B. Ringe

Transplantation einer Spenderleber auf zwei Empfänger (Splitting-Transplantation) - Eine neue Methode in der Weiterentwicklung der Lebersegmenttransplantation

Tumor surgery in this field is no longer such a high risk as previously. Prolonged survival can be achieved by resection of hepatocellular carcinomas in non-cirrhotic livers (3-year survival 58%, n = 54 patients) and for colorectal liver metastases (3-year survival 44%, n = 124 patients). But surgery is rarely successful for the most frequent type of liver malignancy, the hepatocellular carcinoma in cirrhosis. Central bile duct carcinomas are now resected more frequently than in the past. Liver grafting seems indicated in special cases of liver and bile duct tumors. The future developments of operating on the in situ-perfused liver was discussed and the first operation on an ex situ-liver was demonstrated.SummaryA donor liver was divided in such a way that the left part (segment 11 and III without caval vein) could be transplanted into a child, the right part (segment I, IV, V to VIII) into an adult successfully. Common bile duct and common hepatic artery remained with the left part of the liver, portal vein with the right one. In the recipient of the left part of the liver the own caval vein was preserved and anastomosed with the left hepatic vein; the other anastomoses were carried out in the typical way. In the recipient of the right part of the liver the right hepatic artery of the graft was anastomosed with the recipients common hepatic artery using a saphenous interponate. Two separate intrahepatic bile ducts were anastomosed with a Roux-en-Y loop of the jejunum. The other anastomoses were carried out in the typical way. Thus the possibility of using one donor liver for two recipients (splitting transplantation) has been demonstrated.ZusammenfassungEin Spenderleberorgan wurde so getrennt, daß der linke Teil (Segment II und III ohne Vena cava) auf ein Kind, der rechte Teil (Segment 1, IV, V bis VIII) auf einen Erwachsenen erfolgreich transplantiert werden konnte. Choledochus und Arteria hepatica communis bzw. propria blieben beim linken Leberteil, Vena portae beim rechten. Beim Empfänger der linken Seite blieb die eigene Vena cava erhalten; in sie wurde die linke Vena hepatica anastomosiert; die übrigen Anastomosen wurden in üblicher Weise durchgeführt. Beim Empfänger des rechten Leberteiles wurde die spenderseitige Arteria hepatica dextra mit einem Saphenainterponat verlängert und mit der Arteria hepatica communis des Empfängers anastomosiert; zwei getrennte Hepaticusäste wurden mit einer Jejunumschlinge anastomosiert. Die übrigen Anastomosen wurden in typischer Weise ausgeführt. Die Möglichkeit der Verwendung einer Spenderleber für zwei Empfänger (Splitting-Transplantation) ist damit gezeigt.

LIGNOCAINE METABOLITE FORMATION AS A MEASURE OF PRE-TRANSPLANT LIVER FUNCTION

A method for rapid assessment of hepatic function in liver donors based on the formation of the lignocaine metabolite monoethylglycinexylidide (MEGX), was used in a prospective study of 69 donor-recipient pairs. The probability of graft survival over 120 days was significantly higher for livers from donors with MEGX test values above 90 micrograms/l than for those from donors with MEGX values of 90 micrograms/l or below. Other liver function tests (bilirubin, prothrombin time, activity of aminotransferases, glutamate dehydrogenase, and cholinesterase, indocyanine green clearance, and galactose elimination capacity) were inefficient at predicting early outcome of transplantation. For a 20-day graft survival, the MEGX test showed prognostic sensitivity of 73% and specificity of 78%. These findings suggest that the MEGX formation test could be valuable for selection of donor organs.

Liver transplantation for metastatic neuroendocrine tumors

OBJECTIVE This article describes the experience with liver transplantation in patients with irresectable neuroendocrine hepatic metastases. SUMMARY BACKGROUND DATA Liver transplantation has become an established therapy in primary liver cancer. On contrast, there is little experience with liver transplantation in secondary hepatic tumors. So far, in the majority of patients being transplanted for irresectable liver metastases, long-term results have been disappointing because of early tumor recurrence. Because of their biologically less aggressive nature, the metastases of neuroendocrine tumors could represent a justified indication for liver grafting. METHODS In a retrospective study, the data of 12 patients who underwent liver transplantation for irresectable neuroendocrine hepatic metastases were analyzed regarding survival, tumor recurrence, and symptomatic relief. RESULTS Nine of 12 patients currently are alive with a median survival of 55 months (range, 11.0 days to 103.5 months). The operative mortality was 1 of 12, 2 patients died because of septic complications or tumor recurrences or both 6.5 months and 68.0 months after transplantation. all patients had good symptomatic relief after hepatectomy and transplantation. Four of the nine patients who are alive have no evidence of tumor with a follow-up of 2.0, 57.0, 58.0, and 103.5 months after transplantation. CONCLUSIONS In selected patients, liver transplantation for irresectable neuroendocrine hepatic metastases may provide not only long-term palliation but even cure. Regarding the shortage of donor organs, liver grafting for neuroendocrine metastases should be considered solely in patients without evidence of extrahepatic tumor manifestation and in whom all other treatment methods are no longer effective.

A new technique of hepatic vein reconstruction in partial liver transplantation

The shortage of pediatric donor livers has stimulated the development of advanced surgical approaches such as partial liver transplantation, which produces the same results as whole organ replacement. Differences in body weight between donor and recipient of more than four times, however, usually necessitate extended reduction hepatectomy and modified ways of performing vascular reconstruction. Therefore, following ex vivo “trisegmentectomy”, a new technique of hepatic venous drainage was developed with an end-to-side anastomosis of the left donor hepatic vein to the preserved recipient inferior vena cava. This operative technique was applied to four children, one of whom had a retransplantation performed in exactly the same fashion. There were no specific complications related to this particular surgical technique. From our preliminary experience we conclude that reduced-size liver transplantation can be safely performed with the described type of hepatic vein reconstruction, especially when large donor organs have to be used for small children.

HTK-solution (Bretschneider) for human liver transplantation. First clinical experiences.

ZusammenfassungDie kardioplegische Lösung HTK nach Bretschneider ist bisher noch nicht im Bereich der klinischen Lebertransplantation verwendet worden. Hier werden die ersten Ergebnisse von 14 Patienten vorgestellt, denen eine mit HTK-Lösung protektionierte Leber transplantiert wurde. Die Eignung der HTK-Lösung konnte gezeigt werden. Alle Transplantate zeigten eine Primärfunktion mit Ausnahme eines Transplantates, bei dem die initiale Nichtfunktion zweifelsfrei spenderbedingt war. Die höchsten friihpostoperativen Werte der Transaminasen, die als Zeichen des Ischämieschadens herangezogen wurden, waren durchschnittlich und vergleichbar mit den Transaminasenausschüttungen nach anderen Lösungen. Unter Verwendung der HTK-Lösung konnte eine Primarfunktion selbst bei solchen Transplantaten erzielt werden, die prospektiv als solche von problematischer oder geringer Qualität eingeschätzt worden waren, and Lebern mit schlechten Funktionstesten (MegX) funktionierten von Beginn an. Deshalb scheint die HTK-L6sung die Ausweitung der Akzeptanzkriterien für Spenderlebern zu ermöglichen. Es war nicht das Ziel dieser Studie, die kalte Ischämiezeit zu verlängern, aber drei Transplantate mit 11 h and 12 h 25 min nahmen unmittelbar nach Reperfusion ihre Funktion auf. Wie weft die kalte Ischämiezeit ausgedehnt werden kann, ist noch eine offene Frage. Alle Spenderlebern wurden aufgrund der geringen Viskosität der HTK-Lösung schlagartig gekühlt und homogen perfundiert. Alle Lebern hatten eine weiche Konsistenz nach der Perfusion, was kein oder nur ein geringes Zellödem bedeutet. Aus diesen Gründen ist HTK eine effektive Lösung für die Leberkonservierung.SummaryThe cardioplegic HTK-solution (Bretschneider) has not been used in human liver transplantation as yet. Herein the first results obtained from 14 patients with HTK-preserved liver grafts are presented. The suitability of HTK-solution could be shown. All grafts functioned primarily except one, where initial non-function was obviously due to donor reasons. The early postoperative peak values of transaminases as a sign of ischemic damage were average and similar to the values of other flushout solutions. Using HTK primary function could be achieved even in livers prospectively assessed as only of fair quality, and livers with poor donor function tests (MegX) functioned from the beginning. HTK-solution therefore seems to allow widening of the acceptance criteria for donor livers. It was not the aim of this trial to extend cold ischemic time, but 3 livers with 11 h and 12 h 25 showed immediate function. How far cold ischemic time can be extended is a still open question. All livers were rapidly cooled and homogeneously flushed out due to the low viscosity of HTK-solution. All livers had a soft consistency after perfusion indicating a low degree of cell edema. HTK therefore is an effective solution for liver preservation.

Immunoprophylaxis with a monoclonal anti-IL-2 receptor antibody in liver transplant patients.

The immunosuppressive effect of a monoclonal antibody (moAb), BT563, directed to the alpha-chain of the IL-2R (CD25), was analyzed in a prospective nonrandomized trial and a prospective randomized trial. Primary objectives were evaluation of the incidence of acute rejections and infections; secondary objectives were safety and tolerability of the moAb. A total of 28 patients were enrolled (phase II) to receive 10 mg/day of BT563 (12 days) as immunoprophylaxis in combination with cyclosporine, azathioprine, and low-dose steroids. Subsequently 32 patients were randomly assigned (phase III) to receive BT563 (10 mg/day) for 12 days or ATG (5 mg/kg/day) for 7 days in addition to cyclosporine and low-dose steroids. No side effects of the BT563 treatment were noted. The actuarial survival was 82% at 12 months in the phase II trial and 92% at 12 months in both arms of the phase III trial. There was one acute rejection in the phase II trial. No acute rejections were noted in the BT arm of the phase III trial and 5 acute rejections were treated in the ATG arm. In the phase II trial 7 infectious episodes were observed, while one infection was seen in the BT arm and 7 in the ATG arm of the triple immunosuppression phase III trial. In all patients circulation of coated CD25+ lymphocytes was observed during BT563 treatment; there was no evidence of depletion or modulation of CD25+ cells. Mean serum levels of BT563 ranged from 1.6 to 7.6 microgram/ml throughout the therapy. An antimurine response was seen in 82% (phase II) and 100% (phase III) of the patients. Antirabbit antibodies were found in 56% of the patients treated with ATG. Analysis of the antimurine response specificity revealed in 56% blocking anti-isotypic antibodies and only in 3% of the patients an anti-idiotypic response. The data of the study presented suggest that therapy with an anti IL-2R moAb is at least equal to ATG application according to the incidence of acute rejections and infections.

Liver transplantation in children with chronic end stage liver disease: factors influencing survival after transplantation.

To identify pretransplant factors that are influencing survival after orthotopic liver transplantation a Cox proportional hazards regression model was applied to 118 children with chronic terminal liver failure transplanted at Medical School Hannover during the period of 1978 to 1994. The response variable was survival, as covariates a total of 19 pretransplant variables were entered--i.e. age, diagnosis (biliary cirrhosis, metabolic cirrhosis, postnecrotic cirrhosis, cryptogenetic cirrhosis) sex, laparotomy prior to OLT, height, weight, standard deviation scores for height and weight, date of first OLT, serum alanine aminotransferase, asparagine aminotransferase, albumin, total bilirubin, cholinesterase activity, glomerular filtration rate, and prothrombin time. Significant independent predictors of survival after OLT were bilirubin (P=0.0024), SDS for weight (P=0.034), and albumin (P=0.039). In a subsequent discriminant analysis cut off points for these variables could be identified--i.e., bilirubin >340 micromol/L, SDS for weight <-2.2 and albumin < 33 g/L. Patients with one or more of these risk factors were grouped as urgent indication group (n=76) and those with no risk factor as elective indication group (n=42). Comparing the posttransplantation survival in these groups there is a statistically significant difference at 1 year (57% vs. 90.5%) and 4 years (49% vs. 90.5%) after OLT (P=0.0001, log rank test). It is concluded that the risk of OLT is much higher if liver function is very poor. Optimal nutritional support prior to transplantation is mandatory to optimise the clinical status of the children and to improve the results of OLT.

Arterial ketone body ratio as a predictor of donor liver viability in human liver transplantation

The viability of the donor liver was assessed with regard to early postoperative survival in human liver transplantations from 40 brain-dead donors at Hannover Medical College and 13 living donors at Kyoto University by measuring the arterial ketone body ratio (AKBR). Of 40 grafts harvested from brain-dead patients in Hannover, 35 survived the first week after operation, but 5 developed initial nonfunction of the transplanted graft within the first week. The mean AKBR values were 1.11±0.11 for grafts that survived and 0.44±0.10 for grafts that failed (P<0.01). The AKBR values of the 5 initially nonfunctioning cases were all below 0.7. Of 13 grafts harvested from the living donors in Kyoto, all survived the first week. The AKBR values of the donors were all above 1.0, with a mean value of 1.87±0.23. Among all 53 cases, the survival rate of the grafts with AKBR above 0.7 was significantly higher than that of the grafts with AKBR below 0.7 (100% vs. 62%, P<0.01). NO other donor parameters, including age, dose of dopamine administered, and clinical laboratory findings, were significantly related to differences in graft survival rates. AKBR is a useful index for the evaluation of donor liver viability. Grafts used from donors with AKBR of less than 0.7 have a significantly increased risk of early nonfunction. Grafts from donors with AKBR of greater than 1.0 have, in our experience, always been viable after transplantation.

Evaluation of the liver graft before procurement : Significance of arterial ketone body ratio in brain-dead patients

Hepatic energy metabolism was assessed by measuring the blood ketone body ratio (KBR), that is, the ratio of acetoacetate to β-hydroxybutyrate in the arterial blood, in 31 brain-dead patients in an intensive care unit (ICU) in Japan and in 25 donors just before procurement of the liver for transplantation in Germany. In the study in Japan, 7 of the 12 brain-dead patients treated with highdose catecholamine showed significantly decreased KBRs, revealing the detrimental effect of catecholamine on livermmetabolism. In contrast, 8 of the 9 untreated patients with blood pressure below 80 mm Hg showed almost normal KBRs. In the 25 donors in Germany, KBR was maintained within the normal range. Based upon conventional criteria, 21 livers were selected for use and the other 4 were discarded. Nineteen of the grafts were able to normalize KBR within 24 h after reperfusion, while 2 failed to function and required a second transplantation. It was suggested that a KBR in the normal range in donors is a prerequisite to immediate recovery of metabolic function of the liver graft after transplantation, and that hypotensive donors as a potential source of liver grafts may warrant further study.

Conversion from cyclosporin to FK 506 after liver transplantation

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious — and potentially irreversible — disturbances in liver function are observed.