Mortality in Cushings 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 posiPublished online: September 10, 2010 R.N. Clayton University Hospital of North Staffordshire, City General Hospital Stoke on Trent ST4 6QG (UK) Fax +44 1782 553 427, E-Mail r.n.clayton @ keele.ac.uk © 2010 S. Karger AG, Basel 0028–3835/10/0925–0071$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /4 /2 01 7 6: 12 :0 1 P M Clayton Neuroendocrinology 2010;92(suppl 1):71–76 72 poor prognosis, estimated 5 years’ survival of 50% [3] , though this is dramatically improved to 86% after bilateral adrenalectomy [4] . The main causes of the poor outcome in untreated patients are vascular disease, (strokes, myocardial infarction), uncontrolled diabetes mellitus and infections. Long-term outcome studies in patients with Cushing’s syndrome are very limited. In contrast to patients with acromegaly and non-functioning tumours where there are now extensive data on factors which determine mortality, no such data are available for Cushing’s syndrome. For example, we know that in acromegaly the duration of disease before diagnosis is a predictor for mortality as is age at diagnosis and the presence of hypertension or cardiac disease at diagnosis [5] . It is not known whether similar variables predict mortality in CD, though intuitively this would seem likely. Further, we know that a specific biochemical target with respect to GH and IGF-1 is predictive of mortality in acromegaly [6] . Is there such a relationship for plasma cortisol in Cushing’s syndrome? The question is whether elimination of hypercortisolism, even if present for several years before treatment as is often the case, can restore mortality rates to that of the reference population. The purpose of this brief review is to examine what data are available and define criteria for optimal long-term survival. Methods Since 80% of Cushing’s syndrome is caused by ACTH-secreting pituitary adenomas (CD), this review is restricted to those reports where CD can be distinguished from subgroups with ectopic ACTH syndrome and primary adrenal pathologies. A search of PubMed using the terms Cushing’s syndrome and long-term outcomes/results and mortality yielded six reports between 1994– 2007. It was surprising to find that many centres with an international reputation which have published extensively on the diagnosis and management of Cushing’s syndrome have not reported on mortality outcomes despite having treated many patients over many years. There are limitations to extrapolating from the six published papers since data are not reported uniformly, making comparisons between them difficult. This review concentrates on (long-term) mortality (excluding that deemed to be immediately post-operative) and the causes of death. It does not discuss surgical remission rates per se, only if relevant to mortality.