Mortality in Cushing's disease

The causes of premature death in untreated Cushing's syndrome are vascular disease (myocardial infarction/stroke), uncontrolled diabetes mellitus and complications and infections. Long-term mortality outcome studies on pituitary-dependent Cushing's disease (CD) are limited to six studies in the English language literature. This paper reviews these studies on CD, other causes of Cushing's syndrome being excluded, because CD represents 80% of patients with the syndrome. The period covered by these studies (1970-1990) is when transsphenoidal surgery was well established as primary treatment for CD. Two studies were exclusively from surgical centres and are likely biased in favour of surgically resectable adenomas, so this needs to be borne in mind when interpreting their results. The criteria for remission of hypercortisolism and persistent disease were variable. The overall number of patients in each report is small, and the number of deaths even smaller by epidemiological standards giving very wide confidence intervals to the standardised mortality ratios (SMR). Moreover, follow-up time was relatively short (median 10-12 years) for a disease diagnosed in the patients' late 30s. Notwithstanding the above limitations of retrospective studies, and potential for positive bias, the overall SMR of around 1.5 was not significantly different from the relevant normal population for those patients deemed in remission. However, SMR was significantly worse for those patients with persistent disease. Where it was possible to analyse contributing factors to mortality, the presence of hypertension and diabetes mellitus, in addition to persistence of hypercortisolism, was shown to be significant. It remains possible that an overall SMR in 'cured' patients would be significant given a larger cohort, followed for longer, and with more deaths. What is clearly required is a multicentre prospective cohort study with >30 years' follow-up to answer the question definitively and identify the contributing factors in detail in order to achieve optimum long-term outcome.