Advances in Pathogenesis and Management of Pruritus in Cholestasis

Abstract

Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, μ-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the μ-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis.

Pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolines: Novel compounds that reverse ABCG2-mediated resistance in cancer cells

“…The possible activation of PXR by IND-1 and IND-3 to -8 was examined with HepG2 cell-based luciferase reporter gene assays, in which the expression of luciferase was controlled by the human PXR-regulated CYP3A4 promoter. As expected, rifampicin [33], an agonist of human PXR, induced PXR transactivation of CYP3A4 promoter activity. In contrast, IND-7 and IND-8 did not affect PXR transactivation function (Fig.…”

Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver

“…However, for those substances neither a correlation between serum and/or tissue concentration and itching severity nor a causative link have ever been established. Serum activity of ATX correlates with itching intensity and response to treatment in patients with cholestatic pruritus but not with other forms of itching (191)(192)(193) . Treatment options for pruritus in cholestasis remain limited to a few evidence-based therapies (68,193) .…”

“…Serum activity of ATX correlates with itching intensity and response to treatment in patients with cholestatic pruritus but not with other forms of itching (191)(192)(193) . Treatment options for pruritus in cholestasis remain limited to a few evidence-based therapies (68,193) . Therapeutic interventions should primarily focus on an adequate therapy of the underlying hepatobiliary disease, such as: 1) to remove of the pruritogens from the enterohepatic cycle by nonabsorbable anion exchange resins such as cholestyramine 4-16 g per day.…”

“…The pain induced by vigorous scratching is associated with relief of pruritus. In female patients, it exacerbates in the premenstrual period and in late pregnancy (192)(193)(194) . The precise mechanism of cholestatic pruritus remains unclear.…”

Emerging drugs for the treatment of pruritus

“…A recent cross-sectional study in dialysis units revealed that 25.2% of patients suffered from CP at the time of the investigation (point prevalence) and more than a third of HBD patients (35.2%) had experienced CP at least once during their life (lifetime prevalence) [5]. Pruritus is described to be a symptom of HBD with or without cholestasis occurring in nearly 80 --100% of patients [6]. For example, CP in HBD may occur in primary biliary cirrhosis in up to 70% of affected patients but detailed epidemiological data are still missing [3,6].…”