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Context: Thyroid hormone, requiring adequate maternal iodine intake, is critical for fetal neurodevelopment. Perchlorate decreases thyroidal iodine uptake by competitively inhibiting the sodium/iodide symporter. It is unclear whether environmental perchlorate exposure adversely affects thyroid function in pregnant women. Thiocyanate, derived from foods and cigarette smoke, is a less potent competitive sodium/iodide symporter inhibitor than perchlorate. Objective: Our objective was to determine whether environmental perchlorate and/or thiocyanate exposure is associated with alterations in thyroid function in pregnancy. Design and Setting: We conducted a cross-sectional study at health centers in Cardiff, Wales, and Turin, Italy. Patients: During 2002–2006, 22,000 women at less than 16 wk gestation were enrolled in the Controlled Antenatal Thyroid Screening Study. Subsets of 261 hypothyroid/hypothyroxinemic and 526 euthyroid women from Turin and 374 hypothyroid/hypothyroxinemic and 480 euthyroid women from Cardiff were selected based on availability of stored urine samples and thyroid function data. Main Outcome Measures: Urinary iodine, thiocyanate, and perchlorate and serum TSH, free T4 (FT4), and thyroperoxidase antibody were measured. Results: Urinary iodine was low: median 98 μg/liter in Cardiff and 52 μg/liter in Turin. Urine perchlorate was detectable in all women. The median (range) urinary perchlorate concentration was 5 μg/liter (0.04–168 μg/liter) in Turin and 2 μg/liter (0.02–368 μg/liter) in Cardiff. There were no associations between urine perchlorate concentrations and serum TSH or FT4 in the individual euthyroid or hypothyroid/hypothyroxinemic cohorts. In multivariable linear analyses, log perchlorate was not a predictor of serum FT4 or TSH. Conclusions: Low-level perchlorate exposure is ubiquitous but did not affect thyroid function in this cohort of iodine-deficient pregnant women.

In Hashimoto's thyroiditis (HT), there is evidence for activation of peripheral T-lymphocytes that predominantly express a T helper 1 (T(H)1) cytokine bias. However, the immunomodulatory factors involved in regulating this response have so far received scant attention. In this study, we examine the effects of the glucocorticoid, dexamethasone, and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, rosiglitazone on the expression of interferon (IFN)-gamma (T(H)1) and interleukin (IL)-4 (T(H)2) by activated peripheral CD4(+) and CD8(+) lymphocytes in patients with HT (n = 10) and healthy control subjects (n = 12).Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with phorbolmyristate acetate (PMA) and ionomycin in the presence or absence of varying doses of dexamethasone and rosiglitazone (0.01 microM, 1.0 microM, and 100 microM). Cytokine expression was determined by flow cytometry.CD4(+) and CD8(+) IFN-gamma expression was greater in HT than controls (14.87 versus 9.25; p0.05 and 21.34 versus 10.16; p0.01, respectively). A dose-dependent inhibition of IFN-gamma expression was seen with dexamethasone and rosiglitazone. Inhibition of CD4(+) and CD8(+) IFN-gamma expression with both dexamethasone and rosiglitazone was greater in control subjects than in patients (p0.05). There was no significant difference in IL-4 expression between patients and control groups and its expression remained unaffected by either compound.We show that CD4(+) and CD8(+) T lymphocytes from HT patients express a type 1 cytokine bias that is significantly more resistant to in vitro modulation by rosiglitazone and dexamethasone. Further studies are needed to clarify if this resistance plays a role in the pathogenesis of autoimmune thyroid disease (AITD).

Introduction: We previously reported a high thyroglobulin autoantibodies (TgAb) prevalence in healthy Sri Lankans after iodine supplementation. In the present study 58 TgAb-positive schoolgirls were followed up after 5 years of continued iodination. The objectives were: (1) to observe the longitudinal profile of TgAb epitope specificities and (2) to examine the relationship between these specificities and the course of thyroid autoimmunity in this population. Methods: Paired subjects' sera (at onset and at 5-year follow-up) were tested for TgAb, thyroid peroxidase antibody (TPOAb), and TgAb epitope-specificity. Epitope reactivity was determined by employing a panel of 10 murine monoclonal antibodies (Tg-mAbs) directed against 6 Tg antigenic clusters (I–VI) in competitive enzyme-linked immunosorbent assay (ELISA) reactions with test sera. Results: The overall pattern of epitope recognition in individual subject's sera remained preserved over the time period. Nine subjects showed restricted specificities while majority of the subjects were broadly heterogeneous. At follow-up, median TgAb concentration in the restricted group was higher than in the unrestricted (1650 versus 110 kIU/L; p < 0.005). Epitope specificity was a stronger determinant of TgAb persistence than the height of the initial TgAb response or the TPOAb status of subjects. Conclusion: Tg epitope reactivity pattern in iodised populations may identify subjects at greater risk of developing autoimmune thyroid disease (AITD).

Thyroid peroxidase antibodies (TPOAb) in pregnancy are a marker for postpartum (PPTD) and long-term thyroid dysfunction, with variable sensitivity and specificity in PPTD prediction. To test its utility in prediction, we recruited 308 TPOAb-positive (147 developed PPTD (PPTD group) and 161 remained euthyroid [PPTE group]) and 102 TPOAb-negative women (none developed PPTD), in early pregnancy (median, 18; range, 9-19 weeks' gestation). TPOAb levels were higher in the PPTD group (median) (125.2 kIU/L; p < 0.001), and in its hypothyroid (162.4 kIU.; p < 0.0001), hyperthyroid (114.2 kIU/L; p < 0.007), and biphasic (105.1 kIU/L; p < 0.02) variants, compared to the PPTE group (66.7 kIU/L) The incidence of PPTD was significantly higher with TPOAb levels above 58.2 kIU/L (early pregnancy versus postpartum; relative risk, 1.37 [95% confidence interval [CI] 1.17-1.61] versus 0.78 [95% CI 0.5-1.2]) compared to levels below. The integrated postpartum TPOAb response was higher in the PPTD group (median) (159 kIU/L per week) and its variants (hypothyroid; 199 kIU/L per week; biphasic, 180 kIU/L per week; hyperthyroid, 120 kIU/L per week), compared to the PPTE group (86 kIU/L per week p < 0.004). Median early pregnancy TPOAb levels in the PPTD and PPTE groups correlated well with the postpartum antibody response (r = 0.58, p < 0.001). The sensitivity of TPOAb in PPTD prediction was 100% (early pregnancy and postpartum), specificity 62% (early pregnancy) versus 41% (postpartum) and positive predictive value 48% (early pregnancy and postpartum). The timing of TPOAb testing, the sensitive assay used and the absence of PPTD in TPOAb-negative subjects contributed to this high sensitivity. We recommend TPOAb in early pregnancy as a useful predictor of PPTD, particularly in populations where PPTD does not occur in TPOAb-negative women.

Summary background There is experimental evidence that leptin is required for the development of T helper 1 (Th1)-mediated autoimmune diseases. However, to our knowledge, there are no studies demonstrating such a role in human autoimmune thyroid disease. objective In the present study we have retrospectively examined patients developing postpartum thyroiditis (PPT), as a model of autoimmune disease, for changes in serum leptin levels during the postpartum period. materials and methods The study group included 61 women in the first month postpartum who were positive for thyroid peroxidase antibodies (TPOAb+ve). Twenty TPOAb-negative (–ve), age and body mass index (BMI)-matched, postpartum women were enrolled as the control group. All subjects were evaluated for BMI, serum leptin values, thyroid function [serum free-triiodiothyronine (FT3), free-thyroxine (FT4), thyrotropin (TSH)] and autoimmunity [TPOAb levels and complement activity index (C3 index)] at 4, 12, 16, 20 and 24 weeks’ postpartum. During the postpartum period, 32 of 61 TPOAb+ve women (52·4%) showed one or more episodes of thyroid dysfunction (PPTD group), whereas the remaining 29 TPOAb+ve women remained euthyroid throughout the study period (PPTE group). None of the control group developed thyroid dysfunction. results Four weeks postpartum, TPOAb+ve women showed higher serum leptin values than TPOAb–ve women, despite comparable BMI. At this time, PPTE and PPTD patients showed no significant differences in leptin levels or leptin/BMI ratio. Throughout the postpartum period, PPTD patients maintained significantly higher leptin values and leptin/BMI ratio compared to the healthy women. In PPTE women, however, a significant reduction in leptin levels and leptin/BMI ratio was seen at 12 weeks’ postpartum. This decrease was transient and correlated negatively with the variation in C3 index at the same time. No significant correlation was found between serum leptin variations and FT4 or TSH levels. conclusions This study has demonstrated that women developing postpartum thyroiditis have higher leptin values compared to the healthy women. The higher levels were maintained for 6 months postpartum. This result would suggest an involvement of leptin in the pathogenesis of postpartum thyroid disease, although further studies are needed to characterize the reciprocal effects of leptin, immune system and thyroid hormones during the course of this disease.

OBJECTIVE: To study the evolution of thyroid autoimmunity, in relation to the change in goitre prevalence, during 3 Years of iodine prophylaxis in Sri Lanka. METHODS: Two groups of Sri Lankan schoolgirls between the ages of 10.8 and 17.5 Years were studied in 1998 (401 girls) and 2001 (282 girls). A prospective study was performed in 42 schoolgirls who were thyroid autoantibody (Ab)-positive (+ve) in 1998. Anthropometric measures, urinary iodine excretion (UIE), thyroid Volume, free thyroxine, free tri-iodothyronine, TSH, and thyroglobulin (Tg) and thyroid peroxidase (TPO) Ab were evaluated in all 683 girls. RESULTS: Goitre prevalence was significantly lower in 2001 compared with 1998 related to age (2.9% compared with 20.2%) and body surface area (11.6% compared with 40.8%), although UIE was unchanged. Prevalence of thyroid Ab in 2001 was also lower (23.4% compared with 49.9%); among those with the Ab, 34.8% had TgAb alone and 46.9% had a combination of TgAb+TPOAb, compared with 82.0% TgAb alone in 1998. In 2001, subclinical hypothyroidism was more frequent in Ab+ve (6.3%) than Ab-negative girls (1.0%). A cohort of 42 Ab+ve schoolgirls in 1998 (34 with TgAb alone, eight with TgAb+TPOAb) were evaluated again in 2001. Only 10 of them (23.8%) remained Ab+ve (mostly TPOAb+/-TgAb) in 2001. CONCLUSIONS: This study demonstrates that: (1) in 2001, goitre prevalence and thyroid autoimmunity rates were significantly lower than in 1998; (2) the pattern of thyroid Ab was different in the two surveys; (3) in 2001 alone, the occurrence of hypothyroidism was correlated with the presence of thyroid autoimmunity. These results indicate an evolution of thyroid autoimmune markers during the course of iodine prophylaxis, which has not been described before.

objective We previously reported a high prevalence of raised thyroglobulin autoantibodies (TgAb) in apparently healthy Sri Lankan schoolgirls following salt iodination. To characterize these antibodies further we determined the epitopes on thyroglobulin (Tg) with which they react and compared these with serum obtained from both healthy subjects and established autoimmune thyroid disease (AITD) patients from the UK. To extend our study to a wider population within Sri Lanka, we in addition determined the epitopes recognized by a group of AITD patients selected from a thyroid clinic in Sri Lanka, as well as apparently healthy female Sri Lankan tea workers of distinct ethnicity from the schoolgirls and AITD patients. design Sri Lankan schoolgirls (n = 282) and adult female tea estate workers (n = 208) were examined for thyroid autoimmune markers. Sera with high TgAb (> 98 kIU/l) were selected from these two groups (n = 36 and 45, respectively) to study epitope-binding patterns. We also examined the sera from 16 AITD patients attending a thyroid clinic in Colombo, 16 patients with AITD from the thyroid clinic at the University Hospital of Wales and 16 sera from healthy control UK women with no evidence of thyroid disease. To determine the epitopes on Tg recognized by the subjects’ TgAb, we employed a panel of Tg mouse monoclonal antibodies labelled with alkaline phosphatase in a competitive enzyme-linked immunosorbent assay reaction with the subjects’ serum. results and conclusions A majority of the Sri Lankan schoolgirls did not react with the immunodominant epitopes and did not differ significantly from healthy subjects from the UK in their Tg epitope recognition pattern. On the other hand, tea estate workers and Sri Lankan AITD patients recognized typical autoimmune thyroid disease epitopes and, in addition, recognized a separate cluster not previously associated with either the autoimmune state or the healthy state. The significance of this cluster requires further clarification.

Background: Postnatal depression is more common in women positive for thyroid autoantibodies, independent of thyroid hormone dysfunction, but the basis of this association is unclear. Aims: The objective of the work reported here has been to investigate from data obtained from previously published research, a possible association between life events, postnatal depression and the development of thyroid dysfunction in women who are positive for thyroid autoantibodies. Method: A cohort of pregnant women whose thyroid antibody status was positive ( N = 115), was identified at antenatal booking (approximately 16 weeks). These, and a group of women negative for thyroid antibodies ( N = 123), were assessed for depression at six to eight weeks postpartum and then at 12, 20 and 28 weeks postpartum according to Research Diagnostic Criteria (RDC). The number and type of life events over the preceding year were also assessed at eight weeks postpartum using Paykel's Life Event Schedule. At four weekly intervals postpartum until six months, thyroid antibody levels and thyroid function (plasma T3 T4 and TSH) were measured. Results: As anticipated, the thyroid antibody status remained the same throughout the study, and there was no difference in the number or type of life events reported in the preceding year, between antibody positive and antibody negative women. Postnatal depression was associated with an excess of both total and negative life events, independent of thyroid antibody status or actual thyroid hormonal status. Women who developed thyroid dysfunction did not report an excess of life events (total, negative or neutral) in the preceding year. Conclusion: There was an excess of reported total and negative life events in women with postnatal depression, but this was independent of thyroid antibody status or function.

Postpartum thyroid dysfunction (PPTD) develops during the first 9 months in up to 50% of women who have thyroid peroxidase antibodies (anti-TPOAb +ve). Humoral immunity in PPTD has been well documented, but the cellular immunological events accompanying the Th2 to Th1 state postpartum are less clear. Peripheral blood lymphocyte cytokine secretion was examined in 48 TPOAb +ve and 33 TPOAb -ve women at 36 wk gestation and at 6, 12, and 24 wk postpartum. Eighteen women with PPTD had significantly greater secretion of interferon gamma and IL-4 than euthyroid women at 36 wk gestation with no significant differences in cytokine secretion at other time points. Also, at 36 wk gestation, the median plasma cortisol concentration in the PPTD group was significantly lower than the euthyroid group (442 nmol/liter vs. 567 nmol/liter, P0.02). There were no differences between the groups in levels of prolactin, progesterone, or estradiol. These data suggest that there may be less immunological suppression at 36 wk in TPOAb +ve women destined to develop PPTD possibly because of lower levels of cortisol. Thus, the immunological determinants of PPTD may in part occur antenatally, although the mechanism(s) for this is still unclear.

BackgroundWomen who are positive for thyroid antibodies in early gestation are prone to post-partum depression, apparently independent of thyroid dysfunction, as measured by serum levels of free thyroxine, free triodothyroxine and thyroid-stimulating hormone. This finding may be due to infrequent monitoring of thyroid function, because hyperthyroidism, hypothyroidism and combinations of both may occur post-partum.AimsTo test the hypothesis that stabilising thyroid function post-partum by administering daily thyroxine reduces the rate of occurrence and severity of associated depression.MethodIn a randomised double-blind placebo-controlled trial, 100 of thyroxine or placebo was given daily to 446 thyroid-antibody-positive women (342 of whom were compliant) from 6 weeks to 6 month spost-partum, assessing their psychiatric and thyroid status at 4-weeklyintervals.ResultsThere was no evidence that thyroxine had any effect on the occurrence of depression. The 6-month period prevalence of depression was similar to that reported previously.ConclusionsThe excess of depression in thyroid-antibody-positive women in the post-partum period is not corrected by daily administration of thyroxine.

OBJECTIVE Postpartum thyroiditis (PPT) is an autoimmune thyroid disease which shares immunological and clinical features with autoimmune hypothyroidism and Graves' disease, and is believed to be caused by a combination of genetic and environmental factors. Recently, an association has been described between Graves' disease or autoimmune hypothyroidism and a polymorphism in the CTLA-4 gene, which encodes a T cell receptor for the B7 family of ligands, and we wished to test whether a similar association exists with PPT. DESIGN A population-based case-control study of a CTLA-4 gene microsatellite polymorphism was performed, to look for an association with PPT. PATIENTS Caucasoid women (n = 122) were studied; 58 had thyroid antibodies (against thyroglobulin or thyroid peroxidase) alone during the postpartum period (PPT−) and 64 had thyroid antibodies and some form of postpartum thyroid dysfunction (PPT+). RESULTS There was no significant difference between this whole group of women and 161 local Caucasoid thyroid antibody-negative women for the CTLA-4106 base pair (AT)n microsatellite polymorphism (relative risk = 1.3; P = 0.3), nor did the PPT+ group differ from controls when analysed separately (P = 0.2). When the postpartum women were subdivided in groups according to clinical pattern of PPT and the type of thyroid antibodies, there were no associations within the subgroups. CONCLUSIONS No significant association exists between postpartum thyroiditis and a polymorphism in the CTLA-4 gene. Furthermore, a natural variation in the prevalence of the polymorphism in healthy UK populations underscores the need to select appropriately matched normal subjects in future case-control studies.

Postpartum thyroid dysfunction (PPTD) is an autoimmune-mediated thyroid destructive process. Human interleukin-6 (IL-6) is a cytokine found to be increased in subacute thyroiditis, amiodarone-induced thyrotoxicosis, Graves' disease, and other thyroid destructive processes. We report serum IL-6 levels in PPTD in two independent studies. New York Study: In a previous prospective study we demonstrated that PPTD occurred in 25% (7/28) of women with type 1 diabetes mellitus. IL-6 determinations were made on the frozen serum samples of these 28 women during each trimester of their pregnancy and at 1.5, 3, 6, 9, and 12 months postpartum. IL-6 levels were found to be similar in women with PPTD compared with women without PPTD (mean 3.06+/-2.25 vs. 2.51+/-2.21 pg/mL; p = 0.15). No difference in IL-6 levels was found between the pre- and the postpartum periods (mean 2.67+/-1.82 vs. 3.04+/-2.44 pg/mL; p = 0.30) in all 28 women. Cardiff Study: Serum IL-6 levels were measured on frozen serum samples of 30 women with PPTD. IL-6 levels were below the detection limit (25 fmol/L or 0.65 pg/mL) in 94 (67%) of these samples. No significant difference in the mean serum IL-6 levels were found between any time points in the study. There was no correlation between serum IL-6 levels, thyroid peroxidase (TPO)- antibodies and serum thyrotropin (TSH) levels at any time point. IL-6 levels during pregnancy or postpartum were not found to be significantly different in women with PPTD compared with women without PPTD.

Depressive illness has a high prevalence in the puerperium (Paykel et ai 1980). Antenatal psychiatric disorders have received less attention; however, there are now several studies that suggest that rates of antenatal depression are comparable to those of postnatal depression (see review: Green and Murray 1994). Little is known about the etiology of antenatal depression. Studies have shown that women positive for thyroid antibodies, independent of thyroid hormone status, are prone to episodes of postnatal depression (Hams et al 1989, 1992; Pop et al 1991). No study to date has investigated whether the presence of gestational thyroid antibodies are associated with antenatal mood disturbance. The aim of this study was to assess prevalence of antenatal depressive symptoms and the relationship, if any, to thyroid antibody status.

Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function.We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T(4)). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T(4) levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments.Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], -1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, -2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results.Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. (Funded by the Wellcome Trust UK and Compagnia di San Paulo, Turin; Current Controlled Trials number, ISRCTN46178175.).

Postpartum thyroiditis (PPT) affects half of the 10% of women who have elevated circulating thyroid autoantibodies during the postpartum year. Because of the similarities between PPT and Hashimoto's thyroiditis, the pathogenic role of complement in PPT has been investigated. Complement fixation by thyroid peroxidase antibodies (TPO Abs) (expressed as log reciprocal titer) in serum from euthyroid TPO Ab-positive women (n = 29) was 0.91 at 1 month postpartum and increased to 1.45 by 12 months postpartum; complement C3 activation, measured by enzyme-linked immunosorbent assay, in a similar group of women (n = 75) was 0.05 at delivery and increased to 0.33 by 6 months postpartum. In women with PPT, there was greater TPO Ab-related complement activation during the postpartum year; complement fixation increased from 1.00 at 1 month postpartum to 1.48 at 4 months postpartum (P0.005) (n = 25), and C3 activation increased from 0.11 at delivery to 0.63 at 6 months postpartum (P0.005) (n = 73). Bioactive TPO Ab (TPO Ab x C3 index) was significantly higher in PPT women (55 kilo international units of activity (kIU)/L at 6 months postpartum) (Hashimoto range, 30-108 kIU/L) compared with euthyroid TPO Ab-positive women (9 kIU/L at all time points; P0.005). Serum samples from TPO Ab-negative control women showed no interaction with complement in either assay at any time during the postpartum year (complement fixation0.7; complement C3 activation index0.01). This detailed examination of the role of complement in the pathogenesis of PPT shows that TPO Ab-driven complement fixation is a marker for thyroid dysfunction in TPO Ab-positive women. The levels of bioactive TPO Ab in PPT fall within the range seen in Hashimoto's thyroiditis, suggesting similarities in their pathology.

OBJECTIVE: The aim of this study was to assess whether autoimmune thyroid damage in post-partum thyroiditis was accompanied by a significant rise in the concentration of thyroglobulin in the serum and whether its measurement could be useful in the prediction of the risk and severity of an episode of post-partum thyroid dysfunction. PATIENTS: Fifty-one women, who had taken part in a larger survey of post-partum thyroiditis, were selected at random for this study. Fourteen women without elevated circulating thyroid autoantibodies and 21 with raised thyroid autoantibodies remained euthyroid throughout the post-partum year. A third group of 14 women had raised thyroid autoantibody levels and showed one or more episodes of thyroid dysfunction during the course of the first year post partum. MEASUREMENTS: Thyroid autoantibodies were measured by ELISA, free T3 and free T4 by the Amerlex M method and TSH by an immunoradiometric method. Serum thyroglobulin was measured by a method free from interference by circulating endogenous thyroglobulin autoantibodies. Thyroid ultrasonography was performed using a General Electric RT3600 scanner operating at 7.5 MHz. RESULTS: Fourteen control women had a mean serum thyroglobulin concentration of 3.3 micrograms/l (SD 4.4; range < 1-12 micrograms/l; 95% confidence interval up to 6.0 micrograms/l). Twenty-one thyroid autoantibody positive euthyroid women had a mean serum thyroglobulin level of 5.8 micrograms/l (SD 6.2; range < 1-36 micrograms/l) which was not significantly different from that seen in the control group. Sixteen thyroid autoantibody positive women who showed one or more episodes of thyroid dysfunction during the post-partum period had a mean serum thyroglobulin of 31 micrograms/l (SD 24.8; range up to 88 micrograms/l) and this was significantly elevated compared with both the control and antibody positive groups (P < 0.001). Serum thyroglobulin concentrations at 3 months post partum correlated with the degree of post-partum hypothyroidism (as indicated by the maximum TSH and the minimum free thyroxine concentrations post partum) and, in those cases where thyroid ultrasound examinations were performed, with the degree of lymphocytic infiltration of the thyroid gland. CONCLUSIONS: The data presented in this paper confirm the destructive nature of post-partum thyroiditis and indicate that the measurement of serum thyroglobulin concentration could assist in the identification of those women at risk of post-partum thyroiditis.

Summary BACKGROUND Post-partum thyroid disease occurs in 50% of anti-thyroid peroxidase (TPO) antibody positive women (detected at 16 weeks' gestation) and is characterized by a transient episode of hyper, hypo or hyper-hypo thyroidism. In approximately 20% of these women the hypothyroidism is permanent. However, the extent of long-term thyroid dysfunction, possibly mediated by immune attack, in those anti-TPO Ab + ve women who have had only transient or no thyroid dysfunction during the postpartum period is not clear. OBJECTIVE We have therefore studied the frequency of iodide organification defects by iodide perchlorate discharge testing, and of thyroid morphological abnormalities by ultrasound scanning in euthyroid women following their episode of post-partum thyroiditis (PPT). DESIGN The study group comprised 17 women with previous PPT (PPT +ve) and 12 women who had positive anti-TPO antibodies during pregnancy but who did not develop PPT (PPT-ve). Women were studied 15-47 months following their episode of PPT. RESULTS Iodide perchlorate discharge tests were positive (more than 10% discharge) in 7 (41 %) PPT + ve and 5 (42%) PPT-ve subjects (P = NS). Morphological abnormalities on thyroid ultrasound were detected in 7 of 14 (50%) PPT + ve and 7 of 9 (77%) PPT-ve subjects (P = NS). There was a strong association between abnormalities of iodide organification and morphology: of 11 subjects with positive iodide perchlorate discharge tests, 10 had abnormal (positive) ultrasound scans; of 12 subjects with negative iodide perchlorate discharge tests 8 had negative ultrasound scans (P= 0.013, Fisher's exact test). CONCLUSIONS Long-term subtle defects of thyroid function and morphology are common in women with anti-TPO antibodies in pregnancy, whether or not they develop postpartum thyroiditis. The clinical significance of these findings is unclear but a continuing thyroid pathological process is suggested.

The natural history and pathogenesis of lymphocytic hypophysitis remain poorly understood. We describe a 34-yr-old woman with postpartum thyroiditis and ACTH deficiency, studied at monthly intervals for 18 months after pregnancy. A significant titer of thyroid peroxidase autoantibodies was detected at 16 weeks gestation, and she was recruited into a prospective study of postpartum thyroid function. Four months postpartum she developed mild hyperthyroidism [free T4 (fT4), 27 pmol/L; TSH, less than 0.2 mU/L] and showed a rise in thyroid peroxidase and thyroglobulin autoantibodies. At 9 months postpartum, serum fT4 and fT3 levels were low normal (8.0 and 1.7 pmol/L, respectively), but TSH was not raised (0.4 mU/L). Subsequent investigation showed a low basal plasma cortisol level (28 nmol/L) in association with undetectable ACTH, and subnormal cortisol responses to depot Synacthen (535 nmol/L at 6 h) and hypoglycemia (peak, 145 nmol/L). FSH, LH, GH, and PRL function and computerized tomography of the pituitary were normal. Retrospective analysis of serum samples taken throughout the postpartum year showed developing hypocortisolemia between 3-9 months postpartum. Each sample was also tested for pituitary autoantibodies using a specific indirect immunofluorescent assay; none was detected. The ACTH deficiency recovered spontaneously, with normal cortisol responses to depot Synacthen (greater than 1380 at 6 h) and hypoglycemia (peak, 590) 14 and 18 months postpartum, respectively. This case illustrates that postpartum pituitary deficiencies are potentially reversible. The pattern of pituitary deficit and postpartum thyroiditis supported a diagnosis of autoimmune hypophysitis.

Three women are described from a study of patients with postpartum thyroiditis whose sera gave spuriously increased concentrations of free thyroid hormone because of antibody binding of radiolabeled thyroxin (T4) and triiodothyronine (T3) analogs. All of the women showed increased serum concentrations of thyroid autoantibodies. The antibody binding of radiolabeled analogs and its effect on free T4 and free T3 assays disappeared by 48 weeks postpartum. Postpartum women who develop thyroid autoantibodies have approximately 2% prevalence of increased binding of radiolabeled analogs, which can result in an interference in thyroid hormone assays involving T4 and T3 analogs.

To investigate the long-term outcome of postpartum thyroiditis (PPT), 43 patients with PPT and 171 control women were evaluated 3.5 (range 2-4) years postpartum. Ten (23%) PPT patients were hypothyroid compared to none of the controls (P less than 0.001). Factors associated with the development of hypothyroidism were high antimicrosomal antibody titre measured at 16 weeks gestation (P less than 0.01), severity of hypothyroid phase of PPT, multiparity, and a previous history of spontaneous abortion. The presence of microsomal antibody but no PPT in one pregnancy did not prevent the occurrence of PPT in the next pregnancy in two patients and a further five patients had PPT in two successive pregnancies. There was no association between HLA haplotype, family history of thyroid disease, smoking or frequency of oral contraception, and the development of long-term hypothyroidism after PPT. It is concluded that permanent hypothyroidism is an important sequel to PPT and patients with PPT should be followed up appropriately.

Background: Statins have apoptotic effects on many cell types. Hashimoto’s thyroiditis (HT) is an autoimmune disease in which cell-mediated autoimmune mechanisms are pathogenetically involved.Objective: The aim of this study was to evaluate thein vivoeffects of Simvastatin on thyroid function, lymphocyte subtypes and also to investigate the apoptotic effects of Simvastatin, Mevastatin, Pravastatin and Cerivastatin on lymphocytes from patients with HT.Methods: In the first part of the study, 11 patients with HT and subclinical hypothyroidism (SH) were given Simvastatin (20 mg/day) for 8 weeks. Ten patients with SH and HT served as the control group. No treatment was given to controls. Thyroid function, C-reactive protein (CRP) levels and lymphocyte subtypes of both groups were determined before the study and after 8 weeks. In the second part of the study, the apoptotic effects of statins on lymphocytes were evaluated in patients with HT (n= 10) and normal subjects (n= 10)in vitro. Apoptosis was investigated by using Annexin-V and propidium iodide. Lymphocytes from patients and controls were incubated with different concentrations of Simvastatin, Cerivastatin, Mevastatin and Pravastatin.Results: An increase in serum free tri-iodothyronine and free thyroxine levels and a decrease in TSH levels were observed (P< 0.05) with Simvastatin treatment. CD4 + cells and B lymphocytes increased whilst CD8 + cells, natural killer cells and activated T lymphocytes decreased significantly in the treatment group (P< 0.05). The CRP level of the group also decreased with Simvastatin but it did not reach significance (P= 0.057). None of parameters was found to be different from the baseline in the control group. Inin vitroexperiments, apoptosis was observed in CD3 + (both in CD8 + and CD4 + cells) with all statins in both patient and control samples. Mevalonate, which was used in experiments, reversed apoptosis in some but not all samples.Conclusions: The results of this study suggested that Simvastatin is an immune modulatory agent and improves thyroid function in patients with HT. This effect is probably mediated via lymphocyte apoptosis as demonstrated within vitroexperiments and is not confined to Simvastatin since Mevastatin, Pravastatin and Cerivastatin also induced apoptosis in lymphocytes.

Thyroid antibodies were measured sequentially in 25 pregnant women from a Sri Lankan population. A high prevalence of antithyroid antibodies, particularly antithyroglobulin antibodies (TgAb) had previously been demonstrated in female schoolchildren drawn from this population. In the present study TgAb were detected in 36.8% of nonpregnant controls while thyroid peroxidase antibody (TPOAb) positivity was present in 26.3%. The prevalence of both antibodies in the pregnancy study group showed a progressive decline compared to nonpregnant controls throughout gestation becoming undetectable in the third trimester. The results are consistent with an immunosuppressive effect of pregnancy in a population in whom high thyroid autoantibody titers may have resulted from a recent salt iodization program.

Background: Serum antibodies against thyroglobulin (TgAbs) are common in patients with differentiated thyroid cancer (DTC) and can interfere in thyroglobulin (Tg) assays. We identified the epitopes on Tg recognized by TgAb-positive sera from patients with DTC and examined the association between epitope specificity patterns and Tg recovery. Methods: We tested 50 DTC sera for Tg epitope specificity, TgAbs, and Tg recovery. Epitope recognition was determined by use of a panel of 10 well-characterized Tg monoclonal antibodies directed against 6 Tg antigenic clusters (I–VI) in competitive reactions with test sera. Tg was measured by the Thyroglobuline IRMA (CIS bio international). Recovery of added Tg (TgREC) was determined by an in-house assay. Results: Epitope recognition was restricted to immunodominant clusters in 58% of patients, whereas the rest were either broadly heterogeneous (16%) or nonreactive (26%). Median Tg recovery did not differ between sera with restricted and unrestricted specificities (69% vs 80%; P >0.05). TgREC was inversely correlated with the total number of epitopes recognized by sera (r = −0.66; P Conclusions: TgAbs with both restricted and broad specificities are present in patients with DTC. TgAb interference is related to the number of epitopes recognized by sera rather than the pattern of epitope recognition.

C-reactive protein (CRP) levels have not been routinely used to diagnose thyroid disease, although many thyroid conditions involve inflammation. This study was intended to determine whether CRP levels could differentiate between inflammatory and noninflammatory thyroid conditions, especially between type II inflammatory amiodarone-induced thyrotoxicosis (AIT) and type I iodine-induced AIT. Serum high-sensitivity CRP levels were measured in 100 euthyroid controls (7 taking amiodarone) and 353 patients with one of the following thyroid conditions: AIT, subacute thyroiditis, toxic diffuse goiter, nodular goiter, Hashimoto's thyroiditis, shortterm hypothyroidism, or postpartum thyroiditis. No patients with nontoxic multinodular goiter (n = 34), toxic nodular goiter (n = 23), or toxic diffuse goiter, either untreated (n = 49) or euthyroid while taking methimazole (n = 33), had positive CRP levels (>10 mg/L). The occurrence of positive CRP levels among patients with Hashimoto's thyroiditis (n = 35), short-term hypothyroidism (n = 38), and postpartum thyroiditis (n = 70) did not differ significantly from controls. The occurrence of positive CRP values did not differ significantly between patients with type I and type II AIT and controls. Six of 7 patients (86%) with untreated subacute thyroiditis had positive CRP levels (p < 0.00001). These results indicate that there is only a limited role for measurement of CRP levels in the diagnosis of thyroid diseases other than subacute thyroiditis.

Background: Postpartum thyroid dysfunction (PPTD) develops in 50% of pregnant women who have raised levels of circulating thyroid peroxidase autoantibodies (TPOAb) at booking. Although these antibodies are able to activate the complement cascade in vitro, it is not known whether complement activation plays any role in the pathogenesis of this disease. Aim: To investigate potential and actual activation of the complement system in women with postpartum thyroiditis. Design: Complement activation was monitored on a weekly basis in 24 postpartum women who had raised TPOAb at 16 weeks gestation, attending an antenatal clinic in Mid‐Glamorgan, Wales. Methods: ELISA procedures were used to measure both in‐vitro complement C3 activation by TPOAb and circulating terminal complement complexes (TCC) in serum. Results: Higher levels of bioactive TPOAb activity were seen in women who developed PPTD when compared to those who did not. However, TCC remained undetectable in serum throughout the period of study. Conclusions: In PPTD, despite the presence of circulating bioactive TPOAbs, the extent of complement activation is inadequate to cause detectable increases in peripheral blood TCC, suggesting that the complement system may not play a major role in PPTD pathogenesis.

OBJECTIVE: Iodine deficiency was the likely cause of a high prevalence of goitre previously in Sri Lankan schoolchildren. Salt iodination was made compulsory in 1993 but there has been no recent study, using modern techniques, of its benefits or harmful effects. METHODS: Three hundred and sixty-seven schoolgirls between the ages of 11 and 16 years had ultrasound thyroid volume, free thyroxine (T4), free tri-iodothyronine (T3), thyrotrophin (TSH), anti-thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) antibodies, and urine iodine concentrations measured. RESULTS: Median ultrasound thyroid volume ranged from 4.8 ml (11-year-old girls) to 8.6 ml (16-year-old girls) with an age-related increase. Median urine iodine concentrations ranged from 105 to 152 microg/l. Free T4 and free T3 were normal in all, but TSH was elevated in four subjects (5. 53-41.29 mU/l). However, the prevalence of TgAb was markedly raised, ranging between 14.3% (11-year-old girls) and 69.7% (16-year-old girls) (P

Postpartum thyroid dysfunction (PPTD) occurs in 5% of women, with hypothyroidism developing in 23% of these after 3-5 yr. We have determined the prognostic significance of thyroid peroxidase antibody (TPOAb), thyroid ultrasound morphology (U/S), human leukocyte antigen haplotype, and postpartum thyroid status on the development of thyroid dysfunction 77-81 months after PPTD. Ninety-eight TPOAb-positive [48 who had developed PPTD (group 1) and 50 without PPTD (group 2)] and 70 TPOAb-negative (group 3) women (derived from 145 TPOAb-positive and 229 TPOAb-negative cohorts at the index pregnancy), with comparable ages, parity, pregnancies after index pregnancy, and follow-up duration, were studied. Thyroid dysfunction occurred in 46% of group 1 vs. 4% of group 2 (P0.001) and 24.5% of groups 1 and 2 vs. 1.4% of group 3 (P0.001). Factors predictive of thyroid dysfunction included a hypothyroid form of PPTD, TSH more than 20 mU/L, and higher TPOAb levels (213.8 kIU/L in group 1 vs. 131.8 kIU/L in group 2; P0.002) during the postpartum period. Although TPOAb was higher in group 1 than in group 2 at follow-up (166 vs. 97.7 kIU/L; P0.03), there was no significant fall in TPOAb levels within either group during the period of follow-up. The prevalence of ultrasound hypoechogenicity was higher in group 1 than in group 2 at follow-up (76% vs. 52%; P0.006), but U/S improved in 62.5% of group 1 during the period of follow-up. Human leukocyte antigen DR10 was lower in those who developed late thyroid dysfunction. These data, representing the longest follow-up of PPTD women, clearly show that the hypothyroid form of PPTD, high TPOAb levels, and a hypoechogenic U/S pattern lead to a high risk (relative risk, 32) of long term thyroid dysfunction. This compares with a relative risk of 12.9 for TPOAb- and PPTD-positive women, who remained euthyroid at the end of the first postpartum year, and 2.8 for TPOAb-positive but PPTD-negative women, all compared to TPOAb-negative women. Therefore, long term surveillance of TPOAb- and PPTD-positive women (group 1) is indicated.

Urinary iodone (UI) excretion and sonographically measured thyroid volume were investigated in 195 subjects living in 6 separate villages in the Casamance region of southeastern Senegal, West Africa. A comparison of goiter prevalence using thyroid palpation and volume measurement and of iodine excretion expressed as micrograms per gram (microg/g) creatinine or micrograms per deciliter (microg/dl) urine was undertaken, and possible pathogenetic factors were investigated. Ultrasound measured thyroid volumes were above the recommended upper limit of the reference range for an area replete in iodine in 83.1% or females, 52.3% of males, and 80.0% of children aged 13 years or younger. Overall sensitivity and specificity for palpation compared to sonographically demonstrated thyroid enlargement was 51.7% and 91.5%, respectively. Thyroid enlargement was not associated with ethnic origin, thiocyanate ingestion, HLA DR/DQ phenotype frequency, or thyroid growth-stimulating immunoglobulin (TGI) positivity. Median UI was 32 microg/g creatinine with 65.0% having values consistent with iodine deficiency (50 microg/g). When results were expressed as micrograms per deciliter, the percentage having values consistent with iodine deficiency (5.0 microg/dl) increased to 95.7%. The findings suggest a primary role for iodine deficiency in goitrogenesis in the study population. They demonstrate that classification of the severity of the endemia in this or other study populations in areas of iodine deficiency is dependent on the methods used to determine goiter prevalence (palpation or ultrasound measured thyroid enlargement), or dietary iodine status (iodine excretion expressed as micrograms per gram creatinine or micrograms per deciliter urine).

Parkes AB, Darke C, Othman S, Thomas M, Young N, Richards CJ, Hall R, Lazarus JH. Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis. Eur J Endocrinol 1996;134:449–53. ISSN 0804–4643 The objective was to re-evaluate the association between class II HLA-DR and DQ MHC antigens and postpartum thyroiditis (PPT) and to determine the prevalence of the class III complement allotypes of Properdin factor B (Bf), C4A and C4B in this condition. Two hundred and sixty-five (of 2897) pregnant women screened positive for thyroid autoantibody activity took part. Further blood samples were obtained for HLA class II (185) and complement (193) typing. The severity of the ensuing PPT was assessed by measuring thyroid function during the postpartum year. The HLA-DR and DQ phenotypes were assigned from restriction fragment length polymorphism analysis, and Bf, C4A and C4B allotypes were determined by immunofixation with anti-Bf or anti-C4 antibodies after electrophoresis. A weak association between the HLA class II antigens and PPT, as indicated by a reduced frequency of DR15 and DQ6 together with an increased frequency of DR5 and DQ7. was confirmed. However, only the change in DR5 frequency remained significant after correction (corrected p < 0.05). Postpartum thyroiditis was also associated with frequency disturbances in Bf and C4A allotypes but not C4B allotypes. Whilst this study has not provided evidence of a strong marker gene for PPT, it does not preclude the involvement of the MHC in this condition. These data show disturbances in complement allotype frequencies, suggesting that the class III region may provide a useful focus for further study of this pathology. AB Parkes, Autoimmunology Research Unit, Section of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK

The role of stress proteins in the pathology of autoimmune thyroid disease (AITD) has aroused considerable controversy in recent years1. Thyroid cells in tissue culture are known to synthesise a range of stress proteins (hsp) in response to elevated temperatures or toxic chemicals2. Hsp70 over expression has been demonstrated in thyroid tissue from patients with Graves' disease3 and intra-thyroidal T-cells from these patients can also be induced to expand in response to hsp70 from a variety of sources4. Unpublished data from our own laboratory shows that the incorporation of [3H] thymidine into peripheral lymphocytes from patients with AITD is also enhanced when these cells are cultured in the presence of stressed thyroid cells. However, in the same experiments, lymphoproliferation was also enhanced by PPD, a preparation rich in Mycobacterial hsp, which is a common immunogen in the population.

Parkes AB, Othman S, Hall R, John R, Lazarus JH, Role of complement in the pathogenesis of postpartum thyroiditis: relationship between complement activation and disease presentation and progression. Eur J Endocrinol 1995;133:210–5. ISSN 0804–4643 The aim of this study was to assess whether the presentation and progression of autoimmune postpartum thyroiditis (PPT) was related to the degree of thyroid peroxidase autoantibody (TPO-ab)-mediated activation of the complement cascade. One hundred and forty-eight thyroid autoantibodypositive women have been followed during their postpartum year. Seventy-five women remained euthyroid during this time whilst the remaining 73 showed one or more episodes of thyroid dysfunction. Fourteen women showed hyperthyroid PPT, 23 showed a biphasic PPT and the remaining 36 showed hypothyroid PPT. Hyperthyroid PPT was always transient but 29 of the 59 women with hypothyroidism remained hypothyroid or still required thyroxine replacement therapy at the conclusion of the study. Thyroid autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), free triiodothyronine and free thyroxine by the Amerlex M methods and thyrotrophin by the Amerlite TSH (monoclonal) assay. Complement component C3b, immobilized as a result of classical complement pathway activation in the presence of TPO/TPO-ab complexes in vitro, was measured by ELISA. Bioactive TPO-ab were calculated as the product of the C3 index and TPO-ab level. Basal levels of complement C3 activation were seen in the euthyroid TPO-ab-positive women (C3 index 0.06 at delivery rising to 0.36 at 12 months postpartum; bioactive TPO-ab activity 0.4kIU/l at delivery rising to 10.4kIU/l at 12 months' postpartum (N = 75). These parameters were elevated progressively as the severity of the clinical syndrome increased. In 14 hyperthyroid PPT women the C3 index was 0.47 at 8 months' postpartum (bioactive TPO-ab activity=20kIU/l; p vs euthyroid group, NS). In 23 biphasic PPT women the C3 index had risen to 0.65 by 7 months' postpartum (p < 0.005 vs euthyroid group), with bioactive TPO-ab activity 81kIU/l (p < 0.005), and in 36 women with hypothyroid PPT the C3 index was 0.7 by 6 months' postpartum (p < 0.005), with bioactive TPO-ab activity 76kIU/l (p < 0.005). In women with persistent PPT the C3 index had risen to 0.76 by 5 months' postpartum, with bioactive TPO-ab activity 116kIU/l; both parameters were statistically higher in the persistent group than in the remaining 44 cases where the C3 index was 0.56, with bioactive TPO-ab activity 33 kIU/l (p < 0.005 vs euthyroid; p < 0.05 vs transient). This study of the role of complement in the pathogenesis of PPT shows that the severity and duration of the thyroid dysfunction correlates with the degree of complement activation by TPO-ab measured in vitro. AB Parkes, Autoimmunology Research Unit, Section of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK

There is very little information on iodine intakes or their adequacy in Britain. Studies in the 1960s suggested that iodine intake was around 100μg per day and less than this in some goitrous areas (1). The Department of Health and Social Security suggested an intake of 150μg/day in 1969 would be adequate for health but recognised that this may be difficult to achieve without iodisation of salt. Studies of patients with non-toxic goitre in Scotland in this decade showed evidence of iodine deficiency (a subnormal plasma inorganic iodine). The Ministry of Agriculture, Fisheries and Food evaluated the iodine content of British food in 19 76 based on historical values for iodine content. The main iodine sources (% daily intake) were fish and fish products (26%), milk and milk products (19%), cereals (14%) and vegetables (12%). Total intake was 86.3μg/person/day. A survey between 19 77 and 19 79 in which nearly 200 individual food samples were analysed showed that fruit and sugars (which included glace cherries containing erythrosine) accounted for 29% of daily intake and milk for 28% (2).

OBJECTIVE--To define the relation between mood and autoimmune thyroid dysfunction during the eight months after delivery. DESIGN--Double blind comparison of the psychiatric status of women positive and negative for thyroid antibodies. Clinical examination and blood sampling for free triiodothyronine and thyroxine, thyroid stimulating hormone, and thyroid antibody concentrations at four weekly intervals. Psychiatric assessment at six, eight, 12, 20, and 28 weeks post partum. SETTING--Outpatient department of district hospital. PATIENTS--145 antibody positive women and 229 antibody negative women delivering between August 1987 and December 1989. MAIN OUTCOME MEASURES--Thyroid status. Number of cases of mental ill health by the general health questionnaire, research diagnostic criteria, Hamilton 17 item depression scale, hospital anxiety and depression scale, and Edinburgh postnatal depression scale. RESULTS--Six weeks after delivery the general health questionnaire showed 62 (43%) antibody positive women and 65 (28%) antibody negative women had mental ill health (chi 2 = 8.18, p less than 0.005). Follow up of 110 antibody positive and 132 antibody negative women showed significantly greater depression by research diagnostic criteria in antibody positive women (47%) than antibody negative women (32%) regardless of thyroid dysfunction. Antibody positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003). CONCLUSION--Depressive symptoms are associated with positive thyroid antibody status in the postpartum period.

During the postpartum period about 50% of women with circulating thyroid autoantibodies develop a transient autoimmune thyroiditis. To determine the sonographic appearances in postpartum thyroiditis (PPT), serial ultrasound (US) scans of the thyroid were performed in 135 postpartum women who were divided into three clinical groups: Group 1, 37 antibody positive subjects who developed PPT; Group 2, 28 antibody positive subjects in whom thyroid function remained normal; Group 3, 70 antibody negative controls. Thyroid hypoechogenicity was observed in 14/31 patients (45%) who were scanned between 4 and 8 weeks postpartum and who subsequently developed PPT (Group 1) compared with 4/24 patients (17%) in Group 2 (P less than 0.05) and 1/65 patients (1.5%) in Group 3 (P less than 0.001). In antibody positive patients, the positive predictive value of an abnormal scan during this period was 78%. Between 15 and 25 weeks postpartum thyroid hypoechogenicity was present in 32/37 patients (86%) in Group 1 compared with 11/28 patients (39%) in Group 2 (P less than 0.001) and 2/70 patients (3%) in Group 3 (P less than 0.001). Sonographic abnormality persisted beyond 32 weeks postpartum in 36/41 antibody positive patients (87%) who had exhibited thyroid hypoechogenicity earlier during the study and who had late scans. The characteristic US appearance in PPT is thyroid hypoechogenicity. The role of sonography in the prediction, diagnosis and follow up of patients with PPT is discussed.

Endemic goitre and its response to orally administered iodized oil has been studied in seven villages 25–30 km south of Velingara, Eastern Casamance, Senegal. In 502 adults aged > 15 years goitre prevalence was 62% with 18.2% having goitre grade 2 or 3. Mean free T4 (FT4) was 11.9±3.5 (sd) pmol/l and iodine deficiency was confirmed by noting median urinary I of 0.079 μmol/l (14.9 μmol 1/mol creatinine) with elevated free T3 (FT3)FT4 ratios. Serum selenium concentrations were normal. The response to 480 mg of oral iodized oil assessed at 6 and 12 months was characterized by a 35.8% increase in FT4, a 25% decrease in FT3 and a 50% decrease in TSH (all p

To investigate the etiologic role of iodine intake in postpartum thyroiditis (PPT), we have measured postpartum urinary iodine excretion serially in a large prospective study of PPT. A total of 1996 women were screened for thyroid microsomal antibody during the second trimester of pregnancy. One hundred fifty-two of the 235 antibody-positive women and an equal number of age-matched antibody-negative controls were followed postpartum with measurements of urinary iodine and thyroid function at monthly intervals for 12 months. Iodine excretion in the immediate postpartum period did not differ between the 73 women who developed PPT and the antibody-negative controls. In women with PPT with hyperthyroidism, hypothyroidism, or hyperthyroidism followed by hypothyroidism, increased urinary iodine excretion was observed between 8 and 16 weeks postpartum, which preceded the hormonal disturbances among the women with hypothyroidism. The height of the rise in urinary iodine excretion during the first 20 weeks postpartum correlated with the serum free thyroxine levels (r = 0.61, p less than 0.001). Iodine intake is unlikely to affect the prevalence of PPT. However, these data show that the hyperthyroid phase of PPT is associated with a significant release of intrathyroidal iodine due to thyroid destruction and that the same process also occurs to a lesser extent before the hormonal disturbances associated with hypothyroid PPT.

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.

OBJECTIVE The aim of the study was to evaluate the risk of exposure to an increase in dietary iodide intake amongst potentially susceptible population groups in Britain. DESIGN A randomized controlled trial was performed in healthy women and in women with underlying thyroid abnormalities due to subclinical Hashimoto's thyroiditis (diagnosed on the basis of antithyroid antibodies) or previous iodide deficiency of supplementation with 500 micrograms/day iodide (giving a total intake of approximately 750 micrograms/day) for 28 days versus placebo. PATIENTS Two hundred and twenty-five women aged 25-54, randomly selected from a general practice in Cardiff, were screened for thyroid microsomal antibody. Antibody positive women (n = 20), and antibody negative controls (n = 30) were recruited into the trial comparing iodide and placebo. In addition, groups of patients aged 60-75 randomly selected from the Cardiff practice (n = 29), an iodide sufficient area, and a practice in Dowlais (n = 35), a previously iodide deficient area, were also enrolled into the trial. MEASUREMENTS Changes in free thyroxine and thyrotrophin levels were measured after 14 and 28 days of iodide supplementation. RESULTS All the iodide supplemented groups responded in the same way with a small fall in free thyroxine and rise in thyrotrophin levels (combined fall in free thyroxine 14 days after the start of supplementation -1.22 (95% confidence interval -0.59 to -1.84) pmol/l and at 28 days -0.86 (-0.30 to -1.43) pmol/l and rise in thyrotrophin at 14 days 0.55 (0.19 to 0.92) mU/l and at 28 days 0.59 (0.12 to 1.07) mU/l). In two of the iodide supplemented subjects thyrotrophin levels rose above the laboratory reference range and in a further three subjects initially elevated thyrotrophin values increased further. In contrast, no changes in thyroid function were observed in the placebo treated controls and none developed biochemical hypothyroidism. CONCLUSIONS Dietary iodide intakes of 750 micrograms/day or more may adversely affect thyroid function, especially in individuals with borderline hypothyroidism.

Summary A patient with post-partum thyroiditis is described. She was a 22 year old with a negative family history of autoimmune thyroid disease who was noted to have a high titre of antithyroid microsomal antibody during pregnancy. She developed mild hyperthyroidism 8 weeks post-partum but at 12 weeks she had a mildly painful enlarged thyroid gland. At 20 weeks post-partum she had severe thyroidal pain with dysphagia. The thyroid was exquisitely tender to palpation. She was treated with L-thyroxine and the pain resolved within 4 weeks. This is the first report documenting pain in the thyroid as a feature of post-partum thyroiditis.

Stress has, for many years, been linked to the onset of autoimmune disease and, in particular, autoimmune thyroid disease (AITD). Whilst the exact mechanism of this association is unknown, it is clear that episodes of stress can induce profound changes in the immune system. More specifically, recent studies from several laboratories have shown an association between the expression of stress proteins and, particularly, the Hsp70 family with AITD. Our own studies describe a thyroid-specific Hsp70 which shares antigenicity with the key thyroid autoantigen, thyroid peroxidase. Further studies on the molecular basis for this observation are, however, hampered by the lack of a suitably validated thyroid cell model. In this paper we compare the response of primary cultures of human thyrocytes to hyperthermia with the response seen in the immortalized human thyroid cell line HTori3. Both cell types responded in a broadly similar manner, synthesizing proteins from two of the major stress protein families, Hsp70 and Hsp90. In the primary human thyrocyte cultures the 70 kDa proteins showed a 7.5-fold increase and the 90 kDa proteins a 2.7-fold increase with hyperthermia whilst in the HTori3 cells the increases in response to hyperthermia were 10- and 6.5-fold, respectively. We also show a dose-dependent stress response in HTori3 cells cultured in the presence of arsenite ions. We conclude that the response of this highly differentiated and stable thyroid cell line to stress is similar to that seen in primary cultures of human thyroid cells and that these immortalized cells will afford a convenient and effective model for the further study of the role of stress in the pathology of AITD.

SUMMARY The ability of sera from patients with thyroid disease to block TSH stimulation of cyclic AMP release from isolated porcine thyroid cells has been assessed and the blocking activity characterized. TSH receptor binding activity was also measured. No blocking or receptor binding activity was detectable in patients with primary myxoedema (n= 23), Hashimoto's disease (n= 11), multinodular goitre (n= 6), or rheumatoid arthritis (n= 10). However, analysis of sera from 23 patients (out of an initial screen of 110 patients) with treated Graves' disease which did not stimulate cyclic AMP production in the bioassay showed that two of these sera contained powerful blocking and receptor binding activity. Both these patients had been treated with 131I, Analysis of the two sera by gel filtration on Sephadex G-200 indicated that blocking and TSH receptor binding activity were associated only with the IgG fraction. Digestion of the IgG with pepsin followed by reduction showed that both (Fab)2 and Fab fragments contained high levels of blocking and binding activity. Antibody divalency was not necessary therefore for TSH antagonist activity. However, our studies suggest that autoantibodies of this type with TSH antagonist activity do not occur frequently in patients from the Cardiff region with primary myxoedema, Hashimoto's or treated Graves' disease.

The TSH receptor binding and thyroid stimulating properties of (Fab)2 and Fab fragments of Graves' IgG have been investigated. (Fab)2 fragments were prepared by pepsin digestion of IgG and Fab fragments by reduction of (Fab)2 or papain digestion of IgG. (Fab)2 and Fab were effective in inhibiting TSH binding to its receptor with all five patients' sera studied and both preparations stimulated cyclic AMP release from isolated thyroid cells. However Fab fragments were less active thyroid stimulators than their parent (Fab)2 in all five cases. These studies indicate that antibody divalency is not essential for thyroid stimulation by TSH receptor antibodies.

The ability of Graves' sera to interact with the TSH receptor crosslinked to a 125I-labelled photoactive derivative of TSH has been investigated. Crosslinked complexes were prepared using non-purified detergent solubilized human thyroid and guinea pig fat TSH receptors. Affinity purified porcine TSH receptor preparations wee also used. After crosslinking, the crosslinked TSH-TSH receptor complexes were separated from aggregates and free TSH on Sephacryl S-300, incubated with test sera followed by immunoprecipitation using anti-IgG or Protein A. Using non-purified human TSH receptors crosslinked to TSH, a mean +/- SD of 12.1 +/- 4.9% of the crosslinked complex was immunoprecipitated with Graves' sera (n = 7) compared with 10.3 +/- 2.6% with Hashimoto sera (n = 6; P greater than 0.14) and 3.8 +/- 1.0% with normal sera (n = 6; P less than 0.004). These values were markedly reduced when TSH receptor preparations free of other thyroid autoantigens (guinea pig fat TSH receptors) were used. Under these conditions immunoprecipitation with Graves' sera (n = 24) was 1.6 +/- 1.3% compared with 0.8 +/- 0.6% for Hashimoto sera (n = 13) and 0.8 +/- 0.4% for normal sera (n = 12; P less than 0.003). In addition complexes formed between TSH and affinity purified porcine TSH receptors gave low immunoprecipitation values for Graves' (1.44 +/- 0.73%; n = 20) and Hashimoto sera (1.7 +/- 0.94; n = 11) which were not significantly different (P greater than 0.4). Overall, therefore, the effects of Graves' and Hashimoto sera were similar and the amounts of material immunoprecipitated were markedly reduced when TSH receptor preparations containing reduced amounts of other autoantigens were used. Consequently the Graves' sera did not appear to interact specifically with crosslinked TSH-TSH receptor complexes. However the Graves' sera studied did contain TSH receptor antibodies which could inhibit the binding of labelled TSH to TSH receptors in the preparations used and our results suggest that the binding of TSH and these antibodies to the receptor is mutually exclusive. There is considerable evidence that serum from patients with Graves' disease contains antibodies to the TSH receptor (Rees Smith, 1981). Several studies have suggested that binding of the receptor antibody and TSH to the TSH receptor is mutually exclusive (Manley et al., 1977; Petersen et al., 1977; Rickards et al., 1981) but recently the formation of termolecular complexes consisting of detergent solubilized receptors, labelled TSH and Graves' IgG has been reported (Konishi et al., 1982; De Bruin et al., 1984).(ABSTRACT TRUNCATED AT 400 WORDS)

Porcine peripheral lymphocytes were incubated in Medium 199 with 10% calf serum in the presence and absence of phytohaemagglutinin (10 μg/ml) for 48 hours. The incorporation of radioactive precursors and the glucose uptake and lactic acid production indicated that ‘blast transformation’ was taking place in the phytohaemagglutinin treated cells. Assays of phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase in the lymphocyte homogenates showed a progressive decrease in activity in the control cells over the experimental period whilst the phytohaemagglutinin treated lymphocytes showed significantly elevated activities of these enzymes at 24 hours which were sustained over the 48 hour period. These results suggest that phytohaemagglutinin is able to influence specific enzyme production.

Normal pregnancy is associated with two major series of alterations in the endocrine system. On the one hand hormonal changes necessary for the maintenance of pregnancy must occur and on the other pregnancy itself may influence the function of endocrine glands, such as the thyroid, which are not themselves directly involved in the maintenance of the pregnancy. In pregnancy therefore, and as a result of these normal physiological regulatory mechanisms, thyroid function must be interpreted with caution (Table 1). The situation is further complicated in those women with known (or previously unrecognised) thyroid disease, particularly if the aetiological basis of their disease is autoimmune (Table 1). In these women pregnancy may have a profound impact on their disease with amelioration during the pregnancy itself but with exacerbation in the post-partum period. In addition and as a result of their thyroid disease, alterations in the function of the foetal and neonatal thyroid may occur. Considerable interest has been focussed recently on alterations in thyroid function in pregnancy and the post-partum period in both normal women and women with known autoimmune thyroid disease and has been extensively reviewed (1-3). In the present study we have sought to examine prospectively the thyroid function of a group of normal women with no known history of thyroid disease, through pregnancy and the post-partum period. Our aim was to define the true prevalence of post-partum thyroid dysfunction (PPTD) in such women, to characterise the syndromes of PPTD developing and to determine the factors associated with their development.