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Background: Macrovesicular steatosis is assumed to be an important risk factor for early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT)., Aim: To evaluate the impact of steatosis in combination with other risk factors on the outcome of OLT., Methods: The degree of steatosis was analysed in 165 consecutive OLTs and was classified by histological examination as non (M0), mild (<30%, M1), moderate (30-60%, M2) or severe steatosis (>60%, M3). Recipients were analysed for EAD., Results: EAD was observed in 28% of patients with M0, 26% with M1, 53% with M2 and 73% with M3 (P < 0.001). Patients with EAD had a significantly shorter graft survival after liver transplantation (P = 0.005) but did not correlate with survival. In multivariate regression analysis, the grade of steatosis, donating after cardiocirculatory death (DCD) grafts and duration of cold ischaemia time were significantly associated with EAD (P < 0.001, P = 0.01 and P = 0.001, respectively)., Conclusion: Livers with severe (M3) steatosis from DCD donors, combined with a prolonged CIT have a high risk for developing EAD which is correlated with shorter graft survival. Therefore M3 livers should only be considered for OLT in selected recipients without the presence of additional risk factors., (© 2011 International Hepato-Pancreato-Biliary Association.)

Ischemic-type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia-reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The efficacy of anti-viral intravenous immunogobulins (anti-HBs Ig and anti-CMV Ig) in preventing acute rejection after liver transplantation was assessed in a retrospective analysis, and correlated to their effects on immune cells in vitro. HBs Ag-positive liver graft recipients (n = 40) treated prophylactically with anti-HBs Ig had a significantly lower incidence of acute rejection compared with recipients without viral hepatitis (n = 147) (12% vs. 34%; p = 0.012), while the incidence of rejection in HCV-positive recipients (n = 29) was similar to that in the control group. Treatment with anti-CMV Ig (n = 18) did not protect against rejection. In vitro, anti-HBs Ig suppressed functional maturation of and cytokine production by human blood-derived dendritic cells (DC) at concentrations similar to the serum concentrations reached during anti-HBs Ig treatment of liver graft recipients. In addition, anti-HBs Ig inhibited allo-antigen- and lectin-stimulated proliferation of peripheral T cells. Anti-CMV Ig suppressed functional DC-maturation and alloantigen-stimulated T-cell proliferation, but not lectin-driven T-cell proliferation. In conclusion, anti-HBs Ig protects against acute rejection after liver transplantation, probably by functional inhibition of the two principal immune cells involved in allograft rejection, DC and T cells.

In experimental animals inhibition of T cell co-stimulation immediately after organ transplantation effectively prevents rejection. We investigated whether the expression of co-stimulatory molecules is enhanced in cadaveric liver transplants, whether their expression is influenced by the transplantation procedure, and whether variation in expression between liver transplants is related to the occurrence of acute rejection. Expression of CD80, CD86 and the macrophage marker CD68 were determined by immunohistochemistry in biopsies from 40 clinical liver transplants obtained at different time-points during the transplantation procedure, and in normal liver tissue obtained from 10 human livers. Expression of CD80 and CD86 on Kupffer cells was graded by comparison with CD68-staining. In a subgroup CD80 and CD86 mRNA was quantified by real-time detection polymerase chain reaction. CD86 was expressed in all liver transplants and normal livers on the majority of Kupffer cells. CD80 was absent or sporadically expressed in normal liver tissue, but in 18 of 40 liver transplants at least one-quarter of Kupffer cells expressed CD80. CD80- and CD86-mRNA and protein expression in liver transplants did not change during the warm ischaemic and reperfusion phases of the transplantation procedure. CD80-expression on Kupffer cells varied strongly between individual donor livers; this variation was, however, not significantly related to the occurrence of acute rejection after transplantation. In conclusion, in nearly half of cold-preserved cadaveric liver transplants an increased proportion of Kupffer cells express CD80 at the time of transplantation in comparison with normal liver tissue. The expression was not further induced by warm ischaemia and reperfusion. However, the observed variation in CD80-expression between liver transplants is not a accurate predictive measure for acute rejection.

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intra-operative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband. Metabolic correction was initially seen in all groups, but ligation led to portal hypertension and early mortality. In the free-flow group, correction was lost after 7 days, while banding preserved correction until 6 weeks. We conclude that acute ligation can lead to portal hypertension and free-flow leads to hypoperfusion and early loss of metabolic correction. Banding divided the portal blood flow between host liver and graft and prolonged metabolic correction., (Copyright 2003 S. Karger AG, Basel)

Individuals may differ in their capacity to produce cytokines. Since cytokines play a key role in allograft rejection, we investigated whether inter-individual differences in cytokine production by in vitro stimulated PBMC are related to the occurrence of acute liver transplant rejection. Our study group comprised 49 liver transplant recipients and 30 healthy individuals. Rejection, which occurred within one month after liver transplantation, was defined in 22 patients ("rejectors") as biopsy-proven rejection, treated with high dose prednisolone. Patients who never experienced rejection episodes were termed as "nonrejectors" (n=27). PBMC of healthy individuals and of liver transplant recipients, collected late after transplantation (mean 3.5 years), were cultured in the presence and absence of Concanavalin A. The production of TNF-alpha, IFN-gamma, IL-10, and IL-13 was measured in supernatant after 1, 2, 3, 4, and 7 days of cell culture. In cell culture, stimulated PBMC of rejectors were found to produce significantly higher levels of TNF-alpha, while there was a trend towards higher production of IFN-gamma and IL-10 as compared to nonrejectors. After grouping patients into high or low cytokine producers based upon reference levels of the healthy individuals using multivariate analysis it was found that occurrence of acute liver transplant rejection correlated to high production of TNF-alpha and low production of IL-13. After stimulated cell culture PBMC of liver transplant recipients show a differential production of TNF-alpha and IL-13 which is correlated with the occurrence of acute liver transplant rejection.

Background: Auxiliary partial orthotopic liver transplantation (APOLT) has successfully been performed in patients with noncirrhotic metabolic diseases. It remains, however, unclear if intervention in the portal venous inflow is necessary to ensure adequate portal blood flow to graft and host liver. In this experimental study we evaluate the hepatic flow during APOLT., Methods: Left lateral/medial segmental grafts were transplanted from beagle to dalmatian dogs. Vascular structures were anastomosed end-to-end. The effect of diversion of the portal flow was studied in three groups: in the ligation group (n=3) the host portal vein was tied off, the free flow group (n=6) had random flow to both livers. In the banding group (n=11) the host portal vein was banded with a adjustable strapband to restore the pretransplantation flow distribution., Results: After reperfusion the blood flow through the common portal vein decreased from 49 to 36 ml/kg/min (P<0.03) in all animals. Flow through the left portal vein decreased from 26 to 5 ml/kg/min (P<0.0001). Banding restored the flow in the left portal vein to 12 ml/kg/min, although the flow in the free-flow group remained 4 ml/kg/min. In the ligation group the total portal flow was forced toward the graft leading to the highest perfusion: 24 ml/kg/min (P<0.005). Adverse effect of this ligation was the development of portal hypertension., Conclusions: This experimental study confirms that diversion of the portal flow is necessary for adequate graft perfusion in APOLT. Banding can restore the pretransplantation flow distribution, without compromising the flow in the common portal vein.

Background/aims: The purpose of this study was to characterize the clinical, histological and virological events in an orthotopic liver transplant (OLT) recipient with recurrent hepatitis B infection who was initially managed with hepatitis B immune globulin (HBIg) and when viral recurrence occurred, with nucleoside analogue salvage therapy. The aims were to document the mutations occurring in the hepatitis B virus (HBV) polymerase gene as a consequence of HBIg escape, famciclovir non-response and subsequent lamivudine resistance., Methods: Throughout the follow-up of 796 days, the patient was seen at least at 4-week intervals. Clinical, biochemical and virological data were registered according to protocol. HBV DNA was quantified throughout the treatment period. The viral polymerase gene was sequenced from serum samples collected at representative time intervals. Consecutive liver biopsies were scored according to the modified Knodell classification., Results: Clinically, the patient was in excellent condition until the development of acute hepatitis during the lamivudine therapy period, 765 days post-OLT. Until this terminal event, serum transaminase activity was only 1-2 times the upper limit of normal with serum bilirubin and prothrombin time within the normal range. Subsequent liver biopsies showed chronic active hepatitis with no signs of fibrosis. The post-mortem biopsy showed severe acute hepatitis B with massive necrosis. The HBV polymerase gene was sequenced during HBIg, famciclovir and lamivudine treatment. One mutation I533L was detected during HBIg treatment. No amino acid changes were selected during famciclovir treatment. Three amino acid changes were selected while the patient was on lamivudine treatment, which include L533I, S559T and M550I., Conclusions: We have documented HBV recurrence in a liver transplant recipient with the emergence of a multidrug resistant HBV which caused graft loss. The primary resistance to famciclovir in spite of therapeutic penciclovir levels may be as a result of a combination of the mutations found in the polymerase region. After 300 days of lamivudine treatment, a drug-resistant population emerged which was associated with a greater than three log increase in HBV DNA and contributed to loss of graft function. This is the first report of such an adverse clinical outcome due to the emergence of a mutant virus as a consequence of immunoprophylactic and antiviral therapy in a liver transplant recipient.

To study T-cell/macrophage interactions at the molecular level in clinical allograft rejection, we measured intragraft mRNA expression of the T-cell derived cytokine IL-2 and the macrophage derived chemokine IL-15, a novel cytokine associated with T-cell activation, in post-transplant liver biopsies (n = 33) and in non-transplanted control liver tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). We analyzed biopsies without evidence of rejection (n = 12), with spontaneously resolving histological rejection (n = 10), or with histological rejection accompanied with clinical rejection (n = 11) defined by rising serum bilirubin and aspartate amino transaminase levels. IL-15 mRNA expression was present in the majority of post-transplant liver biopsies (91%, 30/33) and was significantly upregulated as compared with non-transplanted liver tissue (p = 0.005). However, the increased intragraft IL-15 mRNA level was not indicative for rejection. In contrast to intragraft IL-15 mRNA expression, IL-2 mRNA transcription was measured in the minority of the post-transplant liver biopsies (15%, 5/33) and not detectable in control specimens. In addition, IL-2 mRNA was almost specifically measured in rejection biopsies concurrent with graft dysfunction (36%, 4/11 versus 1/22 without clinical rejection; p = 0.03). No relation between intragraft IL-2 and IL-15 mRNA expression was found. The IL-15 mRNA expression levels were not higher in the IL-2 negative rejections compared with those in IL-2 positive rejections. To conclude, in contrast to IL-2, the function of IL-15 in T-cell mediated rejection remains unclear. The overall high IL-15 mRNA levels in sites of immune responses suggests that the macrophage-derived mediator IL-15 is involved in a constant flow of T-cells from the circulation into the graft.

The objective of this study was to develop an animal model to evaluate the biology of hepatocellular carcinoma (HCC) recurrence after liver transplantation. HCC was induced in Brown Norway (BN) rats (n = 45) by diet-hylnitrosamine (DEN) administered continuously through the drinking water. Starting from day 14, rats were sequentially autopsied or syngeneically transplanted according to Kamada's cuff technique. After 74 days of DEN administration, neoplastic liver lesions appeared and after a mean of 102 days (SD +/- 6) the animals died of abdominal haemorrhage from liver tumours. At this time lung metastases were present in three-fifths animals. Transplantation success was dependent on the DEN consumption and thereby the tumour stadium. After 74 days of DEN administration BN rats could no longer be transplanted because of anaesthetic problems or technical problems due to tumour adhesion to surrounding tissues. No recurrence was found in the transplants. In conclusion, we believe that timing of the operation in this HCC model is essential because the physical condition of the animals prohibits orthotopic liver transplantation in an advanced tumour stage. With a different DEN dosage scheme this problem may be solved.

Liver transplantation for hepatitis B virus (HBV)-related liver disease is complicated by HBV recurrence and, consequently, poor patient and graft survival. Patients transplanted for hepatitis delta virus (HDV)-related cirrhosis are reported to have a diminished incidence of HBV recurrence and improved graft survival. However, only a few reported HDV-infected patients had active HBV replicative disease before liver transplantation. In our experience, we transplanted two HDV-infected patients, both of whom had active HBV replication before liver transplantation. In one patient, hepatitis B surface antigen (HBsAg) recurred four months after transplantation. Two months later, Hepatitis Be antigen (HBeAg) and HBV-DNA became positive, and the patient died of fulminant recurrent hepatitis B and hepatitis delta. In the other patient, HBV persisted after transplantation, and 2 months later the patient required retransplantation for fulminant recurrent hepatitis B and hepatitis delta. With the second graft, the patient remained free of HBV infection for 1 year. Thereafter, the patient experienced HBV recurrence with active replication and died of fulminant hepatitis B and delta recurrence. In the first case and in the second graft of the second case, hepatitis B immunoglobulin (HBIG) immunoprophylaxis was administered in an attempt to prevent recurrence of HBV. The literature suggests that an HDV infection inhibits the replication of HBV and therefore plays a role in preventing the recurrence of HBV and improving survival. Our experience with two patients suggests that HDV infection, in the presence of active HBV replication, may not play a protective role.

The mechanism underlying spontaneously resolving allograft rejection following clinical liver transplantation is unidentified. In this process, immunoregulatory T helper (Th)-2 cytokines like IL-4, often identified with down-regulation of the Th1-dependent (IL-2) cell-mediated response, might play a significant but unknown role. For this reason, we analyzed mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) in 57 biopsies derived from 19 recipients. Specimens included biopsies without evidence of rejection (n = 36), biopsies with histological evidence of rejection (n = 10) not followed by clinical signs of graft rejection, and biopsies with histological rejection that were accompanied with clinical rejection (n = 11), defined by rising serum bilirubin and aspartate amino transaminase (ASAT) levels. Intragraft IL-4 mRNA expression significantly correlated with spontaneously resolving rejections. In 70% (7/10) of these biopsies, IL-4 mRNA was detectable, while only 19% (7/36) of the biopsies without signs of rejection (p < 0.01; Fisher's exact test) and 18% (2/11) of the rejection biopsies concurrent with graft dysfunction expressed the IL-4 gene (p = 0.03). In contrast, IL-2 mRNA expression was not detectable in biopsies derived from the spontaneously resolving rejections. None (0/10) of these samples expressed the IL-2 gene, which was not significantly different from the proportion of biopsies transcribing the IL-2 gene in the absence of rejection (11%, 4/36). IL-2 mRNA expression was found more often in biopsies associated with graft dysfunction (36%, 4/11). These results show that IL-4, in contrast to IL-2 mRNA expression, is associated with spontaneously resolving liver rejection. This suggests that Th2 cells down-regulate the Th1-dependent cell-mediated immune response after clinical liver transplantation.

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intraoperative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband. Metabolic correction was initially seen in all groups, but ligation led to portal hypertension and early mortality. In the freeflow group, correction was lost after 7 days, while banding preserved correction until 6 weeks. We conclude that acute ligation can lead to portal hypertension and freeflow leads to hypoperfusion and early loss of metabolic correction. Banding divided the portal blood flow between host liver and graft and prolonged metabolic correction. [ABSTRACT FROM AUTHOR]