Hepatic Allograft Research Articles

Posttransplantation lymphoproliferative disorders in solid organ recipients are predominantly aggressive tumors of host origin.

Patients immunosuppressed after organ transplantation have an increased frequency of lymphoproliferative disorders, known as posttransplantation lymphoproliferative disorders (PTLDs). In recipients of bone marrow allografts. PTLDs are often of donor origin. In only a few cases of lymphoma arising in solid-organ transplant recipients has the origin from host or donor lymphocytes been established. The authors have analyzed 11 cases of PTLD from Massachusetts General Hospital, arising in seven male and four female patients, aged 8 to 63, five with renal, four with cardiac, and two with hepatic allografts. Using the polymerase chain reaction (PCR) to investigate genetic polymorphism at the D4S174 locus on chromosome 4, the Rb1.20 locus on chromosome 13, and the D19S178 locus on chromosome 19, only one tumor (previously reported) was of donor origin, whereas 10 were of host origin. Follow-up revealed that six patients died of PTLD, one was alive with recurrent PTLD, and four were alive and well or had died of other causes, including the patient with donor-origin PTLD. Based on these cases and on a review of previously reported cases, the authors conclude that the majority of PTLDs in solid organ recipients are of host origin. There appears to be a trend toward a greater likelihood of persistent or recurrent PTLD among solid organ recipients with host-origin tumors than among those with donor-origin tumor.

31P nuclear magnetic resonance evaluation of rat liver preserved in UW solution.

A persistent problem in orthotopic liver transplantation is primary nonfunction (PNF) of the hepatic allograft. In an attempt to reduce the incidence of graft failure, the feasibility of pretransplant assessment of graft viability was investigated by 31P nuclear magnetic resonance (NMR) spectroscopy. The level of adenosine triphosphate (ATP) was measured as an indicator of liver function by 31P NMR spectroscopy after a 30 min normothermic reperfusion following cold-storage in University of Wisconsin (UW) solution. The mean +/- SD beta-ATP/Pi ratio after preservation for 0, 12, 24 or 48 h was 1.40 +/- 0.34, 0.85 +/- 0.27, 0.64 +/- 0.14 and 0.38 +/- 0.09, respectively. Significance was observed between 12h and 24h and between 12h and 48h of preservation. These results correlated well with the morphological changes in endothelial cells and sinusoidal lining cells examined by transmission electron microscopy. It is suggested strongly that microcirculatory disturbances due to endothelial cell injury impairs the recovery of ATP levels after reperfusion, and that ATP determination by 31P NMR spectroscopy, as a non-invasive modality, may help in the prediction of PNF after liver transplantation.

A Comparison of Spontaneous Versus Induced Tolerance in an Experimental Model of Rat Hepatic Allograft Transplantation

In some rodent haplotype combinations, spontaneous tolerance (ST) develops after orthotopic liver transplantation (OLT) without any immunosuppression [e.g., Lewis (Lew, RT1 1) into Wistar Furth (WF, RT1 a)] whereas in other combinations vigorous, progressive rejection rapidly leads to the death of the recipients. We (and others) have induced tolerance (IT) in a rejecting strain combination [Dark Agouti (DA, RT1 a) into Lew] by intrathymic inoculation of donor bone marrow cells and 1 cc of antilymphocyte serum (ALS) 7-14 days prior to OLT. We hypothesized that cellular immunity in the two groups of animals was similar. We first compared survival in each group of animals and found that there was no difference in the number of animals surviving >100 days (8/11 vs 16/17, ST vs IT, respectively, P = 0.11). Liver function studies were similar in these animals at 2 and 4 weeks after OLT and comparable to syngeneic Lew into Lew OLT animals, but significantly lower than in the rejecting DA into Lew combination treated with only ALS. Animals that were unresponsive to their allografts demonstrated donor-specific tolerance by the acceptance of donor strain ( n = 4, ST and IT) and rejection of third party ( n = 1 and n = 2, ST and IT groups, respectively) heterotopic heart allografts. One-way mixed lymphocyte cultures (MLC) of peripheral blood lymphocytes against donor and third party antigen were suppressed to donor and third party stimulators versus the MLC of unmanipulated animals. Naive host strain responder lymph node cells and purified T cells demonstrated strong proliferative responses to donor strain antigen in both the ST and IT animals. Peripheral blood lymphocytes expressing donor MHC class I molecules were not detectable by flow cytometry in the ST animals using the monoclonal antibody (mAb) I-1.69 which is directed against Lew MHC class I molecules. There was variable expression (023%) of donor MHC class I molecules on peripheral lymphocytes in IT animals using the mAb C3, directed against DA MHC class I molecules. In summary, animals unresponsive to their liver allografts demonstrate donor-specific tolerance and functionally intact cellular immunity in vivo by acceptance of donor strain and rejection of third party heart allografts. The MHC class II response is suppressed to donor and third party stimulators in vitro in both groups of animals. In conclusion, cellular immunity in rats after liver allografting in the Lew into WF spontaneously tolerant strain combination is similar to that after tolerance induced by intrathymic manipulation in the DA into Lew combination.

Characterization of Hepatic Allograft Infiltrates in Rats Pretreated with Donor-Specific Blood Transfusion (DST)

A single intravenous injection of 1 ml freshly heparinized donor blood given 7 days prior to transplantation prolonged significantly the survival of subsequent hepatic allografts in fully allogeneic ACI(RT1 a)-to-LEW(RT1 1) rats. The cellular identity of allograft infiltrates was investigated at various times after transplantation using OX8 (CD8) and W3/25 (CD4) monoclonal antibodies. The number of CD8 + cells increased rapidly and reached a peak on Day 3 after transplantation of the untreated allografts. Similarly, the number of CD8 + cells in the allografts from DST-treated rats was maximum on Day 3 and decreased gradually thereafter. The maximum number of CD4 + cells was found on Day 3 in untreated allografts. In contrast, no significant infiltration of CD4 + cells occurred during the first 7 days after transplantation in DST-treated allografts. Thereafter, the number of CD4 + cells increased rapidly and reached a peak on Day 14. CD4 + cells remained persistently elevated in hepatic allografts of rats pretreated with DST, but did not become functionally competent or initiate rejection. These findings suggest that persistent infiltration by CD4 + cells is a characteristic feature of long-surviving hepatic allografts in rats pretreated with DST.

Case Report

Fulminant multicentric Kaposi’s sarcoma developed in an American-born HIV-negative patient 8 months after orthotopic liver transplantation. Despite its rarity in liver transplantation, Kaposi’s sarcoma should be considered in the differential diagnosis in hepatic allograft recipients presenting with rapidly growing cutaneous or polylymphadenopathic lesions.

Risk factors for systemic fungal infections in liver transplant recipients.

The risk factors for systemic fungal infections were analysed retrospectively in 186 orthotopic liver transplant procedures performed in 152 patients between June 1985 and January 1993. The total incidence of systemic fungal infections was 16.5% (25/152). The incidence of disseminated candidiasis, aspergillosis, and combined candidiasis and aspergillosis was 6.5% (n = 10), 7.2% (n = 11) and 2.6% (n = 4), respectively. Mortality associated with systemic fungal infections was 80% (20 of 25 patients). There were ten cases of disseminated candidiasis, with 4 patients surviving, and 11 cases of invasive aspergillosis, with 1 patient surviving. All patients with combined systemic fungal infection died. To identify perioperative risk factors, 39 variables were used to compare patients with systemic fungal infections versus those without fungal infections. Fourteen variables were significantly associated with systemic fungal infections by univariate analysis. A consecutive logistic regression analysis revealed that the amount of fresh frozen plasma transfused due to poor initial function of the allograft and acute renal failure requiring hemofiltration were independently significant risk factors for systemic fungal infections. There was no statistical correlation between systemic fungal infections and the underlying liver disease, previous long-term corticosteroids and the postoperative immunosuppressive therapy. Risk factors identified in this study should be considered in the postoperative care of the individual liver transplant recipient. In our study a poor initial function of the hepatic allograft substantially increased the risk of systemic fungal infection.

Impact of older donors on hepatic allograft viability: [formula omitted] Department of Surgery, Rush Presbyterian St Lukes Medical Center, Chicago, Illinois

Impact of older donors on hepatic allograft viability: [formula omitted] Department of Surgery, Rush Presbyterian St Lukes Medical Center, Chicago, Illinois

Improved Viability of Hepatic Allografts from Fasted Donors Is Associated with Decreased Peripheral TNF Activity

Despite improvements in preservation solutions, hepatic allografts continue to be lost from primary nonfunction. Previous work by this group and others has established that donor fasting improves the viability of hepatic allografts. We have also established an association between viability of stored organs and serum TNF levels. The purpose of this study was to determine whether improved viability of hepatic allografts from fasted donors is associated with lower peripheral serum TNF levels. TNF was measured using a bioassay employing a WEHI cell line. Transplanted livers from fasted donors displayed gross deglycogenation had less bile flow postrevascularization and increased postoperative AST, but had significant improvement in viability and were associated with significantly less TNF recovered from the peripheral circulation. The association of improved viability and diminished serum TNF and previous work that links changes in postrevascularization TNF levels with changes in Kupffer cell activity suggest a possible cause for improved survival of recipients of fasted allografts.

Structural Integrity and Identification of Causes of Liver Allograft Dysfunction Occurring More Than 5 Years After Transplantation

The clinicopathologic features of liver allograft dysfunction occurring in 51 symptomatic recipients after more than 5 years' survival (mean 7.1 years) with the same hepatic allograft were compared with those of a similar group of 14 asymptomatic patients (mean survival, 9.9 years) who underwent a nonclinically indicated protocol liver biopsy evaluation. Predictably, patients who had clinically indicated biopsies more frequently showed histopathologic alterations (76% versus 36%, p < 0.002). After detailed clinicopathologic correlation, the changes in the symptomatic patients were attributed primarily to definite or presumed viral hepatitis in 17 of 51 (33%) patients, 11 of whom had recurrent viral disease; seven of 51 (14%) had nonviral recurrent original disease, three (6%) had obstructive cholangiopathy, and 11 (22%) had acute and/or chronic rejection. In 13 of 51 (25%) of the symptomatic patients, the clinical and pathologic abnormalities were minimal. Long-term liver allograft survival in nine of 14 (64%) of the asymptomatic patients was associated with minimally abnormal histologic alterations. Two of the asymptomatic patients had obstructive cholangiopathy; two others has recurrence of the original disease and one has possible viral hepatitis. Viral hepatitis types B and C, alcoholic liver disease, autoimmune hepatitis, granulomatous hepatitis (not otherwise specified), and probably primary biliary cirrhosis and primary sclerosing cholangitis were shown to recur after hepatic transplantation. The histopathologic changes associated with acute and chronic rejection frequently overlapped with other syndromes causing late dysfunction, such as chronic viral or autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis; more than one insult could be identified in 15 cases, which made the differential diagnosis of causes of late liver allograft dysfunction much more difficult than early after hepatic transplantation. It is important to correlate the biopsy findings with the liver injury tests, the results of viral and autoimmune antibody serologic studies, and review of previous biopsies and to be aware of the original disease, recent changes in immunosuppression, and results of therapeutic intervention(s) to identify correctly the causes of liver allograft dysfunction in this patient population.

A double-blind, randomized, placebo-controlled trial of prostaglandin E1 in liver transplantation

A double-blind placebo-controlled trial of intravenous prostaglandin PGE 1 (40 μg/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE 1; 82 placebo). Patient and graft survival were similar (PGE 1: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE 1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE 1: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE 1: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support ( P = .03) or surgical intervention other than retransplantation ( P = .02) were also noted with PGE 1 use. Further, PGE 1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE 1 administration, (PGE 1: 9; controls: 4). These results suggest that PGE 1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions.

A double-blind, randomized, placebo-controlled trial of prostaglandin E 1 in liver transplantation

A double-blind placebo-controlled trial of intravenous prostaglandin PGE1 (40 micrograms/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE1; 82 placebo). Patient and graft survival were similar (PGE1: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE1: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE1: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support (P = .03) or surgical intervention other than retransplantation (P = .02) were also noted with PGE1 use. Further, PGE1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE1 administration, (PGE1: 9; controls: 4). These results suggest that PGE1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions.

FK 506 rescue therapy for hepatic allograft rejection: Experience with an aggressive approach

FK 506 rescue therapy for hepatic allograft rejection: Experience with an aggressive approach

Daily determination of individual serum bile acids allows early detection of hepatic allograft dysfunction

Acute graft rejection is still a major cause of morbidity after orthotopic liver transplantation, and its diagnosis necessitates an invasive liver biopsy. Our aim has been to determine whether changes in individual serum bile acid levels after engraftment are sensitive, specific and reliable indicators of graft function and whether these changes can antedate other biochemical indicators of hepatic allograft rejection. Individual bile acids in 200 serum samples taken serially from eight adult liver transplant patients were measured. Patients with biopsy-confirmed graft dysfunction due to rejection or nonrejection causes (n = 6 episodes) had significantly higher serum concentrations of glycocholate plus glycochenodeoxycholate and taurocholate/taurochenodeoxycholate ratios than did noncomplicated grafts (n = 3). These changes antedated any other conventional biochemical parameters by at least 48 hr and were 100% sensitive and specific. None of the conventional liver function tests could match this. Acute rejection episodes (n = 3) were then compared with nonrejection causes of graft dysfunction (n = 3). In acute rejection we noted a significant increase in the concentration of glycodeoxycholate plus deoxycholate and a significant decrease in the cholate/chenodeoxycholate ratio compared with that in nonrejection graft malfunction. Both of these changes antedated any other biochemical parameters by 24 hr. In conclusion, individual serum bile acid assays, after orthotopic liver transplantation, can detect graft dysfunction resulting from any cause at an earlier time than routine biochemical tests, and they are sensitive, specific and reliable for early detection of graft dysfunction. In addition, acute rejection can be distinguished from other causes of graft dysfunction.

Advances in diagnosis, prevention, and management of hepatic allograft rejection

Despite recent improvements in immunosuppressive therapy, hepatic allograft rejection remains a major cause of morbidity and late graft loss in patients undergoing liver transplantation. Although some biochemical tests suggest hepatic allograft damage, the gold standard for defining rejection remains based on morphologic findings. Acute cellular rejection usually occurs within the first 3 weeks posttransplantation and the incidence varies between 40% and 70%. Ductopenic rejection occurs in 5-10% of patients undergoing initial liver transplantation and usually occurs between 6 weeks and 6 months after the procedure. Induction and maintenance of immunosuppression with triple-drug therapy (cyclosporine, prednisone, and azathioprine) and other combinations that include anti-lymphocyte preparations have led to an overall decrease in the incidence of both cellular and ductopenic rejection. In addition, the availability of FK506 as a rescue therapy has saved grafts in some patients experiencing chronic (ductopenic) rejection. Overall, the correlation between the degree of biochemical liver dysfunction and the presence and severity of histologic rejection remains poor. Histologic severity of rejection, however, suggests which patients will require more immunosuppressive therapy and which patients may need antilymphocyte therapy to control the rejection episode. Some rejection episodes remain resistant to all known therapy and eventually lead to graft loss. New immunosuppressive agents and regimens are needed to improve graft and patient survival, decrease the incidence of cellular and ductopenic rejection, minimize drug-related side effects and complications, and reduce the high cost of immunosuppressive therapy.

The Eosinophil As An Effector Cell of the Immune Response During Hepatic Allograft Rejection

Objective: To evaluate the role of the eosinophil granulocyte during hepatic allograft rejection. Design: (a) A retrospective case–control study and (b) a prospective study of consecutive liver transplant recipients. Patients: In the retrospective study, eight patients with severe rejection in the first month after liver transplantation were compared with six patients without rejection. In the prospective study, 20 consecutive patients were studied for the presence of liver allograft rejection between March 1989 and October 1989. Measurements: Absolute eosinophil counts were determined whenever blood was drawn. Serum was analyzed for the presence of two eosinophil granule proteins, major basic protein and eosinophil–derived neurotoxin, on days 7, 14 and 21 after transplantation. Liver biopsy specimens were stained for the presence of major basic protein by means of immunofluorescence using a double–antibody staining technique. The degree of eosinophil infiltration and degranulation was graded using a panel of representative slides. Results: Blood eosinophilia was increased in patients with hepatic allograft rejection (p &lt; 0.05). Serum major basic protein and eosinophil–derived neurotoxin concentrations were similar in patients with and without rejection. Many portal tracts of patients with rejection contained an abundance of eosinophils, and staining for major basic protein revealed the presence of intact eosinophils. In addition, extracellular major basic protein was seen, sometimes in the absence of intact eosinophils or an extensive infiltrate. In patients with severe allograft rejection, major basic protein staining was present in littoral cells lining the sinusoids. Conclusions: Patients with severe rejection in the first month after liver transplantation often have blood eosinophilia and marked infiltration of portal tracts with eosinophils or evidence of eosinophil degranulation. The presence of major basic protein likely is direct evidence of tissue destruction and may indicate active rejection (major basic protein in eosinophils and extracellular major basic protein, presence of portal infiltrate) or the immediate postinflammatory rejection state (extracellular major basic protein and major basic protein inside littoral cells, absence of portal infiltrate and eosinophils, bile ducts damaged or vanished). These findings underline the importance of the eosinophil as an intergral part of the rejection process. We conclude that the presence of eosinophils or their secretion products in the first month after liver transplantation is an indicator of ongoing or recent allograft rejection. (Hepatology 1994;20:654-662).

Alpha-interferon treatment of hepatitis C in patients with liver allografts treated with either FK-506 or cyclosporin A

Objectives: To examine the efficacy of interferon therapy of hepatitis C in liver transplant recipients, to determine the effect of interferon on allograft rejection rates, and to examine the effect of the primary immunosuppressive agent (FK-506/cyclosporin) on the above. Design: A non-randomized consecutive patient treatment study. Patients: Fifty-two liver allograft recipients with hepatitis C virus (HCV) associated liver disease. All 52 patients had abnormal serum alanine aminotransferase (ALT) levels and in all, a liver biopsy confirmed the finding of post-transplant viral hepatitis. Interventions: All patients were treated with interferon at a dose of 5 million units three times weekly, administered subcutaneously for 6 months. Main outcome measures: Normalization of serum ALT levels was defined as a full response. A 50% reduction in serum ALT levels without normalization was defined as a partial response. Results: No difference in entry ALT levels or white blood cell counts was evident for the two groups based in the type of immunosuppression used, either cyclosporin or FK-506. Similarly, no difference in the response rate to interferon was observed based on the type of immunosuppression used. Improvement in ALT levels was not accompanied by a concomitant improvement in hepatic histology. Overall, Knodell scores for histology deteriorated in two-thirds of the patients despite interferon treatment. Conclusions: The use of interferon in liver transplant recipients reduces serum ALT levels but has little effect, if any, on hepatic allograft histopathology. In most patients, histology worsens despite interferon therapy. No difference in interferon response rates were observed between liver allograft recipients receiving either cyclosporin or FK-506.

Hepatic artery stenosis and thrombosis in transplant recipients: Doppler diagnosis with resistive index and systolic acceleration time.

To assess the value of resistive index (RI) and systolic acceleration time (SAT) for diagnosis of stenoses and thromboses of the hepatic artery in liver transplant recipients. Doppler sonograms and angiograms in 125 liver transplant recipients were correlated and analyzed for any statistically significant difference in the RI or SAT of patients with and without arterial stenosis or thrombosis. Sensitivity and specificity were calculated for RI, SAT, peak arterial systolic velocity, and absence of arterial flow. Forty-seven patients had a marked stenosis; 16 had thrombosis. There was a statistically significant difference (P < .05) in the RI and SAT of patients with stenosis or thrombosis versus those with normal arteries but not in patients with stenosis versus thrombosis. RI and SAT parameters allowed detection of abnormalities not found with peak velocity and no-flow parameters. Combined parameters produced 97% sensitivity and 64% specificity for marked arterial disease. Doppler spectral wave form analysis provides excellent screening for detection of hepatic allograft arterial stenosis or thrombosis.

Isolation, phenotype, and allostimulatory activity of mouse liver dendritic cells.

Donor liver-derived dendritic cells (DC) have recently been identified within various lymphoid and nonlymphoid tissues of organ allograft recipients, including nonimmunosuppressed mice transplanted with and permanently accepting major histocompatibility complex (MHC)-disparate hepatic allografts. These findings have raised questions about the basis of the tolerogenicity of the liver--and, in particular, about the properties of liver-derived DC. To study further the structure, immunophenotype and allostimulatory activity of leukocytes resident in normal mouse (B10.BR;H-2k, I-Ek) liver, a procedure was developed to maximize the yield of viable, nonparenchymal cells (NPC) obtained following collagenase digestion of perfused liver fragments and density centrifugation (Percoll). These cells comprised populations expressing lymphoid and myeloid cell surface antigens. As compared with spleen cells, they proved good allostimulators of naive (B10; H-2b, I-E-) splenic T cells when tested in primary mixed leukocyte reactions (MLR). After overnight (18-hr) incubation of the NPC, enrichment for transiently adherent, low-density (LD) cells on metrizamide gradients permitted the recovery of low numbers of cells (approx. 2-5 x 10(5) per liver), many of which displayed distinct DC morphology. Flow cytometric analysis revealed that these cells were CD3-, CD4-, CD8-, and B220-, but strongly expressed CD45 (leukocyte-common antigen), and mild-to-moderate levels of CD11b, heat-stable antigen, and CD44. The cells also expressed moderate intensity of NLDC 145 but not 33D1, DC restricted markers which have been shown to be differentially expressed on mouse DC isolated from various organs. This DC-enriched population was more strongly MHC class II(I-Ek)+ than NPC, as determined by immunocytochemistry and flow cytometry and exhibited much more potent allostimulatory activity for naive T cells. These findings demonstrate that freshly isolated murine liver NPC, and perhaps their counterparts in situ, exhibit allostimulatory activity that is enhanced in the non-adherent, low-density (DC-enriched) fraction after overnight culture. They further suggest that the maturation of liver DC may play a key role in determining the immunogenicity and or tolerogenicity of hepatic allografts.

Serum hyaluronic acid for the assessment of graft viability in porcine liver transplantation.

For the assessment of graft viability, serum hyaluronic acid (HA) levels during porcine orthotopic liver transplantation were measured in two groups: group 1 (viable: n = 5) in which allografts were transplanted following a minimal cold (4 degrees C) preservation, and group 2 (nonviable: n = 4) in which allografts were transplanted after cold static storage (4 degrees C) for 24 h in University of Wisconsin solution. The changes in the HA levels reached a significant difference between the two groups at 30 min after reperfusion (P < 0.02). In group 1, all animals survived for over 4 days, while all animals in group 2 died within 24 h. The serum HA also demonstrated a significant correlation with prothrombin time, beta-glucuronidase, and aspartate aminotransferase at 120 min after reperfusion. These results suggest that the measurement of serum HA is a potentially effective index for evaluating hepatic allograft viability.

Apoptosis of bile duct epithelial cells in hepatic allograft rejection

Liver biopsy remains the 'gold standard' for monitoring rejection in liver transplant patients. Portal inflammation, bile duct damage and endothelialitis are recognized features of hepatic allograft rejection. The pathogenesis of the bile duct injury during rejection, however, remains unclear. To define the mechanism of bile duct damage, we studied the light- and electronmicroscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Of the 25 orthotopic liver transplant rejection cases examined, 17 were mild, seven were moderate and one was severe rejection. Light microscopy examination of the damaged bile duct epithelium revealed evidence of apoptosis which was confirmed by electronmicroscopy. Furthermore, there appeared to be a positive correlation between the grade of rejection and the number of apoptotic cells. Also included in the study were 13 cases of chronic active hepatitis and 10 normal livers which showed the least apoptotic cells. We conclude that the identification of apoptotic cells in damaged bile ducts in allograft biopsies might be helpful in the diagnosis of rejection and in assessment of the severity of rejection.