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Multisystem Processes & Disorders


Diagnosis and reasoning

This middle aged woman has presented with a classical, almost florid cushingoid phenotype; Cushing's syndrome (CS) immediately leaps to mind.


Exogenous steroid administration is the most common cause for this presentation, and should be considered first; however, this patient's history is negative in this respect.


Thus, it is rational to screen her for hypercortisolism via a Low-Dose Dexamethasone Suppression Test (LD-DST); this is found to be elevated.


The LD-DST results should be reconfirmed, either by repeating the investigation or via a different screening test, such as a 24 hour Urinary Free Cortisol (UFC) assay. This too is elevated, and thus, CS can indeed be considered to be present.


While hypercortisolism can be caused by exogenous causes such as chronic alcoholism or depression ("pseudocushing syndrome"), there is no history suggestive in this respect; furthermore, these patients rarely present in such a florid manner.


Thus, endogenous CS is a real possibility; determini

ng if the hypercortisolism is ACTH-independent or dependent should be the next step. While the hyperpigmentation seen here is suggestive of the latter, this is by no means definite.


The above can be confirmed by estimation of ACTH levels on two separate occasions, with the persistently elevated values seen here confirming the clinical suspicion of an ACTH-dependent process; this is most often secondary to a pituitary tumor.


Neuroimaging should follow; a gadolinium-enhanced MRI reveals an 8mm mass suggestive of a pituitary microadenoma, showing the diagnosis to be Cushing's Disease (CD).


Note that the latest recommendations indicate that any pituitary mass >6mm on MRI provides a definitive diagnosis for pituitary adenoma, with further imaging being unnecessary.


Trans-sphenoidal surgery will be curative and should be arranged as early as is feasible. Prophylactic low-dose heparin should be commenced beforehand, as high cortisol levels predispose to hypercoagulability.


While she does show impaired glucose tolerance secondary to the hypercortisolism, this will resolve after surgery; Metformin would only be indicated if she continues to exhibit elevated fasting glucose levels afterward.


In addition, while hypercortisolism is associated with decreased bone density and osteoporosis, current guidelines recommend that bisphosphonate therapy should only be commenced following calculation of fracture risk (FRAX scores).

Discussion

Cushing's disease is a rare disorder characterized by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, secondary to a benign, slow-growing microadenoma; it is the most common endogenous cause of Cushing's syndrome (CS).


The incidence is estimated to be 1 to 3 cases per million per year, with a prevalence of about 40 cases per million. The condition peaks in adults in the 3rd or 4th decade, with a female to male ratio of approximately 3:1.


While most cases are sporadic, some individuals may develop Cushing's disease due to an inherited tendency to develop endocrine gland tumors, e.g. in multiple endocrine neoplasia type I (MEN-I), or familial isolated pituitary adenomas (FIPA).


Note that in normal persons, ACTH is released from the pituitary in response to corticotropin-releasing hormone (CRH) from the hypothalamus. The resulting increased levels of cortisol cause a negative feedback response, resulting in reduced CRH production, and thus a reduction in the release of ACTH.


In Cushing's disease, however, the excess plasma ACTH levels cause excessive cortisol production. The hypothalamus will respond by producing less CRH, but because the tumor is producing ACTH independently, the negative feedback mechanism to the pituitary is lost.


Well recognized symptoms of Cushing's disease include obesity (usually central); fatty deposits, especially in the face ("moon" face), and in the high upper back (buffalo hump); and violaceous striae on the breasts, arms, abdomen, and thighs.


Other common symptoms are thin skin that bruises easily, infections, wounds which are slow to heal, acne, fatigue, muscle weakness, glucose intolerance, polyuria, polydipsia, hypertension, headache, cognitive dysfunction, anxiety, irritability, and depression.


Most patients also develop metabolic syndrome, which increases the risk of cardiovascular disease. Hypercortisolism also causes suppression of TSH and impaired conversion of thyroxine (T4) to trioiodothyronine (T3). Osteoporosis and pathological fractures may also occur.


Furthermore, reproductive function is often affected in Cushing's disease. Women may notice extra facial and body hair as well as oligomennorhoea or anovulation. Men may have hypogonadotropic hypogonadism and develop erectile dysfunction, loss of libido, or decreased fertility.


Symptoms may occur due to the space-occupying effect of the pituitary adenoma itself; these include headache, visual field defects (due to involvment of optic chiasm), and rarely, lesions of the cranial nerves 3,4, and 6, following involvement of the cavernous sinus.


Children with Cushing's disease are usually obese and have a slower rate of growth.


Note that the severity of symptoms is based on the degree of cortisol excess, with mild to moderate hypercortisolism resulting in a milder phenotype, with glucose intolerance, dyslipidemia, metabolic bone disease, and weight gain. As cortisol levels increase, more prominent features such as striae, supraclavicular fat pads, and proximal muscle weakness develop.


To diagnose Cushing's disease, one must first confirm the presence of hypercortisolism; this can be established by the low dose dexamethasone suppression (DST), 24hr urinary free cortisol (UFC), or midnight serum cortisol (MSC) tests (with at least two of these usually performed).


Once hypersecretion of cortisol is confirmed, the next step is to confirm that the pathologic state is ACTH-dependent by measuring late-afternoon ACTH levels; values >10 pg/mL are suggestive in this regard. Note that positive results should be re-confirmed by a repeat test.


Where the above test is indeterminate, the CRH stimulation test can be performed; here, 1 μg/kg of CRH is administered intravenously, and ACTH and cortisol levels measured before and after injection. A ≥20% increase in cortisol from basal levels, or a ≥50% rise in ACTH levels from the base supports an ACTH-dependent lesion.


Note that the CRH stimulation test can be combined with prior dexamethasone suppression. This increases the sensitivity and specificity to almost 100%.


Once ACTH-dependency is established, a high-dose DST combined with cranial MRI studies will help localize the site of ACTH overproduction. Note that MRI results must be interpreted cautiously because small lesions may not be visualized.


Cranial CT is not an acceptable substitute for MRI, because these only identify about 50% of pituitary lesions.


If the results of the workup to this point are equivocal, inferior petrosal sinus sampling is indicated; this is considered the gold standard for definitive diagnosis of ACTH-dependent lesions. While expensive and invasive, morbidity rates are low in experienced centers


Transphenoidal removal of the tumor is the treatment of choice for Cushing's disease. Reduction of cortisol levels within days to weeks afterwards signifies success.


Note that most patients will experience a hypoadrenal state post-surgically; this may last for months, during which glucocorticoid replacement therapy may be necessary. Long-term follow-up to monitor for signs and symptoms of tumor recurrence is also essential.


Pituitary irradiation is a good tool to induce remission if symptoms reoccur, and is successful in about 50% of patients who deteriorate after surgery; failure may necessitate total bilateral adrenalectomy to control symptoms.


Ketoconazole, metyrapone, and etomidate inhibit adrenal steroid biosynthesis and can be used pre-operatively to reduce the clinical effects of hypercortisolism.


Other medical therapies include glucocorticoid receptor antagonists like mifepristone, and ACTH-lowering agents such as cabergoline and temozolomide.


Left untreated, patients with Cushing's disease experience considerable morbidity and mortality due to cardiovascular complications, muscle loss and weakness, high blood pressure, increased risk of thromboembolism due to hypercoagulable states, infections, mass effects by the pituitary tumor, and kidney stones.


Even following treatment, there is evidence that some the effects of hypercortisolism may continue to exist.

Take home messages

1. Cushing's disease is the most common endogenous cause of Cushing's syndrome.

2. Depending on the degree of hypercortisolism, the presenting phenotype can range from metabolic syndrome alone, to florid classical signs and symptoms.

3. Confirmation of the diagnosis requires establishment of ACTH-dependent hypercortisolism, and detection of a pituitary tumor.

4. Transphenoidal removal of the pituitary adenoma is curative in most cases. However, patients may experience short to intermediate term hypoadrenalism post-surgery.

References

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