Nguyen_2026_Clin.Liver.Dis_30_571

Cholestatic liver disease disrupts bile acid homeostasis and triggers systemic metabolic, immune, and neuroimmune changes that underpin complex symptom biology. Cholestasis-associated pruritus arises from proposed interacting peripheral mechanisms (eg, bile acids, autotaxin-lysophosphatidic acid, interleukin-31, endogenous opioids) and central itch processing within defined brain networks. Fatigue similarly reflects a convergence of peripheral immune and autonomic disturbances with central alterations in thalamic and basal ganglia connectivity, motor network control, and cognition, rather than simple muscle dysfunction.