Graves’ disease (GD), or diffuse toxic goiter, is the most common form of hyperthyroidism. It affects approximately 1.2 percent of the population, and roughly four million people in the United States alone.1 Graves’ disease is seven to eight times more common in women than men.2 It usually occurs in middle age, but children, adolescents, and the elderly can also have this disorder.3 Chances are we all know someone afflicted with the disease. A number of years ago, GD became more prominent in the public mind when it was reported that both former President George H.W. Bush and his wife Barbara Bush suffered from the disease. Other well-known people with Graves’ disease have included Olympic sprinter Gail Devers, musician Missy Elliot, and the late actor-comedians Marty Feldman and Rodney Dangerfield.
Pathology of Graves’ disease
GD is an autoimmune disorder in which the immune system produces autoantibodies called thyroid-stimulating immunoglobulin (TSI) that bind to thyroid-stimulating hormone (TSH) receptor sites on the thyroid follicular cells. These are the same sites that TSH binds to activate thyroid hormone production. TSI competes with TSH for binding on the TSH receptor and mimics the action of TSH, thereby stimulating the thyroid to produce excess amounts of thyroid hormone (triiodothyronine [T3] and thyroxine [T4]).4 The negative feedback system that normally regulates thyroid hormone production cannot function properly in the presence of TSI and therefore is unable to control the overproduction of thyroid hormones. In certain phases of the disease, the profile and properties of the autoantibodies can switch and block thyroid hormone production and lead to hypothyroidism, creating a confusing clinical picture.
Hyperthyroidism, including GD, can produce symptoms that are often vague and non-specific, and can mimic other conditions. These symptoms include:
- Anxiety and irritability
- Hand tremors
- Heat sensitivity and increased perspiration
- Weight loss, despite normal eating habits
- Goiter (enlarged thyroid gland)
- Thick, red skin usually on the shins or tops of the feet (Graves’ dermopathy)
- Rapid or irregular heartbeat
In addition, up to 40 percent of GD patients exhibit a condition called Graves’ ophthalmopathy (GO), also known as thyroid associated orbitopathy (TAO).5 TSH-R-stimulating Igs (TSIs) mediate metabolic changes in TSH-R-positive fibroblasts, target cells of orbital tissues, and lead to GO.6 Smoking is the most important known risk factor for the development or worsening of GO.1 The clinical presentation in GO may vary from very mild disease to severe, irreversible, sight-threatening complications. The most frequent sign in GO is eyelid retraction, which affects 90 percent to 98 percent of patients and causes the eyes to bulge.5
Differential diagnosis of hyperthyroidism can often be challenging. However, it is critical in order to provide the appropriate patient treatment, since treatment may vary depending on the cause of hyperthyroidism. Many patients with hyperthyroidism present with atypical symptoms or have subclinical hyperthyroidism with no apparent symptoms, low to borderline-low thyroid-stimulating hormone (TSH), and normal thyroid hormone levels. In these patients, diagnosis of GD may be delayed for months, which can impact the patient’s health and quality of life.1
Classically, three therapeutic approaches are used for Graves’ disease treatment:
- Anti-thyroid drugs (ATDs) given for a long period, commonly one to two years. During therapy most patients enter remission, but relapses are frequent (around 50 percent) after withdrawal of medication.
- Radioiodine (131I) therapy: This may initially aggravate the autoimmune reaction, but most patients become euthyroid or hypothyroid, due to the reduction in thyroid follicular cell mass.
- Partial or total thyroidectomy.7
Graves’ disease in pregnancy
Pregnant women with Graves’ disease face a unique challenge. Disease activity persists in some pregnant patients, and occasionally patients may develop the disease while pregnant. The recommended therapy for GD during pregnancy is administration of ATDs (propylthiouracil, methimazole or carbimazole).7 While thyroid hormones produced by or given to the mother cross the placenta in only limited amounts, both TSI and ATDs readily cross the placenta and affect fetal thyroid function. TSI disappears much more slowly and may stimulate the thyroid during the first weeks or months of life. Delayed neonatal hyperthyroidism may therefore develop, constituting a potentially life-threatening medical condition. In addition, ATDs tend to over-treat the fetus when the mother with GD is made euthyroid. This can cause fetal hypothyroidism or goiter.7 It is therefore critical to monitor the thyroid status of both the mother throughout her pregnancy and the high-risk neonate.
Diagnosing GD: current practice and trends
A sensitive TSH test is typically the first thyroid function test routinely ordered for the evaluation of thyroid status. In the case of overt hyperthyroidism, TSH values are typically low, while free thyroxine (FT4) values are increased. However these two hormones alone do not provide any additional information on the cause of the hyperthyroid state and therefore are limited in their contribution for differential diagnosis. This is important because, depending on the cause of the hyperthyroidism, the course of action may be different.
The most commonly used test for diagnosis of GD is the thyroid radioactive iodine uptake and scan (RIUS), which is quite expensive. Recently published guidelines have promoted the use of TSIs as an alternative. Assessing the presence of TSI can help verify the presence of Graves’ disease, since TSIs are present in almost all untreated Graves’ disease patients. The addition of antibody measurement into the testing algorithm can help speed the time to diagnosis and the start of proper therapy. A study by McKee et al was conducted to determine whether the utilization of TSI would reduce overall diagnostic costs to payers and shorten the time to GD diagnosis. It was found that the use of TSI algorithms offers more efficient differential diagnosis of GD and reduces the likelihood of misdiagnoses of subclinical patients. Based on the high sensitivity and positive predictive value of the test, TSI was estimated by physicians to reduce GD misdiagnosis rate by 85 percent. Compared with non-TSI algorithms, 100 percent use of TSI algorithms resulted in 46 percent faster time to diagnosis, with a 47 percent overall cost savings due to reductions in costly procedures and office visits.8
Differences between TRAb and TSI assays
Anti-TSH receptor antibodies comprise several types, responsible for two distinct clinical conditions. Thyroid stimulating autoantibodies (TSAb)—that is, TSI—are the direct cause of Graves’ disease, while thyroid blocking antibodies (TBAb), which inhibit TSH binding to the thyroid receptor, can cause hypothyroidism.9 Currently, there are a variety of assays on the market that measure anti-TSH receptor antibodies. The majority of TRAb assays detect both TSI and TBAb. They can be either automated or manual (ELISA, RIA). Despite efforts at standardization, some important inter-method differences still remain. Only a few available assays were designed to detect only TSI, the specific cause of GD. One is a qualitative bioassay, the other a recent quantitative automated immunoassay. The clinical sensitivities and specificities of these assays have improved over the years and are now very good, but can vary from method to method. The results among TRAb and TSI assays can sometimes be discordant. This may be due to variations in clinical sensitivity, the individual patient, and the antibody being detected: TBAb or TSI.
Graves’ ophthalmopathy assessment
Approximately 80 percent of cases of GO occur in association with hyperthyroidism, yet the onset may not coincide with the onset of the hyperthyroid state. In relation to hyperthyroidism, GO may present well before the onset of thyroid dysfunction, during thyroid dysfunction, or when the patient is euthyroid following therapy.10 Therefore, the clinical picture may be confusing to the clinician when eye involvement is present but thyroid function tests come back normal. It has been shown that TSIs are present in 98 percent of GO patients and correlate with GO activity and severity. TSI levels were higher in moderate to severe ophthalmopathy than in the mild cases.11
In one study, all patients with active GO were positive for antibodies using the TSI assay, while only 84 percent were positive using a TRAb assay. It was concluded that the TSI assay showed more significant association with clinical features of GO than the TRAb assay and that TSI may be regarded as functional biomarkers for GO. Patients with higher initial antibody levels have a greater risk of severe disease outcomes.11 Clinical sensitivity (97 percent vs. 77 percent) and specificity (89 percent vs. 43 percent) of the TSI assay were greater than for TRAb assays in GO, according to one study by Lytton et al.6 Thus, antibody measurement in early GO periods would provide important prognostic information on future GO course.
Monitoring pregnant mothers and neonates
Because thyroid receptor antibodies freely cross the placenta and can stimulate the fetal thyroid, these antibodies should be measured in high-risk mothers. Various guidelines generally recommend the following criteria for TRAb measurement in pregnancy: mothers with 1) current GD; 2) a history of GD and treatment with 131I or thyroidectomy before pregnancy; 3) a previous neonate with GD; and 4) previously elevated TRAb. Women who are negative for antibodies and do not require ATDs have a very low risk of fetal or neonatal thyroid dysfunction.12,13
In the pregnant woman who takes ATDs for GD to keep thyroid function normal, thyroid receptor antibodies should be measured in the last trimester. If antibodies are absent, or the levels low, neonatal hyperthyroidism is unlikely. If antibody levels are high, evaluation for neonatal hyperthyroidism is needed. Clinical evaluation and thyroid function tests on cord blood and again after four to seven days should be performed to detect early and delayed hyperthyroidism in the newborn.7
Monitoring ATD treatment
In addition to its value in differential diagnosis of GD, TSI is an important tool for monitoring ATD treatment and remission or relapse of the disease. ATD treatment effectively achieves euthyroidism in patients with GD. It is important to know whether a patient with GD goes into remission during ATD treatment. TSI titers are closely associated with the active phase and relapse of GD. TSI titer measurement at the time of drug withdrawal is a generally accepted predictive parameter for long-term remission or relapse. Most previous studies have indicated a higher likelihood of remission with negative or mildly elevated TSI titers. With the disappearance of TSI, one study indicated that 60 (82%) of the 73 patients were reported to achieve remission.14
Thyroid blocking antibodies (TBAb) can also be present during the course of GD. The concentrations of the two types of autoantibodies may change through therapeutic intervention (e.g., LT4, and ATDs). Thus, ATDs may reduce TSAb levels, leading to TBAb dominance.15 TSI assays have a theoretical advantage over TRAb assays in the case of ATD monitoring since they provide an exact measurement of the circulating TSAb activating the thyroid. Conversely, TRAb assay titers will be affected by the various concentrations of TSI, and/or TBAb since these assays detect both antibody types.
The story of Graves’ disease and its immunopathogenesis, assessment, and diagnostic testing technology continues to evolve. It shapes current and future recommendations and guidelines to the benefit of patients around the world. Clinicians now have better diagnostic tools necessary to make the right decisions and faster delivery of results: from the latest imaging innovations such as ultrasound elastography to highly sensitive and specific fully automated thyroid assays such as TSI.
- Bahn RS. Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: Management Guidelines of the ATA and AACE. Endocr Pract. 2011;17(3) 457-520.
- National Institutes of Health.”Graves’ Disease”. 2012 Aug 10. www.niddk.nih.gov.
- Nikiforov YE, Biddinger PW, Nikiforova, L. Diagnostic Pathology and Molecular Genetics of the Thyroid. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins: 2012. p.69.
- Pedersen IB, Handberg A, Knudsen N, Heickendorff L, Laurberg P. Assays for thyroid-stimulating hormone receptor antibodies employing different ligands and ligand partners may have similar sensitivity and specificity but are not interchangeable. Thyroid. 2010;20(2):127-133.
- Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J Ophthalmol. 2012;60(2):87-93.
- Lytton SD, Ponto KA, Kanitz M, Matheis N, Kohn LD, Kahaly GJ. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metab. 2010;95(5):2123-2131.
- Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi J. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. Euro J Endocrinol. 1998;139(6):584–586.
- McKee A, Peyerl F. TSI assay utilization: impact on costs of Graves’ hyperthyroidism diagnosis. Am J Manage Care. 2012;18(1):1-15.
- McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid. 2013;23(1):14-24.
- Wiersinga WM, Smit T, van der Gaag R, Koornneef L. Temporal relationship between onset of Graves’ ophthalmopathy and onset of thyroidal Graves’ disease. J Endocrinol Invest. 1988;11(8):615–619.
- Ponto KA, Kanitz M, Olivo PD, Pitz S, Pfeiffer N, Kahaly GJ. Clinical relevance of thyroid-stimulating immunoglobulins in Graves’ ophthalmopathy. Ophthalmol. 2011;118(11):2279-2285.
- Stagnaro-Green A, Abolovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1-45
- De Groot L, Abalovich M, Alexander EK, Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(8):2543-2565.
- Liu X, Shi B, Li H. Valuable predictive features of relapse of Graves’ disease after antithyroid drug treatment. Annales d’Endocrinologie. 2015;76(6):679–683.
- Takasu N., Matsushita M. Changes of TSH-stimulation blocking antibody (TSBAb) and Thyroid Stimulating Antibody (TSAb) over 10 years in 34 TSBAb-positive patients with hypothyroidism and in 98 TSAb-positive Graves’ patients with hyperthyroidism: reevaluation of TSBAb and TSAb in TSH-receptor-antibody (TRAb)-positive patients. J Thyroid Res. 2012. doi:10.1155/2012/18276.
Vera Chuma-Bitcon, MS, MT(ASCP), serves as Senior Global Marketing Manager for the Thyroid and Reproductive Endocrinology business for Siemens Healthineers. She has over 25 years of experience in the medical diagnostics industry, including marketing management in the U.S. and international markets.
Damien Gruson, EurSpeLM, PhD, FESC, is Specialist in Laboratory Medicine and a member of the department of laboratory medicine of the Cliniques Universitaires Saint Luc in Brussels, Belgium. He is also a member of the research unit on Endocrinology, Diabetes and Nutrition of the Catholic University of Louvain.