Hypercortisolism : Cushing's syndrome and Cushing's disease
Introduction
Cushing's syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid, by excessive activation of glucocorticoid receptor.
The most common cause is iatrogenic, due to prolong administration of synthetic glucocorticoids such as prednisolone.
About 40% of cases are due to Cushing "disease," by which is meant the manifestations of hypercortisolism due to ACTH hypersecretion by the pituitary.
About 15% of cases are due to ACTH from a source that cannot be initially located.
About 30% of cases are due to excessive autonomous secretion of cortisol by the adrenals—independently of ACTH, serum levels of which are usually low.
Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal.
Etiology
ACTH-dependent
Pituitary adenoma secreting ACTH (i.e. Cushing's disease)
Ectopic ACTH syndrome (e.g. bronchial carcinoid, small-cell lung carcinoma, pancreatic neuro-endocrine tumour)
latrogenic (ACTH therapy)
Non-ACTH-dependent
Iatrogenic (chronic glucocorticoid therapy, e.g. for asthma)
Adrenal adenoma
Adrenal carcinoma
Pseudo-Cushing's syndrome, i.e. cortisol excess as part of another illness
Alcohol excess (biochemical and clinical features)
Major depressive illness (biochemical features only, some clinical overlap)
Primary obesity
Clinical features
Hypercortisolism promotes the deposition of adipose tissue in characteristic sites, notably the upper face (producing the typical "moon" facies), the interscapular area (producing the "buffalo hump"), supraclavicular fat pads, and the mesenteric bed (producing "truncal" obesity)
Catabolic responses in peripheral supportive tissue causes muscle weakness and fatigability, osteoporosis,
Broad violaceous cutaneous striae and easy bruisability (secondary to weakening and rupture of collagen fibers in the dermis).
Osteoporosis may cause collapse of vertebral bodies and pathologic fractures of other bones.
Increased hepatic gluconeogenesis and insulin resistance can cause impaired glucose tolerance.
Hypertension is common, and emotional changes may be profound, ranging from irritability and emotional lability to severe depression, confusion, or even frank psychosis.
The face appears plethoric, even in the absence of any increase in red blood cell concentration.
Pigmentation occurs only with ACTH-dependent causes.
In women, increased levels of adrenal androgens can cause acne, hirsutism, and oligomenorrhea or amenorrhea.
Some signs and symptoms in patients with hypercortisolism—i.e., obesity, hypertension, osteoporosis, and diabetes—are nonspecific and therefore are less helpful in diagnosing the condition.
On the other hand, easy bruising, typical striae, myopathy, and virilizing signs (although less frequent) are, if present, more suggestive of Cushing's syndrome.
A cushingoid appearance can be caused by excess alcohol consumption (pseudo-Cushing's syndrome) - the pathophysiology is poorly understood.
Impaired glucose tolerance or frank diabetes are common, especially in the ectopic ACTH syndrome.
Hypokalaemia due to the mineralocorticoid activity of cortisol is common with ectopic ACTH secretion.
Clinical features in decending order of frequency
Typical habitus (centripetal obesity)a 97%
Increased body weight 94%
Fatigability and weakness 87%
Hypertension (blood pressure > 150/90) 82%
Hirsutisma 80%
Amenorrhea 77%
Broad violaceous cutaneous striaea 67%
Personality changes 66%
Ecchymosesa 65%
Proximal myopathya 62%
Edema 62%
Polyuria, polydipsia 23%
Hypertrophy of clitoris 19%
Investigations
Investigations to confirm the diagnosis include:
48-hour low-dose dexamethasone test. Normal individuals suppress plasma cortisol to < 50 nmol/L.
Patients with Cushing's syndrome fail to show complete suppression of plasma cortisol levels (although levels may fall substantially in a few cases).
This test is highly sensitive (> 97%). The overnight dexamethasone test is slightly simpler, but has a higher false-positive rate.
The hypothalamic-pituitary adrenal axis may escape from supression by Dexamethasone if more potent influence such as psychological stress supervenes.
24-hour urinary free cortisol measurements.
This is simple, but less reliable - repeatedly normal values (corrected for body mass) render the diagnosis most unlikely, but some patients with Cushing's have normal values on some collections (approximately 10%).
Circadian rhythm.
After 48 hours in hospital, cortisol samples are taken at 0900 h and 2400 h (without warning the patient).
Normal subjects show a pronounced circadian variation;
Those with Cushing's syndrome have high midnight cortisol levels (> 100 nmol/L), though the 0900 h value may be normal.
Other tests.
There are frequent exceptions to the classic responses to diagnostic tests in Cushing's syndrome.
If any clinical suspicion of Cushing's remains after preliminary tests then specialist investigations are still indicated, these may include insulin stress test, desmopressin stimulation test and CRH tests.
Differential diagnosis of the cause:
This can be extremely difficult since all causes can result in clinically identical Cushing's syndrome.
The classical ectopic ACTH syndrome is distinguished by a short history, pigmentation and weight loss, unprovoked hypokalaemia, clinical or chemical diabetes and plasma ACTH levels above 200 ng/L.
But many ectopic tumours are benign and mimic pituitary disease closely both clinically and biochemically.
Biochemical and radiological procedures for diagnosis include:
Adrenal CT or MRI scan.
Adrenal adenomas and carcinomas causing Cushing's syndrome are relatively large and always detectable by CT scan.
Carcinomas are distinguished by large size, irregular outline and signs of infiltration or metastases.
Bilateral adrenal hyperplasia may be seen in ACTH-dependent causes or in ACTH-independent nodular hyperplasia.
Pituitary MRI.
A pituitary adenoma may be seen but the adenoma is often small and not visible in a significant proportion of cases.
Plasma potassium levels.
Hypokalaemia is common with ectopic ACTH secretion. (All diuretics must be stopped.)
High-dose dexamethasone test
Failure of significant plasma cortisol suppression suggests an ectopic source of ACTH or an adrenal tumour.
Plasma ACTH levels. Low or undetectable ACTH levels (< 10 ng/L) on two or more occasions are a reliable indicator of non-ACTH-dependent disease.
CRH test. An exaggerated ACTH and cortisol response to exogenous CRH suggests pituitary-dependent Cushing's disease, as ectopic sources rarely respond.
Chest X-ray is mandatory to look for a carcinoma of the bronchus or a bronchial carcinoid. Carcinoid lesions may be very small; if ectopic ACTH is suspected, whole-lung and mediastinal CT scanning should be performed.
Treatment
Untreated Cushing's syndrome has a 50% 5-year mortality.
Death result from hypertension, myocardial infarction, infection and heart failure.
Most patients are treated surgically with medical therapy given for a few weeks prior to operation.
The usual drug is metyrapone, an 11β-hydroxylase blocker, which is given in doses of 750 mg to 4 g daily in three to four divided doses.
Ketoconazole (200 mg three times daily) is also used and is synergistic with metyrapone.
Plasma cortisol should be monitored, aiming to reduce the mean level during the day to 150-300 nmol/L, equivalent to normal production rates.
Aminoglutethimide and trilostane (which reversibly inhibits 3β-hydroxysteroid dehydrogenase) are occasionally used.
Cushing's disease
Trans-sphenoidal surgery with selective removal of the adenoma is the treatment of choice.
Selective adenomectomy nearly always leaves the patient ACTH-deficient immediately postoperatively, and this is a good prognostic sign.
Overall, pituitary surgery results in remission in 75-80% of cases.
External pituitary irradiation alone is slow acting, only effective in 50-60% even after prolonged follow-up and mainly used after failed pituitary surgery.
Medical therapy to reduce ACTH (e.g. bromocriptine, cyproheptadine) is rarely effective.
Bilateral adrenalectomy is an effective last resort if other measures fail to control the disease.
This can be performed laparoscopically.
Adrenal tumours
Adrenal adenomas are removed via laparoscopy or a loin incision.
Adrenal carcinomas are resected if possible, the tumour bed irradiated and the patient given the adrenolytic drug mitotane.
Cytotoxic chemotherapy may retard disease progression in patients with metastases.
Ectopic ACTH syndrome
Localised tumours causing this syndrome (e.g. bronchial carcinoid) should be removed.
During treatment or palliation of non-resectable malignancies, it is important to reduce the severity of the Cushing's syndrome using medical therapy.
