Find out more about distinguishing features, red flags, and patterns that may prompt clinicians to consider elevated cortisol as a culprit.

Early Recognition is Critical

Spotting hypercortisolism in practice can be challenging. Because presentations can vary widely from one person to the next, clinicians often do not recognize distinguishing features and characteristic symptom patterns that should raise suspicion. As a result, the diagnosis may be delayed for months or years, needlessly prolonging exposure to elevated cortisol, which increases both the risk of complications such as myocardial infarction, venous thromboembolism, and stroke, as well as mortality at least two (2) times higher than in the general population. These adverse consequences call for an increased awareness of the clinical clues that should raise suspicion of hypercortisolism in clinical practice.

Classic Features

Hypercortisolism can present with a wide range of symptoms. While the classic Cushing syndrome presentation is obvious, milder cases can be difficult to diagnose due to the broad range of possible clinical features, including many that are by no means unique to this condition. That said, among the many possible signs and symptoms, several in particular are key to differentiating people with Cushing syndrome from those who do not have it:

Common Clinical Presentations

Unfortunately, these classic signs that point most clearly to Cushing syndrome are not among the most common presenting features in those with clinically less apparent manifestations of hypercortisolism. As shown in the table below, hypercortisolism is associated with a wide variety of coinciding symptoms, signs, and comorbidities, such as impaired memory, obesity, T2D, hypertension and osteoporosis. These diverse clinical presentations associated with excess cortisol make assessment difficult, as many symptoms are nonspecific and frequently occur in the general population.

Clinical Clues in Difficult-to-Manage Type 2 Diabetes (T2D)

For many people, managing T2D remains challenging. In many of those cases, hypercortisolism may be the culprit. In the CATALYST study, which looked specifically at people with difficult-to-manage T2D (see Inclusion Criteria below), the prevalence of hypercortisolism was 24%. This was defined as having an HbA1c between 7.5% and 11.5% despite the use of multiple standard-of-care therapies.

Remarkably, the prevalence of hypercortisolism in the CATALYST study was even higher, nearly 37%, in people with difficult-to-manage T2D who were taking 3 or more blood pressure medications. Based on these findings, clinicians should have a high index of suspicion for hypercortisolism in people who have difficult-to-manage T2D, especially if they have difficult-to-manage hypertension despite appropriate therapy.

Beyond A1c and medication burden, there are other factors in people with difficult-to-manage T2D that increase the odds of having hypercortisolism. In CATALYST, the prevalence of hypercortisolism rose from 24% overall to approximately 33% in participants with a cardiac disorder.

Additional factors that increased the odds of having hypercortisolism in difficult-to-manage T2D include older age and lower BMI. Notably, those with a BMI <30 kg/m² were nearly twice as likely to have hypercortisolism as those with a BMI ≥30 kg/m² (odds ratio: 1.639; P = 0.004); this finding confirms that obesity alone is not a sufficient predictor of elevated cortisol and serves as a reminder that clinical suspicion of the disorder should not be based solely on physical appearance.

Key Takeaways

• Hypercortisolism often goes unrecognized in clinical practice, delaying appropriate treatments that could reduce the risk of cardiometabolic morbidity and mortality while improving quality of life.
• Certain features, such as easy bruising, wide reddish-purple striae, facial plethora, and proximal muscle weakness, are the classic clues that should raise suspicion of hypercortisolism.
• However, many people with hypercortisolism present with nonspecific signs and symptoms that are similar to those seen in other common conditions.
• Difficult-to-manage T2D should prompt a high index of suspicion for hypercortisolism, especially when paired with difficult-to-manage hypertension.
• Additional factors, such as older age and presence of cardiac disorders further increase the likelihood of hypercortisolism in people struggling to achieve glycemic targets. 

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