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Original Investigation |

The Colorado Thyroid Disease Prevalence Study FREE

Gay J. Canaris, MD, MSPH; Neil R. Manowitz, PhD; Gilbert Mayor, MD; E. Chester Ridgway, MD
[+] Author Affiliations

From the Division of General Internal Medicine, Department of Medicine, University of Nebraska Medical Center, Omaha (Dr Canaris); Knoll Pharmaceutical Co, Mt Olive, NJ (Drs Manowitz and Mayor); and the Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Health Science Center, Denver (Dr Ridgway). Dr Mayor is currently with the Mayor Group LLC, Morristown, NJ.


Arch Intern Med. 2000;160(4):526-534. doi:10.1001/archinte.160.4.526.
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Published online

Context  The prevalence of abnormal thyroid function in the United States and the significance of thyroid dysfunction remain controversial. Systemic effects of abnormal thyroid function have not been fully delineated, particularly in cases of mild thyroid failure. Also, the relationship between traditional hypothyroid symptoms and biochemical thyroid function is unclear.

Objective  To determine the prevalence of abnormal thyroid function and the relationship between (1) abnormal thyroid function and lipid levels and (2) abnormal thyroid function and symptoms using modern and sensitive thyroid tests.

Design  Cross-sectional study.

Participants  Participants in a statewide health fair in Colorado, 1995 (N = 25,862).

Main Outcome Measures  Serum thyrotropin (thyroid-stimulating hormone [TSH]) and total thyroxine (T4) concentrations, serum lipid levels, and responses to a hypothyroid symptoms questionnaire.

Results  The prevalence of elevated TSH levels (normal range, 0.3-5.1 mIU/L) in this population was 9.5%, and the prevalence of decreased TSH levels was 2.2%. Forty percent of patients taking thyroid medications had abnormal TSH levels. Lipid levels increased in a graded fashion as thyroid function declined. Also, the mean total cholesterol and low-density lipoprotein cholesterol levels of subjects with TSH values between 5.1 and 10 mIU/L were significantly greater than the corresponding mean lipid levels in euthyroid subjects. Symptoms were reported more often in hypothyroid vs euthyroid individuals, but individual symptom sensitivities were low.

Conclusions  The prevalence of abnormal biochemical thyroid function reported here is substantial and confirms previous reports in smaller populations. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health. Individual symptoms were not very sensitive, but patients who report multiple thyroid symptoms warrant serum thyroid testing. These results confirm that thyroid dysfunction is common, may often go undetected, and may be associated with adverse health outcomes that can be avoided by serum TSH measurement.

Figures in this Article

THE PREVALENCE of abnormal thyroid function continues to be debated. Numerous studies from various countries differ in their prevalence estimates for both hypothyroidism and hyperthyroidism. The difficulty with many of these studies lies in the variable definitions of disease states, the poorly defined and diverse populations studied, and the historically insensitive measures of thyroid function. In perhaps the best longitudinal study conducted to date, Tunbridge et al1 found that 7.5% of women and 2.8% of men of all ages in Whickham, England, had serum thyrotropin (thyroid-stimulating hormone [TSH]) levels greater than 6 mIU/L. After reviewing 12 such studies across many different cultures, Vanderpump and Tunbridge2 concluded that primary thyroid gland failure (TSH >6 mIU/L) occurs in 5% of multiple populations.

Several factors may affect prevalence. For example, virtually all studies report higher prevalence rates for hypothyroidism in women and with advancing age,27 with rates as high as 24% among women older than 60 years recruited from several senior citizens' centers and ambulatory clinics.4 Dietary iodine is another factor. The Framingham Study showed that 13.6% of US women older than 60 years had TSH levels greater than 5 mIU/L.5 In Italy, where dietary iodine is low, serum TSH levels greater than 5 mIU/L were found in only 1.5% of similarly aged women.8

Abnormal thyroid function has important public health consequences. Suppressed TSH levels have been associated with decreased bone density in some but not all studies9,10 and with an increased risk of atrial fibrillation11 and premature atrial beats.12 It has been known for decades that overt hypothyroidism contributes to elevated serum cholesterol levels,1321 and recent studies suggest this may also be true with subclinical hypothyroidism.2226 However, the impact of various degrees of thyroid dysfunction remains unsettled, perhaps caused in part by differing laboratory definitions and small study populations.2730

Identifying thyroid disease clinically can be challenging. Symptoms often develop so insidiously that they go unnoticed.31 When symptoms are reported, they are frequently confused with other health problems.3133 Clinicians have tried to identify patients with a higher likelihood of hypothyroidism based on physical findings and symptoms and have suggested using symptoms to guide testing.3439 Similar strategies may also apply to subclinical hypothyroidism and subclinical hyperthyroidism, since both have been associated with reversible clinical symptoms when assessed by controlled symptom questionnaires.4042

In the present study, a large cohort provided a unique opportunity to conduct a cross-sectional study of abnormal thyroid function. The principal inquiries were (1) the prevalence of abnormal thyroid function, (2) the relationship of abnormal thyroid function to abnormal serum lipid concentrations, and (3) the relationship between abnormal thyroid function and symptoms of hypothyroidism using modern and sensitive tests of thyroid function.

STUDY POPULATION

The Colorado 9Health Fair is an annual statewide event that provides testing for such disorders as hypertension, colon cancer, glaucoma, and skin cancer, with optional blood analysis available at a nominal fee. Participants also complete a demographic survey at the time of their screening. In 1995, sensitive tests of thyroid function were added to the menu of blood analyses, and a questionnaire for hypothyroid symptoms was included with the survey. (The Thyroid Health Survey is available upon request from the authors.) Written informed consent was obtained from all participants.

THYROID HEALTH SURVEY

The Thyroid Health Survey was one page of the Colorado 9Health Fair questionnaire. Questions on personal history, family history, and demographic characteristics were included. There were also 14 questions on symptoms of hypothyroidism, which were chosen based on the results of a previous study.34 In this study of traditional hypothyroid symptoms, symptom questions were asked in 2 ways: Was the symptom present at the time the questionnaire was completed ("current" symptom)? Was the symptom new from the previous year ("changed" symptom)? Three "current" and 11 "changed" symptoms became the Colorado 9Health Fair Thyroid Health Survey symptom questions.

SERUM ASSAYS

Subjects who opted for blood analysis were requested to fast for 12 hours prior to having their blood drawn. All serum assays were performed by a central laboratory (Quest Diagnostics Inc, Denver Co [formerly Corning Clinical Laboratories]). Serum TSH concentrations were measured by a third-generation immunochemiluminescent procedure having a functional detection limit of 0.01 mIU/L and a normal range of 0.3 to 5.1 mIU/L, inclusive.43 Serum total thyroxine (T4) concentrations were measured by enzyme immunoassay. Serum lipid levels were determined using the autoanalyzer method. Age- and sex-adjusted reference ranges were used to define the limits of normality for serum lipid levels. Thyroid status was defined as follows:

  • Euthyroid (TSH level within the normal range, 0.3-5.1 mIU/L, inclusive)

  • Hypothyroid (TSH level >5.1 mIU/L and T4 level <57.9 nmol/L, [<4.5 µg/dL])

  • Subclinical hypothyroid (TSH level >5.1 mIU/L and T4 level ≥57.9 nmol/L [≥4.5 µg/dL])

  • Hyperthyroid (TSH level ≤0.01 mIU/L)

  • Subclinical hyperthyroid (TSH level, 0.01 to <0.3 mIU/L)

Because total (T4) and not free (FT4) thyroxine levels were used in this study, some total T4 concentrations may have been slightly elevated because of increases in thyroid hormone binding proteins in patients who were receiving certain concomitant medications; for example, estrogens. We therefore categorized hyperthyroid states according to TSH levels alone, as above, assuming that virtually all hyperthyroid patients have undetectable serum TSH levels. Similarly, the population of patients with subclinical hypothyroidism may be overestimated because of concomitant estrogen administration.

DATA COLLECTION

Data were entered directly from the Colorado 9Health Fair Survey forms and verified using double entry. Laboratory results collected by the Colorado 9Health Fair were later linked to survey information by site and subject identification number. The Colorado Medical Society, Englewood, provided appropriate medical follow-up for participants with abnormal laboratory test results identified through the Colorado 9Health Fair.

DATA ANALYSIS

All data were analyzed using SAS statistical software package (SAS Institute, Cary, NC). Measures of significance between groups were calculated using the χ2 test and analysis of variance (ANOVA). The Pearson correlation coefficient was calculated between the TSH level and the percentage of reported symptoms in order to relate symptoms to progressively worsening thyroid function. Logistic regression was used to determine which symptoms were independent predictors of a disease state, while controlling for other symptoms. Receiver operating characteristic (ROC) areas were calculated using the ROC Curve Analyzer, version 6 (R. Centor and J. Keightley, University of Alabama, Birmingham). The symptom index was calculated in the manner of Billewicz et al.35 The Billewicz group assigned a weight to each sign and symptom of hypothyroidism. For each patient, the numerical weights of the patient's reported symptoms, present and absent, were summed to calculate the Billewicz score. These patient scores may discriminate between hypothyroid and euthyroid persons better than individual symptoms. In our study population, symptom weights were calculated using the overt hypothyroid group relative to a randomly chosen subset of the euthyroid group. This subgroup, of equal size to the hypothyroid group, was matched with the hypothyroid group for age, sex, and whether or not the individual was taking thyroid medication.

POPULATION DEMOGRAPHICS

There were 33,661 subjects who presented to the 118 Colorado 9Health Fair screening sites. We excluded 6319 subjects for not returning the Thyroid Health Survey, nonevaluable responses, or inconsistent demographic data that made matching survey responses to laboratory data potentially inaccurate. Another 1480 subjects did not have blood drawn. Demographic data on the remaining 25,862 individuals, representing 111 testing sites, are shown in Table 1. When compared with the general population of Colorado, the study population was older and had more women, a greater proportion who were white, and more high school and college graduates. Similar population characteristics have been reported by other community health fairs.44,45

THYROID FUNCTION TESTS

Based on the above definitions of thyroid status, an abnormal serum TSH concentration was found in 11.7% of subjects (Table 2). There were 2450 subjects (9.5%) with an elevated TSH concentration, most of whom were subclinically hypothyroid. Among those with an elevated serum TSH concentration, 1799 subjects (74%) had a level between 5.1 and 10 mIU/L; 619 subjects (26%) had a value greater than 10 mIU/L. The distribution of subjects with an elevated TSH level is shown by age and sex in Figure 1. The percentage of subjects within each decade of age and with an elevated TSH concentration is shown, ranging from about 4% to 21% in women and from 3% to 16% in men. The percentage of subjects with an elevated TSH concentration was greater for women than men in each decade of age, reaching statistical significance for each decade after age 34 years (P<.01). There were 570 participants with a low TSH concentration (2.2%). The remaining 22,842 participants (88.3%) had normal serum TSH concentrations. Among patients not taking thyroid medication, 8.9% had increased TSH and 1.0% had low TSH concentrations. Thus, 9.9% of the population had a thyroid abnormality that had most likely gone unrecognized.

Table Graphic Jump LocationTable 2. Prevalence of Thyroid Abnormalities
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Figure 1.

The percentage of subjects with an elevated thyrotropin (thyroid-stimulating hormone [TSH]) level by sex and decade of age. Percentages of hypothyroidism ranged from 4% to 21% in women and from 3% to 16% in men.

Graphic Jump Location

In the total study population, men were more often euthyroid than women (P<.001). Subclinical hypothyroidism and subclinical hyperthyroidism were both more common in women (P<.001). Interestingly, there was no statistically significant difference between women and men with regard to overt hypothyroidism, perhaps owing in part to the small number of overt hypothyroid individuals. Also, women who were taking estrogen preparations may have been misclassified into the subclinically hypothyroid group (from the overt hypothyroid group) because thyroid status was defined using T4 rather than FT4 levels.

Of the 25,862 participants, 1525 (5.9%) reported taking thyroid medication at the time of the survey. The medications reported may have been taken for thyroid hormone replacement or for suppression therapy. The proportion of individuals in each thyroid classification is shown in Table 2. Participants taking thyroid medication were significantly more likely to have an abnormal serum TSH level (39.9%) than those not taking thyroid medications (9.9%; P<.001). More than one fifth of the population taking thyroid medication was either hyperthyroid or subclinically hyperthyroid. Of the patients in the total population with a low serum TSH concentration (n = 570), 57.7% were taking thyroid medication, whereas only 11.4% of subjects with an elevated TSH concentration (n = 2450) were taking thyroid medication (P<.001).

To better evaluate the possible impact that estrogen may have had on the results, we looked at the information on estrogen supplementation that was available for the 1288 women who reported taking thyroid medication. Of the women taking thyroid medication, 506 (39%) reported also taking a form of estrogen. The proportion of women in each disease state (ie, overt hypothyroid or euthyroid) was not significantly different between women reporting supplemental estrogen and those not taking estrogen.

SERUM LIPID CONCENTRATIONS

Mean serum lipid concentrations are presented according to disease state in Table 3. The trends across disease states for mean serum total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and triglyceride levels were statistically significant (P<.001 for TC and LDL cholesterol; P = .02 for triglycerides). The relative proportions of elevated, low, and normal serum lipid levels by disease state are shown in Figure 2. A higher proportion of hypothyroid subjects had elevated serum levels of TC (P<.001) and LDL cholesterol (P<.001) compared with the euthyroid group. A higher proportion of subclinically hypothyroid subjects had elevated TC levels compared with subjects with normal thyroid function (P<.001).

Table Graphic Jump LocationTable 3. Mean Lipid Levels by Disease State*
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Figure 2.

The proportions of elevated, normal, or low lipid levels in 25,862 subjects according to thyroid function status. Thyroid function was defined by serum thyrotropin (thyroid-stimulating hormone [TSH]) and thyroxine (T4) concentrations as follows: euthyroid (TSH level within the normal range, 0.3-5.1 mIU/L), hypothyroid (TSH level >5.1 mIU/L and T4 level <57.9 nmol/L [<4.5 µg/dL]), subclinical hypothyroid (TSH level >5.1 mIU/L and T4 level ≥57.9 nmol/L [≥4.5 µg/dL]), hyperthyroid (TSH level ≤0.01 mIU/L), or subclinical hyperthyroid (TSH level, 0.01 to <0.3 mIU/L). LDL indicates low-density lipoprotein; HDL, high-density lipoprotein.

Graphic Jump Location

To further investigate the relationship between declining thyroid function and serum lipid concentrations, the total study population was divided into incremental TSH levels. Mean serum TC (Figure 3) and LDL cholesterol concentrations progressively increased with increasing serum TSH levels (P<.001). Serum triglyceride and high-density lipoprotein (HDL) cholesterol levels did not change significantly. The percentage of patients with elevated serum TC and LDL cholesterol levels also rose progressively with incremental increases in TSH levels (P<.001).

Place holder to copy figure label and caption
Figure 3.

Mean total cholesterol levels for categories of increasing serum thyrotropin (thyroid-stimulating hormone [TSH]) levels in 25,862 subjects. All mean cholesterol levels are significantly different from the mean cholesterol level of the euthyroid participants (TSH level, 0.3-5.1 mIU/L; P<.003).

Graphic Jump Location

The mean serum TC level among patients with serum TSH levels between 5.1 and 10 mIU/L was significantly higher than the mean TC level in euthyroid subjects (5.8 mmol/L [223 mg/dL] vs 5.6 mmol/L [216 mg/dL]; P<.003). The mean LDL cholesterol level among those with serum TSH concentrations between 5.1 and 10 mIU/L was also significantly greater than that of the euthryoid group (3.7 mmol/L [144 mg/dL] vs 3.6 mmol/L [140 mg/dL]; P<.003). Other serum lipid levels were not significantly different.

Women had higher serum HDL cholesterol levels across all disease states than men, contributing to their slightly higher TC levels (Table 4). The difference in TC levels cannot be attributed to age, since there was no difference in age between men and women. Lipid levels also differed between women who reported taking supplemental estrogen and women who did not. For the women who reported taking thyroid medication, those who were also taking estrogen had higher total cholesterol levels than women not taking estrogen (5.9 mmol/L [227.1 mg/dL] vs 5.7 mmol/L [220.5 mg/dL]). The women taking supplemental estrogen also had higher HDL cholesterol levels (1.6 mmol/L [63.3 mg/dL] vs 1.4 mmol/L [54.5 mg/dL]) but lower LDL cholesterol levels (3.5 mmol/L [135.5 mg/dL] vs 3.7 mmol/L [141.8 mg/dL]). The mean age of these 2 groups did not differ (P = .04, α = .02).

SYMPTOMS

Overt hypothyroid subjects reported a greater percentage of symptoms than did the subclinically hypothyroid group (Table 5). Overt and subclinically hypothyroid subjects all reported significantly more total symptoms than euthyroid individuals (P<.001). The association between disease state and the percentage of reported symptoms was statistically significant (P<.001), but weak (ANOVA, r2 = 0.003; Pearson correlation coefficient, r = 0.03). Each symptom except one (deep voice) was reported more frequently by hypothyroid than euthyroid subjects. Only the symptoms of hoarser voice and deeper voice did not differ significantly between those with elevated vs normal TSH levels (Figure 4).

Table Graphic Jump LocationTable 5. Reported Symptoms by Disease State
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Figure 4.

The percentage of euthyroid subjects compared with those with an elevated thyrotropin (thyroid-stimulating hormone [TSH]) level who reported each symptom.

Graphic Jump Location

Although some symptoms attained high specificity, sensitivities were generally low (2.9%-28.3%) for individual symptoms reported by subjects with elevated TSH levels (Table 6). Thus, the absence of a symptom would not rule out thyroid disease. Positive predictive values were also low (8%-12%), representing the proportion of all subjects reporting the symptom who also had disease. Likelihood ratios (LRs) were calculated to express the odds that a symptom would be reported by someone with hypothyroidism as opposed to someone who is euthyroid. The LRs for individual symptoms were modest (<2.0). However, when calculated for the overt hypothyroid group, LRs exceeded 2.0 for current constipation and the changed symptom, feeling colder. Multiple logistic regression analysis with disease state (overt hypothyroid or euthyroid) as the dependent variable and the 14 symptoms (age and sex as independent variables) identified 2 significant symptoms (P<.05). These were current constipation and feeling colder than the previous year.

The proportion of overt hypothyroid subjects reporting a certain number of symptoms rose as the number of symptoms increased (Figure 5). That is, as more symptoms were reported, the subject was more likely to be overtly hypothyroid. Subclinically hypothyroid individuals were intermediate between overt hypothyroid and euthyroid subjects.

Place holder to copy figure label and caption
Figure 5.

The percentage of euthyroid, subclinical hypothyroid, and hypothyroid subjects who reported no, 1, 2, 3, or 4 or more symptoms. Euthyroid subjects were more likely to have no symptoms, whereas hypothyroid subjects were more likely to have 3 or more symptoms.

Graphic Jump Location

Symptom scores were generated in the manner of Billewicz et al35 (see "Data Analysis" section) because weighted scores using multiple symptoms may discriminate between hypothyroid and euthyroid persons better than individual symptoms. The calculated weights are listed in Table 7. The symptoms with the greatest discriminating ability were used to calculate the final cumulative score for each study subject. These 8 symptoms included the current symptoms of constipation, hoarse voice, and deep voice, and the changed symptoms of more constipation, hoarser voice, feeling colder, having puffier eyes, and having weaker muscles. The final cumulative scores for study subjects ranged from 25 to 250. Scores were divided into quintiles to show the percentage of overt hypothyroid and euthyroid subjects within each range of symptom scores. The proportion of hypothyroid individuals increased with increasing symptom score (Figure 6), as it did with the raw symptoms.

Place holder to copy figure label and caption
Figure 6.

The percentage of overt hypothyroid and euthyroid subjects within the defined ranges of subject symptom scores. Subject symptom scores were calculated by the method used by Billewicz et al35 and represent the sum of individual numerically weighted symptoms as reported by each patient. Higher scores reflect greater symptomatology. The percentage of overt hypothyroid subjects within each symptom score range increased with increasing symptom score.

Graphic Jump Location

The test characteristics for different cutoffs of symptom scores are shown in Table 8. The LRs (reflecting the likelihood of overt hypothyroidism) increased with increasing symptom score. The positive predictive values also increased with increasing thresholds of symptom scores, so that 80% of all subjects with a symptom score greater than 200 were hypothyroid (Table 8). As may be expected, sensitivity declined with increasing thresholds of symptom scores. An ROC curve was constructed to evaluate symptoms as a test for hypothyroidism. The greater the area under the ROC curve, the better the test, with an equivocal test having an area of 0.50. The ROC analysis found the area under the curve for the symptom score cutoffs of Table 8 to be 0.64. Thus, our symptom scores did not discriminate as well as those reported by Billewicz et al35 or Seshadri et al.36 This may be expected when applying the Billewicz et al scoring method to an unselected population. The populations previously studied by the Billewicz group and the Seshadri group were enrolled specifically because of suspected hypothyroidism. When inclusion criteria similar to those used by Seshadri et al were applied to our population, the discriminating value of hypothyroid symptoms rose considerably.

Abnormal thyroid function has multiple implications for public health. However, the magnitude of the problem is not entirely known, nor are the exact relationships to other health problems well delineated.

The prevalence of an elevated serum TSH level in this population of 9.5% is within the range seen in the literature, and it is consistent with findings in an iodine-replete population.1,4,5,46,47 The proportion of subjects with an elevated TSH level was greater among women than men and increased with advancing age (Figure 1), both of which are supported in the literature.27 However, the prevalence of overt hypothyroidism was lower than some previous estimates.2 Diverse study populations and various definitions of overt disease in other studies may account for this. In our study, concomitant estrogen use could have raised serum T4 concentrations, reducing the number of overtly hypothyroid women while increasing the number who were classified as subclinically hypothyroid. However, since the proportion of women in each disease category was not significantly different between women reporting supplemental estrogen usage and those not taking estrogen, this may not be a significant factor. The low prevalence of overt disease may also be a phenomenon of the health fair itself. Nearly three quarters of those attending the Colorado 9Health Fair had participated in a previous fair, and the majority (62.5%) had seen a health care provider in the past year. This would suggest that prior testing may have detected overt hypothyroidism before the Colorado 9Health Fair, thus lowering the observed disease rate.

Of the 24,337 subjects who did not report taking thyroid medication, 9.9% had a functional abnormality of the thyroid gland that was apparently unknown. Most of these individuals (90%) had thyroid gland failure with an elevated serum TSH level. By extrapolation, there may be more than 165,000 adult cases of undetected thyroid gland failure in Colorado. If the Colorado experience can be generalized, there may be in excess of 13 million cases of undetected thyroid gland failure nationwide.

Of the group who reported taking thyroid medication, nearly 40% had an abnormal serum TSH level (Table 2). More than one fifth had a TSH level that was suppressed below normal. These observations are consistent with those of Ross et al,48 who reported in a retrospective study that 32% of patients receiving levothyroxine replacement had abnormal TSH concentrations. Interestingly, 92% of the people taking thyroid medications had seen a health care provider in the previous year. These data show that there is an excess of patients who are not in the normal range of thyroid function. Such patients may be at risk for organic consequences of overtreatment or undertreatment or (in the case of those with suppressed TSH levels) may be taking thyroid hormones for reasons other than replacement.

One consequence of declining thyroid function is rising serum lipid levels, as observed in this study. Most hypothyroid individuals had an elevated lipid level. Mean TC, LDL cholesterol, and triglyceride levels rose with a significant trend across grades of thyroid function (Table 3). Not all investigators have found that triglyceride levels increase with increasing TSH levels.14,17,22 The difference may be explained by the markedly larger population in this study.

It was notable in this study that the mean TC level of subjects with modest elevations of serum TSH (ie, between 5.1 and 10 mIU/L) was higher than that of the euthyroid group (5.8 mmol/L [223 mg/dL] vs 5.6 mmol/L [216 mg/dL]). While several studies have linked hyperlipidemia with cardiovascular morbidity,4951 it is arguable whether this reflects a clinically significant difference. Normalizing subclinical hypothyroidism may have a role in the treatment of hyperlipidemia and perhaps the prevention of associated cardiovascular morbidity, but to what degree is unclear.

Lipid levels varied by sex. Women taking estrogen supplementation had higher serum HDL cholesterol levels than women not reporting supplemental estrogen usage, who in turn had higher HDL cholesterol levels than did men. The higher TC levels seen in women may be explained in part by the difference in HDL cholesterol levels. It is unlikely that age affected lipid levels, but thyroid status may be another factor, since there were more women than men with elevated TSH levels.

More symptoms were reported by hypothyroid than euthyroid subjects in this study. Reporting more symptoms, particularly symptoms that had changed in the previous year, increased the likelihood of disease. Furthermore, there was a positive association between the proportion of symptoms reported and progressive thyroid failure, although the relationship was weak. Sensitivities were low, so that not reporting a specific symptom did not rule out disease, and poor positive predictive values suggested a high number of false-positive individual symptoms. Several investigators support the use of multiple symptoms as a diagnostic tool.23,3439 Seshadri et al36 recognized the usefulness of a symptom score, but this group concluded that cutoff points must be individualized to the population under study. The lower, more sensitive symptom score thresholds of our study (Table 8) may be useful to identify who would be appropriate for subsequent TSH testing.

These results may be confounded by variables that cannot be controlled in the population studied. Health fair participants are a self-selected population. The demographic characteristics of this group may not be completely generalizable, but they may be more representative than many selected study populations in the literature.

Despite these constraints, the large study population provided enlightening information. The magnitude of thyroid dysfunction was confirmed. Nearly 10% of subjects not taking thyroid medications had a thyroid abnormality, which was probably unknown to them, and the abnormality was detected because of testing. Results from this study also highlighted the large number of patients taking thyroid hormones who were not in the therapeutic range. Clinicians may therefore consider monitoring patients on thyroid replacement more frequently. Regarding lipids, even modest elevations of TSH levels were shown to correspond to changes in cholesterol levels, perhaps affecting cardiovascular outcomes. The clinical scoring system of Billewicz et al, when applied to this population, identified persons more likely to be hypothyroid. Although the efficacy of this instrument was much less than that of serum TSH measurement, symptom scores may prove a useful adjunct in the diagnosis of hypothyroidism. Symptom scores may enhance the cost-effectiveness of thyroid testing, which compares favorably with other generally accepted practices in the analysis by Danese et al.52 The potential benefit of testing for abnormal thyroid function needs to be readdressed, and health care providers may have a higher index of suspicion for those not yet diagnosed when traditional symptoms are reported.

Accepted for publication April 22, 1999.

This study was supported by Knoll Pharmaceutical Co, Mt Olive, NJ.

The authors gratefully acknowledge the assistance of the following individuals: Fred Ullrich, BA (University of Nebraska, Omaha), Aruna Desu, MS (Knoll Pharmaceutical Co, Mt Olive, NJ), Marge Bell-Kohler, BA, and Jerry Kirkegaard, BS (Quest Laboratories Inc, Denver, Colo), and Vicki Godbey (Colorado 9Health Fair, Denver).

Corresponding author: Gay Canaris, MD, MSPH, Section of General Internal Medicine, Department of Medicine, 983331 Nebraska Medical Center, Omaha, NE 68198-3331 (e-mail: gcanaris@unmc.edu).

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Kuusi  TTaskinen  MRNikkila  EA Lipoproteins, lipolytic enzymes, and hormonal status in hypothyroid women at different levels of substitution. J Clin Endocrinol Metab. 1988;6651- 56
Link to Article
Kutty  KMBryant  DGFarid  NR Serum lipids in hypothyroidism: a re-evaluation. J Clin Endocrinol Metab. 1978;4655- 56
Link to Article
Valdemarsson  SHansson  PHedner  PNilsson-Ehle  P Relations between thyroid function, hepatic and lipoprotein lipase activities, and plasma lipoprotein concentrations. Acta Endocrinol. 1983;10450- 56
Elder  JMcLelland  AO'Reilly  DSPackard  CJSeries  JJShepard  J The relationship between serum cholesterol and serum thyrotropin, thyroxine and tri-iodothyronine concentrations in suspected hypothyroidism. Ann Clin Biochem. 1990;27110- 113
Link to Article
Pazos  FAlvarez  JJRubies-Prat  JVarela  CLasuncion  MA Long-term thyroid replacement therapy and levels of lipoprotein(a) and other lipoproteins. J Clin Endocrinol Metab. 1995;80562- 566
Franklyn  JADaykin  JBetteridge  J  et al.  Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol. 1993;38453- 459
Link to Article
Staub  JJAlthaus  BUEngler  H  et al.  Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med. 1992;92631- 642
Link to Article
Althaus  BUStaub  JJRyff de Leche  AOberhansli  AStahelin  HB LDL/HDL changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol. 1988;28157- 163
Link to Article
Arem  RPatsch  W Lipoprotein and apolipoprotein levels in subclinical hypothyroidism: effect of levothyroxine therapy. Arch Intern Med. 1990;1502097- 2100
Link to Article
Arem  REscalante  DAArem  NMorisett  JDPatsch  W Effect of L-thyroxine therapy in overt and subclinical hypothyroidism, with special reference to lipoprotein(a). Metabolism. 1995;441559- 1563
Link to Article
Garber  AMBrowner  WSHulley  SB Clinical guideline, part 2: cholesterol screening in asymptomatic adults, revisited. Ann Intern Med. 1996;124518- 531
Link to Article
Bogner  UArntz  HRPeters  HSchleusener  H Subclinical hypothyroidism and hyperlipoproteinemia: indiscriminate L-thyroxine treatment not justified. Acta Endocrinol. 1993;128202- 206
Tunbridge  WMGEvered  DCHall  R  et al.  Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin Endocrinol (Oxf). 1977;7495- 508
Link to Article
Caron  PCalazel  CParra  HJHoff  MLouvet  JP Decreased HDL cholesterol in subclinical hypothyroidism: the effect of L-thyroxine therapy. Clin Endocrinol (Oxf). 1990;33519- 523
Link to Article
Gavin  LA The diagnostic dilemmas of hyperthyroxinemia and hypothyroxinemia. Adv Intern Med. 1988;33185- 203
Larsen  PRIngbar  SH The thyroid gland. Wilson  JDFoster  DWeds.Williams Textbook of Endocrinology 8th ed. Philadelphia, Pa WB Saunders Co1992;357- 487
Schectman  JMKallenberg  GAShumacher  RJHirsch  RP Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med. 1989;149861- 864
Link to Article
Canaris  GJSteiner  JFRidgway  EC Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med. 1997;12544- 550
Link to Article
Billewicz  WZChapman  RSCrooks  J  et al.  Statistical methods applied to the diagnosis of hypothyroidism. Q J Med. 1969;38255- 266
Seshadri  MSSamuel  BUKanagasabapathy  ASCherian  AM Clinical scoring system for hypothyroidism: is it useful? J Gen Intern Med. 1989;4490- 492
Link to Article
White  GHWalmsley  RN Can the initial clinical assessment of thyroid function be improved? Lancet. 1978;2933- 935
Link to Article
Helfand  MCrapo  LM Screening for thyroid disease. Ann Intern Med. 1990;112840- 849
Link to Article
Zulewski  HMuller  BExer  PMiserez  ARStaub  JJ Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82771- 776
Cooper  DSHalpern  RWood  LCLevin  AARidgway  EC L-Thyroxine therapy in subclinical hypothyroidism: a double-blind, placebo-controlled trial. Ann Intern Med. 1984;10118- 24
Link to Article
Nystrom  ECaidahl  KFager  GWikkelso  CLundberg  PALindstedt  G A double-blind cross-over 12-month study of L-thyroxine treatment of women with "subclinical" hypothyroidism. Clin Endocrinol (Oxf). 1988;2963- 75
Link to Article
Biondi  BFazio  SCarella  C  et al.  Control of adrenergic overactivity by beta-blockade improves the quality of life in patients receiving long term suppressive therapy with levothyroxine. J Clin Endocrinol Metab. 1994;781028- 1033
Spencer  CALoPresti  JSPatel  A  et al.  Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab. 1990;70453- 460
Link to Article
Adler  JJBloss  CM  JrMosley  KT The Oklahoma State Department of Health Mobile Multiphasic Screening Program for Chronic Disease, I. Am J Public Health Nations Health. 1966;56918- 925
Link to Article
Bletzer  KV Review of a health fair screening program in mid-Michigan. J Community Health. 1989;14149- 157
Link to Article
Parle  JVFranklyn  JACross  KWJones  SCSheppard  MC Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;3477- 83
Link to Article
Rosenthal  MJHunt  WCGarry  PJGoodwin  JS Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA. 1987;258209- 213
Link to Article
Ross  DSDaniels  GHGouveia  D The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic. J Clin Endocrinol Metab. 1990;71764- 769
Link to Article
Martin  MJHulley  SBBrowner  WSKuller  LHWentworth  D Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet. 1986;2933- 936
Link to Article
Not Available, Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease. JAMA. 1984;251351- 364
Link to Article
Not Available, The Lipid Research Clinics Coronary Primary Prevention Trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251365- 374
Link to Article
Danese  MDPowe  NRSawin  CTLadenson  PW Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. JAMA. 1996;276285- 292
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The percentage of subjects with an elevated thyrotropin (thyroid-stimulating hormone [TSH]) level by sex and decade of age. Percentages of hypothyroidism ranged from 4% to 21% in women and from 3% to 16% in men.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The proportions of elevated, normal, or low lipid levels in 25,862 subjects according to thyroid function status. Thyroid function was defined by serum thyrotropin (thyroid-stimulating hormone [TSH]) and thyroxine (T4) concentrations as follows: euthyroid (TSH level within the normal range, 0.3-5.1 mIU/L), hypothyroid (TSH level >5.1 mIU/L and T4 level <57.9 nmol/L [<4.5 µg/dL]), subclinical hypothyroid (TSH level >5.1 mIU/L and T4 level ≥57.9 nmol/L [≥4.5 µg/dL]), hyperthyroid (TSH level ≤0.01 mIU/L), or subclinical hyperthyroid (TSH level, 0.01 to <0.3 mIU/L). LDL indicates low-density lipoprotein; HDL, high-density lipoprotein.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mean total cholesterol levels for categories of increasing serum thyrotropin (thyroid-stimulating hormone [TSH]) levels in 25,862 subjects. All mean cholesterol levels are significantly different from the mean cholesterol level of the euthyroid participants (TSH level, 0.3-5.1 mIU/L; P<.003).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

The percentage of euthyroid subjects compared with those with an elevated thyrotropin (thyroid-stimulating hormone [TSH]) level who reported each symptom.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

The percentage of euthyroid, subclinical hypothyroid, and hypothyroid subjects who reported no, 1, 2, 3, or 4 or more symptoms. Euthyroid subjects were more likely to have no symptoms, whereas hypothyroid subjects were more likely to have 3 or more symptoms.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

The percentage of overt hypothyroid and euthyroid subjects within the defined ranges of subject symptom scores. Subject symptom scores were calculated by the method used by Billewicz et al35 and represent the sum of individual numerically weighted symptoms as reported by each patient. Higher scores reflect greater symptomatology. The percentage of overt hypothyroid subjects within each symptom score range increased with increasing symptom score.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Prevalence of Thyroid Abnormalities
Table Graphic Jump LocationTable 3. Mean Lipid Levels by Disease State*
Table Graphic Jump LocationTable 5. Reported Symptoms by Disease State

References

Tunbridge  WMGEvered  DCHall  R  et al.  The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977;7481- 493
Link to Article
Vanderpump  MPJTunbridge  WMG The epidemiology of thyroid disease. Braverman  LEUtiger  RDeds.The Thyroid 9th ed. Philadelphia, Pa Lippincott-Raven Publishers1996;474- 482
Eggersten  RPetersen  KLundberg  PANystrom  ELindstedt  G Screening for thyroid disease in a primary care unit with a thyroid stimulating hormone assay with a low detection limit. BMJ. 1988;2971586- 1592
Link to Article
Sawin  CTChopra  DAzizi  FMannix  JEBacharach  P The aging thyroid: increased prevalence of serum thyrotropin levels in the elderly. JAMA. 1979;242247- 250
Link to Article
Sawin  CTCastelli  WPHershman  JMMcNamara  PBacharach  P The aging thyroid: thyroid deficiency in the Framingham study. Arch Intern Med. 1985;1451386- 1388
Link to Article
Okamura  KUeda  KSone  H  et al.  A sensitive thyroid stimulating hormone assay for screening of thyroid functional disorder in elderly Japanese. J Am Geriatr Soc. 1989;37317- 322
Livingston  EHHershman  JMSawin  CTYoshikawa  TT Prevalence of thyroid disease and abnormal thyroid tests in older hospitalized and ambulatory persons. J Am Geriatr Soc. 1987;35109- 114
Roti  EMontermini  MRobuschi  G  et al.  Prevalence of hypothyroidism and Hashimoto's thyroiditis in two elderly populations with different dietary iodine intake. Pinchera  AIngbar  SHMcKenzie  JFenzis  GFeds.Thyroid Autoimmunity New York, NY Plenum Press1987;555- 557
Ross  DSNeer  RMRidgway  ECDaniels  GH Subclinical hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-thyroxine. Am J Med. 1987;821167- 1170
Link to Article
Paul  TLKerrigan  JKelly  AMBraverman  LEBaran  DT Long-term L-thyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA. 1988;2593137- 3141
Link to Article
Sawin  CTGeller  AWolf  PA  et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;3311249- 1252
Link to Article
Biondi  BFazio  SCarella  C  et al.  Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab. 1993;77334- 338
Lithell  HBoberg  JHellsing  K  et al.  Serum lipoprotein and apolipoprotein concentrations and tissue lipoprotein lipase activity in overt and subclinical hypothyroidism: the effect of substitution therapy. Eur J Clin Invest. February1981;113- 10
Link to Article
Friis  TPedersen  LR Serum lipids in hyper and hypothyroidism before and after treatment. Clin Chim Acta. 1987;162155- 163
Link to Article
Series  JJBiggart  EMO'Reilly  DSPackard  CJShepard  J Thyroid dysfunction and hypercholesterolemia in the general population of Glasgow, Scotland. Clin Chim Acta. 1988;172217- 222
Link to Article
Ballantyne  FCEpenetos  AACaslake  MForsythe  SBallantyne  D The composition of low-density lipoprotein and very-low-density lipoprotein subfractions in primary hypothyroidism and the effect of hormone-replacement therapy. Clin Sci (Colch). 1979;5783- 88
Kuusi  TTaskinen  MRNikkila  EA Lipoproteins, lipolytic enzymes, and hormonal status in hypothyroid women at different levels of substitution. J Clin Endocrinol Metab. 1988;6651- 56
Link to Article
Kutty  KMBryant  DGFarid  NR Serum lipids in hypothyroidism: a re-evaluation. J Clin Endocrinol Metab. 1978;4655- 56
Link to Article
Valdemarsson  SHansson  PHedner  PNilsson-Ehle  P Relations between thyroid function, hepatic and lipoprotein lipase activities, and plasma lipoprotein concentrations. Acta Endocrinol. 1983;10450- 56
Elder  JMcLelland  AO'Reilly  DSPackard  CJSeries  JJShepard  J The relationship between serum cholesterol and serum thyrotropin, thyroxine and tri-iodothyronine concentrations in suspected hypothyroidism. Ann Clin Biochem. 1990;27110- 113
Link to Article
Pazos  FAlvarez  JJRubies-Prat  JVarela  CLasuncion  MA Long-term thyroid replacement therapy and levels of lipoprotein(a) and other lipoproteins. J Clin Endocrinol Metab. 1995;80562- 566
Franklyn  JADaykin  JBetteridge  J  et al.  Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol. 1993;38453- 459
Link to Article
Staub  JJAlthaus  BUEngler  H  et al.  Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med. 1992;92631- 642
Link to Article
Althaus  BUStaub  JJRyff de Leche  AOberhansli  AStahelin  HB LDL/HDL changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol. 1988;28157- 163
Link to Article
Arem  RPatsch  W Lipoprotein and apolipoprotein levels in subclinical hypothyroidism: effect of levothyroxine therapy. Arch Intern Med. 1990;1502097- 2100
Link to Article
Arem  REscalante  DAArem  NMorisett  JDPatsch  W Effect of L-thyroxine therapy in overt and subclinical hypothyroidism, with special reference to lipoprotein(a). Metabolism. 1995;441559- 1563
Link to Article
Garber  AMBrowner  WSHulley  SB Clinical guideline, part 2: cholesterol screening in asymptomatic adults, revisited. Ann Intern Med. 1996;124518- 531
Link to Article
Bogner  UArntz  HRPeters  HSchleusener  H Subclinical hypothyroidism and hyperlipoproteinemia: indiscriminate L-thyroxine treatment not justified. Acta Endocrinol. 1993;128202- 206
Tunbridge  WMGEvered  DCHall  R  et al.  Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin Endocrinol (Oxf). 1977;7495- 508
Link to Article
Caron  PCalazel  CParra  HJHoff  MLouvet  JP Decreased HDL cholesterol in subclinical hypothyroidism: the effect of L-thyroxine therapy. Clin Endocrinol (Oxf). 1990;33519- 523
Link to Article
Gavin  LA The diagnostic dilemmas of hyperthyroxinemia and hypothyroxinemia. Adv Intern Med. 1988;33185- 203
Larsen  PRIngbar  SH The thyroid gland. Wilson  JDFoster  DWeds.Williams Textbook of Endocrinology 8th ed. Philadelphia, Pa WB Saunders Co1992;357- 487
Schectman  JMKallenberg  GAShumacher  RJHirsch  RP Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med. 1989;149861- 864
Link to Article
Canaris  GJSteiner  JFRidgway  EC Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med. 1997;12544- 550
Link to Article
Billewicz  WZChapman  RSCrooks  J  et al.  Statistical methods applied to the diagnosis of hypothyroidism. Q J Med. 1969;38255- 266
Seshadri  MSSamuel  BUKanagasabapathy  ASCherian  AM Clinical scoring system for hypothyroidism: is it useful? J Gen Intern Med. 1989;4490- 492
Link to Article
White  GHWalmsley  RN Can the initial clinical assessment of thyroid function be improved? Lancet. 1978;2933- 935
Link to Article
Helfand  MCrapo  LM Screening for thyroid disease. Ann Intern Med. 1990;112840- 849
Link to Article
Zulewski  HMuller  BExer  PMiserez  ARStaub  JJ Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82771- 776
Cooper  DSHalpern  RWood  LCLevin  AARidgway  EC L-Thyroxine therapy in subclinical hypothyroidism: a double-blind, placebo-controlled trial. Ann Intern Med. 1984;10118- 24
Link to Article
Nystrom  ECaidahl  KFager  GWikkelso  CLundberg  PALindstedt  G A double-blind cross-over 12-month study of L-thyroxine treatment of women with "subclinical" hypothyroidism. Clin Endocrinol (Oxf). 1988;2963- 75
Link to Article
Biondi  BFazio  SCarella  C  et al.  Control of adrenergic overactivity by beta-blockade improves the quality of life in patients receiving long term suppressive therapy with levothyroxine. J Clin Endocrinol Metab. 1994;781028- 1033
Spencer  CALoPresti  JSPatel  A  et al.  Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab. 1990;70453- 460
Link to Article
Adler  JJBloss  CM  JrMosley  KT The Oklahoma State Department of Health Mobile Multiphasic Screening Program for Chronic Disease, I. Am J Public Health Nations Health. 1966;56918- 925
Link to Article
Bletzer  KV Review of a health fair screening program in mid-Michigan. J Community Health. 1989;14149- 157
Link to Article
Parle  JVFranklyn  JACross  KWJones  SCSheppard  MC Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;3477- 83
Link to Article
Rosenthal  MJHunt  WCGarry  PJGoodwin  JS Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA. 1987;258209- 213
Link to Article
Ross  DSDaniels  GHGouveia  D The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic. J Clin Endocrinol Metab. 1990;71764- 769
Link to Article
Martin  MJHulley  SBBrowner  WSKuller  LHWentworth  D Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet. 1986;2933- 936
Link to Article
Not Available, Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease. JAMA. 1984;251351- 364
Link to Article
Not Available, The Lipid Research Clinics Coronary Primary Prevention Trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251365- 374
Link to Article
Danese  MDPowe  NRSawin  CTLadenson  PW Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. JAMA. 1996;276285- 292
Link to Article

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