Histopathological evaluation of recurrent hepatitis C after liver transplantation:A review

Although the morphological features of hepatitis C virus(HCV)recurrence after orthotopic liver transplantation(OLT)have been well established in the last decades,the differential diagnosis still represents a challenge for the pathologist,especially early recurrent hepatitis C vs mild acute cellular rejection.The present review focuses on the role of the pathologist and the pathology laboratory in the management of recipients with recurrent hepatitis C,the usefulness of early and late post-OLT liver biopsies,and the potential role of ancillary techniques(immunohistochemistry and reverse transcription-polymerase chain reaction,RT-PCR).The English literature on the topic is reviewed,focusing on the histopathology,the immunohistochemistry and the use of RT-PCR on HCV-positive post-OLT biopsies.The different histopathological illustrations of early and chronic recurrent hepatitis C are presented,with special focus on the main differential diagnoses and those features with prognostic relevance(cholestasis above all).The usefulness of ancillary techniques are discussed,especially HCV RNA quantitation by RT-PCR.Finally,the usefulness of long-term protocol biopsies is addressed:their usefulness for the study of allograft disease progression is clear,but their meaning in the long term is still debated.The significance of plasma cell infiltrate in HCV-positive allografts,the prognostic weight of graft steatosis,and the impact of donor age in recurrent hepatitis C also represent additional open issues.

The Reliability of Fibro-test in Staging Orthotopic Liver Transplant Recipients with Recurrent Hepatitis C

Background and Aims:Liver biopsy remains the gold stand-ard for staging of chronic liver disease following orthotopic liver transplantation.Noninvasive assessment of fibrosis with Fibro-test(FT)is well-studied in immunocompetent populations with chronic hepatitis C virus infection.The aim of this study is to investigate the diagnostic value of FT in the assessment of hepatic fibrosis in the allografts of liver transplant recipients with evidence of recurrent hepatitis C.Methods:We retro-spectively compared liver biopsies and FT performed within a median of 1 month of each other in orthotopic liver transplan-tation recipients with recurrent hepatitis C.Results:The study population comprised 22 patients,most of them male(19/22),and with median age of 62 years.For all patients,there was at least a one-stage difference in fibrosis as assessed by liver biopsy compared to FT,while for the majority(16/22)there was at least a two-stage difference.The absence of correlation between the two modalities was statistically demonstrated(Mann-Whitney U test,p=0.01).In detecting significant fib-rosis(a METAVIR stage of F2 and above),an FT cut-off of 0.5 showed moderate sensitivity(77%)and negative predictive value(80%),but suboptimal specificity(61%)and positive predictive value(58%).Conclusions:In post-transplant pa-tients with recurrent hepatitis C,FT appears to be inaccurately assessing the degree of allograft fibrosis,therefore limiting its reliability as a staging tool.

Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients

AIM: To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients.

Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy

BACKGROUND Persistent inflammation on histology after successful hepatitis C(HCV)treatment has been reported.However,data regarding the long-term impact in liver transplant recipients is limited,particularly after using direct-acting antiviral(DAA)therapies.AIM To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients.METHODS We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014.All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy.Only patients with at least one liver biopsy at or after treatment were included.We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA.RESULTS Persistent inflammation was seen in 12/13 patients on end of treatment biopsy.Inflammation was still seen in the available five follow-up biopsies(range 38-48 wk after the end of treatment).Intrahepatic HCV RNA was undetectable in all biopsies.All patients had preserved graft function for a mean follow-up of 2.5 years,except one that developed chronic rejection.CONCLUSION After successful HCV treatment with DAAs,liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA.The clinical outcome remained favorable in most patients.Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.

Corticosteroid-free immunosuppression in liver transplantation: An evidence-based review

Thirty-six randomized controlled trials and two metaanalyses were reviewed. With respect to adult patients undergoing first orthotopic liver transplantation(OLT), steroid replacement resulted in fewer cases of overall acute rejection in the corticosteroid free-immunosuppression arm. Initial steroid administration for two weeks and early tacrolimus monotherapy is a feasible immunosuppression regimen without steroid replacement, although further investigations are needed in view of chronic rejections. No significant differences were noted between the treatment groups in terms of patient and graft survival independently of steroid replacement. Renal insufficiency, de novo hypertension, neurological disorders and infectious complications did not differ significantly among steroid and steroidfree groups. Diabetes mellitus, cholesterol levels and cytomegalovirus infection are more frequent in patients within the steroid group. With respect to diabetes mellitus and hypercholesterolemia, the difference was independent of steroid replacement. In relation to transplanted hepatitis C virus patients, mycophenolate mofetil does not appear to have a significant antiviral effect despite early reports. Male gender of donors and recipients, living donors, cold ischemia times, acute rejection, and early histological recurrence were related to the development of advanced hepatitis. There is sufficient scientific clinical evidence advocating avoidance of the ab initio use of steroids in OLT.

De novo autoimmune hepatitis in liver transplant: State-of-the-art review

In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necroinflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of nonorgan specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.

G-CSF in Peg-IFN induced neutropenia in liver transplanted patients with HCV recurrence

AIM:To evaluate the efficacy of granulocyte colony stimulating factors(G-CSF)in liver transplanted patients with hepatitis C(HCV)recurrence and Pegylated-IFN α-2b induced neutropenia,and to evaluate the impact of G-CSF administration on virological response. METHODS:Sixty-eight patients undergoing antiviral treatment for post-liver transplantation(OLT)HCV recurrence were enrolled.All patients developing neutropenia received G-CSF. RESULTS:Twenty three(34%)received G-CSF.Mean neutrophil count at the onset of neutropenia was 700/mmc(range 400-750/mmc);after 1 mo of G-CSF it increased to 1210/mmc(range 300-5590/mmc) (P<0.0001).Three patients did not respond to G-CSF. Treatment duration was similar in neutropenic and non-neutropenic patients.No differences in the rate of discontinuation,infections or virological response were observed between the two groups.G-CSF was protective for the onset of de novo autoimmune hepatitis(P<0.003). CONCLUSION:G-CSF administration is effective in the case of Peg-IFN induced neutropenia increasingneutrophil count,prolonging treatment and leading to sustained virological response(SVR)rates comparable to non-neutropenic patients.It prevents the occurrence of de novo autoimmune hepatitis.