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 (kappa = 0.94 and kappa = 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.

Cirrhosis of mixed etiology (hepatitis C virus and alcohol): Posttransplantation outcome-Comparison with hepatitis C virus-related cirrhosis and alcoholic-related cirrhosis.

Hepatitis C virus (HCV)-related liver disease is enhanced by alcohol consumption. Of HCV-related liver transplantation (LT) recipients, 25% have a history of alcohol intake. The purpose of this research was to determine whether LT outcome differs between patients with cirrhosis of mixed etiology compared to HCV or alcohol alone. Of 494 LT (1997-2001), recipient/donor features, post-LT histological, metabolic complications [hypertension, diabetes-diabetes mellitus (DM)], and de novo tumors were compared in 3 groups [HCV-related cirrhosis = 170 (HCV group), alcohol-related cirrhosis (alcohol group) = 107, and cirrhosis of mixed etiology (mixed group) = 60]. Protocol biopsies were done in HCV patients. Severe recurrent HCV disease was defined as: 1-year fibrosis >1, cholestatic hepatitis, recurrent cirrhosis, or HCV-related liver retransplantation (reLT) within 5 years. Patients in the mixed group were younger (mean age: HCV group = 59 years; mixed group = 49 years; alcohol group = 53 years; P < 0.05) and mainly men (% men: HCV group = 51%; mixed group = 97%; alcohol group = 87%). Hepatocellular carcinoma (HCC) was more frequent in HCV patients (HCV group = 44%; mixed group = 35%; alcohol group = 18%; P = 0.05). Five-year survival was lowest in the HCV group (HCV group = 49% versus mixed group = 73% versus alcohol group = 76%; and P < 0.01 for the HCV group versus the alcohol group or the HCV group versus the mixed group; P = 0.74 for the alcohol group versus the mixed group). Metabolic complications and de novo tumors were more frequent in the alcohol groups. Severe HCV disease was similar in the HCV+ groups (HCV group = 45%; mixed group = 45%; P = 0.66). Patients with in the mixed group were more frequently treated with antivirals (32% versus HCV group = 18%; P = 0.03). In HCV patients, factors independently associated with lower survival were older donor age, LT indication (HCV alone), and increased body mass index (BMI). Antiviral therapy was a protective factor. Post-LT survival was lower in the isolated HCV group compared to the alcohol or mixed groups despite a similar recurrence of HCV disease. A greater use of antiviral therapy in the mixed group may explain these differences. The incidence of metabolic complications and de novo tumors was greater in the alcohol groups.

Worse recent efficacy of antiviral therapy in liver transplant recipients with recurrent hepatitis C: impact of donor age and baseline cirrhosis.

We hypothesized that antiviral efficacy [sustained virologic response (SVR)] has improved in recent years in the transplant setting. Our aim was to assess whether the efficacy of pegylated interferon (PegIFN)-ribavirin (Rbv) has improved over time. One hundred seven liver transplant patients [74% men, 55.5 years old (range: 37.5-69.5), 86% genotype 1a or 1b] were treated with PegIFN-Rbv for 355 (16-623) days at 20.1 (1.7-132.6) months after transplantation. Tacrolimus was used in 61%. Sixty-seven percent had baseline F3-F4 (cirrhosis: 20.5%). Donor age was 49 (12-78) years. SVR was achieved in 39 (36.5%) patients, with worse results achieved in recent years (2001-2003: n = 27, 46.5%; 2004: n = 23, 43.5%; 2005: n = 21, 35%; 2006 to January 2007: n = 36, 24%; P = 0.043). Variables associated with SVR in the univariate analysis included donor age, baseline viremia and cirrhosis, bilirubin levels, rapid virologic response and early virologic response (EVR), premature discontinuation of PegIFN or Rbv, and accumulated Rbv dose. In the multivariate analysis, the variables in the model were EVR [odds ratio (OR): 0.08, 95% confidence interval (CI): 0.016-0.414, P = 0.002] and donor age (OR: 1.039, 95% CI: 1.008-1.071, P = 0.01). Variables that had changed over time included donor age, baseline viremia, disease severity (cirrhosis, baseline bilirubin, and leukocyte and platelet counts), interval between transplantation and therapy, and use of growth factors. In the multivariate analysis, variables independently changing were donor age (OR: 1.041, 95% CI: 1.013-1.071, P = 0.004), duration from transplantation to antiviral therapy (OR: 1.001, 95% CI: 1.000-1.001, P = 0.013), and baseline leukocyte count (OR: 1.000, 95% CI: 1.000-1.000, P = 0.034). In conclusion, the efficacy of antiviral therapy with PegIFN-Rbv has worsened over time, at least in our center. The increase in donor age and greater proportion of patients treated at advanced stages of disease are potential causes.

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.

Severe hypoglycemia after gastric bypass surgery for morbid obesity.

Recently, hypoglycemia with endogenous hyperinsulinemia has been described after undergoing bariatric surgery because of morbid obesity. It has been theorized that after a gastric bypass surgery, some trophic factors affecting pancreatic beta cells could emerge. The authors present a case of morbidly obese patient with severe hypoglycemia 3 months after bariatric surgery. An abdominal helicoidally computed tomography scan showed a 1.7 cm tumor in the tail of the pancreas. Histopathology revealed an insulinoma with well-defined contours surrounded by pancreatic tissue with atrophic signs and with hyperplasia and hypertrophic phenomena compatible with nesidioblastosis in adjacent islets of the pancreatic duct. Authors hypothesize that maintenance of the stimulus produces hyperplasia/hypertrophy of the pancreatic islets and reemphasizes the dynamic qualities of pancreatic beta cells and the possibility of producing hyperplasia from the extreme resistance to insulin present in morbidly obese patients.

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.

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.

A model to predict severe HCV-related disease following liver transplantation.

Post-transplantation recurrence is increasing in patients with HCV. Early antiviral therapy may be of benefit in this setting. Thus, accurate and early prediction of progression may help select candidates for treatment. We developed a model based on pre- and/or early post-transplantation variables, which may predict progression to severe disease. Clinical and histologic outcomes were assessed in 554 liver recipients. A total of 1,353 biopsy specimens obtained after 1 year (median of 2 biopsies per patient; range, 1-8) were scored. Two outcome measures were used: cumulative probability of developing severe disease (fibrosis 3 and 4) within 5 years and actual progression to severe disease in 2 years. We used Cox proportional hazard survival analysis for the whole cohort. Predictors analyzed included HCV genotype and recipient, donor, and transplant-related variables. The cumulative risk of progressing to fibrosis 3 and 4 was significantly greater in patients transplanted recently (P <.001) and was present in all centers. Factors increasing this risk were genotype, induction with mycophenolate, donor age, short course of azathioprine, and prednisone (<12 months). To create a model of prediction, 285 patients with 2-year follow-up were used to create a logistic regression analysis. The estimated probability of being at high risk for severe disease was calculated from a formula that included donor age and recipient therapy as critical variables. In conclusion, we have developed a model that uses early post-transplantation variables to predict severe HCV recurrence. Accuracy of the model is not perfect (c-statistic 0.80), probably reflecting the complexity of HCV in the liver transplant setting.