Overview
Pseudo-Cushing syndrome (PCS), or as it has been more recently renamed "non-neoplastic hypercortisolism," [1, 2] is a group of conditions associated with clinical and biochemical features of Cushing syndrome, but the hypercortisolemia is usually secondary to other factors. [3] It is very important to rule out these conditions before making a diagnosis of Cushing syndrome, as it may subject the patient to unnecessary investigations and possible harmful interventions. [4] Some frequently occurring illnesses can induce a phenotype that largely overlaps with Cushing syndrome and is accompanied by hypercortisolism. [5]
These illnesses include the following:
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Physical stress
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Eating disorders
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Uncontrolled diabetes
A particular type of hypercortisolism presenting during the above conditions, named functional hypercortisolism, is caused by chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis. It is usually mild and disappears when the underlying disorder is resolved. [5]
PCS initially was described by Smalls et al, in 1976; the investigators reported 3 cases of alcoholic patients who had the physical and biochemical abnormalities of Cushing syndrome. [7] Most of the abnormalities disappeared after 1-3 weeks of alcohol abstinence. Similar abnormalities have also been described in patients with severe endogenous depression. [8, 9, 10, 11, 12] Abnormal cortisol secretion usually disappears after remission of depression. [13]
Epidemiology
In a study of 56 men in an alcohol detoxification unit, 18% had nonsuppressible serum cortisol levels. Many of these patients lacked the physical stigmata of Cushing syndrome, and some biochemical abnormalities resolved in a few days. [14] Hypercortisolemia is evident in approximately 50% of depressed patients and is particularly characteristic in the melancholic subtype. [15] In a study of 190 patients with type 2 diabetes, 63 subjects (33%) had high cortisol concentrations. [16]
PCS can occur at any age; it can even develop in infants exposed to alcohol in breast milk. [17]
Causes and Complications
Etiology
The mechanism behind PCS is unclear. Most evidence suggests central stimulation of a corticotropin-releasing hormone (CRH), either at the hypothalamic or suprahypothalamic level. [6, 18] Rats given 15% alcohol for 3 months showed a greater number of corticotropin-producing cells with increased secretory activity. [19] A two-hit hypothesis has been considered for alcohol induced PCS. In alcoholic chronic liver disease, there is an increased cortisol secretion rate with impaired cortisol metabolism, instead of impaired cortisol secretion, and that is actually leading to increased cortisol levels. [20] Some studies suggest that there is a direct stimulatory effect of alcohol in the cortisol secretion. Also AVP levels are elevated in patients with decompensated liver disease and may stimulate HPA axis. [3] The reason that some alcoholic patients develop PCS and others do not is unknown. Attempts to find a genetic predisposition have been unsuccessful.
Similar mechanism of HPA axis hyperactivity is presumed for depressed patients. [21] Anorexia nervosa is associated with CRH-driven hyperactivity of the HPA axis due to starvation and therefore represents a model of functional hypercortisolism that shares similar pathophysiologic mechanisms as seen in other causes of PCS. [22, 23] In obesity, postulated mechanisms of hyperactivation of HPA axis include hyper-responsiveness to different neuropeptides, stress events, dietary factors, as well as a stimulation caused by augmented peripheral metabolism and clearance of cortisol by reduced conversion of cortisone to cortisol by 11β-HSD1 and increased conversion of cortisol to 5α-reduced derivatives. [24, 25, 26] In PCOS, activation of the HPA axis is secondary to increased cortisol metabolism due to augmented 5α- and 5β-reductase and decreased 11β-HSD1 activity. [27, 28]
Sutinen et al reported that highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophy and hypertriglyceridemia, which resembles Cushing syndrome, but in this case plasma cortisol is not elevated. [29]
Complications
Disorders leading to PCS usually are associated with systemic complications, mainly of a metabolic/cardiovascular nature (eg, hypertension, insulin resistance, diabetes mellitus, coronary heart disease, osteoporosis), which are also present in Cushing syndrome. [5] With abstinence from alcohol, all biochemical abnormalities return to their reference ranges. [6] This may indicate that long periods of excessive alcohol intake are required for the full syndrome to develop. Relapse is frequent in patients with chronic alcoholism.
Because of the high prevalence of alcohol abuse and the possibility that the test results in these cases may be identical to those in Cushing disease, clinicians should be familiar with this disorder to avoid misdiagnosis and inappropriate therapy. [30]
History and Physical Examination
History
The above causes should be excluded before considering diagnosis of Cushing syndrome. The most important part of the history is the extent and duration of alcohol abuse. The condition is suspected usually in patients with an ongoing history of heavy alcohol intake and biochemical or clinical evidence of alcoholic liver disease. [14] Similar factors should be assessed with regard to depression. [8, 9, 10, 11, 12] . Of note, it should also be kept in mind that many patients with Cushing syndrome are depressed.
Physical examination
Some patients have only a few symptoms or no physical evidence of glucocorticoid excess. Others may present with the features of full-blown Cushing syndrome that include the following:
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Truncal obesity
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Plethoric moon face
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Buffalo hump
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Supraclavicular fat pads
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Hirsutism in women
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Thin skin with easy bruising and wide, purplish striae
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Myopathy
Laboratory Studies
With many overlapping clinical and biochemical features, it becomes a diagnostic challenge to distinguish PCS from Cushing disease, especially in a milder form.
Cortisol
Cushing syndrome may be difficult to distinguish from PCS based on physical findings or urinary cortisol excretion. [31] The 24-hour urinary-free cortisol excretion level is moderately increased, most commonly no more than 2-3 times the reference range. [32] Also, there has been a case report of fenofibrate causing false elevation of urinary free cortisol by interfering with high-performance liquid chromatography. [33] Overall, although urinary free cortisol (UFC) estimations exhibit relatively high sensitivity, they are associated with a relatively low specificity. [34]
Plasma free cortisol is of limited value in the differential diagnosis of hypercortisolism. [35]
The overnight dexamethasone suppression test (DST) involves the oral administration of 0.5–2.0 mg dexamethasone (most commonly 1 mg) at 23:00 hours to midnight, after which a fasting plasma cortisol sample is obtained at 8:00 am the next morning. Suppression of the post-dexamethasone plasma cortisol to 50 nmol/L (1.8 μg/dL) or less, effectively excludes Cushing syndrome or PCS. [36, 37, 38] Patients with PCS do exhibit resistance to dexamethasone suppression, so it is less reliable in these patients.
A midnight serum cortisol level of less than 7.5 µg/dL has 96% sensitivity and 100% specificity in differentiating pseudo-Cushing from true CS. [39] Measurement of late-night salivary cortisol concentrations is increasingly used as a screening test in suspected CS. [40] One study showed that a threshold value of 9.3 nmol/L (0.33 mcg/dL) could be used to differentiate between CS and PCS with a PPV of 94% and NPV of 100%. [41] The advantage of salivary cortisol is that in can be done as outpatient.
A cortisol midnight to morning ratio of more than 0.67 is highly suggestive of Cushing disease (positive predictive value [PPV] 100% and negative predictive value [NPV] 73%). [41]
Yanovski et al suggest that a CRH test after administration of low-dose dexamethasone (2 mg/d for 2 days) can help to separate these two syndromes: a serum cortisol level above 38 nmol/L (1.4 µg/dL) 15 min after the injection of CRH was found in all persons with true Cushing syndrome. [42] Revised cortisol threshold of more than 55 nmol/L (2 μg/dL) [43] and 87 nmol/L (3.15 μg/dL) [41] have been proposed in an attempt to increase diagnostic accuracy with a PPV of 100% and NPV of 100%
There have been case reports of using insulin induced hypoglycemia test to differentiate PCS in patients with depression, who show an appropriate rise in serum ACTH and cortisol level with hypoglycemia [37, 44] , as well as use of opioid agonist loperamide causing suppression of ACTH and cortisol secretion in normal patients as compared to Cushing syndrome. [45] However, all of these tests are very rarely used in clinical practice.
IV desmopressin has been shown to increase serum cortisol as well as ACTH in patients with Cushing syndrome when compared to healthy individuals as well as patients with depression. [46] . Another study also showed that both the dexamethasone-CRH test and the desmopressin test had excellent sensitivity of 96.6% and specificity of 100% in distinguishing patients with PCS and CS. [47] However, desmopressin being less expensive, and more readily available, makes the desmopressin test the most attractive option for the diagnosis. Consensus guidelines from the Pituitary Society note that because of the wider availability of the desmopressin test, this is actually increasingly replacing the CRH stimulation test for the diagnosis of PCS. [48]
Distinguishing patients with alcohol-induced PCS from CS may sometimes be challenging. A detectable blood alcohol level will be of great use for discrimination from Cushing syndrome. Admission of the patient to an acute investigation ward may allow closer observation, and in patients with alcohol-induced PCS, the sleeping midnight plasma cortisol value has been shown to become undetectable within 5 days of hospitalization. [49]
Use of the DST and midnight plasma cortisol measurement are recommended as first-line diagnostic tests in equivocal cases. [43]
Other
Prostate-specific antigen (PSA) gene expression and protein production have been found to be upregulated by steroid hormones, such as androgens, glucocorticoids, mineral corticoids, and progestins. Serum total PSA concentrations appear to be higher in female patients with Cushing disease than in healthy women. Coiro et al reported significantly higher serum total PSA levels in women with Cushing disease than in subjects with PCS and normal controls (24 pg/mL vs 5 pg/mL respectively). [50]
Serum transaminase levels are usually elevated, suggesting alcohol-induced hepatitis.
Treatment and Management
Appropriate medical care depends on the patient’s reason for seeking help.
Depressed patients should be evaluated for suicidal ideations and treated appropriately.
Because PCS may be caused by chronic ingestion of alcohol, alcohol withdrawal syndrome is likely to occur and should be anticipated and prevented. Acute withdrawal of alcohol can cause delirium tremens in a patient with chronic alcoholism, which can lead to injury of the patient as well as others.
Patients with alcohol-induced PCS usually require treatment in an alcohol detoxification and rehabilitation unit.
Treatment of the underlying disorder usually leads to resolution of PCS.
Consultations
Consult endocrinologists for patients with features of florid Cushing syndrome. Consult psychiatrists for treatment of depression or alcohol abuse.
Diet
Most patients with chronic alcoholism have varying degrees of malnutrition and would benefit from nutritional consult.
Medication
No specific medications are required except those for alcohol withdrawal or depression, which are beyond the scope of this article.
Patient education
The physician should stress the deleterious effects of the disorder on health status and lifespan.
Follow-up
Obtain an overnight dexamethasone suppression test or 24-hour urinary cortisol in 6-8 weeks. Monitor patients until all test results are within normal reference ranges.
