MARS: The ultimate warrior against pruritus of cholestasis?
Article Outline
Pruritus is the most prevalent symptom of cholestasis. Although it is often under-appreciated by physicians, pruritus is more than just an annoyance for patients with cholestasis. It reduces quality of life and can lead to significant disability. When very severe, it may sometimes cause the patient to even contemplate suicide. The pruritus of cholestasis is a difficult clinical problem to manage and current medical treatments accepted as conventional are unsatisfactory in a considerable proportion of cases, causing distress and exasperation to the patient as well as to the doctor [1]. Progress in the study of pruritus has been hampered by two major problems. One is the subjective and multi-dimensional nature of pruritus, which makes objective assessment difficult. The dimensions include: (1) a sensory signal (itch), (2) an emotional reaction (discomfort, stress) and (3) a behavioural response (scratching); the latter two components appear to be susceptible to great individual variability and the former cannot yet be measured. The other major problem is the poorly defined pathogenesis of pruritus in cholestasis. Peripherally acting pruritogens and altered central neurotransmission have been implicated as causing pruritus in cholestasis. Unfortunately, the pruritogen(s) are not yet identified although bile salts, progesterone metabolites, histamine, and endogenous opioids have been proposed to induce pruritus [2]. A new potential player in this field has recently emerged, namely lysophosphatidic acid (LPA) which is a potent neuronal activator and is formed from lysophosphatidylcholine by the enzyme autotoxin (ATX) [3]. Nevertheless, and as a consequence, current anti-pruritic treatments are mostly empirical and not consistently effective.
Therapeutic efforts should always include an adequate therapy of the underlying hepatobiliary disease, as it may result in relief of pruritus. The specific treatment of pruritus can be categorized as (1) procedures aimed at the removal of pruritogens from the body, including non-absorbable anion-exchange resins which bind many hydrophobic substances in the intestinal lumen, and invasive procedures such as hemodialysis, plasmapheresis, extracorporeal albumin dialysis (mainly the molecular adsorbent recirculating system or MARS), nasobiliary drainage or even surgical partial biliary diversion; (2) drugs aimed at altering the metabolism of presumed pruritogens or more generally at modifying itch perception which is an intimately intertwined process with that of pain [4]. Practice guidelines have been recently provided by the European Association for the Study of Liver Diseases (EASL) [5] and by the American Association for the Study of Liver Diseases (AASLD) [6]. Consensual recommendations have emerged. The first line of treatment is the anion-exchange resin, the best-known being cholestyramine, although the evidence based to support its efficacy is limited. This agent (4
g up to four times daily) often gives rise to gastrointestinal disturbance and is poorly tolerated in some patients but appears to be effective in patients with mild pruritus. It needs to be spaced away from any other oral medication by at least 4h. The second line of therapy is the antibiotic rifampicin and has a strong evidence base. Rifampicin is an enzyme inducer and a pregnane X receptor (PXR) agonist. The usual dose is 300mg daily. Patients do need to be monitored for complications such as hepatitis, haemolytic anemia and renal dysfunction, even though they are rare. The third-line therapy is the opioid antagonists, given in very low doses initially and increasing the dose as the patient is able to tolerate the symptoms typical of opiate withdrawal. Sertraline, a serotonin re-uptake inhibitor, may be regarded as fourth-line treatment. Patients resistant to the above agents can be treated with drugs with anecdotal support or referred to specialized centers, where more invasive approaches should be considered. Among these ones, nasobiliary drainage deserves a special attention in benign recurrent intra-hepatic cholestasis because it is able to induce a fast and long-lasting remission [7]. Lastly, liver transplantation should only be considered when all available interventions listed above have proven ineffective after exclusion of psychiatric co-morbidity that might contribute to the itch [8].
In this issue of the Journal, Pares et al. report on the use of albumin dialysis in patients with resistant pruritus [9]. The so-called MARS procedure is as an extracorporeal hemofiltration system using an albumin-enriched dialysate to remove albumin-bound substances in patients with liver failure [10]. The authors studied 20 patients with chronic cholestatic liver disease or chronic liver graft rejection. Two MARS sessions were performed in most patients (either one day apart or in consecutive days). Pruritus dramatically decreased immediately after the procedure (by 72% as assessed by visual analog score) and partially resumed after 30days but its severity was still significantly lower as compared to baseline (by 51%). This improvement was observed in all but one patient and was associated with a significant decrease in serum markers of cholestasis including bile acids. The magnitude of pruritus improvement correlated negatively with baseline serum bile acid and cholesterol levels. No major side-effects were observed. Surprisingly, a number of patients remained virtually free of pruritus after a prolonged follow-up (up to 8.6years).
The authors have to be congratulated for performing this observational case series study that is the largest ever reported on the use of MARS in patients with resistant pruritus. As a placebo effect cannot be ruled out, randomized placebo-controlled trials are the best way to address therapeutic issues, especially when the primary end-point is, at least in part, subjective. However, such trials are virtually unfeasible when an invasive procedure is tested. Despite their obvious limitations, retrospective non-randomized studies may provide useful information in this context. Clearly, the tremendous improvement reported here indicates that this procedure has to be considered in patients with severe cholestasis and intractable pruritus. Furthermore, it has recently been shown that albumin dialysis could be proposed as an “out-patient” service for itch [11]. However further development in technology are warranted to reduce the high costs associated with MARS treatments.
Interestingly, the limitations of this work illustrate well the difficulties inherent to studies dealing with the treatment of resistant pruritus. First and generally speaking, the number of patients with refractory pruritus is limited (only 20 patients were included in 3 reference centers along several years). Secondly, resistance to medical treatment should be clearly defined; in the present paper, no details were provided and, surprisingly, a number of patients seemed to have only a moderate cholestasis as reflected by normal bilirubin levels in half and relatively mild increase of serum bile acids levels (mean=40μM). In addition, among those with long-term follow-up available, only a minority suffered from severe pruritus recurrence. Although there is no strict correlation between the degree of cholestasis and the severity of pruritus, this is, in my experience, neither the biochemical profile nor the course usually observed in patients with “intractable” pruritus. Thirdly, pruritus severity should be assessed by the same validated tool in the different participating centers. The current recommended methodologies for measuring pruritus are a visual analog score (VAS) or the more recent 5-D questionnaire which is a multi-dimensional tool that encompasses the duration, degree, disability, and distribution of pruritus [12]. An objective assessment of itch through physical measurement of scratching activity has been advocated as a more appropriate measure but, in practice, is only a research tool. Fourthly, all extracorporeal blood purification techniques are directed towards elimination of putative peripherally or centrally acting pruritogens that accumulate in plasma and tissues of patients with cholestasis and pruritus. However, the major pruritogen removed by these interventions has not been clearly defined and there is currently no validated serum marker of itch intensity although ATX activity looks promising [13]. As a consequence, objective corroboration of the symptomatic improvement is lacking. The authors focused on the potential role of bile acids in the pathogenesis of pruritus. However and as recently reviewed [14], the evidence for a key role of bile acids is weak: itch is not seen in every patient with liver disease and high serum levels of bile acids; despite ongoing cholestasis and persistently elevated levels of bile acids, pruritus improves in some patients; there is no established correlation between severity of itch and concentrations of bile acids in circulation and in skin; finally kinetics of bile acids do not correlate with the course of pruritus in patients treated with extra corporeal blood purification techniques or nasobiliary drainage.
In conclusion, albumin dialysis appears to have a real place in the management of resistant pruritus. However, efficacy is only transient in most cases and, before using this sophisticated invasive treatment modality that has a high cost and potential side-effects, it is recommended to use a stepwise medical approach (including optimized administration of the different drugs) according to the current EASL clinical practice guidelines on the management of cholestatic liver diseases. Thus, the indication to use invasive procedures should be largely restricted and only include patients with severe intractable pruritus resistant to medical treatment that have a major reduction in quality of life, and be mainly used as an alternative or bridge to liver transplantation. Further clinical studies (including those evaluating the optimal duration of MARS) should adopt strict and validated methodologies. However, a major therapeutic breakthrough is unlikely to occur until pruritogens are not identified. In this regard, the help of Esculape (god of medicine) would be more appropriate than that of Mars (god of war)!
Conflicts of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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PII: S0168-8278(10)00413-7
doi:10.1016/j.jhep.2010.04.007
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Treatment of resistant pruritus from cholestasis with albumin dialysis: Combined analysis of patients from three centers , 07 May 2010
