High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

BACKGROUND & AIMS: Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. METHODS: In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. RESULTS: For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001). CONCLUSIONS: Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.

Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Mutations in SEC63 cause autosomal dominant polycystic liver disease.

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.

Liver transplantation for unresectable hepatocellular carcinoma in normal livers.

BACKGROUND & AIMS: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC.

Influence of liver-disease etiology on long-term quality of life and employment after liver transplantation.

The etiology of liver disease would expectedly affect health-related quality of life (HRQoL) and employment after liver transplantation (LT), but studies are scarce. We sent the 15D HRQoL instrument and an employment questionnaire to all 401 adult LT patients alive in Finland in 2007. The response rate was 89% (n = 353; mean of eight yr since LT). In age-adjusted analysis, patients transplanted for primary sclerosing cholangitis (PSC; n = 56), primary biliary cirrhosis (PBC; n = 72), acute liver failure (ALF; n = 76), alcoholic cirrhosis (n = 38), or liver tumor (n = 22) exhibited comparable HRQoL, whereas the combined group of miscellaneous chronic liver diseases (n = 89) exhibited significantly higher HRQoL scores (p = 0.003). Among working-aged patients (20-65 yr at LT), employment rates were highest in the PSC (56%) group and lowest in the ALF (39%) and PBC (29%) groups. In age-adjusted logistic regression, patients with PSC or alcoholic cirrhotics were 2.4- and 2.5-fold more likely to resume work after LT than patients with PBC. In conclusion, HRQoL scores late after LT were in general relatively high and comparable among disease groups. Patients with PSC or alcoholic cirrhosis were most likely to resume work after LT. The relatively low employment among patients with ALF may merit enhanced rehabilitation efforts.

Effect of the aetiology and severity of liver disease on oral health and dental treatment prior to transplantation.

Elimination of dental infection foci has been recommended before liver transplantation (LT) because lifelong immunosuppression may predispose to infection spread. Association between pre-LT oral health and the aetiology and severity of chronic liver disease (CLD) was investigated retrospectively. A total of 212 adult patients (median age 51.1) who had received LT during 2000-2006 in Finland were included. Their oral health had been pre-operatively examined. Patients were divided into seven different CLD groups. Common indications for LT were primary sclerosing cholangitis (PSC 25.5%), alcohol cirrhosis (ALCI 17.5%) and primary biliary cirrhosis (PBC 14.6%). Patients were also categorized by the Model for End stage Liver Disease (MELD) scoring system. Medical, dental and panoramic jaw x-ray data were analysed between groups. PBC patients had the lowest number of teeth with significant difference to PSC patients (19.7 vs. 25.6, P < 0.005, anova, t-test). ALCI patients had the highest number of tooth extractions with significant difference in comparison to PSC patients (5.6 vs. 2.5, P < 0.005). Lower MELD score resulted in fewer tooth extractions but after adjusting for several confounding factors, age was the most important factor associated with extractions (P < 0.005). The aetiology of CLD associated with the oral health status and there was a tendency towards worse dental health with higher MELD scores.

Cost of a quality-adjusted life year in liver transplantation: the influence of the indication and the model for end-stage liver disease score.

Cost issues in liver transplantation (LT) have received increasing attention, but the cost-utility is rarely calculated. We compared costs per quality-adjusted life year (QALY) from the time of placement on the LT waiting list to 1 year after transplantation for 252 LT patients and to 5 years after transplantation for 81 patients. We performed separate calculations for chronic liver disease (CLD), acute liver failure (ALF), and different Model for End-Stage Liver Disease (MELD) scores. For the estimation of QALYs, the health-related quality of life was measured with the 15D instrument. The median costs and QALYs after LT were €141,768 and 0.895 for 1 year and €177,618 and 3.960 for 5 years, respectively. The costs of the first year were 80% of the 5-year costs. The main cost during years 2 to 5 was immunosuppression drugs (59% of the annual costs). The cost/QALY ratio improved from €158,400/QALY at 1 year to €44,854/QALY at 5 years, and the ratio was more beneficial for CLD patients (€42,500/QALY) versus ALF patients (€63,957/QALY) and for patients with low MELD scores versus patients with high MELD scores. Although patients with CLD and MELD scores > 25 demonstrated markedly higher 5-year costs (€228,434) than patients with MELD scores < 15 (€169,541), the cost/QALY difference was less pronounced (€59,894/QALY and €41,769/QALY, respectively). The cost/QALY ratio for LT appears favorable, but it is dependent on the assessed time period and the severity of the liver disease.

Liver transplantation for cholangiocarcinoma: selection is essential for acceptable results.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is considered a contraindication for liver transplantation by most liver transplant centers. The aim of this study has been to report our results as well as to explore factors that influence patient survival after liver transplantation for CCA. PATIENTS: All transplant patients with CCA in Norway, Sweden and Finland during 1984-2005 were included (n = 53). Thirty-three patients (62%) had intrahepatic CCA. Twenty-one patients (40%) had a more advanced tumor (>TNM stage 2). Thirty-four of the 53 recipients (64%) had primary sclerosing cholangitis (PSC). RESULTS: Patients with TNM stage ≤ 2 transplanted after 1995 had a 5-year survival rate of 48%. The overall 5-year patient survival rate was 25%. There was no difference in survival between patients with extrahepatic and intrahepatic CCA. The 5-year survival rate among patients with TNM stage ≤ 2 was 36%. Patients with TNM stage >2 had a 10% 5-year survival rate; the difference was significant at p < 0.01. Patients transplanted after 1995 had a significantly better 5-year survival rate than pre-1995 patients (38% vs. 0%, p < 0.01). Patients transplanted after 1995 with TNM ≤ 2 and CA 19-9 ≤ 100 had the 5-year survival of 58%. CONCLUSION: By selecting CCA patients with TNM stage ≤ 2 and a CA 19-9 ≤ 100 a reasonable 5-year survival rate is possible. We think that CCA in selected cases can be an acceptable indication for liver transplantation.

Hepatic IL-8 release during graft procurement is associated with impaired graft function after human liver transplantation.

In experimental models, brain death induces inflammatory cascades, leading to reduced graft survival. Thus far, factors prior to graft preservation have gained less attention in clinical setting. We studied pre-preservation inflammatory response and its effects on graft function in 30 brain dead liver donors and the respective recipients. Before donor graft perfusion, portal and hepatic venous blood samples were drawn for phagocyte adhesion molecule expression and plasma cytokine determinations. Donor intensive care unit stay correlated with donor C-reactive protein (R = 0.472, p = 0.013) and IL-6 (R = 0.419, p = 0.026) levels, and donor (R = 0.478, p = 0.016) and recipient gamma-glutamyl transferase (R = 0.432, p = 0.019) levels. During graft procurement, hepatic IL-8 release was observed in 17/30 donors. Grafts with hepatic IL-8 release exhibited subsequently higher alkaline phosphatase [319 (213-405) IU/L vs. 175 (149-208) IU/L, p = 0.006] and bilirubin [101 (44-139) micromol/L vs. 30 (23-72) micromol/L, p = 0.029] levels after transplantation. Our findings support the concept that inflammatory response in the brain dead organ donor contributes to the development of graft injury in human liver transplantation.

Health-related quality of life and employment status of liver transplant patients.

Health-related quality of life (HRQoL) is one preferable outcome measure of medical interventions such as liver transplantation (LT). The aim of this study was to compare HRQoL of LT patients with that of the general population and to assess the employment status of LT patients. HRQoL was measured with the 15D instrument, a validated, non-disease-specific, 15-dimensional, self-administered HRQoL instrument. The questionnaire was sent to all adult LT patients in Finland (401 patients) alive in June 2007. The response rate was 89% (353 patients). The results were compared to those of 6050 age-standardized and gender-standardized controls from the general population. LT patients (mean age, 55 years; range, 20-82) had slightly worse HRQoL scores than the general population (mean 15D score, 0.889 versus 0.907; P < 0.002). Survival time and retransplantation did not affect HRQoL significantly in age-adjusted and gender-adjusted analyses. HRQoL decreased with increasing age (P < 0.0001). Patients transplanted for acute liver failure (ALF) or chronic liver disease (CLD) had significantly worse HRQoL than the general population (P = 0.014 and P = 0.040). Forty-four percent of working-age patients were employed at the time of the study. Persons that were employed had significantly better HRQoL than those unemployed (15D scores, 0.934 versus 0.859; P < 0.0001). Eighty-seven percent of patients experienced improved working capacity after LT. Early retirement was the most common cause of unemployment (56% of unemployed patients), and those patients presented with worse HRQoL than patients unemployed for other reasons. In conclusion, HRQoL of LT patients is very close to that of the general population. Older age, CLD, and ALF impair HRQoL. Employment is an indicator of HRQoL.

Human herpesvirus 6 infection of the gastroduodenal mucosa.

BACKGROUND: Human herpesvirus 6 (HHV-6) infections are usually asymptomatic reactivations in adult liver transplant recipients, but they may also cause fever or graft dysfunction. HHV-6 infection can also present symptoms of gastroenteritis. In this study, we investigated the presence of HHV-6 in the gastroduodenal mucosa of liver transplant recipients and in immunocompetent patients undergoing gastroscopic examination because of dyspeptic symptoms. METHODS: HHV-6 and cytomegalovirus (CMV) examinations were performed on gastroduodenal biopsy specimens obtained during upper gastrointestinal endoscopic examinations from 90 liver transplant recipients and from 31 immunocompetent patients with upper gastrointestinal symptoms. In the gastroduodenal mucosa, HHV-6 and CMV was demonstrated by immunohistochemistry in frozen sections using monoclonal antibodies against HHV-6- and CMV-specific antigens. RESULTS: HHV-6-positive cells were found in biopsy specimens from 21 (23%) of the liver transplant recipients and 6 (19%) of the immunocompetent patients, CMV-positive cells were found in specimens from 55 (61%) of the transplant recipients and 7 (23%) of the immunocompetent patients, and 12 transplant recipients were found to have both HHV-6 and CMV infection. Fifteen transplant recipients with positive HHV-6 findings in the gastroduodenal mucosa also had HHV-6 antigenemia, whereas 30 patients with HHV-6 antigenemia did not have gastroduodenal involvement. Endoscopic findings in these patients included biliary complications in 10 patients and gastritis in 2 patients. Histopathological findings were nonspecific and included very mild inflammation. A total of 30 (94%) of the transplant recipients with biliary complications also had HHV-6 or CMV detected in the duodenal mucosa. CONCLUSIONS: HHV-6-positive cells and CMV-positive cells were frequently found in the gastroduodenal mucosa of liver transplant recipients and of immunocompetent patients undergoing gastroscopic examination because of dyspeptic symptoms.

Risk of malignant neoplasms after liver transplantation: a population-based study.

Posttransplant malignancies have become a serious long-term complication after liver transplantation. Our aim was to compare the incidence of posttransplant cancers with national cancer incidence rates. The study included all Finnish liver transplant patients transplanted at the Helsinki University Central Hospital between 1982 and 2005. The cohort was linked with the nationwide Finnish Cancer Registry. Observed numbers of cancers were compared to site-specific expected numbers based on national cancer incidence rates stratified by age, sex, and calendar time. The standardized incidence ratios (SIRs) were calculated as observed-to-expected ratios. Thirty-nine posttransplant de novo cancers and 11 basal cell carcinomas were found in the cohort of 540 patients during 3222 person years of follow-up. The overall SIR was 2.59 (95% confidence interval 1.84-3.53). SIR was higher for males (SIR 4.16) than for females (SIR 1.74), higher among children (SIR 18.1) than among adults (SIR 5.77 for ages of 17-39 years and 2.27 for ages >/= 40 years), and more elevated in the immediate posttransplant period (SIR 3.71 at < 2 years) compared to later periods (SIR 2.46 at 2-10 years and 1.53 at >10 years). The most common cancer types were nonmelanoma skin cancer (SIR 38.5) and non-Hodgkin lymphoma (SIR 13.9). Non-Hodgkin lymphoma was associated with male gender, young age, and the immediate posttransplant period, whereas old age and antibody induction therapy increased skin cancer risk. In conclusion, cancer incidence is increased among liver transplant patients compared to the general population. This study points out the importance of cancer surveillance after liver transplantation.

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation.

High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P < 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-alpha or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P = 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r = 0.497, P = 0.03) and peak postoperative alanine aminotransferase levels (r = 0.588, P = 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation.

High frequency of gastroduodenal cytomegalovirus infection in liver transplant patients.

The prevalence and significance of cytomegalovirus (CMV) detected in biopsy specimens from the gastroduodenal mucosa of liver transplant patients, patients with chronic or acute liver failure and immunocompetent patients with dyspeptic symptoms were evaluated. 80 liver transplant patients with upper gastrointestinal symptoms, 132 patients with chronic and 25 with acute liver failure, and 33 immunocompetent, dyspeptic patients underwent oesophagogastroduodenoscopies, with biopsies from the duodenum and stomach. CMV was demonstrated by immunohistochemistry in frozen sections, using a monoclonal antibody against CMV-specific antigens (pp65 matrix protein), and in paraffin sections by a monoclonal antibody against delayed early protein (p52). 71% of the liver transplant patients, 45% of the patients with chronic liver disease, 20% with acute liver failure, and 45% of the immunocompetent, dyspeptic patients had CMV-positive findings in the gastroduodenal mucosa (liver transplant patients vs other groups, p<0.01). Histopathological findings in CMV-positive samples were focal inflammation, including increased inflammation of the lamina propria, infiltrating leukocytes intra-epithelially, regenerative changes in the epithelial cells and inclusion bodies. In conclusion, CMV-positive cells and inclusions are often found in the gastroduodenal mucosa of liver transplant patients, as well as in patients suffering from chronic liver disease or even in otherwise healthy patients with dyspeptic symptoms.

Cytokine profiles in acute liver failure treated with albumin dialysis.

Cytokines are released within the liver in response to hepatic injury, and acute liver failure (ALF) triggers systemic inflammation. Pro-inflammatory (tumor necrosis factor-alpha [TNF-alpha] and interleukin-8 [IL-8]) and anti-inflammatory (interleukin-10 [IL-10] and interleukin-6 [IL-6]) cytokines and the lymphocyte activation marker (interleukin-2-soluble receptor alpha chain [IL-2sRalpha]) were monitored in 49 ALF patients considered for liver transplantation and treated with albumin dialysis (molecular adsorbent recirculating system [MARS]). Twenty-six patients were categorized by clinical outcome as "good" (native liver recovered) and 23 as "poor" (patient bridged to liver transplantation or deceased). MARS did not clearly affect cytokine profiles during treatment; only IL-10 levels decreased in the whole patient population and mostly in patients with the worst prognosis. In the good outcome group, IL-8 and IL-6 levels decreased during treatment; on the contrary, in poor outcome patients IL-6 levels even increased. Initial IL-2sRalpha levels were higher in poor outcome patients relative to the good outcome subset. Cytokine profiles seem to differ in ALF according to patient outcome. A deeper understanding of cytokine patterns during pathogenesis could reveal prognostic markers and aid the development of immunomodulating ALF therapies.

Infectivity-enhanced adenoviruses deliver efficacy in clinical samples and orthotopic models of disseminated gastric cancer.

PURPOSE: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective and safe modality for the treatment of cancer. However, expression of the primary coxsackie-adenovirus receptor is variable in advanced cancers, and therefore, the use of heterologous receptors could be advantageous. EXPERIMENTAL DESIGN: Here, we used capsid-modified adenoviruses for increasing the transduction and subsequent antitumor efficacy. 5/3 chimeric viruses have a serotype 3 knob which allows binding to a receptor distinct from coxsackie-adenovirus receptor. The fiber of Ad5lucRGD is modified with an integrin-targeted motif. Polylysine motifs, pK7 and pK21, bind to heparan sulfates. Oncolytic adenoviruses replicate in and kill tumor cells selectively. Gastric cancer cell lines and fresh clinical samples from patients were infected with transductionally targeted viruses. Capsid-modified oncolytic adenoviruses were used in cell killing experiments. To test viral transduction and therapeutic efficacy in vivo, we developed orthotopic mouse models featuring i.p. disseminated human gastric cancer, which allowed the evaluation of biodistribution and antitumor efficacy in a system similar to humans. RESULTS: Capsid modifications benefited gene transfer efficiency and cell killing in gastric cancer cell lines and clinical samples in vitro and in vivo. Modified oncolytic adenoviruses significantly increased the survival of mice with orthotopic gastric cancer. CONCLUSIONS: These preclinical data set the stage for the clinical evaluation of safety and efficacy in patients with disease refractory to current modalities.

Pretransplant human herpesvirus 6 infection of patients with acute liver failure is a risk factor for posttransplant human herpesvirus 6 infection of the liver.

BACKGROUND: Acute liver failure (ALF) is a significant cause of liver transplantation. We have previously reported that human herpesvirus-6 (HHV-6) was found in most livers of patients with ALF of unknown origin ending up with liver transplantation. In this study, we investigated the posttransplant HHV-6 infection of the liver graft in these patients. METHODS: Thirty-two patients transplanted due to ALF were included in this retrospective study. Twelve of the 15 patients with unknown cause and four of 17 patients with a known cause of ALF had HHV-6 antigens in the explanted liver. Altogether, 18 patients had some pretransplant evidence of HHV-6. After transplantation, the patients were frequently monitored for the viruses, and biopsy histology was performed in every case of graft dysfunction. HHV-6 was demonstrated in liver tissue by immunohistochemistry. RESULTS: During the follow-up of 6 months, hepatic HHV-6 infection was demonstrated in 9 of the 18 patients, at a mean 19 days (6-38 days) after transplantation. All patients with posttransplant HHV-6 showed graft dysfunction. In biopsy histology, seven out of these nine patients demonstrated viral infection, one of them also having CMV antigens in the liver. None of those patients without evidence of pretransplant HHV-6 showed HHV-6 in the posttransplant biopsies. Posttransplant HHV-6 was not treated and the virus had no effect on 1-year patient or graft survivals. CONCLUSION: Pretransplant hepatic HHV-6 infection of patients with ALF is a risk factor for posttransplant HHV-6 infection and liver dysfunction, but has no effect on 1-year graft or patient survival.

Post-transplant reactivation of hepatitis C virus: lymphocyte infiltration and the expression of adhesion molecules and their ligands in liver allografts.

Hepatitis C virus (HCV) recurrence after liver transplantation has been associated with chronic rejection. Biopsies from 10 patients with post-transplant HCV were examined for expression of adhesion molecules ICAM-1, VCAM-1, and ELAM-1, number of lymphocytes positive for their ligands LFA-1, VLA-4, and SLeX, and activation markers MHC class II antigens and IL2-R by immunohistochemistry. The phenotypes of the graft-infiltrating lymphocytes were determined. Results were compared to those for patients with normal graft function or rejection. Five recipients with HCV reactivation and one with de novo HCV had a biopsy available showing induction of ICAM-1 in sinusoidal endothelium (p<0.05) and hepatocytes (p<0.01), and Class II antigens in hepatocytes (p<0.01), compared to normal controls. Lymphocytes in the graft infiltrate expressed LFA-1, VLA-4, and Class II antigens, but IL2-R was not significantly expressed. CD3+, CD4+, and CD8+ cells were observed. In our study, HCV recurrence was not associated with acute or chronic rejection, and the inflammation was due to the viral infection.

HHV-6 DNA in peripheral blood mononuclear cells after liver transplantation.

BACKGROUND: Human herpesvirus-6 (HHV-6) infections have been reported after liver transplantation. In this study, the detection of HHV-6 DNA in peripheral blood mononuclear cells (PBMC) was compared with HHV-6 antigenemia in liver transplant patients. OBJECTIVES: Forty-three adult liver recipients were frequently monitored by HHV-6 antigenemia test, which detects the viral antigens in PBMC, but is rather qualitative than quantitative. STUDY DESIGN: From the same PBMC specimens HHV-6 DNA was demonstrated by in situ hybridization using a biotinylated probe and quantified as positive cells/10, 000 PBMC. Altogether 330 blood specimens were analyzed. RESULTS: During the first 6 months (mean 12 days) after transplantation, 35/43 patients developed HHV-6 antigenemia. Concurrently, HHV-6 DNA-positive cells with mean peak number of 661(+/-574)/10, 000 were detected in 33/35 patients. Seven patients received ganciclovir treatment because of concurrent CMV infection with mean peak number of HHV-6 DNA-positive cells 381(+/-336) before and 34(+/-59)/10, 000 after the treatment (p = 0.03). All CMV infections responded to ganciclovir, but HHV-6 DNAemia disappeared slowly, within 79 days (mean 36 days). Without antivirals, HHV-6 DNAemia/antigenemia lasted usually longer. CONCLUSIONS: Detection of HHV-6 DNA in PBMC correlated well with HHV-6 antigenemia, and may be used in the monitoring of transplant patients.

Monitoring of EBV-DNAemia by quantitative real-time PCR after adult liver transplantation.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) causes significant morbidity and mortality in transplantation. The clinical significance of Epstein-Barr virus (EBV) in the development of PTLD is clear, but not all EBV-reactivations cause PTLD. OBJECTIVES: We retrospectively analyzed EBV-DNAemia in liver transplant patients by a quantitative TaqMan-based real-time plasma PCR. STUDY DESIGN: Altogether 1284 specimens, obtained from 105 patients for frequent monitoring of cytomegalovirus (CMV) and human herpesvirus-6 and -7 (HHV-6, HHV-7) during the post-transplant year, were retrospectively tested for EBV-DNA. RESULTS: Altogether, 14/105 (13%) patients showed EBV-DNAemia, which usually occurred within 3 months after transplantation and subsided within a few weeks. EBV-DNAemia occurred concurrently with CMV in 10/14, with HHV-6 in 11/14, and with all three betaherpesviruses in 4/14 cases. The peak viral loads were relatively low (median 2100 EBV-DNA copies/ml, range 568-6600), except in one patient who first had low-level EBV-DNA (562-3022 copies/ml) in the early post-transplant period, but on day 175 after transplantation developed high-level DNAemia (9851-86,975copies/ml) which continued for 6 months and developed into PTLD at 6 months after transplantation. CONCLUSION: Low-level EBV-DNAemia is common after liver transplantation, often occurring together with betaherpesviruses, but seldom leads to high viral loads or PTLD. However, monitoring of EBV-DNA levels in the patients can be useful.