The relationship between thyroid antibody titer and levothyroxine dose in patients with overt primary hypothyroidism

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1 The reltionship between thyroid ntibody titer nd levothyroxine dose in ptients with overt primry hypothyroidism Nln Okuroglu, Ali Ozdemir, Ysr Sertbs, Sed Snck b From the Deprtment of Internl Medicine nd b Deprtment of Endocrine nd Metbolism, Fith Sultn Mehmet Egitim ve Arstirm Hstnesi, Istnbul, Turkey Correspsondence: Ali Ozdemir Deprtment of Internl Medicine, Fith Sultn Mehmet Egitim ve Arstirm Hstnesi, E-5 Ylu Uzeri Bostnci Atsehir, Istnbul 34752, Turkey T: / lemoz2004@yhoo.com Ann Sudi Med 2017; 37(3): DOI: / BACKGROUND: Both excess nd insufficient thyroid hormone replcement my produce dverse effects in vrious trget tissues; therefore, understnding fctors tht ffect chievement of trget TSH levels is crucil. OBJECTIVE: Investigte the reltionship between ntibody titers nd levothyroxine dose. DESIGN: Retrospective, review of dt in medicl records. SETTING: Thyroid center of Ftih Sultn Mehmet Eduction nd Reserch Hospitl, Istnbul, Turkey. PATIENTS AND METHODS: The study popultion consisted of ptients tht hd been dignosed s hving overt primry hypothyroidism nd were tking levothyroxine for t lest one yer. The serum TSH level for n euthyroid stte ws between miu/l. The levels of nti-thyroid peroxidse (TPOAb) considered positive for ntibodies were <5.6 IU/mL nd for nti-thyroglobulin (TgAb) utontibodies <4.10 IU/ ml. MAIN OUTCOME MEASURE: Dily levothyroxine doses of ntibody-positive nd negtive ptients nd ssocition of dily drug requirement with ntibody titers. RESULTS: The study popultion consisted of the 303 ptients (273 femles nd 30 mles with the men [SD] ge of 46.6 [13.2] yers). In the ntibody-positive group (n=210) verge dily levothyroxine dose ws sttisticlly significntly higher thn in the ntibody-negtive group (n=93) (men of 78.8 [36.7] vs 64.2 [27.1] mg/dy, P=.001, respectively). There ws low but sttisticlly significnt positive reltionship between the TPOAb (r=0.217, P<.01) nd TgAb levels (r=0.158, P<.05) nd levothyroxine doses in the ntibody-positive group. CONCLUSION: Antibody titers re positively ssocited with lrger levothyroxine (LT-4) replcement dosing in ptients with utoimmune thyroiditis. LIMITATION: Unknown ntibody titers before strting levothyroxine use. Hypothyroidism, both overt nd subclinicl forms is one of the most prevlent hormonl disorders in the world, with prevlence of 4% to 15% in the generl popultion. 1,2 Iodine deficiency in res of iodine insufficiency nd chronic utoimmune thyroiditis in res of iodine sufficiency re the most frequent cuses of primry hypothyroidism. 3 Understnding fctors tht ffect chievement of trget TSH levels is crucil since both excess nd insufficient thyroid hormone replcement my produce dverse effects in vrious trget tissues. Chronic utoimmune thyroiditis (Hshimoto thyroid- itis) is chrcterized by polyclonl utontibodies trgeting the thyroid glnd, T-cell infiltrtion nd poptosis of thyroid folliculr cells. 4 Typicl utontibodies in the serum of ptients with utoimmune thyroiditis represent response to the ongoing inflmmtory rection rther thn plying direct role in the pthogenesis of the disese. 5 Anti-thyroid peroxidse (TPOAb) nd nti-thyroglobulin (TgAb) utontibodies re often correlted with disese ctivity. 6 Willms et l reported tht mrkedly decresed echogenicity, heterogeneity, nd multifocl pseudonodulr hypoechoic infiltrtion re indictive of high level of inflmmtory ctivity, ANN SAUDI MED 2017 MAY-JUNE 189

2 nd these sonogrphic findings were ssocited with significntly higher TPOAb ctivity. 7 Also, the presence of TPOAb is ssocited with n incresed risk of overt hypothyroidism. 8 In the tretment of ptients with primry hypothyroidism, the min gol is to normlize thyrotropin (TSH) levels with thyroxine replcement. Since both excess nd insufficient thyroid hormone replcement my produce dverse effects in vrious trget tissues, it is crucil to dminister levothyroxine (L-T4) in sufficient doses. The optimum dily dose lrgely depends on the degree of hypothyroidism, body weight nd ptient ge. 9,10 Fctors such s low ptient complince or reduced L-T4 bsorption resulting from ccompnying chronic disese or some drugs used simultneously ffect the dily demnd for L-T As fr s we know, the reltionship between the levels of thyroid utontibodies nd the dily L-T4 doses hs not been investigted. Tking into considertion informtion on the reltionship between thyroid ntibodies nd disese ctivity from previous studies, we investigted whether there ws reltionship between thyroid ntibody level nd dily L-T4 doses. PATIENTS AND METHODS This retrospective review of medicl records included ptients with overt hypothyroidism dignosis who were receiving L-T4 therpy for t lest 1 yer nd who pplied to our thyroid polyclinics between Jnury 2015 nd December All ptients were treted by the sme stndrd of cre nd ll were euthyroid ccording to the guidelines with TSH vlues between with 0.5 to 4 miu/l. Ptients who hd been dignosed with subclinicl hypothyroidism nd overt hypothyroidism s result of rdioiodine or surgicl tretment were excluded. No ptients hd liver dysfunction, renl filure, diseses of the pituitry glnd or hypothlmus such s secondry hypothyroidism, mlbsorption diseses, pregnncy, or lcohol buse. The study protocol ws pproved by the ethics committee nd informed written consent ws tken from ll prticipnts. The demogrphic dt of the prticipnts including ge, gender, weight, body mss index (BMI), nd blood pressure were recorded. The disese durtion, smoking sttus nd ny other drug usge ffecting levothyroxine bsorption like proton pump inhibitors (PPI) or iron supplements were noted. All ptients were receiving levothyroxine sodium tblets. The ptients were on different dily dose mngement rther thn stndrd fixed dose in order to rech the pproprite TSH levels. For ech ptient the dily levothyroxine dose by clculted by weekly dose divided into seven. ANTIBODY TITERS AND LEVOTHYROXINE DOSE Hormone ssys After 8-10 hours overnight fsting blood smples were obtined for TSH, TPOAb nd TgAb. TSH, TPOAb nd TgAb levels were mesured by the sme ssy using the chemiluminescent microprticle immunossy (CMIA) method (Architect i2000, Abbott Lbortories). The serum TSH level for euthyroid stte ws between miu/l. The level of TPOAb ws <5.6 IU/mL nd TgAb <4.10 IU/ ml, respectively. Vlues bove these levels were considered positive for ntibodies. Sttisticl nlysis Dt ws nlyzed using SPSS version 22 pckge (IBM SPSS, Armonk, NY USA). Results were expressed s men nd stndrd devition for the prmeters showing norml distribution, medin nd rnges for the prmeters showing nonprmetric distribution. The t test ws used for the comprison of the prmeters with norml distribution. The Mnn-Whitney U test ws used for dt tht were not normlly distributed. The reltionship between the TPOAb nd TgAb levels with L-T4 dose nd disese durtion were nlyzed by the Spermn rho test. P<.05 ws considered sttisticlly significnt. RESULTS The study popultion consisted of 303 ptients (273 femles nd 30 mles with men [stndrd devition] ge of 46.6 [13.2] yers, rnge yers). Ptients were divided into two groups with respect to the thyroid utontibody sttus: ntibody-positive group (n=210) nd ntibody-negtive group (n=93). Disese durtion in the ntibody-positive group rnged from 1 yer to 34 yers with men (SD) of 6.2 (5.4) yers nd medin of 5 yers. In the ntibody-negtive group, disese durtion rnged from 1 yer to 30 yers with n verge of 5.3 (5.4), nd medin 3 yers. There were no sttisticlly significnt differences in ge, weight nd body mss index between the groups. There were nonsignificnt differences in TSH vlues of both groups. There ws sttisticlly significnt difference in sex distribution between the groups (P<.01). In the ntibodynegtive group the percentge of mle ptients ws 17.2%, while in the ntibody- positive group it ws 6.7% (Tble 1). In the ntibody positive group the men L-T4 dose ws significntly higher thn in the ntibody-negtive group (Tble 2). The mle ptients hd higher but sttisticlly insignificnt L-T4 doses thn the femle ptients in both the ntibody-negtive nd ntibody-positive group (men [stndrd devition] of 72.6 [34.6], medin 67.9 vs 62.5 [25.2], medin 50, P=.175 nd 190 ANN SAUDI MED 2017 MAY-JUNE

3 ANTIBODY TITERS AND LEVOTHYROXINE DOSE men of 87.1 [46.0], medin 87.5 vs 78.3 [34.9], medin 75, P=0.372, respectively). There ws low but sttisticlly significnt positive reltionship between the TPOAb levels nd L-T4 doses in the ntibody positive group (r=0.217; P<.01). Similrly, sttisticlly significnt positive reltionship ws found between the TgAb levels nd the L-T4 doses (r=0.158; P<.05). There ws no sttisticlly significnt reltionship between TPOAb nd TgAb levels nd L-T4 doses in the ntibody-negtive group (P>.05) (Tble 3). There ws wek but sttisticlly significnt negtive reltionship between TPOAb level nd disese durtion in the ntibody-positive group (r=-0,159; P<.05). On the other hnd, there ws no sttisticlly significnt reltionship between TgAb level nd disese durtion (P>.05) (Tble 4). There ws no sttisticlly significnt difference mong L-T4 dose nd smoking sttus, nd other medictions including PPIs nd iron supplements (Tble 5). Similrly, there ws no sttisticlly significnt difference between smoking, dditionl drug use nd L-T4 dosge in the ntibody-negtive group. As we expected, there ws wek but sttisticlly significnt reltionship between the drug dose nd weight (r=0.241, P=.008) nd BMI (r=0.157, P=.024) in the ntibody-positive group. There ws no sttisticlly significnt reltionship between the drug dose nd weight nd BMI in the ntibody-negtive group. DISCUSSION L-T4, which is converted to T3 in peripherl tissues, is the stndrd tretment option for ptients with hypothyroidism. The dily requirement for thyroxine vries from ptient to ptient. Mny fctors such s the degree of hypothyroidism, body weight, ge, poor ptient complince, ccompnying chronic diseses nd some drugs used simultneously ffect the dily requirement. Our results suggest tht thyroid ntibody titer my lso be ssocited with dily replcement need. It is uncertin whether the typicl utontibodies present in the serum of Hshimoto thyroiditis ptients ply direct role in the pthogenesis of the disese. In the erly 1990s, some studies showed tht experimentl utoimmune thyroiditis in mice ws induced by using thyroglobulin or thyroid peroxidse ntigens nd they suggested tht these ntigens might ply role in the pthogenesis of utoimmune thyroiditis in humns. 17,18 In erly studies it hs lso been reported tht TPOAbs fix complement nd, t lest in vitro, cn produce ntibody-dependent cell cytotoxicity. 19 Hshimoto thyroiditis the ntithyroid immune response begins with the ctivtion of the thyroid ntigen-specific helper T cells. Once they re ctivted, they induce B cells to secrete originl rticle Tble 1. Demogrphic chrcteristics of study popultion (n=303). Antibodypositive Antibodynegtive P vlue Age (yers) (12.58) (14.51).207 Weight (kg) (14.39) (12.37).961 BMI (kg/m²) (5.55) (4.43).432 Femle 196 (93.3%) 77 (82.8%).007 b Mle 14 (6.7%) 16 (17.2%) Dt re men (stndrd devition) or number (percentge). t test; b Fisher exct test Tble 2. Reltionship of drug dose nd ntibody groups. Drug dose Men (SD) Medin P Antibody-positive (35.66) 75 Antibody-negtive (27.013) 50 Mnn-Whitney U test.001 Tble 3. The reltionship between nti-thyroid peroxidse (TPOAb) nd ntithyroglobulin (TgAb) utontibody levels with levothyroxine doses. Drug dose TPO Ab level TgAb level r P r P Antibody-positive b Antibody-negtive Spermn rho test P<.01 b P<.05 Tble 4. The reltionship between nti-thyroid peroxidse (TPOAb) nd nti-thyroglobulin (TgAb) utontibody levels nd disese durtion in the ntibody-positive group. Antibody positive r Disese durtion TPOAb TgAb Spermn rho test P<.05 thyroid ntibodies. 20 The utoimmune destruction of the thyroid glnd with circulting TgAb nd TPOAb my lso led to the fibrosis of the prenchym. As result, in ptients with subclinicl hypothyroidism, high TPOAb levels re ssocited with progression to overt hypothyroidism. 20 On the other hnd, Dussult et l reported tht neontes born to mothers with circulting TPOAb hd norml thyroid glnd nd this result hs P ANN SAUDI MED 2017 MAY-JUNE 191

4 ANTIBODY TITERS AND LEVOTHYROXINE DOSE Tble 5. The reltionship between smoking sttus, use of proton-pump inhibitors (PPI), iron nd other medictions with levothyroxine dose in the ntibody-positive group. Antibody positive n Men (SD) L-T4 dose (µg/dy) Medin P Smoking None (32.48) Use (48.54) 93 PPI None (36.44) Use (31.64) 75 Iron None (34.79) Use (43.44) 75 Additionl mediction None (37.3) Use (30.52) 75 Mnn-Whitney U test chnged the view of the pthogenic role of circulting thyroid ntibodies in utoimmune thyroiditis. 21 Lter, mny uthors reported tht TPOAb correlted with the mount of lymphocytic infiltrtion nd disese ctivity. 6 Currently, it is ccepted tht thyroid utontibodies indicte response to n ongoing inflmmtory rection rther thn direct pthogenic role. The degree of hypothyroidism is n importnt fctor in determining the need for thyroid hormone replcement therpy. Residul thyroid tissue tht functions is n importnt fctor in determining the degree of hypothyroidism. Some studies hve shown tht the degree of dmge in the thyroid tissue is ssocited with ntibody titers. Antibody-negtive utoimmune thyroiditis hs milder course, 22 while the presence of TPOAb is ssocited with n incresed risk of overt hypothyroidism. 8 From ll these dt we cn expect tht ptients with higher ntibody levels my need more hormone replcement. Our study showed tht the hormone replcement requirement to chieve trget TSH levels ws higher in ntibody-positive ptients thn in ntibody-negtive ptients nd there ws positive correltion between ntibody titers nd L-T4 doses. This result is consistent with the conclusion tht the ntibody titer is ssocited with disese ctivity. Inequlity in gender distribution cn be seen s confounding fctor. Since the number of mle ptients ws higher thn femles in the ntibody-negtive group, the thyroid replcement dose should be higher in the ntibody-negtive group thn the positive group if we consider the verge replcement dose of mle ptient ws higher thn in femle ptient in both ntibody-negtive nd positive groups. Therefore, we cn sy tht the difference between the two groups is relted to utontibody presence nd titer. We cn lso sy tht the presence of thyroid peroxidse ntibodies is not only relted to the risk of progression to overt hypothyroidism, 8 but lso to the need for more hormone replcement. The results of the present study would not indicte need to chnge the clinicl prctice of bringing the level of TSH to norml in the tretment of hypothyroidism, but we cn ssume tht we need higher dose of hormone replcement to rech the trget TSH level. This study hs some limittions. First, it involved ptients who were lredy under replcement therpy. There re mny studies exmining the long-term course of thyroid ntibodies nd their levels in chronic utoimmune thyroiditis with or without L-T4 tretment, but they hve conflicting results. A wide vribility hs been reported in ntibody levels. Some studies show tht L-T4 tretment cn modulte thyroid sttus by reducing the lymphocyte infiltrtion nd progression of the disese process. 23,24 Thus, present ntibody titers my not reflect the bseline titers. In our study, negtive correltion between ntibody titers nd the durtion of the disese lso suggests tht the titer of ntibody decreses over time, either with levothyroxine effect or independently of the drug. Second, there were no histopthologicl findings. Our results suggest tht thyroid ntibody titer my be ssocited with dily replcement need. The reltionship between ntibody titers nd thyroid hormone requirement should be investigted in ptients with newly dignosed utoimmune thyroiditis by prospective, lrge-scle nd long-term studies. 192 ANN SAUDI MED 2017 MAY-JUNE

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