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Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106cells) with irradiated donor PBMCs (20 × 106cells) from eight human leukocyte antigen-mismatched responder–donor pairs in the presence of either 2D10.4/IT2.2 (3 μg/106cells) or belatacept (40 μg/106cells). After 14 days of coculture, the frequencies of CD4+T cells, CD8+T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-γ and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.

Cancer remains one of the most serious long‐term complications after liver transplantation (LT). Data for all adult LTpatients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer‐registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age‐specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LTpatients during a mean 6.6‐year follow‐up. The overall SIRwas 2.22 (95% confidence interval [CI], 2.02‐2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIRfor cancers occurring within 10 years post‐LTwas observed from the 1980s: 4.53 (95%CI, 2.47‐7.60), the 1990s: 3.17 (95%CI, 2.70‐3.71), to the 2000s: 1.76 (95%CI, 1.51‐2.05). This was observed across age‐ and indication‐groups. The sequential decrease for the SIRof non‐Hodgkin lymphoma was 25.0‐12.9‐7.53, and for nonmelanoma skin cancer 80.0‐29.7‐10.4. Cancer risk after LTwas found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study. This multicenter study from four countries finds that overall cancer incidence after liver transplantation has decreased over time relative to the general population, especially for immunosuppression‐related cancer types.

Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler‐Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ≈600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor‐specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novoDSAs after hepatocyte transplantation associated with graft loss. The authors report two cases of hepatocyte transplantation with partial hepatectomy preconditioning in patients with Crigler‐Najjar syndrome type I, in which after initial successful allograft function, donor hepatocytes are lost in association with emergence of donor‐specific human leukocyte antigen antibodies.

Maribavir is an oral benzimidazole riboside with potent in vitroactivity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double‐blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV‐seronegative liver transplant recipients with CMV‐seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)‐confirmed CMV disease within 6 months of transplantation. In a modified intent‐to‐treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: −0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC‐confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non‐CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well‐tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

The efficacy and safety of dual‐therapy regimens of twice‐daily tacrolimus (BID; Prograf) and once‐daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were compared in a multicenter, 1:1‐randomized, two‐arm, parallel‐group study in 475 primary liver transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy‐proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per‐protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval −7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve‐month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID.

The first liver transplantation (LTx) in Sweden was performed in 1984, but brain death as a legal death criterion was not accepted until 1988. Between November 1984 and May 1988, we performed 40 consecutive LTxs in 32 patients. Twenty‐four grafts were from donors after cardiac death (DCD) and 16 grafts from heart‐beating donors (HBD). Significantly, more hepatic artery thrombosis and biliary complications occurred in the DCD group (p < 0.01 and p < 0.05, respectively). Graft and patient survival did not differ between the groups. In the total group, there was a significant difference in graft survival between first‐time LTx grafts and grafts used for retransplantation. There was better graft survival in nonmalignant than malignant patients, although this did not reach statistical significance. Multivariate analysis revealed cold ischemia time and post‐LTx peak ALT to be independent predictive factors for graft survival in the DCD group. In the 11 livers surviving 20 years or more, follow‐up biopsies were performed 18–20 years post‐LTx (n = 10) and 6 years post‐LTx (n = 1). Signs of chronic rejection were seen in three cases, with no difference between DCD and HBD. Our analysis with a 20‐year follow‐up suggests that controlled DCD liver grafts might be a feasible option to increase the donor pool.

Abstract: Background: Laparoscopic donor nephrectomy has become the first choice for living donor kidney transplantation, offering advantages over open donor nephrectomy. This study aimed to evaluate kidney tissue metabolism during and after pneumoperitoneum using a microdialysis technique. Methods: Eight pigs underwent laparotomy and implantation of two microdialysis catheters: one in the cortex and one in the medulla of the left kidney. After laparotomy, the abdominal wall was closed, and pneumoperitoneum was induced with a constant standard pressure of 16 to 18 mmHg for 4 h, followed by rapid desufflation. In microdialysis samples collected from intrarenal catheters, markers of ischemia (glucose, lactate, pyruvate, and lactate–pyruvate ratio) and the marker of cell membrane injury (glycerol) were monitored. Results: There were no changes in glucose, lactate, or pyruvate level before, during, or after pneumoperitoneum, either in the cortex or in the medulla. Additionally, the calculated lactate–pyruvate ratio did not show signs of ischemia during or after pneumoperitoneum. However, with regard to the marker of cell injury, glycerol increased in the medulla after decompression from 22.57 ± 3.76 to 35.67 ± 5.43 mmol/l (p < 0.01). This release of glycerol in the medulla was significantly higher than in the cortex (area under the curve [AUC], 22.18 ± 4.87 vs 34.79 ± 7.88 mmol/l; p < 0.01). Conclusions: The pattern of metabolic changes monitored in the kidney during and after pneumoperitoneum indicates some kind of cell injury predominant in the medulla without any signs of kidney ischemia. This nonischemic injury could be related to hyperperfusion of the kidney after decompression or injury to cells attributable to mechanical cell expansion at the point of rapid decompression.

Orthotopic liver transplantation (LTx) is currently the only available treatment that has been proven to halt the progress of familial amyloidotic polyneuropathy (FAP). The aim of this study was to assess mortality and symptomatic response to LTx for FAP. All 86 FAP patients transplanted at our hospital between April 1990 and November 2005 were included in the study. Five patients underwent retransplantation. The 1-, 3- and 5-year patient survival rates in patients transplanted during 1996-2005 were 94.6, 92.3 and 92.3, respectively, a significant difference from the rates of 76.7, 66.7 and 66.7, respectively, during 1990-1995 (p 0.0003). Multivariate analysis revealed that the age at the time of LTx (?40 years), duration of the disease (?7 years) and modified body mass index (mBMI) (<600) were independent prognostic factors for patient survival. A halt in the progress of symptoms was noted in most patients, but only a minority experienced an improvement after LTx. To optimize the posttransplant prognosis, LTx should be performed in the early stages of the disease, and close post-LTx monitoring of heart function by echocardiography and of heart arrhythmia by Holter ECG is mandatory.

Survival after liver transplantation for fulminant hepatic failure has been reported to be less favorable than survival for patients with chronic liver diseases.

Abstract: Although involvement of the liver is common in systemic amyloidosis, clinical manifestations of hepatic dysfunction and liver biochemical abnormalities are often absent or only mild. Here we report on a patient with primary amyloidosis and rapid development of liver failure, who was successfully treated by liver transplantation. The patient is a 61-year-old Swedish man who was admitted to the local hospital for spontaneous rupture of the spleen. Before admission, he had suffered from diffuse upper abdominal discomfort, diminished appetite, and had lost 15 kg in 6 months. Shortly after splenectomy, he developed cholestatic liver failure with moderate hepatomegaly, jaundice, ascites and hyponatremia. Over a period of 3 weeks his liver failure progressed, renal function deteriorated rapidly, and he developed encephalopathy. Liver transplantation was performed on the 35th day after splenic rupture. Histological examination revealed extensive deposits of amyloid in the spleen and liver. N-terminal amino acid sequence analysis of the amyloid protein, purified from the patient's native liver, revealed an AL protein of kappa I-type origin. The postoperative course was uncomplicated, apart from one episode of sepsis and one course of treatment for acute rejection. He was discharged from hospital with normal liver function and good kidney function. One year after surgery, he was in good condition, with normal liver function. However, a liver biopsy taken at the same time showed de novo amyloid deposits in the grafted liver. We conclude that liver transplantation may be indicated as a life-saving procedure in rapidly progressing hepatic amyloidosis with cholestatic jaundice, although the underlying disease has not changed.

We report on a patient with primary hepatic carcinoma, most probably developed after a chronic hcpatitis‐B infection, to whom doxorubicin was given when serum alpha‐fetoprotein (AFP) reappeared early after liver transplantation. With this treatment the tumor marker disappeared initially but later clinical metastatis developed. Still, the finding indicates that early adjuvant treatment with anti‐tumor drugs might affect tumor development after liver replacement for malignancy.

The effect of FK506 monotherapy on pancreaticoduodenal allotransplantation was studied in a primate model. The recipients were made diabetic by total pancreatectomy, thus glycemic control depended on the graft. In control animals hyperglycemia occurred after 14±3 days and the animals died after 36±15 days. For FK506-treated animals, the time until development of hyperglycemia was 60±12 days (P<0.05). The animals were then sacrificed by day 90 (P<0.05). All three control animals lost their graft function because of severe rejection, as verified by postmortem examination. Only one of the five treated animals showed evidence of a moderate-to-severe rejection at 90 days, one animal having a mild rejection as judged by the histological findings. The drug was clinically well tolerated in all except one animal that became apathetic and refused to eat. Hyperglycemia and an elevated serum creatinine level, which were probably related to the FK506 treatment, occurred in one animal each. Both of these side-effects were reversed by reducing the dose. Thus the use of FK506 permits successful single pancreatic transplantation in primates.

Abstract. Bacterial infections, especially cholangitis, are still common complications after liver transplantation (LTx). During recent years, multiresistant enterococci have become a nosocomial problem in transplant units. The present prospective study on 26 patients, including 24 patients with chronic liver disease, demonstrated that enterococci were the predominant micro‐organism involved in post‐LTx bacterial infections. They were cultured in the feces and in other sites of 10 out of 13 (77 %) patients who underwent extensive examinations. Ampicillin‐resistant Enterococcus faeciumstrains were isolated in urine or feces of 2 of the 13 patients prior to LTx. Similarly, resistance to ampicillin and gentamicin, the empirically used antibiotics for patients with fever of unknown origin, was found in E. faeciumstrains in 3 and 2 patients, respectively. Moreover, multiresistant E. faeciumand E.faecalisstrains were demonstrated in 46 % of the patients in the postoperative period (3 months). However, no vancomycinresistant enterococci were isolated. The use of antibiotics within 4 months prior to LTx significantly increased the risk of developing ampicillin‐resistant bacteria at the time of LTx and of infections with bacteria of enteric origin after LTx (P =0.03 and 0.01, respectively). We conclude that stool and urine cultures performed prior to LTX may be useful for selecting prophylactic antibiotic regimens.

The utility of duplex Doppler ultrasonography (US) for monitoring was evaluated after 19 liver transplantations. the assessment of the resistive index (RI) of the hepatic arteries showed no significant difference in the RI measured in grafts with stable function compared with grafts with ischemic damage, acute rejection, chronic rejection, or cytomegalovirus hepatitis. Nor was there any correlation between the levels of RI and the severity of acute rejection. in 2 out of 5 liver transplants in which hepatic artery pulsations were not identified with US, hepatic artery thrombosis was found at angiography. Although high echogenicity of the parenchyma was often observed during acute rejection episodes, it was not diagnostic for rejection. Fluid collections observed around the grafts resolved spontaneously. Thus, duplex Doppler US for monitoring liver transplants is especially useful for the diagnosis of hepatic artery thrombosis. It was not helpful for the diagnosis of acute or chronic rejection

Familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant disorder. Progressive peripheral and autonomic neuropathy are associated with neural and visceral deposition of amyloid, derived most commonly from the Met-30 variant of the plasma protein transthyretin. We have reported previously that orthotopic liver transplantation causes prompt replacement of variant transthyretin by the donor wild-type in the plasma. We now report clinical outcome 1-2 years after transplantation.

Until December 1988, 38 patients with primary biliary cirrhosis (PBC) had been transplanted in the Nordic countries. The observed survival probability in accordance with Kaplan-Meier analysis was around 75% 2-3 months after surgery, with few deaths during the next 3 years. The observed survival curve was compared with the expected survival calculated from the experience of a recent English PBC transplant series; the patterns are very similar. Secondly, the observed survival was compared with the expected survival curve, calculated from the survival experience of an international trial of medical treatment - that is, the expected survival had the patients not been transplanted; after the first 2-3 months the observed survival stayed better than the expected survival. Finally, the merits of transplantation for each particular patient was evaluated by means of the ratio of probability of survival when transplanted to probability of survival when medically treated 3, 6. and 8 months after surgery. The ratio increased with time, indicating a relative increase in the benefit of transplantation with time after surgery.

Background: Low serum vitamin A levels are observed in many liver diseases, such as primary biliary cirrhosis (PBC) and alcoholic liver disease. The aim of this study was to investigate serum vitamin A in patients with advanced liver diseases before and after orthotopic liver transplantation (OLT). Methods: Serum vitamin A (retinol) concentrations were investigated in 54 patients before (OLT) and in 21 patients 1, 2, 3, and 4 weeks and 2 and 3 months after OLT. Ten healthy subjects and 19 patients with inflammatory bowel disease (IBD) served as control groups. Results: The mean serum retinol concentration before OLT was 0.64 ± 0.1 μmol/l in patients with alcoholic and postnecrotic cirrhosis (n = 24), 1.06 ± 0.48 μmol/l in patients with PBC (n = 14), 0.96 ± 0.64 μmol/l in sclerosing cholangitis (n = 7), and 1.02 ± 0.73 μmol/l in liver cancer (n = 9). These results were significantly lower than in healthy controls (2.34 ± 0.54 μmol/l) and patients with IBD (2.7 ± 0.74 μmol/l) (p < 0.001). Conclusions: After OLT, serum retinol levels increased significantly already after 1 week (1.4 ± 0.1 μmol/l) (p < 0.001), normalized after 2 weeks (2.2 ± 0.4 μmol/l), and remained normal during the observation.

We investigated clinical, biochemical, and histopathological parameters in FK506‐treated cynomolgus monkeys. Eight monkeys given oral FK506, 1 (n= 4) or 10 (n= 4) mg/kg daily, survived the 90 days of treatment apparently in good health and without significant changes in biochemical and histopathological parameters, as did 2 control monkeys except one monkey on 10 mg/kg/day FK506 orally, who was found to have a malignant lymphoma. In contrast, monkeys given intramuscular FK506 1 mg/kg daily (n= 4) had to be sacrificed at day 20, 25, 32, and 47 because of severe illness. They showed abnormal biochemical parameters (increased serum urea and aspartate aminotransferase activity) and major histopathological changes in the kidney (mesangial cell proliferation and acute tubular necrosis), pancreas (depletion of beta cells), liver (steatosis), and heart (cardiomyopathy). Intramuscular administration of 1 mg/kg daily resulted in serum levels ranging from 10 to 15 ng/ml, while oral administration at a dose of 1 or 10 mg/kg daily resulted in equal or even higher serum levels (range 2–70 ng/ml). Thus, the height of the serum trough level of FK506 using the enzyme immunoassay is not related to the toxicity of FK506 in cynomolgus monkeys.

Pancreas transplantation for the better treatment of diabetes mellitus is becoming an important part of the service offered to diabetic patients requiring renal transplantation. Improvements in surgical technique make this a useful option. A major problem, limiting more extensive use of pancreas transplantation to other diabetic patients, remains the inadequacies of present immunosuppressive regimens. A relatively new agent, FK506 or tacrolimus, is being used increasingly because of perceived benefits over older therapeutic agents. There are concerns about the diabetogenic effect of tacrolimus. These may be dose‐related, and low‐dose tacrolimus regimens, by allowing reduction in dosage of other diabetogenic immunosuppressive agents, have produced encouraging results in pancreas transplantation in many centres. Further improvements in immunosuppressive regimens may widen the clinical implications for pancreas transplantation but identifying the patient group who will most benefit remains a priority. © 1997 John Wiley & Sons, Ltd.

The first 49 consecutive patients who underwent orthotopic liver transplantation between 1984 and 1989 in our department were studied with regard to symptomatic and asymptomatic post-transplantation infections. The major infections carrying a risk of fatal outcome are presented. During the first 4 weeks, fungal and bacterial infections predominated, the percentages of patients affected being 27% and 35%, respectively. Eight patients (17%) suffered from bacterial septicemia, which in six cases was due to gram-negative micro-organisms. The bacterial septicemia was often associated with severe ischemic damage to the graft, rejection, or cholangitis. In addition, a concomitant invasive fungal infection supervened in seven out of eight septic patients, further aggravating the patients' condition. Seventeen of the 49 patients (35%) died after transplantation within 3.3 years. Infection was the cause of death in nine patients (18%), with bacterial septicemia and/or fungemia in eight of these. Cytomegalovirus (CMV) disease was the dominant cause of illness after the 1st month. While only 5 of the 49 patients developed CMV disease during the 1st month (10%), as many as 16 of the 40 recipients who survived beyond that time suffered from symptomatic CMV viremia (40%). CMV mismatching, i.e., the donation of a CMV-positive organ to a CMV-seronegative recipient, entailed the highest risk for CMV disease. Pneumocystis carinii pneumonia occurred within 4 months in 10% of the patients. The four liver recipients affected were among the 20 patients not receiving trimethoprim-sulfamethoxazole prophylaxis. None of the 28 patients who received this prophylaxis over a 12-month period developed this complication (P<0.05). The time-related panorama of infectious complications observed in this study has immediate clinical implications for the screening, prophylaxis, and therapy of infections following liver transplantation.

The aim of this study was to develop a model for pancreatic transplantation in the primate in order to test a new immunosuppressive drug. Initially, streptozotocin was used to induce insulin-dependent diabetes mellitus, but it was found to be ineffective and associated with a high morbidity. Furthermore, streptozotocin-induced insulin-dependent diabetes mellitus did not always persist, thus invalidating the evaluation of pancreatic graft function. Therefore, total pancreatectomy was introduced and combined with the pancreatic allotransplantation as a single procedure. Enteric diversion of the pancreatic juice was chosen since this avoids exocrine pancreatic insufficiency and facilitates the oral administration of the test drug. Intra-arterial monitoring of blood pressure and blood gases during the operation and avoidance of hypothermia in the animal were found to be the most improtant factors contributing to a successful outcome from the operative procedure.

We studied 27 liver transplants in 24 patients performed between November 1984 and January 1988. We investigated retrospectively the importance of donor reactive HLA class I and class II and of non-HLA antibodies for graft survival in these patients. In order to determine the specificity and class of the antibodies, we used monoclonal antibodies to HLA-A,-B,-C and DR and DQ antigens to block cytotoxicity of sera and the reagent dithiothreitol to characterize the immunoglobulin class. We found that humoral immunity to HLA antigens in liver-grafted patients, demonstrable as the presence of cytotoxic antibodies reactive with donor splenic T and/or B cells in the pretransplantation period, is associated with significantly lower graft survival as compared with patients without demonstrable preformed HLA antibodies (P=0.01). In addition we found that a substantial proportion of patients had donor-reactive cytotoxic antibodies which were not HLA specific. Thus, our study shows that HLA immunity can influence liver allograft survival, and that it is useful to have patient cytotoxic antibodies characterized with regard to HLA reactivity prior to transplantation.

Background: The aim of this study was to determine bone mass at different skeletal sites in patients with end-stage liver disease and the effect of liver transplantation on bone mineralization.Methods: Bone mineral density in different skeletal regions was measured by photon absorptiometry in 25 patients with chronic liver disease, and the measurements were repeated in nine patients after orthotopic liver transplantation.Results: In patients with liver failure bone mass values were not significantly different from those of controls. After liver transplantation bone mass decreased significantly during the first 6 posttransplant months at the distal radius, lumbar spine, and femur (p < 0.01) and was still below pretransplant values at the 12th posttransplant month. Serum osteocalcin increased significantly from the 3rd month after transplantation (from 6.9 ± 4.4 to 12.0 ± 6.5 μg/l; p < 0.0001) and remained increased throughout the first posttransplant year.Conclusion: Early and accelerated bone loss occurred after liver transplantation. This bone reduction seems to be mainly the result of increased bone resorption, possibly related to corticosteroid therapy.

A recombinant enzyme‐linked immunosorbent assay (ELISA) followed by a neutralization test (NT) and recombinant immunoblot assay (RIBA) were used for the detection of antibody to hepatitis C virus (anti‐HCV) in 71 patients receiving 84 orthotopic liver grafts between 1984 and 1990. Before the liver transplantation (LTX) anti‐HCV was present in six of the 71 recipients (8.5%) who were accepted for LTX because of acute or chronic liver failure. After LTX anti‐HCV could not be detected in one of the patients, but it was continuously present in the others for more than 12 months. Detectable HCV antibodies were not present in the three patients who underwent LTX because of clinical evidence of fulminant NANB hepatitis. Two of 48 (4.2%) previously HCV seronegative recipients, who survived more than 3 months, seroconverted 9 and 16 months, respectively, after transplantation. The postoperative seroconversion was probably due to the transfer of virus via perioperative blood transfusions. Thus, these liver recipients may be able to respond by producing anti‐HCV despite immuno‐suppressive therapy. None of the seven post‐transplant HCV‐seropositive patients developed symptoms such as icterus or fatigue, which would suggest the presence of liver insufficiency due to HCV infection. However, two of them had increased transaminase levels and histological signs of mild hepatitis. No significant difference was found in 1‐year survival, prothrombin complex, albumin levels or the risk for retransplantation in post‐transplant anti‐HCV‐seropositive patients, compared with those without detectable HCV antibodies (71% vs 69%, respectively). Thus, during the study period of 1–5 years, the clinical course of HCV infection was milder than that reported for hepatitis B infection in liver recipients.

AbstractThe purpose of the present study was to evaluate the impact of liver transplantation on familial amyloidotic polyneuropathy (FAP met‐30) patients' survival. Forty‐five FAP patients were involved in the study; 15 non‐transplanted FAP patients and 30 liver‐transplanted patients. All patients' records were scrutinised for information on disease duration. Preoperative nutritional status was evaluated in all patients. No difference in survival was observed for transplanted patients overall compared to historical controls. However, for cases in good nutritional status, an increased survival can be expected as a significantly increased mortality rate for malnourished patients was observed (P< 0.05). Increased survival has so far not been found for transplanted FAP patients. However, none of the transplanted cases has yet reached the expected survival time for non‐transplanted FAP control patients, which is 14 years. A high fatality rate of malnourished patients transplanted late in the course of the disease contributed significantly to the mortality among transplanted patients.

AbstractOrally given ursodeoxycholic acid (UDCA) has beneficial effects on laboratory parameters in different cholestatic conditions. In order to investigate the effect on early graft function after liver transplantation, 33 patients were randomized to receive either UDCA 15 mg/kg per day or placebo from the 1st postoperative day until 3 months after transplantation. All liver grafts produced bile within 24 h after revascularization. In both groups there was an increasing bile flow each day until day 5 after transplantation. This increase was more pronounced in the UDCA group where the flow on day 2 reached a mean value of 183 ± 28 ml/day compared to 106 ± 17 ml/day in the placebo group (P< 0.05). The average daily volume of bile produced during the first 10 days was also found to be higher in the UDCA group compared to the placebo group (242 ± 20 ml vs 176 ± 18 ml, P< 0.02). In the UDCA group a significant decrease in total bile acid output between the 5th and 10th postoperative days was found, while in the placebo group the amount of bile acids excreted remained stable over time. The composition of bile differed between the two groups with an increase in the portion of UDCA in the UDCA group from the 2nd postoperative day (25 % vs 4.6 %, P< 0.0003). The fraction of UDCA then remained high during the whole study period with a peak at day 3 when 38.1 ± 6.6% of the bile acids consisted of UDCA. In the placebo group, the fraction of UDCA was low from the beginning and diminished further over time. Prophylactic UDCA treatment was found to have a significant positive impact on the ALT level during the 4th and 5th postoperative days, but had no effect on bilirubin or GGT in the early postoperative phase (days 1–10). No differences in cyclosporin requirement were found between the two groups.

The influence of suppression of CD4+ and CD8+ T cells on the humoral responses to hepatitis C virus (HCV) core and nonstructural 3 proteins was studied. An increasing viral burden cannot substitute for the lack of functional T cells in maintaining humoral HCV-specific responses.

A 9‐month‐old boy with a suggested candidemia was treated with liposomal amphotericine B (AmBisome, Vestar) after a liver transplant due to an inherited glycogenosis (Pompe's disease). This is believed to be the youngest patient in which this new therapeutic agent has been utilized. Ein 9 Monate alter Junge wurde wegen angeborener Glykogenose (Pompe‐Krankheit) lebertransplantiert und wegen wahrscheinlicher Candidihnie mit liposomalem Amphotericin B (AmBisome, Vestar) behandelt. Dies ist wahrscheinlich der jüngste Patient, bei dem dieses neue Therapieprinzip angewendet wurde.