The Scientific Basis of Cholestatic Liver Disease and Its Symptom Complex.

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.