Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial.

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.

Alpha-1-antitrypsin deficiency: outcomes after liver transplantation.

Alpha-1-antitrypsin deficiency (AAT) is the most common inherited metabolic disease leading to liver transplantation (LT) in children and adults. The aim of the study was to determine transplantation trends and survival of LT recipients with AAT. Using the UNOS (United Network for Organ Sharing) database, we identified 567 patients who underwent LT and 3 who received lung and LT from 1995 to 2004. AAT accounted for 1.06% of all adult LTs and 3.51% for pediatric LT. The 1-, 3-, and 5-year patient survival was 89%, 85%, and 83%, respectively, for adults versus 92%, 90%, and 90% for pediatric patients (P = .04), and graft survival was 83%, 79%, and 77% for adults versus 84%, 81%, and 78% for pediatric patients (P = .51). By regression analysis, age was the only predictor for patient survival (P = .04). In conclusion, adult and pediatric LT recipients with AAT are predominantly of Caucasian ethnicity and have an excellent post-LT survival.

Managing chronic hepatitis C in relapsers and non-responders.

Chronic hepatitis C virus (HCV) infection poses a challenge for a growing number of infected patients who exhibit disease complications, including cirrhosis, hepatocellular carcinoma, and liver failure. Treatment with pegylated interferon (peg-IFN) plus ribavirin improves hepatic markers and eradicates the virus in about 50% of patients; however, a significant number of patients do not respond to therapy or relapse following treatment discontinuation. Several viral, hepatic, and patient-related factors influence response to IFN therapy; many of these factors cannot be modified to improve long-term outcomes. Identifying risk factors and measuring viral load early in the treatment can help to predict response to IFN therapy and determine the need to modify or discontinue treatment. Treatment options for complicated cases of chronic HCV infection are limited. Retreatment with peg-IFN has been successful in some patients who exhibit an inadequate response to conventional IFN treatment, particularly those who have relapsed. Consensus IFN, another option in treatment-resistant patients, has demonstrated efficacy in the retreatment of non-responders and relapsers. Although optimal duration of retreatment and benefits and safety of maintenance therapy have not been determined, an extended duration is likely needed. Anti protease inhibitor drugs, the new frontier of HCV treatment, are now searched as the future answer in the treatment of difficult patients. Unfortunately the results are still confined in a preliminary phase. This article reviews risk factors for HCV treatment resistance and discusses assessment and management of difficult-to-treat patients such as non responders or relapsers to previous treatment.

Acquired platelet dysfunction with spontaneous intramuscular hematoma and compartment syndrome in cirrhosis.

Cirrhosis patients are at high risk for bleeding as a result of decreased platelet counts and impaired function, defective production of coagulation factors and abnormalities in clot lysis. The authors report the case of a 58 year-old man with cryptogenic cirrhosis who presented initially with intramuscular hematoma in the thigh which progressed to compartment syndrome. The patient developed disseminated progressive intramuscular hematomas in the muscles of chest, abdomen and finally retroperitoneal hemorrhage secondary to probable accelerated intravascular coagulation and fibrinolysis (AICF) culminating in death. This case highlights many of the common coagulation abnormalities seen in cirrhosis. The authors speculate the sequence of events in our patient at every level of the coagulation cascade which could have lead to this fatal outcome.

Long-term analysis of primary nonfunction in liver transplant recipients.

UNLABELLED: Long-term allograft and patient survival following liver transplantation continues to improve with the development of new surgical techniques and immunosuppressive agents. Complications such as primary nonfunction (PNF) have not been well characterized in terms of long-term allograft and patient survival. The aim of this study was to determine the incidence of PNF in liver transplant recipients and patient and graft survival, in addition to identifying temporal trends in these parameters. METHOD: Data were obtained from the United Network for Organ Sharing/Organ Procurement and Transplant Network for all adults (>18 years old) who received a deceased donor liver transplant between January 1990 and December 2004. RESULTS: Of the 58,576 liver transplant recipients, 2061 had PNF, an overall incidence of 3.5%. There was a 30% annual increase in the incidence of PNF between 1990 and 2000; the incidence of PNF peaked at 7%, and then decreased by 20% annually thereafter. No differences in donor and perioperative variables were identified to account for this variation. One-, 3-, and 5-year patient and graft survival for patients with PNF who underwent retransplant were significantly lower than those with primary liver transplant. In conclusion, there has been decreased incidence of PNF among liver transplant recipients in the last decade.

Outcomes in adult and pediatric liver transplantation among various ethnic groups.

BACKGROUND: The reported patient and graft survivals among adults post-orthotopic liver transplantation (OLT) are variable, with an apparent discrepancy between ethnic groups. The aim of this study was to evaluate the impact of ethnicity on patient and graft survivals among adult and pediatric patients. METHODS: A retrospective analysis from the UNOS/OPTN databank between January 1995 and December 2006 was performed on adult and pediatric liver transplant recipients. Patients were divided into 4 groups based on ethnicity: African Americans, Hispanic, Caucasians, and other. Kaplan-Meier (KM) analysis was used to calculate patient and graft survival. Log-rank tests were used to compare survival rates between groups. RESULTS: In our study 42,710 OLT patients were included in the analysis, 90% of whom were adults. Of the 38,639 adult recipients, 29,432 (76.1%) were Caucasian, 4369 (11.3%) were Hispanic, 2963 (7.7%) were African American, and the remaining 1875 (4.9%) were of other ethnicities. KM estimates and Cox regression analyses demonstrated that there was a significant ethnic difference in both patient and graft survivals at 1, 3, 5, and 10 years. African Americans showed a lower rate (P<.001). Of the 4341 pediatric recipients, 2461 (56.7%) were Caucasian, 797 (18.4%) were Hispanic, 824 (18.9%) were African American, and the remaining 259 (5.9%) were of other ethnicities. Unlike the adults, there were no significant differences among ethnic groups in terms of patient (P=.31) and graft (P=.33) survival at 1, 3, 5, and 10 years after OLT. CONCLUSION: These results showed that adult African American OLT patients have a reduced transplantation rate and a worse survival rate when compared with other ethnicities in the adult but not in the pediatric population. This information suggests that further studies are indicated to identify the causes of racial differences in transplant access and outcomes in the adult patient population.

Intestinal schistosomiasis following orthotopic liver transplantation: a case report.

Recent World Health Organization (WHO) reports estimate that 500-600 million people worldwide are at risk of schistosomiasis. In areas of high prevalence of hepatitis C (HCV) and schistosomiasis there is an increased risk for end-stage liver disease. Liver transplant is a viable option for those with HCV or other liver pathology and schistosomiasis. Posttransplant recurrence of schistosomiasis has rarely been described. We report a case of posttransplant recurrence of schistosomiasis.

Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy.

INTRODUCTION: Patients with end-stage liver disease often develop hepatic encephalopathy. The loss in cognitive abilities results in marked economic loss to the patient and health care community. We report hospital admission rates and economic impact of patients with end-stage liver disease suffering from hepatic encephalopathy. METHODS: The medical records were reviewed involving liver transplant patients started on lactulose or rifaximin therapy after presenting with stage 2 hepatic encephalopathy from January 2004 to November 2005. Information collected included demographics, hospitalizations required for hepatic encephalopathy, economic data, and Model for End-stage Liver Disease (MELD) score. RESULTS: Thirty-nine patients met study criteria: 24 patients treated with lactulose (group one) and 15 with rifaximin (group two). Group one included 18 men and six women of mean age 48 (range 39 to 58), average MELD 14 (range 10 to 19). Group two included 10 men and five women of mean age 47 (range 42 to 58), average MELD 15 (range 10 to 19). Group one patients required 19 hospitalizations overall: three patients with three hospitalizations, four patients with two hospitalizations, and two patients required one hospitalization. Total drug cost per month was 50 dollars(group one) and 620 dollars(group two). The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 13,284.96 dollars for a total of 318,839 dollars (range 5005 dollars to 26,255 dollars, including drug cost and hospital care). Group two required three hospitalizations, all three with one visit. The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 7958.13 dollars for a total of 119,372 dollars (range 6005 dollars to 19,255 dollars, including drug cost and hospital care). The total cost of therapy per patient per year was 13,285 dollars (group one) versus 7958 dollars (group two). The average length of stay was shorter in group two [3.5 days (range 3 to 4)] versus group 1 [5.0 days (range 3 to 10); P < .0001]. CONCLUSION: These pilot data demonstrate the marked difference in economic costs for the treatment of hepatic encephalopathy. The results also show that in comparative groups, the economic gains are quickly lost when using lactulose.

Fulminant hepatic failure from herpes simplex virus: post liver transplantation acyclovir therapy and literature review.

INTRODUCTION: Herpes simplex virus (HSV) is seen throughout the world and can be treated with acyclovir. We present a case of fulminant hepatic failure (FHF) as a result of disseminated HSV infection in a pregnant patient during the second trimester. METHODS: The medical records of a patient suffering from HSV-related fulminant hepatic failure were collected. A review of the literature was collected and reported. RESULTS: A previously healthy female presented with fulminant hepatic failure at a local emergency room complaining of a 5-day history of fever, nausea, vomiting, and right side abdominal pain that radiated to the back. She was diagnosed with fulminant hepatic failure and progressed into a coma. The patient underwent orthotopic liver transplantation (OLT) prior to the diagnosis of HSV and then treated successfully with acyclovir. CONCLUSION: Treatment of HSV fulminant hepatitis is dependent up on early suspicion and prompt intervention. In addition, antiviral therapy may need to be lifelong.

Prostate cancer prior to solid organ transplantation: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Prostate adenocarcinoma (PCA) is the second leading cause of cancer-related deaths in men, and with routine prostrate specific antigen (PSA) screening, is being diagnosed with increasing frequency. To date, reported experiences with transplantation in men with a history of PCA are limited to only a few patients. This study presents the first series of transplant recipients with a history of PCA. METHODS: Analysis of transplant recipients with a history of pretransplant PCA was performed on the Israel Penn International Transplant Tumor Registry database. PCA were staged using American Joint Committee on Cancer criteria. Statistics analysis was performed by chi-square and Student t tests. RESULTS: Ninety patients with preexisting PCA were identified: 77 renal, 10 heart, and three liver transplant recipients. Mean age at PCA diagnosis was 61.3 +/- 6.3 years. Median interval between diagnosis and transplantation was 19.3 months, and median follow-up after transplantation was 20.5 months. Median time to PCA recurrence was 10.6 months after transplantation and median survival time with recurrent PCA was 49.2 months after transplant. Patient mortality was 28.8%, and PCA-related death rate was 7.8%. PCA recurrence rate was 17.7%. Tumor recurrence rates in stage I and II disease (14 and 16%) were lower than in stage III disease (36%). CONCLUSIONS: In conclusion, death rate to disease other than PCA is three times that due to PCA. PCA recurrence rates are relatively low in patients who initially presented with stage I and II disease, and are half that of patients with stage III disease.

The importance of clinical parameters when differentiating cholestatic hepatitis C virus from allograft rejection.

BACKGROUND: The exact cause and appropriate treatment for cholestasis following liver transplantation in recipients with hepatitis C virus recurrence (RHCV) are difficult to determine. Our objective was to determine the diagnostic accuracy of clinical and histological parameters in liver transplant recipients with RHCV and concurrent cholestasis. METHODS: A retrospective analysis from June 1996 to May 2003 was performed on adult liver transplant (OLT) recipients with hepatitis C virus. Patients with cholestasis (bilirubin >5 mg/dL, 6 months after OLT) were selected. Demographics, etiology, immune suppression, clinical and histologic outcomes, and virologic features were evaluated. Patients were divided into two groups based on clinical and histological criteria: (1) patients with parameters suggestive of cholestatic HCV; and (2) patients with parameters consistent with acute cellular rejection. RESULTS: Thirty-seven patients met study criteria (20 males). The average age was 54 years (range = 14-72), and time from transplant to jaundice was 769 days (range = 48-2981). The groups were comparable regarding HCV viral load, age, gender, time from transplant, and United Network of Organ Sharing status at time of transplant. Retransplantation was performed in two patients in group 1, neither of whom survived, and in three patients in group 2, all of whom survived. Clinical parameters correlated well with diagnosis of cholestasis (r = 0.85, P < .001) whereas histological evaluation did not (r = 0.11, P = .53). Mortality in group 1 was 78% (7 of 9) vs. 50% (13 of 26) in group 2. Median duration of survival following liver transplantation in group 1 was 132 days versus 435 days in group 2. CONCLUSION: Clinical diagnosis parameters for RHCV with cholestasis appear more accurate than histology parameters and should be the primary consideration in directing therapy. Despite timely diagnosis, cholestatic RHCV LTx recipients have a poor prognosis.

An update in liver transplantation in patients with hepatitis B and hepatitis C.

Chronic hepatitis C virus (HCV) infection is an epidemic that currently represents the number one indication for liver transplantation (LTx). Hepatitis B virus (HBV) infection is associated with better outcomes following LTx since the advent of hepatitis B immune globulin and lamivudine. The impact of HCV and HBV in LTx is well known. Therapeutic interventions, however, are less standardized and often depend upon institutional protocol. This review article will provide a comprehensive review of the literature and address many issues and complications with transplantation in patients suffering from chronic liver disease as a result of HCV or HBV.

Review article: current status of liver transplantation in HIV-infected patients.

The increases in survival of patients infected with human immunodeficiency virus is attributed to the introduction of combination human immunodeficiency virus antiviral therapy, better known as highly active anti-retroviral therapy. In fact, survival statistics have improved such that individuals often succumb to other disease entities, notably liver failure and not from acquired immunodeficiency syndrome complications. Liver transplantation has been introduction in this patient population in several centres around the world. This review will discuss the current clinical status of liver transplantation in individuals suffering from human immunodeficiency virus infection.

Ten years of sirolimus therapy in orthotopic liver transplant recipients.

BACKGROUND: Sirolimus therapy has been used in orthotopic liver transplant (OLT) recipients diagnosed with a variety of diseases; chronic graft rejection (CR), calcineurin associated renal toxicity, preemptive immune suppression, calcineurin related neurotoxicity, preemptive therapy in transplant recipients with history of hepatocellular carcinoma, and steroid resistant allograft rejection. METHODS: A search for the medical literature and experiences involving sirolimus was done. RESULTS: Several animal and human reports evaluating the use sirolimus in liver transplant recipients are found and discussed. CONCLUSION: Sirolimus has been used for multitude of indications, primarily based on anecdotal experiences. However, reports of sirolimus related side effects have decreased the transplant communities' enthusiasm towards promoting this agent as a safe immune suppression agent.

Sirolimus therapy in orthotopic liver transplant recipients with calcineurin inhibitor related chronic renal insufficiency.

UNLABELLED: Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. Our clinical experience has revealed sirolimus to be an effective agent in treating renal insufficiency related to calcineurin inhibitor toxicity. METHODS: We performed a retrospective review of the medical records of OLT recipients suffering from chronic renal insufficiency and treated with sirolimus at the University of Miami. RESULTS: Fourteen patients (nine men and five women) of mean age 57 years who had been treated with tacrolimus for at least 30 days were converted to sirolimus after developing nephrotoxicity. Mean creatinine clearances collected on day 0, 30, 60, and 90 after conversion were 40.1 mL/min, 49.6 mL/min, 53.9 mL/min, and 51.4 mL/min, respectively. Episodes of acute cellular rejection were not increased during the sirolimus conversion. CONCLUSION: This retrospective review suggests that OLT patients suffering from tacrolimus-related renal insufficiency successfully converted to sirolimus may benefit from this therapy.

Liver transplant for the septuagenarians: importance of patient selection.

With the increasing success of liver transplantation (OLT), more patients above 70 years of age are being considered for OLT. There is not enough data about the predictors for survival in this patient population. We retrospectively analyzed the medical records of 33 patients at least 70 years of age who received 34 OLT from July 1995 to July 2002. There were 16 women and 17 men of mean age 73.7 years. Etiologies of end-stage liver disease (ESLD) were: HCV (17/33, 52%), cryptogenic cirrhosis (8/33, 24%), PBC (3/33, 9%), Laennec's cirrhosis (2/33, 6%), and others (3/33, 9%). According to the UNOS classification, 15/34 (44%) were status 3, 16/34 (47%) status 2, and 3/34 (9%) status 1. Among 13/33 patients who died (39%), 1-year and 3-year survival rates were 78.79% and 71.43%, respectively. Based on UNOS criteria, 4/15 (26%) were status 3; 6/16 (37%), status 2; and 3/3 (100%), status 1 (P value = .04 for status 1 patients). There was no statistical differences between the scores using the Model for End-Stage Liver Disease (MELD) among those who died (MELD (19) versus MELD (17.35) respectively (P = .50). There was a statistically significant difference in cold ischemia time (CIT) and warm ischemia time (WIT) between those who died (P = .024 and.010, respectively). These results suggest that in this group of patients UNOS status classification, CIT and WIT correlate with survival. The sample size was too small to derive a conclusion about the association with the MELD score.

The long-term effects of immune suppression on liver transplant recipients with recurrent hepatitis C viral infection.

INTRODUCTION: Adequate immune suppression following liver transplantation in recipients with recurrence of hepatitis C virus (HCV) is not standardized. The aim of this study was to evaluate the association between immune suppression protocol and the clinical/histological parameters in HCV transplant recipients with an HCV recurrence. METHODS: A retrospective analysis was performed on recipients of liver transplants from June 1998 to October 2003 who experienced HCV recurrence. Only patients with liver biopsies at 3 to 5 years following liver transplantation were included in the analysis. The data set included: patient demographics, immune suppression, antiviral therapies, as well as histology to evaluate ductopenia and chronic rejection. Patients divided into groups of high, medium, and low immune suppression were subdivided by treatment with versus without interferon. A control group with similar demographics suffering from cryptogenic cirrhosis was used for comparison. RESULTS: During this period 45 patients had liver biopsies at 3 to 5 years posttransplantation. Their mean age was 56.5 years and mean time from transplant to biopsy was 1543 days. Their average posttransplant survival was 1964 days. There was no difference among the three groups with respect to HCV RNA levels (log(10) IU/mL), age, gender, time from transplant, donor age, and UNOS status. Median HCV RNA levels within the three groups were comparable at various time periods pre- and posttransplant. CONCLUSION: The development of chronic allograft damage following transplantation in recipients with recurrent HCV tended to be worse among patients with low levels of immune suppression, suggesting the importance of therapy to maintain allograft function.

Topical testosterone treatment for chronic allograft failure in liver transplant recipients with recurrent hepatitis C virus.

INTRODUCTION: Liver transplant recipients with allograft failure due to recurrent hepatitis C virus (HCV) infection often develop marked muscle wasting and ascites prior to death and are denied repeat liver transplantation. We sought to determine whether topical testosterone therapy is associated with improved muscle mass and survival in patients with chronic allograft failure post-liver transplant. METHODS: We performed a retrospective review of liver transplant recipients with chronic allograft failure. Group 1 patients were treated for >6 months with testosterone gel 1%; group 2 patients were untreated. RESULTS: Fourteen patients were identified with stage 3 or 4 fibrosis, muscle wasting, and allograft failure due to recurrent HCV. Group 1 (n=9) patients had statistically significant improvement in albumin, testosterone, muscle strength, well-being, and MELD/CTP scores, while there was no improvement seen for any of these parameters in group 2 (n=5). There were no deaths in group 1, while four of five patients in group 2 died on average 84 days posttransplant. Adverse effects of testosterone treatment included lower extremity edema (which resolved upon dose adjustment), hypertension, and pruritus. CONCLUSIONS: Topical testosterone gel appears to increase muscle strength, stimulate albumin synthesis, and improve survival in patients with allograft failure post-liver transplant.

The role of coronary calcium score in the risk assessment of liver transplant candidates.

BACKGROUND: Coronary artery disease (CAD) is a common cause of morbidity and mortality in liver transplant (LT) recipients. To date there is no consensus on the preferred screening tests to detect CAD in the pre-LT population. Therefore the aim of this study was to: 1) evaluate the utility of a noninvasive tool (cardiac computerized tomography [CT] scan); and 2) determine the prevalence of CAD in low-risk LT candidates. METHODS: Using our transplant database we identified all LT candidates classified as low risk for CAD. All low-risk candidates underwent cardiac CT scan for coronary calcium score (CCS) estimation. Those with CCS >100 underwent coronary angiogram, and those with <100 underwent stress test and if stress test was positive then coronary angiography was performed. The Agatston calcium score was classified as: normal (0), mild (1-100), moderate (101-400), severe (401-1,000), or extensive (>1,000). RESULTS: Eighty-five LT candidates were classified as low risk and underwent cardiac CT scan. The mean calcium score was 325 (range, 0-3,707). In our study cohort, 21% had normal CCS score, 43% mild, 13% moderate, 11% severe, and 12% extensive. A calcium score >400 was significantly associated with CAD on angiography (P = .02). Although male sex was significantly associated with the presence of CAD (P = .006), there was no correlation with age, ethnicity, liver diagnosis, or Model for End-Stage Liver Disease score. CONCLUSIONS: Prevalence of asymptomatic CAD in this low-risk population is relatively high. Cardiac CT is well tolerated and is a useful noninvasive screening tool in LT candidates. Future studies to determine its utility as a prognostic tool after LT will be invaluable.

Social determinants of orthotopic liver transplantation candidacy: role of patient-related factors.

INTRODUCTION: Eligibility for orthotopic liver transplantation (OLT) requires careful selection of the best possible candidate. The aim of this study was to identify factors associated with transplantation ineligibility. METHOD: This was a retrospective cohort study of all patients evaluated for OLT at our center (2004-2006) and deemed not eligible. We identified all patients who were evaluated using information from our transplantation database. We extracted demographic data, insurance status, laboratory data, and clinical information including psychosocial evaluations. RESULTS: During the study period 242 evaluated candidates were not listed for transplantation. The most common reason for ineligibility for transplantation listing was early referral (n=59; 24.4%), followed by psychosocial (18.6%), medical contraindications (17.3%), death during evaluation (n=32; 13.2%), malignancy (n=22; 9.1%), declined evaluation or transfer to other transplantation center (n=21; 8.7%), and other reasons (8.7%). In contrast to whites, psychosocial factors were the most common reason among African American candidates. CONCLUSION: This study provides insight into factors contributing to OLT ineligibility among candidates of various ethnic backgrounds.