, 1982 20. Caruso D, Mazzaferri E: Fine needle aspiration biopsy in the management of thyroid nodules. Endocrinologist 1:194, 1991 21. Christensen SB, Ericsson UB, Janzon L, et al: The prevalence of thyroid disorders in a middle-aged female population with special reference to the solitary thyroid nodule. Acta Chir Scand 150:13, 1984 22. Christensen SB, Bondeson L, Ericsson UB, et al: Prediction of malignancy in the solitary thyroid scan, fine-needle biopsy and serum thyroglobulin. Acta Chir Scand 150:433, 1984 23. Cohen KL, Swigar ME: Thyroid function screening in psychiatric patients. JAMA 242:254, 1979 24. Cooper DS: Subclinical hypothyroidism. Adv Endocrinol Metab 2:77, 1991 25. Crile G: Cancer of the thyroid. J Clin Endocrinol Metab 10:39, 1961 25a. Danese MD, Powe NR, Sawin CT, et al: Screening for mild thyroid failure at the periodic health examination: A decision and cost-effectiveness analysis. JAMA 276:285, 1996 26. DeGroot LJ, Mayor G: Admission screening by thyroid function tests in an acute general care teaching hospital. Am J Med 93:558, 1992

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Address reprint requests to Lawrence M. Crapo, MD, PhD Division of Endocrinology Santa Clara Valley Medical Center 751 South Bascom Avenue San Jose, CA 95128