Pruritus of cholestasis is a devastating symptom which impairs quality of life to such an extent that patients can be driven to suicide. Typically, pruritus of cholestasis manifests itself initially without any visible skin manifestations and exacerbates at night. The resulting scratching can lead to excoriations and in chronic forms to marked thickening of the cutis and subcutis.
The etiology is still unclear; it stands to reason, however, that some cholephile is involved. The main contenders remain bile acids and endorphins (1). Treatment should follow a step-wise approach described and referenced below. There are three particular conditions where an alternative algorithm should be employed:

• Cholestasis due to deficiency in BSEP/MDR3 (BRIC). This should be thought off when hepatic alkaline phosphatase is markedly elevated and g-glutamyl transpeptidase normal. This usually does not respond to cholestyramine.
• Intrahepatic cholestasis of pregnancy (ICP); in this situation, UDCA should be started immediately. Cholestyramine has no effect.
  
• Pruritus in hepatitis C (Pruritus in hepatitis C). This is probably a multifactorial symptom which can be quite difficult to treat.

Treatment of pruritus usually starts with pharmacological treatments but in some instances moderately invasive procedures are required. If the pruritus is due to ductopenia such as in end-stage primary biliary cirrhosis or primary sclerosing cholangitis, liver transplantation might have to be considered. The different treatment modalities are listed with increasing side effects / invasiveness. In most instances, going through the list pruritus should be alleviated at level 3 to 4.

• Cholestyramine / Colestipol. These are organic anion binding resins. Cholestyramine will successfully treat pruritus in 90 % of the cases (exceptions see above). It should be taken an hour ahead of breakfeast and one to two hour ahead of other medication and at bed-time - again separated by at least two hours from any other medication. Its taste is disagreeable; therefore, I recommend to swirl it up in half a glass of an opaque fluid (milk or orange juice), down it rapidly and flush with a glass of water. Usual dosage: 2 x 4 - 8 g/d.
• Enzyme inducers. Rifampicin induces canalicular transporters and detoxifying enzymes via the pregnane X receptor. A meta-analysis on a very limited number of patients has proclaimed it to be effective in 77 % of patients and to be safe (2). However, cases of hepatotoxicity have been described and adequate monitoring is required (3). It has supplanted phenobarbital since it is more effective and better accepted by patients. Usual dosage is 10 mg/kg. I start with 600 mg. An effect can be seen after about 5 days - if after 10 days pruritus persists, alternatives should be explored.
• Opiate antagonists. Their effects can be quite impressive but at the expense of an opioid withdrawal syndrome which can be very disturbing to the unprepared patient. A thoughtful editorial (4) references my approach: I hospitalize the patient and start naloxone at 0.002 mg/kg/h. If tolerated, the infusion rate is increased at 6 - 12 h intervals up to 0.2 mg/kg/h. If effective, the patient is switched to oral naltrexone 12.5 mg b.i.d. and naltrexone is increased as needed up to 250 mg/d (in most cases 2 x 50 mg will suffice).
• Other pharmacological agents: H3-antagonists such as ondansetrone, SSRI such as sertraline and THC-agonists have been reported to be effective in small case series. No controlled studies are available. A trial of such agents may be justified before stepping up to more invasive procedures as described below.
  
• Ursodeoxycholic acid: Is clearly effective in ICP (see above) but in other conditions its effects are moderate at best. Since it takes a long time to exert its effect I usually do not employ it as a first line drug - again with the exception of ICP.
  
• Plasmapheresis / Anion absorption techniques: A variety of techniques including plasmapheresis alone, combined with anion absorption or hemodialysis techniques with anion absorption such as MARS or PROMETHEUS have been used successfully in case report and small series. No controlled studies are available.
  
• Endoscopic / surgical biliary diversion: Surgical internal or external biliary diversion is an accepted treatment for PFIC. Nasogastric biliary drainage can alleviate severe pruritus (5).
  
• Liver transplantation should be considered in patients with diseases known to progress when all measures fail even if liver function is good.