Alcohol-induced pseudo-Cushing's Syndrome Research Articles

Induction of hepatic 11β‐hydroxysteroid dehydrogenase type 1 in patients with alcoholic liver disease

The alcohol-induced pseudo-Cushing's syndrome is an important differential diagnosis of hypercortisolism that is poorly understood. Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert hormonally active cortisol (F) and inactive cortisone (E). Previously we have shown higher urinary F:E metabolite ratios (a reflection of global 11beta-HSD activity) in patients with alcoholic liver disease (ALD) compared to patients with chronic liver disease (CLD) of other aetiologies, suggesting that the phenotype of alcoholic pseudo-Cushing's may relate to altered metabolism of F. We performed selective venous sampling of the hepatic, renal and peripheral veins measuring F and E concentrations (using in-house radioimmunoassay) in 20 patients with histologically confirmed ALD and 19 patients with CLD. Six patients who also had selective venous sampling for investigation of suspected hyperaldosteronism were used as 'normal' controls. There was a significant difference in the hepatic F gradient (mean +/- SEM) between groups, indicating increased F production in the liver in patients with ALD (34.5 +/- 21.7 nmol/l) compared to those with CLD (-21.0 +/- 18.5 nmol/l) (P < 0.05) and normals (-19.7 +/- 17.2 nmol/l) (P < 0.05). 11beta-HSD1 mRNA expression was increased fivefold in the ALD group compared with normal controls (P < 0.01). These results indicate significant induction of HSD11B1 gene expression and activity in patients with ALD during short- and long-term abstinence from alcohol. The mechanism is unknown but might be explained on the basis of alcohol-induced changes in intracellular redox potential or as a protective mechanism to limit liver inflammation and injury. Selective 11beta-HSD1 inhibitors may offer a novel therapeutic approach to treat alcoholic pseudo-Cushing's.

On the mechanism of alcohol-induced pseudo-Cushing's syndrome.

I. Introduction Cushing's syndrome is clinically characterized by truncal obesity, moon face, supraclavicular fat pads, buffalo hump, hirsutism, blue-red striae, easy bruisability, osteoporosis, hypertension, and proximal myopathy. Biochemically, impaired glucose tolerance and hypokalemic alkalosis can be present. Leukocytosis with lymphocytopenia and decreased numbers of eosinophils are often found. Hormonal testing shows an increased secretion of cortisol, which is not suppressed by the overnight dexamethasone test (1 mg). Depending on the etiology of the syndrome, decreased or increased secretion of ACTH is found. In patients with chronic alcohol abuse, clinical or biochemical features or both of Cushing's syndrome can be found. Because both the physical and the hormonal abnormalities disappear after discontinuation of alcohol this phenomenon was called alcohol-induced pseudo-Cushing's syndrome (1, 2). Alcohol-induced pseudo-Cushing's syndrome is indistinguishable from true Cushing's syndrome, although...

On the mechanism of alcohol-induced pseudo-Cushing's syndrome

On the mechanism of alcohol-induced pseudo-Cushing's syndrome

11 beta-Hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD), found predominantly in liver and kidney, is responsible for the shuttling of active cortisol to cortisone. A defect in this shuttle mechanism, e.g. after liquorice ingestion, results in an increase in the ratio of urinary cortisol [tetrahydrocortisol (THF)] to cortisone [tetrahydrocortisone (THE)] metabolites. The plasma cortisol half-life is prolonged, but concentrations remain normal because of a concomitant fall in cortisol production. Alcohol-induced pseudo-Cushing's syndrome is an ill defined cause of Cushing's syndrome. Because many of the documented cases have abnormal liver function tests, we have investigated whether abnormal hepatic 11 beta HSD activity may play a role in the pathogenesis of the condition. Fourteen patients with alcoholic (ALD) and 14 patients with non-alcoholic (CLD) chronic liver disease had marked deficiency of 11 beta HSD [5 alpha-THF + THF/THE: ALD, 1.94 +/- 0.38 (+/- SEM); CLD, 1.82 +/- 0.20] compared to controls (0.94 +/- 0.04; P < 0.01 and 0.001, respectively). In the CLD group, the daily cortisol production rate (as assessed by summation of principal cortisol metabolites) was reduced appropriately [median, 3,510; range, 1,101-8,940 micrograms/24 h; controls, 5,492 (range, 3,818-14,996) micrograms/24 h; P < 0.001], and normal 0900 h plasma cortisol and urinary free cortisol levels were maintained. However, in the ALD group, there was no concomitant fall in the cortisol production rate (sum of cortisol metabolites, 5,043 micrograms/24 h; range, 520-27,344). As a consequence, 0900 h plasma cortisol in the ALD group was significantly elevated (633 +/- 52 nmol/L) compared to values in the CLD group (487 +/- 48 nmol/L; P < 0.05) and controls (432 +/- 27 nmol/L; P < 0.001). Our findings of glucocorticoid excess in patients with chronic ALD may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism. The latter is mediated by defective hepatic 11 beta HSD activity; the former by either abnormal glucocorticoid feedback or stimulation of cortisol secretion at the level of the hypothalamus/pituitary.

Alcohol-induced pseudo-Cushing's syndrome

In 4 patients corticosteroid hypersecretion associated with excessive intake of alcohol led initially to an erroneous diagnosis of Cushing's syndrome. If diagnostic errors are to be avoided, a history of alcohol intake should always be sought in a patient in whom the diagnosis of Cushing's syndrome is entertained. The abnormalities of pseudo-Cushing's syndrome revert to normal on ethanol withdrawal.

Alcohol-induced pseudo-Cushing's disease: A study of prevalence with review of the literature

Alcohol-induced pseudo-Cushing's syndrome has been described in numerous case reports, yet the patients have been thoroughly evaluated in only a few cases and the prevalence of hypercortisolism in the alcoholic population is not known. We studied a group of 56 alcoholic men on admission to a detoxification ward using the overnight 1 mg dexamethasone suppression test as a screening test. Most (82%) had normal cortisol suppression, and of those who did not (18%), three of four who could be retested became normal within four days. A smaller group of 14 patients was evaluated with measurement of 24-hour urinary free cortisol, baseline plasma ACTH and serum cortisol measurements, and measurement of ACTH and cortisol after dexamethasone. One patient with sustained abnormal suppression of serum cortisol by dexamethasone (up to 18 days) also demonstrated a striking lack of suppression of plasma ACTH by dexamethasone, compared to the other alcoholics studied. The data obtained on this patient, as well as information obtained from published case reports, are consistent with the concept that alcohol-induced pseudo-Cushing's syndrome is a centrally mediated defect that occurs uncommonly in alcoholics.

Alcohol-induced pseudo-cushing's syndrome mimicking cushing's disease in a patient with an adrenal mass

Alcohol-induced pseudo-Cushing's syndrome is a disorder in which patients exhibit clinical and/or biochemical features similar to those in patients with Cushing's syndrome, but these features, related to alcohol abuse, may be transient and resolve during abstinence from alcohol. In most previous reports of alcohol-induced pseudo-Cushing's syndrome, detailed endocrinologic data supporting a diagnosis of Cushing's syndrome have been lacking. This report describes a patient with clinical features of Cushing's syndrome, increased plasma ACTH values, and elevated levels of basal urinary free cortisol and 17-hydroxysteroids that were not suppressed by low-dose dexamethasone but were suppressed by high-dose dexamethasone. Detailed test results were indistinguishable from those in Cushing's disease, which had been the initial diagnosis. When an occult history of alcohol abuse was discovered, the suspicion of alcohol-induced pseudo-Cushing's syndrome was raised. During an extended hospitalization and abstinence from alcohol, abnormal endocrinologic test results gradually became normal. This patient also demonstrated a further complicating feature, a left adrenal mass, which appeared to be a benign, coincidental lesion. Because of the high prevalence of alcohol abuse and the possibility that test results may be identical to those in Cushing's disease, clinicians should be familiar with this disorder to avoid misdiagnosis and inappropriate therapy.

Lack of effect of ethanol on plasma cortisol in man.

The effects of acute administration of ethanol were studied in a total of 18 normal male subjects. Sixteen men were given oral ethanol (2.5 ml/kg vodka or gin) and four received intravenous infusions of ethanol (1 ml/kg), at two times of day, 0900 h and 1800 h. Neither intravenous nor oral ethanol caused a specific rise in plasma cortisol, in contrast to previously reported work. There was no evidence for circadian variation in response. Since ethanol does not release plasma cortisol in normal individuals, the pathogenesis of 'alcohol-induced pseudo-Cushing's syndrome' should be re-considered.

Hormone Secretion in Alcohol-Induced Pseudo-Cushing's Syndrome

We describe the clinical and biochemical characteristics of alcohol-induced pseudo-Cushing's syndrome in two patients with signs and symptoms of Cushing's syndrome and slight disturbances in liver function. An insufficient suppression of plasma cortisol to the overnight administration of 1 mg of dexamethasone was accompanied by an absent diurnal rhythm of plasma cortisol and an increased cortisol secretion rate. The plasma cortisol levels at 8 AM normalized during hospital admission (ie, alcohol withdrawal) at the same rate or parallel with the serum gamma-glutamyl transferase concentration. A normal increase of plasma cortisol, adrenocorticotropic hormone, and growth hormone in response to an insulin induced hypoglycemia was not compatible with the diagnosis Cushing's syndrome. However, the result of a differential diagnostic test with metyrapone was compatible with the presence of Cushing's disease. An erroneous diagnosis of Cushing's disease can be easily made in patients with alcohol-induced pseudo-Cushing's syndrome.

Hormone secretion in alcohol-induced pseudo-Cushing's syndrome. Differential diagnosis with Cushing disease

Hormone secretion in alcohol-induced pseudo-Cushing's syndrome. Differential diagnosis with Cushing disease

Psychiatric Manifestations of Cushing's Syndrome: Response to Lowering of Plasma Cortisol

The incidence of psychiatric abnormalities has been assessed in 38 patients with Cushing's syndrome and two with alcohol-induced pseudo-Cushing's syndrome. Twenty-six patients were examined by one of us using a standardized psychiatric interview, and this group included all those with severe to moderate psychiatric disorders. Depression was the commonest symptom: five patients (13%) were markedly or severely depressed, four (10%) were moderately depressed and 13 (32%) were mildly depressed. Four patients exhibited other, non-depressive psychiatric symptoms and only 14 (35%) were judged free from psychiatric abnormality. The first line of treatment was to reduce the circulating cortisol level either by adrenalectomy or by treatment with oral metyrapone; both patients with alcohol-induced pseudo-Cushing's syndrome were treated by alcohol withdrawal. Once the plasma cortisol level was successfully controlled, depressive symptoms were relieved in all five patients with marked or severe depression and in three of the four who were moderately depressed. Mild depressive symptoms were relieved in six of the 13 affected. It is concluded that metyrapone may be of considerable value in the management of the acute psychiatric states which may occur in Cushing's syndrome and these findings are discussed in the light of their possible pathogenesis.