Keith Rolles

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.

A systematic review of the performance of the model for end-stage liver disease (MELD) in the setting of liver transplantation.

The Model for End‐Stage Liver Disease (MELD) score is now used for allocation in liver transplantation (LT) waiting lists, replacing the Child‐Turcotte‐Pugh (CTP) score. However, there is debate as whether it is superior to CTP score to predict mortality in patients with cirrhosis on the LT waiting list and after LT. We reviewed studies comparing the accuracy of MELD vs. CTP score in transplantation settings. We found that in studies of the LT waiting list (12,532 patients with cirrhosis), only 4 of 11 showed MELD to be superior to CTP in predicting short‐term (3‐month) mortality. In addition, 2 of 3 studies (n = 1,679) evaluating the changes in MELD score (ΔMELD) showed that ΔMELD had better prediction for mortality than the baseline MELD score. The impact of MELD on post‐LT mortality was assessed in 15 studies (20,456 patients); only 6 (9,522 patients) evaluated the discriminative ability of MELD score using the concordance (c) statistic (the MELD score had always a c‐statistic < 0.70). In 11 studies (19,311 patients), high MELD score indicated poor post‐LT mortality for cutoff values of 24‐40 points. In re‐LT patients, 2 of 4 studies evaluated the discriminative ability of MELD score on post‐LT mortality. Finally, several studies have shown that the predictive ability of MELD score increases by adding clinical variables (hepatic encephalopathy, ascites) or laboratory (sodium) parameters. On the basis of the current literature, MELD score does not perform better than the CTP score for patients with cirrhosis on the waiting list and cannot predict post‐LT mortality. Liver Transpl 12:1049–1061, 2006.

Interrelationships among Quantity of Human Cytomegalovirus (HCMV) DNA in Blood, Donor-Recipient Serostatus, and Administration of Methylprednisolone as Risk Factors for HCMV Disease following Liver Transplantation

Longitudinal analysis of 162 liver transplant recipients identified 51 patients who were viremic. Virus load was determined in 47 of these patients using quantitative-competitive polymerase chain reaction. Peak virus load was significantly higher in 20 symptomatic patients than 27 asymptomatic patients (P < .0001). Elevated virus load, donor seropositivity, and total methylprednisolone dosage were risk factors for human cytomegalovirus (HCMV) disease (odds ratio [OR], 2.22/0.25 log10 increase in virus load, P = .001; OR, 4.11, P = .05; OR, 1.30/1-g increment in methylprednisolone, P = .01). Methylprednisolone and virus load were independent risk factors in a multivariate analysis (OR, 2.70/1-g increase, P = .003; OR, 1.61/0.25 log10 increase, P = .03, respectively). Virus loads of 10(4.75)-10(5.25) genomes/mL of blood were associated with an increased disease probability; the latter was shifted to lower virus loads with increasing quantities of methylprednisolone. These data illustrate the central role of virus load in HCMV pathogenesis.

Human herpesviruses 6 and 7 as potential pathogens after liver transplant: Prospective comparison with the effect of cytomegalovirus†

Because cytomegalovirus (CMV) is an important opportunistic infection after liver transplant, we conducted a prospective study to see if the same applied to human herpesviruses (HHV)‐6 and ‐7. We used polymerase chain reaction (PCR) methods optimised to detect active, not latent, infection and studied patients not receiving antiviral prophylaxis for CMV. Post‐transplant, 536 blood samples were tested by PCR (median 7; range 4–50). Active infection with CMV was detected in 28/60 (47%), HHV‐6 in 19/60 (32%), and HHV‐7 in 29/60 (48%) of patients. The PCR‐positive samples were tested by quantitative‐competitive PCR to measure the virus load of each betaherpesvirus. The median peak virus load for CMV was significantly greater than that for HHV‐6 or HHV‐7. Detailed clinicopathological analyses for the whole population showed that CMV and HHV‐6 were each significantly associated with biopsy‐proven graft rejection. Individual case histories suggested that HHV‐6 and HHV‐7 may be the cause of some episodes of hepatitis and pyrexia. It is concluded that HHV‐6 is a previously unrecognized contributor to the morbidity of liver transplantation, that HHV‐7 may also be important and that both viruses should be included in the differential diagnosis of graft dysfunction. J. Med. Virol. 59:496–501, 1999.

Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation

Liver transplantation (LT) is the only therapeutic option for end‐stage primary sclerosing cholangitis (PSC), but PSC can recur (rPSC) in some patients after LT. The aim of our study was to evaluate the risk factors associated with rPSC. Between 1989 and 2004, 69 patients receiving transplantation for PSC (42 male, mean age 41.9 yr). Clinical and laboratory data, activity/extension and treatment of ulcerative colitis (UC), post‐LT cytomegalovirus (CMV) infection, and immunosuppression were evaluated. Determination of rPSC was made by radiological and histological findings. Exclusion criteria were ABO blood group incompatibility, hepatic artery stenosis, and biliary strictures occurring in <3 months post‐LT. A total of 48 (70%) patients had PSC and UC pre‐LT. rPSC occurred in 7 of 53 (13.5%, 2 patients with de novo UC) who were alive 1 yr after LT and/or met inclusion/exclusion criteria: median 60 (4‐120) months. No patient without post‐LT UC had rPSC: 0 of 20 vs. 7 of 26 with post‐LT UC (P = 0.027). The multivariate logistic regression analysis showed that maintenance steroids for UC (>3 months) post‐LT was the only risk factor significantly associated with rPSC (P = 0.025). In conclusion, the presence of UC post‐LT, and the need for maintenance steroids post‐LT, which is an independent factor, are associated with rPSC. These findings could help elucidate a possible mechanism of PSC pathogenesis. Liver Transpl, 2007.

Ulcerative colitis has an aggressive course after orthotopic liver transplantation for primary sclerosing cholangitis

Background—The course of inflammatory bowel disease after liver transplantation has been reported as variable with usually no change or improvement, but there may be an increased risk of early colorectal neoplasms. In many centres steroids are often withdrawn early after transplantation and this may affect inflammatory bowel disease activity. Aims—To evaluate the course of inflammatory bowel disease in primary sclerosing cholangitis transplant patients who were treated without long term steroids. Methods—Between 1989 and 1996, there were 30 patients transplanted for primary sclerosing cholangitis who survived more than 12 months. Ulcerative colitis was diagnosed in 18 (60%) patients before transplantation; two had previous colectomy. All patients underwent colonoscopy before and after transplantation and were followed for 38 (12–92) months. All received cyclosporin or tacrolimus with or without azathioprine as maintenance immunosuppression. Results—Ulcerative colitis course after transplantation compared with that up to five years before transplantation was the same in eight (50%) and worse in eight (50%) patients. It remained quiescent in eight and worsened in four of the 12 patients with pretransplant quiescent course, whereas it worsened in all four patients with pretransplant active course (p=0.08). New onset ulcerative colitis developed in three (25%) of the 12 patients without inflammatory bowel disease before transplantation. No colorectal cancer has been diagnosed to date. Conclusions—Preexisting ulcerative colitis often has an aggressive course, while de novo ulcerative colitis may develop in patients transplanted for primary sclerosing cholangitis and treated without long term steroids.

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.

Immunosuppression and Donor Age With Respect to Severity of HCV Recurrence After Liver Transplantation

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13–73) and median follow‐up of 38 months (1–155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short‐term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage ≥ 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76‐4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23‐0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage. (Liver Transpl 2005;11:386–395.)

Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens

BACKGROUND The role of the type of immunosuppression in the natural history of post-transplant hepatitis C virus (HCV) infection is unclear. AIMS To evaluate the fluctuation of HCV viraemia and the early course of infection, and their relation to the type of immunosuppression in HCV transplant patients. METHODS In 47 HCV transplant patients, serum HCV RNA levels were determined pretransplant and at one and two weeks, and three and 12 months after transplant. Initial immunosuppression was triple (cyclosporin, azathioprine, prednisolone) in 31, double (cyclosporin, prednisolone) in five, and single (cyclosporin or tacrolimus) in 11 patients. Prednisolone was withdrawn at a median of six months. RESULTS At three months, HCV RNA levels were higher in patients with single than with triple or double initial therapy. At 12 months, HCV RNA levels correlated only with duration of prednisolone treatment and were relatively higher in patients with triple compared with single initial immunosuppression. A higher necroinflammatory activity at 12 months post-transplant was found in patients with post-transplant acute hepatitis compared with those without. Extent of fibrosis at 12 months was associated with the 12 month HCV RNA level and occurrence of post-transplant acute hepatitis. CONCLUSIONS HCV RNA levels at three months after transplant are higher in patients treated with single initial immunosuppressive therapy, but at 12 months are higher in patients with longer duration of steroid treatment. HCV viraemia at 12 months seems to be particularly important, as its levels are strongly correlated with the severity of fibrosis.

A Simulation Modelling Approach to Evaluating Alternative Policies for the Management of the Waiting List for Liver Transplantation

A shortage of donor liver grafts unfortunately results in approximately 10% of patients dying whilst listed for a liver transplant in Europe and the United States. Thus it is imperative that all available organs are used as efficiently as possible. This paper reports upon the application of a simulation modelling approach to assess the impact of several alternative allocation policies upon the cost effectiveness of this technology at one liver transplant centre in the UK. The impact of changes in allocation criteria on the estimated net life expectancy, average net costs and overall cost effectiveness of the transplantation programme were evaluated. The incremental cost effectiveness ratio (ICER) for the base case allocation policy, based upon the time spent on the waiting list (i.e., longest wait first) was £11,557 at 1999 prices. The ICERs associated with an allocation policy based upon age (lowest age first), and an allocation policy based upon the severity of the pre-transplant condition of the patient (with most severely ill patients given a lower priority) were lower than the base case at £10,424 and £9077, respectively. The results of this modelling study suggest that the overall cost effectiveness of the liver transplantation programme could be improved if the current allocation policy were modified to give more weight to the age of the patient and the reduced chances of success of the most severely ill patients.