Adrenal Masses and Type 2 Diabetes: Proceed with Caution

The presence of adrenal incidentalomas appears increasingly more common and detecting these benign tumors reflects an increased rate of type 2 diabetes but any direct clinical meaning remains elusive, according to recent study findings.

with Chienying Liu, MD, Stewart G. Albert, MD, and Irina Bancos, MD

Intent on assessing for comorbidities in patients at risk for type 2 diabetes, a team of Italian researchers shed light on the possibility that silent adrenal incidentalomas (masses) discovered during imaging might serve to rule out distinct conditions unrelated to the adrenal glands;1 these findings were published in the Journal of Clinical Endocrinology and Metabolism.

The authors sought to verify any increased risk of type 2 diabetes, although it is not clear if cortisol secretion may play a role or influence the relationship with adrenal tumors, 1 according to experts who discussed what the findings may mean in clinical practice.

Adrenal tumors may signal increased risk for type 2 diabetes.

As Adrenal Tumors Rise So Too Does Type 2 Diabetes

In framing the rationale for this study, researchers from San Luigi Gonzaga Hospital in Orbassano, Italy, reported: Adrenal tumors are among the most common human neoplasms, and the frequency of detection is on the rise given the increased application of high-resolution cross-section imaging in modern medicine.1

Most often, these benign masses are detected serendipitously, often detected when patients undergo abdominal screening for conditions or suspected diseases unrelated to any adrenal-related concern.1

The evidence, over the years, has reflected an increase in the frequency of adrenal incidentalomas detected such that in the 1980s and 1990s, the rate of adrenal masses reported was under 2%  in the United States population but more recently the trend has been reaching closer to 5%.1-3

As such, in this most recent assessment, Reimondo et al reported a frequency of 7.3%  across the population with a compelling association between the presence of adrenal tumors and an increased risk of type 2 diabetes (T2D).1

Even with the strength of these findings, ''it is premature to recommend computerized tomography (CT) imaging [to identify the presence of such tumors] for all persons with diabetes mellitus," said Stewart Albert, MD, professor of internal medicine-endocrinology at St. Louis University in Missouri, who reviewed the findings for EndocrineWeb.

However, it does ''seem reasonable to both clinically and biochemically evaluate all aspects of glucocorticoid metabolism including urinary free cortisol levels in a patient with an adrenal nodule before embarking on surgery or medical therapy aimed at decreasing cortisol production," Dr. Albert said.

Adrenal Masses as Potential Marker of Comorbidities

The research team recruited 601 patients who were scheduled for an abdominal CT scan for a wide variety of medically necessary considerations, such as assessing for abdominal symptoms, changes in liver function tests, or irregular pancreatic enzyme levels, among other indications. Their aim was to pinpoint the frequency of comorbid conditions as related to the hormonal workup of patients found to have adrenal tumors.1

The average age of the patients was 63.5 years; the average body mass index (BMI) was 25.4 kg/m2. Among the patient population, 15.5% had type 2 diabetes—comparable to that of the general population in the region. In addition, 55.4% of the cohort had diagnosed hypertension, 17.3% had dyslipidemia, and 17% of the patients had a history of previous cardiovascular-related events.

While 14.2% of the patients without detection of adrenal incidentalomas on imaging were diagnosed as having type 2 diabetes, 31.8% of the study group in whom these tumors had been detected also had T2D (P < 0.0038).1

The finding that individuals with an adrenal tumor were at increased diabetes risk was made free from ascertainment bias, according to the authors because those with the tumors were drawn from a cohort with the same risk of diabetes as the general population.1

Role of Cortisol as Predictive of Diabetes Onset

Most adrenal tumors are benign cortical adenomas that may have secretary activity, the research team reported. However, not all patients present with classic stigmata of adrenal steroid excess. In fact, in up to 30% of these adrenal masses, an autonomous cortisol secretion is found that may have clinical consequences.

In recognition, the European Society of Endocrinology and the European Network for the Study of Adrenal Tumors guidelines recommend a 1 mg overnight dexamethasone suppression test (DST) to rule out cortisol overproduction. (Levels of under 50 nmol/L exclude this secretion; levels above 138 nmol/L are clear evidence of excess levels; a lab finding that falls within these two levels may be evidence of autonomous cortisol secretion.4

Autonomous cortisol, defined as subclinical Cushing's syndrome, may be diagnosed at levels that fall in the lower end of the range, and evidence links cortisol with increased risk of metabolic and cardiovascular diseases and related adverse effects on morbidly and mortality.5

Gathering Data on Detection of Adrenal Masses and Diagnosis of Type 2 Diabetes

Among study participants, CT scans were taken between January 2017 and June 2019. The researchers obtained measures of patient weights, heights, and body mass index. The minimal tumor size to be classified as an adrenal incidentaloma was 10 mm. Tumors meeting the study parameters were found in 44 patients, or 7.3%; median size was 21 mm but ranged from 10-50 mm in size.

The 1-mg DST was conducted on 40 patients for which half of them did not show cortisol suppression while post-DST levels were above 138 nmol/L in four 4 individuals.1 Participants with adrenal tumors were more likely to (P < 0.0038):

  • be male
  • have a higher BMI
  • more likely to have diabetes.

The link between increased risk of diabetes in those with the tumors and age was not fully linear, so age alone could not explain the finding, the researchers said.

Bottom line: Patients with adrenal incidentalomas are likely to develop an adverse metabolic profile, specifically associated with increased cardiovascular risk.1,5

The observation that diabetes may be independently predicted when adrenal tumors are present is supported by the established relationship with insulin resistance, said the authors, and, it may be bidirectional.1 While these adrenal masses may have a role in fostering insulin resistance, the elevated glucose sensitivity actually may facilitate the development of adrenal tumors.6-8

Despite any limitations in study design, the authors believe their research ''provides evidence for a better understanding of whether adrenal incidentalomas are associated with comorbid conditions." And because the incidence of adrenal masses arising in patients with type 2 diabetes was even higher than in previous studies, the issue is one of public health importance,1  they said.

Clinical Implications of Diabetes in Patients with an Adrenal Mass

Chienying Liu, MD, professor of medicine at the University of California/San Francisco School of Medicine, also reviewed the findings at the behest of EndocrineWeb: "There is a valid association," yet we cannot yet say whether there is causation between presence of adrenal masses and T2D.

That said, the take-away for clinicians is to expect a higher likelihood of type 2 diabetes in the presence of adrenal incidentalomas, said Dr. Liu. "We all know what causes type 2 diabetes—obesity and insulin resistance," and since some of the tumors secrete cortisol, that may be the route to development of obesity, which in turn may raise the risk of diabetes.

"I think this [study] brings awareness to community physicians that adrenal masses need to be worked up," she said, and that monitoring is necessary as well; however, she added, there are no good studies on whether taking the tumor out will reverse the diabetes or lessen the patient’s risks, which would be very valuable.

Related content: Endocrine Society Guidelines on Adenal Insufficiency

Is the management of diabetes different for these patients? "Not at all," Dr. Liu said, ''because we don’t yet know if the presence of adrenal tumors are causal [for diabetes]." Therefore, the best management strategy, at present, is to continue to approach the risk of diabetes as usual, and not to jump to any conclusions about metabolic concerns if an adrenal incidentaloma is detected during imaging for other concerns.

Dr. Albert concurred: "Although the findings are provocative, many questions remain." For example, he said, there is lack of information about the implications for people who may have been on medication that may speed the metabolism of dexamethasone, giving false positive results, and whether the dose of 1 mg is adequate and definitive to achieve sufficient hormone suppression, regardless of other factors such as body weight.

Addressing Adrenal Tumors Regardless of Diabetes Status

Irina Bancos, MD, an endocrinologist and associate professor of medicine at the Mayo Clinic in Rochester, Minnesota, who often cares for such patients suggests a more preemptive approach. "Once an adrenal mass is discovered, we need to proceed with evaluation to answer 2 questions – 1) is it cancerous or benign, and 2) is it hormonally active or not. Most patients with adrenal tumors have benign adrenal adenomas," she said.

Dr. Bancos told EndocrineWeb: "The dexamethasone suppression test should be performed in any patient with an adrenal adenoma. Cortisol after dexamethasone suppression of greater than 1.8 mcg/dl is consistent with autonomous cortisol secretion from the adrenal mass.”

Interestingly, in the Reimondo study, the prevalence of autonomous cortisol secretion (ACS) was 50%, so quite high, she said. As such, “patients with elevated ACS do present higher prevalence of diabetes mellitus. In these situations, we would either proceed with adrenal surgery to remove the mass or manage with medical therapy targeted towards controlling blood sugar and managing comorbid conditions associated with type 2 diabetes.:

“However, at present, it is unclear whether medical management is as good as adrenalectomy so the decision will need to be individualized to each situation," said Dr. Bancos.

Dr. Albert and Dr. Liu have no financial conflicts to disclose while Dr. Bancos reported serving as a consultant/advisory board member for HRA Pharma and Corcept.

Continue Reading:
Six Clinical Insights for Better Management of Adrenal Insufficiency
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