Postpartum thyroiditis

Post partum thyroiditis occurs in 50% of TPO AB+ve women and is characterised by transient hyperthyroidism followed by transient hypothyroidism during the first six months, post partum. A third of the latter group develop permanent hypothyroidism. The syndrome is seen in 5-9% of women and post partum thyroid dysfunction (PPTD) reoccurs in 75% of women in a subsequent pregnancy. An increase in depressive symptomatology is seen in women with PPTD as well as in ante TPO Ab+ve women without PPTD. The immunology of PPT is associated with the presence of TPO antiboides with those IgG subclasses best able to activate the complement cascade. The HLA-DR frequencies seen in PPT suggest that PPT may be related to Hashimoto's thyroiditis. TPO Ab driven complement fixation is seen in PPT and complement activation relates to the extent and progression of thyroid damage. Recent studies have shown an increase in both Th2 and Th1 cytokine release from lymphocytes in ante partum women destined to develop PPTD. More data are required on the cellular immune changes both ante partum and post partum in PPT.     

Anti-thyroid peroxidase antibodies during pregnancy and postpartum. Relation to postpartum thyroiditis

The frequency of autoantibodies to thyroid microsomes (MAb), thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) was studied in 736 women during and after pregnancy. The aim was to study the relationship between TPO Ab and post-partum thyroid disease, and to compare their behaviour with MAb. Seventy-five (10%) were either MAb or TgAB positive, of whom 36 were sampled serially at 18, 30 and 36 weeks of pregnancy and 1, 6 and 12 months post partum. Twenty of the antibody negative mothers were selected at random for controls. Twelve of the 36 antibody positive mothers developed post-partum thyroid dysfunction (group 1), 24 did not (group 2) compared with none of the 20 controls (group 3). Six months post partum, TPO Ab titres rose overall in both groups 1 and 2, but only in those with measurable TPO Ab during the first trimester. A TPO Ab was less frequently positive than MAb, but the difference was not statistically significant. TPO Ab are not superior to MAb for predicting post partum thyroid disease in pregnant women.     

Prospective study of post-partum thyroid immune dysfunctions in type 1 diabetic women and in a healthy control group living in a mild iodine deficient area

Second to diabetes mellitus, thyroid diseases are the most common endocrinopathies seen in pregnancy. The incidence of post-partum thyroid dysfunction (PPTD) in women with type 1 diabetes mellitus is three-fold increased. We determined the incidence of thyroid abnormalities in a well-defined group of young subjects with type 1 diabetes and in an age-matched healthy controls during and six months after pregnancy in an area of mild iodine deficiency. Twenty-five out of twenty-eight pregnant women completed the study. Fifteen were affected by type 1 diabetes and ten were controls. Our protocol of study consisted of four evaluations of each subject: in the first, in the second trimester, at delivery and six months after. At each control the patients were submitted to physical examination, thyroid ultrasonography, and determination of fT3, fT4, TSH, Antithyroglobulin antibodies (TgAbs), Antithyroperoxidase antibodies (TPOAbs). The variation of thyroid volume is statistically significant in both the diabetics and in the controls during the different times of observations. Four out of the fifteen diabetic pregnant patients (27%) developed a thyroid disease: two cases of post-partum thyroiditis (PPT) and two cases of euthyroid benign nodular goiter, as confirmed by cytological examination. Two out ten controls (20%) developed positive antibodies (TPO Abs and TgAbs) since the first observation and showed an autoimmune thyroiditis six months after delivery. Both of them showed a familial history of thyroid disease. Our study suggests that in an area of mild iodine deficiency the incidence of thyroid autoimmunity in pregnant women is similar, whether diabetic or not; moreover, thyroid volume is increasing in the diabetics as much as in the non diabetics during pregnancy.     

Clinical aspects of recurrent postpartum thyroiditis.

BACKGROUND: Postpartum thyroiditis (PPT), characterized by transient hyperthyroidism and transient hypothyroidism, occurs in 5-9% of women. It is accompanied by the presence of circulating antithyroid peroxidase antibodies (TPOAb) which have been associated with an increase in depressive symptomatology compared with TPOAb-negative women. AIM: To assess the frequency and nature of the syndrome in patients studied in detail after more than one pregnancy, as there are only sparse data on recurrence of PPT. METHOD: Fifty-four patients were identified who had participated in at least two of three detailed postpartum studies of thyroid and psychiatric function during the past 12 years in the Caerphilly and Cardiff regions of South Wales. They included two women who had had three pregnancies. All patients had been followed monthly postpartum for at least six months, and 44 had been followed for 12 months. RESULTS: Of the 13 patients who developed PPT after their first pregnancy, nine had a recurrence of dysfunction after a further pregnancy and four remained TPOAb positive. Of the 24 women who were euthyroid anti-TPO positive after the first pregnancy, six developed thyroid dysfunction after a subsequent delivery, 14 remained antibody positive and euthyroid, while four underwent seroconversion and were antibody negative. The control group of 17 women were antibody negative after the first pregnancy; 16 remained negative after a further pregnancy and one became anti-TPO positive. The severity of PPT was slightly, but not significantly worse after the second recorded pregnancy (67% hypothyroid versus 44% hypothyroid). Neither the maximum anti-TPO titre following the first pregnancy, nor the rise in titre during this period were predictive of outcome after a subsequent pregnancy. Data from 26 women showed that recurrent depression was seen in 15.4%; a further six were depressed after the first pregnancy only, and two during a further postpartum period. CONCLUSION: There was a 70% chance of developing recurrent PPT after a first attack, and a 25% risk even in women who were only anti-TPO positive without thyroid dysfunction during the first postpartum period. The recurrence of postpartum depression was not related to thyroid function. Patients noted to have thyroid dysfunction or just to be euthyroid but anti-TPO positive after pregnancy should be assessed carefully after a subsequent pregnancy.     

Prospective Observation of 5-Year Clinical Course of Subclinical Hypothyroidism in Korean Population

Subclinical hypothyroidism (SCH) is a common clinical condition, whereas it''s natural course has not been identified distinctly. We evaluated the natural history of 169 SCH patients over 5-yr and the prognostic factors including thyroid autoantibodies and thyroid ultrasonographic (USG) findings related to develop overt hypothyroidism. After 5 yr, 47.3% of patients showed normalization of TSH, while 36.7% of patients remained persistence of high level of TSH, and overt hypothyroidism developed in 11.2% of patients. There were painless thyroiditis (2.9%) and hyperthyroidism (1.7%) during 5 yr follow-up. The thyroid nodule was seen in 48.6% of patients. Most of patients had 1 to 2 nodules whereas only 3% of patients with thyroid nodule had more than 6 nodules. Overt hypothyroidism patients had more heterogenous echogenecity in USG compared to patients with normalization or persistent SCH (76.5% vs 50.0% vs 35.0%, P = 0.048) and higher prevalence positive anti-thyroid peroxidase (anti-TPO Ab) and anti-thyroglobulin antibody (anti-Tg Ab) and titer of anti-TPO Ab than other two groups. The cut off values for prediction of overt hypothyroidism were TSH > 7.45 µIU/mL, free T₄ < 1.09 ng/dL and Anti-TPO Ab > 560 IU/mL. SCH has various courses and initial TSH, free T₄, presence of thyroid autoantibody, titer of thyroid autoantibody; and thyroid USG findings can serve as a prognostic factor for progression of overt hypothyroidism. These parameters suggest consideration to initiate thyroid hormone treatment in SCH.     

Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice

Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 x CBA)F(1) mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3(+) mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.     

Association of CT60 cytotoxic T lymphocyte antigen-4 gene polymorphism with thyroid autoantibody production in patients with Hashimoto's and postpartum thyroiditis

Strong genetic contribution has been demonstrated to influence the development of autoimmune thyroid disease (AITD) as well as thyroid autoantibody production. In order to assess the relation between CT60 cytotoxic T lymphocyte antigen‐4 (CTLA‐4) gene polymorphism and thyroid autoantibody production, we investigated 180 consecutive newly diagnosed patients with two forms of AITD, 105 with Hashimoto's thyroiditis (HT) and 75 with postpartum thyroiditis (PPT). We evaluated thyroid function, measured antibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg), and determined CT60 CTLA‐4 gene polymorphism. In HT, TPO antibody median value was significantly lower in the AA compared to the AG and GG genotypes (65, 122 and 319 U/ml, P < 0·005), while the Tg antibody median value was lower in the AA compared to the AG genotype (91 and 189 U/ml, P < 0·02). In PPT, the frequency of thyroid autoantibody‐positive patients was higher among G‐allele‐carrying genotypes (P < 0·04). Similar to HT, the TPO antibody median value was lower in the AA compared to the AG and GG genotypes (12, 130 and 423 U/ml, P < 0·006). Hypothyroid PPT patients were more often thyroid autoantibody‐positive (P < 0·005) and the TPO antibody median value was higher compared to hyperthyroid PPT patients (500 and 32 U/ml, P < 0·0001). The frequency of the G‐allele was significantly higher among hypothyroid patients (P < 0·05). Our data suggest that in both HT and PPT, the CT60 CTLA‐4 gene polymorphism contributes importantly to thyroid autoantibody production. In PPT, the genotype also seems to influence thyroid function, as patients with the polymorphous allele are more prone to develop hypothyroid form of PPT.     

Screening for thyroid disease in pregnancy

Although gestational hyperthyroidism is uncommon (0.2%), hypothyroidism (autoimmune disease or suboptimal iodine intake) occurs in 2.5% of women and is predictive of reduced neonatal and child neuropsychological development and maternal obstetric complications. Postpartum thyroid dysfunction (PPTD) occurs in 5-9% of women and is associated with antithyroid peroxidase antibodies (antiTPOAb) in 10% of women in early pregnancy. Therefore, screening for thyroid dysfunction in pregnancy should be considered. T4 and thyroid stimulating hormone measurements could be used to screen for hypothyroidism, which would require levothyroxine intervention treatment. T4 supply is crucial to fetal nervous system maturation; currently, the recommended daily iodine intake is 200 microg, and this is not always achieved, even in the UK. At present, a randomised prospective trial is ongoing to provide the evidence base for this screening strategy. Meanwhile, it is reasonable to (a) optimise iodine nutrition during pregnancy; (b) ascertain women with known thyroid disease; (c) identify women at increased risk of thyroid disease-for example, those with other autoimmune diseases. PPTD can be predicted by measurement of antiTPOAb in early gestation.     

Thyroid autoimmunity and recurrent miscarriage

Citation Ticconi C, Giuliani E, Veglia M, Pietropolli A, Piccione E, Di Simone N. Thyroid autoimmunity and recurrent miscarriage. Am J Reprod Immunol 2011; 66: 452–459 Problem To investigate the role of antithyroid autoantibodies (ATA) in recurrent miscarriage (RM). Methods In this case‐control study, a total of 160 women with RM and 100 healthy women were investigated for the presence of serum ATA directed against thyreoglobulin (TG‐Ab), thyroid peroxidase (TPO‐Ab) and TSH receptor (TSHr‐Ab), which were determined by either chemiluminescence or radioimmunoassay. Results Antithyroid autoantibodies were detected in 46 (28.75%) women with RM and in 13 (13%) women of the control group (P < 0.05). The frequencies for TG‐Ab and TPO‐Ab were higher in RM than in control women. Among the women of RM group, 91.3% of ATA+ women were positive also for other autoantibodies. The majority of study women were euthyroid. Conclusions Antithyroid autoantibodies, particularly TG‐Ab, are associated with RM and could be an expression of a more general maternal immune system abnormality leading to RM. ATA could have a role in RM irrespective of thyroid hormone status.     

Postpartum thyroiditis: an organ specific syndrome which is not associated with a postpartum polyclonal B-cell activation.

Recent reports have detailed the presence of autoantibodies characteristic of non-organ specific autoimmune diseases in the serum of patients with autoimmune postpartum thyroiditis (PPT). These observations suggest that PPT could be part of a polyclonal B-cell activation postpartum. We have measured 4 non-organ specific autoantibodies (anti-DNA, anti-cardiolipin, anti-nuclear factor (ANF) and antibodies against extractable nuclear antigens (ENA)) together with autoantibodies against thyroglobulin and thyroid peroxidase in a group of PPT women at 4 time points during the first year postpartum (early, time of hyperthyroidism, time of hypothyroidism, late). Whilst 18/18 patients showed thyroid specific autoantibody changes there was only a low frequency of occurrence of the non-organ specific autoantibodies (ENA 2/18; ANF 1/18; anti-DNA 2/18; anti-dsDNA 0/18; anti-cardiolipin 0/18) and, when positive, the response was poor. We conclude that PPT is not associated with a polyclonal b-cell activation but is a postpartum rebound of a thyroid specific autoimmune phenomenon.     

Value of combined clinical information and thyroid peroxidase antibodies in pregnancy for the prediction of postpartum thyroid dysfunction

PROBLEM: To investigate the utility of thyroid peroxidase antibodies (TPOAb) in early pregnancy combined with clinical information for prediction of postpartum thyroid dysfunction (PPTD) within 1 year postpartum. METHOD OF STUDY: We studied 98 pregnant women by determining their TPOAb levels in early pregnancy, as well as their serum thyrotropin and free thyroid (fT4) levels at 6 and 12 months postpartum. Furthermore, they answered a questionnaire and physical examination was performed by only one examiner. RESULTS: Of the 98 women, 10 were positive TPOAb in early pregnancy. The overall risk of PPTD within 1 year of follow-up was 10.2% (95% CI 4.1-16.3). Risk of PPTD was significantly higher among women with a family history of thyroid disease, TPOAb positive and presenting goiter in early pregnancy. The sensitivity, specificity and positive predictive value of TPOAb in PPTD prediction were 60.0%, 95.5% and 60%. Restricting screening to women with a family history of thyroid disease or presenting goiter increases the positive predictive value from 60% to 82.4%. CONCLUSION: Our results suggest that TPOAb could be used as a screening test for PPTD prediction at least among women who present a high risk of developing PPTD.     

Thyroid follicular cell function after non-lethal complement membrane attack

Terminal complement complexes have been identified around thyroid follicles in Graves' disease and Hashimoto's thyroiditis, and the concentrations of such complexes are increased in the sera of these patients, suggesting a role for complement activation and membrane attack complexes (MAC) in autoimmune thyroiditis. This has been investigated further using cultured human and rat thyroid cells. Thyrocytes were resistant to lysis by homologous complement, in contrast to the effects of heterologous (rabbit) complement. The formation of non-lethal amounts of MAC, using reactive lysis or classical pathway activation, significantly reduced cAMP production by these cells in response to thyroid-stimulating hormone (TSH) (P less than 0.01); similar effects were seen with thyroid-stimulating antibodies. Thyroid cells were able to recover rapidly from complement attack after washing and incubation for 30 min. Non-lethal MAC formation also resulted in reactive oxygen metabolite production, detected by luminol-dependent chemiluminescence in three out of five thyroid cell preparations tested. Ionomycin, but not TSH, also stimulated reactive oxygen metabolite production. These results suggest that repeated or continuous sub-lethal complement attack on thyroid cells may exacerbate hypothyroidism in Hashimoto's thyroiditis, or partially counter the effects of thyroid-stimulating antibodies in Graves' disease. Furthermore, the production of reactive oxygen metabolites in these circumstances could increase the intra-thyroidal inflammatory response; oxygen radical scavenging by anti-thyroid drugs (which are concentrated by thyrocytes) may account in part for the amelioration of thyroiditis observed with such treatment.     

Disorders of the thyroid gland in neonates and youth: latent hypothyroidism and hyperthyroidism

Etiology and clinical manifestation of subclinical hypothyroidism is different in neonates and in young. In the neonatal period babies present with jaundice and/or constipation due to thyroid hypoplasia, thyroid ectopia or transient hypothyroidism. The main reason for subclinical hypothyroidism in the youth is Hashimoto thyroiditis. Indication for thyroxin therapy in subclinical hypothyroidism is discussed controversial in the literature. For best growing and maturation in childhood thyroxin therapy should be given. Subclinical hyperthyroidism is rare in childhood. The main reasons are Graves' disease or Hashimoto thyroiditis (initial period). The therapy of subclinical hyperthyroidism is the same as in overt hyperthyroidism.     

Thyroid autoimmunity and dysfunction associated with type I interferon therapy

Abstract. Type I interferons are currently used for the treatment of chronic viral hepatitis, multiple sclerosis and several hematological and solid tumors. Side effects are not uncommon, and include multiple alterations in thyroid function, some of which are unrelated to autoimmunity. Review of the literature revealed an overall mean prevalence of incident thyroid dysfunction of 6.2%, hypothyroidism occurring more frequently (3.9%) than hyperthyroidism (2.3%). Destructive thyroiditis characterized by early transient thyrotoxicosis followed by hypothyroidism has also been described. Thyroid dysfunction was mainly subclinical, and spontaneous resolution occurred in almost 60% of patients with or without withdrawal of interferon. Risk factors for developing thyroid abnormalities were female sex and the presence of pre-existing autoimmune thyroiditis. Whether prolonged interferon therapy will increase the likelihood of experiencing thyroid dysfunction, as well as the relationship between incident thyroid autoimmunity and the efficacy of interferon therapy, are still open questions. Although the most-likely explanation for thyroid disease occurring with type I interferon therapy remains an autoimmune reaction or immune system dysregulation, a direct inhibitory effect on thyrocytes may be presumed in patients who developed hypothyroidism without autoimmunity. However, the mechanisms of thyroid damage induced by type I interferons have not yet been clarified in detail. We recommend routine evaluation of serum thyroid-stimulating hormone during interferon therapy. A systematic thyroid assessment is useful only for those patients with pre-existing thyroiditis or incident dysfunction. Although discontinuation of interferon therapy is seldom required, it may be necessary in patients who develop Graves disease and overt hyperthyroidism.     

Thyroid peroxidase and the induction of autoimmune thyroid disease

Animal models of autoimmune thyroid disease are associated with thyroglobulin (Tg) as autoantigen whereas in man the autoimmune response to microsomal antigen/thyroid peroxidase (TPO) appears to play a major role in thyroiditis. Consequently, we have compared the ability of TPO and Tg to induce thyroid autoantibodies and thyroid damage in mice known to be susceptible (CBA/J) or resistant (BALB/c) to thyroiditis induced using murine Tg. Groups of three to five mice were immunized twice using Freund's complete adjuvant with 80-100 micrograms highly purified porcine (p) TPO, pTg, rat (r) Tg, human Tg, bovine serum albumin (BSA) or BSA + 0.2 micrograms pTg (the level of Tg contamination of TPO). Four weeks after immunization with TPO, plasma from CBA/J (but not BALB/c) mice contained IgG class antibodies which bound to TPO-coated tubes in the presence or absence of excess Tg (and could therefore be clearly distinguished from Tg antibodies) but there was no evidence of thyroiditis in either strain of mice. In contrast, in CBA/J mice immunized with rTg and, to a lesser extent in mice that had received pTg, thyroid tissue was infiltrated with lymphoid cells and/or neutrophils and antibodies to pTg (but not pTPO) were present. Our observations demonstrate that induction of TPO antibody alone is insufficient to lead to thyroiditis in CBA/J mice. Further, these studies emphasize the complex interactions between MHC and different thyroid antigens in the processes leading to thyroid destruction.     

HLA-DR factors associated with postpartum hypothyroidism : an early manifestation of Hashimoto''s thyroiditis?

Thirty-three Danish women selected from a prospective study of postpartum thyroiditis were HLA-DR typed. All women had positive titers of antimicrosomal antibodies, and 20 women developed thyroid dysfunction after delivery. DR5 and the phenotype 4.5 were significantly increased in the whole group (p less than 0.001) and strongly associated to hypothyroidism (p less than 0.01), whereas DR3 was insignificantly increased in thyrotoxic women. It is concluded that postpartum hypothyroidism is an autoimmune disorder and may be an early manifestation of Hashimoto's thyroiditis.     

TMA与TGA检测对甲状腺疾病的临床诊断价值

根据174例疑诊患者的TMA、TGA，T3，T4放射免疫测定结果及其临床表现进行诊断，结果表明桥本氏甲状腺炎和甲亢所占的比例(分别为38．51％及31．61％）显著高于甲减和亚急性甲状腺炎(分别为6．32％和4．02％)，P＜0．05。甲减患者TGA TMA的阳性率（81．82％)显著高于甲亢(50．91％)，桥本氏甲状腺炎(50．75％)及亚急性甲状腺炎(57．14％)，P＜0．05。单项抗体阳性者以TMA较TGA为多。本文结果提示在甲状腺疾病中TMA，TGA的阳性结果存在相互重叠现象，与T3、T4联检并结合临床表现进行综合分析有助于甲状腺疾病的鉴别诊断并正确指导治疗。     

Thyroid peroxidase

Thyroid Peroxidase (TPO) is a key enzyme in the synthesis of thyroid hormone and is a major thyroid microsomal antigen corresponding to anti-microsomal autoantibodies in thyroid autoimmune diseases. We studied the autoantigenicity, thyroiditogenicity and gene structure of TPO. In micro-ELISA using human TPO as a target, all sera from patients with anti-microsomal antibodies contained IgG class of antibodies to TPO and some sera had IgM class of antibodies. The competitive inhibition test revealed that TPO is the major thyroid microsomal antigen. Experimental murine thyroiditis was successfully induced by the immunization of porcine TPO. Susceptibility of thyroiditis in each strain was very different from that of thyroiditis induced by thyroglobulin. T-cell line specific for porcine TPO could mediate thyroid lesions. Two kinds of full length cDNAs to human TPO were isolated from cDNA library which was constructed from mRNA purified from thyroid with Graves' disease. The longer one consisted of 3,048 nucleotides and its open-reading-frame was likely to encode 933 amino acids. The shorter one lacked 171 nucleotides at the middle portion of the longer one. The structure-gene for human TPO was located on 2q and consisted of 17 exons. One hundred and seventy-one nucleotides deleted in the shorter cDNA exactly corresponded to the 10th exon.     

Ultrastructural localization of endogenous peroxidase activity in Hashimoto's thyroiditis

Ultrastructural localization and intensity of endogenous thyroid peroxidase (TPO) in Hashimoto's thyroiditis were examined in relation to the serum thyroid hormone level, thyroid-stimulating hormone (TSH) concentration and anti-thyroid autoantibody titer. In Hashimoto's thyroiditis, TPO activity on the microvilli of follicular cells was more intense than that of normal thyroid tissue, but the intensity of the intracytoplasmic peroxidase reaction was generally weaker than that of Graves' or normal thyroid tissue. Microvillar TPO reaction products were positive in all thyroid follicular cells in patients with increased TSH levels, but no TPO activity was observed on the microvilli of patients with normal or low TSH levels, irrespective of their histological type or serum anti-microsomal antibody titer. It is suggested that TPO activity on the surface of microvilli of thyroid follicular cells in Hashimoto's thyroid gland is modulated by thyrotropin but is not affected by anti-thyroid autoantibodies.