Molecular mechanisms of pruritus in cholestasis

Chronic pruritus represents an agonizing symptom accompanying a large variety of dermatological, systemic, neurologic and psychiatric disorders. It is commonly observed in patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis or intrahepatic cholestasis of pregnancy but may accompany, although less frequently, many other liver diseases. Itching may be mild and tolerable in some patients, but may also considerably reduce quality of life, cause severe sleep deprivation, depressive mood and even suicidal ideation in more severe cases. The pathogenesis of pruritus of cholestasis remained largely elusive. Bile salts, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens, however, for these molecules neither a correlation with itch intensity nor a causative link has ever been established.
The aim of this thesis was to unravel the molecular mechanisms of pruritus in cholestasis. Screening sera of cholestatic patients with and without pruritus for neuronal activation we could identify a potent activator as lysophosphatidic acid (LPA). Intradermal injection of LPA caused scratching behaviour in mice. LPA and its forming enzyme, autotaxin (ATX), were strongly increased in cholestatic patients with pruritus compared to those without pruritus or healthy controls. Autotaxin activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Further unravelling of the pathogenesis of itch in cholestasis may help to develop novel, more effective strategies, among which are possibly selective ATX inhibitors and LPA receptor antagonists.