Cushing's syndrome

During the past 30 years, there have been advances in understanding of the pathogenesis of Cushing's syndrome and in differential diagnosis of its various forms. Improved diagnostic tests and procedures have increased the ability to recognise even mild hypercortisolism and have provided the means to obtain an accurate diagnosis. Despite these advances, the occurrence of unusual clinical presentations and laboratory shortcomings may produce diagnostic problems and challenge clinical intuition. This article reviews recent pathogenic views, new tests, and new diagnostic problems in the evaluation of Cushing's syndrome. Atypical clinical presentations of hypercortisolism and some laboratory shortcomings that may confuse the diagnosis of Cushing's syndrome are also reported.     

Cushing's syndrome

The clinical characteristics and current concepts of pathophysiology of Cushing's syndrome have been reviewed. The specific type of pituitary or ectopic ACTH-dependent and ACTH-independent Cushing's syndrome and the underlying pathology can be determined biochemically and with the aid of anatomic localization procedures. Several approaches are available for treating pituitary ACTH-dependent Cushing's syndrome, but transsphenoidal pituitary microsurgery is the ideal type, with remission of the disease being observed in 80 to 90% of cases. When successful, pituitary microsurgery is followed by preservation of normal pituitary function and restoration of normal hypothalamic-pituitary-adrenal function within 6 to 12 months postoperatively. Medical therapy of Cushing's disease includes drugs that inhibit CRH-ACTH secretion, such as cyproheptadine and bromocriptine, and agents that inhibit cortisol synthesis, such as aminoglutethimide, metyrapone, ketoconazole, and mitotane, or that block the action of cortisol at the glucocorticoid receptor level, such as RU-485. With the exception of mitotane, which has adrenalytic effects, the action of the other pharmacologic agents is promptly reversed when treatment is discontinued. Thus, drug therapy is effective only as temporary treatment for Cushing's syndrome when surgical approaches are contraindicated or when attempts are made to improve the patient's clinical and metabolic status in preparation for surgery. Mitotane is effective in extending survival of patients with adrenal carcinoma, particularly when it is administered early as adjuvant therapy or when it is combined with repeated debulking resection of recurrent tumor. The toxicity associated with mitotane administration limits the use of larger and probably more effective doses in these patients. The synthesis of more specific cytochrome P-450 enzyme inhibitors and of mitotane analogues with more limited toxicity may ultimately provide more effective tools in the pharmacologic management of Cushing's syndrome.     

Cushing's syndrome

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.     

Cushing's syndrome

Cushing's syndrome remains one of the most challenging problems in clinical endocrinology. Cushing's disease is caused in the majority of cases by basophil pituitary microadenomas which may be successfully treated by trans-sphenoidal hypophysectomy. Treatment with metyrapone or o,p'-DDD can always induce a clinical remission but not a cure, and neurotransmitter therapy may be effective in a minority of cases. Pituitary irradiation cures about half of cases in the long-term and may be used for surgical failures. Tumours producing ectopic ACTH are frequently benign, small and occult and may produce a syndrome clinically indistinguishable from Cushing's disease. Biochemical investigations cannot absolutely distinguish pituitary from ectopic sources of ACTH and therefore body CT scanning and percatheter venous sampling are essential diagnostic investigations. Tumour localization may result in resection and complete cure, although even small tumours may have a malignant potential. Adrenal tumours are readily diagnosed by plasma ACTH measurement and adrenal CT scanning. Adrenal adenomas are cured by adrenalectomy. Carcinomas may be treated by a combination of adrenalectomy, radiotherapy and o,p'-DDD, but long-term prognosis is poor.     

Imaging in Cushing's syndrome

Once the diagnosis of Cushing's syndrome (CS) has been established, the main step is to differentiate between ACTH dependent and independent disease. In adults, 80% of CS is due to ACTH-dependent causes and 20% due to adrenal causes. ACTH-secreting neoplasms cause ACTH-dependent CS. These are usually anterior pituitary microadenomas, which result in the classic Cushing's disease. Non-pituitary ectopic sources of ACTH, such as a small-cell lung carcinoma or carcinoid tumours, are the source of the remainder of ACTH-dependent disease. In the majority of patients presenting with clinical and biochemical evidence of CS, modern non-invasive imaging can accurately and efficiently provide the cause and the nature of the underlying pathology. Imaging is essential for determining the source of ACTH in ectopic ACTH production, locating the pituitary tumours and distinguishing adrenal adenomas, carcinomas and hyperplasias. In our chapter we review the adrenal appearances in ACTH-dependent and ACTH-independent CS. We also include a discussion on the use of MRI and CT for the detection and management of pituitary ACTH secreting adenomas. CT of the chest, abdomen and pelvis with intravenous injection of contrast medium is the most sensitive imaging modality for the identification of the ectopic ACTH source and detecting adrenal pathology. MRI is used for characterising adrenal adenomas, problem solving in difficult cases and for detecting ACTH-secreting pituitary adenomas.     

Cyclic Cushing's syndrome

Because glucocorticoids are necessary to sustain life and maintain homeostasis, adrenal disorders, if not detected in a timely fashion, can have serious consequences. Cyclic Cushing's syndrome is a disease characterized by rhythmic fluctuations in glucocorticoid production. In patients with this disorder, both clinical and biochemical spontaneous remissions may occur and therefore the activity of the hypothalamic-pituitary-adrenal axis between the cycles may be undisturbed. The clinical manifestation of cyclic Cushing's syndrome may be complex and varied, differing not only between patients but also in the same patient on a daily to monthly basis. The presence of cyclic Cushing's syndrome should always be considered in patients with a clinical presentation of hypercortisolism coexisting with normal glucocorticoid plasma levels and a paradoxical response to the dexamethasone test. We here present a detailed case report on a patient diagnosed with cyclic Cushing's syndrome. We report diagnostic and treatment strategies used in our patient and their impact on the course and outcome of the disease.     

Familial Cushing's syndrome

Cushing's syndrome has been demonstrated in four of seven siblings with clinical manifestations appearing around puberty in three of the four siblings. The only other associated findings in these cases were short stature and disturbed carbohydrate metabolism. Adenomatous hyperplasia of the adrenal glands was demonstrated in 3 of the patients, and a virilizing adrenal carcinoma in the fourth sibling. The pathogenesis of the adrenocortical disorders in these siblings is discussed.     

Factitious Cushing's syndrome

In this report we describe a patient who produced the clinical and laboratory features of Cushing's syndrome by injecting himself for many months with hydrocortisone. Factitious Cushing's syndrome is a variant of the Münchausen syndrome and should be considered if tests used to establish the diagnosis of Cushing's syndrome appear incongruous particularly in subjects with access to medical intelligence and drugs.     

Hypertension and aldosterone overproduction without renin suppression in Cushing's syndrome from an adrenal adenoma.

Adrenal steroids and compenents of the renin-angiotensin system were measured before and after adrenalectomy in a woman with Cushing's syndrome and hypertension from a functioning adrenocortical adenoma. Aldosterone, deoxycorticosterone and cortisol were produced in excess by the adenoma, and were measured in tumor tissue. High plasma renin substrate concentrations, and normal basal and furosemide-stimulated plasma renin activities and plasma renin concentrations which were present before surgery, decreased after adrenalectomy, and the hypertension diminished. The inappropriately normal levels of renin and potassium in this patient, despite autonomous aldosterone overproduction, suggest an ineffective mineralocorticoid action of aldosterone, possibly from interaction with her other adenoma-produced steroids. The decrease in components of the renin-angiotensin system suggests a partial renin-dependence of her hypertension.     

Megestrol-induced Cushing's syndrome

This case describes the first report of a patient developing Cushing's syndrome whilst being treated with the synthetic progestogen, megestrol acetate (Megace). Drugs are the commonest cause of Cushing's syndrome. Some synthetic progestogens are known to have glucocorticoid activity at high doses. On structural grounds neither megestrol nor its major metaboiltes would be expected to interact with the glucocorticoid receptor, though the manufacturers report that it may have ‘weak glucocorticoid activity'.     

Subclinical Cushing's syndrome

Subclinical Cushing's syndrome (CS) is attracting increasing interest since the serendipitous discovery of an adrenal mass has become a rather frequent event owing to the routine use of sophisticated radiologic techniques. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner that is not fully restrained by pituitary feedback, in 5 to 20% of cases depending on study protocols and diagnostic criteria. The criteria for qualifying subclinical cortisol excess are controversial and presently there is no consensus on a gold standard for the diagnosis of this condition. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipemia has been described in patients with subclinical CS; however, there is still no clear demonstration of the long-term complications of this condition whose management remains largely empirical. Either adrenalectomy or careful observation associated with treatment of the metabolic syndrome have been suggested as treatment options.     

Factitious Cushing's syndrome

A woman with pituitary-dependent Cushing's disease remained hypercortisolemic after bilateral adrenalectomy. A search for an adrenal remnant by venous catheterization study suggested persistent cortisol-secreting tissue in the left adrenal bed. During ACTH stimulation, plasma corticosterone concentrations remained low and cortisol remained high, suggesting the cortisol was of exogenous origin. Cushingoid features resolved after confronting the patient with this evidence. Plasma corticosterone concentrations played a novel role in the diagnosis of factitiously induced Cushing's syndrome in this patient.