Close association of diabetes and thyroid dysfunction has clinical implications
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It is not uncommon for endocrinologists to treat adults with both diabetes and thyroid disease.
Type 1 diabetes and thyroid disease are both autoimmune disorders, and people with a specific human leukocyte antigen (HLA) gene have an increased risk for both conditions. Among adults with type 1 diabetes, 17% to 30% also have autoimmune-induced hypothyroidism or hyperthyroidism, researchers estimated in a review published in Endocrine Reviews in 2019.
“The risk for thyroid disease in those with type 1 diabetes is many times higher than in the population of nondiabetic individuals who might have only a 5% to 7% chance over the course of their life of developing thyroid disease,” Ryan Hungerford, MD, FACE, ECNU, an endocrinologist at Southern Oregon Internal Medicine at Rogue Valley Physicians in Medford, Oregon, told Healio | Endocrine Today. “There is a very strong autoimmune disposition to the development of both thyroid disease and type 1 diabetes, and thus patients with one are at higher risk of the other. There’s a common and explainable coexistence.”
The link between type 1 diabetes and thyroid disease is strong enough that the American Diabetes Association recommends regular screening for thyroid disease of all people who have been diagnosed with type 1 diabetes. Linda A. Barbour, MD, MSPH, FACP, professor in endocrinology, metabolism and diabetes and maternal-fetal medicine at University of Colorado Anschutz Medical Campus, said it is important to screen for thyroid disease because untreated thyroid dysfunction could affect glycemic levels and cardiovascular health.
“Thyroid disease is pretty common, so we’re not screening all patients with thyroid disease for type 1 diabetes, but the opposite should occur,” Barbour told Healio | Endocrine Today. “Anyone with type 1 diabetes should be screened at the diagnosis.”
The interplay between these endocrine disorders, reflected by an increased risk for thyroid disease, may not be limited to type 1 diabetes. Some studies have found that adults with type 2 diabetes are more likely to have hypothyroidism than the general public, according to Elizabeth N. Pearce, MD, MSc, professor of medicine in the section of endocrinology, diabetes and nutrition at Boston University School of Medicine and a Healio | Endocrine Today Editorial Board Member. However, the mechanistic reasons for the link between type 2 diabetes and thyroid dysfunction are less clear.
“One reason may be that obesity is a common risk factor for both [hypothyroidism and type 2 diabetes],” Pearce said in an interview. “Leptin is increased by obesity, so more adipose cells will increase leptin signaling. Leptin tends to increase thyroid-stimulating hormone. Confusingly, high TSH also increases leptin levels. It’s a bidirectional relationship.”
Autoimmune link
People with type 1 diabetes — an autoimmune disease — may also be at risk for other autoimmune diseases, including thyroid dysfunction. The link between type 1 diabetes and thyroid disease can be partially explained by genetic makeup, according to Aaron Michels, MD, professor of pediatrics, medicine and immunology and the Frieda and George S. Eisenbarth Clinical Immunology Endowed Chair at the University of Colorado Anschutz Medical Campus.
“The strongest genetic component for type 1 diabetes lies in these HLA genes,” Michels said. “It is true for thyroid and also celiac disease. These genes overlap among the disorders.”
Michels said the HLA-DR3 and HLA-DR4 genes are common in type 1 diabetes and Hashimoto’s thyroiditis, which accounts for about 90% of hypothyroidism cases. Since researchers have identified this shared genetic marker, providers can screen for thyroid peroxidase and thyroglobulin antibodies to determine potential risk for thyroid disease for a person with type 1 diabetes.
“Knowing who is at risk [is important],” Michels said, “That’s where checking these antibodies can come into play, because then you can say, ‘I should measure TSH yearly and have this on my to-do list as I’m seeing this patient over time.’ The worst part with almost all of these autoimmune diseases is we decompensate quite a bit. We don’t want anyone with type 1 diabetes having diabetic ketoacidosis. It’s not great to see anyone with profound hypothyroidism either. If you can pick that up sooner and initiate treatment, you don’t get to a medically challenging [state].”
The risk for developing thyroid disease may be increased for children with type 1 diabetes as well as adults, according to Pearce.
“Children with type 1 diabetes often develop hypothyroidism at an earlier age than the average person,” Pearce said. “Up to 25% of children with type 1 diabetes will have hypothyroidism or thyroid dysfunction.”
Researchers have established a genetic link between type 1 diabetes and thyroid disease, but it is still unknown what triggers these genes to develop those diseases in some people.
“We have genetic haplotypes that are much more common for type 1 diabetes, but additionally the expression of these haplotypes needs an environmental trigger,” Barbour said. “We think COVID-19 was an environmental trigger, and after the pandemic there does seem to be an increase in type 1 diabetes and autoimmune thyroid disease. Is [a trigger] adenoviruses? Is it respiratory viruses? Is it your gut microbiome, breast milk, gluten in cereals, vitamin D? All of these things we need to better understand.”
Research less certain on type 2 diabetes, thyroid disease
The autoimmune connection that ties type 1 diabetes with thyroid disease does not exist with type 2 diabetes. Michels said type 2 diabetes is much more common than type 1 diabetes, making it more difficult to pinpoint a mechanistic association. Barbour said researchers have tried to identify susceptibility genes that are shared between type 2 diabetes and thyroid disease, but much less progress has been made compared with type 1 diabetes.
“[Type 2 diabetes] genes have more to do with leptin and other risk factors that are much less related to the same genes in common with thyroid disease,” Barbour said.
While the link between thyroid dysfunction and type 2 diabetes is less clear, some studies have found a higher prevalence of abnormal thyroid hormone levels with type 2 diabetes risk. In the Rotterdam Study, a prospective cohort study conducted in the Netherlands and published in BMC Medicine in 2016, higher TSH levels were associated with a moderately increased risk for incident diabetes (HR = 1.06; 95% CI, 1-1.13), and each doubling of TSH level was associated with a 13% higher risk for developing type 2 diabetes among adults with prediabetes (HR = 1.13; 95% CI, 1.03-1.24).
More recent research has demonstrated a similar relationship. A study published in Endocrine in 2017 found each 1IU/mL increase in TSH increased the risk for incident type 2 diabetes by 13%. In a systematic review and meta-analysis published in BMC Medicine in 2021, high baseline TSH was associated with a 17% higher risk for type 2 diabetes compared with normal levels. Additionally, low free triiodothyronine and low free thyroxine also were associated with increased risk for type 2 diabetes.
“Hyperthyroid patients have increased insulin secretion,” Pearce said. “In people with prediabetes, it has been shown that if their T3 levels are higher, they will have improved insulin secretion. But at the same time, hyperthyroidism also increases hepatic gluconeogenesis, and it increases peripheral insulin resistance, so therefore, it increases risk for glucose intolerance, which gets better if you correct hyperthyroidism.
“Hypothyroidism is associated with decreased insulin sensitivity,” Pearce said. “It decreases the ability of insulin to increase glucose utilization in muscle, and it downregulates plasma membrane glucose transporters. Hypothyroidism will tend to promote hypoglycemia, and if you treat the hypothyroidism, that does get better.”
Type 2 diabetes may also increase the risk for developing thyroid dysfunction. Hungerford proposed that the higher circulating insulin levels in type 2 diabetes may stimulate thyroid tissue hyperplasia, thyroid gland enlargement and nodule formation. In a meta-analysis published in Current Medical Science in 2019, people with diabetes were more likely to develop thyroid nodules than those without diabetes (OR = 1.78; 95% CI, 1.25-2.55).
“There’s this back-and-forth interplay between thyroid disease and type 2 diabetes with the presence of one increasing the risk of the other,” Hungerford said. “What isn’t certain is whether there’s a single dominant influence that increases the risk of the development of the associated disease or if there are multiple contributing influences that only in combination will increase the risk. That’s where the research into this relationship gets a little fuzzy.”
Treating comorbid diabetes and thyroid disease
Monitoring for thyroid dysfunction among people with type 1 diabetes begins at diagnosis. The ADA Standards of Care recommend screening people with type 1 diabetes for thyroid disease soon after diagnosis and then periodically thereafter. Pearce said her practice is to screen people with type 1 diabetes about every 2 to 3 years as well as anytime a patient reports symptoms suggestive of thyroid dysfunction. Barbour suggested providers may want to screen patients more frequently if they have high levels of thyroid peroxidase antibodies.
“Some providers might consider screening those individuals up to every 6 months with high antibody titers and certainly if they have any thyroid symptoms,” Barbour said. “If you have these antibodies, you’re more likely to develop hypothyroidism over the next 5 years. If the antibodies are negative, it’s reasonable to wait longer to rescreen.”
Barbour added that screening for thyroid disease is especially important for pregnant women with type 1 diabetes. She suggested screening a woman with type 1 diabetes preconception and immediately after she becomes pregnant.
“The fetus is completely dependent on maternal thyroid hormone up to the first 18 weeks of pregnancy,” Barbour said. “That thyroid hormone is critical to normal brain development. For that reason, there’s no question that [pregnant] women with type 1 diabetes should be screened for thyroid disease and treated.”
In addition, Barbour said, postpartum thyroiditis affects about 5% of all pregnant women and about 20% of pregnant women with type 1 diabetes. She said providers should measure thyroid hormones at 3, 6 and 12 months postpartum and be alert for symptoms such as depression, anxiety or fatigue.
Beyond screening, Hungerford said, providers must recognize the link between type 1 diabetes and thyroid disease.
“Awareness of the relationship between the two conditions is important and should lead the clinician to perform some basic screening measures,” Hungerford said. “That evaluation may simply consist of a periodic fasting glucose level when measuring the thyroid hormone level in a patient with thyroid disease. Or it may consist of a periodic TSH measurement for patients with diabetes.” Pearce agrees that monitoring both thyroid hormone levels and blood glucose levels is essential, especially for people with both conditions.
“It’s possible that if thyroid hormone is impacting gluconeogenesis, insulin sensitivity and beta-cell function, treating thyroid dysfunction could shift blood glucose levels and requirements for diabetes medications,” Pearce said. “It’s important to be monitoring blood sugars after initiation of therapy for thyroid dysfunction.”
Providers also should pay close attention to diabetes medication use for those with both conditions. Pearce said metformin is associated with lower TSH, and providers should monitor thyroid function after metformin initiation to see whether medication adjustments are needed.
Barbour said people with diabetes who develop thyroid disease should receive more aggressive treatment to reach normal thyroid hormone levels quickly. With type 1 diabetes, Barbour said, subclinical hypothyroidism should also be treated because it may increase one’s risk for diabetes complications.
Pearce said it may be worthwhile for providers to monitor people with type 2 diabetes and subclinical hyperthyroidism, as type 2 diabetes may increase the risk for progression to overt hyperthyroidism. However, more research is needed to explore that connection.
More studies on mechanisms, treatments needed
There are several gaps in the research on thyroid dysfunction and diabetes. Pearce said more studies are needed on how type 2 diabetes interacts with thyroid function.
“We need more epidemiologic studies, ideally prospective, longitudinal studies to better understand how type 2 diabetes risk interplays with thyroid function, and whether that should be informing screening protocols,” Pearce said. “There are a lot of studies that have gotten at different aspects of the mechanisms that might underlie connections between type 2 diabetes and thyroid dysfunction, but they’re complicated, and some of the effects of thyroid hormone shift toward worse glycemic control, and some toward better depending on balance. Understanding those mechanisms better would be valuable.”
Hungerford said studies should examine whether more aggressive diabetes management after diagnosis can reduce the risk for developing thyroid disease and, similarly, whether early, aggressive treatment of thyroid disease can reduce diabetes risk.
“We know that early, aggressive management of type 2 or type 1 diabetes reduces the risk for microvascular complications years down the road,” Hungerford said. “But does early, aggressive management of diabetes reduce the risk of thyroid dysfunction in the future? This isn’t clear.” Another area to examine is the effects of GLP-1 receptor agonists on thyroid health. Pearce said GLP-1 agents may increase the risk for medullary thyroid cancer, and providers should consider other agents for people with a family history of medullary thyroid cancer.
Barbour said the impact of radioactive iodine therapy for people with hyperthyroidism and diabetes is another area that needs more research.
“One of the ways we treat Graves’ disease, which causes hyperthyroidism, is to give radioactive iodine and that causes destruction of the thyroid, but by causing destruction of the thyroid, it releases a lot of antigens,” Barbour said. “That results in your TSH receptor antibodies increasing, at least in the short term. Whether that is a good thing or, alternatively, whether that stimulates the autoimmune system when you have type 1 diabetes is not known.”
Michels said he believes that the autoimmune connection between type 1 diabetes and thyroid disease allows potential therapies that can benefit both conditions, and possibly other autoimmune diseases, in the future.
“We’re now in the era of precision medicine,” Michels said. “Can we now do more defined genetic studies to understand more about risk and burden so we can identify those people early on? As we start to understand some of the molecular mechanisms and pathways, can we get a treatment that’s actually going to treat diabetes, treat thyroid disease, treat celiac disease? From my perspective, that’s what I really want.”
- References:
- Biondi B, et al. Endocr Rev. 2019;doi:10.1210/er.2018-00163.
- Chakar L, et al. BMC Med. 2016;doi:10.1186/s12916-016-0693-4.
- ElSayed NA, et al. Diabetes Care. 2022;doi:10.2337/dc23-Srev.
- Jun JE, et al. Endocrine. 2017;doi:10.1007/s12020-016-1221-1.
- Rong F, et al. BMC Med. 2021;doi:10.1186/s12916-021-02121-2.
- Zhang HM, et al. Curr Med Sci. 2019;doi:10.1007/s11596-019-2076-5.
- For more information:
- Linda A. Barbour, MD, MSPH, FACP, can be reached at lynn.barbour@cuanschutz.edu.
- Ryan Hungerford, MD, FACE, ECNU, can be reached at hungerfordr@rvpdocs.com.
- Aaron Michels, MD, can be reached at aaron.michels@cuanschutz.edu.
- Elizabeth N. Pearce, MD, MSc, can be reached at elizabeth.pearce@bmc.org.
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