Effect of bile drainage and rifampicin on recovery of obstructive cholestatic patients.

The antibiotic rifampicin is identified as an activator of the nuclear receptor pregnane X receptor (PXR). In vitro and in vivo studies have shown that rifampicin, by being a PXR-ligand, has several possible pharmacological targets for the treatment of cholestasis and thereby improves liver cell secretion and cholestasis-induced pruritus. In a pilot study eleven patients with progressive hepatocellular secretory failure (serum bilirubin >255µmol/L) were successfully treated with rifampicin, resulting in amelioration of bilirubin levels, and pruritus also improved rapidly (article under submission). Rifampicin is effective in cholestasis associated pruritus. It is shown that short-term treatment with PXR agonists such as rifampicin is highly effective and safe. Rifampicin for short duration, not longer than two weeks, is associated with a low risk of hepatotoxicity, Rifampicin-induced hepatitis is only seen after 2-3 months of treatment.

We would like to study the effect of alleviation of obstructive cholestasis by biliary drainage with or without rifampicin on serum bilirubin levels. On the other hand we also study want to study the effect on cholestatis-induced pruritus. Various cholestatic disorders are associated with pruritus. Recent results of our group suggest that lysophosphatidic acid (LPA) and autotaxin (ATX) play a critical role in cholestatic pruritus. However, the source of increased serum ATX levels remains to be elucidated. Certain substances in bile may induce gene expression of autotaxin. It is our aim to reveal the nature of these substances. Without adequate therapy chronic cholestatic diseases can progress through stages of inflammation and fibrosis to cirrhosis. The function of bile salts during cholestasis is ambiguous: they act as pro-inflammatory agents on the one hand and as signaling ligands via membrane bound and nuclear receptors on the other hand. It is not known how hepatocytes and cholangiocytes gain resistance against these noxious compounds in bile. Our group hypothesized an import role for HCO3- secretion in the biliary tract as a defense mechanism against noxious compounds in bile.

We postulate that:

1. Restoration of bile flow by means of bile drainage during obstructive cholestasis affects the composition of bile and serum including total bilirubin concentrations and thereby improves jaundice and cholestasis;

2. Restoration of bile flow by means of bile drainage during obstructive cholestasis affects the composition of bile and serum including serum LPA and ATX concentrations, and, thereby, relieving pruritus and improving quality of life in the cholestatic patient;

3 The potent PXR agonist and antipruritogen, rifampicin, does not only beneficially affect pruritus in addition to biliary drainage, but also enhances impaired hepatocellular secretory capacity thereby accelerating clinical and biochemical recovery and, thereby, quality of life of the cholestatic patient;

4. Biliary HCO3- secretion as a protective mechanism against bile acid-induced cholangiocyte damage is impaired more severely in preexistent bile duct disease, than under conditions of local bile duct obstruction and recovers more effectively after drainage and rifampicin treatment.

1. At baseline (T=0);

2. Day 1;

3. One week after baseline;

4. Four weeks after baseline.

Treatment with rifampicin 150 mg bd for seven days and blood sampling and questionairres.

Controls will not receive additional rifampicin.