Immunosuppression and HCV recurrence after liver transplantation

SummaryHCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens.From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency.There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed

Ursodeoxycholic acid improves bilirubin but not albumin in primary biliary cirrhosis: further evidence for nonefficacy.

BACKGROUND/AIM: In randomised controlled trials (RCTs) of ursodeoxycholic acid (UDCA), although serum bilirubin is frequently reduced, its effect on disease progression and mortality is unclear. As serum albumin is an established independent prognostic marker, one might expect less deterioration of serum albumin values in a UDCA-treated group. We therefore modelled the typical evolution of serum bilirubin and albumin levels over time in UDCA-untreated patients and compared it with the observed levels in UDCA RCTs. METHODS: Multilevel modelling was used to relate the evolution of serum albumin to serum bilirubin and time since patient referral. For each considered RCT, the derived model was used to predict the relationship between final mean serum albumin and bilirubin concentration, adjusted for mean serum albumin at referral and followup duration. RESULTS: Five RCTs were eligible in terms of available data, of which two had long followup. In all trials, serum albumin did not significantly differ between UDCA- and placebo-treated patients, despite the UDCA effect on serum bilirubin. Therefore, there is no evidence over time for changes or maintenance of albumin levels for UDCA-treated patients above the levels predicted for placebo-treated patients. CONCLUSIONS: Our findings suggest that UDCA does not alter serum albumin in a way that is consistent with its effect on serum bilirubin. Therefore, reductions in serum bilirubin of UDCA-treated PBC do not parallel another validated and independent prognostic marker, further questioning the validity of serum bilirubin reduction with UDCA as a surrogate therapeutic marker

Letter to the editors

We read with interest the study by Manzia et al. [1] onthe effect of maintenance of mycophenolate mofetil(MMF) monotherapy on progression of recurrent hepati-tis C virus (HCV) after liver transplantation.The authors concluded: MMF ''monotherapy may cur-rently represent the preferred immunosuppressive alterna-tive for the long-term management of liver transplantrecipients with HCV infection''. However, we believe thatthey should exert great caution in coming to this conclu-sion, as their results [1] have not been properly evaluatedwithin the context of the complete picture of the pub-lished literature on the subject.Our group recently published a review on the role ofMMF and azathioprine in liver transplantation withregard to acute rejection, renal dysfunction and HCVrecurrence [2]. Considering HCV recurrence, we showedthat between 2001 and 2007, 17 studies evaluated MMFand HCV recurrence; among these, only two studies [3,4]found a decreased severity of HCV recurrence with MMFand one of these had no multivariate analysis [3] – citedby Manzia et al. Nine studies (reported in reference 2)documented similar severity of HCV recurrence; however,six studies [5–10] showed increased severity of HCVrecurrence, but only one of these [10] was cited byManzia et al.Therefore, the study by Manzia et al. [1] representsonly the third study out of 18 (17%) showing a beneficialtherapeutic effect of MMF on HCV progression after livertransplantation, whereas 33% shows a deleterious effect.For this reason, in omitting to cite this literature, Maniaet al. have gone against the available evidence in statingthat MMF is the preferred immunosuppressive alternativefor long-term regimen in patients transplanted for HCV-related cirrhosis.Moreover, although Manzia et al. [1] showed in theirpatient cohort a positive association between a favorableeffect of MMF monotherapy on the progression of hepa-tic fibrosis in HCV liver transplant patients, there are sev-eral methodological issues. There was no multivariateanalysis evaluating MMF with respect to fibrosis progres-sion. This is especially important, as the study was retro-spective and nonrandomized and with only 15 patientsper arm. Although other studies have also been retrospec-tive and nonrandomized [2], several have included multi-variate analyses.Thus, overall, the current published evidence for MMFwith respect to the severity of fibrosis and HCV recur-rence does not suggest a beneficial effect. If anything, apotential adverse effect is shown as we pointed out in ourreview [2], although we acknowledged then, and now thatthe evidence is weak.Giacomo Germani

Reply to: Platelet function in patients with cirrhosis

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Primary Biliary Cirrhosis Associated with Systemic Sclerosis: Diagnostic and Clinical Challenges

Patients with primary biliary cirrhosis (PBC) often have concurrent limited systemic sclerosis (SSc). Conversely, up to one-fourth of SSc patients are positive for PBC-specific antimitochondrial antibodies (AMA). The mechanisms responsible for the co-occurrence of these diseases are largely unknown. Genetic, epigenetic, environmental, and infectious factors appear to be important for the pathogenesis of the disease, but the hierarchy of events are not well defined. Patients with SSc and PBC have an increased morbidity and mortality compared with the general population, but whether the presence of both diseases in an affected individual worsens the prognosis and/or outcome of either disease is not clear. Some case reports suggested that the presence of SSc in PBC patents is associated with a more favorable prognosis of the liver disease, whereas others report an increased mortality in patients with PBC and SSc compared to patients with PBC alone. This paper discusses the features of patients with PBC-associated SSc. Our aims are to clarify some of the pathogenetic, diagnostic, and clinical challenges that are currently faced in the routine management of these patients. We also intend to provide some practical hints for practitioners that will assist in the early identification of patients with PBC-associated SSc