Induction of hepatic 11beta-hydroxysteroid dehydrogenase type 1 in patients with alcoholic liver disease.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Ahmed
Adeeba
A
Department of Endocrinology, Division of Medical Sciences, Queen Elizabeth Hospital, Birmingham, UK.
Saksena
Sushma
S
Sherlock
Mark
M
Olliff
Simon P
SP
Elias
Elwyn
E
Stewart
Paul M
PM
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis / Q000235:genetics; D003348:Cortisone / Q000097:blood; D004573:Electrolytes / Q000097:blood; D004790:Enzyme Induction / Q000502:physiology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007668:Kidney / Q000098:blood supply; D008099:Liver / Q000098:blood supply; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger
D004573:Electrolytes; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone