L. R. Fassati

Split and whole liver transplantation outcomes: A comparative cohort study

A specific split liver transplantation (SLT) program has been pursued in the North Italian Transplant program (NITp) since November 1997. After 5 yr, 1,449 liver transplants were performed in 7 transplant centers, using 1,304 cadaveric donors. Whole liver transplantation (WLT) and SLT were performed in 1,126 and 323 cases, respectively. SLTs were performed in situ as 147 left lateral segments (LLS), 154 right trisegment liver (RTL) grafts, and 22 modified split livers (MSL), used for couples of adult recipients. After a median posttransplant follow‐up of 22 months, SLTs achieved a 3‐yr patient and graft survival not significantly different from the entire series of transplants (79.4 and 72.2% vs. 80.6 and 74.9%, respectively). Recipients receiving a WLT or a LLS showed significantly better outcomes than patients receiving RTL and MSL (P < 0.03 for patients and P < 0.04 for graft survival). At the multivariate analysis, donor age of >60 yr, RTL transplant, <50 annual transplants volume, urgent transplantation (United Network for Organ Sharing (UNOS) status I and IIA), ischemia time of >7 hours, and retransplantation were factors independently related to graft failure and to significantly worst patient survival. Right grafts procured from RTL and either split procured as MSL had a similar outcome of marginal whole livers. In conclusion, in 5 yr, the increased number of pediatric transplants due to split liver donation reduced to 3% the in‐list children mortality, and a decrease in the adult patient dropout rate from 27.2 to 16.2% was observed. Such results justify a more widespread adoption of SLT protocols, organizational difficulties not being a limit for the application of such technique. Liver Transpl 12:402–410, 2006.

Unusual peripheral T cell lymphoma presenting as acute liver failure and reappearing in the liver allograft

A 25-year-old man presented with fulminant hepatic failure from an unusual peripheral T cell lymphoma involving the liver and spleen without lymphadenopathy. He underwent liver transplantation before establishing a definitive diagnosis and 21 days later, died from liver allograft failure because of recurrent lymphoma. In both the native liver and hepatic allograft, the lymphoma presented as a sparse cytologically atypical malignant infiltrate intermixed with numerous reactive macrophages, which showed marked angio- and epitheliotropism and irregular areas of coagulative necrosis. The malignant cells were CD3+/ granzyme B+/TIA1+/CD8-/CD56-/S100-- with variable staining for beta F1, CD5, and CD7. Multiplex polymerase chain reaction (PCR) showed rearrangement of the T cell receptor gamma chain gene in the native and transplanted liver and spleen. Even in the absence of a mass lesion or lymphadenopathy, peripheral T cell lymphoma should be included in the differential diagnosis of fulminant hepatic failure in young patients who show no evidence of viral or autoimmune diseases.

Gene Expression Profiling Reveals Multiple Protective Influences of the Peptide α-Melanocyte-Stimulating Hormone in Experimental Heart Transplantation

Novel therapies are sought to increase efficiency and survival of transplanted organs. Previous research on experimental heart transplantation showed that treatment with the anti-inflammatory peptide α-melanocyte-stimulating hormone (α-MSH) prolongs allograft survival. The aim of the present research was to determine the molecular mechanism of this protective activity. Gene expression profile was examined in heart grafts removed on postoperative days 1 and 4 from rats treated with saline or the synthetic α-MSH analog Nle4DPhe7 (NDP)-α-MSH. On postoperative day 1, the peptide induced expression of cytoskeleton proteins, intracellular kinases, transcription regulators, metallopeptidases, and protease inhibitors. Conversely, NDP-α-MSH repressed immune, inflammatory, cell cycle, and protein turnover mediators. Later effects of α-MSH treatment included down-regulation of oxidative stress response and up-regulation of ion channels, calcium regulation proteins, phosphatidylinositol signaling system, and glycolipidic metabolism. NDP-α-MSH exerted its effects on both Ag-dependent and -independent injury. The results indicate that NDP-α-MSH preserves heart function through a broad effect on multiple pathways and suggest that the peptide could improve the outcome of organ transplantation in combination with immunosuppressive treatments.

Sclerosing Cholangitis and Liver Transplantation in Langerhans Cell Histiocytosis: A 14-Year Follow-Up

Langerhans cell histiocytosis (LCH) is a rare disorder characterized histologically by the proliferation of cells with features similar to the Langerhans cell of the epidermis. Clinical presentation varies from benign localized forms to fulminant multisystem disease associated with high rates of morbidity and mortality [1]. Among the organ localizations, liver involvement is present in about one third of children with disseminated LCH [2] whereas it is considered to be less common in adults; it may occur without signs of hepatic dysfunction but can also lead to serious complications, most notably sclerosing cholangitis (SC) [3]. We report here the case of a 41-year-old woman having multisystem LCH who developed SC 2 years after the diagnosis of LCH. Interestingly, the patient received a successful liver graft and has shown no evidence of active LCH lesions following transplantation for 14 years.

No hepatitis recurrence using combination prophylaxis in HBV-positive liver transplant recipients with YMDD mutants

Recurrence of hepatitis B impairs the outcome of liver transplantation (OLT). In serum hepatitis B virus (HBV)‐DNA‐positive recipients, prophylaxis using lamivudine and immunoglobulins (HBIg) reduces the risk of recurrence, but it is undefined whether this regimen also protects candidates with YMDD mutants. Seventeen OLT viraemic candidates received pre‐emptive lamivudine followed by post‐OLT prophylaxis with lamivudine and HBIg. Both sera and liver biopsies were prospectively collected and high‐sensitive polymerase chain reaction (PCR) assay was applied for HBV‐DNA detection. Finally, the presence of YMDD mutants was explored in all PCR‐positive samples. All patients remained hepatitis B recurrence‐free after a mean follow up of 32 months. By PCR, serum HBV‐DNA was detectable in 64.3% of cases at OLT‐baseline, in 64.7% under combined prophylaxis and in 58.8% in patients (70.5% of the total) with a minimum follow up of 24 months. At OLT‐baseline, YMDD mutants were found in 44.4% of patients. After OLT, mutants were present in 50% of patients but only in 16.6% of cases in the long period. Although 41% of the native livers and 42.8% of the analysed grafts harboured HBV‐DNA, YMDD mutants were detected in 57% of the native positive livers. YMDD mutants were largely detected both at OLT‐baseline and post‐OLT, but their presence decreased over time. Regardless of the presence of YMDD mutants, no hepatitis B recurrence was observed in our OLT recipients using pre‐emptive lamivudine followed by continuous prophylaxis with lamivudine and HBIg.

The First Report of Orthotopic Liver Transplantation in the Western World

Until the present time, the first experimental liver transplant which led to the development of human liver transplantation is attributed to C. Stuart Welch who performed a heterotopic transplant in the canine species in 1955. In 1956, Jack Cannon is credited with the first animal orthotopic liver transplant although the species was not disclosed. This report is intended to set the historical record straight by acknowledging that Vittorio Staudacher in 1952 was the first to perform a liver transplant in a large animal model.

Orthotopic transplantation of partially hepatectomized liver in the pig.

One of the major technical obstacles to liver transplantation in children is to find a liver of appropriate size because of the rarity of child donors. To overcome this difficulty an experimental study was carried out using only a portion of the donor liver (right liver) transplanted orthotopically in pigs. A group of 15 allotransplants were performed. A left hepatectomy of the liver graft was performed ex situ and the right liver amounted to 55% of the whole liver. A total of 13 animals survived for more than 5 days (5 to 30 days, with an average of 16). Upon killing, the liver weight was considerably more than that of the part transplanted. The absence of technical complications suggests that this procedure is safe and feasible.

Rescue FK506 early conversion for refractory rejection after pediatric liver transplantation: experience in 20 children

Abstract Tacrolimus (FK506) is an effective and relatively safe novel immunosuppressant able to revert refractory rejection after pediatric liver transplantation (LTx). Between April 1993 and October 1996, 20 pediatric patients were converted to tacrolimus for biopsy‐proven, steroiD‐resistant liver rejection. The mean follow‐up was 18 months. The median time from LTx to switch was 20 days. Tacrolimus was administered per os at a mean dosage of 0.23 mg/kg per day to maintain median blood levels of 10.8 ng/ml at 1 week and 9.2 ng/ml at 1 year from the switch. Of the 20 patients, 15 are alive and they all recovered from rejection without the need of OKT3 after conversion. The major causes of death were: one multiorgan failure, two infections (cytomegalovirus Aspergillus), one bowel perforation, and one posttransplant lymphoproliferative disease. One patient experienced late side effects and was reconverted to cyclosporine when she was already rescued from hepatic allograft rejection. The results confirm that an earlier conversion to tacrolimus should be recommended after pediatric liver transplantation in order to revert hepatic allograft rejection with the best safety profile.

Post‐hepatitis primary disease does not influence 6‐year survival after liver transplantation beyond 1 year

Abstract Orthotopic liver transplantation (OLT) is used as a definitive treatment for enD‐stage liver disease and prolonged posttransplant survival has already been reported. The incidence of late mortality and graft morbidity is, however, not well defined and the role of primary viral disease in the long‐term follow‐up results is not clear. Data of posttransplant follow‐up in 213 patients, 156 adults and 57 children, who survived at least 1 year were reviewed in order to define causes of graft dysfunction, graft loss and death. In 98 patients, 103 persistent graft dysfunctions were found. Thirty‐four grafts were later lost [28 deaths and 6 successful re‐transplantations (re‐OLT)]. The results were reviewed grouping patients according to their age and viral hepatitis status at the time of the transplantation. HBV‐positive patients (51) showed 4 re‐OLT (1 HBV), 3 liver‐related deaths (2 HBV), 24 graft dysfunctions (8 HBV, 5 HCV), and 85.2% 6‐year survival (based on 100% survival at 1 year). HCV‐positive adults (28) showed 1 re‐OLT, 3 HCV‐related deaths, 24 graft dysfunctions (19 HCV), and 68.8 % 6‐year survival. HBV‐HCV‐positive patients (14) showed no graft loss and death, 10 graft dysfunctions (7 HCV, 1 HBV, 2 HBV‐HCV), and 81.8 % 6‐year survival. HBV‐HCV‐negative adults (63) showed 3 non‐hepatitis‐related re‐OLT, 5 liver‐related deaths (2 HCV), 24 graft dysfunctions (6 HCV, 2 HBV), and 83.1 % 6‐year survival. HBV‐HCV‐negative children (49) showed no re‐OLT, 1 HCV‐related death, 14 graft dysfunctions (3 HCV), and 92.6% 6‐year survival. HCV‐positive children (8) showed 1 HCV‐related re‐OLT, 2 HCV‐related deaths, 4 graft dysfunctions (3 HCV), and 81.3% 6‐year survival. The main cause of graft dysfunction was hepatitis (45 HCV and 13 HBV), followed by technical complications (21), rejection (16), recurrent alcoholism (3), HIV infection (1), and unknown causes (4). In this long‐term post‐transplant follow‐up series, viral hepatitis led to graft dysfunction in 58/103 (56.3%) cases, late graft failure was viral hepatitis‐related in 11/20 (55 %) cases, and, as a total, HCV infection was present in 45/58 (77.5 %) cases of viral hepatitis‐related graft damage. Looking at the timing of hepatitis‐related graft failure, in 70% of cases death occurred after the 5th post‐transplant year. In our experience, the occurrence of hepatitis, particularly HCV induced, was common and led to abnormal graft function, but the 6‐year post‐transplant survival (based on 100% survival at 1 year) in patients surviving for at least 1 year did not differ on the basis of the pretransplant viral hepatitis status. This finding may be consistent with the slow progression of the viral damage and longer follow‐up results remain to be established. Nevertheless, data from the present study suggest that in long‐term liver transplant survivors, the risk of deteriorating liver damage and eventual failure after 5 years remains only in those patients experiencing a viral hepatitis infection.

Serotonin (5-HT): An enteroendocrine marker of reperfusion injury after liver-small bowel allotransplantation in the pig

Abstract HISTOMORPHOLOGIC and functional aspects of preservation/reperfusion injury, after small bowel transplantation, have been well investigated after different modalities and types of perfusion solutions. Experimental and clinical studies on bowel preservation damage have well defined the modifications of enteric and Goblet cells, vascular structures, myoenteric nerves, and ganglia. The enteroendocrine system is not so well studied. In recent studies of Lai et al, 1 on auxiliary small bowel allotransplantation in the dog without immunosuppression, biopsies of the small bowel were done daily and at time of death; specimens were stained with immunohistochemical methods for chromogranin A and somatostatin. Also, in animals with severe rejection, this type of enteroendocrine cell did not present any evident modification. Kaihara et al 2 suggested serotonin as a good marker of ischemia/reperfusion injury after allotransplantation of the small bowel in the rat. In their experience, the release of serotonin in the lumen bowel after reperfusion inversely correlated with the number and quality of serotonin cells. Our previous experiences with normothermic preservation in Ringer lactate solution, up to 20 hours in the pig, showed good preservation of argentaffin and serotonin cells up to 6 hours with a progressive marked reduction in the following hours. 3 The bowel perfused and preserved ipothermically with 4°C Wisconsin solution up to 36 hours, showed normal argentaffin cells up to 20 hours, after which time these cells were numerically reduced and degranulated. On the basis of these previous observations, we decided to analyze the modifications of enteroendocrine cells in a pig model of orthotopic liver-small bowel allotransplantation with different preservation/reperfusion times.