THYROIDVolume 13, Number 8, 2003© Mary Ann Liebert, Inc.

The Prevalence of Undiagnosed Thyroid Disorders in aPreviously Iodine-Deficient Area

Henry Völzke,1 Jan Lüdemann,2 Daniel M. Robinson,3 Knut W. Spieker,3 Christian Schwahn,4

Axel Kramer,5 Ulrich John,1 and Wieland Meng3

Objective: The aim of the present study was to analyze the current status of morphologic and functional thy-roid abnormalities in a previously iodine-deficient area. Methods: The population based Study of Health inPomerania (SHIP) comprised 4310 participants, aged 20–79 years. Thyroid function (thyrotropin [TSH] free tri-iodothyronine [FT3], and free thyroxine [FT4]) and serum autoantibodies to thyroperoxidase (TPOAb) wereevaluated from blood samples. Thyroid structure and size were measured by ultrasound. Data from 3941 par-ticipants with no known thyroid disorders were analyzed. Results: The median iodine urine excretion was 12.4mg/dL. The rate of decreased serum TSH levels (,0.3 mIU/L) was 11.3%; 2.2% of participants had suppressedserum TSH levels (,0.1 mIU/L). The prevalence of subclinical hyperthyroidism was 1.8%, the prevalence ofovert hyperthyroidism 0.4%. Elevated TSH levels were found in 1.2% of individuals. Subclinical hypothyroidismwas observed in 0.5%, overt hypothyroidism in 0.7% of the sample. Elevated TPOAb were detected in 7% ofsubjects, 4.1% of participants had TPOAb greater than 200 IU/mL. The prevalence of goiter was 35.9%. An in-homogeneous echo pattern was detected in 35.2% and nodules in 20.2% of participants. Diffuse autoimmunethyroiditis was diagnosed in 47 subjects (1.2%). Conclusion: There are a number of thyroid disorders in this pre-viously iodine-deficient region. Further studies are required to investigate the change of thyroid disorders dur-ing iodine supplementation programs.

803

Introduction

IODINE DEFICIENCY is a risk factor for goiter, thyroid nodu-larity and hyperthyroidism (1). Iodine-induced hyperthy-

roidism occurs more often in regions of long-term iodine de-ficiency (2). Little is known about the prevalence of thyroiddisorders after iodine supplementation in previously iodine-deficient regions.

West Pomerania, a region located in northeast Germany,was a previously iodine-deficient area with endemic goiter(3,4). The prophylactic procedures that were gradually in-troduced in 1983 were different between the eastern andwestern part of Germany. In East Germany, iodine supple-mentation was improved by mandatory iodine prophylaxis.However, after the reunification of Germany in 1989 and theadaptation of the “voluntary principle” the iodine intake de-creased again (5). In December 1993, improved legislationconcerning the iodization of table salt became effective.These changes contributed considerably to an increase in theuse of iodized salt for food production. The median urinaryiodine concentration in adolescents of the study area in-

creased from 6.0 mg/dL in 1994 to 9.9 mg/dL in 1998 and to12.0 mg/dL in 2000 (1). Furthermore, the increase of iodinecontent of food and breast milk (6), and the decrease of thy-roid volume in adolescents (7,8) indicate the improved io-dine supply. But the effect of long-term iodine supplemen-tation on preexisting thyroid disorders is not wellunderstood, especially in middle-aged and older people. Epi-demiologic studies on evaluation of iodine supplementationprograms are rare. Iodine prophylaxis programs were evensuspected to cause iodine-induced hyperthyroidism in olderpeople (9).

The aim of the present study was to analyze the currentstatus of morphologic and functional thyroid abnormalitiesin West Pomerania as a previously iodine-deficient area.

Materials and Methods

The Study of Health in Pomerania (SHIP) is a cross-sec-tional epidemiologic survey in West Pomerania, a region innortheast Germany including the 3 cities of Greifswald, Stral-sund, Anklam, and 29 surrounding communities (10). The

1Department of Epidemiology and Social Medicine, 2Department of Clinical Chemistry, 3Medical Department, 4Department of Biosta-tistics, 5Department of Hygiene and Environmental Medicine, Ernst Moritz Arndt University Greifswald, Germany.

total population was 212,517 inhabitants. A two-stage clus-ter sampling method was adopted from the WHO MONICAProject Augsburg, Germany (11) and yielded twelve five-year age strata (20–79 years) for both genders, each includ-ing 292 individuals. Data collection started in October 1997and was finished in March 2001. In all, 7008 people were in-vited to participate and 4310 (68.8% of eligible subjects) did.All participants gave written informed consent. The studywas approved by the Ethics Committee of the University ofGreifswald.

There were 349 (62 men and 287 women) of 4310 subjectswith known thyroid disease. The disease was diagnosedwithin the past year in 50 of these participants (14.4%). Twohundred eighty persons (80.5%) reported taking thyroidmedication (iodine, thyroid hormone replacement, suppres-sion therapy, or thyrostatics). These individuals and an ad-ditional 20 participants (9 men and 11 women) with uncer-tainty regarding a possible thyroid disorder were excludedfrom further analysis. This resulted in a total study popula-tion of 3941 participants (2046 men and 1895 women) withno or undiagnosed thyroid disorders.

Sociodemographic characteristics and medical histories onthyroid disorders were assessed by computer-aided face-to-face interviews. Laboratory parameters were analyzed in acentral laboratory. Spot urine samples of 3858 participantswere collected and analyzed for iodine concentration by pho-tometric procedure (Photometer ECOM 6122, Eppendorf,Hamburg, Germany) with Sandell and Kolthoff reaction(12). One hundred sixty-six of the 3941 participants had noblood drawn. Serum thyrotropin (TSH), free thyroxine (FT4),and free triiodothyronine (FT3) levels were measured by im-munochemiluminescent procedures (FT3, LUMItest, Brahms,Berlin, Germany; TSH and FT4, LIA-mat, Byk Sangtec Diag-nostica GmbH, Frankfurt, Germany). The functional sensi-tivity of the TSH assay was 0.03 mIU/L. Reference rangeswere: TSH, 0.3–3 mIU/L; FT4, 10–25 pmol/L; FT3, 3.4–7.1pmol/L. Serum FT3 or FT4 levels were not available for 13persons. Thyroid status was defined as follows: euthyroid,TSH, FT4, and FT3 levels within the normal ranges; decreasedTSH level, TSH level less than 0.3 mIU/L; suppressed TSHlevel, TSH level less than 0.1 mIU/L; subclinical hyperthy-roid, suppressed TSH level and FT4 and FT3 levels withinthe normal ranges; hyperthyroid, suppressed TSH level andFT4 greater than 25 pmol/L and/or FT3 greater than 7.1pmol/L; subclinical hypothyroid, TSH level greater than 3mIU/L and FT4 and FT3 levels within the normal ranges; hy-pothyroid, TSH level greater than 3 mIU/L and FT4 less than10 pmol/L and/or FT3 less than 3.4 pmol/L.

Serum autoantibodies to thyroperoxidase (TPOAb) weremeasured by an enzyme immunoassay (VARELISA, EliasMedizintechnik GmbH, Freiburg, Germany). The functionalsensitivity of this assay was 1 IU/mL. The normal range wasless than 60 IU/mL for men and less than 100 IU/mL forwomen. TPOAb were not available in 16 subjects. TheTPOAb status was defined as follows: normal, less than 60IU/mL in men; less than 100 IU/mL in women; elevated, 60IU/mL or more in men; or more 100 IU/mL in women; pos-itive, greater than 200 IU/mL (13).

Thyroid ultrasonography was performed with an Ultra-sound VST-Gateway with a 5-MHz linear array transducer(Diasonics, Santa Clara, CA) in 3915 participants. Thyroidvolume was calculated as length 3 width 3 depth 3 0.479

(mL) for each lobe (14). Goiter was defined as a thyroid vol-ume exceeding 18 mL in women and 25 mL in men (15). Thenormal thyroid echo pattern was classified as homogenous.A homogeneous echo pattern with reduced echogenicity wasdefined as hypoechogenic. An autoimmune thyroiditis wasassumed, if a hypoechogenic echo pattern of both thyroidlobes was combined with TPOAb positivity. If the echo pat-tern was not homogeneous, showing small lesions or distinctdiffuse abnormalities in the echotexture of the gland, it wasclassified as inhomogeneous (14). Nodular changes exceed-ing 10 mm in diameter were defined as nodules.

Statistics

Data on quantitative characteristics are expressed as me-dian and range. Data on qualitative characteristics are ex-pressed as percent values or absolute numbers as indicated.Comparisons between groups were made using x2-test(nominal data) or Mann-Whitney U test (interval data). Age-adjusted analyses were done by logistic regression. Odds ra-tio (OR) and its 95% confidence interval (95% CI) are given.A value of p , 0.05 was considered statistically significant.All statistical analyses were performed with SPSS software(SPSS GmbH Software, Munich, Germany).

Results

We analyzed a final population of 3941 participants withno known thyroid disorders, between the ages of 20 and 79years. Age and gender distributions were similar between 20and 59 years of age. Above the age of 60 years, however, thenumber of subjects decreased progressively and because ofthe exclusion of individuals with known thyroid disordersand more women excluded from the analysis, there were rel-atively fewer women (by 29.7%) (Fig. 1).

The median iodine urine excretion was 12.4 mg/dL. An io-dine excretion of less than 10 mg/dL was seen in 37% of par-ticipants and less than 5 mg/dL in 10.8%. Only 60 partici-pants (1.5%) had an iodine urine excretion less than 2 mg/dL(Fig. 2). These data define the current status as a non-io-dine–deficient area (16,17). There were no significant differ-ences between the iodine urine concentration over the 4 yearsof study.

Four hundred twenty-eight of the 3775 participants withblood drawn (11.3%) had decreased serum TSH levels lessthan 0.3 mIU/L. The distribution of decreased serum TSHlevels were age-dependent with higher percentages in olderdecades, but similar among women and men (Fig. 3). Sup-pressed TSH levels less than 0.1 mIU/L were found in 82subjects (2.2%) without a clear gender-related trend. How-ever, data obtained statistical significance for the increasewith age.

Sixteen persons (8 women and 8 men) of the 82 subjects(19.5%) with suppressed serum TSH levels were hyperthy-roid, 8 having elevated serum FT3 levels; 4, elevated serumFT4 levels; and 4, both increased serum FT3 and FT4 levels.The overall prevalence of overt hyperthyroidism was 0.4%,its distribution being age-dependent with a higher preva-lence in older decades. The remaining 66 persons (1.8%) withsuppressed TSH levels were classified as subclinical hyper-thyroid. The distribution of subclinical hyperthyroidism was

VÖLZKE ET AL.804

also age-dependent with higher percentages in older decadesbut similar among women and men.

Forty-five of 3775 (1.2%) subjects had TSH levels greaterthan 3 mIU/L. There was no continuous age-dependent in-crease of elevated TSH levels. Increased TSH levels weremore often detected in women compared to men (p forpooled data , 0.05; OR 2.77; 95% CI 1.44–5.3). There were 18persons (0.5%) with subclinical hypothyroidism. Among the45 participants with elevated TSH levels there were 27 (0.7%)with overt hypothyroidism, 22 of them having decreased FT4

levels; 2, decreased FT3 levels; and 3, both decreased FT4 andFT3 levels. The prevalence of overt hypothyroidism was notage-dependent and was more common in women comparedto men (p for pooled data , 0.05; OR 3.2; 95% CI 1.35–7.61).Elevated TPOAb activities were found in 265 subjects (7.0%)(Fig. 4). The distribution of increased TPOAb activities wasage- and gender-dependent with a higher prevalence in olderdecades and in women (p for pooled data , 0.05; OR 2.49;95% CI 1.91–3.26). A positive finding of TPOAb greater than200 IU/mL was detected in 153 subjects (4.1%). The preva-lence of positive TPOAb in older decades was significant inan overall statistical analysis. Women more often had posi-tive TPOAb than men (p for pooled data , 0.05; OR 4.75; 95%

CI 3.16–7.32). There was a strong relationship between TSHand TPOAb. Among participants with TSH levels 3 mIU/Lor less, 3.5% had positive TPOAb, whereas TPOAb positiv-ity was found in 47.3% of subjects with subclinical hy-pothyroidism and in 63.0% of participants with yet unknownovert hypothyroidism (p , 0.05).

Goiter was diagnosed in 1414 subjects (35.9%) (Table 1).The prevalence of goiter increased with age (p , 0.05). Therewas an age-adjusted tendency toward a higher prevalenceof goiter in men compared to women (p for pooled data 50.067; OR 1.13; 95% CI 0.99–1.29). The median serum TSHwas 0.51 mIU/L in subjects with goiter compared to 0.76mIU/L in subjects without goiter (p , 0.05).

The ultrasound investigation revealed 1389 positive find-ings (35.2%) of an inhomogeneous thyroid echo pattern(Table 1). An inhomogeneous thyroid echo pattern of the leftlobe was diagnosed in 385 subjects and of the right lobe in425 persons. Five hundred seventy-nine persons had an in-homogeneous echo pattern of both thyroid lobes. The dis-tribution of this ultrasound finding was age-dependent witha higher prevalence in older age groups (p , 0.05). Femalesubjects were more often affected than male participants (pfor pooled data , 0.05; OR 2.05; 95% CI 1.78–2.36). All par-

UNDIAGNOSED THYROID DISORDERS 805

FIG. 1. Age and gender distribution of the study population.

FIG. 2. The urine iodine excretion in the study population. The number of individuals per group is shown on the graphs.The rate of individuals per group is given in boxes.

ticipants with nodules were recommended to visit an en-docrinologist for further diagnostic tests. Results of thosetests, in particular data on the prevalence of definite thyroidcancer and its histologic classification were not available.Median serum TSH levels were not significantly different insubjects with an inhomogeneous echo pattern and in sub-jects with a homogenous echo pattern (0.62 mIU/L vs. 0.69mIU/L; p , 0.05). The goiter frequency was 44.8% in partic-ipants with an inhomogeneous thyroid echo pattern and31.4% in subjects with an homogeneous echo pattern (p ,0.05).

There were 791 participants (20.2%) with positive ultra-sound findings of thyroid nodules (Table 1). In 267 persons

nodules were detected within the left lobe and in 319 per-sons they were within the right lobe. Both lobes were affectedin 205 participants. More women had nodules compared tomen (p for pooled data , 0.05; OR 1.69; 95% CI 1.43–1.99).The prevalence of thyroid nodules increased with everydecade of age (p , 0.05). Subjects with nodules had a lowermedian TSH level (0.53 mIU/L) than subjects without thy-roid nodules (0.7 mIU/L) (p , 0.05). The prevalence of nod-ules in goiter was 62.7% vs. 29.4% in nongoiter persons (p ,0.05).

A hypoechogenicity of both thyroid lobes was found in182 subjects (4.6%) (Table 1). The prevalence was age-de-pendent with continuous increases over the decades (p ,

VÖLZKE ET AL.806

FIG. 3. Decreased serum thyrotropin (TSH) levels with respect to age and gender. *p , 0.05.

FIG. 4. Elevated serum autoantibodies to thyroperoxidase (TPOAb) levels with respect to age and gender. *p , 0.05.

UNDIAGNOSED THYROID DISORDERS 807

TABLE1.

THYROID

ULTRASO

UNDFI

NDIN

GS

WIT

HRESP

ECT

TOA

GE

ANDG

ENDER

Goiter

Inhomogeneous echo pattern

Nodules

Hypoechogenicity

(n 5

1414)

(n51389)

(n5791)

(n5182)

Age group

Male (n 5

776)

Female (n 5

638)

Male (n 5

600)

Female (n 5

789)

Male (n 5

354)

Female (n 5

437)

Male (n 5

42)

Female (n 5

140)

[years]

[%]

[%]

[%]

[%]

[%]

[%]

[%]

[%]

20–2

46.1

10.1

8.1

12.6

4.7

1.3

1.3

1.3

25–2

921

.421

.113

.518

.26.5

9.4

02.8

30–3

431

.230

.216

.430

.05.8

10.0

0.6

3.9

35–3

939

.233

.318

.529

.510

.411

.50

6.6

40–4

444

.338

.821

.540

.416

.922

.81.1

9.4

45–4

947

.336

.229

.044

.114

.819

.22.4

7.9

50–5

438

.527

.834

.643

.918

.423

.53.9

8.6

55–5

937

.742

.734

.656

.118

.926

.02.7

11.6

60–6

452

.338

.437

.658

.328

.438

.42.0

12.6

65–6

947

.342

.345

.270

.026

.145

.43.7

9.2

70–7

442

.949

.546

.661

.028

.852

.40.6

8.6

75–7

942

.253

.243

.762

.825

.247

.96.7

8.5

0.05) but with a marked decrease in women older than 70years. Women were more often affected than men (p forpooled data , 0.05; OR 4.15; 95% CI 2.91–5.91). The fre-quency of elevated TSH levels in subjects with and withouthypoechogenicity of both thyroid lobes was 11.7% vs. 0.7%(p , 0.05), the frequency of elevated TPOAb 26.3% vs. 3.0%(p , 0.05). Diffuse autoimmune thyroiditis as defined by thepresence of hypoechogenicity and TPOAb positivity was de-tected in 47 subjects (1.2%; 45 women and 2 men). The func-tional status of these participants was as follows: 13 subjects(27.7%) were hypothyroid, 3 (6.4%) subclinically hypothy-roid, 30 (63.8%) euthyroid, and 1 (2.1%) subclinically hyper-thyroid. Goiter was present in 9 of these participants (19.1%).

Discussion

The present study is a cross-sectional survey of thyroidabnormalities in a previously iodine-deficient area. The cur-rent median iodine urine excretion shows that the iodinesupplementation is now effective. However, there is still arelevant fraction of participants with low and very low uri-nary iodine levels indicating an insufficient iodine supply inthose people and a suboptimal current iodine supplementa-tion in the studied region.

There are three explanations for the high prevalence of de-creased serum TSH of 11.3% in all participants and of ap-proximately 20% in older decades. First, because of prior io-dine deficiency, older subjects especially had a significantlyhigher rate of nodularity with a hypothesized relevant partof autonomous adenoma included. Second, because oldersubjects more frequently had positive antibodies, Graves’disease may have caused decreased serum TSH levels. How-ever, there were only 17 of 385 participants (4.4%) with de-creased serum TSH who were also positive for TPOAb, ex-cluding an effect of Grave’s disease relevant for thesepopulation-based findings. Third, the lower TSH limit of 0.3mIU/L may have been responsible for the high prevalenceof decreased serum TSH levels. The borderline low TSH levelused in population based or epidemiological studies rangesfrom the functional sensitivity of the used assay (18) to 0.4mIU/L (19) indicating the need for international standard-ization.

Subclinical and overt hyperthyroidism were defined byfurther measurement of elevated FT3 and/or FT4 levels.There are few population based studies (13,19,20) that havebeen performed with this intensive approach. The preva-lence of hyperthyroidism of 0.64% found here was similar tothat reported for areas with sufficient iodine supplementa-tion (18,21) and mild iodine-deficient areas (13), whereas rel-evant hyperthyroidism could be detected in up to 2.9% of allcases in moderately iodine-deficient areas (22).

Women more often had thyroid nodules than men. How-ever, there was no gender-related trend for decreased andsuppressed serum TSH as well as for subclinical and overthyperthyroidism, and even a tendency towards a higher goi-ter prevalence in men. This might be related to selection ofthe study population that only comprised participants withas yet undiagnosed thyroid disorders. Females were moreoften excluded because of a known thyroid disorder thanmale participants. Thus, these findings may be explained byan earlier diagnosis of subclinical and overt hyperthyroidismin women compared to men.

The low prevalence of hypothyroidism in our populationis consistent with other studies from low to normal dietaryiodine uptake (13,23). An epidemiologic study from south-ern Germany (20) also revealed a prevalence of hypothy-roidism of 0.7% in people with as yet no known thyroid dis-eases. Studies performed in areas with high iodine uptake(18,21,24) revealed a prevalence of hypothyroidism from0.4% (25) up to 4.6% (18). In contrast to other studies (18,19)the distribution of hypothyroidism was not age-dependentand even showed a small decline in older age decades. Thisfinding should be interpreted with caution, because it is froma cross-sectional study.

Positive findings of TPOAb were more often found inolder persons and were more prevalent in women and insubjects with hypothyroidism. These results are consistentwith other studies (13,18,22,25,26). We differentiated be-tween elevated and positive TPOAb findings, because itcould be shown, that TPOAb levels greater than 200mIU/mL are much better associated with thyroid dysfunc-tion than mildly increased TPOAb levels (13).

Epidemiologic data on autoimmune thyroiditis defined bycombined characteristics of ultrasound and serum TPOAbare rare. Aghini-Lombardi and coworkers (22) found an au-toimmune thyroiditis prevalence of 3.5% in an Italian iodine-deficient community. Iodine deficiency increases the risk ofgoiter and this may overexpose the immune system to thy-roid antigens, leading to humoral and cell-mediated reac-tions that result in an elevated prevalence of autoimmunethyroiditis (22). Thus, the lower prevalence in our study maybe related to the improved iodine supplementation.

The prevalence of thyroid nodules of 20.2% is consistentwith the prevalence found in other study regions (27–31).Data from prospective studies (32,33) showed an annualgrowth of thyroid nodules of approximately 10%. Thisgrowth rate could not be decreased by use of iodide and/orlevothyroxine (34). This suggests that further improvementof iodine supply will probably not diminish the noduleprevalence in older decades. However, the high prevalenceof nodules in contrast to the low prevalence of overt hyper-thyroidism may indicate a beneficial functional effect of nu-tritional iodization.

The prevalence of goiter in people with as yet unknownthyroid disorders was 35.9%. Ultrasound studies from Ger-many in adults revealed a goiter prevalence of 42.6% (27)and 49.7% (28). Differences may result from selection bias.One study performed was clinical based (27) and the otherin elderly subjects older than 60 years (28). The lower goiterprevalence in our study area may also reflect the first posi-tive effects of an effective iodine food supplementation. Ithas been shown that the goiter prevalence decreased from36% in 1992 to 9% in 1998 in adolescents aged 11 to 17 yearsin the SHIP region (7). Other studies (8,34) from neighbor-hood regions confirmed these findings. The goiter preva-lence of 15% in the 20 to 29-year-age group of the SHIP pop-ulation and the low goiter prevalence in individuals youngerthan 40 years reported from Austria (35) correspond withthese results. The high goiter prevalence in older people in-dicates that a generation is probably needed to eradicate en-demic goiter by salt iodization.

A limitation of this cross-sectional study is that it does notallow the evaluation of changes in thyroid disorders by com-paring the situation “before” (when iodine deficiency was

VÖLZKE ET AL.808

present) to that of the “present time” (with corrected iodinedeficiency). However, further studies are required to inves-tigate the change of thyroid disorders during iodine sup-plementation programs. SHIP-1 is a 5-year follow-up surveythat was started in October 2002 and is designed to investi-gate this change. SHIP-1 is accompanied by public educationactivities with the aim to further increase iodine intake inour study population.

In conclusion, there are still a huge number of thyroid dis-orders in this previously iodine-deficient region. There is afurther need to inform the public about iodine nutrition, tostabilize and to improve iodine supplementation, to preventthyroid disease on a legislative level, and to control these ef-forts by accompanying studies in regions with a similar io-dine nutrition status.

Acknowledgments

This research work was funded in part by grants from theGerman Federal Ministry for Education and Research(BMBF, grant no. 01ZZ96030), from the Ministry for Educa-tion, Research and Cultural Affairs and the Ministry for So-cial Affairs of the State Mecklenburg-West Pomerania.

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Address reprint requests to:Henry Völzke, M.D.

Department of Epidemiology and Social MedicineErnst Moritz Arndt University

Walther Rathenau Str. 48D-17487 Greifswald

Germany

E-mail: voelzke@uni-greifswald.de

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