New ATA Guidelines Tackle Paradigm Shifts in Graves' Disease

Miriam E Tucker

August 30, 2016

New American Thyroid Association evidence-based guidelines on hyperthyroidism address "new paradigms" for evaluating thyrotoxicosis, the management of Graves' hyperthyroidism in general and during pregnancy, and the preparation of patients for thyroid surgery.

The document, 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis, runs 272 pages and contains 124 recommendations. It was published online August 17 in Thyroid by a multinational writing panel chaired by Douglas S Ross, MD, professor of medicine at Harvard Medical School and codirector of Thyroid Associates at Massachusetts General Hospital, Boston, Massachusetts.

The ATA's last guidelines on hyperthyroidism/thyrotoxicosis were published in 2011. Since then, "a huge amount of literature has been published, so we felt it was time to update the guidelines and address many of the issues that have come up," Dr Ross told Medscape Medical News.

Some of the new guidelines reflect differences in approaches between American and European clinicians regarding the use of antithyroid drugs vs definitive treatment: In the United States, the preference has been to use radioactive iodine (RAI) ablation, whereas the Europeans have tended to favor use of antithyroid drugs. New data informing those approaches are included in the guidelines.

The document also reflects the ongoing clinical challenge of managing hyperthyroidism in and around pregnancy, especially given new findings about teratogenicity of antithyroid medications and the limitations of the current data. The guidelines present several options, but "strategies for dealing with hyperthyroidism in women who desire pregnancy are still imperfect," Dr Ross said.

The guidelines use the term "thyrotoxicosis" to refer to a clinical state resulting from inappropriately high thyroid-hormone action in tissues, and "hyperthyroidism" as a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone by the thyroid. In the United States, approximately 1.2% of the population has hyperthyroidism, with Graves' disease being the most common type.

Greater Reliance on Antibody Testing

After the initial biochemical evaluation, including serum thyroid-stimulating hormone measurement, the new guidelines advise either the use of thyrotropin-receptor antibody measurement, RAI uptake, or measurement of thyroidal blood flow on ultrasound for determining the etiology of thyrotoxicosis.

The availability of two third-generation antibody tests with 97% to 100% sensitivity and specificity led the panel to shift away from the 2011 advice to measure RAI uptake first.

"We still list this as an option, but we suggest that physicians might start with thyrotropin-receptor antibody testing because it's more cost-effective and convenient for the patient who has a likely diagnosis of Graves' disease — ie, symmetric thyroid enlargement, moderate to severe hyperthyroidism, or recent-onset orbitopathy — and it allows you to avoid exposing the patient to even minimal radioactivity. This is a major change. The older antibody tests weren't as sensitive," Dr Ross said.

For the same reason, the new guidelines also advise greater use of the antibody tests to follow patients with Graves' disease over time, with a new recommendation to check the antibodies after 12 to 18 months of antithyroid drug treatment and use the results to guide further treatment decisions, including continuing the antithyroid medications.

In pregnant women, the new guidelines call for use of the antibody test during the first trimester. If elevated, a repeat measure is advised at 18 to 22 weeks, and if still positive in the third trimester, the neonate should be assessed for possible hyperthyroidism after birth. The 2011 document advised simply checking once in the second trimester.

Even among pregnant women who are given permanent treatment for Graves', either by RAI ablation or surgical removal, measurement of antibodies is still advised because they pose a risk to the fetus/neonate, Dr Ross pointed out.

Long-Term Antithyroid Drug Treatment: A Multinational Divide

In the past, recommendations in the United States had called for stopping antithyroid treatment after 12 to 18 months and, if the patient wasn't in remission, considering definitive therapy with RAI ablation or surgery. This advice primarily stemmed from concern about rare but potentially serious side effects of the drugs, including agranulocytosis and liver damage.

"There has been more concern about this in the United States than in Europe and Asia, where the drugs have been used much longer," Dr Ross noted.

However, several papers published since 2011 have begun to shift that thinking among American experts. These include two papers on agranulocytosis and two on liver disease, finding overall that 93% of the former and nearly 100% of the latter adverse events occurred within the first 180 days of treatment.

"The concern that long-term antithyroid therapy would be risky is probably not validated by the current studies. We didn't have those data in a very strong form before," Dr Ross said.

Moreover, two studies published in the past few years have shown safety for the use of the medications for up to 10 years. "So it's becoming more acceptable to use these drugs long term," he noted.

To be sure, the guidelines still offer RAI ablation or surgical excision as options for patients who are not yet in remission after 12 to 18 months, but continuation of antithyroid medication is now offered as an option, with patient preference being the deciding factor in most cases.

"Now we're saying that if the patient prefers nonablative therapy, there is no compelling argument against it, except in the case of women of childbearing potential, where the decision to continue antithyroid drugs long term is complicated," he said.

And even for toxic nodular goiter, which doesn't ever go into remission, the new guidelines still offer antithyroid drugs as an option based on patient preference.

Interestingly, in surveys of members of the ATA and the European Thyroid Association done in 2011, only 41% of US thyroidologists preferred continuing antithyroid drugs compared with 86% in Europe. On the other hand, 59% in the United States believed early RAI ablation or surgery was the best approach for Graves' disease patients, compared with just 14% in Europe.

A Rock and a Hard Place: Hyperthyroidism in Pregnancy

Managing hyperthyroidism in pregnant women and those who desire pregnancy has been a clinical conundrum and remains so. The writing panel incorporated the latest available information regarding teratogenicity of both methimazole (MMI) and propylthiouracil (PTU), which have further complicated the picture since 2011.

In general, the guidelines advise the use of MMI for most patients who chose antithyroid-drug therapy for Graves' disease, except during the first trimester of pregnancy, when PTU is preferred. That recommendation was made in 2011 because MMI is known to cause major birth defects, including esophageal atresia and omphalocele, in about 4% of exposed fetuses.

However, in 2011 the US Food and Drug Administration put a boxed warning on PTU about its liver-failure risk. And more recently, data from the Danish Health Registry revealed that PTU use in the first trimester was also associated with a 2.3% increase in the rate of birth defects, although they were less serious ones, such as cystic lesions around the ear and hydronephrosis. However, women using both drugs sequentially during pregnancy experienced the highest overall rates of both severe and nonsevere birth defects.

Given that there are no data to guide women with Graves' disease who are well-controlled on MMI and desire pregnancy, the panel recommended four equal options: Definitive therapy prior to pregnancy — again, far less preferred in Europe; switching to PTU before trying to conceive; switching to PTU as soon as pregnancy is diagnosed; or attempting to withdraw from all therapy as soon as pregnancy is diagnosed, with weekly monitoring of thyroid function and tolerating mild hyperthyroid symptoms until organogenesis is complete.

The authors note, however, that there are no data to support the fourth approach.

"I worry that what we're suggesting in 2016 might be as problematic as what we recommended in 2011," Dr Ross acknowledged.

In this situation, he advised, "Have a long conversation with the woman and see what her fears are and what she wants to do. Different people have different takes on this. Some are scared of RAI, others are more scared of even minor birth defects, and some prefer surgery. It's complicated."

One possible alternative is mentioned in the guidelines but not offered as a recommendation due to insufficient evidence: Nonradioactive iodine, which was used to treat Graves' disease in the early 20th century. One retrospective Japanese study of 283 pregnant women found that although potassium iodide didn't control thyroid function as well as MMI, its use in the first trimester was associated with significantly lower rates of major birth defects (1.53% vs 4.14%).

"It's just one paper, so no one is making a recommendation to do this, but it's mentioned as a thought," Dr Ross noted.

Preparing the Patient for Surgery

In another significant change for 2016, the guidelines suggest preoperative assessment of calcium and 25-OH-vitamin D levels for patients undergoing thyroidectomy. And, particularly in low-volume settings, supplementation with oral calcium and/or vitamin D 2 weeks prior to surgery can be considered for patients who may be at risk for postoperative hypocalcemia in the event of parathyroid damage. "That's a brand-new section in the guidelines," Dr Ross said.

Dr Ross is a paid reviewer for the MTC Registry Consortium.

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Thyroid. Published August 17, 2016. Article

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