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 .