Search

Retransplantation of the liver (re-OLTx) accounts for approximately 10% of all liver transplants in the United States. The decision to offer a patient a second liver transplant has significant financial, ethical, and outcome implications. This large, single-center experience describes some outcome and financial data to consider when making this decision. One thousand three liver transplants were performed in 921 patients at our center. Patients were divided into adult and pediatric groups, and further by whether they received a single transplant or more than one. Overall survival, variation in survival by timing of re-OLTx, and survival in adults with hepatitis C were investigated, as were hospital charges and cost of re-OLTx. Adults, but not children, had a significant decrement in survival following a second transplant. Second transplants more than double the cost of the initial transplant, but there is a significantly higher cost associated with early retransplantation compared to the cost associated with late retransplantation (costs of first and second transplants included in both cases). This difference is due to a longer length of stay and associated cost in the ICU. Adult patients retransplanted early have the same overall survival compared to those done late. The sample size of the adult HCV re-OLTx population was too small to reach statistical significance despite their observed poorer outcome.

Cirrhosis secondary to hepatitis C virus (HCV) is a very common indication for liver transplant. Unfortunately recurrence of HCV is almost universal in patients who are viremic at the time of transplant. The progression of fibrosis has been shown to be more rapid in the post-transplant patients than in the transplant naive, hence treatment of recurrent HCV needs to be considered for all patients with documented recurrent HCV. Management of recurrent HCV is a challenging situation both for patients and physicians due to multiple reasons as discussed in this review. The standard HCV treatment with pegylated interferon and Ribavarin can be considered in these patients but it leads to a lower rate of sustained virologic clearance than in the non-transplanted population. Some of the main challenges associated with treating recurrent HCV in post-transplant patients include the presence of cytopenias; need to monitor drug-drug interactions and the increased incidence of renal compromise. In spite of these obstacles all patients with recurrent HCV should be considered for treatment since it is associated with improvement in survival and a delay in fibrosis progression. With the arrival of direct acting antiviral drugs there is renewed hope for better outcomes in the treatment of post-transplant HCV recurrence. This review evaluates current literature on this topic and identifies challenges associated with the management of post-transplant HCV recurrence.

There is limited information on the direct role of the neutralizing antibody responses against hepatitis C virus (HCV) infection or methodologies to study them. Previously we have demonstrated that interleukin-10 (IL-10) administered to chronic hepatitis patients led to a decrease in disease activity, but an increase in HCV viral burden. The mechanism behind this is unknown. The objective of this study was to examine the antibody response in IL-10-treated patients. To establish a neutralization antibody assay, HCV-positive and HCV-negative sera were collected and incubated with HCV strain JFH-1 particles before culture with Huh 7.5 cells. Viral replication was measured a week later by either indirect immunofluorescence assay (iIFA) or real-time reverse transcriptase polymerase chain reaction (RT-PCR). After validation of the methodology, the sera from 30 previously-described subjects of a group previously treated with IL-10 were tested for the neutralization capacity of their antibodies. The amount of total anti-HCV antibody in the sera was also measured by direct staining of HCV full-length replicon cells. With this validated neutralization assay for anti-HCV antibodies we found that HCV-neutralizing antibodies are universally present, but with significantly different titers. In patients who were treated with IL-10, the total anti-HCV antibody titers appear to be constant, but with significantly decreased antibody neutralization activity. Our study validates an assay to quantitatively determine the presence and strength of HCV-specific neutralizing antibodies. We have found that IL-10-treated patients have significantly lower HCV antibodies, but maintain the total anti-HCV antibody titer, suggesting a novel mechanism by which IL-10 treatment increases viral load in patients.

Hepatitis C after liver transplantation leads to graft cirrhosis in up to 30% of patients within 5 years, but limited data exist regarding the clinical course of cirrhosis after transplantation. The aims of this study were to report the natural history of hepatitis C cirrhosis after liver transplantation and to identify risk factors for decompensation and survival. Hepatitis C patients underwent protocol liver biopsies yearly after liver transplantation. After cirrhosis was identified by biopsy, the outcomes of interest were the development of decompensation, death, or retransplantation for hepatitis C. Kaplan-Meier and Cox regression analysis was used to determine survival and risk factors for decompensation and mortality. Out of 502 liver transplants performed for hepatitis C, 88 patients (18%) had cirrhosis within 3.7 years. Seventy-one patients were compensated at diagnosis. The cumulative probability of decompensation 1 year after cirrhosis was 30%. A Model for End-Stage Liver disease score >or= 16 was predictive of decompensation and poor survival, whereas successful interferon treatment was found to reduce this risk (relative risk = 0.05). Once decompensation occurred, 1-year survival was 46%. In conclusion, the results confirm an accelerated natural history of hepatitis C cirrhosis after liver transplantation and demonstrate poor survival after decompensation. The Model for End-Stage Liver Disease can stratify risk for decompensation and survival, whereas successful antiviral therapy may be protective.

Viral hepatitis is the third major cause of liver dysfunction in allogeneic transplant recipients and has become a significant concern in patients with hematological malignancies receiving chemotherapy. Thus, identification of patients at risk for viral hepatitis is very important when evaluating and treating hematological malignancies. Serologic screening for all patients should include anti-HCV, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) testing. Current therapies for hepatitis B (HBV) virus infection are aimed at viral suppression, while treatment for hepatitis C (HCV) virus can eradicate infection in many treated patients. To prevent HBV viral reactivation, prophylaxis with nucleoside analogues should be initiated for all HBsAg-positive patients. HCV infection appears to have little impact on short-term survival after bone marrow transplantation (BMT), but eventually can impact long-term survival due to progression of liver disease. In this review we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.

Background. While the main effect of hepatitis C virus (HCV) is hepatitis, HCV is also known to cause a variety of systemic immunologic inflammatory abnormalities. The effect of HCV infection on the biliary tract after liver transplantation (LT) is not well understood. The aim of the current study is to determine if recurrence of hepatitis C affects biliary complications after LT, with special reference to late biliary anastomotic strictures (LBAS). Methods. A total of 688 consecutive adult LT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005 were reviewed. Biliary anastomotic stricture was confirmed by endoscopic retrograde cholangiopancreatography. LBAS was defined as stricture that occurred 30 days or more after LT. Early HCV recurrence was defined as recurrence within 6 months after LT. Results. LBAS occurred in 55 patients (8% of total). Patients with HCV infection had a higher occurrence of LBAS than non-HCV patients (11% vs. 5%, P=0.0093). Among HCV patients, those with early HCV recurrence had an exceedingly high rate of LBAS (16%). In multivariate analyses, early recurrence of hepatitis C (P

Aim To investigate whether sonographic (US) surveillance of polytetrafluoroethylene covered transjugular intrahepatic portosystemic shunts (TIPS) is necessary. Materials and methods We identified 128 patients who underwent TIPS for complications of portal hypertension between January 2001 and December 2005 at a large tertiary centre. Procedural data were retrospectively analysed. US surveillance of the TIPS was performed at baseline with scheduled follow-up or whenever shunt dysfunction was suspected. Clinical and radiology reports were compared to assess US surveillance of the TIPS. Results Four hundred and twenty-six US studies were performed, with a median of three per patient (range 1–5). The median follow-up period was 378 days (range 1–1749 days). Twenty-three patients (18%) had baseline US studies performed only whereas 105 (82%) also had follow-up studies. Forty-one (32%) of 128 patients [32 (78%) Wallstent, nine (22%) Viatorr] had Doppler ultrasound abnormalities noted. Venography was performed in all 41 patients. Abnormal venography and elevated hepatic venous pressure gradient (HVPG) was seen in 34 (82.9%) of the 41 patients [29 (85.3%) Wallstent, five (14.7%) Viatorr]. Among the 34 patients, 17 (50%) [13 (76.5%) Wallstent, four (23.5%) Viatorr] had venographic abnormalities noted at the hepatic venous end accompanied by increased HVPG. All four of the Viatorr patients had minor narrowing at the hepatic venous end and HVPG measurements that ranged 3–4 mm Hg above 12 mm Hg. Conclusion Considering the improved patency of covered stents in TIPS, US surveillance may be superfluous after the baseline study.

Dysfunction of the host immune system in cancer patients can be due to a number of factors, including suppression of tumor-associated antigen reactive lymphocytes by CD4(+)CD25(+) regulatory T (Treg) cells. Several studies suggest that Tregs are elevated in cancer patients and that depletion of Tregs may enhance the antitumor immunity of host, but the pathogenic and mechanistic relationship between cancer and Tregs is still unclear. In this report, we show that Tregs are increased in peripheral blood mononuclear cells (PBMCs) from hepatocellular carcinoma (HCC) patients and positively correlate with tumor burden. When PBMCs are co-cultured with human hepatoma cell lines Huh7, HepG2, and Hclone5, CD4(+)CD25(+)-T cell populations increase in frequency and undergo phenotypic and functional changes. CD45RA, CD45RO, CD69, CD62L, GITR, CTLA-4, Ki67, granzyme A, granzyme B, and FOXP3 expression were upregulated in CD4(+)CD25(+) cells after in vitro exposure to HCC cell lines. CD4(+)CD25(+) T cells from PBMCs that were co-cultured with Huh7 cells also have higher suppressor ability compared to that of the CD4(+)CD25(+) T cells from control PBMC. Huh7 culture supernatants appear to promote CD4(+)CD25(+) T-cell proliferation and inhibit CD4(+)CD25(-) T-cell proliferation. In conclusion, these results strongly suggest that tumor-related factors not only induce and expand CD4(+)CD25(+) cells, but also enhance their suppressor ability.

A 45-year-old Caucasian woman, with no known liver disease, was referred to hepatology clinic for liver biopsy after abnormal image findings during a recent adult chicken pox infection. She presented with mildly elevated alkaline phosphatase of 170 U/L and γ-glutamyltransferase of 267 U/L. In clinic, she was asymptomatic with a negative review of systems. Initial laboratory evaluation, including a basic metabolic panel, complete blood count, aspartate aminotransferase, alanine aminotransferase and direct/indirect bilirubin …

Background: Amiodarone is associated with heart block in patients with atrial fibrillation and heart failure. The safety of amiodarone use in patients with amyloid is unknown. We sought to identify the prevalence of heart block in patients with amyloid and heart failure who received amiodarone and compare them to those without amyloid in elderly patients. Methods: We searched Explorys (Explorys Inc, Cleveland, Ohio), a database that aggregates electronic health records of 45 million patients from 23 integrated health systems in the United States. We included patients who are at least 55 years of age who have heart failure and atrial fibrillation and receive amiodarone therapy. We compared those to age adjusted controls with heart failure and atrial fibrillation without amyloidosis. Results: We identified 640 patients with amyloid and 87280 patients without amyloid. Prevalence of block was higher in patients with amyloid on amiodarone (43.8% vs 30.0%, p!0.0001). When adjusted for age, odds ratio of block was as follows: 55-59 (1.9 [1.4-2.5], p50.0017), 60-64 (1.8 [1.42.4], p50.0002), 65-69 (2.1 [1.7-2.5], p!0.0001), 70-74 (1.2 [0.9-1.6], p50.31), 7579 (1.5 [1.3-1.8], p50.0001), 80-84 (1.2 [1.0-1.5], p50.09), 85-89 (1.3 [1.0-1.8], p50.052), and 90+ (1.2 [0.9-1.7], p50.25), figure. Conclusion: Elderly patients

Viral hepatitis is the third most common cause of liver disease in allogeneic transplant recipients and causes significant morbidity and mortality. When treating patients with hematological malignancies, an emphasis should be placed on identification of patients at risk for viral hepatitis with appropriate screening. Initial screening serology should include anti-HCV, HBsAg, anti-HBs, and anti-HBc testing. When hepatitis B exposure has been documented, prophylaxis of viral reactivation for all HBsAg-positive patients with a nucleoside analogue should be implemented. HCV infection appears to have little short-term impact on survival after bone marrow transplantation, but is a risk factor for veno-occlusive disease (VOD) and graft-versus-host disease (GVHD). In the long-term survivor, HCV infection can lead to significant morbidity and mortality due to the development of cirrhosis, decompensation, and liver cancer. Since effective antiviral therapies are available for both hepatitis B and C, routine screening and selected intervention is recommended once reactivation and disease recurrence is documented. In this chapter we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.

The implementation of the model for end-stage liver disease (MELD) score decreased mortality of those awaiting liver transplantation (LT); however, the impact of the MELD allocation system on the risk of chronic renal disease after LT remains unknown. We conducted a non-concurrent single-center cohort study of 174 patients undergoing LT at our center. We compared patients who underwent LT one year prior to MELD implementation (pre-MELD cohort) to those patients who underwent LT 1 year following MELD implementation (MELD cohort). All patients were followed for at least 2 years after LT. Stage 3 chronic renal disease (CRD-3) was defined by an estimated creatinine clearance (CL(Cr)) below 60 ml/min/1.73 m2, and stage 4 chronic renal disease (CRD-4) was defined by an estimated CL(Cr) below 30 mL/min/1.73 m2 according to the validated Modification of Diet and Renal Disease (MDRD) formula. Requirement of kidney transplantation and need for hemodialysis were also evaluated following LT. The pre-MELD cohort (n=97) and the MELD cohort (n=77) were comparable in baseline characteristics, prevalence of diabetes and hypertension, and immunosuppression. Mean calculated MELD score in the pre-MELD cohort was significantly lower than in the MELD cohort (16 vs. 19, P < 0.05). The estimated CL(Cr) at time of LT was lower in the MELD cohort compared with the pre-MELD cohort (75 vs. 95, P < 0.01). However, the incidence and prevalence of CRD-3 and CRD-4 at 6, 12, and 24 months after LT were comparable between the two cohorts. Need for kidney transplantation or hemodialysis after LT was comparable between the groups. In multivariate analysis, serum creatinine at LT was the only variable associated with the development of CRD-3 in the first 2 years after LT. In conclusion, the implementation of the MELD allocation system is not associated with increased mortality or occurrence of CRD-3 or CRD-4 in the first 2 years after LT.

Adult to adult right hepatic lobe living donor liver transplantation (LDLT) accounts for 10% of all liver transplants performed in the United States. Although the overall morbidity and mortality to the donor is low, complications resulting in death and/or need for transplantation have been previously reported. Five cases of donor related complications resulting in three deaths have been documented in the United States to date. Two of the three deaths occurred early in the postoperative period, and the third was not related to surgery, but rather due to a suicide 2 years post donation. Listing for liver transplantation was required for two donors, one for acute Budd Chiari syndrome and the other for subfulminant hepatic failure. All of these cases, with the exception of the suicide, were complications that occurred early in the post operative period following liver donation. We report a late biliary tract complication resulting in chronic liver disease likely related to a perioperative surgical complication.

Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti-viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus-based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine-based immunosuppression (n = 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus-based therapy (n=59, P = 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose-dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon-based therapy and should be studied in a prospective randomized trial. Liver Transpl 12:51–57, 2006. © 2005 AASLD.

A 56-year-old Caucasian female with end-stage liver disease secondary to 1-antitrypsin deficiency and end-stage renal disease secondary to idiopathic membranous nephropathy presented with a one-week history of increased bilateral lower extremity edema and anasarca. On admission, the patient complained of raised hardened areas especially prominent on the upper medial thighs that were painful, warm, and nonpruritic. She denied any constitutional symptoms and denied using any new medications. On exam, the patient was found to be afebrile with stable oxygen saturation. The abdomenwas distended with evidence of hepatomegaly. Bilateral lower extremity edema to the groin were present, and hyperpigmented plaques (Fig. 1) (tender, indurated, and warm) were noted on the upper medial aspects of her thighs, but not involving the groin. There was no visible face or upper extremity involvement. Laboratory tests did not reveal leukocytosis or eosinophilia. ESR was 40 and ANA test was negative. Serum protein electrophoresis was negative for paraproteinemia. Doppler ultrasound did not reveal deep venous thromboses. The patient received a short course of antibiotics without any clinical improvement. A skin punch biopsy revealed increased dermal fibroblast proliferation, thick collagen bundles with surrounding clefts, elastic fibers, and increased mucin deposition consistent with NFD (Fig. 2 and 3). The patient declined any steroid treatment and was subsequently discharged. Eventually the patient underwent liver transplant and received oral prednisone as part of the immunosuppression regimen, which has led to some improvement of the cutaneous lesions. Currently she has extensive skin contraction involving her calves and shins with decreased range ofmotion, and she has become largely wheelchair bound. Nephrogenic Fibrosing Dermopathy (NFD) is a recently described derma

Recurrent hepatitis C infection is an important cause of progressive fibrosis, cirrhosis, and graft loss following orthotopic liver transplantation. Treatment for posttransplant recurrence of hepatitis C with interferon-based therapy is difficult but results in loss of detectable virus in up to 30% of patients. However, the durability of viral clearance and the associated histologic response in this setting is unknown. The aim of this study was to determine whether viral loss in response to antiviral therapy is durable and associated with improvement in liver histology. All liver transplant recipients who received interferon-based treatment for recurrent hepatitis C virus (HCV) at the University of Florida from 1991 to 2002 were included in this study. Patients who lost detectable HCV after treatment with interferon alone or in combination with ribavirin were followed to assess the durability of viral response and its impact on liver histology. One hundred nineteen transplant recipients were treated with interferon or combination therapy. Twenty-nine (20 men, 9 women; mean age, 54 yrs [range, 42-74 yrs]) lost detectable HCV RNA and remained virus negative for at least 6 months after discontinuing therapy (sustained viral response[SVR]). The mean follow-up after discontinuing therapy was 24.7 months (range, 6-70 mos). Our study cohort included one patient with SVR following interferon monotherapy and 28 patients with SVR following combination therapy with interferon plus ribavirin. All patients remained HCV RNA negative (assessed by polymerase chain reaction or branched-DNA assay) during follow-up of up to 5 years. Liver histology assessed 2 years after treatment showed less inflammation compared with before treatment in 50% and showed no change in 38%. By 3 to 5 years post-treatment (n = 15 recipients), inflammation was reduced in 60% and remained unchanged in 33%. Fibrosis stage at 2 years improved byor = 1 stage in 27 %, remained unchanged in 38 %, and worsened in 35% despite viral clearance. At 3 to 5 years, the fibrosis stage had improved in 67%, remained unchanged in 13%, and worsened in 20%. Both grade of inflammation and fibrosis stage improved by 3 to 5 years posttreatment compared with baseline histology (p0.05). In conclusion, loss of HCV after treatment of recurrent chronic hepatitis C with interferon and ribavirin is durable, and the durability of the SVR is associated with improvement in hepatic inflammation and regression of fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression.

e14598 Background: Treatment with sorafenib (S) is reserved for advanced, unresectable hepatocellular carcinoma (HCC) but may provide greater efficacy when combined with transarterial therpay (T) i...

Listeria monocytogene is a well-recognized cause of bacteremia in immunocompromised individuals, including solid organ transplant recipients, but has been rarely reported following orthotopic liver transplantation. We describe a case of listeria meningitis that occurred within a week after liver transplantation. The patient developed a severe headache that mimicked tacrolimus encephalopathy, and was subsequently diagnosed with listeria meningitis by cerebrospinal fluid culture. The infection was successfully treated with three-week course of intravenous ampicillin. Recurrent hepatitis C followed and was successfully treated with interferon alfa and ribavirin. Fourteen cases of listeriosis after orthotopic liver transplantation have been reported in the English literature. Most reported cases were successfully treated with intravenous ampicillin. There were four cases of listeria meningitis, and the mortality of them was 50%. Early detection and treatment of listeria meningitis are the key to obtaining a better prognosis.

Recurrent hepatitis C virus (HCV) infection is an important cause of fibrosis and cirrhosis after liver transplantation (LT), with histological recurrence developing in at least 50% of patients within the first year. The aim of this study is to assess the safety and efficacy of interferon alfa-2b plus ribavirin in treating histological recurrent HCV after LT. Since 1998, patients with HCV with significant histological recurrence (fibrosis > 3 and/or histological activity index > 5) or progressive cholestatic disease after LT were treated with interferon alfa-2b (3 million units subcutaneously three times weekly) plus ribavirin (800 to 1,000 mg/d) for 12 months. Immunosuppression was tapered to cyclosporine/FK506 monotherapy. HCV RNA was assessed at entry, week 24, end of treatment, and 6 months after therapy. The primary end point was loss of HCV RNA 6 months after therapy, whereas the secondary end point was histological response. Fifty-four patients met criteria for treatment and have completed follow-up. Patients were mainly men (71% men; mean age, 51 5 years) with genotype 1 infection (88%) and high viral load (mean HCV RNA, 38 9 mEq/mL). Dose modification was required in 72% of patients because of cytopenia or side effects. Intent-totreat analysis showed that serum HCV RNA was undetectable in 19 patients (35%) week 24, 21 patients (38%) week 48, and 16 patients (30%) at the 6-month follow-up. Paired liver biopsy results (before and within 6 months after treatment) were available for 35 patients. Patients who achieved viral eradication had no significant progression of fibrosis after 1 year of therapy. In summary, combination therapy is a reasonable antiviral option for recurrent HCV infection for established post-LT hepatitis and appears to prevent histological progression of disease if viral eradication is successful. (Liver Transpl 2002;8: 1000-1006.)