Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...

https://www.thyca.org/download/document/486/PregnancyandPostpartum.pdf

2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)61452-9.pdf

Selenium and human health

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

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The complex role of estrogens in inflammation

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

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Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum

Background Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

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2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis

OBJECTIVE
Approximately 35% of patients with Graves' ophthalmopathy do not respond to immunosuppressive treatment. A possible explanation for this finding is that only patients with active ophthalmopathy respond to immunosuppressive treatment, whereas patients with fibrotic end stage disease do not. To distinguish between these two groups and to predict the outcome of immunosuppressive treatment, we developed a clinical activity score (CAS) based on four of the five classical signs of inflammation and tested its efficacy in a double-blind, prospective study.

DESIGN, PATIENTS AND MEASUREMENTS
The CAS was determined by an ophthalmologist before, on the day of, and after the start of either oral prednisone or retrobulbar irradiation in 43 patients with moderate to severe Graves' ophthalmopathy. The therapeutic outcome was determined by a second ophthalmologist unaware of the CAS stores given. Success of treatment was defined as an improvement in NOSPECS class or grade.

RESULTS
Responders (22) and non-responders (21) did not differ in age, sex, duration or severity of their Graves' ophthalmopathy. The pretreatment CAS, however, was significantly higher in responders than in non-responders. Twelve of 22 responders and three of 21 non-responders had a CAS  ≥  4 (80% vs 36%; P  <  0.01). Using this CAS cut-off point, the accuracy of CAS in predicting the therapeutic outcome was: specificity 86%, sensitivity 55%, positive predictive value 80%, negative predictive value 64%. Patients with a CAS  ≥  4 had a similar duration of Graves' ophthalmopathy as patients with a CAS  <  4.

CONCLUSIONS
The clinical activity score has a high predictive value for the outcome of immunosuppressive treatment in Graves' ophthalmopathy. Disease activity, and not disease duration, is the prime determinant of therapeutic outcome.

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Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy

Patients with serious inflammatory Graves' ophthalmopathy should be treated with anti-inflammatory drugs or radiotherapy to prevent complications like fibrosis, while those with non-inflammatory ophthalmopathy may be treated by surgery immediately. It is often difficult, however, to distinguish inflammatory from non-inflammatory Graves' disease. We therefore present a simple clinical classification here to differentiate between these two conditions. This classification is based on the classical signs of inflammation--pain, redness, swelling, and impaired function. After two consecutive clinical examinations an 'activity score' can be determined, ranging from 0 to 10 points. In a retrospective study testing the efficacy of this classification we found that patients with an activity score of 3 or more at the beginning of therapy responded well to anti-inflammatory drugs, while those with a lower activity score mostly did not. Comparing the pretreatment activity score with the degree of enlargement of the extraocular muscles on the CT scan, we found a significant correlation between these two parameters: the higher the activity score, the more the enlargement of the muscles. We conclude that this classification facilitates the proper selection of patients for treatment.

https://bjo.bmj.com/content/bjophthalmol/73/8/639.full.pdf

Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach.

At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P = 0.01) and slowed the progression of Graves’ orbitopathy (P = 0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. Conclusions Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves’ orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.)

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Selenium and the Course of Mild Graves' Orbitopathy

Objective. —To assess if smoking is associated with Graves' disease and, if so, to ascertain whether this association persists when controlling for confounding factors. Design. —Consecutive entry case-control study with two age- and sex-matched control subjects from two different populations per case patient. Setting. —University hospital. Patients. —Five groups were studied: (1) Graves' ophthalmopathy and Graves' hyperthyroidism (n=100; divided in four subgroups according to the severity of the eye disease); (2) Graves' hyperthyroidism without clinical eye involvement (n=100); (3) sporadic nontoxic goiter (n=100); (4) autoimmune hypothyroidism (n=75); and (5) toxic nodular goiter (n=75). The study comprised 200 subjects from a hospitalbased population, and 200 from a population-based group served as control subjects. Main Outcome Measure. —Smoking status was determined from a questionnaire at the time of onset of the disease to exclude any effect of the disease itself on smoking. Results. —Smoking greatly increased the risk for Graves' ophthalmopathy (odds ratio, 7.7; 95% confidence interval, 4.3 to 13.7), but patients with Graves' hyperthyroidism alone were also more often smokers than control subjects (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.2). Smoking was not associated with the other thyroid diseases studied. Essentially similar results were obtained after adjustment for differences in education between case patients and control subjects. Among the patients with Graves' ophthalmopathy, smokers had more severe eye disease than nonsmokers, but no association was found between the number of cigarettes smoked per day or the duration of smoking and the severity of the ophthalmopathy. However, there was a significant increase in the odds ratios in patients with more severe eye disease. Conclusions. —Smoking is associated with Graves' disease, and it especially increases the risk for the development of more severe ophthalmopathy. Thus, smoking appears to be one of the multiple factors inducing Graves' disease in genetically predisposed individuals. ( JAMA . 1993;269:479-482)

https://jamanetwork.com/journals/jama/articlepdf/403015/jama_269_4_034.pdf

Smoking and risk of Graves' disease.

It is uncertain what is the most appropriate medical therapy for patients with severe Graves' ophthalmopathy. Therefore, we carried out a single-blind, randomized clinical trial to compare the efficacy of prednisone with that of cyclosporine in 36 patients who had been euthyroid for at least two months. The two groups, each consisting of 18 patients, were similar in age, sex, and the duration and severity of ophthalmopathy. The initial dose of cyclosporine was 7.5 mg per kilogram of body weight per day, and that of prednisone was 60 mg per day, which was subsequently tapered to 20 mg per day. During the 12-week treatment period, 11 prednisone-treated and 4 cyclosporine-treated patients responded to therapy (61 percent vs. 22 percent; P = 0.018); response was manifested by decreases in eye-muscle enlargement and proptosis and improved visual acuity and total and subjective eye scores. There were no differences at base line between the patients who later responded and those who did not. Prednisone was tolerated less well than cyclosporine. After 12 weeks, patients who did not respond were treated for another 12 weeks with a combination of cyclosporine and a low dose of prednisone. Among the 9 patients who initially received prednisone, the addition of cyclosporine resulted in improvement in 5 (56 percent); among the 13 patients who received cyclosporine initially, 8 (62 percent) improved after the addition of prednisone. Combination therapy was better tolerated than prednisone treatment alone. We conclude that single-drug therapy with prednisone is more effective than cyclosporine in patients with severe Graves' ophthalmopathy. The combination can be effective in patients who do not respond to either drug alone.

https://www.nejm.org/doi/pdf/10.1056/NEJM198911163212002?listPDF=true

Mark F. Prummel

Papers

Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy

Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach.

Selenium and the Course of Mild Graves' Orbitopathy

Smoking and risk of Graves' disease.

Prednisone and Cyclosporine in the Treatment of Severe Graves' Ophthalmopathy