Rising Suspicion of Addison's Disease in Patients with Type 1 Diabetes

For the first time, predictive clinical signs of Addison's disease have been identified in people with type 1 diabetes, making an earlier diagnosis possible.

With Dimitrios Chantzichristos, MD, PhD, and Janet McGill, MD

It is well known that patients with one autoimmune disorder, such as type 1 diabetes mellitus (T1D), are at increased risk for having another autoimmune disorder. 

Just last week, the issue of polyautoimmunity was the focused topic of news brief.1  the combination of multiple autoimmune disorders is associated with increased morbidity and mortality, necessitating prompt recognition and management of the second (or third) autoimmune disorder.

One of the more uncommon comorbidities facing patients with type 1 diabetes (T1D) is Addison’s disease;2,3 however, having these dual conditions places a patient at  a four-fold increased risk of premature death when compared to T1D alone.4

Of even greater concern, the risk of developing AD is more than 10 times higher in patients with T1D than in the general population,3 [Chantzichristos 2018a] underscoring the heightened need for clinicians to be able to identify telltale signs and early clinical indicators of Addison’s disease in diabetes patients.

Until now, making an accurate, early diagnosis has been impeded because of the lack of specific signs and symptoms to help tip them off.5 Researchers in Sweden set out to determine if there were any early clinical indicators that might be indicative of Addison’s disease patients with T1D.3

Seeking Factors Predictive of Addison’s Disease and Type 1 Diabetes  

This observational, matched-cohort study reviewed 36,514 adult patients with T1D between 1998-2013, using data from Swedish national registries (the National Diabetes Register [NDR], the Inpatient Register, and the Prescription Drug Register); a total of 66 patients also had been diagnosed with concomitant Addison’s disease.3

Each of the patient cases with a dual diagnosis was matched to five controls with only type 1 diabetes. (n=330). The study excluded individuals who had been diagnosed with Addison’s disease prior to receiving a diagnosis of T1D.3

There were no significant differences between the cases and matched controls at baseline regarding mean hemoglobin A1c (HbA1c) or frequency of diabetic complications; although, the patient cases had a greater frequency of infections requiring hospitalization and of prescriptions for thyroid medications than did controls.3

However, the investigators observed a higher frequency of numerous diabetic complications, particularly retinopathy (12.2% vs 2.1%, respectively), as well as a higher rate of infections requiring hospitalization when compared with the control group (16.7% vs 2.1%, respectively) in the two years leading up to the diagnosis of Addison’s disease.3

In addition, nearly 29% of patients with both T1D and Addison’s disease were on medications for thyroid disorders compared with 7% of the controls, and 18% of them were receiving glucagon versus 6% of controls.3

The additional diagnosis of comorbid Addison’s disease did not appear to affect mean HbA1c levels, the frequency of diabetic complications, or prevalence of cardiovascular disease (eg, coronary heart disease, acute myocardial infarction, congestive heart failure, stroke) or any forms of cancer.3

Medical treatment for thyroid disease, reports of severe infection requiring hospitalization, and diabetic retinopathy occurred more often in patients with T1D and Addison’s disease than among those with T1D only,3 according to the lead author of the study, Dimitrios Chantzichristos, MD, PhD, at the Sahlgrenska University Hospital, Department of Endocrinology-Diabetes-Metabolism in Gothenburg, Sweden.

Several Factors May Alert Clinicians to Consider Possibility of Addison’s Disease

“Our data suggested that even infections requiring hospitalization, prescription of glucagon (reflecting the risk of acute hypoglycemia) and diabetic retinopathy in patients with type 1 diabetes may raise physician awareness of undiagnosed concomitant Addison’s disease,” Dr. Chantzichristos told EndocrineWeb.

In addition, “as there is sound evidence that a patient with one autoimmune disorder is at increased risk of developing other autoimmune diseases, the presence of autoimmune thyroid disease in a patient with type 1 diabetes may raise the suspicion of undiagnosed concomitant Addison’s disease,” said Dr. Chantzichristos.

The finding of a higher prevalence of diabetic retinopathy among patients with both Addison’s disease and T1D was unexpected, as there were no differences between the groups regarding the length of diabetes duration or poor glycemic or blood pressure control normally associated with diabetic retinopathy,3 he said.

Prior to receiving a diagnosis of Addison’s disease, patients in this study were noted to have a higher use of glucagon prescriptions, which has been supported by findings from earlier studies showing higher pre-prandial and basal insulin doses and lower total daily insulin doses in patients with both conditions versus T1D alone.6

Criteria Identified to Alert Clinicians of Addison’s Disease

“Patients with both Addison’s disease and T1D had higher rates of hypoglycemia, especially prior to the diagnosis of Addison’s disease, and they also had an increase in microvascular complications compared to persons with T1D without Addison’s disease,” said Janet McGill, MD, professor of medicine in the  Division of Endocrinology, Metabolism and Lipid Research at Washington University School of Medicine in St. Louis, Missouri.

“Interestingly,” she told EndocrineWeb, “there was an increase in the rate of infections requiring hospitalization in persons with both type 1 diabetes and Addison’s disease, and not surprisingly, a greater autoimmune disease burden.”  

The study authors noted that the elevated infection rate was less likely owing to the lower threshold for patients with type 1 diabetes due to dysregulated glycemic control upon hospitalization since the control group all had T1D. Rather, Dr. Chantzichristos et al suggested that this finding supports prior research noting a higher frequency of infections specific to patients with Addison’s disease.3,7-9 

“Management of T1D is clearly more challenging in persons with concomitant Addison’s disease, given that the chance of better outcomes may be more compromised in this population,” said Dr. McGill. In this study,3 a higher proportion of patients diagnosed with both type 1 diabetes and Addison’s disease were prescribed antihypertensive drugs, suggesting an increased risk of cardiovascular disease, which was shown in earlier research.10 

This new study also noted higher prescriptions for hypnotics, sedatives, and/or antidepressants in patients with both Addison’s disease and type 1 diabetes, supporting prior findings of increased anxiety, higher levels of distress, and reduced sleep quality reported in patients with Addison’s disease.7,11

What Is the Impact of Autoimmune Disease Management Going Forward

As this was an observational study, Dr. McGill, MD, told EndocrineWeb, “whether some of these patients had genetic predispositions to this combination of disorders, such as mutations in the autoimmune regulator (AIRE) gene is, as yet, unknown.”

When asked if/how these findings might influence current screening practices, diagnosis patterns, or disease management, Dr. Chantzichristos said, “these findings are important for the follow-up of patients with type 1 diabetes.

Our data support a low threshold for biochemical evaluation of Addison’s disease development among patients with type 1 diabetes in the presence of these early clinical indicators.

The latest recommendations from the American Diabetes Association concerning the assessment of comorbidities suggest the routine evaluation of TSH for thyroid-associated diseases in patients with type 1 diabetes,12 but not for Addison’s disease.”

The authors concluded that thyroid disorder in patients with T1D is likely both a predictive and predisposing factor in the development of Addison’s disease, and that severe infections, diabetic retinopathy, and hypoglycemia, requiring glucagon, are likely early indicators of the eventual development of Addison’s disease.3

“In our opinion, the study data support the re-evaluation of a screening strategy for Addison’s disease in patients with type 1 diabetes during their follow-up care. How this is best done in patients with type 1 diabetes is unclear as the sensitivity and specificity of the assessments of choice for the diagnosis of Addison’s disease are not known for patients with type 1 diabetes,” said Dr. Chantzichristos.

Nevertheless, said Dr. McGill, “Addison’s disease is rare in persons with T1D and occurs across the age spectrum, so screening of all patients is not advised. However, understanding the warning signs may help clinicians make an earlier diagnosis.”

This is important since a delayed diagnosis of Addison’s disease may precipitate the autoimmune destruction of the adrenal cortex, allowing for the gradual deterioration of adrenal function. Consequently, early detection may be life-saving for patients with type 1 diabetes.

Continue Reading:
Multiple Autoimmune Syndrome on the Rise, Clinical Vigilance Needed
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