Mariah Zebrowski Leach, JD, MS

In very young children with type 1 diabetes, even a single episode of moderate/severe diabetic ketoacidosis (DKA) can potentially have long-term effects on cognitive abilities and brain growth, a study shows.

Multiple studies have reported cognitive differences in children with type 1 diabetes, particularly in those diagnosed before 5 years old. While the mechanisms for these differences are unknown, the severity of DKA at diagnosis may be a contributing factor, particularly since the incidence of severe DKA is higher in children younger than 5 years old.

This is the first study to specifically examine the after effects of moderate/severe DKA in young children and its effect on brain development and cognitive brain function longitudinally. Led by Tandy Aye, M.D., of Stanford University School of Medicine, the study was published in the March issue of Diabetes Care.

Researchers analyzed cognitive and brain imaging data from 144 children with type 1 diabetes, ages 4-10 years old who participated in the Diabetes Research in Children Network study. Participants were divided into two subgroups according to the severity of the past DKA event: 86 individuals with none; 12 individuals with mild past events; 18 moderate cases; and, 12 with severe past events.

Data for neurocognitive testing were available for 137 subjects, with anatomical and diffusion-weighted images analyzed for 128 subjects. Compared with the none/mild DKA group, the moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months. Participants in the moderate/severe DKA subgroup were also observed to have significantly lower Full Scale Intelligence Quotient (IQ) scores and cognitive performance compared with the none/mild DKA subgroup.

For the subgroups matched for age and glycemic HbA1c exposure, growth difference in total and regional gray matter volume and white matter volume became even more prominent relative to the overall sample. The same was true for the performance differences in cognitive scores.

“These structural and cognitive results for the matched subgroups suggest that DKA severity, rather than onset age or 18-month HbA1c exposure, contributes to the observed group differences,” the researchers conclude. “Our data indicate that even a single episode of moderate/severe DKA in very young children with type 1 diabetes can potentially have long-term effects.”


	Aye T, Mazaika P, Mauras N, et al. “Impact of Early Diabetic Ketoacidosis on the Developing Brain.” Diabetes Care. March 2019. DOI: 10.2337/dc18-1405

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Early Diabetic Ketoacidosis may Impact Brain Development

The optimal A1C target for adults with type 2 diabetes was addressed at ENDO 2019 on March 23 in New Orleans.

An A1C measurement shows the patient’s average level of blood sugar over the past two to three months. The test can be used to monitor a patient’s blood sugar to ensure that it is staying within a target range, but there’s disagreement about exactly what the target range should be.

For roughly the past 20 years, the American Diabetes Association (ADA) has maintained that a reasonable A1C target for most adults is less than 7 percent. However, last year, the American College of Physicians (ACP) released a new guidance statement supporting an A1C target goal of between 7-8 percent. Just four days later, the ADA, the Endocrine Society, the American Association of Clinical Endocrinologists (AACE), and the American Association of Diabetes Educators (AADE) issued a joint statement strongly disagreeing with the ACP.

At ENDO 2019, two experts offered perspectives on either side of this controversial issue. John B. Buse, M.D., Ph.D., of the University of North Carolina School at Chapel Hill, argued the ADA’s lower A1C target of less than 7 percent is necessary for optimal glycemic control. Timothy J. Wilt, M.D., MPH, of the Minneapolis VA Health Care System in Minneapolis, argued the ACP’s 7-8 percent target is reasonable for most adult patients. The debate was moderated by Marie E. McDonnell, M.D., of Brigham and Women’s Hospital in Boston.

In support of the ADA’s lower target, Dr. Buse provided evidence from a study demonstrating that an A1C greater than 7 percent was the strongest predictor of stroke and heart attack in patients with type 2 diabetes. He cited clinical trials showing lower rates of microvascular complications of over 5-10 years with an average A1C of 7 percent, compared to 8-9 percent. When the study subjects were followed long-term, the data suggested improved cardiovascular outcomes and sustained benefits of over 20 years for A1C of less than 7 percent.

Dr. Buse emphasized that a target is only a target, and that how these levels are achieved and approached is what is crucial. For example, in certain individual patients, he argued physicians might reasonably suggest an even more stringent A1C goal, such as less than 6.5 percent, provided it can be reached without significant hypoglycemia or other adverse effects. Rather than viewing the target as a precise objective, Dr. Buse emphasized that targets should be viewed as a strategy or tactic for minimizing the risks of complications while maintaining quality of life for patients.

On the opposite side of the debate, Dr. Wilt maintained that the ACP’s treatment target of 7-8 percent is preferred for most adults with type 2 diabetes. “The evidence convincingly demonstrates that targeting an A1C with pharmacologic measures to get below 7 percent does not provide any clinical benefits and instead may actually increase harms and costs,” Dr. Wilt said. He cited evidence from several large, long-term, randomized trials that showed no clinical benefit to the lower target. He also mentioned a study targeting treatment to an aggressive A1C level below 6.5 percent that had to be stopped due to increased mortality.

In addition to the lack of clinical benefits and potential harms, Dr. Wilt maintained the lower target could greatly increase the treatment burden and costs for many patients. Increased treatment burdens can include the need for patients to take more medications at higher doses, more frequent glucose monitoring, and the likelihood of additional clinic visits or hospitalizations. Furthermore, high costs can become a significant issue for patients, particularly with the use of newer medications and different types of insulin. Dr. Wilt concluded with his strong belief that patients will receive better care by following the ACP guidelines.

As this debate was organized by the Endocrine Society, one of the contributors to the joint statement against the ACP target, it’s not surprising that the pre-debate poll showed a skeptical audience, with only 18 percent agreeing with the ACP guidelines. The end of debate poll, however, showed more than a doubling of support, with 43 percent in favor of the ACP guidelines. Still, with the closing numbers so close to 50-50, it’s clear this is still a controversial issue.


	McDonnell M, Buse J, and Wilt T. “E03. For Debate: A Reasonable A1c Goal for Many Nonpregnant Adults is <7% (53mmol/mol).” Presented at ENDO 2019 in New Orleans, LA on March 23, 2019.

At ENDO 2019, two experts offered differing perspectives on optimal A1C targets. Blood sugar levels, one doctor said, should fall under 7 percent. Another physician argued for 7-8 percent. Learn more about the debate in this article.

Is less than 7 percent a reasonable A1C goal?

For decades, primary care providers, endocrinologists and obstetricians have been challenged with the question of whether to screen all pregnant women for thyroid disease. This issue was addressed at ENDO 2019 on March 26 in New Orleans.

Screening allows providers to identify individuals at an increased risk of thyroid disease, allowing these individuals to be offered treatment to reduce the risks of disease. Most providers agree that overt thyroid disease needs to be identified and treated during pregnancy to prevent adverse pregnancy outcomes. The debate over whether to screen all pregnant women springs primarily from the unknown clinical implications of subclinical thyroid disease during pregnancy.

While several small studies provide evidence that mild thyroid disease may have a negative impact on pregnancy, there haven’t been any large randomized trials to show that finding and treating subclinical thyroid disease will lead to better pregnancy outcomes. Without this evidence, disagreement persists over whether universal screening is worthwhile and cost-effective, leaving providers to make this decision for each of their patients individually.

Alex Stagnaro-Green, M.D., of the University of Illinois, presented the argument in favor of screening all pregnant women for thyroid disease. Kristien Boelaert, M.D., Ph.D., of the University of Birmingham in the United Kingdom, argued against universal screening. The debate was moderated by Davis S. Cooper, M.D., of Johns Hopkins University.

Taking the position that universal screening for thyroid disease during pregnancy should be instituted immediately, Dr. Stagnaro-Green focused on a set of classic screening criteria developed by Wilson and Junger in 1968. These ten criteria for determining whether or not universal screening is appropriate include a high prevalence rate, cost-effectiveness, and whether identifying and treating the disease will decrease adverse outcomes. The Wilson and Junger criteria have been adopted by the World Health Organization.

Dr. Stagnaro-Green said there is clear evidence that overt hypothyroidism and overt hyperthyroidism meet all ten criteria. For example, to demonstrate high prevalence rate, he said that 1.15 percent of pregnant women have underdiagnosed overt hypothyroidism or overt hyperthyroidism. The only disease currently screened for during pregnancy that has a higher prevalence is gestational diabetes. Since screening for overt hypothyroidism and overt hyperthyroidism do meet all the Wilson and Junger criteria, Dr. Stagnaro-Green maintained that the focus on subclinical hypothyroidism is irrelevant to the screening debate. He concluded the evidence in favor of screening is clear despite the lack of information concerning the clinical implications of subclinical thyroid disease on pregnancy outcomes.

Dr. Boelaert argued against universal screening of pregnant woman for thyroid disease. While she agrees there is clear evidence that treating overt thyroid disease during pregnancy results in improved pregnancy outcomes, she emphasized there is no evidence that treatment of subclinical hypothyroidism results in improved outcomes. There is, however, evidence that overzealous treatment of thyroid disease during pregnancy could potentially result in harm, particularly if serum fT4 concentrations become high.

The cost of universal screening was also an area of concern for Dr. Boelaert. Although the cost-effectiveness of universal screening was demonstrated in two randomized trials of mild iodine deficiency, there are additional costs that need to be considered. Overall costs include infrastructure set-up, personnel training, and the burden of potential overdiagnosis and treatment. When combined with the evidence of potential harm, Dr. Boelaert concluded there are too many areas of uncertainty to support the implementation of universal screening. Instead, she supports targeted screening of high-risk pregnant women or those who demonstrate symptoms.


	Cooper D, Stagnaro-Green A, and Boelaert K. “E22. Endocrine Debate: Thyroid Disease in Pregnancy: To Screen, or Not to Screen?” Presented at ENDO 2019 in New Orleanse, LA on March 26, 2019.

Primary care providers, endocrinologists and obstetricians have been challenged with the question of whether to screen all pregnant women for thyroid disease. The debate springs primarily from unknown clinical implications of subclinical thyroid disease during pregnancy. This issue was addressed at ENDO 2019.

Should Pregnant Women be Screened for Thyroid Disease?

The American Thyroid Association guidelines recommend repeat fine-needle aspiration, molecular testing, or diagnostic surgical resection if thyroid nodule size increases significantly, but a new study shows there is little evidence that significant tumor growth is a predictor of malignancy, especially in architectural atypia of undetermined significance (AUS-A) cases.

While several methods currently exist for evaluating thyroid nodules, the evaluation and treatment of thyroid nodules with a Bethesda category III cytology AUS  remains problematic. The malignancy rate for AUS nodules is only about six to 30 percent on final surgical pathology, and nodules classified as AUS-A could be at a substantially lower risk for malignancy than those classified as AUS with nuclear atypia (AUS-N).

But despite the relatively low risks, a significant number of patients with AUS nodules will undergo diagnostic and potentially unnecessary thyroid surgery. Thus, efforts to improve the way AUS nodules are treated have focused on identifying clinical characteristics that could be used to better predict malignancy. Led by Minjin Kim, M.D., of Pusan National University Hospital in Korea and published in the February 2019 issue of 

, this study is the first to assess tumor growth for predicting malignancy risk in the AUS-A subcategory.

This retrospective cohort study included 172 patients who underwent diagnostic thyroid surgery for a nodule with an AUS-A cytology between January 2014 and November 2017 at the Asan Medical Center in Seoul, Korea. Over a median follow-up of 52.6 months, researchers assessed the natural growth kinetics of AUS-A nodules by serial preoperative neck ultrasonography (US). Significant growth was defined as an increase of 20 percent or more in at least two nodule dimensions, each representing at least a 2mm increase from baseline diameter or a greater than 50% increase in nodule volume.

The pathologic results showed 112 (65 percent) of patients had benign nodules and 60 (35 percent) had malignant nodules. Researchers found the size of both types of thyroid nodules increased linearly, and there was no significant difference in the growth rates. The estimated median time to significant tumor growth from baseline was not significantly different in malignant nodules (1.92 years) as compared to benign nodules (1.71 years). The results suggest that growth kinetics cannot predict malignancy in the AUS-A subcategory.

“Clinical surveillance based on changes in size on serial neck US has limited value in patients with AUS-A nodules, especially in those without highly suspicious clinical or sonographic features,” the researchers conclude. “Although the nodules of this cohort were not evaluated with molecular markers, tumor growth should probably not be considered a surrogate of benignity in nodules with negative molecular marker test results, as has recently been proposed.”


	Kim M, Jeon M, Han M, et al. “Tumor Growth Rate Does Not Predict Malignancy in Surgically Resected Thyroid Nodules Classified as Bethesda Category III with Architectural Atypia.” 

. Published online February 12, 2019. DOI: 10.1089/thy.2018.0366

The American Thyroid Association guidelines recommend repeat fine-needle aspiration, molecular testing or diagnostic surgical resection if thyroid nodule size increases significantly, but a new study shows there is little evidence that significant tumor growth is a predictor of malignancy, especially in architectural atypia of undetermined significance (AUS-A) cases.

Mariah Zebrowski Leach, JD, MS

Articles

Early Diabetic Ketoacidosis may Impact Brain Development

Is less than 7 percent a reasonable A1C goal?

Should Pregnant Women be Screened for Thyroid Disease?

Tumor Growth Rate Doesn’t Predict Malignancy in AUS-A Thyroid Nodules