Salvador Benlloch

Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C†

There are unresolved issues regarding sustained virological response (SVR), tolerance and risk of rejection following antiviral therapy in liver transplantation (LT). The aim of our study was to determine efficacy, rejection risk and factors associated with SVR. HCV‐infected LT patients with at least 6 months of follow‐up following end‐of‐therapy (EOT) received combination therapy of ribavirin (Rbvr) + standard (n=31)/pegIFN (n=36) between 1999 and 2004 (95% genotype 1). An EOT and SVR was obtained in 46% and 33%, respectively. Type of antiviral therapy, use of erythropoietin, compliance, and early virologic response (EVR) were predictive of SVR, but only the latter remained in the multivariate analysis. Premature discontinuation, not impacted by the use of erythropoietin or GCSF, occurred in 40% patients. None of the variables predicted rejection (acute n=2, chronic n=4). A SVR occurred in 3/4 patients with chronic rejection. In conclusion, the efficacy of pegIFN‐Rbvr is similar to the non‐transplant population. An EVR at 3 months is useful to predict lack of response. The type of calcineurin inhibitor and history of prior non‐response to IFN before LT do not influence the outcome of therapy. Severe rejection may lead to graft loss, a complication difficult to predict. Liver Transpl 12:1067–1076, 2006.

De Novo Internal Neoplasms after Liver Transplantation: Increased Risk and Aggressive Behavior in Recent Years?

The goal of the study was to determine the incidence and variables associated with post‐liver transplantation (LT) de novo internal neoplasms development, excluding skin tumors and hepatocellular carcinoma. Medical records were reviewed for recipient/donor demographics, viral serology, cause of liver disease, interval from LT to tumor diagnosis, predisposing factors, immunosuppression and survival. Forty‐one neoplasms (31 solid and 10 hematologic) developed in 772 recipients (5.3%) transplanted between 1991 and 2001. Time to tumor diagnosis was longer in patients transplanted before 1995 than in those transplanted afterwards (58 vs. 22 months; p < 0.05). Hematologic neoplasms (HN) appeared earlier than solid (2 vs. 21 months; p < 0.001), were more prevalent in those transplanted after 1995 than before (32% vs. 12.5%), and had lower survival than solid (2 vs. 21 months, p < 0.001). While HCV was the most frequent indication in HN (70%), alcohol was that of solid tumors (71%). Overall, risk factors for de novo neoplasms included alcohol and immunosuppression (p < 0.01). In patients undergoing LT in recent years, there is a higher incidence of HN with de novo internal neoplasms developing at earlier time‐points than in those transplanted years ago. Risk factors for tumor development include alcohol, HCV and possibly strong immunosuppression.

Effect of calcineurin inhibitors on survival and histologic disease severity in HCV‐infected liver transplant recipients

The severity of recurrent hepatitis C virus (HCV) is likely related to several factors. Controversial results have been reported regarding the effect of specific calcineurin‐inhibitors. The aim of this research was to determine whether there are differences on posttransplantation outcome in HCV‐infected patients based on initial immunosuppression. Prospective randomized trial comparing tacrolimus vs. cyclosporine‐based immunosuppression in a cohort of patients undergoing primary orthotopic liver transplantation between 2001 and 2003 was used. Yearly biopsies were performed. Patients with at least 1 protocol biopsy and those with very severe recurrence despite a follow‐up of less than 1 yr (cholestatic hepatitis, progression to bridging fibrosis/cirrhosis) were included. Baseline characteristics (demographics, liver function at transplantation, genotype distribution, donor, surgery, immunosuppression except for the type of calcineurin inhibitor) did not differ between the 2 groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, and/or death due to recurrent disease in the first year) was present in 27 in 90 (30%), and was equally distributed in the cyclosporine and tacrolimus groups (15/46 vs. 12/44, respectively). A total of 33 in 90 (37%) patients had no fibrosis in the first year biopsy with no difference between the cyclosporine and tacrolimus groups (36.5 vs. 37%). The percentage of patients developing recurrent acute hepatitis was also similar (32% vs 35%); time to acute hepatitis though was shorter in the tacrolimus group (59 days [35‐185] vs. 92 days [39‐343] in the cyclosporin group; P = 0.02). Cholestatic hepatitis was observed in 4 of 44 and 5 of 46 patients under cyclosporine and tacrolimus, respectively (P = not significant). In conclusions, the short‐term posttransplantation course of hepatitis C is not related to the calcineurin inhibitor used. Liver Transpl 12:762–767, 2006.

Prediction of fibrosis in HCV‐infected liver transplant recipients with a simple noninvasive index

Recurrent hepatitis C is a frequent event in liver transplantation (LT). Serial liver biopsies remain the best way of monitoring disease progression. Due to the limitations of a liver biopsy, there is an interest in developing noninvasive markers of liver fibrosis. While several models for predicting fibrosis have been constructed in patients who have not undergone transplantation, these are lacking in the transplant population. The aim of this study was to construct one simple model based on routine laboratory data to predict fibrosis in hepatitis C virus (HCV)‐infected LT patients. A total of 510 yearly protocol liver biopsies performed in 188 LT patients (67% male; median age 54 years) were divided into 2 groups: training set (n = 414) and validation set (n = 96). Laboratory variables at time of biopsies were recorded. Multivariate analysis identified 4 variables as independent predictors of fibrosis: prothrombin time (PT), albumin/total protein ratio, aspartate aminotransferase (AST), and time since LT. The area under the receiver operating characteristic (ROC) curves (AUCs) were 0.80 and 0.84 for the training and the validation set, respectively. In the training set, using a cutoff of 0.2, the model had a sensitivity, specificity, positive predictive value, and negative predictive value of 74%, 69%, 42%, and 90%, respectively, to differentiate significant (bridging fibrosis and cirrhosis) from mild fibrosis (none or portal). In the validation cohort, these values increased to 87%, 71%, 49%, and 95%, respectively. In conclusion, in the LT setting, a simple fibrosis index is useful to select HCV‐infected patients with a very low risk of significant fibrosis in whom protocol liver biopsies may be avoided. (Liver Transpl 2005;11:456–462.)

Effect of Calcineurin Inhibitors in the Outcome of Liver Transplantation in Hepatitis C Virus-Positive Recipients

Background. There is a paucity of good studies evaluating the impact of calcineurin inhibitors on posttransplantation outcome in hepatitis C virus (HCV)-infected liver transplant (LT) recipients. Methods. We sought to determine whether there are differences on posttransplantation survival and histologic recurrence in HCV-LT recipients based on initial immunosuppression (IS) by conducting a prospective study comparing tacrolimus (Tac) versus cyclosporine-based IS in patients undergoing LT between 2001 and 2007. Protocol liver biopsies were performed. Results. Baseline characteristics (demographics, liver function at LT, genotype distribution, donor, surgery, and IS except for the type of calcineurin inhibitor) did not differ between groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, or allograft loss or death because of recurrent disease in the first year) was present in 67 of 253 (26.5%) and was equally distributed in the CsA and Tac groups (27% vs. 26%; P=0.68). Two thirds of protocol biopsies performed at 1 year showed some fibrosis without differences between CsA and Tac groups (75% vs. 70%). Advanced fibrosis (bridging fibrosis and cirrhosis) was diagnosed in 30% CsA and 24.5% Tac patients (P=NS). No differences in survival at 1 and 7 years were observed (83% and 67% vs. 78% and 64%, respectively, P=0.4). In summary, in patients undergoing LT for HCV-related liver disease, posttransplantation outcome is not related to the calcineurin inhibitor used.

Prospective validation of a noninvasive index for predicting liver fibrosis in hepatitis C virus–infected liver transplant recipients

We previously developed a mathematical model, the Hospital Universitario La Fe (HULF) index, as an alternative to protocol liver biopsy (PLB) to estimate significant fibrosis (SF) in patients who underwent liver transplantation (LT) for liver damage caused by chronic HCV infection. In the present study, we sought to validate this noninvasive index. The commonly derived clinical and laboratory data for calculating the HULF index were prospectively collected over 2.7 years from patients undergoing LT and PLB. The sensitivity, specificity, positive and negative predictive values, and diagnostic capacity were evaluated with receiver operating characteristic curve analysis. Biopsy was performed 93 times in 86 LT patients. The prevalence of SF (F3‐F4 on the Knodell scoring system) was 32%. The intraobserver and interobserver concordance was high (κ = 0.94 and κ = 0.75, respectively) in identifying SF in PLB. For low scores, the HULF index discarded an SF diagnosis with a sensitivity of 90% and a negative predictive value of 89%. The area under the receiver operating characteristic curve was 0.68. The precision of the HULF index did not improve with the incorporation of donor age and body mass index into the multivariate analysis. Applying the index would have prevented 24% of the biopsy procedures performed. In conclusion, the HULF index was prospectively validated with data commonly obtained in standard clinical practice. Because the index distinguishes a subgroup of HCV LT patients with a low probability of having SF, PLB would be avoided in those patients. Liver Transpl 15:1798–1807, 2009.

Estudio de pacientes remitidos por elevación de la ferritina y/o saturación de la transferrina: importancia del hígado graso no alcohólico

Objetivo Determinar la etiologia de la elevacion de la ferritina y/o de la saturacion de la transferrina en pacientes en los que se han descartado las causas clasicas. Pacientes Y Metodo Se estudio a 43 pacientes (35 varones y 8 mujeres) remitidos tras la deteccion de unos valores de ferritinemia > 300 ng/ml y/o un indice de saturacion de transferrina (IST) > 40%. En todos se analizaron la glucemia, el colesterol, los trigliceridos, el acido urico, la bilirrubina total y fraccionada, las transaminasas, la gammaglutamiltranspeptidasa, la sideremia, el IST, la ferritina, las mutaciones del gen HFE, la ceruloplasmina y las porfirinas totales en orina de 24 h, y se les efectuo una ecografia abdominal. Se realizo una biopsia hepatica a 14 pacientes. Resultados El 53% presentaba sobrepeso y el 19%, obesidad. Se detecto alteracion del metabolismo hidrocarbonado en el 33%, hipercolesterolemia en el 14%, hipertrigliceridemia en el 35% e hiperlipemia de tipo IIb en el 16%. El 32% presentaba una elevacion aislada de la ferritina; el 12%, del IST, y el 56%, una elevacion de ambas. En el 61%, las transaminasas eran normales. En 10 pacientes no se observo ninguna mutacion del gen HFE, mientras que en 18 se detecto la mutacion H63D/wt; en 1, la C262Y/wt; en 5, la C282Y/H63D; en 4, la C282Y/C282Y; en 3, la H63D/H63D, y en 1, la Ser65cys/wt. Se evidencio esteatosis ecografica en 19 pacientes (44%). Los diagnosticos definitivos fueron hemocromatosis ligada al gen HFE (n = 4), hemocromatosis juvenil (n = 1), porfiria hepatocutanea (n = 1) e higado graso no alcoholico (n = 22; 51%). La mayoria de los restantes pacientes podian ser incluidos dentro del sindrome de resistencia a la insulina. Se efectuaron flebotomias en 25 pacientes, con mejoria clinicoanalitica. Conclusiones La deteccion de un higado graso no alcoholico es frecuente en pacientes remitidos por alteracion del metabolismo ferrico. En estos pacientes se debe buscar alteraciones metabolicas y realizar una ecografia hepatica y, si procede, una biopsia. Las flebotomias pueden ser utiles en el tratamiento.

Selección de candidatos para trasplante hepático

Liver transplantation is the treatment of choice in acute and irreversible chronic liver failure of distinct etiologies. Because of the current shortage of donor organs, careful selection of candidates for transplantation is required. In addition to specific prognostic models, there are general models, such as the Child-Pugh classification and the MELD system, which are useful in determining the optimal timing of liver transplantation in most patients with cirrhosis. Once the need for transplantation has been determined and the possibility of other available therapeutic measures has been ruled out, a multidisciplinary evaluation should be performed to assess the patients suitability for this procedure. This evaluation must rule out the presence of medical, surgical or psychological factors that could compromise patient or graft survival, making transplantation futile. The present review analyzes the most frequent contraindications to transplantation, as well as the most important aspects of pretransplantation evaluation.

Pseudoobstrucción colónica crónica secundaria a neurolépticos

Resumen La seudoobstruccion cronica del colon se caracteriza por una dilatacion cronica del colon de causa no mecanica. Es una entidad poco frecuente que puede ser desencadenada por multiples causas, entre ellas las farmacologicas. Presentamos el caso de una paciente psiquiatrica de 74 anos que tras recibir tratamiento con un neuroleptico (decanoato de zuclopentixol) presento distension abdominal, diarrea, alteraciones electroliticas intensas e importante dilatacion radiografica del colon. Tras descartar obstruccion organica y otras causas, el diagnostico final fue de seudoobstruccion colonica cronica secundaria al uso de neurolepticos. Se observo discreta mejoria sintomatica con cisaprida 20 mg/8 h, persistiendo la dilatacion de colon de forma permanente.

Impact of hepatitis C virus (HCV) antiviral treatment on the need for liver transplantation (LT)

Therapies for hepatitis C virus (HCV) infection have revolutionized the treatment of patients with chronic HCV infection. The effect of these therapies on the epidemiology of liver transplantation (LT) has yet to be elucidated.