Pseudo-Cushing Syndrome

Provoked
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Diagnosis and reasoning

This lady has presented with central obesity in association with dysplidemia (i.e. low HDL levels) and hypertension; in other words, she has metabolic syndrome. Given the epidemic of obesity overtaking modern society, this is not an uncommon presentation in primary care; in most cases, the only treatment necessary is management of the co-morbidities, along with a program to achieve weight loss. However, in a small but important few patients, a serious underlying pathology may exist; the trick lies in determining which of these individuals requires a further careful evaluation. Note that this particular lady does have several concerning findings: weight gain over a relatively short period of time (despite an unchanged diet), recent-onset menstrual irregularities, and most importantly, a Cushingoid body habitus. Thus, Cushing syndrome, and pseudo-Cushing syndrome secondary to chronic alcoholism are prominent considerations. Hypothyroidism should also be kept in mind, as these patients can manifest similar clinical findings; it is also far more common. Acromegaly is yet another differential. Note that while polycystic ovarian syndrome (PCOS) can also present in this manner, such patients tend seek medical advice at a younger age, and typically have a longstanding history of menstrual disturbances. Another important possibility is exogenous glucocorticoid administration; however, this is ruled out by the negative drug history. Her thyroid profile reveals normal TSH, T3, and T4 levels, ruling out hypothyroidism; growth hormone levels are also normal, ruling out acromegaly. However, a low-dose dexamethasone suppression test (DST) reveals elevated morning plasma cortisol levels; note that it is mandatory to confirm this finding via a different test. A subsequent urinary free cortisol (UFC) assay is also elevated, definitively establishing the presence of hypercortisolism, and essentially pointing us towards either Cushing syndrome or pseudo-Cushing syndrome. There is considerable controversy on the further workup of such patients; while investigations such as late-night salivary cortisol levels, and the dexamethasone/corticotropin releasing hormone test can be used for differentiation, false positive and negative results are common. Another approach is to treat her alcoholism, and then see if her biochemical and clinical parameters normalize over time; a positive response would confirm the presence of pseudo-Cushing syndrome, while also avoiding expensive investigations. Note also that transsphenoidal surgery is only indicated in patients diagnosed with Cushing disease; pharmacotherapy with Somatostatin analogues and Ketoconazole is best avoided right now. The patient in this case scenario received therapy to combat her alcoholism; several months after cessation of alcohol consumption, a repeat low-dose DST test was found to be negative. Thus, pseudo-Cushing syndrome was considered to be the final diagnosis.


Discussion

Pseudo-Cushing syndrome is characterized by the presence of signs, symptoms and laboratory abnormalities similar to those of Cushing's syndrome, but with the hypercortisolism being due to an alternate pathology such as chronic alcoholism or depression. Detailed statistics are unavailable, but studies have shown that the condition may occur in as many as 75% of alcoholics, and in upto 80% of patients with major depression. While the exact pathophysiology of pseudo-Cushing syndrome is unclear, it has been postulated that central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis plays a key role; in alcoholics, hepatic dysfunction may also contribute, as cortisol metabolism predominantly takes place in the liver. The condition was first identified in association with chronic alcoholism; it is also encountered in patients with alcohol withdrawal syndrome, polycystic ovary syndrome, poorly controlled diabetes mellitus, and visceral obesity. Pseudo-Cushing syndrome is also associated with psychiatric disorders such as major depression, anorexia nervosa, panic disorder, and chronic anxiety; furthermore, it may be caused by the physiological response to surgery, severe illness, and marked emotional and physical stress. The signs and symptoms of the condition are essentially the same as those of Cushing syndrome, although the presentation is often less florid; nevertheless, it is impossible to differentiate between these two entities via clinical findings alone. The first step in the diagnosis of pseudo-Cushing syndrome should be exclusion of alternate causes for the Cushingoid phenotype - particularly glucocorticoid excess, and other endocrinopathies. Following this, the presence of hypercortisolism should be established; this can be performed via any of the following 4 screening tests: - Urinary Free Cortisol - Late-night salivary cortisol - The 1-mg overnight dexamethasone suppression test (DST) - The longer low-dose DST (2 mg/day for 48 h) Note that a positive result in one test should be confirmed by performing a different test. Once hypercortisolism has been confirmed, if a likely etiology for pseudo-Cushing syndrome exists, one option is to treat it, and then see if the hypercortisolic state resolves afterwards. This precludes the need for further tests. Where further investigation is considered necessary, the key goal is to differentiate pseudo-Cushing syndrome from Cushing syndrome. Tests which can be used in this regard include midnight serum cortisol levels (MserC), late-night salivary cortisol levels (LNSC), the dexamethasone-CRH (Dex-CRH) test, and assessment of the circadian rhythm of serum cortisol levels. Note that the MserC, LNSC, and circadian rhythm tests are based on the assumption that patients with Cushing syndrome lose the normal diurnal pattern of cortisol secretion and demonstrate persistently elevated cortisol levels throughout the day; this is as opposed to individuals with pseudo-Cushing syndrome, in whom the rhythm is preserved (although absolute levels may be slightly elevated). The Dex–CRH test is based on the fact that following suppression with dexamethasone, patients with Cushing disease are able to mount a pituitary–adrenal response to administration of exogenous CRH; conversely, individuals with pseudo-Cushing syndrome are usually unresponsive to CRH stimulation. It is important to appreciate that there is considerable debate about the optimal cut-off values for the above tests; thus, depending on the ranges used, both false positives and false negative results are not uncommon. In general, treatment of the underlying etiology results in complete resolution of pseudo-Cushing syndrome. Thus, chronic alcoholics should be aided to cease alcohol consumption; obese patients should be encouraged to lose weight, and individuals with psychiatric disorders should receive appropriate treatment. Follow-up testing using the low dose-DST should be performed to confirm resolution of the hypercortisolic state. Note that in patients with pseudo-Cushing syndrome secondary to alcoholism, studies have shown that the HPA axis returns to normal following abstinence for 2 to 4 months; with other etiologies, the duration of resolution may potentially vary.


Take home messages

  1. Pseudo-Cushing Syndrome and Cushing Syndrome can present with essentially the same clinical findings.
  2. In a patient with hypercortisolism, the presence of an associated pathology such as chronic alcoholism or depression should raise suspicion of pseudo-Cushing Syndrome.
  3. While several tests exist to differentiate between pseudo-Cushing Syndrome and Cushing syndrome, false positives and negatives are common due to controversy about cut-off values.
  4. Treatment of the underlying condition giving rise to hypercortisolism usually results in spontaneous resolution of pseudo-Cushing Syndrome.

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