Extracorporeal artificial liver support systems in the management of intractable cholestatic pruritus

Abstract

Pruritus can occur as a severe complication of cholestasis. Several hypotheses suggest an important role for the accumulation of bile acids, endogenous opioids and – mire recently – lysophosphatidic acid. Bile acid sequestrants are the first-line therapeutic agents. In refractory cases, a stepwise approach using rifampicin, oral opiate antagonists and the selective serotonine reuptake inhibitor sertraline should be tested. Recent case series reported effective relief of pruritus using extracorporal liver support systems and plasmapheresis.

Definition and clinical relevance

Pruritus is defined as a sensation that causes the desire to scratch (1). Itch may occur as a consequence of a variety of diseases and is classified into six groups: dermatological, systemic, neurological and psychogenic itch, furthermore mixed and other (kryptogenic) forms of itch. About 20 per cent of all cases of generalized pruritus are a consequence of systemic diseases. Cholestatic pruritus can occur as a consequence of almost every hepatic disease. However, it is frequently associated with primary biliary cirrhosis, primary sclerosing cholangitis, chronic viral hepatitis and carcinoma of the bile ducts(1–3).

Clinical symptoms can range from sleeping disorders, disabled activities of daily life, depression and in severe cases even attempted suicide. The intensity of the sensations varies in a wide range in patients with cholestasis. Fluctuation of the sensations both with circadian rhythm (worsening at night time) and with seasonal changes (worsening during wintertime) is a typical feature of cholestatic pruritus (2). Although several therapeutic measures are available, pruritus may necessitate liver transplantation in intractable and refractory cases.

Pathogenesis

The mechanism of cholestatic pruritus has not been clearly elucidated (1). Itch perception comprises a complex network of pruritogens, its receptors and neuronal pathways that contributes to cerebral processing of the sensation in thalamic nuclei and the cortex. The sensation of itch is transferred via unmyelinated C fibres distinct from fibres that send up pain (4).

Several hypotheses suggest bile acid accumulation as a key player in the pathogenesis of pruritus: intradermal application of bile salts induces an itching sensation. Furthermore, cholestatic pruritus diminishes following relief of major bile duct stenoses. Nasobiliary drainage has also been reported for the relief of pruritus (5). However, many patients with cholestatic liver disease and elevated bile salt levels in plasma do not suffer from itch and pruritus may even improve during end-stage liver disease. Furthermore, the severity of pruritus frequently does not correlate with bile salt levels in the plasma and skin (6).

Endogenous opioids seem to play a central role in the pathogenesis of pruritus as a consequence of increased synthesis or reduced elimination in cholestatic liver disease (1). Endogenous opioid plasma levels were increased in cholestatic patients with primary biliary cirrhosis. However, there are only limited data investigating whether endogenous opioid serum levels correlate with itch perception. Experimental data suggest that μ-opioid receptor antagonists mitigate pruritus whereas κ-opioid-receptor antagonists enhance itch sensations.

Recently, Kremer et al. (7) could identify albumin-bound, amphiphilic lysophosphatidic acid (LPA) as a major mediator of cholestatic pruritus. Autotaxin is the serum enzyme that converts lysophophatidlycholine into LPA. It is significantly increased in patients with cholestatic pruritus compared with cholestatic patients without itching sensations. Autotaxin serum levels correlated significantly with the intensity of pruritus.

Diagnosis

The objective quantification of itch is difficult. Perception of pruritus is a subjective sensation that varies in a distinctive way individually. To date, the visual analogue scale (VAS) is a commonly used tool. The scratching activity monitoring system (SAMS) (scratch registration using piezo-electric crystals on fingernails) is another method that is mainly used in studies. Recently, a multidimensional tool encompassing the duration, degree, disability and distribution of pruritus (5-D questionnaire) was introduced (8). Furthermore, quality-of-life scores and evaluation of cutaneous scratch lesions may also illustrate the significance of pruritus and the effect of therapeutic measures.

Therapy

The primary therapeutic measure is the treatment of the underlying hepatobiliary disease that led to the development of pruritus. Biliary drainage by endoscopic stenting, biliodigestive anastomoses or transcutaneous drainage can effectively eliminate itch in many patients with extrahepatic obstruction. In contrast, no curative therapy is established in intrahepatic cholestasis. However, several measures can ameliorate or even free patients from disruptive itch.

Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend a stepwise approach in the management of cholestatic pruritus (2, 3).

Initially, cholestyramine should be administered with a starting dose of 4 g twice per day and an increase in the dosage up to 4 g four times daily. Cholestyramine and colestipol are nonabsorbable alkaline polystyrenes that bind anions including bile acids in the intestinal lumen. However, as they decrease, the sensation of itch also in noncholestatic pruritus like uraemia, anion exchange resins may also bind other pruritogen substances, which are not yet identified. Recently, a randomized-controlled study could not demonstrate an effect of colesevelam, a novel bile acid sequestrant, on pruritus.

In the case of treatment failure, EASL propose a stepwise approach starting with rifampicin – in case of intolerance or lack of benefit of cholestyramine – followed by naltrexone, sertraline and finally other treatment options like extracorporeal detoxification devices (2).

Rifampicin (300–600 mg/day) may decrease pruritus due to accelerated detoxification and elimination of pruritogen compounds by induction of hepatic enzymes and key membrane transporters. Aminotransferase levels should be monitored regularly as rifampicin may cause hepatotoxicity in about 10% of cases.

Several studies reported a significant reduction in the perception of pruritus and scratching activity by opioid antagonists like naltrexone (25–50 mg/day orally) or intravenous naloxone in emergency treatment (bolus of 0.4 mg, followed by 0.2 μg/kg/min for 24 h). Generally, opioid antagonists are well tolerated. Withdrawal syndromes were reported under rare circumstances within the first days of treatment.

The selective serotonin reuptake inhibitor sertraline (75–100 mg/day) is another option in cholestatic pruritus. Studies reported positive effects of phenobarbital, propofol, phototherapy, androgens and cannabinoids (1). However, future randomized-controlled studies are necessary to evaluate the therapeutic impact in cholestatic pruritus.

Ursodeoxycholic acid (UDCA) is a naturally occurring dihydroxy bile acid and makes the bile acid pool more hydrophilic after oral administration (dose 10–30 mg/kg/day). It is a standard medical treatment in patients with primary biliary cirrhosis. However, EASL and AASLD do not recommend UDCA as a therapeutic option for cholestatic pruritus (except in the context of interhepatic cholestasis of pregnancy) (2, 3).

The indication for extracorporeal liver support systems in patients with cholestatic pruritus is the lack of efficacy or intolerance of the drugs mentioned above.

Liver transplantation may be the final therapeutic option in patients with severe pruritus refractory to all therapeutic measures. However, before evaluation for liver transplantation or while patients are on the waiting list, extracorporeal liver support devices offer promising therapeutic options.

Extracorporeal liver support devices in refractory cholestatic pruritus

Invasive procedures like haemodialysis, plasmapheresis, extracorporeal albumin dialysis, endoscopic or surgical intervention in the biliodigestive system aim to remove pruritogens from the body. The majority of published manuscripts on extracorporeal liver support devices for refractory pruritus used the multipass albumin dialysis system with a charcoal adsorber and an ion exchanger [molecular adsorbent recirculating system (MARS^® Gambro, Lund, Sweden)] (8–10, due to a limited number of endorsed references, we are not able to cite every published report of MARS^® in refractory pruritus). One small case series reported the effects of a haemodialysis- and plasmapheresis-based system (Prometheus^® Fresenius Medical Care AG, Bad Hamburg, Germany) on severe pruritus refractory to medical treatment efforts (9). MARS^® and Prometheus^® have been commercially available in Europe since many years. The advantage of these systems is that they are able to eliminate albumin-bound substances that are accumulated during cholestasis like bile acids in addition to water-soluble toxins like in conventional renal replacement modalities.

The largest series reports the effect of MARS^® in 20 patients with chronic cholestatic liver disease or chronic graft rejection following liver transplantation (10). All patients have been previously treated with established drugs like resins, rifampicin or naltrexone without relief of symptoms. Patients received median 2 (range 1–5) MARS^® sessions via a double-lumen catheter in the femoral vein. The duration of the sessions ranged between 7 and 9 h. Anticoagulation of the extracorporeal circuit was performed by heparin. MARS^® treatment resulted in a significant decrease of pruritus in all but one patient assessed by VAS. Although pruritus increased again in nine patients after 1 month, symptoms were still lower than that before treatment. Apart from a slight decrease of the platelet count following MARS^® that resumed to normal during follow-up, no adverse events were reported. Interestingly, an improvement of the symptoms was achieved by only two MARS^® sessions on average.

A smaller case series reported a decline of the pruritus intensity (70–100% reduction immediately after MARS^® treatment and 25–50% 6 months thereafter in comparison with the baseline values) (11).

Rifai et al. (9) reported on 7 patients that who treated with the Prometheus^® system for refractory cholestatic pruritus. Patients underwent three to five treatment sessions. Six out of seven patients reported a significant improvement of itch following treatment with Prometheus^®. However, improvement of pruritus 1 month after the end of treatment could be maintained only in four patients. No serious adverse events occurred during the study period. Subanalysis revealed that only patients with elevated bilirubin levels and increased serum bile acid levels benefited from fractionated plasma separation and adsorption. This is in accordance to Bellmann et al. (12), who made a comparable observation in patients treated with MARS^®.

Twenty-five years ago, Cohen et al. (13) reported improvement of intractable pruritus in five patients with primary biliary cirrhosis using plasmapheresis. Patients underwent on average 63 plasmapheresis sessions during a mean study period of 26 months (range 20–37 months). However, several times they observed ‘…uritcaria and transient hypotension … with rapid response to fluid, albumin and adrenaline’ (13). The safety of plasmapheresis has improved during the following decades. Recently, a Canadian group reported two cases of severe cholestatic pruritus during pregnancy who were safely and effectively treated with plasmapheresis (14).

Whether patients should undergo liver transplantation after new onset or a new deterioration of cholestatic pruritus following extracorporeal liver support systems or whether they should have extracorporeal therapy once again is a matter of debate and should be decided from case to case. Invasiveness, the potential side effects and costs of the extracorporeal liver support devices should be balanced by the patient's medical condition and alternative therapeutic options. We suggest that patients who are listed for liver transplantation due to refractory pruritus should undergo extracorporeal liver support as bridging therapy.

In conclusion, case series have demonstrated that treatment with extracorporeal liver support devices provides a safe and effective therapeutic option in patients with cholestatic pruritus refractory to medical therapeutics.

Acknowledgements

Conflict of interest: The author declares that he has no conflicts of interest.