Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation.

The demand for liver transplantation (LT) exceeds supply, with rising waiting list mortality. Utilization of high-risk organs is low and a substantial number of procured livers are discarded. We report the first series of five transplants with rejected livers following viability assessment by normothermic machine perfusion of the liver (NMP-L). The evaluation protocol consisted of perfusate lactate, bile production, vascular flows, and liver appearance. All livers were exposed to a variable period of static cold storage prior to commencing NMP-L. Four organs were recovered from donors after circulatory death and rejected due to prolonged donor warm ischemic times; one liver from a brain-death donor was declined for high liver function tests (LFTs). The median (range) total graft preservation time was 798 (range 724-951) min. The transplant procedure was uneventful in every recipient, with immediate function in all grafts. The median in-hospital stay was 10 (range 6-14) days. At present, all recipients are well, with normalized LFTs at median follow-up of 7 (range 6-19) months. Viability assessment of high-risk grafts using NMP-L provides specific information on liver function and can permit their transplantation while minimizing the recipient risk of primary graft nonfunction. This novel approach may increase organ availability for LT.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice.

BACKGROUND: Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) ≥10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) ≥60% measurement success rate. OBJECTIVES: To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. METHODS: We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. RESULTS: Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator's first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut-off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). CONCLUSIONS: Fibroscan requires minimal operator training (≥10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice.

CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.

We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68(+) macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell line in both of which apoptosis was induced, not only by cross-linking Fas directly but also via CD40 activation. Our data suggest that CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.

Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation.

Late allograft dysfunction is a significant problem following liver transplantation and its pathogenesis is uncertain. HLA-C is the major inhibitory ligand for killer immunoglobulin-like receptors (KIRs) that regulate the cytotoxic activity of natural killer (NK) cells. HLA-C alleles can be allocated into two groups, termed HLA-C1 and HLA-C2, based on their KIR specificity. HLA-C2 interactions are more inhibiting to NK cell activation. We studied the clinical importance of HLA-C genotype in a large liver transplant cohort and found that possession of at least one HLA-C2 allele by the donor allograft was associated with less histological evidence of chronic rejection and graft cirrhosis, a 16.2% reduction in graft loss (p = 0.003) (hazard ratio: 2.7, 95% CI 1.4-5.3) and a 13.6% improvement in patient survival (p = 0.01) (hazard ratio: 1.9, 95% CI 1.1-3.3) at 10 years. Transplantation of an HLA-C2 homozygous allograft led to a particularly striking 26.5% reduction in graft loss (p < 0.001) (hazard ratio: 7.2, 95% CI 2.2-23.0) at 10 years when compared to HLA-C1 homozygous allografts. Donor HLA-C genotype is therefore a major determinant of clinical outcome after liver transplantation and reveals the importance of NK cells in chronic rejection and graft cirrhosis. Modulation of HLA-C and KIR interactions represents an important novel approach to promote long-term graft and patient survival.

Cholangiocarcinoma complicating primary sclerosing cholangitis: a 24-year experience.

AIM: To report the prevalence and outcome of cholangiocarcinoma arising in primary sclerosing cholangitis for a British tertiary referral centre. METHODS: All patients diagnosed with primary sclerosing cholangitis and concurrent cholangiocarcinoma were identified from a prospectively maintained departmental database, and the mode of presentation, management and outcome were determined. RESULTS: Of 370 patients with primary sclerosing cholangitis, 48 patients (13%) were diagnosed with a cholangiocarcinoma within a median time of 0.51 months (range: 0-73.12) from presentation to the unit. Mode of presentation included: inoperable tumours (n = 14); incidental findings in transplant hepatectomy specimens (n = 13); primary sclerosing cholangitis follow-up (n = 9); transplant work-up (n = 5); transplant waiting list (n = 5); suspected tumour confirmed at transplant (n = 1), and incidental finding at cholecystectomy (n = 1). The diagnosis was confirmed by: radiology-guided biopsy (n = 27); MRI (n = 3); CT (n = 2); laparoscopy or laparotomy (n = 2), and frozen section at transplant (n = 1). Management consisted of: transplantation (n = 14, including 1 abandoned); hepatic resection (n = 8), and palliation through stenting (n = 26). The overall median survival of the cohort was 4.9 months (range: 0.09-104.5). Median survival ranged from 2.6 months (range: 0.09-35.3) for palliation to 7.6 months (range: 0.6-99.6) for transplantation and 52.8 months (range: 3.7-104.5) for resection. There was no difference in survival between the transplant and resection groups (p = 0.14). CONCLUSIONS: Cholangiocarcinoma is a common finding in primary sclerosing cholangitis and regular screening of this cohort of patients at referring centres is advocated to detect early tumours, as surgical treatment at an early stage offers significantly better outcomes for this cohort of patients.

Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease.

BACKGROUND: Validated diagnostic tools that are accurate, cost effective and acceptable to patients are required for disease stratification and monitoring in NAFLD. AIMS: To investigate the performance and cost of multiparametric MRI alongside existing biomarkers in the assessment of NAFLD. METHODS: Adult patients undergoing standard of care liver biopsy for NAFLD were prospectively recruited at two UK liver centres and underwent multiparametric MRI, blood sampling and transient elastography withing 2 weeks of liver biopsy. Non-invasive markers were compared to histology as the gold standard. RESULTS: Data were obtained in 50 patients and 6 healthy volunteers. Corrected T1 (cT1) correlated with NAFLD activity score (ρ = 0.514, P < .001). cT1, enhanced liver fibrosis (ELF) test and liver stiffness differentiated patients with simple steatosis and NASH with AUROC (95% CI) of 0.69 (0.50-0.88), 0.87 (0.77-0.79) and 0.82 (0.70-0.94) respectively and healthy volunteers from patients with AUROC (95% CI) of 0.93 (0.86-1.00), 0.81 (0.69-0.92) and 0.89 (0.77-1.00) respectively. For the risk stratification of NAFLD, multiparametric MRI could save £150,218 per 1000 patients compared to biopsy. Multiparametric MRI did not discriminate between individual histological fibrosis stages in this population (P = .068). CONCLUSIONS: Multiparametric MRI accurately identified patients with steatosis, stratifies those with NASH or simple steatosis and reliably excludes clinically significant liver disease with superior negative predictive value (83.3%) to liver stiffness (42.9%) and ELF (57.1%). For the risk stratification of NAFLD, multiparametric MRI was cost effective and, combined with transient elastography, had the lowest cost per correct diagnosis.

Incidence and characterization of serum transaminases elevations in pegylated interferon and ribavirin treated patients with chronic hepatitis C.

BACKGROUND: A virological response to pegylated-interferon and ribavirin is typically associated with a prompt fall in serum transaminases. For some patients, transaminases rise during treatment. AIM: To assess the frequency and define factors associated with elevations of serum transaminases. METHODS: A total of 169 treated patients were studied. Transaminase elevations were graded by WHO criteria - grade 0: no value > baseline, grade 1: 1-2x baseline, grade 2: 2.1-5x baseline, grade 3: >5x, grade 4: any rise with evidence of liver failure. Results 60/169 (35%) patients experienced transaminase elevations: 52 grade 1, 6 grade 2, 1 grade 3, 1 grade 4. Overall, end of treatment response and sustained virological response rates were 72% and 55%. Lower rates were observed in the grade 1 elevation group (63% and 40%) compared with patients with grade 0 (79% and 65%) and grade > or =2 elevations (85% and 71%). Grade 1 elevations tended to occur earlier during treatment than grade > or =2 elevations. Transaminase elevations were associated with greater pre-treatment body weight (P = 0.006), steatosis (P = 0.008) and poorer sustained virological response rates (P = 0.007). CONCLUSIONS: Transaminase elevations during treatment of chronic Hepatitis C virus with pegylated interferon and ribavirin are common but rarely severe. Mild rises may reflect ongoing viral activity in treatment non-responders. More significant rises are frequently observed despite a virological response, and may be because of an immuno-modulating effect of interferon in susceptible patients.

Primary hepatocellular cancer in the explanted liver: outcome of transplantation and risk factors for HCC recurrence.

AIM: To evaluate the risk of recurrence of hepatocellular cancer (HCC) after liver transplantation (LT). METHODS: The clinical records of 104 patients with HCC in the explanted liver were examined. RESULTS: HCC recurrence occurred in 12 patients. Recurrence was observed in all patients with a single nodule greater than 5 cm. Among the 5 patients with more than 3 tumours with a maximum diameter of 4.5 cm, no recurrence occurred. The survival rates were 81% and 64% at 1 and 5 years, respectively; the recurrence-free survival at 1 and 5 years was, respectively, 93% and 82%. Pre-LT alpha-fetoprotein (AFP) increased at a greater magnitude in patients who experienced recurrence, compared to those who did not. Tumour diameter, differentiation, satellitosis, AFP and the magnitude of AFP increase were predictive of recurrence. The 1- and 5-year recurrence-free survival for the 68 patients who had a single nodule up to 5 cm, or up to 3 nodules all less than 4.5 cm and with a maximum cumulative diameter of 8 cm, or more than 3 nodules all less than 2.5 cm, were 95% and 92%, respectively. For the 13 patients not meeting these criteria, the 1- and 5-year recurrence-free survival was, respectively, 75% and 54% (log Rank test p=0.019). CONCLUSIONS: Patients with more than 3 small HCC nodules before LT could still have a good outcome without recurrence. A rapid increase in AFP could be useful in identifying patients with a greater risk of post-LT HCC recurrence.

CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells.

Fas-mediated mechanisms of apoptosis are thought to be involved in the bile duct loss that characterizes diseases such as primary biliary cirrhosis (PBC). We have previously shown that activation of CD40 on hepatocytes can amplify Fas-mediated apoptosis; in the present study, we investigated interactions between CD40 and Fas in biliary epithelial cells (BEC). We report that the bile ducts in PBC liver tissue frequently express increased levels of Fas, Fas ligand (FasL), and CD40 associated with apoptotic BEC. The portal mononuclear infiltrate contains CD40L+ve T cells and macrophages, thereby demonstrating a potential mechanism for CD40 engagement in vivo. Primary cultures of human BEC also expressed Fas, FasL, and CD40 but not CD40L protein or mRNA. Activation of CD40 on BEC using recombinant CD40L increased transcriptional expression of FasL and induced apoptosis, which was inhibited by neutralizing antibodies to either Fas or FasL. Thus, CD40-induced apoptosis of BEC is mediated through Fas/FasL. We then investigated the intracellular signals and transcription factors activated in BEC and found that NF-kappaB and AP-1 were both activated after CD40 ligation. Increased functional NF-kappaB was seen early after CD40 ligation, but returned to baseline levels after 4 h. In contrast, the rapid up-regulation of AP-1 was sustained over 24 h. This study provides further functional evidence of the ability of CD40 to induce Fas/FasL-dependent apoptosis of liver epithelial cells supporting the importance of cross-talk between tumor necrosis factor (TNF) receptor family members as an amplification step in apoptosis induction. Sustained activation of AP-1 in the absence of NF-kappaB signaling may be a critical factor in determining the outcome of CD40 engagement.

Are parenchymal changes in early post-transplant biopsies related to preservation-reperfusion injury or rejection?

BACKGROUND: The progression of parenchymal changes in liver allograft biopsies due to preservation-reperfusion injury (PRI) and their differentiation from rejection related changes is poorly understood. The aim of this study was to determine which changes in a 1-week posttransplant biopsy could be attributed to PRI and which to acute rejection. METHODS: One week protocol liver transplant biopsies from patients with mild PRI (day 1 AST<400 IU/L) were compared with those from patients with severe PRI (day 1 AST>2000 IU/L). Parenchymal changes (cholestasis, ballooning, steatosis, necrosis) and rejection-related inflammatory features (portal tract inflammation, bile duct inflammation, portal vein endothelial inflammation, hepatic vein endothelial inflammation, and centrilobular inflammation) were blindly assessed semiquantitatively. RESULTS: Fat, cholestasis, and hepatocyte ballooning were significantly worse in the severe PRI group, and these features showed no correlation with histological features related to acute rejection. Centrilobular hepatocyte necrosis correlated with hepatic venular endothelial inflammation and centrilobular inflammation but not with rejection related features in portal tracts or with PRI. These findings suggest that centrilobular necrosis is a manifestation of a rejection-related parenchymal injury and may involve different pathogenetic mechanisms to rejection-related features in portal tracts. CONCLUSIONS: This study indicates that in early posttransplant biopsies, fat, cholestasis, and ballooning can largely be attributed to PRI. By contrast, centrilobular hepatocyte loss should be suspected as a rejection related phenomenon, even if typical portal tract changes are not prominent, and augmentation of immunosuppression should be considered.

Hepatic endothelial cells. Targets in liver allograft rejection?

Hepatic endothelial cell damage was evaluated in patients following liver transplantation using 2 serum markers: hyaluronic acid (HA), which measures hepatic endothelial cell function, and factor VIII related antigen (VIIIRAg), an indicator of generalized endothelial damage. HA was elevated in rejection (median 22.3 x control) when compared with stable patients (3.7 x control; P less than 0.00001) and those with posttransplant complications not related to rejection (6.8 x control; P less than 0.0005). The highest levels were seen in patients with chronic rejection (28.7 x control). Levels were also elevated in acute rejection (21.3 x control), and the highest levels in this group were seen in patients who subsequently developed chronic rejection (25.2 x control). Serial studies demonstrated that HA increased 24 hr before serum bilirubin in patients developing acute rejection. VIIIRAg was elevated in all posttransplant patients with no significant difference between rejection and other complications. These results show that hepatic endothelial dysfunction occurs during acute and particularly chronic rejection of liver allografts suggesting that VECs may be an important target of the immune response. Measurement of HA may allow for the early diagnosis of acute rejection and the identification of patients at risk of developing chronic rejection.

Recurrence of autoimmune hepatitis after liver transplantation.

BACKGROUND: The literature data on the recurrence of autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLTX) is scanty. METHODS: We analyzed the frequency of recurrent AIH in 47 patients who had been transplanted for AIH and survived at least 1 year after surgery. The following criteria were applied to diagnose recurrence: (1) positive autoantibodies in the titer> or =1:40; (2) hypertransaminasemia; (3) histological features of chronic hepatitis; (4) need of reintroduction or significant increase of steroids; and (5) lack of serum markers of viral hepatitis. RESULTS: A total of 13 patients (1 male/12 females) developed recurrent AIH after an interval of 6-63 months after OLTX (mean 29 months). Mean AST level at recurrence was 542+/-129 U/L. Three patients from this group needed regrafting. Mismatch of DR3+ recipient and DR3- donor was not more common in the recurrent disease group (37%) compared to the nonrecurrence group (31%) (P=NS). CONCLUSIONS: Recurrence of AIH after OLTX was diagnosed in a high proportion of patients and some of them required regrafting. DR3+ patients are not particularly prone to develop recurrence.

Differential expression of chemokines and chemokine receptors shapes the inflammatory response in rejecting human liver transplants.

BACKGROUND: Graft rejection after liver transplantation is associated with a lymphocytic infiltrate, the nature of which will be determined by, among various factors, the local activity of chemokines that attract particular subsets of effector cells to the graft. METHODS: The expression of chemokines and receptors in human liver allografts was studied by immunohistochemistry of tissue and flow cytometry of blood and liver-derived lymphocytes. Receptor function was assessed with in vitro chemotaxis. RESULTS: We report increased expression of chemokine receptors CXCR3, CXCR4, and CCR5 on circulating and graft-infiltrating lymphocytes after liver transplantation. Liver-derived T cells responded to the ligands for these receptors in vitro, which suggests that the receptors are functionally active. The chemokine ligands for these receptors were detected in rejecting allografts. CXCR3 ligands interferon-inducible protein 10 and monokine-induced by gamma interferon were detected on sinusoidal endothelium and interferon-inducible T-cell alpha chemoattractant was detected on portal and hepatic vascular endothelium, whereas the CXCR4 ligand, stromal-derived factor (SDF), was restricted to biliary epithelium. CCR5 ligands have previously been shown on portal endothelium. An in vitro model of T-cell alloactivation demonstrated a similar pattern of expression of functional CXCR3, CXCR4, and CCR5 on T cells. Increased expression of chemokine receptors, especially CCR3 and CCR5, was associated with redistribution of activated Kupffer cells in rejecting grafts. CONCLUSIONS: The patterns of chemokine expression in liver allografts during rejection suggest that the recruitment and positioning of lymphocytes is mediated by specific chemokines. Although ligands for the receptors CXCR3 and CCR5 are important for recruitment, the restriction of SDF to bile ducts suggests that CXCR4 may be involved in the retention of alloactivated lymphocytes at sites of graft damage.

Vanishing bile-duct syndrome following liver transplantation--is it reversible?

Loss of bile ducts is a characteristic feature of chronic rejection in the liver allograft (also known as irreversible rejection and vanishing bile-duct syndrome). Typically, this occurs as a progressive lesion resulting in irreversible damage and graft failure requiring retransplantation. In this study, we describe 6 patients who developed a transient loss of bile ducts following liver transplantation. This occurred in a series of 138 patients who underwent the first 160 liver transplant operations in the Birmingham Liver Transplant Programme (incidence = 4.4% of patients, 3.7% of grafts). Forty needle biopsies were obtained from the 6 patients between 6 and 1303 days after transplantation. Thirteen specimens, taken between 8 and 1253 days posttransplant (median 98 days) showed an absence of bile ducts in more than 50% of portal tracts. Other histologic features of chronic rejection, inflammatory bile-duct lesions, perivenular cholestasis, and hepatocyte dropout were also seen in these biopsies, and severe cholestasis was present biochemically (median serum bilirubin level 240 mumol/L). The histologic and biochemical changes were thought to be compatible with a diagnosis of chronic/irreversible rejection, but the decision to carry out retransplantation was deferred on the basis of stable and, subsequently, improving biochemistry. Follow-up biopsies showed recovery of duct loss and other histologic abnormalities. All 6 patients are currently alive and well with good graft function. It is concluded that a transient, reversible bile-duct loss can occur after liver transplantation and that cases with this condition are indistinguishable from those who subsequently develop irreversible graft damage. In view of the risks associated with additional immunosuppression and/or retransplantation, caution is advocated in the interpretation of ductopenia in posttransplant liver biopsies. We suggest that the term "early chronic rejection" might be appropriate to describe cases in which a definite diagnosis of irreversible graft damage cannot be made.

Timing, significance, and prognosis of late acute liver allograft rejection.

Liver allograft rejection is usually divided into acute (cellular) rejection and chronic (ductopenic) rejection. Most cases of acute rejection occur within four weeks of transplantation. There is a paucity of published literature on late acute rejection (LAR) in liver allografts and little is known about factors affecting its occurrence and outcome. To study the predisposing factors, clinical presentation, and prognosis of LAR, data prospectively collected on consecutive adult patients who underwent liver transplantation between 1982 and 1994, were analyzed. LAR was defined as histologically confirmed acute cellular rejection occurring 30 or more days after liver transplantation. Of the 717 patients, 59 (7.5%) had 71 episodes of LAR. Fifty-seven episodes were seen during the first year after transplantation, the remaining occurring between 1 and 6 years. Age, sex, pretransplant diagnosis, donor match of HLA, and blood groups was not associated with risk of LAR. Twenty-seven (38%) episodes were preceded by subtherapeutic blood levels of cyclosporine/FK506 (< 100 ng/ml and < 5 ng/ml, respectively) while an additional 6 (8%) had marginally low blood levels (< 150 ng/ml and < 10 ng/ml, respectively). Treatment with high-dose prednisolone resulted in complete resolution of rejection in 36 (51%) episodes, partial response in 21, and no response in 14 patients. Sixteen patients (27%) developed chronic rejection and graft loss. Development of chronic rejection was not affected by age or sex of the patient, timing of LAR, or histological severity of AR. Delayed response to therapy during an earlier episode of AR, and histological findings of centrilobular necrosis or bile duct loss at the time of diagnosis of LAR were associated with high risk of progression to chronic rejection and graft loss.

Hepatic expression of macrophage inflammatory protein-1 alpha and macrophage inflammatory protein-1 beta after liver transplantation.

Two local events that are crucial for T cell emigration into tissue are (1) activation of T cell integrins to permit binding to endothelial counter-receptors and (2) directed migration through the endothelium and into tissue in response to chemotactic factors. Because the chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta can activate adhesion and induce migration of T cells in vitro, we investigated their expression in human liver allografts to determine whether they might be involved in regulating the recruitment of T cells to allografts in vivo. Both chemokines were expressed strongly by infiltrating leukocytes during rejection and could be detected immunohistochemically on biliary epithelium, an important target for T cell mediated graft damage. Both chemokines, but particularly MIP-1 beta, were detected on the vascular and sinusoidal endothelium of rejecting liver allografts, where they were coexpressed with the T cell beta 1-integrin receptor vascular cell adhesion molecule-1. In situ hybridization with complementary ribonucleic acid probes showed no MIP-1 alpha or MIP-1 beta mRNA in normal liver but dramatic expression of both chemokines in infiltrating leukocytes and graft endothelium during rejection. Expression was reduced after successful corticosteroid treatment of rejection but persisted in patients progressing to chronic rejection. Increased MIP-1 alpha and MIP-1 beta mRNA expression was already found in biopsies taken at the end of the transplant operation, suggesting that early induction of chemokines, possibly in response to graft reperfusion, might promote the subsequent development of graft rejection. These data demonstrate for the first time that MIP-1 alpha and MIP-1 beta are (1) expressed in human liver allografts, (2) produced by endothelial cells in vivo, and (3) induced early after transplantation. They suggest that MIP-1 alpha and MIP-1 beta produced by graft infiltrating leukocytes and graft endothelium might play a crucial role in regulating T cell recruitment to liver allografts in vivo.

Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis: assessment of risk factors.

BACKGROUND/AIM: It remains uncertain whether autoimmune hepatitis (AIH), as an original indication for orthotopic liver transplantation (OLTX), predisposes to the development of chronic rejection (CR) after surgery and published reports on heterogeneous groups of patients provided conflicting data. In this work we analyzed the incidence and risk factors for CR in a large cohort of adult patients transplanted for AIH in our unit. RESULTS: A total of 1190 adult patients received OLTX in our center between 1982 and 1998. A total of 77 patients (6.5%) were transplanted for AIH and 12 (15.6%) patients from this group developed clinical and histological features of CR within a median time of 3.5 months after OLTX. Patients with AIH who developed CR were younger than other AIH patients at OLTX (32 vs. 44.2 ys; P=0.015) and more often had histological features of moderate or severe acute rejection (83 vs. 34%; P=0.002) on early post-OLTX biopsies. The incidence of CR in AIH patients was significantly higher than in subjects transplanted for other indications such as primary biliary cirrhosis (8.2%; P<0.05), primary sclerosing cholangitis (5.2%; P<0.05) or alcoholic cirrhosis (2.0%; P<0.001). Also, we observed a tendency to decreased incidence of CR with time in all transplanted subjects. CONCLUSIONS: Apart from younger age at OLTX and higher incidence of severe acute rejection, patients with AIH who developed CR did not differ from other subjects transplanted for this indication. Unlike other studies, not stratified by diagnosis, recipient CMV negative status, young donor age, and HLA DR matching were not identified as risk factors for CR in AIH.

Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: long-term follow-up.

BACKGROUND: This open, multicenter study was conducted to evaluate the efficacy and safety of lamivudine prophylaxis given to chronic hepatitis B virus-(HBV) infected patients before and after orthotopic liver transplantation (OLT). We now present long-term data that follow our previous short-term report. METHODS: Twenty-three patients were treated with lamivudine (100 mg orally, daily); 13 (57%), were serum HBV DNA positive (Abbott Genostics, Abbott Laboratories, Chicago, IL) at study entry. Patients received lamivudine for at least 4 weeks before OLT, and for up to 50 months (median 25 months) after OLT. RESULTS: Of the 23 treated patients, 17 survived to undergo OLT. Eleven patients (65%) survived up to 4 years (median 36 months) after OLT. One of the survivors stopped lamivudine because of a possible adverse reaction 9 months post-OLT, and prophylaxis with HBV immune globulin was then established. Ten survivors continue lamivudine. Eight long-term survivors have normal liver function without evidence of HBV reinfection. Of the 17 transplanted patients, 6 died. Four patients died (3 days to 5 months post-OLT) without evidence of graft reinfection. Two further patients died at 19 and 23 months post-OLT from graft failure. Both patients had YMDD variant detected at 12 months post-OLT. Two other patients with YMDD-variant HBV remain alive on lamivudine, 9 and 15 months after development of the variant. CONCLUSIONS: Lamivudine, given before and after OLT, prevents significant graft reinfection for the majority of treated patients. The study has also shown that lamivudine is extremely well tolerated by liver failure patients and for a prolonged period after transplantation.