Avascular necrosis of bone: a manifestation of Cushing's disease

Cushing's disease is endogenous hypercortisolism due to a pituitary adenoma. Although exogenous hypercortisolism is a well known cause of avascular necrosis and although there have been many reports of avascular necrosis associated with endogenous Cushing's syndrome, there has only been a single well documented case report associating avascular necrosis of bone with Cushing's disease. We report four new cases of avascular necrosis of bone in patients with well documented Cushing's disease.     

Laboratory differentiation of Cushing's syndrome

Cushing's syndrome (CS) is a complex of signs and symptoms due to chronic glucocorticoid excess from a variety of causes. Although CS is considered a rare disease, recent studies have suggested that it may be more frequent than previously expected in various clinical settings (i.e. subjects suffering from diabetes, osteoporosis or metabolic syndrome). If confirmed in large population-based studies, more widespread screening for CS may be warranted. Missed diagnosis of CS may have detrimental consequences because hypercortisolism, even if not clinically apparent, increases the probability of future cardiovascular events through induction/amplification of several risk factors (hypertension, central adiposity, thrombophilic state, etc.). Identifying CS has represented one of the most challenging problems for the clinical endocrinologist since no test is 100% sensitive and specific. This review article will be focus on diagnostic laboratory procedures that support a rationale approach in the screening evaluation and in the differential diagnosis of the endogenous CS. Notwithstanding the difficulties derived from laboratory reliability and the adoption of a hormonal cut-off close to the sensitivity of many commercially available assays, an increasing amount of data have provided novel information aimed to meet the demand of inexpensive, convenient and reliable laboratory procedures.     

Secondary hypertension. A streamlined approach to diagnosis

Among the many potential causes of secondary hypertension are renal parenchymal disease, occlusive renal arterial disease, adrenocortical abnormalities, and pheochromocytoma. Renovascular hypertension can result from either renal parenchymal or occlusive renal arterial disease. Laboratory testing can help in identification and differentiation. Parenchymal diseases usually modify the urine substantially without producing urographic abnormalities, while occlusive arterial lesions produce urographic abnormalities but the urine remains normal. The diagnosis of renal occlusive arterial disease is best defined by arteriography. The only definite criterion for the existence of hypertension of renal origin is cure by either nephrectomy or renal revascularization. Adrenocortical causes of hypertension include enzymatic deficiencies, Cushing's syndrome, and primary aldosteronism. In enzymatic deficiencies, the physical findings provide the most important clues to the type of enzyme deficiency involved. In Cushing's syndrome, accurate determination of the cause of the hypercortisolism is important in terms of choice and success of treatment. The diagnosis of primary aldosteronism rests primarily on the demonstration of nonsuppressible aldosterone excretion rate during salt loading; the presence of inappropriate kaliuresis and/or suppressed plasma renin activity provides corroborative evidence of primary aldosteronism, but the absence of either or both does not preclude the diagnosis. Pheochromocytoma, although rare, is a serious and potentially fatal cause of hypertension. Definitive diagnosis depends on laboratory test results, and the tumor is usually localized by computed tomography.     

Corticotropin releasing factor as an aid in the diagnosis of Cushing syndrome

6 patients with Cushing's syndrome were investigated with regard to the effect of synthetic ovine corticotropin-releasing factor (o-CRF), administered as an intravenous bolus of 100 micrograms, on peripheral plasma concentrations of ACTH and cortisol. The purpose of this study was to evaluate the usefulness of this "CRF test" in the differential diagnosis of Cushing's syndrome as compared with conventional diagnostic procedures. 100 micrograms CRF caused a rise in plasma ACTH and cortisol in patients with bilateral adrenal hyperplasia (n = 3). However, in patients with cortisol-producing adrenal adenoma (n = 2) and ectopic ACTH overproduction (n = 1), no increase in plasma cortisol and ACTH was induced by exogenous CRF. We conclude from these findings that the CRF test will prove a valuable diagnostic tool to differentiate pituitary from extrapituitary forms of endogenous hypercortisolism in patients with Cushing's syndrome.     

Salivary cortisol for the evaluation of Cushing's syndrome

Cortisol concentrations were measured in matched plasma and salivary samples from 8 healthy controls, 8 patients with Cushing's syndrome and 4 patients suspected of having spontaneous hypercortisolism. In healthy subjects, the circadian rhythm in salivary cortisol paralleled that in plasma. Absence of the diurnal rhythm in Cushing's syndrome was seen in saliva as well as in plasma. After ACTH stimulation, mean peak cortisol in saliva showed a 3-fold increase while in plasma there was a 2.5-fold increment above baseline. Cushing's syndrome, due to pituitary or adrenal adenoma was diagnosed equally well by measuring the cortisol response to cosyntropin in either plasma or saliva. Finally, the low- and high-dose dexamethasone suppression test was reflected equally well in both plasma and saliva. In patients suspected of having Cushing's syndrome dynamic tests can be performed in both plasma and saliva. However, in some samples, the salivary cortisol measurement appears advantageous over plasma cortisol determination.     

Medical treatment for Cushing's syndrome

Systemic cortisol plays an important role in the metabolism of glucose, lipids and proteins, as well as in the regulation of electrolyte balance. It is well known that the development of the microvascular disease of various organs such as the heart and kidney, in patients with diabetes mellitus, hyperlipidemia and hypertension of which disorders are frequently associated with Cushing's syndrome. Thus, we should treat Cushing's syndrome as soon as possible, since many complications, including cardiovascular diseases and infections, will soon occur when the definite diagnosis is delayed. Adrenalectomy is essential for treatment for Cushing's syndrome even in the patients with pituitary or ectopic ACTH-producing tumor. Some case can not be treated with surgical procedures because of worsened conditions with several complications of infection and diabetes. Then we choose medical treatment. Medical adrenalectomy is achieved by using with mitotane which is usually used for adrenocortical cancer. We commonly treat the patients with Cushing's syndrome due to adrenal tumor and pituitary or ectopic ACTH producing tumor by using metyrapone which mainly inhibits 11-hydroxylase. Metyrapone is also recommended to treat the patients who are not well differentiated Cushing's disease from ectopic ACTH syndrome. We rarely use trilostane which is an inhibitor against 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Replacement therapy with hydrocortisone should be considered if adrenal failure will occur during treatment with those drugs.     

Diagnosis of corticotropin-producing bronchial carcinoid tumors causing Cushing's syndrome

Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (corticotropin) has been recognized for many years. Traditionally, clinicians have thought that most cases were due to lung carcinomas and that the clinical manifestations differed from those for pituitary-dependent Cushing's syndrome. We report two cases of corticotropin-producing bronchial carcinoid tumors that were clinically and biochemically indistinguishable from pituitary-dependent Cushing's syndrome. Review of the literature revealed that bronchial carcinoid tumors are the most common cause of Cushing's syndrome due to ectopic secretion of corticotropin. On biochemical and anatomic studies, they are frequently indistinguishable from pituitary-dependent Cushing's syndrome and thus may be difficult to diagnose. Inferior petrosal sinus sampling for corticotropin and computerized imaging of the chest may be the best aids in making the diagnosis.     

Pseudallescheria boydii arthritis and osteomyelitis in a patient with Cushing's disease

Pseudallescheria boydii infection involving the left distal femur and knee joint developed in a patient with Cushing's disease, and recurred after treatment with both intravenous miconazole and intravenous amphotericin B. The patient subsequently had synovectomy and arthrodesis, and received ketoconazole, 600 mg per day orally for one year. Concurrent with the start of ketoconazole, a bilateral adrenalectomy was done to control endogenous hypercortisolism. The patient's infection then resolved, and one year afterward there is no clinical or radiologic evidence of recurrent infection.     

Prim?re pigmentierte nodul?re adrenokortikale Dysplasie (PPNAD) im Rahmen des Carney-Komplexes als Ursache eines Cushing-Syndroms

Zusammenfassung Hintergrund: Die primäre pigmentierte, adrenokortikale Dysplasie (PPNAD) ist eine seltene Erkrankung der Nebennieren, die gehäft bei Patienten mit dem Carney-Komplex auftritt. Der Carney-Komplex ist ein autosomal-dominantes Neoplasiesyndrom, das vor allem durch Lentigines, Myxome und Nebennierentumoren charakterisiert ist. Fallbericht: Eine 37jährige Frau entwickelte nach mehreren Phasen von Gewichtszunahme/Depression und Gewichtsabnahme/Manie als Anzeichen für einen zyklischen Hyperkortisolismus ein manifestes Cushing-Syndrom, das mit bilateraler Adrenalektomie behandelt wurde. Die Patientin hatte eine PPNAD im Rahmen eines Carney-Komplexes. Schlußfolgerung: Eine PPNAD kann als 1. präklinisches Cushing-Syndrom mit aufgehobenem Cortisoltagesrhythmus, 2. als Ursache eines zyklischen Hyperkortisolismus und 3. als manifestes Cushing-Syndrom auftreten. Ein präklinischer und zyklischer Hyperkortisolismus bei PPNAD kann mit dem sechstägigen Liddle-Test, der typischerweise eine paradoxe Cortisolstimulation nach Dexamethasongabe zeigt, diagnostiziert werden. Die Behandlung der Wahl stellt die bilaterale Adrenalektomie dar, um die Langzeitfolgen des Hyperkortisolismus zu bermeiden. Abstract Background: Primary pigmented adrenocortical dysplasia (PPNAD) represents a rare disorder of the adrenal glands and frequently occurs in patients with the so-called Carney complex. Carney complex is an autosomal dominant neoplasia syndrome including skin and mucosal lentigines, myxomas, and PPNAD. Case Report: A 37-year-old women suffered from several episodes of weight gain/depression and weight loss/mania indicating cyclic hypercortisolism. Finally, she developed a full-blown Cushing's syndrome (CS) treated by bilateral adrenalectomy. She had PPNAD in the setting of Carney complex. Conclusion: PPNAD may lead to different clinical manifestations: 1. sub-clinical hypercortisolism, 2. intermittent hypercortisolemia, and 3. full-blown CS. It can be diagnosed with the 6-day Liddle test that typically shows a paradoxical stimulation of cortisol secretion after dexamethasone administration. The treatment of choice for PPNAD is bilateral adrenalectomy in order to prevent devastating long-term effects of hypercortisolism.     

An unusual cause of Cushing's syndrome: primary pigmented nodular adrenal dysplasia

We report a case of Cushing's syndrome due to primary pigmented nodular adrenal dysplasia (PPNAD) and discuss the diagnostic process and management of this rare case. The diagnosis of PPNAD is discussed in the context of other causes of Cushing's syndrome. Eighty-five per cent of cases of Cushing's syndrome are due to a pituitary corticotrophic tumour (Cushing's disease). Rarer causes include cortisol secreting adrenal adenoma and ectopic ACTH secretion. In the routine investigation of Cushing's disease it is not unusual to find bilateral adrenal nodules on the CT scan. We present a case of Cushing's syndrome in which this radiographic finding was present and yet the biochemical diagnosis was one of ACTH independent disease. Histology revealed PPNAD.     

Particular cases of Cushing's syndrome--one with adrenocortical carcinoma and the other with double adenomas

Two particular cases of adrenocortical tumors associated with Cushing's syndrome were documented. In the first case, the steroid pattern suggested a malignancy, and the histology of the excised tumor confirmed it. In the second case, the left adrenal had two distinct tumors; one dark-brown, and the other yellow in color. Recent trends in the diagnosis and treatment of Cushing's syndrome were discussed.     

Cushing's syndrome with cranial and pulmonary lesions: necessity for tissue diagnosis.

This report describes two cases of Cushing's syndrome associated with radiologic abnormalities in the lung and brain. In both cases, the pathologic diagnosis of the intracranial lesion was unsuspected and prompted changes in management. These cases illustrate that the etiology of pulmonary and central nervous system mass lesions in patients with Cushing's syndrome may not be predicted on clinical grounds or by conventional radiologic methods. A tissue diagnosis is essential as a guide to appropriate management, and biopsies of such lesions are indicated.     

Diagnosis and pathophysiology of Cushing's syndrome

Cushing's syndrome is the consequence of a sustained overproduction of cortisol (hydrocortisone) by the adrenal cortex. This may be due to excessive secretion of cortisol by functioning adrenocortical tumors or to "nontumorous" adrenocortical hyperfunction. The latter may be a result of stimulation of the adrenal cortex by increased release of corticotropin (ACTH) from a small pituitary tumor or from nonpituitary nonadrenal tumor. Carcinoids or carcinomas of the lung or pancreas, and even pheochromocytomas have caused the syndrome of ectopic ACTH production. The problems involved in the diagnosis of Cushing's syndrome are establishing its presence and determining the underlying cause. Treatment is then dependent upon the underlying pathogenetic lesion.     

Psychiatric aspects of Cushing's syndrome

Patients with Cushing's syndrome were studied (n=209, 78% females). Control patients had pituitary adenomas secreting growth hormone or prolactin. Age at diagnosis of Cushing's syndrome was 8-74 (mean 39) years. Duration of symptoms was 0.2-9 (median 2.0) years. Adverse life events within the 2 years preceding the onset of Cushing's syndrome were not significantly commoner than in controls. Depressive illnesses were associated with the presence of adverse life events (p<0.001). Depressive illness was more common in females (p<0.01). There were no significant differences in the severity of depression in the different types of Cushing's syndrome. Pathological anxiety had been diagnosed in 26 patients (12%), mania or hypomania in six patients (3%) and confusion in three patients (1%). Psychotic illness had been diagnosed in 16 patients (8%) and was more common in adrenal carcinomas (p<0.01). Significant psychiatric illness, usually depressive preceded the onset of all symptoms and signs of Cushing's syndrome in 25 patients (12%); 23 of these developed pituitary Cushing's disease, and two adrenal adenomas. When Cushing's syndrome was diagnosed, significant psychiatric illness, usually depression, was present or had been a feature of Cushing's syndrome in 120 (57%) patients.      

Cushing's syndrome. How to pinpoint and treat the underlying cause

In addition to prolonged glucocorticoid therapy (not discussed here), at least five other conditions cause Cushing's syndrome. They are excessive corticotropin secretion by the pituitary gland (which results in Cushing's disease), ectopic production of corticotropin by malignant nonpituitary tumors, benign adrenal adenoma, adrenal carcinoma, and primary adrenocortical nodular dysplasia. Each can be distinguished by a specific pathophysiologic process that triggers the adrenal glands to overproduce glucocorticoids. At present, diagnosis of Cushing's syndrome or disease relies heavily on the dexamethasone (Decadron, Hexadrol) suppression test. After diagnosis, other studies, including computed tomography, magnetic resonance imaging, and corticotropin radioimmunoassay, can be used to localize the site of the lesion. Treatment, of course, depends on the underlying cause.     

Endocrinopathies of hyperfunction: Cushing's syndrome and aldosteronism.

Increased function of the adrenal cortex is a normal response in times of physiologic and psychologic stress. Adrenal cortical secretions (e.g., glucocorticoids, aldosterone) orchestrate a multitude of internal processes aimed at maintaining homeostasis and psychologic integrity. Many patients admitted to a critical care unit will manifest some increase, even minor, in adrenal function. However, excessive secretions of these hormones can have a lethal effect of fluid and electrolyte balance, energy metabolism, and immune function. Cushing's syndrome denotes a disorder characterized by increased circulating levels of glucocorticoids (primarily cortisol). An easily recognizable disorder, it may arise from pathology of the adrenal cortex or the anterior pituitary glands, ectopic secretions from a nonendocrine tumor, or from excessive doses of exogenously administered glucocorticoids. Cushing's syndrome is rarely an admitting diagnosis to critical care but is a disorder that can seriously affect recovery from coexisting illnesses if not treated. Aldosteronism, although rare, will often be diagnosed after admission to a critical care unit for management of troublesome hypertension, hypokalemia, congestive heart failure, and various dysrhythmias. Suspicion of the diagnosis should always arise when these manifestations occur, particularly when hypokalemia is refractory to potassium supplementation. Without timely diagnosis and treatment, these patients will succumb to lethal dysrhythmias.     

Cushing's syndrome due to primary multinodular corticotrope hyperplasia

In this report, a case of Cushing's syndrome due to primary multinodular corticotrope hyperplasia is described. The patient had typical features of Cushing's syndrome and dynamic pituitary-adrenal testing, which suggested an ectopic adrenocorticotropic hormone (ACTH) syndrome. Results of petrosal sinus catheterization indicated that the pituitary gland was the source of excess ACTH. Total hypophysectomy resulted in complete remission of Cushing's syndrome. Light microscopic and immunohistochemical studies revealed multinodular corticotrope hyperplasia. Plasma corticotropin releasing hormone (CRH) was undetectable, and computed tomography of the chest and abdomen disclosed no neoplastic source of CRH. We speculate that either an abnormality in hypothalamic CRH secretion or corticotrope hypersensitivity to CRH might have been responsible for Cushing's syndrome in this patient.     

Sarcoidosis emerging after adrenalectomy for Cushing's syndrome

Cushing's syndrome is characterised by circulating steroid excess; the mainstay of treatment of systemic sarcoidosis is steroid therapy. We describe a case of sarcoidosis emerging after treatment for Cushing's syndrome.     

Fatal pulmonary thromboembolism after successful transsphenoidal hypophysectomy for Cushing's disease

We have reported the case of a 30-year-old woman with Cushing's disease who died of massive pulmonary thromboembolism 5 weeks after successful transsphenoidal hypophysectomy. Glucocorticoid excess appears to cause a hypercoagulable state, and consideration of this thromboembolic propensity and its potential duration after cure is indicated in all patients with Cushing's syndrome during the perioperative period. At the present time, we recommend the routine perioperative use of intermittent pneumatic compression in all patients with Cushing's disease or Cushing's syndrome.     

Cushing's disease: clinical manifestations and diagnostic evaluation

The most common endogenous cause of Cushing's syndrome is Cushing's disease. Frequent clinical findings include weight gain, truncal obesity, striae, hypertension, glucose intolerance and infections. Cranial nerve II may be affected by enlarging pituitary adenomas in Cushing's disease; cranial nerves III, IV and VI may also be affected. The evaluation of patients with suspected Cushing's disease and syndrome requires an understanding of the proper use and limitations of the tests commonly included in the diagnostic work-up. The best screening test for Cushing's syndrome is a 24-hour urine collection with analysis for urinary free cortisol excretion. Low-dose and high-dose dexamethasone suppression tests, corticotropin assays, a corticotropin-releasing hormone stimulation test and inferior petrosal sinus catheterization may be required for a definitive diagnosis. Magnetic resonance imaging is useful in localizing the lesion. Surgical removal of the lesion by a transphenoidal approach is usually successful, but long-term follow-up is required. Some patients require lifetime glucocorticoid replacement therapy.