Azathioprine and prednisolone immunosuppression versus maintenance triple therapy including cyclosporine for orthotopic liver transplantation. A comparative biochemical and histologic study in one center.

Improvement of graft survival after orthotopic liver transplantation is often attributed to cyclosporine. In order to assess the effects on liver function and histology, we compared the results of conventional immunosuppression (azathioprine/prednisolone = group I) and a triple drug regimen, which included CsA (group II) during the first year after transplantation. Group I consisted of 33 patients; group II of 18 patients. Significant differences are present in favor of the CsA regimen with regard to transaminases and cholestatic parameters. Liver synthesis function was slightly better, though already very good under conventional immunosuppression. One week after transplantation, normal histology was not observed in group I, while 90% of the patients showed acute rejection. In group II, 53% of the patients showed normal histology; only 40% of the patients in group II showed acute rejection (P less than 0.0002). One year after transplantation, liver histology was normal in 57% of the conventionally treated patients and in 90% of the CsA-treated patients. Also, less rejection occurred in group II during the first year after transplantation. One-year graft survival was 67% in group I and in group II 75%, which is not statistically different. Creatinine clearance did not differ in both groups. However compared with pretransplantation creatinine clearances, kidney function in the CsA-treated patients decreased with approximately 20 ml/min. These results show that liver synthesis and liver function are better under the CsA-containing triple-drug-maintenance regimen, which is supported by the far better liver histology. Kidney function is reduced, even under low dose CsA treatment.

Assessment of the quality of life before and following liver transplantation. First results.

Analysis of quality-of-life effects is part of the current technology assessment of the Dutch orthotopic liver transplant-program. Data are collected by means of computer-assisted interviewing, including one interview before transplantation and annual follow-up interviews. Data on psychiatric morbidity are obtained from medical records. This article shows preliminary results of a cross-sectional analysis of data collected from 1987 to 1989. Eighty-eight measurements were obtained from 46 adult patients (response rate 82%). Pretransplant scores suggest major restrictions on all domains of life, especially a low amount of energy. After transplantation all indicators show improvement, although the level of the general population is not always attained. Improvement of subjective quality of life is more marked, possibly due to euphoria at surviving the hazardous procedure. Psychiatric events occurred only infrequently. We conclude that orthotopic liver transplantation contributes positively to the quality of life of surviving patients. In addition, computer-assisted interviewing proved to be a feasible survey technique, even when very ill patients were involved.

Prediction of recurrent cytomegalovirus disease after treatment with ganciclovir in solid-organ transplant recipients.

CMV disease often recurs after initially successful antiviral therapy. We retrospectively determined in a group of 36 organ transplant patients whether clinical, virological, or immunological parameters during or shortly after cessation of antiviral therapy can identify those at high risk of relapse. Eleven of 36 patients had recurrent CMV disease after ganciclovir therapy. Neither donor or recipient CMV serostatus, type of baseline immunosuppression, antirejection treatment, indication for antiviral treatment, nor presence of CMV in the blood during or after therapy (as detected by antigenemia, viremia, or a positive polymerase-chain-reaction signal) were helpful in identification of patients with subsequent relapse. However, quantitative monitoring of antigenemia fascilitated early diagnosis of relapse since 10 of 11 patients with > or = 10 antigen-positive cells per 50,000 PMNs relapsed (99.1%, 95% CI 58.7-99.8). IgM and IgG responses against CMV during primary infection were comparable in relapsing and nonrelapsing patients. During secondary infection relapse occurred only in the 4 patients with the lowest IgG responses. The number of activated CD8bright lymphocytes in the peripheral blood as determined by flow cytometry at the end of antiviral therapy was a strong risk factor for the subsequent clinical course: 6 of 7 patients (85.7%, 95% CI 42.1-99.6%) with < 100 x 10(3) HLADR+CD8bright cells/ml blood relapsed, while 8 of 8 (100%, 95% CI 63-100) with activated CD8bright cells above that level remained asymptomatic (P < .025). These data show that patients with a high risk of relapse of CMV disease can be identified at the end of antiviral therapy.

Low HLA-DR expression on monocytes as a prognostic marker for bacterial sepsis after liver transplantation.

BACKGROUND: Low HLA-DR expression on monocytes is associated with an increased risk of infection after surgery or trauma. We determined the value of this parameter as a marker for sepsis after liver transplantation. METHODS: The percentage of monocytes expressing HLA-DR was determined by flow cytometry before and after liver transplantation in nine patients. Five lung and 20 kidney transplant recipients served as controls. RESULTS: Bacterial sepsis occurred in 5 of 9 liver transplant patients and 0 of 24 control patients. Monocyte HLA-DR expression decreased <50% in all five patients with sepsis. HLA-DR expression dropped before (n=4) or at the time of sepsis (n=1), and remained low for 13 weeks. HLA-DR expression remained >50% in the four liver transplant patients without sepsis. Only 1 of 25 control patients had persistently low monocyte HLA-DR expression. CONCLUSIONS: Monitoring of monocyte HLA-DR expression may be helpful in identifying liver transplant patients who have an increased risk of imminent bacterial sepsis.

Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study.

BACKGROUND: Large transfusion requirements, i.e., excessive blood loss, during orthotopic liver transplantation (OLT) are correlated with increased morbidity and mortality. Recombinant factor VIIa (rF-VIIa) has been shown to improve hemostasis in a variety of conditions, but has never been studied in liver transplantation. METHODS: We performed a single-center, open-label, pilot study in adult patients undergoing OLT for cirrhosis Child-Pugh B or C, to assess efficacy and safety of rFVIIa. rFVIIa (80 microg/kg) was administered at the start of the operation, to be repeated according to predefined criteria. Packed red blood cells (RBC), fresh-frozen plasma, and platelet concentrates were administered according to predefined criteria. Perioperative transfusion requirements in study patients were compared with matched controls. RESULTS: Six patients were enrolled in the study. All received a single dose of rFVIIa. Transfusion requirements (given as median, with range in parentheses) were lower in the study group than in matched controls: 1.5 (0-5) vs. 7 (2-18) units of allogeneic RBC (P=0.006), 0 (0-2) vs. 3.5 (0-23) units of autologous RBC (P=0.043), total amount of RBC 3 (0-5) vs. 9 (4-40) units (P=0.002). Transfused fresh-frozen plasma was 1 (0-7) vs. 8 (2-35) units (P=0.011). Blood loss was 3.5 L (1.4-5.3) vs. 9.8 L (3.7-35.0) (P=0.004). One study patient developed a hepatic artery thrombosis at day 1 postoperatively. CONCLUSIONS: A single dose of 80 microg/kg rFVIIa significantly reduced transfusion requirements during OLT. Further study is needed to establish the optimally effective and safe dose of rFVIIa in orthotopic liver transplantation.

Quantitation of immunosuppression by flow cytometric measurement of the capacity of T cells for interleukin-2 production.

BACKGROUND: Methods to quantitate the effects of immunosuppressive drugs on immune reactivity might be helpful for monitoring immunosuppressive treatment. Cyclosporine (CsA) inhibits the induction of cytokine synthesis in T cells, and measurement of interleukin (IL)-2 production might constitute a parameter of this drug's effect. METHODS: We determined the percentages of CD4+ and CD8+ lymphocytes producing IL-2 upon stimulation by phorbol myristate acetate and calcium ionophore in whole blood culture, using immunostaining of intracytoplasmatic and membrane markers, followed by multiparameter flow cytometry. A total of 38 clinically stable transplant patients on various immunosuppressive protocols were studied. RESULTS: The percentage of CD4+ T cells producing IL-2 was strongly reduced in patients compared with healthy controls (23% [range, 3-68%] vs. 59.0% [range, 41-70%]; P=0.000035). The percentage of CD4+ T cells producing IL-2 was negatively correlated with the CsA level (Rc=-0.0821, P=0.00002297) but not with prednisolone or azathioprine doses. Fewer CD8+ T cells produced IL-2 in transplant patients compared with controls, but the difference failed to reach statistical significance. The percentage of CD8+ T cells capable of producing IL-2 was inversely correlated to CsA levels (Rc=-0.0375, P=0.0011). CONCLUSIONS: These data suggest that the functional effects of CsA in transplant recipients can be quantitatively determined and that the capacity of CD4+ T cells to produce IL-2 upon stimulation constitutes a functional parameter of CsA effects on the immune system. Prospective studies are required to determine whether this method is useful for clinical monitoring.

Changes in portal hemodynamics and acute rejection in the first 2 weeks after orthotopic liver transplantation. A prospective Doppler ultrasound study.

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables of the portal vein in relation to liver biopsy findings, the authors performed a prospective study of 316 Doppler ultrasound examinations in the first 2 weeks after orthotopic liver transplantation on 23 patients. METHODS: Recordings were obtained daily from the portal vein (diameter, maximum velocity, and flow). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: In our series of 23 patients, acute rejection was diagnosed by liver biopsy in nine of them (39%). Changes in portal vein diameter, maximum velocity, and flow did not correlate consistently with liver biopsy findings, due to a multifactorial origin. Changes in portal hemodynamics were observed in patients with hepatic artery thrombosis, portal vein stenosis, acute rejection, and sepsis. CONCLUSIONS: Although routine screening using Doppler ultrasound proved to be useful for the determination of rapid changes in portal hemodynamics within a short time, serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Doppler ultrasound of the hepatic artery and vein performed daily in the first two weeks after orthotopic liver transplantation. Useful for the diagnosis of acute rejection?

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients. METHODS: Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis. Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05). CONCLUSION: Serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Successful pregnancy after orthotopic liver transplantation.

A successful pregnancy occurred in the first year after liver transplantation. The patient was treated with prednisolone, azathioprine, and low-dose cyclosporine A. A healthy girl of 2260 g (fifth to tenth percentile) was born at 38 weeks.

Cost effectiveness of selective decontamination of the digestive tract in liver transplant patients.

OBJECTIVE: To assess the cost effectiveness of selective decontamination of the digestive tract (SDD) in liver transplant patients. DESIGN: Randomised, placebo-controlled, double-blind trial with an integrated economic evaluation. SETTING: Two university hospitals in The Netherlands. Cost effectiveness was assessed from a societal perspective. PATIENTS AND PARTICIPANTS: 58 patients who underwent liver transplantation and received SDD (n = 29) or placebo (n = 29) pre- and postoperatively. INTERVENTIONS: SDD medication and placebo. MAIN OUTCOME MEASURES: Infection episodes, days of infection, costs of SDD and routine cultures, mean other direct medical costs per patient and additional costs of severe infection. RESULTS: Costs of SDD medicine and routine cultures were on average 3,100 US dollars ($US; 1997 values) per patient who underwent SDD. Both preoperatively and postoperatively, costs other than SDD and cultures did not significantly differ between the SDD and the placebo groups (preoperative, $US2,370 vs $US2,590; postoperative, $US25,455 vs $US24,915). Additional postoperative costs of severe infections were $US250 per day per patient. There were no significant differences in the mean number of infection episodes between groups. CONCLUSIONS: SDD leads to the additional costs of SDD medication and routine cultures, whereas no savings in other costs and no improvement in infection episodes are realised. Consequently, SDD may be considered as a nonefficient approach in patients undergoing liver transplantation. The additional costs of severe infection are considerable.

Blood loss in orthotopic liver transplantation: a retrospective analysis of transfusion requirements and the effects of autotransfusion of cell saver blood in 164 consecutive patients.

Liver transplantation is associated with excessive blood loss. In order to identify factors influencing blood loss and to provide a basis for a pilot study to evaluate recombinant activated factor VII as a haemostatic agent, a retrospective study was performed in 164 consecutive patients with cholestatic or noncholestatic liver disease, who underwent orthotopic liver transplantation at a single centre between 1989 and 1996. Transfusion of allogeneic and autologous (cell saver) blood was used as a measurement of blood loss. Transfusion requirements were associated with age, gender, primary disease, Child-Pugh classification, serum levels of activated partial thromboplastin time, antithrombin III, urea and creatinine, platelet number, year of transplantation, length of cold ischaemia time and autologous blood transfusion. Of these variables, Child-Pugh classification (P = 0.001), urea (P = 0.0007), year of transplantation (P = 0.002), cold ischaemia time (P = 0.01) and autologous blood transfusion (P < 0.0001) were independent predictors of transfusion requirements by multivariate analysis. Thus, blood loss and transfusion requirements depend primarily on the severity of liver disease, quality of the donor liver, experience of the transplantation team and use of autologous (cell saver) blood transfusion. These findings emphasize the need for appropriate drug therapy and a critical reappraisal of current transfusion policy.

Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation.

Besides the conventional laboratory tests, thromboelastography (TEG) is used to monitor hemostasis during liver transplantation. A previous pilot study suggested a beneficial effect of recombinant activated factor VII (rFVIIa) on transfusion requirements in liver transplantation. In the present study, we assess the effects of rFVIIa on coagulation variables and TEG. In six study patients, the prothrombin time (PT), the activated partial thromboplastin time (aPTT) and TEG variables [reaction time (r), kinetic time (k), or clot formation time, alpha angle (alpha), and maximal amplitude (MA)] were recorded before and after the administration of a bolus of 80 microg/kg rFVIIa. These patients were compared with six controls who did not receive rFVIIa. In contrast with the control group, a significant shortening of PT (P = 0.028) and aPTT (P = 0.028), r (P = 0.046) and k (P = 0.043) values, and a significant incline of the alpha angle (P = 0.028) were noticed after injection of rFVIIa, whereas MA increased not significantly (P = 0.075). rFVIIa rapidly improved coagulation variables in liver transplant patients including PT and aPTT. Of the TEG variables, r, k and alpha angle significantly improved, and MA showed a trend to increase. These data suggest that rFVIIa not only influences the speed of clot formation, but also the physical properties of the clot, which cannot be detected by routine coagulation tests.

[Orthotopic liver transplantation in The Netherlands 1979-1988]. / Orthotope levertransplantatie in Nederland 1979-1988.

In 1979 the Dutch orthotopic liver transplant programme started in Groningen. Until July 1988, 73 orthotopic liver transplantations were performed in 66 adults. A survey is given of selection criteria, indications, complications and results.

[Liver transplantation: patients' experiences]. / Levertransplantatie: ervaringen van getransplanteerden.

The Dutch orthotopic liver transplant programme was evaluated recently. This article focuses on the physical functioning, the pattern of activities, the social functioning and the level of wellbeing of 31 transplant patients. Data were generated by means of questionnaires and interviews. The majority of the patients look upon themselves as 'healthy'. Their physical potential has greatly improved. Three-quarters of the patient group think they are able to go back to work. However, from the interviews it appears that one third of the patient group suffered from more or less serious psychological problems following transplantation.

Long-term results after liver transplantation in adults.

The prospects for patients who survive the first year after liver transplantation are discussed. The 10-year survival for these patients is more than 80%. The quality of life is good, as measured on self-assessment scales. Pregnancy is possible. The main side-effects of drugs concern osteoporosis (corticosteroids), deterioration of renal function (cyclosporine), and de novo malignancies. Recurrence of original disease is at present of clinical importance for Budd-Chiari syndrome and hepatitis B and D. Recurrence of primary biliary cirrhosis is still under discussion.

Primary sclerosing cholangitis and liver transplantation.

Primary sclerosing cholangitis is a chronic disease, strongly associated with ulcerative colitis and cholangiocarcinoma. Ulcerative colitis itself does not influence the liver transplant results. However, intensified screening after liver transplantation for carcinoma of the colon may be necessary. Cholangiocarcinoma, although incidentally found in hepatectomy specimens, has a bad prognosis. Initial reports in the literature indicate a far lower survival when liver transplantation is performed for PSC, in comparison to the results achieved in other transplant indications. This might have been due to surgical interventions which nowadays are avoided. Later reports show a better prognosis than the initial ones. We report on the results of liver transplantation for PSC, as indicated in the literature and on the results of the Groningen transplant centre.

Hepatitis B-associated liver cirrhosis as an indication for liver transplantation.

Fourteen HBsAg-positive patients received a liver transplant in Groningen. Two were HBeAg-positive and 12 HBeAg-negative. No anti-HBs immunoglobulin was given at the time. Both HBeAg-positive and 9 of 12 of the HBeAg-negative patients became HBsAg-positive again after transplantation. Virus titers were tested in eight patients. Two HBeAg-negative patients were HBV-DNA-negative at transplantation and are still HBV-DNA-negative one-and-half-years after transplantation, both by the branched DNA hybridization technique and by PCR (cut-off values 0.7 x 10(6) and 10(3) HBV genomes/ml, respectively). One patient who had a low HBV-DNA titer at transplantation remained PCR-positive thereafter, but became HBsAg-negative. All other patients were HBV-DNA-positive and had a recurrence that rapidly led to high HBV titers. The liver histology was characterized by fibrosis and cirrhosis, centrilobular cholestasis and high expression of HBsAg and HBcAg, but with little inflammatory infiltrate. We conclude from these results that without anti-HBs immunoglobulin prophylaxis there is a high rate of HBV recurrence after transplantation. The current policy is that patients who test negative in the HBV-DNA dot-blot assay (< 10(7) genomes/ml) are transplantation candidates and are treated with high-dose anti-HBs immunoglobulin after transplantation. HBV-DNA-positive patients (> 10(7) genomes/ml) remain poor candidates for liver transplantation, even with anti-HBs immunoprophylaxis.