Pathogenesis and Management of Pruritus in PBC and PSC

Abstract

Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, 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 could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX 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. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline-based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the μ-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy, plasmapheresis, albumin dialysis or nasobiliary drainage. This review outlines the current knowledge on pathogenesis of cholestatic pruritus and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients with itch.

A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis

“…However, a significant improvement in pruritus is not typically observed . Individuals also remain unresponsive to recommended agents for the treatment of cholestatic pruritus, which include cholestyramine, rifampicin, naltrexone, and sertraline . New pharmacologic interventions are therefore needed.…”

Treatments for chronic pruritus outside of the box

“…Some of the receptors are predominantly expressed in the peripheral nervous system and include (apart from H1R and H4R) protease‐activated receptors (eg PAR‐2), Mas‐related G protein‐coupled receptors (eg MrgprX1), neurokinin 1 receptor (NK1R), serotonin receptors (eg 5‐HT2R), endothelin‐1 receptors (eg ET A ), neurotrophin receptors (eg TrkA), bile salt receptor (TGR5) and cannabinoid receptors (eg CB 2 ). Other itch‐related G protein‐coupled receptors are primarily expressed in the central nervous system and include gastrin‐releasing peptide and μ‐ and κ‐opioid receptors . While most of these receptors are involved in inducing pruritus, cannabinoid and κ‐opioid receptors are mainly thought to suppress itch signalling.…”

Recent advances in the management of pruritus in chronic liver diseases

“…Recommendations to all patients should include the use of moisturizing and cooling ointments and shortening of the fingernails to avoid secondary skin damage. The principal goals of treatment include[5]: (1) removal of pruritogens such as cholestyramine or biliary drainage in the absence of cholestasis; (2) alteration of the metabolism of presumed pruritogens such as rifampicin; (3) modulation of itch signaling such as opioid receptor acting agents; and (4) removal of potential pruritogens by anion absorption, plasmapheresis or extracorporeal albumin dialysis (Figure 2). …”

“…Pruritus in patients with cholestasis is characterized by a circadian rhythm, with the highest intensity during the evening and early at night[4]. Chronic pruritus generally tends to increase with warmth and at night[4,5]. Women with cholestasis frequently show worsening of pruritus during the progesterone phase of the menstrual cycle, in late pregnancy, and during hormone replacement treatment[4-6].…”