Managing comorbiditites

In 1952, before effective treatment was available, patients with CS had a median survival of 4.6 years. Despite treatments for comorbidities becoming available, patients with active CS continue to have an increased standardised mortality rate that is 1.7–4.8-fold greater than the general population. In contrast, when CS and its associated comorbidities are successfully treated, the standardised mortality rate improves, although it is unclear whether this is similar or not to mortality rates in the general population (Niemann et al., 2015). Recent data suggest that curative therapy with initial surgery is most likely to provide a normalised standardised mortality ratio (Clayton et al., 2016).

Cushing’s Syndrome is associated with a number of risk factors for comorbidities (Figure 7). Many of these strongly impact morbidity and mortality, with cardiovascular and cerebrovascular events being the most common cause of death in CS (Dekkers et al., 2007; Hassan-Smith et al., 2012).

Treatment of comorbidities is therefore important both before addressing the cause of hypercortisolaemia and during long-term follow-up post-treatment until resolution (Nieman et al., 2015). Urgent treatment (within 24–72 hours) should be provided for hypercortisolaemia if life-threatening complications such as infection, pulmonary thromboembolism, cardiovascular complications, or acute psychosis are present (Nieman et al., 2015).

  • Cardiovascular disease: obesity, hyperlipidaemia and hypercoagulability all contribute to cardiovascular complications. It is important to monitor the risk, particularly if treatment does not normalise cortisol levels, or the patient relapses (Arnaldi et al., 2003).
  • Hypertension: seen in 70–80% of patients and is often the first sign of CS. Conventional antihypertensive therapy such as angiotensin-converting enzyme (ACE) inhibitors may be only partially effective but the additional use of cortisol-lowering agents may improve blood pressure control (Arnaldi et al., 2003).
  • Impaired glucose tolerance and diabetes: hypercortisolaemia promotes the development of hyperglycaemia and decreased carbohydrate tolerance by increasing glucose production and decreasing glucose uptake by peripheral tissues. An oral glucose tolerance test may be useful for the assessment of global cardiovascular risk in these patients, although this is rarely necessary (Arnaldi et al., 2003).
  • Psychiatric and psychological disturbances: >70% of patients with CS present with psychiatric symptoms ranging from anxiety to psychosis while 50–80% meet DSM IV criteria for major depression at presentation. Depression is usually treated through surgery to normalise cortisol levels; antidepressants are less effective but may be used until the patient is ready for surgery. Some degree of psychiatric disturbance frequently persists after CS remission (Arnaldi et al., 2003). 
  • Osteoporosis: 50-80% of patients with CS have decreased bone mineral density and osteoporosis (Sharma et al., 2015) with ~30–50% of patients experiencing fractures, often the presenting symptom of CS. This can lead to kyphosis, back pain, height loss, and can indicate further fractures (Arnaldi et al., 2003). Bone mineral density does improve following treatment for CS but specific fracture treatment may also be required (Sharma et al., 2015).
Figure 7. Comorbidities in Cushing’s Syndrome.

Figure 7. Comorbidities in Cushing’s Syndrome. (Adapted from Arnaldi et al., 2003; and Ferrau and Korbonits, 2015).
GH/IGF1: Growth hormone/Insulin-like growth factor 1; IGT:Impaired glucose tolerance.