William C. Stevenson

Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization

Passive immunization with hepatitis B surface antibody (anti-HBs) is important to prevent hepatitis B virus (HBV) recurrence after orthotopic liver transplantation for chronic HBV cirrhosis. Hepatitis B immune globulin (HBIG) dosing regimens have been poorly defined, utilize numerous routes of administration, and result in a high rate of HBV relapse and mortality. Twenty-five of 27 (93%) patients transplanted (four retransplants) for chronic HBV cirrhosis show no evidence of recurrent HBV (range, 2-55 months). Anti-HBs titers necessary to minimize the risk of hepatitis B surface antigen detectability were >500 IU/L for days 0 to 7, >250 IU/L for days 8 to 90, and >100 IU/L thereafter. Pretransplant HBV E antigen (HBeAG)-positive patients required more HBIG to achieve these goals than HBeAG-negative individuals. The elimination of anti-HBs changed continually for the initial 3 posttransplant months. The anti-HBs half-life increased from 0.7 days to 14.1 days. Anti-HBs elimination was significantly different in HBeAG+ and HBeAG- patients for the first week, but was subsequently indistinguishable after week 1. After 3 months, the half-life was statistically less for HBeAG+ patients, but the difference did not influence the clinical treatment regimens. Quantitative hepatitis B DNA levels did not predict the amount of HBIG required. HBV recurrence after orthotopic liver transplantation can be reduced by aggressive passive immunization. Pharmacokinetic analysis of anti-Hbs elimination can improve immunoglobulin therapy and prevent recurrence of clinical hepatitis.

Clinical and histologic patterns of early graft failure due to recurrent hepatitis C in four patients after liver transplantation

Hepatitis C viral recurrence after orthotopic liver transplantation is almost universal. Hepatitis C-induced graft failure may occur, but the clinical and histologic profiles are not well defined. The aim of this study was to describe the pattern of early graft failure in patients with recurrent hepatitis C after liver transplantation. Thirty patients with hepatitis C underwent liver transplantation from October 1989 through September 1994. Four patients were excluded because of death (2 patients), graft failure unrelated to hepatitis C (1 patient), and lost to follow-up (1 patient). Hepatitis C recurred in 24 of the 26 remaining patients. In 4 patients with hepatitis C virus recurrence and cholestasis, graft failure developed at 5.25, 11.0, 11.0, and 18.5 months. The medical records and liver biopsies were reviewed. In all 4 patients, a histologic pattern characterized by centrilobular ballooning degeneration developed and progressed to involve more than two-thirds of the lobules. Moderate to severe cholestasis and bridging fibrosis were present in all grafts at explant. Two patients had portal inflammation on 3-month biopsies consistent with viral hepatitis. All patients had mild macrovesicular steatosis, but only 1 patient had significant lymphoid aggregates. No patient had evidence of hepatic artery thrombosis. One patient had potential drug-induced cholestasis. One patient had 3 episodes of rejection that were not believed to contribute to graft loss. All 4 patients developed clinical features of hepatic failure and were retransplanted. Two patients had early recurrence of graft failure. We conclude that a pattern of progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis occurs in some patients with hepatitis C with early graft failure, similar to fibrosing cholestatic hepatitis seen in some transplant patients with recurrent hepatitis B.

Evidence demonstrating poor kidney graft survival when acute rejections are associated with IgG donor-specific lymphocytotoxin.

The current prospective investigation was conducted to determine whether development of IgG donor-specific lymphocytotoxins detected at the onset of acute rejections was predictive of a poor-prognosis acute rejection. Between January 1990 and August 1993, 206 kidney transplants were performed. Cadaver kidney recipients were managed with antilymphocyte globulin as induction therapy and all recipients (i.e., cadaver and living related donor kidneys) received triple immunosuppressive therapy, i.e., CsA, AZA, and prednisone. Rejections were treated with intravenous Solu-Medrol and OKT3. Presence of donor-specific IgG lymphocytotoxin was detected by using dithiothreitol-pretreated sera (obtained at onset of rejection) and frozen donor cells. In addition, percentage of panel reactive antibody was determined on this dithiothreitol-pretreated sera. Of the 82 patients with biopsy-proven acute rejections, 19 were found to have developed donor-specific IgG lymphocytotoxin and a marked increase in panel reactive antibody. One-year graft survival in this group was dismal (16%), despite OKT3 therapy. Over 90% of these patients lost their graft within 2 months of rejection diagnosis. In 63 recipients who had acute rejections without development of IgG anti-HLA antibody, 1-year graft survival was 72%. The majority of these patients lost their grafts from chronic rejection. No anti-HLA activity was found in patients who did not have rejection episodes. Based on this study, evidence indicates that assaying for IgG donor-specific antibody at time of rejection is a valuable tool for selecting a subset of patients with poor-prognosis acute rejections. Identifying this subset will become important as we enter an era of new immunosuppressive agents.

The lack of long-term detrimental effects on liver allografts caused by donor-specific anti-hla antibodies

Recent reports indicate a higher incidence of both acute and chronic liver allograft rejection when, at the time of transplantation, the recipients serum contains donor-specific anti-HLA antibodies. From 9/89 to 5/91, 133 liver allografts were performed at our institution. Thirteen liver recipients had donor-specific IgG anti-HLA antibodies (complement-fixing) at the time of transplantation. In eleven patients, antibodies reacted to donor class I antigens while in 1 patient the donor-specific antibody had class II reactivity. Twelve patients have been followed for a minimum of 12 months (median 18 months, range 28–12 months). No hyperacute rejection was seen in any of the cases and four patients had acute rejections. Thus far only one of the twelve patients has biopsy evidence suggestive of chronic liver injury. The remaining have normal liver enzymes and bilirubin. Three of these twelve patients died (one from a myocardial infarction and the others from sepsis) accounting for a one-year graft survival of 75%. There was no significant statistical difference in the one-year graft survival in those recipients without donor-specific antibodies (i.e., 80.5%). In eight of the twelve patients, pretransplant preformed antibody level (PRA) was >50%. In six of the thirteen patients donor-specific antibody was present at dilutions greater than 1:64. As previously reported, the donor-specific antibody disappeared from the serum posttransplant within hours and did not reappear. In vitro studies demonstrated no factor in portal or hepatic artery blood that could inhibit rabbit complement mediated lysis of anti-HLA antibodies. We conclude that it is not a contraindication to do liver transplants in the presence of donor-specific anti-HLA antibodies.

Human sphincter of Oddi motility and cholecystokinin response following liver transplantation

The reported incidence of sphincter of Oddi dysfunction following orthotopic liver transplantation has ranged from 3% to 7%. If sphincteric dysfunction is unrecognized, therapy may be inappropriate; when recognized, extensive surgery may be required. To prospectively identify patients with sphincteric dysfunction, we performed sphincter of Oddi motility studies through the t-tube tract three months after transplantation. Baseline sphincter motility and response to intravenous cholecystokinin were evaluated. The results of 10 subjects are reported; nine had normal basal sphincter pressure (16±5.8 mm Hg), and all had normal frequency (3.6±1/min), amplitude (86±31 mm Hg), and duration (4.5±1 sec) of phasic contractions. One subject had an elevated basal pressure (47 mm Hg). All, including the subject with elevated basal pressure, demonstrated a normal response to intravenous cholecystokinin with significant inhibition of phasic contraction frequency and amplitude. We demonstrate that simultaneous studies of the sphincter and duodenum can be obtained via the t-tube tract, providing the opportunity for prospective evaluation of sphincteric function. We conclude that sphincter of Oddi function usually remains normal following liver transplantation with choledochocholedochostomy.

The use of pronase-digested human leukocytes to improve specificity of the flow cytometric crossmatch

Two-color fluorescence cytometry (FCXM) has recently been introduced to improve the detection of anti-HLA antibodies that react to donor cells, especially in recipients receiving kidney allografts. Although this assay system is highly sensitive, it lacks specificity. Between 70% and 90% of potential kidney recipients with a positive FCXM would have been denied transplant if such an assay had been used alone to detect antidonor antibodies. Lack of specificity is principally due to normal or irrelevant IgG in aggregates or immune complexes binding to Fcλ R receptors on lymphocytes including B cells and a significant subset of T cells. To circumvent this problem, we digested Fcλ R receptors on lymphocytes with pronase. We present data demonstrating that pronase digestion of lymphocytes does not alter HLA antigenicity. In addition, pronased lymphocytes allow one to use either single- or two-color FCXM. With single-color FCXM, one can quantitate antibody reactivity to lymphocytes via a cursor (on the fluorescence histogram) that separates lymphocytes that do not bind to antibodies. We present data demonstrating that this modification renders FCXM highly sensitive and specific. In addition, one can discriminate between IgG and IgM antibodies that react to lymphocytes.

Donor lazaroid pretreatment improves viability of livers harvested from non-heart-beating rats

BACKGROUND Lazaroids are potent inhibitors of lipid peroxidation. Whether the compounds can benefit the liver procured from non-heart-beating donors (NHBDs) is unknown. METHODS Donor rats were pretreated with lazaroid U74006F (4.5 mg/kg) 1 hour before cardiac arrest, and transplantation was performed in the rats with donor cardiac arrest from 0 to 60, 100, 120, 140, and 160 minutes as lazaroid pretreated groups. The same number of liver transplantations were done in each paired control group without donor lazaroid pretreatment. Recipient survival rates, bile secretion, serum enzymes, and a lidocaine metabolism test were analyzed. RESULTS Donor lazaroid pretreatment significantly increased recipient 3-day survival rates in groups with 60, 100, and 120 minutes of warm ischemia and 7-day survival with 60 minutes of warm ischemia. Also, the pretreatment increased bile secretion and reduced serum aspartate aminotransferase and lactate dehydrogenase levels in the lazaroid-pretreated groups. CONCLUSIONS Donor U74006F pretreatment improves viability of livers procured from NHBDs.

Need for reduction of cyclosporin dosage in renal transplant patients with hypertriglyceridemia but not hypercholesterolemia

Currently there is a paucity of data regarding the influence of high serum triglyceride levels on cyclosporin A (CyA) levels and dosing. We therefore undertook a retrospective study to determine the relationship of serum lipid levels to CyA levels and CyA dosages. Renal transplant patients at a 0.5-to-3-year post-transplant stage, with a stable CyA dosage, who were not on medications that affect CyA metabolism or renal function, were entered into the study. The CyA dosage was adjusted by clinicians to maintain whole blood. 12-h CyA trough levels between 200 and 250 ng/ml (monoclonal TDX method, which measures the parent compound). Fortyfour patients qualified for the study. The data clearly indicated that high cholesterol levels (>300 mg/dl and with normal triglyceride levels) did not influence the CyA levels or the dosages. Conversely, high triglyceride levels (>500 mg/dl) significantly reduced the amount of CyA required. A decreased clearance of CyA in the presence of hypertriglyceridemia led to high CyA levels in some patients. Reducing the CyA dosage to achieve levels between 200 and 250 ng/ml improved renal allograft function and decreased other side effects attributed to CyA toxicity. These studies indicate that high triglyceride levels, but not high cholesterol levels, increase CyA levels, which can lead to CyA toxicity.

Accuracy and significance of pretransplant liver volume measured by magnetic resonance imaging

Measurement of liver volume in patients with advanced liver disease is used to gauge the appropriate size of donor organs and may have prognostic value. We sought to determine the accuracy of magnetic resonance imaging (MRI) in measuring liver volume in 19 adult patients under consideration for liver transplantation. We also correlated the liver volume determination to the clinical severity of disease. Liver volume was measured at MRI by averaging the calculated volumes from coronal and transverse breath-hold T1-weighted images. These results were compared to the explanted liver volume measured by fluid displacement and the explant mass. The correlation coefficient for MRI liver volume and the explant displacement volume was 0.90. The mean liver volume for Child-Pugh class AB by MRI was 1986 +/- 568 mL (1002-2470 mL) compared to 1433 +/- 379 mL (540-1889 mL) in Child-Pugh class C patients (p = .02). We conclude that MRI offers an anatomically accurate means of determining adult liver volume in vivo. Lower mean liver volumes were observed in Child-Pugh class C patients. In addition to its ability to provide tumor screening and vascular assessment, MRI is able to provide accurate determinations of liver volume in patients undergoing liver transplant evaluations.

Predictive value of intraoperative biopsies and liver function tests for preservation injury in orthotopic liver transplantation

Eighty liver allografts were studied to determine the predictive value of intraoperative biopsies and postoperative liver function tests for the development of preservation injury (PI). Peak transaminase (aspartate transaminase [AST] and alanine transaminase [ALT]) and prothrombin time (PT) values achieved by each patient during postoperative days (POD) 1 through 7 were determined. PI in day 0 preperfusion biopsies (0Pre) (obtained immediately before implantation) and postperfusion biopsies (0Post) (obtained immediately after revascularization) was categorized by histological criteria as present or absent. PI in biopsies taken during POD 2 through 14 was histologically graded as either moderate-to-severe, mild, or absent. Of the 80 allografts, 8 were omitted because of primary nonfunction or postoperative complications. 0Pre and 0Post biopsies were available on 25 of 72 (35%) and 69 of 72 (96%) allografts, respectively. Only 2 (8%) of the 0Pre biopsies showed histological PI compared with 48 (70%) of the 0Post biopsies. Fifty-nine patients were biopsied between POD 2 through 14. Of these, 15, 28, and 16 patients developed moderate-to-severe, mild, or no evidence of PI, respectively. The presence of PI in the 0Post biopsy strongly correlated with the development of PI during POD 2 through 14 (P < .0005). Peak AST and ALT values in patients with moderate-to-severe PI on POD 2 through 14 were significantly elevated compared with those patients with either mild (P = .01 and .03) or no PI (P = .02 and .006). Because of extensive overlap in AST and ALT values between the three groups, however, transaminase values were not useful in predicting the presence or absence of PI in the individual case. The development of PI during POD 2 through 14 correlated with advanced donor age (P = .06) but was unassociated with 0Pre biopsy findings, cold ischemia time, or peak PT values. We conclude that the 0Post biopsy is a valuable tool for the prediction of subsequent PI in the early postoperative period. In contrast, 0Pre biopsy findings and peak AST and ALT values are not useful in the assessment of PI.