Prediction of significant fibrosis in hepatitis C virus infected liver transplant recipients by artificial neural network analysis of clinical factors.

OBJECTIVES: Interest in developing noninvasive markers of liver fibrosis continues to increase, especially in recurrent hepatitis C virus infection after liver transplantation. Recently, a model for predicting significant fibrosis (bridging fibrosis and cirrhosis) on the basis of logistic regression and routine laboratory data has been proposed (logit model). The aim of the present study was to evaluate the accuracy of an artificial neural network, a technique reported to work better than logit models in complex biological situations, built on those same clinical variables and data set of patients, in predicting significant fibrosis. METHODS: The neural network was constructed on the training set of 414 protocol biopsies, from liver transplant recipients, and then tested on the remaining 96 biopsies, as validation set. Model performances of neural network and logit model were evaluated and compared by means of areas under receiver operating characteristic curves. RESULTS: With a cutoff value of >0.4 to predict significant fibrosis, the neural network provided sensitivity, specificity, positive and negative predictive values, respectively, of 100, 79.5, 60.5 and 100%, in the validation set. The performance of the neural network was significantly better than that of the logit model (in the validation set area under the curve = 0.93 vs. 0.84; P = 0.045). CONCLUSIONS: Artificial neural network provides accurate prediction of the presence or absence of significant fibrosis from clinical variables, allowing theoretically protocol liver biopsy to be avoided in several instances, a result of particular interest, given the lack of other types of reliable noninvasive indexes of fibrosis in the setting of transplantation.

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.

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.

Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression.

BACKGROUNDS/AIMS: Recurrent HCV-cirrhosis occurs in a substantial proportion of transplant recipients, with higher rates reported in patients who had recently received a transplant. Over-immunosuppression has been implicated in this more unfavorable outcome. To determine whether the implementation of specific measures aimed at reducing or avoiding negative predictive variables is associated with an improvement in the outcome of recurrent hepatitis C. METHODS: Comparative study between a cohort of patients who had recently received a transplant (2001-2004) and a historical group of HCV-infected patients transplanted before the implementation of two simple measures (1999-2000): (i) use of dual initial immunosuppression (steroids + cyclosporine neoral or tacrolimus); (ii) slow steroid tapering (>6 months). Yearly biopsies were performed in these recipients, and only those with at least one protocol biopsy and those with cholestatic hepatitis (regardless of follow-up) were included in the study. End-point: rate of HCV-related severe disease (defined as bridging fibrosis, cirrhosis or fibrosing cholestatic hepatitis) within the first year post-transplantation. RESULTS: Severe disease was significantly lower in this cohort compared to the historical group (26/90, 29% vs 25/52, 48%; p=0.02). While other factors remained unchanged between the two cohorts, the proportion of patients on triple-quadruple regimes and the number of boluses of methyl-prednisolone were lower and the duration of prednisone therapy longer in more patients who had recently received a transplant. CONCLUSIONS: Improving the outcome of recurrent hepatitis C may be achieved by reducing overall immunosuppression and avoiding abrupt variations in immunosuppression.

3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.

BACKGROUND: Mortality after liver transplantation depends on heterogeneous recipient and donor factors. Our aim was to assess risk of death and to develop models to help predict mortality after liver transplantation. METHODS: We analysed data from 34,664 first adult liver transplants from the European Liver Transplant Registry to identify factors associated with mortality at 3-months (n=21,605 in training dataset) and 12-months (n=18,852 in training dataset) after transplantation. We used multivariable logistic regression models to generate mortality scores for each individual, and assessed model discrimination and calibration on an independent validation dataset (n=9489 for 3-month model and n=8313 for 12-month model). FINDINGS: 2540 of 21,605 (12%) individuals in the 3-month training sample had died by 3 months. Compared with those transplanted in 2000-03, those transplanted earlier had a higher risk of death. Increased mortality at 3-months post-transplantation was associated with acute liver failure (adjusted odds ratio 1.61), donor age older than 60 years (1.16), compatible (1.22) or incompatible (2.07) donor-recipient blood group, older recipient age (1.12 per 5 years), split or reduced graft (1.96), total ischaemia time of longer than 13 h (1.38), and low United Network for Organ Sharing score (score 1: 2.43; score 2: 1.67). However, cirrhosis with hepatocellular carcinoma, alcohol cirrhosis, hepatitis C or primary biliary cirrhosis, donor age 40 years or younger, or less, hepatitis B, and larger size of transplant centre (> or = 70 transplants per year) were associated with improved early outcomes. The 3-month mortality score discriminated well between those who did and did not die in the validation sample (C statistic=0.688). We noted similar findings for 12-month mortality, although deaths were generally underestimated at this timepoint. INTERPRETATION: The 3-month and 12-month mortality models can be effectively used to assess outcomes both within and between centres. Furthermore, the models provide a means of assessing the risk of post-transplantation mortality, giving clinicians important data on which to base strategic decisions about transplant policy in particular individuals or groups.

[Liver retransplantation: outcome analysis in 50 patients]. / Retrasplante hepático: análisis de los resultados en 50 pacientes.

BACKGROUND AND OBJECTIVE: Liver re-transplantation (re-LT) is an accepted indication for some (technical problems, primary non-function [PNF]) but not all indications, particularly recurrence of the original disease, such as hepatitis C. We aimed to determine in our center: a) the rate of survival following re-transplantation for all and each different indication; b) to compare it to that obtained by a control group; c) to assess whether late re-LT, excluding PNF and surgical problems, and re-LT in HCV (+) patients are associated with a higher mortality, and d) to estimate medical costs. PATIENTS AND METHOD: Form 1991 to April 2002, 50 re-LT were done (group 1). Group 2 consisted of 45 primary LT controlled by transplant date. Group 1 was divided in two subgroups: a) re-LT after 6 months of the first LT (recurrence of primary liver disease n = 20, chronic rejection n = 5), b) Re-LT in the first 6 months (PNF n = 13, artery thrombosis n = 12). We analyzed donor, recipient, surgical and immunosuppressive-related variables. RESULTS: The mean age was 50 years (range: 23-63) (72% men). Actuarial survival for re-LT was lower than for the control group: 64%, 57% and 50% vs 84%, 82% and 82% at 1st, 3rd and 5th year, respectively. By indication, the 3-year survival was: PNF: 61% (p = 0.05), HAT: 58% (p = 0.02), recurrence of primary disease: 52% (p = 0.001), chronic rejection: 60% (p = 0.346). Although not reaching statistical significance, survival was lower in late vs early re-LT (p = 0.16) and in HCV-infected versus non-infected patients (p = 0.08). In the HCV (+) group, there were no differences by re-transplant indication (p = 0.8). Medical costs and complications were substantially higher in group 1 vs group 2. CONCLUSIONS: Re-LT is associated with substantial medical costs and mortality, particularly in patients infected with HCV.

Retrasplante hepático: análisis de los resultados en 50 pacientes / Liver retransplantation: outcome analysis in 50 patients

FUNDAMENTO Y OBJETIVO: Existen varias indicaciones para el retrasplante hepático (RTH), entre lasque destacan la disfunción primaria del injerto (DPI), las complicaciones técnicas y la recurrencia de la enfermedad de base, fundamentalmente la hepatitis C. Así como la indicación de RTH está bien consensuada en los fallos técnicos o la DPI, pero no en los pacientes con recurrencia de la hepatitis C. Los objetivos de este trabajo fueron analizar los resultados de RTH en nuestro centro por lo que respecta a: a) la supervivencia tras el RTH, según la indicación, en particular en relación con la infección por el virus de la hepatitis C (VHC), y b) los recursos utilizados frente a un grupo control sometido a un trasplante hepático primario. PACIENTES Y MÉTODO: De 1991 a 2002 se realizaron 50 RTH. Se identificaron dos grupos de pacientes: grupo 1 (n = 50), constituido por pacientes sometidos a RTH (13 por DPI, 12 por trombosis de la arteria hepática, 20 por recurrencia de la enfermedad primaria y 5 por rechazo crónico),y grupo 2 (n = 45), constituido por pacientes sometidos a un primer trasplante hepático controlados por fecha de éste. Se analizaron variables demográficas del donante y receptor, grado de esteatosis del donante, tiempo en unidad de cuidados intensivos (UCI) y sodio del donante, etiología del RTH, variables analíticas del receptor antes del trasplante, tiempos de isquemia y de intubación tras el trasplante y número de complicaciones durante el postoperatorio inicial. RESULTADOS: La edad media fue de 50 años (extremos: 23-63) y predominaban los varones (72%).La supervivencia actuarial al tercer año fue del 57%. Por indicación, la supervivencia fue similar entre los RTH por DPI frente a los RTH por problemas quirúrgicos (el 61 y el 58% a los 3 años, respectivamente). Por el contrario, la supervivencia fue inferior en los RTH por el VHC (el 52% a los 3 años) frente a otras causas (p = 0,08). Al comparar los grupos 1 y 2 se objetivaron las siguientes diferencias: edad del donante (25 frente a 47 años; p = 0,001), tipo de indicación (urgente frente a electivo: 14 frente a 2; p = 0,004), peor situación clínica en los RTH, mayor consumo de recursos y peor pronóstico (p = 0,04). Las variables independientemente relacionadas con la supervivencia fueron la infección por el VHC (p = 0,03), el número de complicaciones ocurridas durante la hospitalización tras el retrasplante (p = 0,01) y el tiempo de isquemia fría (p = 0,014).CONCLUSIONES: El RTH se asocia a un mayor consumo de recursos, con un número mayor de complicaciones y una mayor mortalidad que el trasplante primario. La infección por el VHC y la isquemia quirúrgica se asocian con una mayor mortalidad

BACKGROUND AND OBJECTIVE: Liver re-transplantation (re-LT) is an accepted indication for some (technical problems, primary non-function [PNF]) but not all indications, particularly recurrence of the original disease, such as hepatitis C. We aimed to determine in our center: a) the rate of survival following gre-transplantation for all and each different indication; b) to compare it to that obtained bya control group; c) to assess whether late re-LT, excluding PNF and surgical problems, and re-LT inHCV (+) patients are associated with a higher mortality, and d) to estimate medical costs. PATIENTS AND METHOD: Form 1991 to April 2002, 50 re-LT were done (group 1). Group 2 consisted of 45 primary LT controlled by transplant date. Group 1 was divided in two subgroups: a)re-LT after 6 months of the first LT (recurrence of primary liver disease n = 20, chronic rejection n = 5), b) Re-LT in the first 6 months (PNF n = 13, artery thrombosis n = 12). We analyzed donor, recipient, surgical and immunosuppressive-related variables. RESULTS: The mean age was 50 years (range: 23-63) (72% men). Actuarial survival for re-LT was lower than for the control group: 64%, 57% and 50% vs 84%, 82% and 82% at 1st, 3rdand 5th year, respectively. By indication, the 3-year survival was: PNF: 61% (p = 0.05), HAT:58% (p = 0.02), recurrence of primary disease: 52% (p = 0.001), chronic rejection: 60% (p =0.346). Although not reaching statistical significance, survival was lower in late vs early re-LT(p = 0.16) and in HCV-infected versus non-infected patients (p = 0.08). In the HCV (+) group, there were no differences by re-transplant indication (p = 0.8). Medical costs and complications were substantially higher in group 1 vs group 2.CONCLUSIONS: Re-LT is associated with substantial medical costs and mortality, particularly inpatients infected with HCV

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.

Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy.

BACKGROUND: Recurrent hepatitis C is very common leading to graft cirrhosis in a significant proportion of patients. Preliminary reports of combination therapy with interferon-ribavirin have been promising but generally applied to selected patients with chronic mild disease. Little is known, however, about the efficacy and risk of adverse effects when it is used in general clinical practice. AIMS: To analyse the efficacy (biochemical, virological and histological response) and tolerance of combination therapy in patients with recurrent hepatitis C genotype 1b. METHODS: Twenty-four patients (mean age 54 years; range 37-67 years; 75% male) with recurrent hepatitis C virus (histology at baseline: acute hepatitis (n = 3); chronic hepatitis (n = 21) with F3 or 4 in 77%) were treated with 12 months interferon (1.5-3 MU thrice weekly) + ribavirin (600-1200 mg daily) followed by 6 months ribavirin (58%), at a median of 427 days (56-2812) after transplantation. RESULTS: Seven patients (29%) discontinued therapy due to side effects, mainly anaemia, at a median of 3 months since initiation. Dose modifications were required in 88% of those completing the whole course of therapy. Overall, the sustained virological and biochemical response was 12.5%. This rate was slightly higher (18%) if only the 17 patients who finished the whole course of therapy were analysed. Histological improvement was achieved in 31.5% of treated patients. CONCLUSIONS: Combination therapy has a very limited efficacy in the liver transplant setting, although some benefit may be achieved, even in those with advanced graft fibrosis. Tolerance, however, remains a matter of concern.

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.

Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C.

The association between the severity of chronic hepatitis C and the variability of the hepatitis C virus (HCV) genome remains controversial, but to our knowledge few data are available to date regarding T-cell epitope coding regions in transplant patients. In the current study, we identified 21 human leukocyte antigen (HLA)-A2-positive Spanish patients with chronic hepatitis C, 14 immunosuppressed liver transplant recipients, and 7 immunocompetent controls. Alanine aminotransferase, aspartate aminotransferase, viral load, and rate of fibrosis progression were determined. Genetic distances of HCV isolates and variations in epitopes of the HCV nonstructural 3 protein (NS3-1393 LIFCHSKKK and NS3-1406 KLVALGINAV) were compared between patients with slow or fast progression of fibrosis. Isolates from transplant patients with fast progression were found to be more divergent (P =.03), had a higher mean value of synonymous (dS) variations (P =.02), and some were differentiated in a phylogenetic tree, compared with isolates from patients with slow progression. The HLA-A2-restricted NS3-1406 epitope was found to be more variable (20 of 21 isolates differed from the prototype) compared with the A3-restricted NS3-1392 epitope (19% vs. 1.25% variation). A shift in the viral peptide was not detected in a subset of transplant patients, but was evident in two of three nontransplant patients with follow-up. There was no correlation noted between a particular amino acid variation and fibrosis progression (slow or fast) in either transplant or nontransplant patients. The results of the current study suggest that 1) there may be different HCV-1b strains in our geographic area, 2) immunosuppression appears to have little effect in amino acid variation at the HCV NS3-1406 epitope, and 3) variations over time might be more frequent in nonimmunosuppressed patients.

Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.

The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver transplantations (LTs) performed on 39,196 patients in a 13-year period. After an exponential increase, the number of LTs is plateauing due to a lack of organs. To cope with this, alternatives to cadaveric LT, such as split LT, domino LT, or living-related LT (LRLT) are being used increasingly. They now account for 11% of all procedures. One of the most important findings in the evolution of LT is the considerable improvement of results along time with, for the mean time, a one-year survival of 83%, all indications confounded. The improvement is particularly significant for cancers. This improvement is mainly represented by hepatocellular carcinoma, with a gain of 17% for 5-year survival rate from 1990 to 2000. Increasingly, older donors are used to augment the donor pool and older recipients are transplanted due to improved results and a better selection of patients. More than two thirds of deaths and three quarters of retransplantations occurred within the first year of transplantation. Retransplantation is associated with much less optimal results than first LT. One of the prominent features of recent years is the development of LRLT. LRLT is now performed by almost half of the European centers. As with split LT or domino LT, LRLT aims to provide more patients to be transplanted. Special attention is paid to reducing the risk for the donor, which is now estimated to be 0.5% mortality and 21% postoperative morbidity.

Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?

Although histological hepatitis occurs in the majority of hepatitis C virus (HCV)-infected liver transplant recipients, the natural history is highly variable. Whereas progression to cirrhosis occurs in up to 30% after 3 to 7 years, the disease remains stable in another third of patients, in whom protocol liver biopsies might be avoided. However, there is recent concern that with prolonged follow-up, some patients with initial benign recurrence may develop a late-onset aggressive course. Aims of the study are to determine the incidence and factors associated with this event. Based on yearly protocol biopsies (median, five biopsies; range, three to seven biopsies), we evaluated the histological outcome of 57 HCV type 1b-infected transplant recipients with initial benign recurrence, defined as stable histological state (fibrosis stage F0 or F1) during the first 3 years posttransplantation. Severe late-onset liver damage is defined as progression to F3 or F4 in patients with previous benign recurrence. Potential predictors of this event include demographics, donor-related factors, liver enzyme levels at 1 and 3 (or baseline) years posttransplantation, activity grade and fibrosis stage at 1 and 3 years posttransplantation, nonalcoholic steatohepatitis-related variables occurring within the first 3 years posttransplantation (diabetes, hyperlipidemia, obesity), use of some drugs (renin-angiotensin inhibitors, ursodeoxycholic acid), and the advent of any unusual event. The incidence of severe late-onset liver damage was 35% (n = 20). Twelve transplant recipients progressed to F3, whereas 8 transplant recipients progressed to F4. Sudden histological deterioration was observed on postoperative biopsy 5 in 12 patients; biopsy 6 or 7, in 7 patients; and biopsy 4, in 1 patient. Variables associated with this event in univariate analysis were fibrosis stage and activity grade (and its components) at baseline (P <.0001), recipient female gender (P =.04), alanine aminotransferase (ALT) level at 1 year posttransplantation (P =.02), and aspartate aminotransferase (AST) and ALT levels at baseline (P =.008 and P =.005, respectively). By multivariate analysis, only one variable was retained in the model: fibrosis stage at baseline (relative risk, 11; 95% confidence interval, 3 to 41; P =.0007), whereas AST level almost reached statistical significance (P =.07). In conclusion, delayed HCV-related severe liver damage is not infrequent in transplant recipients with initial benign recurrence, occurring in approximately one third of them. The presence of some degree of fibrosis at baseline appears to predict this sudden change in the natural history of recurrent hepatitis C. Based on these findings, we recommend continuing protocol biopsies and evaluating potential antiviral therapy in transplant recipients with evidence of some fibrosis (even if it is only portal).

Validation and refinement of survival models for liver retransplantation.

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P <.0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P =.004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model chi(2) = 105, P <.0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.

Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus-related graft cirrhosis.

An increase in the number of hepatitis C virus (HCV)-infected transplant recipients at need for repeated liver transplantation is anticipated. To date, there is a certain reluctance to accept these patients because of an increased organ shortage, early reports suggesting a poor outcome, and uncertainty regarding the natural history of recurrent hepatitis C in the second graft. The aim of this study is to determine the outcome of patients undergoing retransplantation for HCV-related graft cirrhosis. Of 49 transplant recipients with HCV-related allograft cirrhosis, 31 patients developed decompensation with criteria for retransplantation. Thirteen patients were denied this option. Of the 18 patients accepted, 6 patients died while on the waiting list (5 patients died of graft cirrhosis at a median of 3.2 months of listing), and 12 patients have undergone retransplantation (median, 10 months since HCV cirrhosis). After retransplantation, 8 patients (67%) died at a median of 8 months, and 4 patients (33%) remain alive after 1.9 years of follow-up. Causes and times of death from retransplantation were: surgical complications, n = 3 (perioperative period); HCV cirrhosis of the second graft, n = 2 (at 9 and 54 months); fibrosing cholestatic hepatitis, n = 1 (at 2 years); lymphoproliferative disorder, n = 1 (at 7 months); and endocarditis, n = 1 (at 3.5 years, with underlying cirrhosis). Of the 4 patients alive, fibrosis stages in the last biopsy specimens are stage 1 (n = 1), stage 3 (n = 1), and stage 4 or cirrhosis (n = 1; one patient has not undergone biopsy), despite antiviral therapy. The outcome of retransplantation for HCV cirrhosis of the first graft is very poor because of multiple complications. The severity of recurrent HCV disease in the second graft seems to be related to that observed in the first graft.

Hepatocellular carcinoma: Can it be considered a controversial indication for liver transplantation in centers with high rates of hepatitis C?

Hepatocellular carcinoma (HCC) is still considered a controversial indication for liver transplantation (LT), mainly because of long waiting times and underlying viral cirrhosis. The goal was to evaluate the outcome of LT in 104 patients with HCC and cirrhosis, mainly hepatitis C virus (HCV)-related, in a center with a short waiting time (median, 105 days). Four groups were formed according to the HCC and HCV status: HCV positive with HCC (group 1, n = 81), HCV negative with HCC (group 2, n = 23), HCV positive without HCC (group 3, n = 200), and HCV negative without HCC (group 4, n = 207). Predictive factors of tumor recurrence were demographics, tumor related (size or number of nodules, capsule, bilobar involvement, vascular or lymphatic invasion, clinical and pathologic TNM staging, pre-LT percutaneous ultrasound-guided ethanol injection or transarterial chemoembolization, alpha-fetoprotein levels), donor and surgery related, and year of transplantation. The same variables and "tumor recurrence (yes/no)" were applied to evaluate the effect on survival. The median follow up was 29 months (range, 0 to 104 months). Patient survival was 70% at 1 year and 59% at 5 years for group 1, 87% at 1 year and 77% at 5 years for group 2, 81% at 1 year and 64% at 5 years for group 3, and 88% at 1 year and 77% at 5 years for group 4 (P =.013). Survival was significantly lower in patients with HCC than in those without (74% and 63% versus 85% and 70%, at 1 and 5 years, respectively; P =.05). The causes of death in those with and without HCC were tumor recurrence (24%) and recurrent HCV (8%) versus sepsis (34%) and recurrent HCV (14%). HCC recurrence occurred in 12 patients (11.5%) at a median of 14 months (range, 3 to 60 months) with a probability increasing from 8% at 1 year to 16% at 5 years. In patients with HCC, tumor recurrence was associated with vascular invasion (P =.0004) by multivariate analysis; variables predictive of survival were donor old age (P =.01), viral-related etiology (P =.02), and tumor recurrence (P =.001). Although LT still remains an adequate indication for HCC in centers with high prevalence of HCV infection and short waiting times, both tumor and HCV-related recurrent diseases hamper significantly the outcomes of these patients.

Contribution of obesity to hepatitis C-related fibrosis progression.

OBJECTIVE: Hepatitis C virus (HCV) disease progression is variable. Identification of factors predictive of rapid progression is an important goal for improving patient management. The aim of this study was to evaluate the predictive role of several variables, including some that are etiologically related to the nonalcoholic steatohepatitis (NASH) syndrome such us obesity, in fibrosis progression in both patients with elevated and normal transaminase levels. METHODS: A total of 114 chronic HCV-infected (HCV-RNA positive) patients were recruited prospectively between 2000 and 2001. All patients had at least one liver biopsy. The annual change in fibrosis stage (fibrosis progression rate) was assessed from the time of presumed infection (fibrosis = 0) among those who had only one biopsy (n = 97) or between two biopsies if these were available (n = 17). Based on published data, we arbitrarily defined a patient as a rapid progressor when the fibrosis progression rate was > 0.2 U/yr. Potential predictors of rapid progression were: age at infection and biopsy, sex, significant alcohol intake (> 50 g/day), risk factor of HCV acquisition (based on answers to a questionnaire), obesity (based on body mass index [BMI]), autoantibodies, iron overload (ferritin, transferrin saturation), diabetes, hyperlipidemia, anti-HBcore IgG, genotype, and viral load. RESULTS: The median fibrosis progression rate was 0.05 U/yr (range 0-1.58 yr). In all, 22 patients (19%) were rapid progressors. Variables associated with progression by multivariate analysis included: advanced age at infection (p = 0.0001), BMI > or = 25 (p = 0.01), and ALT > 1.5 times upper limit of normal (p = 0.01). Among patients with ALT > 1.5 times upper limit of normal, these variables were advanced age at infection, BMI > or = 25, diabetes and transferrin saturation > 45. Among those with normal ALT levels, only BMI > or = 30 was predictive of progression. CONCLUSIONS: Obesity, advanced age at infection, and elevated ALT levels predict rapid disease progression, suggesting that measures aimed at weight reduction may play a significant role in hepatitis C management. The natural history of hepatitis C is independent of the presence of autoimmunity markers.

Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients.

Recurrent hepatitis occurs in the majority of patients undergoing liver transplantation for hepatitis C virus (HCV) cirrhosis, with progression to cirrhosis in up to 30% after 5 years. Based on these data, a decrease in survival can be anticipated with prolonged follow-up. Furthermore, posttransplantation HCV-fibrosis progression has been shown in recent years to increase. Our aims were (1) to describe the natural history of HCV-infected recipients, particularly to determine whether survival has decreased in recent years; (2) to compare this outcome with that observed in non-HCV-infected cirrhosis controls; and (3) to determine the factors associated with disease severity and survival. Among 522 cirrhotic patients undergoing transplantation between 1991 and 2000, 283 (54%) were infected with HCV. Yearly biopsies were performed in these recipients and at 1 and 5 years in the remainder. With similar follow-up, the percentage of deaths in the HCV(+) group was significantly higher than in the HCV- group (37% vs. 22%, P <.001), and patient survival was lower (77%, 61%, 55% vs. 87%, 76%, 70% at 1, 5, and 7 years, respectively; P =.0001). Although survival has increased in the HCV- group in recent years, it has significantly decreased in HCV recipients (P <.0001). The main cause of death among the latter was decompensated graft cirrhosis (n = 23/105, 22%), whereas that of HCV- patients was infections (n = 10/52, 19%). Reasons for the recent worse outcome in HCV+ recipients include the increased donor age and stronger immunosuppression. In conclusion, patient survival is lower among HCV+ recipients than among HCV- ones and has been decreasing in recent years. The aging of donors is a major contributor to this worse outcome.

Implicaciones clínicas del diagnóstico genético de la hemocromatosis / Clinical implications of the genetic diagnosis of hemochromatosis

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