Liver cirrhosis is associated with altered glucocorticoid metabolism related to disease severity

BACKGROUND: Liver cirrhosis (LC) is frequently complicated by adrenal dysfunction; however, whether cirrhosis drives the coordinated, pathway-specific reprogramming of cortisol metabolism remains unclear. OBJECTIVES: We aimed to characterize axis-specific alterations in cortisol metabolism in patients with LC, those with adrenal insufficiency (AI), and controls using integrated serum and salivary steroid profiling. METHODS: This prospective study included adults with LC (n = 33) and control participants without cirrhosis who underwent cosyntropin-stimulation test following transsphenoidal surgery for a nonfunctioning pituitary adenoma (controls, n = 27; AI, n = 10). Serum and saliva samples were collected at baseline, 30 and 60 min after stimulation and profiled for 26 serum and 12 salivary steroids through liquid chromatography-tandem mass spectrometry. Multivariate models were constructed to identify cirrhosis-associated steroid features, and their associations with disease severity. RESULTS: LC was characterized by axis-specific steroid remodeling, including suppressed 11β-hydroxysteroid dehydrogenase 1 and A-ring reduction activity with the 20α-reduction pathway activation. Representative changes included a lower peak cortisol-to-cortisone ratio and reduced tetrahydrocortisone-to-cortisone ratio, alongside increased 20α-reduced metabolites (all p < 0.001). This pattern was distinct from that in AI, in which steroid production and downstream metabolites were uniformly reduced. Iterative model refinement identified a parsimonious seven-steroid signature that discriminated patients with LC from controls. Within the LC cohort, the steroid signature correlated with the Child-Pugh score. CONCLUSION: LC is associated with coordinated, axis-specific cortisol metabolic reprogramming, which is mechanistically distinct from AI. Integrated steroid profiling may provide mechanistic insight into altered glucocorticoid metabolism in cirrhosis and its relationship to disease severity .