F. Agnelli

Transient elastography predicts fibrosis progression in patients with recurrent hepatitis c after liver transplantation

Objective: Transient elastography (TE) allows non-invasive evaluation of the severity of liver disease in patients with chronic hepatitis C. This procedure, however, warrants further validation in the setting of liver transplantation (LT), including patients under follow-up for recurrent hepatitis C. Setting: Tertiary referral hospital. Patients: 95 patients (75 males) transplanted for end-stage liver disease due to hepatitis C virus. Interventions: Paired liver biopsy (LB) and TE were carried out 6–156 (median, 35) months after LT. 40 patients with recurrent hepatitis C sequentially evaluated 6–21 months apart. Main outcome measures: Clinical, laboratory and graft histological features influencing TE results. Results: Median TE values were 7.6 kPa in the 90 patients with a successful TE examination, being 5.6 kPa in the 30 patients with Ishak fibrosis score (S) of 0–1, 7.6 kPa in the 38 with S2–3; 16.7 kPa in the 22 with S4–6, (p<0.0001). Areas under the ROC curves were 0.85 (95% CI, 0.76 to 0.92) for S⩾3, 0.90 (95% CI, 0.82 to 0.95) for S⩾4 with 7.9 and 11.9 kPa optimal TE cut-off (81% and 82% sensitivity, 88% and 94% negative predictive value, respectively). Fibrosis, necroinflammatory activity and higher than 200 IU/l gamma-glutamyl transpeptidase levels independently influenced TE results. During post-LT follow-up, TE results changed in parallel with grading (r = 0.63) and staging (r = 0.71), showing 86% sensitivity and 92% specificity in predicting staging increases. Conclusions: TE accurately predicts fibrosis progression in LT patients with recurrent hepatitis C, suggesting that protocol LB might be avoided in patients with improved or stable TE values during follow-up.

Role of lamivudine in the posttransplant prophylaxis of chronic hepatitis B virus and hepatitis delta virus coinfection.

Background. Posttransplant combined lamivudine (LAM) and immunoglobulin (HBIg) prophylaxis is the gold standard in the case of single hepatitis B virus (HBV), but is still not recommended in the case of patients coinfected with hepatitis delta virus (HDV). Methods. We compared two consecutive groups of chronic HDV carriers who survived >6 months after liver transplantation of the risk of recurrence, survival and HBIg requirements: 21 received passive prophylaxis (HBIg group) and 25 were treated with combined prophylaxis (LAM+HBIg group). The immunoprophylaxis schedule was the same in both groups: intramuscular HBIg targeted to maintain anti-HBs levels of >500 IU/L during the first 6 posttransplant months and >200 IU/L thereafter. Results. The mean length of follow-up in the two groups was significantly different (133 vs. 40 months; P<0.001). None of the patients in either group developed recurrent hepatitis, and the 3-year actuarial survival rate was 100% in both groups. During the first 6 months, HBIg requirement was 38% lower in the LAM+HBIg group although similar anti-HBs target levels were maintained, leading to significantly lower costs (&OV0556;5,000 in the first year and &OV0556;500 in the second). Conclusions. This is the first study of large and homogeneous cohort of long-term HDV coinfected liver transplant survivors showing the absence of HBV recurrence under combined prophylaxis. Although retrospective, our results suggest that combined anti-HBV prophylaxis should also be preferred to single immunoprophylaxis in patients with HDV coinfection because it allows significant cost savings in the first two posttransplant years.

Metabolic syndrome after liver transplantation : short-term prevalence and pre- and post-operative risk factors

BACKGROUND The metabolic syndrome is a common condition among liver transplanted patients and contributes to morbidity and mortality by favouring the development of cardiovascular diseases. AIMS This prospective study assessed the prevalence of metabolic syndrome in the first year after orthotopic liver transplantation, the associated pre-operative and post-operative risk factors and the influence of nutritional factors. METHODS 84 cirrhotic patients (75% male, mean age 53.9±9.3 years) were evaluated at baseline and after liver transplantation. Metabolic syndrome was defined according to 2004 Adult Treatment Panel-III criteria. Nutritional habits were assessed using 3-day food records. RESULTS Prevalence of metabolic syndrome before orthotopic liver transplantation was 14/84 (16.6%); at 3, 6 and 12 months post-orthotopic liver transplantation it was 27/84 (32.1%), 30/84 (35.7%), and 32/81 (39.5%), respectively. Diabetes, family history of diabetes, and excess body weight at baseline independently correlated with incidence of metabolic syndrome. After orthotopic liver transplantation, patients with metabolic syndrome showed a higher increase in the intake of total energy and saturated fats and a higher prevalence of complications, especially cardiovascular events, than subjects without metabolic syndrome. CONCLUSION Occurrence of metabolic syndrome is an early phenomenon after liver transplantation. Pre-operative and post-operative factors predispose patients to metabolic syndrome, which may be reduced by controlling modifiable risk factors, such as body weight and dietary intake.

Prospective study of natural killer cell phenotype in recurrent hepatitis C virus infection following liver transplantation.

BACKGROUND/AIMS Graft re-infection invariably occurs after liver transplantation (OLT) for chronic hepatitis C and disease progression is unpredictable. We prospectively examined peripheral blood mononuclear cells (PBMC) subsets and natural killer (NK) cell receptors (NKRs) in patients with recurrent hepatitis C post-OLT. METHODS PBMC were obtained at baseline and at different time points after OLT. NKRs were identified using monoclonal antibodies by flow cytometry. RESULTS The proportions of NK, natural T (NT), total and gammadelta T cells were significantly reduced (p<0.01) 7 days post-transplant, probably as a result of graft repopulation. NKG2D+ NK cells were significantly higher compared with healthy controls (p<0.01), declined post-OLT and subsequently returned to baseline values. This, together with a progressive increase in the proportion of CD94/NKG2C+ NK cells over time (p< or = 0.01), appeared to be related to hepatitis C recurrence. There was a statistically significant correlation between expression of the natural cytotoxicity receptors (NCRs) and ALT (p<0.05), supporting the hypothesis that NK cells participate in the necroinflammatory process. CONCLUSIONS The data are compatible with homing of immune cells to the liver allograft after surgery, most of which return to pre-OLT levels. HCV recurrence may cause variations in selected NKRs expression akin to other viral infections.

Sclerosing Cholangitis and Liver Transplantation in Langerhans Cell Histiocytosis: A 14-Year Follow-Up

Langerhans cell histiocytosis (LCH) is a rare disorder characterized histologically by the proliferation of cells with features similar to the Langerhans cell of the epidermis. Clinical presentation varies from benign localized forms to fulminant multisystem disease associated with high rates of morbidity and mortality [1]. Among the organ localizations, liver involvement is present in about one third of children with disseminated LCH [2] whereas it is considered to be less common in adults; it may occur without signs of hepatic dysfunction but can also lead to serious complications, most notably sclerosing cholangitis (SC) [3]. We report here the case of a 41-year-old woman having multisystem LCH who developed SC 2 years after the diagnosis of LCH. Interestingly, the patient received a successful liver graft and has shown no evidence of active LCH lesions following transplantation for 14 years.

ERCP and short-term stent-trial in patients with anastomotic biliary stricture following liver transplantation

BACKGROUND Anastomotic biliary stricture represents one of the possible factors leading to liver dysfunction after transplantation. PURPOSE Our aims were to evaluate the role of endoscopic retrograde cholangio-pancreatography and a short-term stenting (stent-trial) in assessment of the clinical relevance of the biliary stricture. MATERIALS AND METHODS Thirty transplanted patients for HCV (n=17) or non-HCV (n=13)-related cirrhosis (27M, median age 53 yr, range 24-67 yr) who developed persistently abnormal liver function tests and presented with an anastomotic biliary stricture suggested by non-invasive cholangiography, underwent endoscopic retrograde cholangio-pancreatography. If the stricture was confirmed, dilation was performed and a plastic stent was placed. Clinical and biochemical evaluation was done one and two months later. Resolution of symptoms and normalization or > 50% reduction of at least one liver function test were needed to consider the stricture as clinically relevant. Patients were followed up for a median of 19 months. RESULTS Endoscopic retrograde cholangio-pancreatography was successful in 29 patients and confirmed the anastomotic biliary stricture in 19 (66%); 14 patients underwent endoscopic dilation and stenting and five patients underwent surgery. The stent-trial suggested the stricture to be clinically relevant in 7 of 14 patients, confirmed by prolonged stenting and follow-up. A trend towards a higher likelihood of a clinically relevant stricture was observed in HCV-negative compared to HCV-positive patients (5 of 7, 71% vs 2 of 7, 29% , respectively; p=0.1). CONCLUSIONS Our data suggest that endoscopic retrograde cholangio-pancreatography is a valuable tool to evaluate the clinical relevance of an anastomotic stricture, when coupled with a short-term stent-trial.

The course of inactive hepatitis B in hepatitis-C-coinfected patients treated with interferon and ribavirin.

BACKGROUND Interferon (IFN) combined with ribavirin (RBV) is an effective therapy for hepatitis C virus (HCV)-infected patients. Those who are coinfected with hepatitis B virus (HBV), however, might suffer from HBV reactivation. The aim of this study was to assess HBV reactivation in HCV-coinfected inactive HBV carriers following IFN/RBV. METHODS A total of 32 HBV carriers with <or=4 log(10) copies/ml HBV DNA and with chronic hepatitis C were consecutively evaluated; 22 (16 men, median age 52 years and 11 with cirrhosis) received RBV associated to either standard IFN (n=14) or pegylated (PEG)-IFN-alpha2b (n=8) for 24 or 48 weeks, according to HCV genotype. Serum alanine aminotransferase (ALT), HBV DNA (lower limit of quantification 2,000 copies/ml) and HCV RNA (limit of detection 25 IU/ml) were evaluated every 3-6 months during the study period. RESULTS Nine (41%) patients had a sustained virological response (SVR). In 3 patients (14%; 1 SVR and 2 non-responders) serum HBV DNA increased to >4 log(10) copies/ml (range 5.2-6.5 log(10) copies/ml); however, these patients had no ALT flare either on treatment (n=2) or off treatment (n=1). During follow-up, 8 (36%) treated patients and 4 controls lost serum hepatitis B surface antigen (HBsAg; annual rate 6.5% versus 6.9%; P-value non-significant), whereas 4 and 2 patients seroconverted to antibodies against HBsAg, respectively. Hepatocellular carcinoma developed in 1 patient with SVR and 1 non-responder under nucleoside therapy for HBV, both with cirrhosis. No patient clinically decompensated. CONCLUSIONS Inactive HBV carriers coinfected with HCV might achieve an SVR following IFN/RBV. Combination therapy carries a low risk of on- and off-treatment HBV reactivation and does not prevent HBsAg seroclearance.

Serum autoantibodies against cytochrome P450 2E1 (CYP2E1) predict severity of necroinflammation of recurrent hepatitis C.

We previously reported that autoantibodies against cytochrome P4502E1 (CYP2E1) are frequent in patients with chronic hepatitis C. As autoimmune reactions are increasingly detected after orthotopic liver transplantation (OLT), this study investigates prevalence and significance of anti‐CYP2E1 autoantibodies in 46 patients with post‐OLT recurrent hepatitis C.

Might rapid virological response be used as a stopping rule in liver transplant recipients treated with pegylated interferon plus ribavirin

We read with interest the article by Hanouneh et al. on the prediction of pegylated interferon plus ribavirin (P/R) response in liver transplant (LT) recipients with histologically proven recurrent hepatitis C. As highlighted by the authors, the management of problematic patients such as graft recipients can be eased by early kinetics of hepatitis C virus (HCV), that is, HCV-RNA clearance at week 4 [rapid virological response (RVR)] and a 2-log drop of HCV-RNA at week 12 [early virological response (EVR)], which predict treatment outcome. However, although in LT patients EVR has an absolute negative predictive value (NPV) for P/R treatment outcome, the NPV and positive predictive value (PPV) of RVR are far from being absolute, even in non-LT patients. We were therefore surprised by Hanouneh et al.’s findings of RVR having 100% PPV and 88% NPV in LT patients receiving P/R. We think that the RVR accuracy discrepancies between this study and other studies might reflect differences in the performance of the studies; for example, many patients (38%) in the present series were not tested for serum HCV-RNA at week 4 of treatment. We treated with P/R 46 patients transplanted for end-stage HCV with inclusion criteria similar to those investigated by Hanouneh et al. The treatment was intended for 48 weeks, being independent of the genotype or virological response to either peginterferon alfa-2a or peginterferon alfa-2b weekly, whereas the ribavirin dosing was less than that in Hanouneh et al.’s study (400-600 versus 1000-1200 mg/day). Serum HCV-RNA levels were assessed at baseline and at 4 weeks, 12 weeks, 48 weeks, and 6 months after the completion of therapy, and most patients received growth factors. The 2 cohorts were similar for clinicovirological features but differed in terms of the prevalence of non-Caucasians and body mass index (lower in our cohort). Cyclosporine A (CSA)–based immunosuppression was higher in our patients than in the American cohort (48% versus 17%). The rates of SVR were 41% and 35%, respectively, with a preference for genotypes 2 and 3 in both (76% versus 87%). The SVR rates in the 2 cohorts are in line with those reported by recent studies on P/R-treated HCV recipients ranging from 30% to 45%. In our patients, RVR had 86% PPV and 78% NPV (see Table 1), that is, midway between the data of Hanouneh et al. and other data. The results indicate that RVR is a good predictor of treatment outcome in LT patients with recurrent hepatitis C; however, it is not accurate enough to become a stopping rule of P/R therapy. In our cohort, CSA-based immunosuppression was independently associated with SVR in multivariate analysis (odds ratio 6.65, 95% confidence interval 1.79-24.7, P 0.005), and this supports the synergic anti-HCV effect of CSA and interferon already demonstrated in vitro and in vivo. This was not investigated by Hanouneh et al. because the majority of their patients received tacrolimusbased immunosuppression. The higher dose of ribavirin in the American patients with respect to ours might have been beneficial in terms of SVR, too.