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J. H. Lazarus, J. C. Kingswood and R. John

Abstract. Twenty hyperthyroid patients were randomly assigned in a double-blind fashion to receive either nadolol 80 mg/day or placebo for 2 weeks; all patients then took carbimazole as well from 2–6 weeks. Twenty-four hour Holter ECG recordings at 0, 2 and 6 weeks showed that nadolol reduced the mean maximum heart rate by 19.9% (P < 0.0005) at 2 weeks and by 30.3% (P < 0.0005) at 6 weeks compared to 5.2% (ns) and 18.3% (P < 0.0005) in patients taking placebo. There was no alteration of the normal circadian variation of heart rate by nadolol. The minimum heart rate before therapy was significantly correlated with FT4 (r = 0.52) and with FT3 (r = 0.44). The percentage of time per hour during which the heart rate was greater than 100 was reduced by 79% at week 2 by nadolol compared to 22% in the placebo group. At the 6 week point the placebo group still had a tachycardia (mean maximum heart rate 101.6 beats/min ± 15.2 sd) compared to the nadolol group (80.4 ± 7.7). Nadolol did not cause excessive bradycardia. It is effective in the early management of hyperthyroidism and should be given for at least the first 4–6 weeks.

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Arthur B Parkes, Sakinah Othman, Reginald Hall, Rhys John and John H Lazarus

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

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John H Lazarus, Arthur B Parkes, Rhys John, Makhtar N'Diaye and Suzanne G Prysor-Jones

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<0.01) at 12 months associated with a significant decrease in goitre size measured in 70 persons when compared to 65 controls not receiving iodine. Urinary iodine rose from 0.071 μmol/l to 0.189 μmol/l (p <0.01) during this time and no adverse effects on thyroid antibodies (anti-thyroid peroxidase and anti-thyroglobulin) were observed. A variation in goitre prevalence between villages was noted which, in such a small geographical area, suggests that etiological factors in addition to iodine deficiency may be important in goitre pathogenesis. Oral iodized oil administration is an effective treatment for iodine deficiency goitre in the short term.

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Peter N Taylor, Onyebuchi E Okosieme, Colin M Dayan and John H Lazarus

Background

Although the detrimental effects of severe iodine deficiency are well recognised, the benefits of correcting mild-to-moderate iodine deficiency are uncertain.

Objectives

We undertook a systematic review of the impact of iodine supplementation in populations with mild-to-moderate iodine deficiency.

Methods

We searched Medline and the Cochrane library for relevant articles published between January 1966 and April 2013, which investigated the effect of iodine supplementation on maternal and newborn thyroid function, infant neurodevelopment and cognitive performance in school-age children. The quality of studies was graded and eligible trials were evaluated in the meta-analysis.

Results

Nine randomised controlled trials (RCTs) and eight observational studies met the inclusion criteria. Controlled trials on infant neurodevelopment were lacking; gestational iodine supplementation reduced maternal thyroid volume and serum thyroglobulin and in some studies prevented a rise in serum thyroid-stimulating hormone. None of the intervention trials recorded an excess frequency of thyroid dysfunction in contrast to observational studies. A pooled analysis of two RCTs which measured cognitive function in school-age children showed modest benefits of iodine supplementation on perceptual reasoning (standardised mean difference (SMD) 0.55; 95% CI 0.05, 1.04; P=0.03) and global cognitive index (SMD 0.27; 95% CI 0.10, 0.44; P=0.002) with significant heterogeneity between studies.

Conclusion

Iodine supplementation improves some maternal thyroid indices and may benefit aspects of cognitive function in school-age children, even in marginally iodine-deficient areas. Further large prospective controlled studies are urgently required to clarify these findings and quantify the risk/benefits of iodine supplementation in regions previously believed to be iodine sufficient such as the UK.

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Sevim Gullu, Rifat Emral, Mehmet Bastemir, Arthur B Parkes and John H Lazarus

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 the in vivo effects 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. In in vitro experiments, 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 with in vitro experiments and is not confined to Simvastatin since Mevastatin, Pravastatin and Cerivastatin also induced apoptosis in lymphocytes.

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Arthur B Parkes, Christopher Darke, Sakinah Othman, Melanie Thomas, Neil Young, Colin J Richards, Reginald Hall and John H Lazarus

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

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Luca Manetti, Arthur B Parkes, Isabella Lupi, Graziano Di Cianni, Fausto Bogazzi, Sonia Albertini, Lisa Linda Morselli, Valentina Raffaelli, Dania Russo, Giuseppe Rossi, Maurizio Gasperi, John H Lazarus and Enio Martino

Objectives

The aim of this study was to evaluate antipituitary antibody (APA) prevalence in a series of patients with postpartum thyroiditis (PPT) during pregnancy and in the postpartum.

Design

We conducted a nested case–control study on consecutive PPT and normal pregnant women at the Centre for Endocrine and Diabetes Sciences in Cardiff and at the Department of Endocrinology in Pisa.

Methods

We enrolled 30 women with PPT: 17 were hypothyroid (Hypo), 7 with hyperthyroidism (Hyper) and 6 with a transient hyperthyroidism followed by hypothyroidism (Biphasic). Twenty-one healthy pregnant women served as controls. APA (measured using indirect immunofluorescence), free thyroxine, free triiodothyronine, TSH, antithyroid autoantibodies, and thyroid ultrasound were performed during pregnancy and postpartum. The stored sera have been sent to Pisa, where serum APA, IGF1, and cortisol were measured.

Results

APA were found in 8 out of the 30 PPT patients (26.7%) and in one normal pregnancy (4.7%, P=0.063). Three out of the seventeen Hypo with PPT (17.6%), three out of the seven Hyper PPT (42.8%), and two out of the six Biphasic PPT (33.3%) were positive for APA. APA prevalence was not significantly different in the PPT subgroups (P=0.453). With one exception, APA all increased in the postpartum period (87.5%, P<0.016). Basal serum IGF1 and cortisol were in the normal range with the exception of two patients with positive APA who presented low serum IGF1 levels (36 and 45 ng/ml).

Conclusions

APA are frequently present in the postpartum period in patients affected by PPT. Further studies are necessary to evaluate whether APA in PPT patients are associated with pituitary function impairment.

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Luigi Bartalena, Lelio Baldeschi, Alison Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Currò, Chantal Daumerie, George J Kahaly, Gerasimos E Krassas, Carol M Lane, John H Lazarus, Michele Marinò, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx and Wilmar M Wiersinga