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.

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

Split liver transplantation using Hemiliver graft in the MELD era: a single center experience in the United States.

Under the "sickest first" Model for End-Stage Liver Disease (MELD) allocation, livers amenable to splitting are most often allocated to patients unsuitable for split liver transplantation (SLT). Our experience with SLT using hemilivers was reviewed. From April 2004 to June 2012, we used 25 lobar grafts (10 left lobes and 15 right lobes) for adult-sized recipients. Twelve recipients were transplanted with primary offers, and 13 were transplanted with leftover grafts. Six grafts were shared with other centers. The data were compared with matched whole liver grafts (n = 121). In 92% of donors, the livers were split in situ. Hemiliver recipients with severe portal hypertension had a greater graft-to-recipient weight ratio than those without severe portal hypertension (1.96% vs. 1.40%, p < 0.05). Hemiliver recipients experienced biliary complications more frequently (32.0% vs. 10.7%, p = 0.01); however, the 5-year graft survival for hemilivers was comparable to whole livers (80.0% vs. 81.5%, p = 0.43). The secondary recipients with leftover grafts did not have increased incidences of graft failure (p = 0.99) or surgical complications (p = 0.43) compared to the primary recipients. In conclusion, while routine application is still controversial due to various challenges, hemiliver SLT can achieve excellent outcomes under the MELD allocation.

Growth of donor-derived dendritic cells from the bone marrow of murine liver allograft recipients in response to granulocyte/macrophage colony-stimulating factor.

Allografts of the liver, which has a comparatively heavy leukocyte content compared with other vascularized organs, are accepted permanently across major histocompatibility complex barriers in many murine strain combinations without immunosuppressive therapy. It has been postulated that this inherent tolerogenicity of the liver may be a consequence of the migration and perpetuation within host lymphoid tissues of potentially tolerogenic donor-derived ("chimeric") leukocytes, in particular, the precursors of chimeric dendritic cells (DC). In this study, we have used granulocyte/macrophage colony-stimulating factor to induce the propagation of progenitors that give rise to DC (CD45+, CD11c+, 33D1+, nonlymphoid dendritic cell 145+, major histocompatibility complex class II+, B7-1+) in liquid cultures of murine bone marrow cells. Using this technique, together with immunocytochemical and molecular methods, we show that, in addition to cells expressing female host (C3H) phenotype (H-2Kk+; I-E+; Y chromosome-), a minor population of male donor (B10)-derived cells (H-2Kb+; I-A+; Y chromosome+) can also be grown in 10-d DC cultures from the bone marrow of liver allograft recipients 14 d after transplant. Highly purified nonlymphoid dendritic cell 145+ DC sorted from these bone marrow-derived cell cultures were shown to comprise approximately 1-10% cells of donor origin (Y chromosome+) by polymerase chain reaction analysis. In addition, sorted DC stimulated naive, recipient strain T lymphocytes in primary mixed leukocyte cultures. Evidence was also obtained for the growth of donor-derived cells from the spleen but not the thymus. In contrast, donor cells could not be propagated from the bone marrow or other lymphoid tissues of nonimmunosuppressed C3H mice rejecting cardiac allografts from the same donor strain (B10). These findings provide a basis for the establishment and perpetuation of cell chimerism after organ transplantation.

Liver transplantation in the United States, 1999-2008.

Changes in organ allocation policy in 2002 reduced the number of adult patients on the liver transplant waiting list, changed the characteristics of transplant recipients and increased the number of patients receiving simultaneous liver-kidney transplantation (SLK). The number of liver transplants peaked in 2006 and declined marginally in 2007 and 2008. During this period, there was an increase in donor age, the Donor Risk Index, the number of candidates receiving MELD exception scores and the number of recipients with hepatocellular carcinoma. In contrast, there was a decrease in retransplantation rates, and the number of patients receiving grafts from either a living donor or from donation after cardiac death. The proportion of patients with severe obesity, diabetes and renal insufficiency increased during this period. Despite increases in donor and recipient risk factors, there was a trend towards better 1-year graft and patient survival between 1998 and 2007. Of major concern, however, were considerable regional variations in waiting time and posttransplant survival. The current status of liver transplantation in the United States between 1999 and 2008 was analyzed using SRTR data. In addition to a general summary, we have included a more detailed analysis of liver transplantation for hepatitis C, retransplantation and SLK transplantation.

Use of tissue plasminogen activator in liver transplantation from donation after cardiac death donors.

Ischemic-type biliary stricture (ITBS) occurs in up to 50% after liver transplantation (LT) from donation after cardiac death (DCD) donors. Thrombus formation in the peribiliary microcirculation is a postulated mechanism. The aim was to describe our experience of tissue plasminogen activator (TPA) administration in DCD-LT. TPA was injected into the donor hepatic artery on the backtable (n = 22). Two recipients developed ITBS including one graft failure. Although excessive postreperfusion bleeding was seen in 14 recipients, the amount of TPA was comparable between those with and without excessive bleeding (6.4 ± 2.8 vs. 6.6 ± 2.8 mg, p = 0.78). However, donor age (41 ± 12 vs. 29 ± 9 years, p = 0.02), donor BMI (26.3 ± 5.5 vs. 21.7 ± 3.6 kg/m(2) , p = 0.03), previous laparotomy (50% vs. 0%, p = 0.02) and lactate after portal reperfusion (6.3 ± 4.6 vs. 2.8 ± 0.9 mmol/L, p = 0.005) were significantly greater in recipients with excessive bleeding. In conclusion, the use of TPA may lower the risk of ITBS-related graft failure in DCD-LT. Excessive bleeding may be related to poor graft quality and previous laparotomy rather than the amount of TPA. Further studies are needed in larger population.

Allogeneic hematolymphoid microchimerism and prevention of autoimmune disease in the rat. A relationship between allo- and autoimmunity.

Conventional allogeneic bone marrow transplantation after myeloablation can prevent experimental autoimmunity and has been proposed as treatment for humans. However, trace populations of donor hematolymphoid cells persisting in solid organ allograft recipients have been associated in some circumstances with therapeutic effects similar to replacement of the entire bone marrow. We therefore examined whether inducing hematolymphoid microchimerism without myeloablation could confer the ability to resist mercuric chloride (HgCl2)-induced autoimmunity. Brown-Norway (BN) rats were pretreated with a syngeneic or allogeneic bone marrow infusion under transient FK506 immunosuppression before receiving HgCl2. They were compared with BN rats receiving either no pretreatment (naive) or FK506 alone. Administration of HgCl2 to naive BN rats induced marked autoantibody production, systemic vasculitis and lymphocytic infiltration of the kidneys, liver and skin in all of the animals and a 47% mortality. In contrast, BN rats pretreated with HgCl2-resistant allogeneic Lewis bone marrow and transient FK506 showed less clinical disease and were completely protected from mortality. More specifically, IgG anti-laminin autoantibody production was decreased by 40% (P < 0.05), and there was less histopathological tissue injury (P < 0.005), less in vitro autoreactivity (P < 0.05), less of an increase in class II MHC expression on B cells (P < 0.01), and 22% less weight loss (P < 0.01), compared with controls. Protection from the experimental autoimmunity was associated with signs of low grade activation of the BN immune system, which included: increased numbers of circulating B and activated T cells before administration of HgCl2, and less autoreactivity and spontaneous proliferation in vitro after HgCl2.

Cross-tolerance of recipient-derived transforming growth factor-beta dendritic cells.

Administration of donor-derived immature dendritic cells (DC) treated with transforming growth factor-beta (TGF-beta) to prevent allograft rejection is not applicable for clinical use. We therefore attempted to explore the use of recipient-derived DC pulsed with donor antigens via the indirect pathway (cross-priming). DC were propagated from C3H (H2(k)) bone marrow (BM) using granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). TGF-beta (0.2 ng/mL) was added at the initiation of culture. The resultant TGF-beta DC were pulsed with B10 (H2(b)) splenocyte lysate. Expression of major histocompatibility complex (MHC) class I and II was not affected, while CD40, CD80, and CD86 costimulatory molecules on DC were significantly inhibited by treatment with TGF-beta. C3H DC pulsed with B10 antigens stimulated a proliferative response in C3H T cells which was inhibited when DC were treated with TGF-beta, and the cytotoxic T-lymphocyte (CTL) activity was also inhibited. This observation correlated with reduced interferon-gamma (IFN-gamma) and increased IL-10 production. A single injection of TGF-beta DC prolonged allograft survival (median survival time [MST] 18 days vs 10 days in no-DC treatment control; P < .05). These data indicated that an approach utilizing recipient DC as a "vaccine" strategy is possible.

Adenosine Increases Hepatic Artery Flow in Liver Transplant Recipients: A Pilot Study.

BACKGROUND: The aim of this study was to assess the effect of low-dose adenosine on hepatic artery flow (HAF) when administered intraoperatively by continuous infusion. MATERIALS AND METHODS: Between January 2009 and August 2009, 74 patients underwent orthotopic liver transplantation (OLT). Ten patients were enrolled for adenosine treatment, and 64 non-study patients served as controls. After arterial reperfusion, a 16-G central venous catheter was placed in the gastroduodenal artery, and adenosine was continuously infused at doses ranging from 0.7 to 2.8 µg/kg/min for 30 min. HAF and portal vein flow were measured using a transit time flow meter before adenosine infusion, during infusion, and 10 min after infusion. Liver function tests were monitored routinely, duplex ultrasonography was performed on postoperative day 1, and the hepatic artery resistive index measured. The patients were followed for 1 year. RESULTS: Adenosine significantly increased HAF at doses from 0.7 to 2.8 µg/kg/min. The smallest increase in HAF was 24% above the baseline; in 80% of patients, the increase in HAF was >50% of the baseline values. In 2 patients, HAF was increased by >300%. The dosing started at 0.7 µg/kg/min, and 6 of 10 patients responded. Three patients required an increase to 1.4 µg/kg/min. Doses >2.8 µg/kg/min did not further increase HAF. One patient showed a minimal response regardless of the dose. There were no differences between the adenosine group and control group with respect to liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and International Normalized Ratio), platelet count on POD2, hepatic artery resistive index, and post-transplant length of stay, intensive care days, or 1-year patient survival rates. CONCLUSIONS: This pilot study established that adenosine administered directly into the hepatic artery produces a similar effect on HAF in cadaveric liver transplant recipients to that found in the laboratory without producing systemic side effects.

Infusion of donor leukocytes to induce tolerance in organ allograft recipients.

To further enhance chimerism, 229 primary allograft recipients have received perioperative intravenous infusion of a single dose of 3 to 6 X 10(8) unmodified donor bone marrow (BM) cells/kg body weight. In addition, 42 patients have been accrued in a concurrent protocol involving multiple (up to three) sequential perioperative infusions of 2 x 10(8) BM cells/kg/day from day 0-2 posttransplantation (PTx). Organ recipients (n = 133) for whom BM was not available were monitored as controls. The infusion of BM was safe and except for 50 (18%), all study patients have optimal graft function. Of the control patients, allografts in 30 (23%) have been lost during the course of follow-up. The cumulative risk of acute cellular rejection (ACR) was statistically lower in the study patients compared with that of controls. It is interesting that, 62% of BM-augmented heart recipients were free of ACR (Grade > or = 3A) in the first 6 months PTx compared to controls. The incidence of obliterative bronchiolitis was also statistically lower in study lung recipients (3.8%) compared with the contemporaneously acquired controls (31%). The levels of donor cell chimerism were at least a log higher in the peripheral blood of majority of the study patients compared with that of controls. The incidence of donor-specific hyporeactivity, as determined by one-way mixed leukocyte reaction, was also higher in those BM-augmented liver, kidney, and lung recipients that could be evaluated compared to controls.

Percutaneous ultrasound-guided pancreas allograft biopsy: a single-center experience.

Percutaneous ultrasound-guided pancreas allograft biopsy is the preferred technique for evaluating pancreas allograft rejection. Experience from large centers has shown it to be safe and effective. We report our experience with 120 percutaneous allograft biopsies performed at a single center. Biopsy tissue was obtained in 54 patients. Thirty-three patients received simultaneous pancreas and kidney transplants, 14 received isolated pancreas transplants, and 7 received a pancreas transplant after kidney transplantation. Biopsies were performed by pancreas transplantation surgeons with the assistance of radiologists under ultrasound guidance using an Acuson XP 128/10 ultrasound machine. One hundred twenty allograft biopsies were performed in 54 patients. Twenty-seven (50%) patients underwent multiple biopsies. In 102 (85%) biopsies the specimens were adequate for examination. Eighteen (15%) biopsy samples had no pancreatic tissue and showed surrounding fat and small bowel. 1 (1.8%) patient bleeding developed that required transfusion of 3 units of packed red blood cells, but no surgical intervention was necessary. One (1.8%) patient had a pancreatic fistula, which healed with nonoperative management. Biochemical evidence of pancreatitis was noted in 5 (9.2%) patients, but none of these patients had clinical signs of pancreatitis. Percutaneous ultrasound-guided pancreas allograft biopsy is a safe procedure with a low complication rate and a high tissue yield for histopathologic examination.

Reversal of acute cellular rejection after renal transplantation with Campath-1H.

Between September 2002 and February 2004, 40 kidney transplant (27 from deceased and 13 from living donors) recipients (25 male and 15 female, aged 50.3 +/- 15.1 years) were treated with Campath 1H (C 1H; 30 mg/dose IV) for biopsy-proven steroid-resistant rejection (SRR) or rejections equal to or worse than Banff 1B. All transplantations occurred between August 2001 and May 2003. All patients had received antibody preconditioning (RATG 5 mg/kg, n = 34; C 1H 60 mg, n = 4; C 1H 30 mg, n = 2) preoperatively and were treated with Tacrolimus monotherapy (target level 10 ng/ml) postoperatively and subsequent spaced weaning. Elevated creatinine levels at follow-up were evaluated by renal transplant biopsy. Rejection was treated with steroids, reversal of weaning, addition of sirolimus, and/or antibody treatment, depending on grade of rejection. The mean duration of follow-up was 453 +/- 163 days after C 1H administration. Twenty-nine patients received C 1H for SRR and 11 patients for Banff 1B or worse rejections; 26 patients received more than 1 dose of C 1H. Graft survival was 62.5% (25 patients); 6 of the 15 allografts (40%) that failed had presented with rejections because of noncompliance. Graft survival in compliant patients with SRR or rejections equal to or worse than Banff 1B was 73.5% (25 of 34). Fourteen patients (35%) had infectious complications, of whom 2 patients (5%) died. C 1H is an effective agent for SRR and Banff 1B or worse rejections, with 95% patient survival and 73.5% graft survival (in compliant patients). The number of doses of 30 mg C 1H should be restricted to two, as there is a high incidence of potentially fatal infectious complications.

Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation.

OBJECTIVE: To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation. METHODS: Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods. RESULTS: The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean +/- SD, 6.4 +/- 5.1) was significantly higher than that after 1 month after surgery (2.1 +/- 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 +/- 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 +/- 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 +/- 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 +/- 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups. CONCLUSIONS: We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after surgery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.

Liver allograft rejection: an overview of morphologic findings.

Recent improvements in patient survival has resulted in widespread use of liver transplantation as therapy for end stage liver disease. The pathologist plays a critical role in the pre- and post-operative care of these patients, and the core needle biopsy of the allograft has become a fairly reliable method of diagnosing acute cellular rejection. Most of the non-rejection related causes of graft dysfunction produce morphologic manifestations similar to those seen in nontransplanted livers (e.g., duct obstruction resembles duct obstruction). Many pathologists are, however, unfamiliar with the histologic changes of the various types of rejection. The following article is an attempt to acquaint pathologists with the morphologic features of liver allograft rejection. As a backdrop to understanding the events in humans, observations in untreated experimental animals are presented and reviewed briefly.

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.

Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?

Post-transplant lymphoproliferative disorders (PTLDs) are usually but not invariably associated with Epstein-Barr virus (EBV). The reported incidence, however, of EBV-negative PTLDs varies widely, and it is uncertain whether they should be considered analogous to EBV-positive PTLDs and whether they have any distinctive features. Therefore, the EBV status of 133 PTLDs from 80 patients was determined using EBV-encoded small ribonucleic acid (EBER) in situ hybridization stains with or without Southern blot EBV terminal repeat analysis. The morphologic, immunophenotypic, genotypic, and clinical features of the EBV-negative PTLDs were reviewed, and selected features were compared with EBV-positive cases. Twenty-one percent of patients had at least one EBV-negative PTLD (14% of biopsies). The initial EBV-negative PTLDs occurred a median of 50 months post-transplantation compared with 10 months for EBV-positive cases. Although only 2% of PTLDs from before 1991 were EBV negative, 23% of subsequent PTLDs were EBV negative (p <0.001). Of the EBV-negative PTLDs, 67% were of monomorphic type (M-PTLD) compared with 42% of EBV-positive cases (p <0.05). The other EBV-negative PTLDs were of infectious mononucleosis-like, plasma cell-rich (n = 2), small B-cell lymphoid neoplasm, large granular lymphocyte disorder (n = 4) and polymorphic (P) types. B-cell clonality was established in 14 specimens and T-cell clonality was established in three (two patients). None of the remaining specimens were studied with Southern blot analysis and some had no ancillary studies. Rearrangement of c-MYC was identified in two M-PTLDs with small noncleaved-like features, and rearrangement of BCL-2 was found in one large noncleaved-like M-PTLD. Ten patients were alive at 3 to 63 months (only three patients received chemotherapy). Seven patients, all with M-PTLDs, are dead at 0.3 to 6 months. Therefore, EBV-negative PTLDs have distinct features, but some do respond to decreased immunosuppression, similar to EBV-positive cases, suggesting that EBV positivity should not be an absolute criterion for the diagnosis of a PTLD.

Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis.

RATIONALE AND DESIGN: The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an "immunosuppression minimization protocol" between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. RESULTS: Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7-329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22-315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. CONCLUSIONS: Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV clearance overlap with those leading to significant rejection.