Thyroid Function in Japanese Adults as Assessed by a General Health Checkup System in Relation with Thyroid-Related Antibodies and Other Clinical Parameters

Abstract

Background:

A limited number of epidemiological studies have attempted to assess thyroid function in the general population of iodine-sufficient countries. The aim of the present study was to determine the underlying thyroid diseases responsible for abnormal thyroid function detected by a general health checkup system in Japan, and to characterize the lipid metabolism in subjects found to have thyroid dysfunction.

Methods:

Serum thyrotropin (TSH), free thyroxine, anti-thyroglobulin antibodies (TgAb), anti-thyroid peroxidase antibodies (TPOAb), and TSH-binding inhibitor immunoglobulins (TBII) were determined in 1818 Japanese adults (804 men and 1014 women; mean age 51.3 ± 9.0 years) who undertook a general health checkup.

Results:

Of the 1818 examinees, 12 (0.7%) had overt hypothyroidism (OH), 105 (5.8%) subclinical hypothyroidism, 13 (0.7%) overt thyrotoxicosis, and 39 (2.1%) subclinical thyrotoxicosis. TgAb or TPOAb tests were positive in 17.7% of men and 31.4% of women. The prevalence of positive tests for TgAb or TPOAb was 14.8% for men and 23.4% for women without palpable goiter. Positive tests for TgAb, TPOAb, TBII, and a palpable goiter were more common in subjects with abnormal thyroid function tests than in subjects with normal thyroid function. At the time that abnormal thyroid function test results were first obtained, the signs of thyrotoxicosis were mild or even absent in all 13 subjects with overt thyrotoxicosis, 8 of whom had Graves' disease and 5 of whom had painless thyroiditis. Of the 12 patients with OH, only 2 patients had a palpable goiter. In the OH group, TgAb tests were positive in eight, TPOAb tests were positive in eight, and TBII tests were positive in two. The prevalence of disturbed lipid metabolism, when adjusted for age, was significantly higher in the subclinical hypothyroidism group than in normal controls (p < 0.001; odds ratio, 1.67; 95% confidence interval, 1.10–2.51).

Conclusions:

In Japanese adults who chose to be screened by a general health checkup system, the prevalence of abnormal thyroid function was nearly 10%. In a high percentage of these patients, abnormal thyroid function could not be detected by their history or physical examination. Just a physical examination without thyroid function tests, particularly serum TSH levels, was not adequate even when performed by a thyroid specialist.

Introduction

A ccording to some studies, subclinical hypothyroidism (SH) is associated with elevated serum cholesterol levels (1 –5), increased risk of coronary heart disease (6 –9), atherosclerosis (6), cardiac dysfunction (3,10) and neurological and mental dysfunction (11,12). Conversely, subclinical thyrotoxicosis (ST) is reported to be associated with increased risk of atrial fibrillation (13) and development of osteoporosis (13,14). However, the degree of urgency needed to treat subclinical thyroid diseases remains to be clarified (15).

The aim of the present study was to evaluate whether the assessment of thyroid function, especially the measurement of thyrotropin (TSH) as a screening test, could provide information of potential clinical significance. A general health checkup system, referred to as “ningen dock,” is now mandatory among employees in Japan, an iodine-sufficient country (16). More than 7 million people participate in this program annually. Those who participate in this program have screening thyroid tests consisting of TSH and free thyroxine (T4), although these tests are performed only in a limited number of institutions. In this epidemiological study, we used the data from this program to assess the prevalence of thyroid dysfunction in relation to associated risks and etiological factors that are thought to be associated with thyroid dysfunction in adults living in Japan. Thus, we assessed serum antibodies to thyroid antigens such as TSH-binding inhibitor immunoglobulins (TBII), anti-thyroglobulin antibodies (TgAb), and anti-thyroid peroxidase antibodies (TPOAb), as well as markers of abnormal lipid metabolism (ALM) that are associated with increased risk of coronary heart disease.

Materials and Methods

Subjects

The participants were those who visited the Takamatsu Red Cross Hospital for a general health checkup in the period between February 14, 2005, and August 9, 2006. There was a total of 3934 individuals (2758 men and 1176 women), mostly employees for whom an annual health checkup is mandated by law.

To undergo the general health checkup protocol at the Takamatsu Red Cross Hospital, the participants were hospitalized for 2 days during which time they received serum TSH, routine hematological, liver, and renal function tests, including electrolytes, blood sugar, HbA1C, total cholesterol, triglyceride, high-density lipoprotein cholesterol, prostate-specific antigen (for men), urinalysis, and stool tests for occult blood test. They also received chest X-ray, electrocardiogram (ECG), upper gastrointestinal tract study by fiberscope or by X-ray, ultrasonography of the abdomen, mammography (for women), gynecological examination (for women), and funduscopy.

Physical examination was performed by one of the authors, all of whom are physicians with more than 15 years' experience. The first author is a thyroid specialist with more than 30 years' experience. All women who participated in the program during the period of study and the men for whom the physical examination was performed by the first author were selected for the present study. Out of 2079 persons (903 men and 1176 women) polled, a total of 2019 subjects (881 men and 1138 women) gave their informed consent to participate in this study. The first author determined the presence or absence of palpable goiter in all of the men and one-third of the women.

Using the excess sera from the blood tests previously described, an aliquot of serum from each subject was sent to Hachioji Laboratory of SRL, Inc. (Tokyo, Japan) for measurement of serum-free T4, and another aliquot was sent to Cosmic Corp. (Tokyo, Japan) for measurement of TBII, TgAb, and TPOAb.

The diagnosis of Graves' disease was based on subnormal serum TSH concentrations, positive TBII or thyroid-stimulating antibodies (TSAb), and increased or normal thyroidal uptake of Tc-99m (17). Painless thyroiditis was diagnosed on the basis of decreased serum TSH, negative TBII, and TSAb, decreased thyroidal uptake of Tc-99m, and spontaneous recovery of thyroid function within 3 months. Thyroidal state with subnormal serum TSH concentrations and increased or normal serum-free T4 concentrations were defined as overt thyrotoxicosis (OT) or ST, respectively. Both subclinical and overt forms of Graves' disease and painless thyroiditis were included in the study.

During the observation period of the study, 77 men and 124 women had two examinations in the general health checkup program with a mean interval between examinations of 11.9 ± 1.0 months (standard deviation). Only the data from their first visit were used in the study. Consequently, the final number of subjects in the present study was 1818 (804 men and 1014 women). Their mean age was 51.3 ± 9.0 years (51.8 ± 9.8 years for men and 50.9 ± 8.4 years for women). Among them, 289 had been taking medication for one or more of the following conditions: hyperlipidemia, hypertension, diabetes mellitus, hyperuricemia, and angina pectoris.

Twenty-three were taking anti-thyroid drugs (n = 8) or thyroid hormones (n = 15). Patients taking these medicines were included in the study.

The diagnosis of ischemic heart disease was based on the patient's history, ECG findings, and information provided by general physicians. An experienced cardiologist reviewed the ECG findings of all participants.

Measurements

Body mass index (BMI) was calculated as kg/m². Low-density lipoprotein cholesterol (mg/dL) was determined according to the Friedewald formula as (total cholesterol −high-density lipoprotein cholesterol − triglyceride)/5 (mg/dL). Serum TSH levels were determined by chemiluminescent enzyme immunoassay using the Lumipulse system (reference range, 0.54‱4.26 mU/L). Free T4 levels were determined by electrochemiluminescence immunoassay using the Modular Analytics system (reference range, 0.9‱1.7 ng/dL). TgAb and TPOAb levels were determined using radioassay kits (RSR, Cardiff, UK) (18). Values less than 0.3 U/mL were regarded as negative for both assays. TBII levels were determined according to the second-generation assay using TSH receptor antibody–coated tube (TRAb CT) kit (Cosmic Corp.), originally from RSR, with values of less than 10% being regarded as negative (19). TSAb levels were assayed using Yamasa kit (reference range, less than 180%) (20).

Statistical analyses

Data were expressed as mean ± standard deviation unless otherwise indicated. The difference was analyzed by χ ²-test or by two-tailed Student's t-test for unpaired data. In the studies of lipid metabolism and the prevalence of coronary heart disease, all data were adjusted for age before comparison. When the prevalence of an elevated low-density lipoprotein cholesterol or taking of lipid-lowering drugs, referred to here as ALM, in each group of patients with abnormal thyroid function was compared, the Mantel-Haenszel procedure was employed for age adjustment and determination of an odds ratio with 95% confidence interval (CI). A p-value less than 0.05 was considered significant.

Results

The prevalence of elevated or reduced serum-free T4 or TSH concentrations

Serum TSH levels were elevated in 117 (6.4%) of 1818 subjects. Among them, 12 had reduced serum-free T4 levels. Thus, the prevalence of overt hypothyroidism (OH) was 0.7%. SH with normal free T4 levels was present in 105 subjects (5.8%). Fifty-two subjects had reduced serum TSH concentrations. Among them, 13 (0.7%) had elevated serum-free T4 concentrations and were considered to have OT, and 39 (2.1%) had normal serum-free T4 concentrations and were considered to have ST (Table 1).

Table 1.

Prevalence of Abnormal Results from Thyroid Function Tests

Thyroidal status	TSH concentration	Free T4 concentration	Number of subjects	Prevalence (%)
Overt thyrotoxicosis	Low	High	13	0.7
Subclinical thyrotoxicosis	Low	Normal	39	2.1
Euthyroidism	Normal	Normal	1633	89.8
Subclinical hypothyroidism	High	Normal	105	5.8
Overt hypothyroidism	High	Low	12	0.7
Others	Normal	High	4a	0.2
	Normal	Low	10b	0.6
	Low	Low	2c	0.1
	High	High	0	0
Total			1818	100

Free T4 and TSH levels were determined in all 1818 subjects. The reference range was 0.54–4.26 mU/L for TSH and 0.9–1.7 ng/dL for free T4.

Free T4 levels ranged between 1.72 and 1.98 ng/dL. None of them were considered to have TSH secreting pituitary adenoma or thyroid hormone resistance.

Central hypothyroidism was not suspected clinically showing normal TSH but slightly decreased free T4 ranging between 0.64 and 0.89 ng/dL.

One with TSH at 0.03 mU/L and free T4 at 0.83 ng/dL was under treatment with T4 after resection of thyroid cancer. Another with TSH at 0.08 mU/L and free T4 at 0.89 ng/dL showed positive TgAb and positive TPOAb.

TSH, thyrotropin; T4, thyroxine.

Sex- and thyroid-related abnormalities

SH was significantly more prevalent (p < 0.001) in women than in men, as were positive tests for TgAb and TPOAb and palpable goiter. Although only about 17.7% of the men had positive tests for TgAb or TPOAb, nearly one-third (31.4%) of the women had positive tests (Table 2).

Table 2.

Comparison of Thyroid Function, Thyroid-Related Antibodies, and Goiter Prevalence Between Men and Women

Thyroid related parameters	Men		Women		Statistical significance
Thyroid related parameters	Number of subjects	Prevalence (%)	Number of subjects	Prevalence (%)	Statistical significance
Elevated free T4	8	1	8	0.8	NS
Reduced free T4	5	0.6	19	1.9	p < 0.05
Elevated TSH	28	3.5	89	8.8	p < 0.001
Reduced TSH	26	3.2	28	2.8	NS
Overt thyrotoxicosis	5	0.6	8	0.8	NS
Subclinical thyrotoxicosis	21	2.6	18	1.8	NS
Subclinical hypothyroidism	25	3.1	80	7.9	p < 0.001
Overt hypothyroidism	3	0.4	9	0.9	NS
Palpable goiter	48	6.0	142	32.8	p < 0.001a
Positive TBII	7	0.9	15	1.5	NS
Positive TgAb	105	13.1	298	29.4	p < 0.001
Positive TPOAb	58	7.2	152	15.0	p < 0.001
Positive TgAb or TPOAb	142	17.7	318	31.4	p < 0.001
Positive TgAb and TPOAb	37	4.6	132	13.0	p < 0.001

The prevalence was assessed in 804 men and 1014 women except that of palpable goiter.

Presence of palpable goiter was judged by the first author (K.K.), a thyroid specialist, in all 804 men and 433 women.

NS, nonsignificant; TBII, TSH-binding inhibitor immunoglobulins; TgAb, anti-thyroglobulin antibodies; TPOAb, anti-thyroid peroxidase antibodies.

Relation between thyroid enlargement and anti-thyroid antibodies

The relation between thyroid enlargement and anti-thyroid antibodies was studied in those evaluated by a thyroid specialist (K.K.) alone. TgAb or TPOAb was positive in 38.0% of women and in 27.1% of men with palpable goiter, while it was positive in 23.4% of women and in 14.8% of men without palpable goiter (Table 3). These parameters were all greater in those with palpable goiter than in those without palpable goiter.

Table 3.

Prevalence of Palpable Goiter in Relation with Anti-Thyroid Antibodies

Sex	Goiter	Number of subjects (prevalence %)
Sex	Goiter	Total	Positive for TgAb	Positive for TPOAb	Positive for both TgAb and TPOAb	Positive for either TgAb or TPOAb
Women	Palpable	142 (100%)	49 (34.5%)	30 (21.1%)	25 (17.6%)	54 (38.0%)
Women	Not palpable	291 (100%)	64 (22.0%)	23 (7.9%)	19 (6.5%)	68 (23.4%)
Men	Palpable	48 (100%)	11 (22.9%)	6 (12.5%)	4 (8.3%)	13 (27.1%)
Men	Not palpable	756 (100%)	94 (12.4%)	52 (6.9%)	34 (4.5%)	112 (14.8%)

The presence of palpable goiter was evaluated by the first author (K.K.), a thyroid specialist.

Effect of aging on thyroid function and detection of antibodies

Aging was significantly associated with an increased prevalence of high TSH (Table 4) (p < 0.001 for women and p < 0.05 for men). It was inversely correlated with low TSH in men (p < 0.05).

Table 4.

Serum Thyrotropin, Anti-Thyroglobulin Antibodies, and Anti-Thyroid Peroxidase Antibodies in Relation with Sex and Age

Women
	Number of subjects (prevalence %)
Age (years)	Total	Increased TSH a	Decreased TSH	Positive TgAb	Positive TPOAb
<40	105	5 (4.8%)	3 (2.9%)	37 (35.2%)	16 (15.2%)
40–50	308	20 (6.5%)	12 (3.9%)	86 (27.9%)	40 (13.0%)
50–60	487	40 (8.2%)	10 (2.1%)	140 (28.7%)	79 (16.2%)
>60	114	24 (21.1%)	3 (2.6%)	35 (30.7%)	17 (14.9%)
Total	1014	89 (8.8%)	28 (2.8%)	298 (29.4%)	152 (15.0%)

Men
	Number of subjects (prevalence %)
Age (years)	Total	Increased TSH b	Decreased TSH b	Positive TgAb	Positive TPOAb
<40	96	1 (1.0%)	6 (6.3%)	14 (14.6%)	4 (4.2%)
40–50	225	6 (2.7%)	12 (5.3%)	30 (13.3%)	14 (6.2%)
50–60	329	9 (2.7%)	4 (1.2%)	38 (11.6%)	22 (6.7%)
>60	154	12 (7.8%)	4 (2.6%)	23 (14.9%)	18 (11.7%)
Total	804	28 (3.5%)	26 (3.2%)	105 (13.1%)	58 (7.2%)

p < 0.001.

p < 0.05.

Prevalence of TBII, TgAb, TPOAb, and palpable goiter in relation with thyroid function

Thyroid dysfunction was associated with increased prevalence of thyroid-related antibodies and palpable goiter. The prevalence of all TBII, TgAb, TPOAb, and palpable goiter in the combined ST and OT, and SH and OH groups was significantly higher than in the euthyroid group (Table 5).

Table 5.

Prevalence of TSH-Binding Inhibitor Immunoglobulins, Anti-Thyroglobulin Antibodies, Anti-Thyroid Peroxidase Antibodies, and Palpable Goiter in Relation with Thyroidal Status

	The number of subjects (prevalence)
	TBII	TgAb	TPOAb	Palpable goiter
OT	6a (46.2%)	7a (53.8%)	6a (46.2%)	6a (54.5%)
ST	4a (10.3%)	12b (30.8%)	8b (20.5%)	7 (29.2%)
Eu	7 (0.4%)	340 (20.8%)	159 (9.7%)	151 (13.3%)
SH	3 (2.9%)	35c (33.3%)	28a (26.7%)	24a (42.1%)
OH	2a (16.7%)	8a (66.7%)	8a (66.7%)	2 (28.6%)

p < 0.001, ^b p < 0.05, and ^c p < 0.01 compared to the euthyroid group. In case of goiter palpation, the prevalence was assessed in 1138 normal subjects, 11 OT, 24 ST, 57 SH, and 7 OH patients, who were examined by the first author (K.K.). The prevalence of TBII and palpable goiter in the combined SH and OH group was significantly higher than that in the euthyroid group (both p < 0.001). The prevalence of palpable goiter in the combined ST and OT group was also significantly higher than that in the euthyroid group (p < 0.001).

OT, overt thyrotoxicosis (n = 13); ST, subclinical thyrotoxicosis (n = 39); Eu, euthyroidism (n = 1633); SH, subclinical hypothyroidism (n = 105); OH, overt hypothyroidism (n = 12).

A comparison between men and women, however, revealed discrepant results in the case of goiter prevalence. The prevalence of palpable goiter was not significantly different either in the combined OT and ST (16.0%; 4/25) or in the combined SH and OH (14.3%; 4/28) groups from that in the euthyroid group (5.3%; 40/751) in men. On the other hand, the prevalence among the three women groups was markedly different: 90% (9/10) for the combined OT and ST group and 61.1% (22/36) for the combined SH and OH group; both groups were p < 0.001 compared to the euthyroid group (28.7%; 111/387).

Subclinical hypothyroidism

In SH patients, positive tests for TgAb and TPOAb and palpable goiter were all more prevalent than in euthyroid subjects (Table 5). In SH patients who were not on lipid- or cholesterol-lowering medications, serum cholesterol was somewhat higher in the older SH group compared to the euthyroid group, but there was no difference in age-adjusted serum cholesterol between these two groups (data not shown). The prevalence of ALM was significantly higher in SH (p < 0.01) than in euthyroid subjects, when adjusted for age (Table 6). Thus, SH was associated with hyperlipidemia with an odds ratio of 1.67 with 95% CI of 1.10–2.51.

Table 6.

Prevalence of Abnormal Lipid Metabolism in Relation with Thyroidal Status

Thyroidal state	The number of subjects with ALM/the total number of subjects	The prevalence of ALM (%)	Odds ratio (95% confidence interval)
OT	0/13	0	–a
ST	9/39	23.1	0.69 (0.33–1.49)
Eu	488/1633	29.9	–
SH	46/105	43.8	1.67b (1.10–2.51)
OH	8/12	66.7	3.37c (1.02–11.1)

Subjects with elevated low-density lipoprotein cholesterol levels (>140 mg/dL) or under anti-lipidemia medication were regarded to have ALM.

p < 0.05, ^b p < 0.001, and ^c p < 0.01 compared with the euthyroid group.

ALM, abnormal lipid metabolism.

Overt hypothyroidism

Among the 12 subjects with OH, 8 had positive tests for TgAb or TPOAb, and 2 had positive tests for TBII. One TBII-positive subject had a blocking-type TSH receptor antibody (21), and another had a history of radioiodine treatment for hyperthyroidism caused by Graves' disease. Thus, the positive tests for TBII, TgAb, and TPOAb were all more prevalent in the OH group than in euthyroid subjects (Table 5). However, goiter was present in only two subjects, including one with undetectable TgAb, TPOAb, and TBII. Goiter was not present in the remaining 10 subjects, 5 of whom were examined by the first author. Hypothyroidism was not associated with habitual dietary ingestion of seaweed (22,23). OH was also associated with hyperlipidemia with an odds ratio of 3.37 with 95% CI of 1.02–11.1 (Table 6).

Subclinical thyrotoxicosis

All TBII, TgAb, and TPOAb were more commonly detected in ST patients than in euthyroid subjects (Table 5). Among the 39 patients, 3 (including 2 with positive TBII) had been treated with antithyroid drugs for Graves' disease, and 4 patients had been taking T4 for hypothyroidism. One patient with positive TBII had euthyroid ophthalmic Graves' disease. One patient with positive TBII became euthyroid in 3 months concomitant with normalization of TBII. The cause of SH was not investigated in the other patients.

Overt thyrotoxicosis

Table 7 shows the clinical features of the 13 subjects with new onset OT. Eight had Graves' disease and five had painless thyroiditis. None of the patients except number 6 had a history of thyroid disease. This patient had been diagnosed as having Graves' disease at another hospital several months before, but refused treatment. The degree of thyrotoxicosis in patients with Graves' disease, as assessed by serum-free T4 concentrations, was relatively mild. Only one with OT caused by Graves' disease had tachycardia, one had an elevated serum concentration of alkaline phosphatase, none had hypocholesterolemia, and five of the eight patients, all of whom were men, did not have clear thyroid enlargement on physical examination. In all of the patients with OT caused by Graves' disease, there were few, if any, unequivocal symptoms of thyrotoxicosis.

Table 7.

Clinical Features of 13 Cases of Overt Thyrotoxicosis

Subject	Sex	Age (years)	FT4 (ng/dL)	TSH (mUL)	TBII (%)	Thyroid stimulating antibodies (%)	Diagnosis	Goiter	HR	T-chol (mg/dL)	ALP (IU/L)
1	Female	45	2.94	<0.01	4.9	127	GD	Diffuse	72	142	86
2	Male	57	2.5	<0.01	5.7	204	GD	np	55	169	165
3	Male	44	2.25	<0.01	26	108	GD	np	72	133	223
4	Female	51	2.18	<0.01	35.4	192	GD	Diffuse	72	162	199
5	Male	46	2.08	<0.01	41.6	408	GD	np	102	191	309
6	Female	55	1.81	<0.01	65.3	819	GD	Diffuse	79	182	364
7	Male	41	1.93	0.05	22.1	187	GD	np	56	192	151
8	Female	44	1.71	0.34	14.1	nd	GD	np*	70	153	202
9	Female	35	3.18	<0.01	5.3	nd	PT	Diffuse	67	115	192
10	Female	54	3.14	<0.01	0.6	138	PT	Diffuse	120	167	206
11	Female	50	2.01	<0.01	0	nd	PT	Diffuse	68	168	211
12	Female	48	3.33	0.02	4.7	nd	PT	np*	68	128	189
13	Male	45	2.18	0.07	0	nd	PT	np	62	175	162
Reference range			0.9–1.7	0.54–4.26	<10	<180				120–220	104–338

None except subject 6 had a history of thyroid disease.

HR, heart rate (beats/minute) determined from the record of electrocardiogram taken at rest; np, not palpable when judged by a thyroid specialist; the first author; np*, not palpable when judged by 2nd–6th authors; nd, not determined; GD, Graves' disease; PT, painless thyroiditis.

The prevalence of all parameters, including TgAb, TPOAb, TBII, and palpable goiter, was all significantly higher than in euthyroid subjects (Table 5). ALM was significantly less common in OT (p < 0.05) than in euthyroid subjects (Table 6).

Relation between serum thyroid function and cholesterol levels

As already stated, ALM was significantly more common in SH and OH patients than in euthyroid subjects (Table 6). BMI higher than 25 was also associated with ALM (p < 0.001) with an odds ratio of 1.53 and 95% CI of 1.38–1.73. The prevalence of hypothyroidism including OH and SH among those with ALM was 9.7%, which was significantly higher (5.1%) than in those without ALM (p < 0.001).

Neither BMI nor HbA1C was significantly different in patients with abnormal thyroid function compared with euthyroid subjects.

Prevalence of ischemic heart disease in patients with thyroid dysfunction

There were no differences in the prevalence of ischemic heart disease between patients with thyroid dysfunction and euthyroid subjects in the same age range.

Discussion

We conducted an epidemiological study in a general health checkup program at our hospital. Although this study may have limitations in terms of random sampling, we would insist that it accurately indicates the medical condition of the typical middle-aged Japanese. The prevalence of thyroid dysfunction was 9.3% consisting of 0.7% of OH, 5.8% of SH, 0.7% of OT, and 2.1% of ST, in accordance with previous studies (2,13,24,25). The age-dependent increase in the prevalence of hypothyroidism was also in accordance with previous studies (2,7,23 –26).

We investigated the underlying thyroid diseases responsible for thyroid dysfunction, focusing on the role of thyroid autoimmunity by measuring TgAb, TPOAb, and TBII levels in all subjects who participated in the present study. A few studies (26 –28) have measured TgAb and TPOAb in the general population by radioimmunoassay, known to be more sensitive than the hemagglutination method (29). Our present results for the prevalence of TPOAb (15.0% for women and 7.2% for men) were similar to those of previous studies (26 –28). Our results for the prevalence of TgAb (29.4% for women and 13.1% for men) were slightly higher than their results (26 –28). Significant association of hypothyroidism with detectable TgAb and TPOAb, which was reported in previous studies as well (7,24,27,29,30), suggests that autoimmune thyroid dysfunction is strongly involved in the etiology of hypothyroidism. In contrast with our result, Hollowell et al. (26) reported that there was no significant association between hypothyroidism and positive TgAb. The reason is unclear, but the use of a different method for measurement of antibodies or some genetic difference might be a factor responsible for the discrepancy. In this regard, Li et al. recently reported that constant intake of high iodine increases the prevalence of positive TgAb and is a risk factor developing hypothyroidism (27), which might explain the high prevalence of TgAb being associated with hypothyroidism in the present study performed in an iodine-sufficient country.

The higher prevalence of TBII in hypothyroidism could indicate the inclusion of data on patients with treated Graves' disease and blocking-type TSH-receptor antibody (21). With regard to the association of thyrotoxicosis with anti-thyroid antibodies, the prevalence of decreased TSH has been reported to be associated with TPOAb alone (26), or with neither antibody (30). The higher prevalence of TgAb, TPOAb, and TBII as well as palpable goiter in thyrotoxic subjects is probably because of the inclusion of data on patients with autoimmune thyroid diseases such as Graves' disease, painless thyroiditis, and euthyroid ophthalmic Graves' disease in this group (31,32).

It is well known that the classical signs of hypothyroidism are present only in severe OH. Diagnosis of hypothyroidism and even mild thyrotoxicosis is frequently missed, unless goiter is palpable in a general outpatient clinic. The question arises whether the presence of palpable goiter is an important clue to predict thyrotoxicosis or hypothyroidism. In the present study, the prevalence of TgAb or TPOAb, known to be associated closely with the histological diagnosis of Hashimoto's thyroiditis (97.6% for positive predictive value, and 89.3% for negative predictive value) (29), was as high as 23.4% for women and 14.8% for men even without thyroid enlargement evaluated by a thyroid specialist. This finding together with the high prevalence of TgAb or TPOAb and nonpalpable goiter in the patients with OH suggests that most euthyroid or hypothyroid subjects with detectable TgAb or TPOAb can be diagnosed as having Hashimoto's thyroiditis irrespective of thyroid enlargement. Thus, the presence of palpable goiter may be a marker to suspect Hashimoto's thyroiditis, but appears not to be an important clue to make such a diagnosis. Considering the difficulty in detecting mild hypothyroidism and Hashimoto's thyroiditis, thyroid screening tests are strongly recommended in suspect cases. In agreement with previous studies (2,7,23 –26,30), women had a higher prevalence of high TSH, low free T4, positive TgAb, positive TPOAb, and palpable goiter, supporting the evidence that women are more frequently affected by Hashimoto's thyroiditis than men.

With regard to the relation between anti-thyroid antibodies and aging, an increased prevalence of TgAb and TPOAb in association with increase in age was reported (2,7,23 –27), suggesting that the age-dependent increase in the prevalence of hypothyroidism is due to development of Hashimoto's thyroiditis (23 –27). However, in the present study, the age-dependent increase in the prevalence of hypothyroidism was not accompanied by an increased prevalence of TgAb or TPOAb. Therefore, some factors other than thyroid autoimmunity might be responsible for hypothyroidism that develops in elderly adults. It may also explain the obtained result that two-thirds or three quarters of SH patients showed negative test results for TgAb or TPOAb, respectively. Age-dependent decrease in the prevalence of low TSH observed in men is inexplicable. There was no age-dependent change in the prevalence of TBII (data not shown) in the present study.

During the observation period, 13 subjects were found to have OT. Graves' disease diagnosed in eight subjects was mild and was probably at an early stage, judging from the weakly positive or negative TBII and TSAb, and a high prevalence of unpalpable goiter. Favorable outcome of anti-thyroid drug treatment can be expected in such cases (17). Thus, early detection of symptom-free biochemical thyrotoxicosis appears clinically important, indicating that TSH measurement is strongly recommended as a screening test in a general health checkup evaluation program.

It is still a matter of debate whether SH is associated with increased risk of hypercholesterolemia and/or ischemic heart disease. It has been reported that serum cholesterol levels were elevated (1 –5) or normal (6,7,13) in SH compared with euthyroid controls. In the present study, the age-adjusted prevalence of ALM was significantly greater in SH. However, low prevalence of SH and OH (9.7%) in the dyslipidemic group indicates that ALM is caused mostly by thyroid-unrelated disorders.

Although SH subjects showed significantly increased prevalence of ischemic heart disease than euthyroid subjects, the statistical difference was abolished when the age-adjusted prevalence was compared in this cross-sectional study. This result is in discordance with other studies (6 –9). Further prospective studies examining a larger group of subjects are required.

Footnotes

Acknowledgments

We thank Prof. Kenichi Sato, Information Science Center, Tohoku Pharmaceutical University, for his assistance with statistical analysis. We also thank SRL, Inc. for measurement of serum-free T4 and Cosmic Corp. for measurement of TBII, TgAb, and TPOAb.

Disclosure Statement

The authors declare that no competing financial interests exist.

References

Miura

, Iitaka

, Yoshimura

, Kitahama

, Fukasawa

, Kawakami

, Sakurai

, Urabe

, Sakatsume

, Ito

, Ishii

. 1994. Disturbed lipid metabolism in patients with subclinical hypothyroidism: effect of L-thyroxine therapy. Intern Med, 33:413–417.

Canaris

, Manowitz

, Mayor

, Ridgway

. 2000. The Colorado thyroid disease prevalence study. Arch Intern Med, 160:526–534.

Kahaly

. 2000. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid, 10:665–679.

Kanaya

, Harris

, Volpato

, Pérez-Stable

, Harris

, Bauer

. 2002. Association between thyroid dysfunction and total cholesterol level in an older biracial population: the health, aging and body composition study. Arch Intern Med, 162:773–779.

Caraccio

, Ferrannini

, Monzani

. 2002. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study. J Clin Endocrinol Metab, 87:1533–1538.

Hak

, Pols

, Visser

, Drexhage

, Hofman

, Witteman

JCM

. 2000. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med, 132:270–278.

Imaizumi

, Akahoshi

, Ichimaru

, Nakashima

, Hida

, Soda

, Usa

, Ashizawa

, Yokoyama

, Maeda

, Nagataki

, Eguchi

. 2004. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab, 89:3365–3370.

Walsh

, Bremner

, Bulsara

, O'Leary

, Leedman

, Feddema

, Michelangeli

. 2005. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med, 165:2467–2472.

Rodondi

, Aujesky

, Vittinghoff

, Cornuz

, Bauer

. 2006. Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med, 119:541–551.

10.

Rodondi

, Newman

, Vittinghoff

, de Rekeneire

, Satterfield

, Harris

, Bauer

. 2005. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med, 165:2460–2466.

11.

Baldini

, Vita

, Mauri

, Amodei

, Carrisi

, Bravin

, Cantalamessa

. 1997. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry, 21:925–935.

12.

Chueire

, Romaldini

, Ward

. 2007. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr, 44:21–28.

13.

Cappola

, Fried

, Arnold

, Danese

, Kuller

, Burke

, Tracy

, Ladenson

. 2006. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA, 295:1033–1041.

14.

Földes

, Tarján

, Szathmari

, Varga

, Krasznai

, Horvath

. 1993. Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for osteoporosis? Clin Endocrinol (Oxf), 39:521–527.

15.

Surks

, Ortiz

, Daniels

, Sawin

, Col

, Cobin

, Franklyn

, Hershman

, Burman

, Denke

, Gorman

, Cooper

, Weissman

. 2004. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA, 291:228–238.

16.

Nagataki

. 2008. The average of dietary iodine intake due to the ingestion of seaweeds is 1–2 mg/day in Japan. Thyroid, 18:667–668.

17.

Ikekubo

, Hino

, Ito

, Koh

, Ishihara

, Kurahachi

, Kasagi

, Hidaka

, Mori

. 1990. Thyrotoxic Graves' disease with normal thyroidal technetium-99m pertechnetate uptake. Ann Nucl Med, 4:43–48.

18.

Beever

, Bradbury

, Phillips

, McLachlan

, Pegg

, Goral

, Overbeck

, Feifel

, Smith

. 1989. Highly sensitive assays of autoantibodies to thyroglobulin and to thyroid peroxidase. Clin Chem, 35:1949–1954.

19.

Kasagi

. 2003. Evaluation of new sensitive solid-phase assays for TSH binding inhibitor immunoglobulins: comparison between DYNOtest TRAb Human (Yamasa) and TRAb CT (Cosmic) kits. (in Japanese) Hormone-to-rinsho, 51:839–849.

20.

Inui

, Kouki

, Yamashiro

, Hachiya

, Ochi

, Kajita

, Sato

, Nagata

. 1998. Increase of thyroid stimulating activity in Graves' immunoglobulin-G by high polyethylene glycol concentrations using porcine thyroid cell assay. Thyroid, 8:319–325.

21.

Konishi

, Iida

, Kasagi

, Misaki

, Nakashima

, Endo

, Mori

, Shinpo

, Nohara

, Matsuura

, Torizuka

. 1985. Primary myxedema with thyrotrophin-binding inhibitor immunoglobulins. Clinical and laboratory findings in 15 patients. Ann Intern Med, 103:26–31.

22.

Kasagi

, Iwata

, Misaki

, Konishi

. 2003. Effect of iodine restriction on thyroid function in patients with primary hypothyroidism. Thyroid, 13:561–567.

23.

Konno

, Yuri

, Taguchi

, Miura

, Taguchi

, Hagiwara

, Murakami

. 1993. Screening for thyroid diseases in an iodine sufficient area with sensitive thyrotrophin assays, and serum thyroid autoantibody and urinary iodide determinations. Clin Endocrinol (Oxf), 38:273–281.

24.

Tunbridge

, Evered

, Hall

, Appleton

, Brewis

, Clark

, Evans

, Young

, Bird

, Smith

. 1977. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf), 7:481–493.

25.

Okamura

, Ueda

, Sone

, Ikenoue

, Hasuo

, Sato

, Yoshinari

, Fujishima

. 1989. A sensitive thyroid stimulating hormone assay for screening of thyroid functional disorder in elderly Japanese. J Am Geriatr Soc, 37:317–322.

26.

Hollowell

, Staehling

, Flanders

, Hannon

, Gunter

, Spencer

, Braverman

. 2002. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III) J Clin Endocrinol Metab, 87:489–499.

27.

, Teng

, Shan

, Teng

, Guan

, Yu

, Fan

, Chong

, Yang

, Dai

, Gu

, Yu

, Mao

, Zhao

, Li

, Chen

, Yang

, Li

, Teng

. 2008. Antithyroperoxidase and antithyroglobulin antibodies in a five-year follow-up survey of populations with different iodine intakes. J Clin Endocrinol Metab, 93:1751–1157.

28.

Pedersen

, Knudsen

, Jørgensen

, Perrild

, Ovesen

, Laurberg

. 2003. Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin Endocrinol (Oxf), 58:36–42.

29.

Kasagi

, Kousaka

, Higuchi

, Iida

, Misaki

, Alam

, Miyamoto

, Yamabe

, Konishi

. 1996. Clinical significance of measurements of antithyroid antibodies in the diagnosis of Hashimoto's thyroiditis: comparison with histological findings. Thyroid, 6:445–450.

30.

Parle

, Franklyn

, Cross

, Jones

, Sheppard

. 1991. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf), 34:77–83.

31.

Kasagi

, Hidaka

, Misaki

, Miyamoto

, Takeuchi

, Sakahara

, Sasayama

, Iida

, Konishi

. 1994. Scintigraphic findings of the thyroid in euthyroid ophthalmic Graves' disease. J Nucl Med, 35:811–817.

32.

Kasagi

, Takeuchi

, Misaki

, Kousaka

, Miyamoto

, Iida

, Konishi

. 1997. Subclinical Graves' disease as a cause of subnormal TSH levels in euthyroid subjects. J Endocrinol Invest, 20:183–188.