- Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD more...
These illnesses include the following:
In these instances, this phenotype is called a pseudo-Cushing syndrome (PCS). Particular type of hypercortisolism caused by the above conditions, named functional hypercortisolism, is caused by chronic activation of hypothalamic-pituitary-adrenal (HPA) axis. It is usually mild and disappears when the underlying disorder is resolved.
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. Most of the abnormalities disappeared after 1-3 weeks of alcohol abstinence. Similar abnormalities have also been described in patients with depression.[4, 5, 6, 7, 8] Abnormal cortisol secretion usually disappears after remission of depression.
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. Hypercortisolemia is evident in approximately 50% of depressed patients and is particularly characteristic of the melancholic subtype. In a study of 190 patients with type 2 diabetes, 63 subjects (33%) had high cortisol concentations.
PCS can occur at any age; it can develop in infants exposed to alcohol in breast milk.
Causes and Complications
The mechanism behind PCS is unclear. Most evidence suggests central stimulation of a corticotropin-releasing hormone (CRH), either at the hypothalamic or suprahypothalamic level.[2, 14] Rats given 15% alcohol for 3 months showed a greater number of corticotropin-producing cells with increased secretory activity.
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 HPA axis hyperactivity is presumed for depressed patients. 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 pathophysiological mechanisms to the other causes of PCS.[17, 18] In obesity, postulated machanism of hyperactivation of HPA axis include hyper-responsiveness to different neuropeptides, stress events, dietary factors, or to the augmented peripheral metabolic clearance of cortisol.[19, 20] 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.[21, 22]
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 which plasma cortisol is not elevated.
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 CS. With abstinence from alcohol, all biochemical abnormalities return to their reference ranges. 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 test results may be identical to those in Cushing disease, clinicians should be familiar with this disorder to avoid misdiagnosis and inappropriate therapy.
History and Physical Examination
Some patients have only a few symptoms or no physical evidence of glucocorticoid excess. In others, the features of full-blown Cushing syndrome may be seen, including the following:
Plethoric moon face
Supraclavicular fat pads
Hirsutism in women
Thin skin with easy bruising and wide, purplish striae
CS may be difficult to distinguish from PCS based on physical findings or urinary glucocorticoid excretion. The 24-hour urinary-free cortisol excretion level is moderately increased, usually by no more than 2-3 times the reference range. So although urinary free cortisol (UFC) estimations exhibit relatively high sensitivity, they are associated with a relatively low specificity.
Plasma free cortisol is of limited value in the differential diagnosis of hypercortisolism.
The overnight dexamethasone suppression test (DST) involves the oral administration of 0.5–2.0 mg dexamethasone (most commonly 1 mg) at 2300 h, after which a plasma cortisol sample is obtained at 8:00 am the next morning. Suppression of the postdexamethasone plasma cortisol to 50 nmol/L (1.8 μg/dL) or less effectively excludes Cushing syndrome or PCS.[29, 30, 31]
A midnight cortisol level of less than 7.5 µg/dL has 96% sensitivity and 100% specificity in differentiating pseudo-Cushing from true CS. Measurement of late-night salivary cortisol concentrations is increasingly used as a screening test in suspected CS.
A cortisol midnight:morning ratio of more than 0.67 is highly suggestive of Cushing disease (positive predictive value [PPV] 100% and negative predictive value [NPV] 73%).
Yanovski et al suggest the CRH test after administration of low-dose dexamethasone (2 mg/d for 2 days) 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. Revised cortisol threshold of more than 55 nmol/L (2 μg/dL) and 87 nmol/L (3.15 μg/dL) have been proposed in attempt to increase diagnostic accuracy.
Use of the DST and midnight plasma cortisol measurement is recommended as first-line diagnostic tests in equivocal cases.
Prostate-specific antigen (PSA) gene expression and protein production has 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).
Serum transaminase levels are usually elevated, suggesting alcohol-induced hepatitis. The blood alcohol level is useful only at the time of admission.
Treatment & Management
Appropriate medical care depends on the patient’s reason for seeking help. Evaluate depressed patients for suicidal ideations and treat 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 to the patient and 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.
Consult endocrinologists for patients with features of florid Cushing syndrome. Consult psychiatrists for treatment of depression or alcohol abuse.
Most patients with chronic alcoholism have varying degrees of malnutrition.
No specific medications are required except those for alcohol withdrawal or depression, which are beyond the scope of this article.
The physician should stress the deleterious effects of the disorder on health status and lifespan.
Obtain an overnight dexamethasone suppression test or 24-hour urinary cortisol in 6-8 weeks. Monitor patients until all test results are within reference ranges.
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