Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Antibody Positivity in Patients with Diffuse Goiter

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1 Philippine Journal of Internal Medicine Original Paper Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Antibody Positivity in Patients with Diffuse Goiter Sheryl N. Tugna, M.D.*; Maria Jocelyn Capuli-Isidro, M.D.* Abstract Background: To determine the thyroid ultrasound findings in association with anti-tpo positivity among patients with diffuse goiter. Design and Methods: We performed a cross-sectional study on patients with diffuse goiter seen at Makati Medical Center out-patient Endocrine clinics from October 1, 2011 to October 1, Patients with anti-tpo (thyroid peroxidase) above 100 pmol/l were considered anti-tpo positive and below this level were considered negative. After excluding patients with other possible causes of thyroiditis, thyroid ultrasound of anti-tpo positive and anti-tpo negative patients were reviewed and compared based on size, echogenicity, echopattern and vascularity of the thyroid parenchyma. Results: In 94 patients who qualified for the study, 43.6% were anti-tpo positive. A higher proportion of anti-tpo positive was seen among females compared to males by almost twofold (49.7% vs 25%, p<0.05). Stratified according to age group for female patients, anti-tpo positivity is relatively higher among years old (51.1%, p =0.753). Among male, anti-tpo positivity is present in all years old which is significantly higher compared to other age group (p <0.01). Based on thyroid ultrasound findings, those with positive anti-tpo has larger thyroid size in all measurement parameters (p = ). Among anti-tpo positive patients, frequent ultrasound findings were: hypoechoic (79% vs. 21%, p < 0.001); heterogenous parenchyma (71% vs. 29%, p < 0.001) and increased vascularity (93% vs. 7%, p < 0.001). Of note is the absence of homogenous parenchyma finding among anti-tpo positive. All 23 (100%) patients who showed combined findings of hypoechoic, heterogenous parenchyma and increased vascularity were anti-tpo positive. Conclusion: Thyroid ultrasound findings that are found frequently among anti-tpo positive are increased thyroid size, parenchyma that are hypoechoiec and heterogenous and increased vascularity. Homogenous echotexture was not seen among anti-tpo positive. The combined sonographic characteristics of hypoechoic, heterogenous pattern and increased vascularity are highly suggestive of presence of anti-tpo (100%). Keywords: Chronic autoimmune thyroiditis; Hashimoto s thyroiditis; Anti-thyroid peroxidase (anti-tpo) antibody; Thyroid Ultrasound Introduction Autoimmune diseases of the thyroid gland present as spectrum of various disorders characterized by lymphocytic infiltrates at the thyroid parenchyma and production of thyroid autoantibodies. Among such disorders, chronic autoimmune thyroiditis, also known as Hashimoto s thyroiditis, is the most frequent cause of hypothyroidism in iodine sufficient regions. 1 In 2006, Weetman reported that the clinical prevalence rate of Hashimoto s thyroiditis was at one in 182 or 0.55% in the US. 2 There are no data regarding its prevalence on the general population in our country which the World Health Organization classified as mildly iodine deficient. 3 A study done by Staii et.al in 2010 showed a prevalence at 13.4% when diagnosis was based on ultrasound guided fine-needle aspiration biopsy *Makati Medical Center, Section of Endocrinology, Diabetes & Metabolism of thyroid nodules. 4 Among patients with thyroid disorders seen at Otorhinolaryngologist clinics in Japan, prevalence of this disease was 53.5%. 5 Patients with this autoimmune disorder usually presents with diffusely enlarged, firm and with irregular surface thyroid gland. A retrospective study done in Turkey of patients with this disease clinically showed that 53.8% of the female and 63.6% of the male manifested with diffuse thyroid enlargement. 6 It is a lifelong autoimmune disease with the enlarged thyroid gland gradually becoming atrophied in association with hypothyroidism. However, some patients are euthyroid or have subclinical hypothyroidism in the presence of goiter and circulating thyroid autoantibodies upon diagnosis. A large cohort study done by Staii et.al has shown that in 13.4% cytologically proven Hashimoto s thyroiditis, 1.2% has subclinical hypothyroidism and 6.2% were euthyroid. 4 According to the 20 year follow-up study of the Whickham cohort, the rate of progression from subclinical to overt hypothyroidism is 4.3% per Volume 52 Number 2 April-June,

2 Tugna S, et al Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase year. 7 Although, euthyroid Hashimoto s thyroiditis exists, its progression to overt hypothyroidism is a matter of time. 4 Hashimoto s thyroiditis is associated with several complications. Carta et. al., has shown its association with mood disorders even without functional impairment. 8 It has also been recognized to have a key role in the development of thyroid malignancy such as Mucosa Associated Lymphoid Tissue (MALT) lymphoma. 9 In addition; unrecognized hypothyroidism is deleterious because of its association with cardiovascular morbidities 10 and in female, its risk of poor obstetrical outcome. 11 The ideal way to diagnose this autoimmune thyroid disorder is through thyroid biopsy. Due to its invasiveness, many patients refuse to undergo the above procedure. When clinically suspected, tests for thyroid autoantibodies such as antibodies to thyroid peroxidase (anti-tpo) or thyroglobulin (anti-tg) and measurement of serum thyrotropin (TSH) concentration are oftentimes sufficient to confirm the diagnosis. The American Association of Clinical Endocrinologist (AACE) Thyroid Task Force guideline suggested that anti-tpo and anti-tg tests can confirm the diagnosis since it has been reported to be positive in 95% of the cases. 12 Thyroid peroxidase is a protein that is located in the apical plasma membrane of thyroid follicular cells. This enzyme catalyzes the oxidation of iodine to iodinating species that forms iodotyrosinases. 13 Anti-TPO is the antibody that acts against this protein. The presence of anti-tpo predicts thyroid failure, 14 subsequent development of post-partum thyroiditis in pregnant women, and increased risk of spontaneous abortion. 15 In identifying patients with Hashimoto s thyroiditis, it was reported that the sensitivity and specificity of anti-tpo are 92% and 93% respectively, while anti-tg was at 82% and 92%. 16 Anti-TPO has a superior diagnostic value since it is positive in more than 90% of the cases of Hashimoto s thyroiditis regardless of presence of hypothyroidism or euthyroidism. 17 In our institution, anti-tpo is determined by monoclonal antibody assisted radioimmunoassay (RIA). In a study done by Mariotti et al., using this test, anti-tpo antibody was detected in 8.4% of normal control, 74% in Grave s Disease, 99.3% in patients with Hashimoto s thyroiditis, 19.2% in patients with differentiated Thyroid carcinoma and 11% in miscellaneous autoimmune thyroid disease. 18 Ultrasonography is the most common and useful modality to image the thyroid gland. It can describe accurately the thyroid region and can explain unclear findings in the physical examination. Ultrasound can also be used to identify patients who have ultrasonographic thyroid patterns that suggest diagnoses such as thyroiditis. Ultrasound has demonstrated 94.6% sensitivity in the diagnosis of autoimmune thyroiditis with the presence of hypoechogenicity. 19 However, it is not specific for Hashimoto s thyroiditis as other autoimmune thyroid diseases may manifest with such characteristic findings. 20 As stated above, ultrasonography is widely used in the evaluation of the thyroid gland since it is widely available, less costly, non-invasive and can provide detailed representation of the thyroid gland. If a strong positive correlation between specific ultrasound findings and anti-tpo positivity can be established, then ultrasound can be used as a diagnostic modality that can help identify patients at risk for autoimmune thyroid diseases, which in the case of Hashimoto s thyroiditis, may eventually lead to clinical hypothyroidism. Clinicians who do not have anti-tpo assay in their places of practice can use these ultrasonographic findings in predicting patients who are at risk for overt hypothyroidism in the future. In this study, we aimed to evaluate the ultrasound findings of the thyroid parenchyma of patients with diffuse thyroid enlargement and with positive anti- TPO - a clinical finding that is common and a test that is sensitive in identifying patients with possible Hashimoto s thyroiditis. Apart from echogenicity, it will include other ultrasonographic parameters such as thyroid size, echotexture and vascularity. Objectives General: In this study, we aimed to determine the thyroid ultrasonographic findings in association with anti-tpo positivity. Specific: 1) To identify thyroid ultrasonographic findings present among patients with diffuse goiter who are anti-tpo positive or anti-tpo negative. And, 2) To determine correlation of anti-tpo positivity with thyroid ultrasonographic parameters such as size, echogenicity, echotexture and vascularity of the thyroid parenchyma. Materials and Methods This is a retrospective cross-sectional study. The subjects are patients seen at Makati Medical Center (MMC) out-patient clinic Endocrine clinics from October 1, 2011 to October 1, Inclusion Included in this study are patients 18 years old and above, male or female with: 1. Serum anti-tpo, TSH and Free Thyroxine (FT4) done at MMC-Nuclear Medicine Department during the 2 Volume 52 Number 2 April-June, 2014

3 Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Tugna S, et al study period. 2. Thyroid ultrasound with color-flow doppler done at MMC- Ultrasound Department. Exclusion Excluded in this study are: 1. Patients with: Thyroid pain and tenderness on clinic evaluation. History of thyroid carcinoma. History of thyroid surgery and radioactive iodine (RAI) treatment. Evidence of clinical and biochemical hyperthyroidism defined as TSH level of less than 0.27 microunits/ ml and FT4 level of above 33 pmol/l. history of intake of anti-thyroid medication 2. Pregnant patients as well as those within 12 months post-partum were also excluded in this study. The study included patients noted to have diffuse thyroid gland enlargement on palpation. These patients have serum anti-tpo assay, TSH and FT4 and thyroid ultrasound with color flow doppler done at MMC-Nuclear Medicine Department and MMC-Ultrasound Department during the study period. Patients who are on thyroid hormone replacement but eligible for the study were included. Patient with anti-tpo above 100 pmol/l were considered to be anti-tpo positive. Patients with anti-tpo equal to or below 100 pmol/l were considered negative. Outpatient charts from Endocrine clinics were reviewed. This was followed by review of thyroid ultrasound with color-flow dopplerreports. The ultrasound reports were analyzed based on the size, echogenicity, echotexture and vascularity of the thyroid parenchyma (Figure 1). For standardization, the interval of testing anti- TPO, TSH, FT4 and thyroid ultrasound should not be more than one week. Anti-TPO antibody was quantified using the radioimmunoassay anti-htpo[125i] RIA kit (Izotop). The thyroid function tests were likewise analyzed using radioimmunoassay with the TSH level by turbo TSH[125] IRMA kit (Izotop) and FT4 level by Beckman Coulter. Ultrasonography of the thyroid gland was performed with subjects in supine position with the neck hyperextended. The ultrasound machines used in MMC-Ultrasound Department were Siemens Acuson Antares, GE Logic P6, GE Logic E9 and Toshiba Xario. The echopattern refers to the texture of the thyroid parenchyma. It is classified as homogenous if the parenchymal texture is uniform and heterogenous if not. Echogenicity was defined based on its comparison with its adjacent structures like connective tissues and neck muscles. A finding of isoechoic was reported if the thyroid parenchymal echogenicity was the same as the adjacent structures.the hypoechoic finding was described if the parenchyma was less echogenic (darker) while hyperechoic if it is more echogenic (brighter). The assessment of vascularity was based on the intensity of the blood flow to the thyroid parenchyma as seen on the Doppler studies. 21 Sonographic findings were interpreted by different Radiologists (Sonologists). The minimum sample size (n) computed is 75 based on 95% confidence interval, 10% margin of error and assumed prevalence of Hashimoto s thyroiditis (54%) as found in the study done by Morinaka S. 5 Statistical Analysis Data was summarized using means and standard deviations or medians and ranges whenever applicable. Categorical data were presented as frequencies and percentages. Overall prevalence and 95% confidence interval was also calculated. Test for association for the two categorical variables done using Fisher s exact test or chi-square test. Mann-Whitney test was used to determine the significant differences of thyroid gland sizes of those with positive and negative anti-tpo. A p-value less than the set level of significance of 0.05 was considered significant. Results Among 566 patients who had anti-tpo done during the study period, 94 were eligible to be part of the study. The median age of the patients was 39 years (age range of years). Seventy-four (79%) of the 94 patients were female and 20 were male (21%) (Table I). Figure 1: Flowchart for determination of eligibilty of patients with anti-tpo for analysis Volume 52 Number 2 April-June,

4 Tugna S, et al Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Table I: Demographic Characteristics of Patients Eligible for the Study Age (in years) VALUES Mean + SD 40.9 ± 12.8 Median 39 Range Category, n(%) (18) (57) (24) Gender, n(%) Male 20 (21) Female 74 (79) Presence of Co-morbidities, n (%) Hypertension 10 (11) Diabetes mellitus 12 (13) Coronary Artery Disease 1(1) Malignancy 1(1) Dyslipidemia 10 (11) Previous Surgery 2 (2) In 94 patients who qualified for the study, 41 (43.6%) were anti-tpo positive and 53 (56.4%) were anti-tpo negative. The overall proportion of anti-tpo positive among patients with goiter in this study was 43.6% (95% CI ). TableII showed the stratified analysis for the presence of anti-tpo positive according to age and gender. Table II: Age-Gender Proportion of Anti-TPO Positive Gender n Proportion (%) p-value Male years years years Female years years years The sizes of the right and left thyroid lobes and isthmus in terms of length, width and anterior-posterior diameter were summarized and compared based presence and absence of anti-tpo positive (Table III) Table III: Sizes of the Thyroid Gland of Anti-TPO Positive and Anti-TPO Negative Patients. Anti-TPO Thyroid Gland Positive Negative p value Right lobe Length 4.8 cm( cm) 4.8 cm( cm) Thickness 1.7 cm ( cm) 1.5 cm ( cm) Width 2.0 cm ( cm) 1.6 cm ( cm) Left lobe Length 4.8 cm( cm) 4.5 ( cm) Thickness 1.6 cm ( cm) 1.3 ( cm) Width 1.8 cm ( cm) 1.6 ( cm) Isthmus 0.4 cm ( cm) 0.3 cm ( cm) Data inside the table are medians (ranges). Mann-Whitney test used to determine differences of thyroid gland sizes. The sonographic features of patients with positive and negative anti-tpo were shown in Table IV. This was stratified based on echogenicity, echopattern and vascularity of the thyroid parenchyma. Table IV: Sonographic Characteristics of Thyroid Parenchyma. Sonographic N Anti-TPO characteristics Positive Negative p-value Echogenicity Isoechoic 51 7 (14) 44 (86) < Hypoechoic (79) 9 (21) Echotexture Homogenous 36 0 (0) 36 (100) < Heterogenous (71) 17 (29) Vascularity Physiologic (22) 51 (78) < Increased (93) 2 (7) The proportion of anti-tpo positive and negative showing combined findings of hypoechoic and heterogenous parenchyma and increased vascularity was shown in Table V. Among 23 patients that manifested the three ultrasound findings all were anti- TPO positive (100%). Among the 71 patients that did not show the above combination findings, 18 (25%) were anti-tpo positive and 53 (75%) were anti-tpo negative. 4 Volume 52 Number 2 April-June, 2014

5 Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Tugna S, et al Table V: Presence of combined ultrasound findings of hypoechoic, heterogenous and increased vascularity of the thyroid parenchyma in relation to anti-tpo status. Combined ultrasound findings Anti-TPO N Positive Negative p-value Present (100) 0 (0) <0.001 Absent 71 18(25) 53(75) Data presented inside the table are frequencies (row percentages) Discussion In this study, the proportion of anti-tpo positive among patients with diffuse thyroid enlargement was 43.6%. This finding is higher than the reported incidence (31.9%) of the anti-tpo positive among patients with goiter in a study done by Chehade et.al. 22 It is likely that the higher proportion can be explained by the fact that patients were already clinically suspected of having autoimmune thyroid disease (based on the presence goiter and their functional thyroid state) when their anti-tpo was evaluated. There was almost twofold higher proportion of positive anti-tpo among females compared to males (49.7% vs. 25%, p<0.05). As were shown by numerous epidemiological studies, female presents with positive thyroid autoantibodies up to three times more than male. 23,24 A potential mechanism for a high female preponderance in thyroid autoimmunity is due to impaired immunotolerance. It was hypothesized that there is a skewed X-chromosome inactivation leading to escape of the X-linked self-antigens from presentation in the thymus with subsequent loss of T-cell tolerance. 24 Stratified according age group for female patients, it seemed that those at age years old had higher proportion of anti-tpo positive(51.1%, p=0.753). This was similar to the result of the study done by Swain et.al, wherein most of patients with autoimmune thyroid disease were women at year age-group. 26 Among male, it is of note that under the same age group, there was absence of anti-tpo positive. There were significant differences on the presence of anti-positivity according to age group (p=0.011). Anti-TPO positivity is present in all years old which is significantly higher than those within age groups (0%) and above 50 years old(33%)( p<0.01). (Table III) The finding of hypoechogenicity (hypoechoic) was noted to be frequent among patients with positive anti-tpo by more than threefold (79% vs. 21%, p <0.001). Marcocci et.al., found a diffuse, low echogenicity in the thyroid in 44 of the 238 patients with goiter and circulating autoantibodies. The degree of hypoechogenicity was significantly correlated with the levels of circulating thyroid autoantibodies (anti- TPO and anti-tg). 19 Gutenkunst et. al., reported that thyroid ultrasonography has 94.6% sensitivity in the diagnosis of autoimmune thyroiditis by the presence of hypoechogenicity. The decreased echogenicity was thought to be a result of lymphocyte infiltration and often correlates with hypothyroidism. 27 On the other hand, isoechoic finding was present only in 14% of the anti-tpo positive patients. Heterogenous finding was commonly seen among patients with positive anti-tpo (71% vs 29%, p <0.001). In a study done in Brazil by Yamashiro et.al., 37 of the 38 thyroid gland diagnosed with different types of thyroiditis presented with heterogenous echo pattern. The heterogenous textural pattern signifies thyroid parenchyma intermixed with focal alteration mimicking nodules. 28 Another important result in this study was the absence of homogenous parenchyma finding among patients with positive anti-tpo. This may indicate that in the presence of homogenous thyroid parenchyma, it is unlikely that a patient is anti-tpo positive. The thyroid parenchyma of patients with positive anti-tpo was thirteen times highly vascular (93% vs7%, p<0.0001). This was consistent with the finding that the thyroid parenchyma in autoimmune thyroiditis can vary from slight to markedly hypervascular. 29 Since the sonographic patterns of hypoechoic, heterogenous parenchyma and increased vascularity were noted to be frequent ultrasound findings among anti-tpo positive (Figure 3), the combination of these three findings in association with anti-tpo positivity was evaluated. All the 23 patients who have the above combination findings were anti-tpo positive. However, the said combination findings was absent among anti-tpo negative. Only 18 (25%) of the 71 patients who did not manifest the above pattern were anti-tpo positive (Figure 4). This may signify that the combined sonographic finding of hypoechoic, heterogenous parenchyma and increased vascularity strongly suggest the presence of autoimmune thyroid disease (p<0.001). Figure 3: Thyroid Ultrasound findings of anti-tpo Positive. Volume 52 Number 2 April-June,

6 Tugna S, et al Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Figure 4: Presence of combined sonographic findings (pattern) of hypoechoic, heterogenous and increased vascularity of the thyroid parenchyma in relation to anti-tpo status. Conclusion and Recommendation In conclusion, autoimmune thyroid disease is common in patients with diffuse goiter (43.6%) with female preponderance (49.7% vs. 25%). Thyroid ultrasound is widely used, safe, repeatable and inexpensive. Thyroid ultrasound findings that are found frequently among anti-tpo positive are increased thyroid size (p=0.0053), parenchyma that are hypoechoiec (79%) and heterogeneous (71%)and increased vascularity (93%). The combined sonographic characteristics of hypoechoic, heterogenous parenchyma and increased vascularity are highly suggestive of positive anti- TPO - thus, an autoimmune thyroid disease. These sonographic findings can support clinical and laboratory findings that suggest Hashimoto s thyroiditis. Furthermore, in patients wherein thyroid ultrasound was the test done initially, the presence of above ultrasound findings warrants further examination and follow-up. It is highly recommended that sonologists should include size, echopattern, echogenicity and vascularity in their thyroid ultrasound reports. References 1. Lindsay RS, Toft AD: Hypothyroidism. The Lancet, 349: , February Weetman AP: Thyroid Disease. In the Autoimmune Disease. Edited by: Rose NR, Mackay IR. Elsevier; , De Benoist B, Andersson M, Egli I, Takkouche B, Allen H: Iodine status worldwide: WHO Global Database on Iodine Deficiency. Department of Nutrition for Health and Development World Health Organization Staii A, Mirocha S, Todorova-Keteva K, Glinberg S, Jaume J: Hashimoto s thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state. Thyroid Res. 3: Morinaka S: On the frequency of thyroid diseases in outpatients in an ENT Clinic. AurisNasus Larynx. 22: Erdogan M, Erdem N, Cetinkalp S, Ozgen AG, Saygılı F, Yilmaz C, Tuzun M, Kabalak T: Demographic, clinical, laboratory, ultrasonographic, and cytological features of patients with Hashimoto s thyroiditis: results of a university hospital of 769 patients in Turkey. Endocrine 36(3): , December Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al.: The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. ClinEndocrinol 43(1): 55 68, July Carta MG, Hardoy MC, Carpiniello B,Murru A, Marci AR,,Carbone F, Deiana L, Cadeddu M, Mariotti S: A case control study on psychiatric disorders in Hashimoto disease and euthyroidgoitre: not only depressive but also anxiety disorders are associated with thyroid autoimmunity. 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Int J Shoulder Surg 4(3):55-62, Jul-Sep Chehade JM, Lim W, Siverberg AB, Mooradian AD: The incidence of Hashimoto s disease in nodular goitre: the concordance in serological and cytological findings. Int J ClinPract 64(1): 29-33, Jan Aghini-Lombardi F, Antonandeli L, Martino E, Vitti P, Macherrini D, Leoli F, Rago T, Grasso L, Valeriano R, Balestrieri A, Pinchera A: The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. J ClinEndocrinolMetab 82(2): , February Swain M, Swain T, Mohenty BK: Autoimmune thyroid disorders-an update. Indian J ClinBiochem 20(1):9-17,January Volume 52 Number 2 April-June, 2014

7 Thyroid Ultrasound Findings Associated with Anti-Thyroid Peroxidase Tugna S, et al 25. Brix TH, Krudsen GP, Kristiansen M, Kyvik KO, Orstavik KH, Hegedus L: High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J ClinEndocrinolMetab 90 (11): , November Swain M, Swain T, Mohenty BK: Autoimmune thyroid disorders-an update. Indian J ClinBiochem 20(1):9-17,January Gutekunst R, Hafermann W, Mansky T, Scriba PC: Ultrasonography related to clinical and laboratory findings in lymphocytic thyroiditis. ActaEndocrinol (Copenh) 121: , July Yamashiro I, Saito O, Chammas MC, Cerri G: Ultrasound findings in thyroiditis. Radiol Bras 40(2): 75-79, April Kerr L: High-resolution thyroid ultrasound: the value of color Doppler. Ultrasound Q 12: Volume 52 Number 2 April-June,