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Matthew Ettleson, MD
University of Chicago Medicine
Chicago, IL
March 16, 2021

The illustrative example of proptosis may be one of the more memorable images in the medical school textbook, but often the more subtle signs and symptoms of thyroid eye disease (also known as Graves’ orbitopathy or ophthalmopathy) can be overlooked. While severe thyroid eye disease is uncommon, up to 40% of patients with Graves’ disease have some signs or symptoms of thyroid eye disease (1). Most patients with mild eye disease have stable symptoms, but those that develop moderate-to-severe disease may benefit from more aggressive therapies, including glucocorticoids and anti-insulin-like growth factor-1 receptor (IGF-1R) therapy.

The diagnosis of thyroid eye disease relies on a focused history and exam of the eyes. Patients may complain of dry eyes or grittiness, excessive tearing, pain with eye movements and blurry or double vision. Patients may present classically with proptosis and lid retraction, but also redness and swelling of the eye lids or conjunctiva may be present. If several of these findings are present, it suggests the patient has active eye disease and thus may be more responsive to medical therapy. Any concern for visual impairment should prompt urgent evaluation by an endocrinologist and ophthalmologist for a more detailed assessment.

What are first steps to take once the diagnosis of thyroid eye disease is made? The patient’s thyroid function should be assessed and, if abnormal, should be treated promptly. Both hyperthyroid and hypothyroid states can contribute to worsening eye disease. For a patient with newly diagnosed Graves’ disease, this usually begins with antithyroid medication followed by more definite therapy, as discussed in the prior blog post by Dr. Oltmann. It is important to note that radioactive iodine (RAI) therapy has been associated with worsening of thyroid eye disease. Thus, RAI therapy should not be given to those with moderate-to-severe eye disease (2). Cigarette smoking has also been associated with progression of eye disease. For some patients, recognizing that smoking leads to worsening eye symptoms may help convince them it’s finally time to quit!

For patients with mild eye disease, local symptom management is key. Treatment strategies include artificial tears, cool compresses, humidifiers, and sunglasses for protection on excessively sunny or windy days. In over 50% of patients with mild eye disease at the time of diagnosis of Graves’ disease, symptoms will resolve over the following 1-2 years (3).

For those with active, moderate-to-severe disease, a course of pulse doses of IV methylprednisolone is first-line therapy, and can be safely done in the clinic. Often, patients will show improvement within the first 4 weeks of treatment, and most will have a good response after 6 months of therapy. Rarely, long-term glucocorticoid therapy is necessary to prevent clinical worsening. The most promising new therapy for moderate-to-severe disease is teprotumumab, a monoclonal antibody against IGF-1R. Teprotumumab was tested in two clinical trials demonstrating significant improvement in those with severe, active eye disease and was recently approved by the FDA for severe thyroid eye disease (4). In patients who do not respond to glucocorticoids, orbital decompression surgery may be necessary. Finally, after thyroidectomy for definitive treatment of Graves’ disease, there can be thyroid eye disease regression in the year following surgery. Therefore, patients may be able to avoid orbital decompression surgery.

Thyroid eye disease is a common complication of Graves’ disease and can contribute significantly to the morbidity of the disease. However, when recognized, thyroid eye disease in most cases can be treated effectively. This is why it’s so important to keep an eye out for thyroid eye disease!

References:
1. Chin YH, Ng CH, Lee MH, Koh JWH, Kiew J, Yang SP, Sundar G, Khoo CM 2020 Prevalence of thyroid eye disease in Graves’ disease: A meta-analysis and systematic review. Clin Endocrinol (Oxf) 93:363-374.
2. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA 2016 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 26:1343-1421.
3. Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, Pariani N, Gallo D, Azzolini C, Ferrario M, Bartalena L 2013 Prevalence and natural history of Graves’ orbitopathy in a large series of patients with newly diagnosed graves’ hyperthyroidism seen at a single center. J Clin Endocrinol Metab 98:1443-1449.
4. Kahaly GJ 2020 Management of Graves Thyroidal and Extrathyroidal Disease: An Update. J Clin Endocrinol Metab 105.

Disclaimer:
The ideas and opinions expressed on the ATA Blogs do not necessarily reflect those of the ATA. None of the information posted is intended as medical, legal, or business advice, or advice about reimbursement for health care services. The mention of any product, service, company, therapy or physician practice does not constitute an endorsement of any kind by ATA. ATA assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in, posted on, or linked to this site, or any errors or omissions.

The post Thyroid Health Blog: Keeping an Eye Out for Thyroid Eye Disease appeared first on American Thyroid Association.

Sarah Oltmann, MD
University of Texas Southwestern, Dallas, TX
November 16, 2020

November marks hyperthyroidism awareness month, so what a fitting topic to discuss for our Thyroid Health Blog!

It is important to remember that hyperthyroidism can occur at any age. While most may present with a rather typical constellation of symptoms, many may present with exacerbation of pre-existing conditions which may make the diagnosis initially elusive. Worsening anxiety, insomnia, fatigue, panic attacks, palpitations, hypertension or diarrhea may not initially signal that the thyroid is involved. Clinicians must have a low threshold to check thyroid function early to rule out a component of hyperthyroidism.

Once a suppressed thyrotropin (TSH) has been detected, further investigation with serum triiodothyronine (T3) and free thyroxine (free T4) can help delineate overt from subclinical disease. A thorough history of past thyroid disease, as well as current medications and supplements, can help detect any pre-existing diagnoses or exogenous sources of thyroid hormone or over supplementation with iodine. More commonly, hyperthyroidism is due to either Graves disease, toxic multinodular goiter or toxic adenoma. Distinction between these can usually be made with the assistance of a thyroid uptake scan, TSH receptor antibody measurement, and thyroid ultrasound. An additional physical exam finding of exophthalmos can further support the diagnosis of Graves’ disease. Understanding the etiology can help guide patient expectations. A small percentage of patients with Graves’ Disease may undergo spontaneous remission after 1 to 2 years, which may prompt patients to wait before considering a definitive treatment option.

With confirmation of the diagnosis of hyperthyroidism, focus is on hormonal control with an antithyroid medication (ATM, most commonly Methimazole in the United States). This may be augmented with beta-blockade, steroids, cholestyramine or SSKI for those who are difficult to control.

Many patients may need further consideration for definitive management with either radioactive iodine ablation (RAI) or thyroidectomy. Your local resources may also influence these options, but it is critical to understand that all three treatments (ATM, RAI and thyroidectomy) are possible options. Certain patient factors and priorities may alter the preferred definitive treatment. Smaller gland size, easy to control hormones, and lack of eye symptoms are factors that may favor continued ATM management. A large goiter with compressive symptoms, difficult to control hormones requiring high dose medications/ multiple modalities, pregnancy, severe eye disease, multiple nodules within the thyroid with or without thyroid cancer, or desire for rapid and reliable hormone control may favor thyroidectomy. RAI is a good option for patients with a smaller gland size, and a desire to pursue definitive management but avoid surgery.

There are also relative contraindications for treatment options. ATMs may have serious side effects, like agranulocytosis or liver failure, which prevent further use, or may cause skin eruptions making long term use intolerable. Additionally, high dose requirements or fluctuating doses may make long term use of ATMs not reliable. Women who are pregnant, wanting to become pregnant in the next 6 months to 1 year, breast feeding or have small children in the home will want to avoid RAI. Patients with severe eye involvement, have a large goiter with compressive symptoms, or are smokers should also avoid RAI. Thyroidectomy will be a poor option for patients with multiple previous neck operations on or around the thyroid due to internal scarring, or who are high risk for general anesthesia. Additionally, if they have a history of previous gastric bypass surgery, they are higher risk for major complications from hypocalcemia/hypoparathyroidism after thyroidectomy.

To help the patient navigate these decisions, it is important to allow them the opportunity to discuss each treatment option with respective physician experts – medical management with endocrinology, RAI with endocrinology and potentially nuclear medicine as well, and thyroidectomy with the thyroid surgeon.

In summary, patients with hyperthyroidism require medical control, as well as a clear understanding of the etiology of their hyperthyroidism. Patients with Graves disease, toxic multinodular goiter and toxic adenoma have more than one treatment option, and it is important for patients to be educated and engaged in treatment decisions.

For Further Reference:
American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis| by the American Thyroid Association

Disclaimer:
The ideas and opinions expressed on the ATA Blogs do not necessarily reflect those of the ATA. None of the information posted is intended as medical, legal, or business advice, or advice about reimbursement for health care services. The mention of any product, service, company, therapy or physician practice does not constitute an endorsement of any kind by ATA. ATA assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in, posted on, or linked to this site, or any errors or omissions.

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1. 1. Dr. Maia Banige will give a presentation titled “Prediction of fetal and neonatal dysthyroidism,” showing how imperfect development and function of the thyroid in fetuses (FD) and newborns (ND) can be predicted from perinatal variables. Dr. Banige is from the Department of Pediatrics-Neonatology and Pediatric Emergency of the French-British Hospital Institute, Levallois-Perret, Ile-de-France.She and her colleagues conducted a retrospective, multicenter study using data from the medical records of all patients monitored for pregnancy from 2007 to 2014 in 10 obstetric centers of the Assistance Publique des Hôpitaux de Paris. Women with Graves’ disease who were positive for thyrotropin receptor antibodies (TRAb) at least once during pregnancy were included. Among 280,000 births, 2,288 medical records of women with thyroid dysfunction were selected and screened, and 417 women with Graves’ disease who were positive for TRAb during pregnancy (0.15%) were finally included in the study.

      Analysis revealed that the TRAb level in the mother and child was the strongest independent predictor of thyroid dysfunction. The risk of FD and ND increases with maternal hormonal imbalance and is also greater in the patients receiving antithyroid drugs (ATDs) during pregnancy. In pregnant women with TRAb levels ≥2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels ≥6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction.

1. 1. A presentation titled “Pre-conception thyroid stimulating hormone level and risk of preterm birth in over 4.3 million rural Chinese women aged 20-49 years: a population-based cohort study” will be given by Dr. Ying Yang of the National Research Institute for Health and Family Planning and the National Human Genetic Resources Center. Dr. Ying and his colleagues studied the association between the pre-conception thyroid stimulating hormone (TSH) levels of women planning for pregnancy and the risk of preterm births (PTB).Researchers conducted a historical cohort study of 4,320,584 rural reproductive-age women who had participated in free National Free Pre-pregnancy Checkups (NFPC) in 2013-2016 in China. Data on preconception TSH, history of pregnancy and diseases, and other variables were obtained from the physical examination record in NFPC. Successful conception and pregnancy outcomes were documented during the follow-up period, June 2013 to December 2017. PTB is defined as any birth within 28 to 37 weeks of gestational age. Participants who failed to become pregnant within 6 months, suffered from fetal death or stillbirth, or had multiple gestations during the period of study were excluded from the analysis. The data documented 283,854 PTB events (6.57%).

      The study identified a V-shaped relationship between maternal pre-conception TSH levels and PTB risk. Either decreasing or increasing pre-conception TSH levels can significantly increase the risk of preterm birth.

1. 1. Dr. George Kahaly of the Department of Medicine at Johannes Gutenberg University Medical Center in Mainz, Germany, and colleagues have undertaken a three-phase clinical trial of the drug teprotumumab. Results from the first phase—a 24-week randomized, double-masked, placebo-controlled treatment trial of the drug, which is an insulin-like growth-factor-1 receptor inhibitory antibody—were reported in the New England Journal of Medicine (NEJM 2017; 376:1748). Compared with a placebo (69% versus 20%), teprotumumab reduced protopsis (protrusion of the eyeballs) significantly beginning at week 6 and continuing over the 24 weeks of the trial. This second-phase report is an assessment of clinical status at weeks 28 and 72.At week 28 (4 weeks after the treatment period), proptosis response was 73.8% in the teprotumumab group versus 13.3% in controls. At week 72 (48 weeks after treatment), 53% of week 24 teprotumumab proptosis responders maintained ≧ 2 mm improvement relative to baseline. Compared to baseline and placebo, clinical activity also decreased at week 28 and was relatively unchanged in the teprotumumab group at week 72. These results indicate no acute rebound of disease following the 24-week treatment.

      Dr. Kahaly’s group conclude that teprotumumab may represent a disease-modifying therapy in TAO by reducing proptosis and clinical activity, with sustained effects seen in most patients 48 weeks after treatment. In phase 3 of the trial, the research group will investigate whether patients would benefit from longer treatment or retreatment with teprotumumab.

1. Dr. Mats Holmberg of Institute of Medicine, Sahlgrenska Academy, and the Karolinska University Hospital, ANOVA, both in Stockholm, Sweden, will present a study titled “Structural brain changes in Graves’ hyperthyroidism may be of autoimmune origin.”  During the hyperthyroid state of Graves’ disease (GD), the volumes of medial temporal lobe (MTL) structures, e.g., the hippocampi, are reduced. This has been attributed to high thyroid hormone levels, but Dr. Holmberg and his colleagues hypothesized that the structural changes and mental symptoms may be due to autoimmunity per se. The aim of their study was to determine the relationship between nonthyroid autoimmunity and MTL volumes during hyperthyroidism in GD.Dr. Holmberg’s project is a longitudinal, observational, prospective case-controlled study in which 65 premenopausal women were evaluated within 2 weeks after a diagnosis of GD and again after 15 months of antithyroid treatment. Thyroid-stimulating hormone receptor antibodies, thyroid-stimulating immunoglobulins, and several additional antibodies were measured in the hyperthyroid state. MTL structures were scanned to determine hippocampal and amygdala volumes. This presentation reports preliminary data on the nonthyroid antibodies at baseline. Data on the thyroid antibodies will be reported separately.

   The data so far support the hypothesis that autoimmunity that is not directly connected to the thyroid may be involved in the impairment of brain function in GD, introducing a new concept that needs further study.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 95^th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

• The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
• Annual scientific meetings
• Biennial clinical and research symposia
• Research grant programs for young investigators
• Support of online professional, public, and patient educational programs
• Development of guidelines for clinical management of thyroid disease and thyroid cancer

The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

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Sandra McLachlan, Ph.D. and colleagues from Cedars-Sinai Research Institute (Los Angeles, CA), have developed a new animal model of Graves’ disease, a research tool that could lead to a better understanding of the underlying cause of Graves’ disease and help in the development of a potential cure. In the presentation entitled “Development of a Unique Mouse Model for Graves’ Disease that Spontaneously Develops Pathogenic TSH Receptor Antibodies,” the authors report transgenic mice on a thyroiditis susceptible background that express a shed component of the human thyroid stimulating hormone receptor (TSHR) and spontaneously develop TSHR antibodies, as occurs in Graves’ disease.

Theo Plantinga, Ph.D., Radboud University Medical Center, (Nijmegen, The Netherlands) and colleagues, used next-generation sequencing technology to perform whole exome DNA sequence analysis and look for  a genetic cause of familial thyrostatic-induced agranulocytosis. Agranulocytosis is a rare side effect of thyrostatic treatment for Graves’ disease. The authors identified five individuals in two different families in whom agranulocytosis developed after treatment with propylthiouracil or thiamazole. Among the 15 genes found to have mutations in all five individuals, the most likely gene to cause agranulocytosis was the NOX3 gene. In their presentation, “Mutations in NOX3 as Genetic Cause of Familial Agranulocytosis during Thyrostatic Treatment of Graves’ Disease,” the authors note that they did not find mutations in NOX3 in the member of one family who had Graves’ disease and did not develop thyrostatic-induced agranulocytosis.

In the poster presentation “Can Thyroid Autoantibody Levels Aid In Treatment Decision-Making for Graves’ Disease?” Dawn Elfenbein, M.D., Ph.D., University of Wisconsin, Madison, describes a retrospective review of more than 450 patients who underwent either radioactive iodine (RAI) therapy (71% of patients) or thyroidectomy (29% of patients) during a six-year period. The percentage of patients who underwent surgery increased significantly over the study period, from 14% to 52%. The authors state that a patient’s decision whether to opt for treatment with RAI or surgery usually depends on the presence of clinical manifestations of Graves’ disease such as eye disease or goiter. Based on their review of measurements of thyroid-specific autoantibodies for patients with and without ophthalmopathy or goiter, they conclude that the autoantibody measurements are not predictive of these clinical features and, though useful for diagnosis, cannot help patients decide between surgery or RAI.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 91^st anniversary, the ATA delivers its mission — of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health — through several key endeavors: the publication of highly regarded professional journals, Thyroid, Clinical Thyroidology, and VideoEndocrinology; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs; and the development of guidelines for clinical management of thyroid disease and thyroid cancer. The ATA promotes thyroid awareness and information through its online Clinical Thyroidology for the Public (distributed free of charge to over 11,000 patients and public subscribers) and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet.

The post Advances in Graves’ Disease, Including a New Mouse Model, Presented at American Thyroid Association Annual Meeting appeared first on American Thyroid Association.

In the presentation “Differentiation of Human Embryonic Stem (hES) Cells into Thyroid Cells,” Risheng Ma and colleagues, Icahn School of Medicine at Mount Sinai and James J. Peter VA Medical Center (New York, NY) describe their research to identify the regulatory factors involved in directing human embryonic stem cells (hES) to differentiate into functional human thyroid cells. Based on studies of mouse embryonic stem cell differentiation, the researchers selected two regulatory transcription factors to over-express in hES cells, PAX8 and NKX2-1, either alone or in combination. They showed that when both transcription factors were over-expressed, several thyroid-specific genes were activated, inducing the stem cells to differentiate into functional thyroid cells.

Naoko Arata, Ph.D., National Center for Child Health and Development (Tokyo, Japan), and colleagues describe the results of a prospective study of women with Graves’ disease who became pregnant, comparing pregnancy outcomes among women who took any dose of the anti-hyperthyroidism drugs methimazole (MMI) or propylthiouracil (PTU), during the first trimester (12 weeks) of pregnancy. The authors sought to determine whether the prevalence of MMI embryopathy–a disorder characterized by various fetal defects–increases if the fetus is exposed to MMI during the first trimester. This research is part of a larger ongoing study to clarify whether stopping MMI in early pregnancy is safe. In the presentation “Pregnancy Outcomes of Exposure to Methimazole (POEM) Study: An Interim Report,” the researchers report five cases of MMI-related embryopathy in 85 live births, which is higher than the estimated general incidence of 0.1%. No cases of MMI-related embryopathy occurred among the live births of women taking only PTU or taking neither drug.

Thyroid cancer is one type of human malignancy that has clear gender disparities. It occurs more often in women but is a more aggressive disease in men. Lisa Zhang, Ph.D., National Cancer Institute, U.S. National Institutes of Health (Bethesda, MD) and colleagues evaluated the effects of sex hormones on thyroid cancer using a mouse model that mimics human follicular thyroid cancer (FTC) development. In the oral presentation “Sex Hormones Regulate Thyroid Cancer Initiation and Progression by Modifying Tumor Suppressor Gene Expression and Tumor Immunity” they show that castration led to lower rates of thyroid cancer in female mice and less advanced cancer in male mice, suggesting that sex hormones play an important role in the development and progression of FTC. In the castrated male mice, giving them testosterone reversed the slowed progression. The researchers found that testosterone regulates the expression of tumor-suppressor genes and affects tumor immunity.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 91^st anniversary, the ATA delivers its mission — of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health — through several key endeavors: the publication of highly regarded professional journals, Thyroid, Clinical Thyroidology, and VideoEndocrinology; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs; and the development of guidelines for clinical management of thyroid disease and thyroid cancer. The ATA promotes thyroid awareness and information through its online Clinical Thyroidology for the Public (distributed free of charge to over 11,000 patients and public subscribers) and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet.

The post Thyroid Cancer and Development Are Focus of Oral Presentations at American Thyroid Association Annual Meeting appeared first on American Thyroid Association.