ECE2016 Guided Posters Receptors & Signalling (10 abstracts)
The changing ‘steroid metabolome’ across the spectrum of non-alcoholic fatty liver disease
Ahmad Moolla 1 , Amin Amin 2 , Bev Hughes 2 , Wiebke Arlt 2 , Zaki Hassan-Smith 2 , Matt Armstrong 3 , Philip Newsome 3 , Tahir Shah 3 , Luc Van Gaal 4 , An Verrijken 4 , Sven Francque 4 , Michael Biehl 5 & Jeremy Tomlinson 1
1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK; 2Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; 3Centre for Liver Research, University of Birmingham, Birmingham, UK; 4University of Antwerp, Antwerp, Belgium; 5University of Groningen, Groningen, The Netherlands.
Introduction: Dysregulated glucocorticoid (GC) metabolism has been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). NAFLD extends from simple steatosis, to inflammation (steatohepatitis/NASH), fibrosis and consequent cirrhosis. It is often regarded as the hepatic manifestation of the metabolic syndrome and is independently associated with increased liver and cardiovascular mortality. Changes in GC metabolism have thus far been described in small numbers of patients. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol (F) from inactive cortisone (E), whilst A-ring reductases 5α and 5β reductase (5αR/5βR) inactivate cortisol to dihydro and subsequently tetrahydro metabolites (THF/5αTHF). Both pathways are implicated in the development and progression of NAFLD.
Methods: Using gas chromatography/mass spectrometry, we analysed steroid metabolites in spot urine samples (corrected for urinary creatinine) in a large cohort of patients with biopsy proven NAFLD/NASH (n=39) alongside patients with cirrhosis (n=44), and compared them to healthy controls without liver disease (n=58).
Results: Total urinary cortisol metabolites were significantly different across all three groups allowing discrete separation (P<0.0001), with the highest levels seen in patients with NASH. Interestingly, 11β-HSD1 activity (reflected by the THF+5αTHF/THE ratio) was significantly increased in patients with cirrhosis in comparison to NASH or healthy controls (P<0.0001). A-ring reductase activity (THF/5αTHF ratio) did not differ significantly across the three groups. Using computerized machine learning analysis, we identified distinct clusters of patients, with complete separation between those with cirrhosis and healthy controls (ROC AUC=0.99).
Conclusion: We have identified steroid metabolic pathways that appear differentially regulated across the spectrum of NAFLD. This not only offers the potential to identify discrete targets amenable to intervention, but through the adoption of an unbiased computational approach, we have raised the possibility of utilizing this technique as a non-invasive assessment of the stage and severity of liver disease.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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